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Section from Genetics Home Reference genetics primer. Includes information on the validity and usefulness of genetic tests

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An introduction to fundamental topics related to human genetics, including illustrations and basic explanations of genetics concepts.

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This website from the Australian Genomics Health Alliance has fact sheets and info graphics about genomic testing for the community

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Genomic testing may be used in your medical care if your doctors think there is a chance of you having a genetic condition. Doctors and researchers are learning more about genomics, and how it can help in different medical situations. But it can be hard to find reliable, up-to-date information on genomic testing, and what it might mean for you.

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Medical Applications of Genetic Technologies

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Medical Applications of Genetic Technologies

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Article from the Kinghorn Centre for Clinical Genomics
(Associated activity available for teachers)

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(also see links under the Genetic Technologies Article- scroll right)

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Fact sheet from the Centre for Genetics Education (click 'open in new window')

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4min video from McGovern Institute for Brain Research at MIT

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DNA Testing and Privacy (Behind the scenes at the 23andMe Lab) - Smarter Every Day 176

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DNA Testing and Privacy (Behind the scenes at the 23andMe Lab) - Smarter Every Day 176

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14min episode of Smarter Every Day covering how online genetic tests work and how samples are handled.

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DNA Testing and Privacy (Behind the scenes at the 23andMe Lab) - Smarter Every Day 176

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A set of consumer health advice documents from Australia's National Health and Medical Research Council (NHMRC)

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NHMRC has produced a range of resources on genetics or genomics and human health for consumers, health professionals, researchers and policy makers which can be accessed via the links below. Genetics is a broad field of study that is concerned with heredity and how particular qualities or traits are passed on from parents to offspring.

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Thinking Ethically About Human Biotechnology

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Thinking Ethically About Human Biotechnology

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Article about ethical reasoning from Markkula Center for Applied Ethics

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Modern biotechnology, with its focus on molecular biology and its concern for increasing human health and life spans, is all about the future. This biotech future presses in daily, sparking imaginations. At the same time, it elicits wariness or even fear that humanity is gaining too much power or too little choice over human evolution and destiny. The political climate, permeated as it is by a ferocious "moral approach" to science policy, heightens this public concern. We seem to have lost our capacity for rational discourse in the public arena. The biotech industry has increasingly realized that not only regulatory schemes but also contentious public and political debate can either enable or constrain research and development. For better or worse, science is political.

We Can, But Must We?
Since the birth of Dolly the cloned sheep, public concern about advancing biotechnology has been enflamed by the suspicion that science is at the mercy of the technological imperative, the propensity to think that because something can be done, it is inevitable. This seemingly easy slide from can to will-because it is technically possible to clone a child into existence, it will become an everyday occurrence, for example-leaves some with a sense of fatedness, a sense that science is unstoppable. Hence, for those people, science is not a subject of ethical concern. In this view, at best, ethics takes a quietistic turn; at worse, it becomes completely irrelevant. A mantra of "if we can, we inevitably will" places troubling limits on our critical thinking and moral imagination. We must recognize that the possible-however captivating, however daunting-is not inevitable.

As human biotech research continues, scientist and layperson alike have the opportunity to deliberate about the ethical ramifications of the possible futures opened by scientific research. The science of ethics asks us to justify our actions and account for our intentions. It is not enough just to intend the good or to do something to bring it about. We must give good reasons why we do what we do. In the realm of biotechnology, our reasoning needs to address three main areas:

Incentives, or the ways that we encourage scientists to do particular kinds of research

Intentions, or the goals of that research

Actions, or the potential applications of research results

When considering ethical reasons for our actions, it is prudent to avoid "the Dolly effect," that is, attempting to slam the ethical door well after the sheep has scurried away. The unanticipated arrival of new biotechnologies-from cloning to xenotransplantation-leaves the public, and the scientific community, without a framework for considering the attendant ethical issues. As we quickly learned after Dolly's birth announcement was published in the New York Times, paying close attention to the direction biotechnology is headed is infinitely better than potentially overreacting once it gets there. To avoid the Dolly effect, the biotech community must initiate ethical discussions within itself and with the wider public.

Questions Come First
To that end, it is well to begin with some questions. Ethics is about questions: about who asks, what they ask for, and how we as individuals and communities respond. In reference to biotechnology, what questions should be posed? What aspects should be considered?

Along with the "golly wow" response to biotech innovation, we must ask, What are the personal and social impacts of biotechnology? What are its potential impacts on our values, our virtues, and our relationships? Does a particular application of biotechnology protect or endanger human or individual rights? Are the benefits and burdens distributed fairly? Does biotechnology advance or impede the common good? What are the risks, burdens, and benefits? On whom do they fall? How are they distributed? What is an acceptable way to achieve a given benefit? May we do anything, as long as the outcome is good on balance? Or are there limits on what we do, even in the name of human health? And, what-or whom-have we not thought about?

The first step in answering any of those questions is quite difficult for people not well-versed in human biology and genetics: Get the facts. Many disagreements result from not grasping the facts of the matter. It is impossible to make sound judgments about the appropriate uses of genetic testing, for example, without understanding some genetic science and the nature of the information gathered through such testing. It is incumbent upon scientists and others working in biotechnology to educate the public in general, and the media in particular, about the scientific method and experimental results. The trend toward releasing experimental results to the press before publication in a peer-reviewed journal, which is problematic in and of itself, at least requires scientifically savvy journalists whose duty is, in turn, to provide an adequate set of facts to the public.

Ethical Reasoning
Of course, facts only describe what is; ethics deals with what ought to be. How do we responsibly move from what is to what ought to be? It is the job of philosophical ethics to provide standards that help us identify what ought to be done.

Utilitarianism: One way to think about "the ought" is through the lens of utility, which looks at various options for action, asking who will be affected and to what extent each stakeholder will be benefited or harmed. In the utilitarian view, an ethical action is the one that produces the greatest balance of good over harm or the greatest good for the greatest number of people. Regarding research in human molecular genetics, for example, the utilitarian might argue that the potential benefit of relieving human suffering outweighs the possible dangers of manipulating human genes and evolution through germ-line intervention.

Rights: A different approach presumes that what makes human beings more than mere things is our ability to choose freely what type of lives to lead and the right to have our choices respected. This view from rights describes an ethical action as that which protects people from being used in ways that they do not choose. Importantly, each human has a right not to be treated as means to another's end, even an undeniably good end. The right not to be used encompasses other rights: the right to be told the truth, the right to privacy, and the right not to be harmed are among those particularly relevant to biotech research and genetic medicine. For example, respecting rights may set limits on human subject research in molecular genetics by requiring adequate informed consent including an honest assessment of risks and benefits, or it may require that experimental gene transfer therapy be undertaken only as a last resort. In this view, actions that violate individual or human rights are wrong.

The justice approach to ethics is rooted in the principle of "treating equals equally and unequals unequally." Justice mandates fairness in that people must be treated the same way unless they differ in ethically relevant ways. For example, when two runners cross the finish line at the same time, it is unfair to award the blue ribbon to Jeff and not to Jake unless, for example, Jake has cheated.

The primary form of justice in medicine and medical research is distributive justice, which is concerned with the fair distribution of benefits and burdens across society. Distributive justice seeks clarity regarding those aspects of individuals and society that may justify drawing distinctions in how benefits and burdens are allocated. That is, it seeks to identify under what conditions treating unequals unequally would be justified. Such material conditions could include distribution based on determinations of need, social worth, contribution, or effort. For example, the principle of need would support mechanisms for providing access to cutting-edge treatments to all who would tangibly benefit irrespective of their ability to pay for them. A principle of contribution might suggest that a family who sponsored research into an illness might have more influence on the direction of the research and greater access to its fruits than the rest of us.

The common good rests on a vision of society in which all people join in the pursuit of shared values and aims. Because individual good is inextricably woven into the good of the whole community, pursuing the common good includes creating a set of general conditions that are equally to everyone's advantage. Together with respecting individual rights and freedoms, the common good approach requires that common goals, such as human health and well being, be pursued through biotech innovation and a stable health care infrastructure.

A consideration of virtue assumes that certain ideals allow for the full development of our humanity. A person who has inculcated these core ideals, or virtues, will do what is right when faced with an ethical choice. Virtues are dispositions that facilitate acting in ways that develop human potential and allow human flourishing. Virtues are good habits in that they are acquired through repetition and practice and, once acquired, they become characteristic of a person. Honesty, integrity, prudence, courage, wisdom, and compassion are examples of virtues. Once a person has developed a virtuous character, his or her inclination is to act in ways consistent with ethical principles. In much the same way as Barry Bonds is inclined to hit home runs, the virtuous person will be inclined to tell the truth and act with compassion and courage.

Virtue ethics, with the emphasis on character and ideals, captures the idea of "the good scientist"-intelligent, honest, compassionate, determined-much more so than the principle-based approaches of utility, justice, and rights. The development of pharmaceuticals for "compassionate use" echoes an ethics of virtue.

Reasoning into Biotech Practice
Those five approaches suggest that biotech ethics should ask five questions.

What benefits and what harms can be predicted for biotech innovations in both the research and application phases, and which courses of action will result in the best consequences overall? It is important to remember that determining consequences is more or less a guessing game. In instances of profound uncertainty and sizable risk, it is best to err on the side of caution when calculating benefits and risks. Neither hopes nor fears should be over-sold.

Who are the ethically relevant stakeholders, and what rights do they have? Which course of action protects those rights? Is human dignity respected? The consideration of specific individual and group rights requires coming to grips with the right to health care-a right that Americans claim but which remains unfulfilled for many.

Which option treats everyone the same unless there is an ethically justified reason to treat them differently? Biotech justice might hold up "need" as a criterion for access to innovative treatments.

Which course of action seeks the common good? Certainly, the recent SARS epidemic has heightened concern for the health of the whole and for the creation of common conditions that maximize individual and communal well being.

Which option best develops virtues? And which virtues, such as trust and compassion, might be particularly relevant to biotech development and human health?

Putting It Together
This framework for ethics does not offer an easy or automatic solution to ethical dilemmas. That is not its goal. The framework helps identify what ethics requires of us: to consider benefits and burdens, rights and justice, virtues and the common good. Each of these approaches gives us key information about ethical options in a given situation. In the end, each of us brings our moral judgment to bear in carefully considering the facts of the matter and what is right-making and wrong-making about our options for acting. When we do this reasoning together, through public discourse, we have a chance to develop a healthcare vision for our society. Such a vision would provide the necessary-and currently absent-criteria for determining which research trajectories to follow and which to ignore.

As we deliberate, we have a further obligation. Because biotech innovations may eventually involve germ-line manipulation, the actions we take today may affect every future generation of human beings, making the coming generations stakeholders in our ethical analysis. Consideration of transgenerational consequences may impose limits on what we do now in the interest of those who come after us. Minimally, we should not knowingly inflict harm. Many indigenous peoples speak of responsibilities that extend to the next seven generations. There is moral wisdom for us in that approach. As we approach cutting-edge issues in biotechnology, this very ancient moral wisdom can serve us well.

Acknowledgements
The general framework for ethical decision making on which this article is based was developed by Manual Velasquez, Claire Andre, Thomas Shanks, and Michael J. Meyer and initially published under the title "Thinking Ethically: A Framework for Moral Decision Making" in Issues in Ethics, a publication of the Markkula Center for Applied Ethics and available on-line at www.scu.edu/ethics.
Margaret R. McLean, Ph.D. is the Director of Biotechnology and Health Care Ethics at the Markkula Center for Applied Ethics at Santa Clara University.

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Thinking Ethically About Human Biotechnology

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Modern biotechnology, with its focus on molecular biology and its concern for increasing human health and life spans, is all about the future. This biotech future presses in daily, sparking imaginations. At the same time, it elicits wariness or even fear that humanity is gaining too much power or too little choice over human evolution and destiny.

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Genetic carrier screening should be recommended to all prospective parents, experts say

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Genetic carrier screening should be recommended to all prospective parents, experts say

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Article from ABC Health & Wellbeing

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Why we should be worried about gene-carrier screening

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Why we should be worried about gene-carrier screening

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Article from The Conversation

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The ability to cheaply and quickly sequence entire genomes is changing the way diseases are identified and treated. But it is also likely to change the way we make some of the most important and personal decisions of our lives: how, and with whom, we have children.

Pre-conception genetic screening (testing for "carrier status" before pregnancy) has usually only been available to couples already known to be at risk of a particular disease. Ashkenazi Jews, for example, are most likely to be carriers of the mutated HEXA gene linked to Tay-Sachs disease, a fatal genetic disorder. Screening for the HEXA mutation is therefore recommended for all Ashkenazi Jews planning children. Today, though, genome sequencing is more affordable and accessible than ever before. It is now (at least, technically) possible to screen everyone to find out if they are a carrier of a genetic disease.

These technological changes have triggered increased enthusiasm for carrier screening. Recently, the American College of Obstetricians and Gynaecologists recommended that carrier screening be offered to everyone, and at the very least to all pregnant women. Similarly, private companies in the UK are now offering pre-conception screening for large panels of genetic conditions, simultaneously.

It is estimated that the average person carries three to five serious genetic conditions, such as spinal muscular atrophy or cystic fibrosis, so the routine use of pre-conception screening could affect a lot of people and the way they approach relationships.

The "genetic compatability" of a couple is set to become an important consideration for future generations, changing the way relationships are formed. Dating apps, for example, which give users snapshot information about a potential mate, could become places where carrier status is disclosed alongside other notable physical characteristics such as hair and eye colour.

Some of these apps are already emerging - one has been dubbed Tinder for Tay-Sachs. Indeed, through the Dor Yeshorim initiative, the Ashkenazi community has long operated an anonymous programme of pre-marital genetic screening for this very purpose.

Unlike an Ashkenazi Jew, who may be more prepared for the news that they are a carrier of Tay-Sachs, research shows that most people who undergo carrier screening are entirely unprepared for a positive result. As most genetic disorders screened for are considered rare, those having the screening will probably have never experienced, or even heard of, the condition they have been found to carry.

Olesia Bilkei/Shutterstock

Impossible judgement

This lack of experience is significant because research shows that it makes an important difference to the way people make decisions about having a baby with that condition. For example, a recent study my colleagues and I conducted showed that people without prior experience of spinal muscular atrophy took a much dimmer view of the condition than families who live with it. They were also more likely than families with spinal muscular atrophy families to consider termination of an affected pregnancy as acceptable.

This contrast highlights that decisions about whether to introduce pre-conception screening, and which conditions it should be used for, are not as straightforward as they initially appear. What may be a liveable disability to one person, may be an intolerable experience to another. Yet pre-conception genetic screening calls on us to make this impossible judgement before that person is even conceived.

Given the wide variability and unpredictability of genetic disease, it may appear logical to avoid all forms of it - as far as current technology allows, anyway. However, the emergence of groups, such as "don't screen us out", which lobby against screening for Down's syndrome, highlight the difficulties that surround such blanket avoidance.

Many people can, and do, live happy and fulfilling lives with a genetic disease. Yet, once introduced on a mass scale, screening programmes can become difficult to refuse. Having a disabled child, when the technology existed to prevent it, could come to be seen as knowingly inflicting that condition on the child.

While personal choice and control are at the heart of the drive towards pre-conception screening, we also need to consider what other choices become closed off by its introduction. Neutralising the genetic gamble does not come without a cost. And, as a society, we need to carefully consider just what sacrifices we are prepared to make for it.

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Why we should be worried about gene-carrier screening

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We may be heading for a future where it will be considered immoral to have a child with a partner who isn't 'genetically compatible'.

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Scroll down in each column for more links. Scroll across for more columns.

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Website from the Kinghorn Centre for Clinical Genomics.

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Clinical genomics is a new and rapidly-changing field. Knowledge of the human genome is far from complete, but there are already uses for genetic and genomic information in the clinic.

Genome sequencing is expected to have the most impact in:

1. characterising and diagnosing rare and inherited disease;

2. stratifying individuals' tumours to guide treatment (precision medicine);

3. providing information about an individual's risk of developing disease or their likely response to treatment (health management)

Characterising and diagnosing inherited disease

Every baby born in Australia is offered screening for approximately 30 genetic conditions (the Guthrie test) and more than 300 tests for genetic disorders are available through the healthcare system.

Clinicians worldwide are beginning to embrace genome sequencing to search for variants implicated in undiagnosed genetic diseases and using this information to guide treatment . In one of the most dramatic cases , a young boy underwent a risky, but seemingly successful, bone marrow transplant that was proposed in response to molecular data.

Stratifying cancer for better treatment

A major focus of genomic medicine is cancer diagnosis and therapy. Clinicians are beginning to use genomic information to predict how a person's cancer will respond to drug therapy or surgery. In some cases, clinicians will profile the DNA and RNA of tumour cells to guide the use of existing treatments or focus on more targeted treatments.

At this stage, some patients have been spared costly and complex procedures based on a molecular diagnosis. Tumour development in a few patients has been stabilised - for a time, at least - by targeting specific molecules or pathways in tumour cells.

, led by the Head of Garvan's Cancer Division and Director of The Kinghorn Cancer Centre, Professor David Thomas, is a research program dedicated to applying genomics to the understanding, early detection, prevention and management of cancer. This program was established as part of the The Genomic Cancer Medicine Program Sydney Genomics Collaborative , a $24 million, four-year investment by the NSW State Government in using genetic technologies to improve patient outcomes.

Health management: understanding disease risk and predicting drug response

The application of genomic medicine is not limited to typically genetic conditions. All diseases have a genetic component, from inherited conditions to complex diseases such as cancer and diabetes. Different people also react differently to parasites, viruses and bacteria according to the information encoded in their genome.

Beyond diagnosis and guiding patient management, the major value for genomics in health is expected to be in: understanding an individual's disease risk; detecting disease early, and, ultimately, preventing disease. Researchers are identifying a broad range of variants - across the genome - that are clinically useful.

Individuals' genetic differences are also thought to be responsible for up to 80% of adverse reactions to drugs and genetic tests for variants involved in drug metabolism are increasingly used in Australia. Comprehensive profiles of an individual's genetic data, integrated with common clinical markers, are expected to provide new insights into disease.

Additional references and commentaries

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Clinical genomics is the use of genome sequencing to inform patient diagnosis and care.

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A list of articles about gene editing technology

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CRISPR: The gene-editing revolution on our doorstep

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CRISPR: The gene-editing revolution on our doorstep

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Infographic from Genioz- an Australian Research Project into consumer expectations of genetic testing

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Genomics: National Insights of Australians | Community Resources

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Welcome! Data from the Genioz study has informed the development of some community resources. They are designed to assist you in thinking about what is important to you if/when deciding to order a personal genomic test/online DNA test.

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Fact sheet from the Centre for Genetics Education (click 'open in new window')

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False-positive results released by direct-to-consumer genetic tests highlight the importance of clinical confirmation testing for appropriate patient care

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False-positive results released by direct-to-consumer genetic tests highlight the importance of clinical confirmation testing for appropriate patient care

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A scientific research paper that shows that 40% of harmful variants reported by direct-to-consumer genetic tests were false positives

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Abstract

Purpose

There is increasing demand from the public for direct-to-consumer (DTC) genetic tests, and the US Food and Drug Administration limits the type of health-related claims DTC tests can market. Some DTC companies provide raw genotyping data to customers if requested, and these raw data may include variants occurring in genes recommended by the American College of Medical Genetics and Genomics to be reported as incidental/secondary findings. The purpose of this study was to review the outcome of requests for clinical confirmation of DTC results that were received by our laboratory and to analyze variant classification concordance.

Methods

We identified 49 patient samples received for further testing that had previously identified genetic variants reported in DTC raw data. For each case identified, information pertaining to the outcome of clinical confirmation testing as well as classification of the DTC variant was collected and analyzed.

Results

Our analyses indicated that 40% of variants in a variety of genes reported in DTC raw data were false positives. In addition, some variants designated with the "increased risk" classification in DTC raw data or by a third-party interpretation service were classified as benign at Ambry Genetics as well as several other clinical laboratories, and are noted to be common variants in publicly available population frequency databases.

Conclusion

Our results demonstrate the importance of confirming DTC raw data variants in a clinical laboratory that is well versed in both complex variant detection and classification.

Introduction

Direct-to-consumer (DTC) genetic tests are advertised and sold directly to the public and offer information that may include ancestry, risks of developing certain conditions, carrier status for autosomal recessive diseases, predicted drug response, and nondisease phenotypic traits such as eye color. Owing to a growing interest in human genetics and personalized health care, there has been an increased demand for this type of testing from the public. There is a growing market for DTC genetic testing, with numerous companies (e.g., Family Tree DNA, My Heritage, 23andMe, ancestry.com) currently offering products to the public. DTC tests can provide genetic information to individuals who might otherwise never have been tested due to circumstances such as lack of a family history of disease, inaccessibility of clinical genetic testing, prohibitive cost, or poor insurance coverage. However, unlike clinical genetic tests, DTC tests are not diagnostic and offer risk information for only a limited set of conditions.

In the United States, the Food and Drug Administration (FDA) restricts DTC genetic testing companies from offering products that function as diagnostic tests.1 In April 2017, the FDA authorized one DTC company, 23andMe, to market genetic health risk tests for 10 specific multifactorial conditions (Parkinson disease, late-onset Alzheimer disease, celiac disease, α-1 antitrypsin deficiency, early-onset primary dystonia, factor XI deficiency, Gaucher disease type 1, glucose-6-phosphate dehydrogenase deficiency, hereditary hemochromatosis, and hereditary thrombophilia).2 The genetic health risk tests authorized by the FDA provide information on an individual's risk of developing a condition. This is based on the presence or absence of a limited list of genetic variants in the sample, which are statistically enriched in affected versus healthy cohorts but not necessarily causal of the conditions because additional factors such as environment and lifestyle influence an individual's risk. None of the genes associated with these conditions are comprehensively sequenced or analyzed in DTC tests, nor do the tests include all of the genes that have been associated with these conditions. For example, 23andMe's genetic health risk test reports on just one variant in each of two genes linked to Parkinson disease: LRRK2 and GBA. 3 However, there are additional known pathogenic variants in these two genes as well as additional genes clinically associated with Parkinson disease that 23andMe does not report on, such as SNCA and PARK2/PARKIN. 4 Therefore, the consumer is not provided with a comprehensive genetic risk assessment.

In contrast, clinical diagnostic genetic tests are ordered by a patient's medical provider and are used to identify or rule out a specific genetic condition. One example is clinical testing for the BRCA1 and BRCA2 genes. If an individual has a pathogenic variant in one of these genes, it is considered diagnostic for hereditary breast and ovarian cancer syndrome, whether or not she or he has a personal diagnosis of cancer. Diagnostic tests are generally comprehensive because the full coding sequences of all genes associated with a disease are analyzed. The test results are intended to be used by a patient's medical provider to guide disease management or surveillance.

While the FDA currently prohibits most DTC companies from offering diagnostic genetic tests, some companies provide customers their raw genotyping data if requested, which may include variants in genes associated with Mendelian diseases, including those recommended by the American College of Medical Genetics and Genomics to be reported as incidental or secondary findings in genomic testing. These genes are implicated in highly penetrant genetic disorders for which surgical or other interventions aimed at preventing or significantly reducing morbidity and mortality are available to pathogenic variant carriers.5 Identification of a pathogenic variant in one of these genes could be diagnostic of a medical condition with potential implications for an individual's medical management.

The raw data are often accompanied by a disclaimer that the information is neither validated for accuracy nor intended for medical use. While DTC companies do not provide interpretation of the raw data, patients can access interpretation services through third-party companies, which may charge a fee.6 One recent study on such third-party companies found that several operate by querying publicly available databases, such as dbSNP, and reporting the classification provided in the database, despite reports that the majority of classifications in some publicly available databases are incorrect.6, 7 As a result, returned results may interpret particular single-nucleotide polymorphisms as pathogenic, even though clinical laboratories may classify the same variants as unknown significance, likely benign variants, or benign polymorphisms. In addition, they are providing information to the consumer with the assumption that variants in the raw data are true calls and not false positives. The misinterpretation and potential inaccuracy of the raw data pose substantial risks to individuals who obtain this type of information from a DTC company. For these reasons, medical providers should order confirmatory genetic testing from an experienced clinical diagnostic laboratory to guide patients' medical care.8, 9, 10

What drives a consumer to pursue DTC genetic testing, their perceived usefulness of the final results, their understanding of how comprehensive a test may or may not have been, and the utilization of a genetic counselor or another health-care provider vary widely.11, 12 DTC results may lead to healthy changes in lifestyle and/or diet,13 but could also result in unfavorable emotions, including anxiety when obtaining unexpected information and disappointment in a lack of comprehensive diagnostic analysis.12 Regardless of whether a health-care provider is involved with the initial ordering of a patient's DTC genetic test, the results can lead to important health-related discussions with medical providers. With the ever-growing shortage of genetic counselors and other highly trained genetic professionals, there is concern regarding how DTC test results are interpreted and used among medical providers who often have minimal genetic training.11 It is therefore imperative that consumers, as well as their medical provider(s), are aware of the wide array of limitations to this type of genetic testing, especially in regard to an individual's clinical management. Recent studies have started to evaluate pre- and post-DTC testing encounters with health-care providers including genetic counselors;14 however, to our knowledge, no studies have described outcomes of raw data confirmatory testing referrals to clinical diagnostic laboratories. We aimed to investigate the types of cases referred to our clinical diagnostic laboratory and evaluate the concordance of confirmatory test results for cases with variants identified in the raw data by DTC genetic testing. We also aimed to investigate whether our variant classification was in agreement with that provided by the DTC testing company or third-party interpretation service.15

Materials and methods

Our internal database was queried to identify patients referred for testing at our clinical diagnostic laboratory (Ambry Genetics, Aliso Viejo, CA)16, 17 with variants previously identified by DTC testing between January 2014 and December 2016. To identify such cases, all communications and curated clinical history information in our laboratory information management system were searched using key phrases including, but not limited to, "direct-to-consumer" and "DTC." For each case identified ( n  = 49), the following information was collected: ordering provider type/specialty, test ordered, DTC results (gene, variant name, variant classification), disease status, and source of DTC results (e.g., copy of DTC report, a copy of a third-party interpretation service report, patient clinic note, information handwritten by clinician on the test requisition form). The data pertaining to the company providing the DTC testing or interpretation service were collected with the sole purpose of being able to resolve any testing discrepancies if necessary and not for publication purposes. DTC genetic test results, including reported variant classifications, were compared with confirmatory test results and were categorized as confirmed (patient determined to be positive for the variant) or not confirmed (patient determined to be negative for the variant).

While the testing methodologies used by DTC companies can vary, all testing at Ambry Genetics was performed by Sanger or next-generation sequencing analysis with Sanger confirmation, depending on the clinical test ordered. Sanger sequencing was performed on samples received for single-site analysis or full-gene analysis.16, 17 Briefly, genomic DNA was amplified with gene-specific primers and bidirectionally sequenced using Big Dye Terminator version 3.1 on an ABI3730xl DNA analyzer (Applied Biosystems, Foster City, CA). Chromatogram analysis was conducted using Sequence Pilot version 4.2.1 (JSI Medical Systems, Boston, MA). Targeted next-generation sequencing was performed on samples received for multigene panels.18, 19 Briefly, customized target-enrichment oligonucleotide libraries were designed using IDT xGen Lockdown probes (Integrated DNA Technologies, Coralville, IA). Genomic DNA was mechanically sheared to 300-bp fragments with an ultrasonicator (Covaris, Woburn, MA) and next-generation sequencing libraries were prepared according to the manufacturer's instructions (Kapa Biosystems, Wilmington, MA). Adapter-ligated DNA was hybridized to custom IDT xGen Lockdown probes, eluted, and polymerase chain reaction-amplified. Final libraries were sequenced on either HiSeq2500 or NextSeq500 instruments generating 150-bp paired-end reads (Illumina, San Diego, CA).20

This study has been determined by regulatory opinion to be exempt from institutional review board review because it does not include human subjects. Sequence analysis is based on the following National Center for Biotechnology Information reference sequences: BRCA1-NM_007294.3, BRCA2-NM_000059.3, CHEK2-NM_007194.3, CFTR-NM_000492.3, MEFV-NM_000243.2, TP53-NM_0000546.4, ATM-NM_000051.3, MLH1-NM_000249.3, COL3A1- NM_000090.3.

Results

Study demographics and test order characteristics

Patient demographics and test order characteristics are shown in Table 1. In total, we identified 49 patients referred for clinical diagnostic testing with variants previously identified in the raw data from DTC genetic testing. There were a total of 26 unique variants submitted for testing including 4 located within deep intronic regions well beyond the analytical range of most clinical laboratories. Nearly all of the individuals in this study were female (91.8%), and most were unaffected with disease at the time of testing (73.5%). Slightly over half of individuals in this study were 30-49 years old (53.1%) and reported Caucasian ancestry (51.1%). While some individuals ( n = 7) who underwent DTC genetic testing had a personal history of disease (affected), the majority ( n  = 35) did not have a personal history of disease reported to our lab by the ordering provider (unaffected). There was one case in which the clinical history was not available (unknown).

Table 1: Demographics of individuals undergoing DTC genetic testing

The majority of the medical providers who ordered the confirmatory testing were medical geneticists/genetic counselors (40.8%) followed by oncologists (20.4%). For 44.9% of all cases, single-site analysis was ordered to confirm DTC raw data findings, and more comprehensive testing via single-gene or multigene panel testing was ordered in 55.1% of cases. Testing of cancer genes comprised 87.8% of the orders. When samples were submitted to our laboratory, the variant of interest was reported to Ambry Genetics on the test requisition form or in a clinic note 53.1% of the time, and in only 26.5% of the cases was a copy of the DTC test results (prior to the FDA regulations) or the raw data information provided. In 20.4% of cases, a copy of the third-party interpretation service report was provided. As shown in Table 1, the vast majority of variants occurred in cancer susceptibility genes (87.8%), with the remaining variants in genes causing cystic fibrosis (8.2%), familial Mediterranean fever (2.0%), and connective-tissue disorders (2.0%).

Variant confirmation

Overall, 60% of the variants analyzed were confirmed, while 40% were not confirmed (false positives) ( Figure 1). All CFTR ( n = 4, all deltaF508) and MEFV variants ( n = 2) were confirmed. Of BRCA1/2 variants identified on DTC genetic testing, pathogenic Ashkenazi Jewish founder variants were confirmed in all cases ( n = 13), as were four additional variants; however, eight BRCA1/2 variants yielded false-positive results. In CHEK2, the common 1100delC pathogenic European founder variant was confirmed in 50% of cases ( n = 2/4) and was a false positive in the other 50% of cases. The single case reporting the CHEK2 p.I157T founder variant was confirmed. A total of six additional variants in cancer susceptibility genes were not confirmed, including TP53 p.R175H ( n = 3), ATM p.M1040V ( n = 1), MLH1 p.H329P ( n = 1), and MLH1 c.1101delC ( n = 1) ( Figure 1, Table 2). Of the 40% of false-positive calls, 94.1% ( n = 16/17) were in cancer-related genes and the remaining 5.9% ( n  = 1) was in a connective-tissue disorder gene.

Figure 1

False-positive variants in clinically actionable genes. The pie chart on the left indicates of the variants analyzed, 60% were confirmed and 40% were false positives. The pie chart on the right shows which genes were involved with the false-positive cases and how often those false calls were detected in this study.

Table 2: Concordance of DTC and confirmatory results from our clinical diagnostic laboratory

Classification discrepancies

Eight variants in five genes ( ATM, BRCA1, BRCA2, COL3A1, and COL5A1) were designated with the "increased risk" classification in DTC raw data or by a third-party interpretation service. These variants are classified as benign at Ambry as well as at several other clinical laboratories21 ( Table 3). In addition, per the Exome Sequencing Project, 1000 Genomes, and dbSNP population frequency databases that are publicly available, these ATM, BRCA1, BRCA2, and COL3A1 gene variants are found in the general population at frequencies too high to be associated with disease ( Table 3) (refs. 22, 23, 24).

Table 3: Classification discrepancies

Case example: Ehlers-Danlos syndrome

An in-depth review of the COL3A1 case revealed that the patient was undergoing evaluation to rule out Ehlers-Danlos syndrome and presented DTC genetic testing results to the clinician revealing one COL3A1 "mutation" and four COL5A1 "mutations." To confirm these findings, the clinician ordered a 22-gene panel for thoracic aortic dilation and dissection, including COL3A1 and COL5A1, and received a negative report. No DTC report was provided at the time, so the precise variants in question were unknown. Upon follow-up communication with the provider to request the DTC report, we received a report from a third-party DTC raw data interpretation service that revealed the following variants for this patient: COL3A1 p.A698T (c.2092G>A), COL5A1 c.655-8689C>T, COL5A1 c.654+2749A>G, COL5A1 c.1827+399C>T, and COL5A1 c.1827+1142T>C. The COL3A1 variant was not detected by our lab in this patient, and it would not have been reported if it had been detected, as our laboratory classifies this as benign. Furthermore, the COL3A1 and all four of the COL5A1 variants were labeled as increasing the patient's risk of disease; however, the COL3A1 variant and three of the COL5A1 variants were classified as benign by our laboratory, with the fourth COL5A1 variant classified as a variant of unknown significance. In addition, all four COL5A1 variants were located in deep intronic regions not included in our analytical range due to unproven association with disease ( Table 3).

Discussion

The recent proliferation of DTC companies increases the general population's access to genetic testing, including healthy individuals. DTC test results are not intended to impact an individual's medical management; however, information obtained from requesting and interpreting raw data could lead to inappropriate changes in their care. While the raw data include disclaimers stating that they have not been validated for accuracy and are therefore not intended for medical use, they could easily be misinterpreted or misused by a consumer or medical provider with little to no training on the complexities of genetics. Both false-positive results and misclassification of variants can result in significant implications for an individual, including unnecessary stress, medical procedures (e.g., surgery, frequent screenings), and testing of family members. All of these factors have the potential to result in unwarranted financial burden on individuals and the health-care system overall.

This study focused on variants reported in the raw data of DTC genetic testing and our two key findings were an alarmingly high false-positive rate (40%) and the incidence of discrepant classification/misinterpretation of variants coming from DTC companies and/or third-party interpretation services. The technical differences between the types of testing methodologies used may explain why 40% of the results in our study were discordant with the raw data from the DTC testing company. Many of the DTC genetic testing laboratories use a form of single-nucleotide polymorphism genotyping array for their assay. This particular methodology is analogous to spot checking an individual's DNA with coverage at only specific preselected sites. This is not comprehensive full-gene sequencing nor does it include gross deletion or duplication analyses, which are both routinely part of clinical diagnostic testing with the use of next-generation sequencing and microarray/multiplex ligation-dependent probe amplification methodologies. Even when comparing single-nucleotide polymorphism arrays between DTC companies, it is possible to see a high degree of variability, as probe coverage varies between companies due to differences in assay design.

Encouraging all laboratories, whether they are DTC or clinical, to share their data is one way to reduce variant classification errors.25, 26, 27 Requiring DTC companies and any associated third-party interpretation services to utilize and review information from well-curated and highly regarded genetic databases could also aid in reducing these types of errors.5 These third-party reporting services typically do not use any form of multievidence algorithms or weigh various interpretation factors, such as classification discrepancies between testing laboratories, despite the availability of this information in some public databases such as ClinVar. In the meantime, it is crucial that clinical confirmatory testing be performed on any variants reported in the raw data provided by a DTC company prior to any changes in medical management to confirm the presence of that variant in the individual as well as an accurate classification.

In addition to concerns regarding false-positive results and inaccurate classification of variants as pathogenic versus benign, all parties involved with these types of test results should be aware that many DTC genetic tests do not include comprehensive gene analysis, and an individual may still need additional clinical diagnostic genetic testing based on personal and/or family history. It is important that consumers and their health-care providers are cognizant of the differences in testing methodologies between clinical diagnostic labs and DTC testing labs so that there is no false reassurance or alarm on the behalf of the individual or the health-care provider.

All of these potential ramifications highlight the need for clinical confirmation testing of raw data variants. The 49 cases represented in this study are from individuals who shared their DTC genetic test results with their medical providers, and they represent the circumstances in which the medical providers knew the results warranted follow-up clinical testing. Unfortunately, these actions on part of both the individual and the medical provider may not be commonplace at this point in time. A limitation of this study design is that we were unable to analyze the complete financial burden that these types of test results may place on our health-care system. While this study has a small sample size ( n = 49), further efforts to gather data on a larger cohort are underway. This will allow us to better determine the extent of discordant results between DTC tests and clinical diagnostic tests. The findings in this study are also limited to the genes for which our clinical diagnostic laboratory offers testing ( https://www.ambrygen.com).

Conclusion

Our analysis revealed a high false-positive rate (40%) in genes with potential clinical impact in the raw genotyping data provided to consumers by DTC genetic testing companies, as well as eight instances of misinterpretation of variants by third-party interpretation services. This emphasizes the limitations in raw genotyping data currently distributed by DTC companies and demonstrates the importance of confirming DTC raw data results in a diagnostic laboratory that is well versed in clinical-grade variant detection and classification. While having access to raw genotyping data can be informative and empowering for patients, this type of information can also be inaccurate and misinterpreted. Genetic testing needs to be interpreted by a qualified health-care professional in the context of several other factors, such as personal and family medical history. It is our hope that confirmatory testing and appropriate clinical management by all health-care professionals accompany DTC genetic testing for at-risk patients.

References

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Wynn J & Chung WK . 23andMe paves the way for direct-to-consumer genetic health risk tests of limited clinical utility. Ann Intern Med 2017; 167:125-126.

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US Food and Drug Administration2017 FDA allows marketing of first direct-to-consumer tests that provide genetic risk information for certain conditions. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm551185.htm. Accessed 2 October 2017.

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Mullin S & Schapira A . The genetics of Parkinson's disease. Br Med Bull 2015; 114:39-52.

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Badalato L , Kalokairinou L & Borry P . Third party interpretation of raw genetic data: an ethical exploration. Eur J Hum Genet 2017; 25:1189-1194.

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Hamilton JG , Abdiwahab E , Edwards HM , Fang ML , Jdayani A & Breslau ES . Primary care providers' cancer genetic testing-related knowledge, attitudes, and communication behaviors: a systemic review and research agenda. J Gen Intern Med 2017; 32:315-324.

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Roberts JS , Gornick MC , Carere DA , Uhlmann WR , Ruffin MT & Green RC . Direct-to-consumer genetic testing: user motivations, decision making, and perceived utility of results. Public Health Genomics 2017; 20:36-45.

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PGen Study GroupNielsen DE PGen Study GroupCarere DA PGen Study GroupWang C PGen Study GroupRoberts JS PGen Study GroupGreen RC PGen Study Group. Diet and exercise changes following DTC personal genomic testing. BMC Med Genomics 2017; 10:24.

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PGen Study GroupKoeller DR PGen Study GroupUhlmann WR PGen Study GroupCarere DA PGen Study GroupGreen RC PGen Study GroupRoberts JS PGen Study Group. Utilization of genetic counseling after direct-to-consumer genetic testing: findings from the impact of personal genomics (PGen) study. J Genet Couns 2017; 26:1270-1279.

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Sanger F , Nicklen S & Coulson AR . DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA 1977; 74:5463-5467.

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Shendure J & Ji H . Next-generation DNA sequencing. Nat Biotechnol 2008; 26:1135-45.

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Mu W , Lu H-M , Chen J , Li S & Elliott A . Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing. J Mol Diagn 2016; 18:923-932.

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1000 Genomes Project Consortium1000 Genomes Project ConsortiumAuton A 1000 Genomes Project ConsortiumBrooks LD et al. 1000 Genomes Project: a global reference for human genetic variation. Nature 2015; 526:68-74.

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ACMG Board Of Directors. Laboratory and clinical genomic data sharing is crucial to improving genetic health care: a position statement of the American College of Medical Genetics and Genomics. Genet Med 2017; 19:721-722.

Download references

Acknowledgements

We express our gratitude to the clinicians who provided all clinical history and DTC/third-party interpretation services testing information to us.

Author information

Affiliations

Ambry Genetics, Aliso Viejo, California, USA

Stephany Tandy-Connor

, Jenna Guiltinan

, Kate Krempely

, Holly LaDuca

, Patrick Reineke

, Stephanie Gutierrez

, Phillip Gray

& Brigette Tippin Davis

Competing interests

All authors are full-time employees of Ambry Genetics Corporation but otherwise declare no conflict of interest.

Corresponding author

Correspondence to Stephany Tandy-Connor.

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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False-positive results released by direct-to-consumer genetic tests highlight the importance of clinical confirmation testing for appropriate patient care

# data[].attributes.attachment_link.description
There is increasing demand from the public for direct-to-consumer (DTC) genetic tests, and the US Food and Drug Administration limits the type of health-related claims DTC tests can market. Some DTC companies provide raw genotyping data to customers if requested, and these raw data may include variants occurring in genes recommended by the American College of Medical Genetics and Genomics to be reported as incidental/secondary findings.

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An interactive infographic from the Royal Society including information on technologies and ethics

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Back to Genetic technologies

Genetic technologies and human health

What if you had the power to prevent a genetic disorder? Or to cure diseases such as leukaemia? Would you do it?

Questions like this once seemed confined to the pages of science fiction. But they have now become a realistic possibility, thanks to rapid developments in genetic technologies over the past 70 years.

Since the discovery of the structure of DNA in the 1950s, geneticists have made new discoveries at a breathtaking rate. In 1982, the first drug (insulin to treat diabetes) was produced using genetic engineering, followed by the first trials of gene therapy in humans in 1990.

At the same time, sequencing a human genome has become simpler than ever. The original Human Genome Project took 13 years and cost $3 billion. Today the same process takes three days and costs less than $1,000.

But before we go any further, let's see what you already know about genetics.

Quiz Question 2

A gene is a short section of DNA. It's how you inherit characteristics from your parents.

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Rapid scientific developments are not uncommon. Less than 70 years after the Wright brothers completed the first successful powered flight, three NASA astronauts flew to the Moon - 385,000 kilometres away.

However, the speed of recent developments in genetic science has thrown up a range of economic, environmental and ethical issues that society is still attempting to process. The fact that your genome can now be sequenced safely and relatively quickly and cheaply means that the difficulty of carrying out related genetic procedures - for example genetic testing or genome editing - is also reduced. It also opens up the technology to a far wider range of individuals and organisations.

So how do you feel about this? How do you think using these technologies might change society? Here we will explore some of the key genetic technologies and probe some of the dilemmas and debates around their use.

Key dates

2003

Genetic technology is already here in the form of genetic testing. This involves tests that identify which variant of a gene you have inherited.

These are some of the ways in which genetic testing is used in the UK:

Patients provide a blood sample, which can be analysed for a gene or genes linked to a specific disorder or that person's entire genetic code.

This is usually processed in a laboratory, although tests for individual genes that can be done on the spot are emerging.

Usually just a few genes are tested, but there are whole-genome approaches that look at every letter in your DNA. These include the 100,000 Genomes Project, which is focussing on cancer and rare diseases.

Poll:

AGREE DISAGREE DON'T KNOW

Poll:

Agree

Disagree

Don't know

23% 69% 8%
of people agree with you, saying that genome editing should be used in humans for cosmetic purposes.*

of people agree with you, saying that genome editing should not be used in humans for cosmetic purposes.*

of people agree with you, saying that they don't know if genome editing should be used in humans for cosmetic purposes.*

Hopes

for genetic testing

If you know you have a genetic disorder, you might be able to get suitable treatment, or act in a way that will reduce the chance of the disease developing.

Effective preventive treatment could reduce costs to health services.

Even if there is no treatment, accessing information about your future health can help you make decisions about your future, including whether or not to have children.

Concerns

about genetic testing

If your genetic data became available to third parties, such as insurance providers, they might offer you a reduced level of service as a result.

The cost of genetic testing could take resources away from other parts of the NHS.

Being told that you or a family member is at risk of a genetic disorder can affect relationships and cause anxiety.

'[Genetic testing could] help to remove inequality, because if you're born with a genetic disease, you can't do anything about it. I think if there's a shift to empower people, [...] that's a benefit.' (Dialogue participant, London)

'If we have too many people, we'd have to lower our standards of living. If everybody lives another five years we'd run out of space and food, resources' (Dialogue participant, London)

CLICK TO SEE A DIFFERENT POINT OF VIEW

Would you want to be tested for key genetic disorders? How should genetic testing be performed and who should have access to the information?

Doctors are not only capable of testing for genetic disorders. Doctors hope to use genome editing to 'find and replace' genes, either replacing faulty genes with healthy ones, or changing genes to make them behave differently.

This animation explains more about what's involved.

For some people, this level of genetic intervention raises concerns. What if there are unforeseen side effects? What if the technology gets into the wrong hands?

Let's take a look at the story of a British baby called Layla to put some of these questions into a real-life context.

Leukaemia is the most common cancer in children under the age of five. In the UK over 85% of affected children survive for five years or more after their cancer is diagnosed. However in 2015, doctors at Great Ormond Street Hospital, London were treating a baby called Layla Richards, whose leukaemia had not responded to any of the conventional treatments.

Knowing that Layla would die without treatment, they turned to an emerging technique which involves extracting a patient's own T-cells (an immune cell that targets cancers) and genome editing them to make them more effective at targeting leukaemia. These T-cells are then returned into the patient's body.

Layla Richards did not have enough of her own T-cells, so doctors used T-cells from a donor. This meant that as well as using genome editing to attack the cancer, doctors also carried out further editing to ensure that the donor T-cells wouldn't be rejected by Layla's immune system. So there were two levels of genome editing - an unprecedented and pioneering achievement.

The treatment worked. Two years on, Layla Richards is healthy and her cancer hasn't returned. Layla's treatment involved somatic cells - which means that the genetic changes in her DNA won't be inherited by her children. She will continue to be monitored to check for any complications. If further trials of this procedure are successful, then the treatment could become more widely available in the future.

agree with using genome editing in patients as a way of curing an otherwise incurable life threatening disease.

believe that genome editing should be used to enhance human abilities (eg to increase a person's strength)

Genome editing is also opening up new treatment opportunities for those affected by other diseases:

CLICK TO FLIP TILE

Cancer

CLICK TO FLIP TILE

Genome editing has become a powerful technique for cancer scientists because it allows them to genetically manipulate cancer cells for laboratory tests, bringing results much sooner.

CLICK TO FLIP TILE

HIV

CLICK TO FLIP TILE

In 2017, genome editing was used to eliminate HIV DNA in mice. This effectively stops the virus from replicating itself.

CLICK TO FLIP TILE

Muscular dystrophy

CLICK TO FLIP TILE

Recent tests have suggested that genome editing may be able to restore the production of the dystrophin protein in cultured muscle cells, offering hope to thousands of muscular dystrophy sufferers.

There are a wide range of opinions on genome editing. For some people and some applications, it is a step too far: we are 'playing God' and crossing an ethical boundary. It also raises concerns about affordability (will it be freely available to all?) and regulation (who will control its use?). For others, the benefits outweigh the risks, particularly for those suffering from otherwise incurable diseases.

'I think the world that we live in faces significant challenges. There's challenges around food, around medicines, around treating people. Those challenges I don't think can be answered with conventional science anymore.' (Dialogue participant, Norwich)

'I think it's unacceptable. You're going to have a generation of people who have never had to accommodate or, never had to think about anything, any tragedy or tragic situation, what will that do for society? It may make people less compassionate.' (Dialogue participant, London)

But it's not just the genomes of children and adults that can be edited using this technology. It is also possible to edit the genomes of embryos.

Because this editing is done at the embryonic level, it means that the change would be permanent, and may be inherited, a process known as germline editing.

It is currently illegal in the UK and US to implant a genetically altered embryo into a woman's womb, which means that this technique could not be used unless the law is changed. Scientists have said much better evidence on whether the treatment is safe and effective, as well as inclusive public debate, is required before any change in the law should be considered.

Those in favour of using genome editing to treat genetic diseases in embryos argue that it diminishes suffering, and could reduce costs to the wider health system. Those opposed believe that it will reduce respect for difference and increase pressure on groups with characteristics that are labelled as a 'disorder'.

Key Dates

1978

Birth of Louise Brown, the first IVF baby. At the time people feared IVF would lead to 'designer babies', but it is now widely accepted.

Over

250,000

IVF babies have been born in the UK

'It's easy for those unaffected by genetic diseases to dismiss scientific progress as a step towards a future in which we start selecting a criterion of eye or hair colour from a design-your-own-baby catalogue. But for people like me, affected by an incurable genetic disease that caused me to go blind, scientific advancements into gene editing and mitochondrial replacement therapy offer nothing but hope. If there is any chance of potentially saving yourself or your baby from illness, don't tell me you wouldn't take the opportunity.'

Alex Lee, a freelance writer with interests in technology, culture and politics, August 2017

'...even if changes to the germ-line turn out to be safe, the underlying ethical concerns of scope and scale that genome editing brings will remain. If a technique can be used widely and efficiently, without careful oversight governing its use, it can readily become a new norm or an expectation. Those unable to access the desired genetic alterations, be they humans with diseases, humans without enhanced genetic characteristics, or farmers without genetically modified animals or crops, may all find themselves gravely and unfairly disadvantaged.'

Anthony Wrigley and Ainsley Newson, both academics specialising in ethics, March 2015

Do you believe that genome editing should be used in the clinic to treat embryos likely to develop genetic disease, rather than just for research? For some, it is unacceptable because there are alternative options for parents who do not wish to pass an inherited genetic condition down to their children. In this argument, genome editing should only be used as a last resort.

These alternative options are:

Parents can choose to adopt. Or they can use a donated embryo that has no direct genetic connection to themselves.

Following IVF, it is possible to screen embryos for an abnormal version of a gene and only implant those that will not develop a genetic disease in the woman's womb.

Some genetic diseases can be managed. For example, in the case of cardiomyopathy, patients can be monitored, can avoid overexertion and can take medication to regulate their heart rate.

Key Dates

2017

August 2017
CRISPR is used in a research effort to remove a genetic predisposition to heart disease in human embryos.

September 2017
CRISPR is used for the first time by researchers to understand the role of a gene in the early development of embryos.

Who should regulate?

The simple fact is that society is still making up its mind about genetic technologies. We all have a role to play in deciding how, where and when they should be used. The laws and regulations around genetic technologies will inevitably change as the technology develops further and we will need to work out as a society what we find ethically acceptable.

When the Royal Society carried out a consultation exercise in 2017, there was widespread agreement about the need for effective and consistent regulation.

Should there be a global regulatory framework for genetic technologies?

Most trusted

to work on genetic technologies

Least trusted

to work on genetic technologies

Based on the Royal Society's public dialogue, there is already a lot of common ground. Most people would agree that genetic technologies have the potential to cure and control disease. There also appears to be agreement on who should be developing these technologies and by whom they should be regulated.

The next step is more complicated: working out how much and how far that technology should be developed and controlled.

This is not just an abstract question. As we grow older, we are all likely to be placed in situations where genetic technologies will offer us or our loved ones an enhanced quality of life. We may find our opinions sharpening or changing in these circumstances. Until then, the Royal Society is continuing to share news and encourage discussions about genetic technologies. Please keep taking part in the conversation on #genetech or find out more about our work in this area and help us to shape the future.

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Genetic technologies and human health | Royal Society

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Try this interactive infographic to find out more about how genetic technologies are changing healthcare and share your results on twitter and facebook.

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Richard Resnick: Welcome to the genomic revolution

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Richard Resnick: Welcome to the genomic revolution

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11min TedX talk

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Richard Resnick: Welcome to the genomic revolution

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Multimedia presentation about a young boy helped by whole genome sequencing (click on each block to see the story).

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Garvan is delighted to share the inspirational story of seven-year-old Alan, whose life-threatening immune disorder has been held at bay through the power of genomic information.

You can see a summary of Alan's story on the ABC website or watch the video below:

Illustration: Kate Patterson/Garvan Institute of Medical Research

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alan; genomic; genetic; disease; diagnosis

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Garvan is delighted to share the inspirational story of seven-year-old Alan, whose life-threatening immune disorder has been held at bay through the power of genomic information.

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Comprehensive point-form article from the National Human Genome Research Institute

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National Human Genome Research Institute (NHGRI)

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The NHGRI Genomic Medicine Working Group (GMWG) has been gathering expert stakeholders in a series of g enomic medicine meetings to discuss issues surrounding the adoption of genomic medicine. Particularly, the GMWG draws expertise from researchers at the cutting edge of this new medical toolset, with the aim of better informing future translational research at NHGRI.

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"What healthy people can learn from getting their genome sequenced"
Article from Genome Magazine

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Michael Snyder never saw it coming. Healthy, trim, and active at age 54, the Stanford geneticist decided to undergo whole genome sequencing (WGS) in 2010, when the technology was just being established at his university. Snyder figured he'd be a "guinea pig" for WGS not only to satisfy his own curiosity, but because, at the time, "a lot of people were concerned about people's ability to handle that information."

What Snyder, director of the Stanford Center for Genomics and Personalized Medicine, couldn't have known was that secrets revealed by his DNA would pose astonishing health challenges in his own life. Sequencing exposed gene mutations predisposing him to type 2 diabetes - a condition entirely at odds with his physique and lifestyle. This knowledge prompted him to diligently track his blood sugar levels for months afterward, revealing drastic glucose spikes in real time.

Careful dietary tweaks and an uptick in exercise have since helped him keep his diabetes largely in check. Snyder also shared the genetic information with his five siblings, four of whom underwent testing that indicated elevated glucose levels.

"It came out of nowhere for me," says Snyder, now 60, whose sequencing results also have him on the alert for developing the skin cancer basal cell carcinoma. "I view getting whole genome sequencing as a more active way of getting your family history."

Health revelations large and small are encoded in our genomes, but only recently has accessing these secrets even been possible. In the scant dozen years since the advent of next-generation sequencing technology, the cost of whole genome sequencing by researchers has plummeted from about $2.7 billion per person to about $1,000 today.

But only a fraction of the several hundred thousand people who have gotten all six billion letters in their DNA sequenced have actually received an interpretation of their whole genome sequencing. In addition, many of these people are scientific research participants. Unlike clinical efforts to help solve baffling birth defects in children or to sequence malignant tumors - which can steer doctors and patients to more effective treatments - deciphering the DNA of healthy people may hold more dubious value, despite its allure, experts say.

"Some healthy people may have a specific interest in their genome because of a family history of rare illnesses, while some are early adopters, and some are just interested in the ultimate selfie, so to speak," says Muin Khoury, founding director of the Office of Public Health Genomics at the Centers for Disease Control and Prevention in Atlanta. "It's a multifactorial proposition as to why."

The Percentage of DNA base pairs that are identical among humans.

For starters, not all genome-decoding techniques are created equal, and comprehensiveness varies. Marked differences distinguish whole genome sequencing from whole exome sequencing. Whole genome sequencing examines every single letter in your genome in both the gene regions (which make up, surprisingly, only about 1.5 percent of the genome) and the non-gene regions (the remaining 98.5 percent). Whole exome sequencing examines just the gene regions. While variants, or mutations, in genes are responsible for most rare single-gene disorders such as cystic fibrosis, Huntington's disease, and sickle cell disease, variants in the non-gene regions of the genome also may be responsible for some common diseases, such as heart disease, cancer, and diabetes, as well as traits like a person's response to certain drugs. So, while whole exome sequencing examines what is considered the meatiest part of the genome, it doesn't deliver quite as complete a picture as whole genome sequencing.

Beyond that, direct-to-consumer DNA tests reveal only a subset of variants in certain genes. Last October, for example, the DNA testing firm 23andMe began marketing a $199 test that could indicate whether someone carries genes linked with 36 disorders such as cystic fibrosis or the blood disorder beta-thalassemia, which causes chronic anemia. Such services don't sequence a customer's whole genome or exome, but instead perform so-called "targeted genotyping" of about 650,000 known genetic variants among the three to four million such mutations found in the average person's genome.

"Most people don't understand that there's a difference between sequencing six billion letters in the genome versus spot-checking certain parts of the genome or certain letters," explains Eric Topol, director of Scripps Translational Institute, a professor of genomics at Scripps Research Institute in La Jolla, California, and a member of Genome 's advisory board.

Increasingly valid answers about the power of our DNA are systematically being gathered from decades of research focusing on which of those three to four million gene variants in each person are linked to the development of disease. The number of mutations may sound huge, but 99 percent of everyone's base pairs are identical, Khoury notes. This reinforces the complexity of scientifically determining the significance - bad, good, or inconsequential - of any individual variant or group of variants.

For healthy people, experts readily point to several reliable uses for genome sequencing - aside from learning about ancestry - that best utilize its established and emerging strengths.

One of those uses is in carrier testing for those rare, single-gene, recessive disorders in which each parent contributes one copy of a variant gene. This test is typically used in reproductive planning by those with a family history of certain conditions, such as cystic fibrosis or sickle cell disease, or hailing from a specific heritage, such as Ashkenazi Jews, who are more prone to the neurological condition known as Tay-Sachs disease. Since 1993, the number of highly predictive gene tests has risen from about 100 tests to more than 4,000 tests now.

A second use for whole genome sequencing is in predisposition testing for so-called highly penetrant dominant disorders, in which people with the gene mutation have a high risk of developing a disease. These include breast and ovarian cancers, for which BRCA mutations confer an extremely elevated risk; colon cancer, for which Lynch syndrome mutations place carriers at an extraordinarily high risk; and some cardiovascular conditions, such as familial hypertrophic cardiomyopathy, which affects 1 in 500 people worldwide and can be life-threatening. Learning whether they've inherited such genetic mutations can help patients lower their risks by frequent monitoring or preventive treatment.

The Percentage of the genome that is examined by whole exome sequencing.

Predisposition testing has arguably captured the most public attention, with Angelina Jolie Pitt becoming the poster child for how BRCA mutation testing can present wrenching but proactive choices to avoid disease. Jolie Pitt, whose mother died of ovarian cancer, had her breasts and ovaries removed in two separate surgeries over the past several years in an attempt to escape the same fate - a decision that generated national attention.

Pharmacogenomic testing to predict how patients will respond to specific medications depending on their genetic makeup is another way in which sequencing can be useful. Certain gene variants can indicate that a medication may be more effective for an individual, while others might increase the risk for severe side effects.

Of sequencing's uses, Topol and Khoury contend that pharmacogenomic data may be the most valuable to the average healthy person. But the ability to actually access this data - all of which isn't yet clinically useful - still lags.

"There are well over 100 drugs where the interaction between DNA and the drug [may determine] if there are serious side effects, if it will or won't work, or if the dose has to be adjusted from the norm," Topol says. "But that information is not really attainable by anyone today, because there's no good, widespread service to get that information."

Finally, whole genome sequencing can reliably determine a wide variety of traits that test subjects may find edifying, intriguing, or just plain odd. These include their blood type; whether they're lactose intolerant, with dairy consumption causing digestive distress; or how quickly or slowly they metabolize caffeine or alcohol.

While some feel drug-specific genomic data isn't yet, as Khoury puts it, "ready for prime time," the same is true of many common gene variants thus far identified by scientists for common diseases like diabetes, schizophrenia, and heart disease. These variants tend to increase a person's risk of disease only slightly, so knowing about them doesn't help a physician to treat or prevent illness. And geneticists don't yet know the best way to compile the subtle health risks posed by many variants predisposing people to everyday disorders in a way that accurately predicts a person's overall risk.

This is one of the reasons the Food and Drug Administration (FDA) shut down 23andMe's initial $99 kit that tested for hundreds of genetic markers. According to a letter the FDA sent to 23andMe in November 2013, the agency had serious concerns "if test results are not adequately understood by patients or if incorrect test results are reported." While the FDA approved 23andMe's new $199 test kit in October 2015, the new kit offers a fraction of the tests in the original kit.

The complexity of these diseases is brought on by a mysterious interplay of genetic, environmental, and lifestyle triggers, says Isaac Kohane, chair of the Department of Biomedical Informatics at Harvard Medical School in Boston. "For most common diseases, the measure of your risk due to heredity is about 50 percent," Kohane says. "Even with perfect omniscience about the genome, for common diseases like heart attacks, strokes, diabetes, Alzheimer's, and so on, a big chunk of risk is still determined by other factors."

Greater use of DNA sequencing tests is also serving to illuminate other increasingly glaring glitches in scientists' ability to correctly forecast rare disorders. Some genetic variants originally identified in people with rare diseases and thought to be highly penetrant - bestowing a high likelihood of developing the condition - are now being found in healthy people as well.

This means the variants aren't as accurate at predicting disease as once believed. "It turns out," Kohane observes, "that we are riddled with abnormalities that will not kill us."

Snyder experienced this shortcoming firsthand, when his WGS results indicated mutations suggesting he should have aplastic anemia, a rare and life-threatening condition in which the bone marrow shuts down blood cell production. Fortunately, however, that warning was wrong. "There's no single gene that's 100 percent predictive of getting something," Snyder says, though he adds that some results are more alarming than others.

To Sequence, Or Not to Sequence

Snyder is a self-described "believer in the whole enterprise" of genome sequencing. He doesn't share the deep worries of those who fear the potential psychological ramifications of learning what's encoded in their genes. Indeed, the technology can open a Pandora's box - both enlightening people about their genetic variations and spurring emotional distress as well as concerns about how others might use the information.

Michael Linderman, an assistant professor in the Department of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai in New York City, and a member of Genome's advisory board, led research published in June 2015 in the European Journal of Human Genetics. The research focused on the motivations, concerns, and preferences of 35 healthy people who chose to have their whole genomes sequenced. The majority expressed interest in learning personal disease risk or health-related information, with one-quarter mentioning concerns about the adverse psychological impact of potential results. Nearly 6 in 10 endorsed concerns related to potential privacy issues about their data, and an equal number gave permission for their data to be used by researchers elsewhere.

Indeed, legislation is still catching up to the rising availability of genetic information. The federal Genetic Information Nondiscrimination Act forbids discrimination based on genetic information with regard to health insurance or employment, but doesn't cover life, disability, or long-term care insurance.

Aside from privacy concerns, experts fret that a deluge of personal genetic data may create a class of "worried well" who engage in ultimately unnecessary diagnostic tests and treatments based on information that's still of questionable value.

"Until we develop the knowledge, I think we have to be 'buyer beware,' " Kohane says. "Just as critical as we should be of any test, the whole genome presents us with literally millions of tests and each will do something potentially helpful or harmful to you. If you're healthy, you have more to lose. If you're not healthy, you have less to lose."

Despite the current drawbacks of the technology for genome sequencing, Kohane and others in the field contend that the more healthy people who take part, the more valid the data will become, with widespread benefits to society. "There will be a day," says Kohane, "when we'll have sequenced thousands of individuals with a variety of diseases who were healthy for a very long time, and we'll understand the meaning of these variants."

For starters, not all genome-decoding techniques are created equal, and comprehensiveness varies. Marked differences distinguish whole genome sequencing from whole exome sequencing. Whole genome sequencing examines every single letter in your genome in both the gene regions (which make up, surprisingly, only about 1.5 percent of the genome) and the non-gene regions (the remaining 98.5 percent). Whole exome sequencing examines just the gene regions. While variants, or mutations, in genes are responsible for most rare single-gene disorders such as cystic fibrosis, Huntington's disease, and sickle cell disease, variants in the non-gene regions of the genome also may be responsible for some common diseases, such as heart disease, cancer, and diabetes, as well as traits like a person's response to certain drugs. So, while whole exome sequencing examines what is considered the meatiest part of the genome, it doesn't deliver quite as complete a picture as whole genome sequencing.

Beyond that, direct-to-consumer DNA tests reveal only a subset of variants in certain genes. Last October, for example, the DNA testing firm 23andMe began marketing a $199 test that could indicate whether someone carries genes linked with 36 disorders such as cystic fibrosis or the blood disorder beta-thalassemia, which causes chronic anemia. Such services don't sequence a customer's whole genome or exome, but instead perform so-called "targeted genotyping" of about 650,000 known genetic variants among the three to four million such mutations found in the average person's genome.

"Most people don't understand that there's a difference between sequencing six billion letters in the genome versus spot-checking certain parts of the genome or certain letters," explains Eric Topol, director of Scripps Translational Institute, a professor of genomics at Scripps Research Institute in La Jolla, California, and a member of Genome 's advisory board.

Increasingly valid answers about the power of our DNA are systematically being gathered from decades of research focusing on which of those three to four million gene variants in each person are linked to the development of disease. The number of mutations may sound huge, but 99 percent of everyone's base pairs are identical, Khoury notes. This reinforces the complexity of scientifically determining the significance - bad, good, or inconsequential - of any individual variant or group of variants.

For healthy people, experts readily point to several reliable uses for genome sequencing - aside from learning about ancestry - that best utilize its established and emerging strengths.

One of those uses is in carrier testing for those rare, single-gene, recessive disorders in which each parent contributes one copy of a variant gene. This test is typically used in reproductive planning by those with a family history of certain conditions, such as cystic fibrosis or sickle cell disease, or hailing from a specific heritage, such as Ashkenazi Jews, who are more prone to the neurological condition known as Tay-Sachs disease. Since 1993, the number of highly predictive gene tests has risen from about 100 tests to more than 4,000 tests now.

A second use for whole genome sequencing is in predisposition testing for so-called highly penetrant dominant disorders, in which people with the gene mutation have a high risk of developing a disease. These include breast and ovarian cancers, for which BRCA mutations confer an extremely elevated risk; colon cancer, for which Lynch syndrome mutations place carriers at an extraordinarily high risk; and some cardiovascular conditions, such as familial hypertrophic cardiomyopathy, which affects 1 in 500 people worldwide and can be life-threatening. Learning whether they've inherited such genetic mutations can help patients lower their risks by frequent monitoring or preventive treatment.

The Percentage of the genome that is examined by whole exome sequencing.

Predisposition testing has arguably captured the most public attention, with Angelina Jolie Pitt becoming the poster child for how BRCA mutation testing can present wrenching but proactive choices to avoid disease. Jolie Pitt, whose mother died of ovarian cancer, had her breasts and ovaries removed in two separate surgeries over the past several years in an attempt to escape the same fate - a decision that generated national attention.

Pharmacogenomic testing to predict how patients will respond to specific medications depending on their genetic makeup is another way in which sequencing can be useful. Certain gene variants can indicate that a medication may be more effective for an individual, while others might increase the risk for severe side effects.

Of sequencing's uses, Topol and Khoury contend that pharmacogenomic data may be the most valuable to the average healthy person. But the ability to actually access this data - all of which isn't yet clinically useful - still lags.

"There are well over 100 drugs where the interaction between DNA and the drug [may determine] if there are serious side effects, if it will or won't work, or if the dose has to be adjusted from the norm," Topol says. "But that information is not really attainable by anyone today, because there's no good, widespread service to get that information."

Finally, whole genome sequencing can reliably determine a wide variety of traits that test subjects may find edifying, intriguing, or just plain odd. These include their blood type; whether they're lactose intolerant, with dairy consumption causing digestive distress; or how quickly or slowly they metabolize caffeine or alcohol.

While some feel drug-specific genomic data isn't yet, as Khoury puts it, "ready for prime time," the same is true of many common gene variants thus far identified by scientists for common diseases like diabetes, schizophrenia, and heart disease. These variants tend to increase a person's risk of disease only slightly, so knowing about them doesn't help a physician to treat or prevent illness. And geneticists don't yet know the best way to compile the subtle health risks posed by many variants predisposing people to everyday disorders in a way that accurately predicts a person's overall risk.

This is one of the reasons the Food and Drug Administration (FDA) shut down 23andMe's initial $99 kit that tested for hundreds of genetic markers. According to a letter the FDA sent to 23andMe in November 2013, the agency had serious concerns "if test results are not adequately understood by patients or if incorrect test results are reported." While the FDA approved 23andMe's new $199 test kit in October 2015, the new kit offers a fraction of the tests in the original kit.

The complexity of these diseases is brought on by a mysterious interplay of genetic, environmental, and lifestyle triggers, says Isaac Kohane, chair of the Department of Biomedical Informatics at Harvard Medical School in Boston. "For most common diseases, the measure of your risk due to heredity is about 50 percent," Kohane says. "Even with perfect omniscience about the genome, for common diseases like heart attacks, strokes, diabetes, Alzheimer's, and so on, a big chunk of risk is still determined by other factors."

Greater use of DNA sequencing tests is also serving to illuminate other increasingly glaring glitches in scientists' ability to correctly forecast rare disorders. Some genetic variants originally identified in people with rare diseases and thought to be highly penetrant - bestowing a high likelihood of developing the condition - are now being found in healthy people as well.

This means the variants aren't as accurate at predicting disease as once believed. "It turns out," Kohane observes, "that we are riddled with abnormalities that will not kill us."

Snyder experienced this shortcoming firsthand, when his WGS results indicated mutations suggesting he should have aplastic anemia, a rare and life-threatening condition in which the bone marrow shuts down blood cell production. Fortunately, however, that warning was wrong. "There's no single gene that's 100 percent predictive of getting something," Snyder says, though he adds that some results are more alarming than others.

To Sequence, Or Not to Sequence

Snyder is a self-described "believer in the whole enterprise" of genome sequencing. He doesn't share the deep worries of those who fear the potential psychological ramifications of learning what's encoded in their genes. Indeed, the technology can open a Pandora's box - both enlightening people about their genetic variations and spurring emotional distress as well as concerns about how others might use the information.

Michael Linderman, an assistant professor in the Department of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai in New York City, and a member of Genome's advisory board, led research published in June 2015 in the European Journal of Human Genetics. The research focused on the motivations, concerns, and preferences of 35 healthy people who chose to have their whole genomes sequenced. The majority expressed interest in learning personal disease risk or health-related information, with one-quarter mentioning concerns about the adverse psychological impact of potential results. Nearly 6 in 10 endorsed concerns related to potential privacy issues about their data, and an equal number gave permission for their data to be used by researchers elsewhere.

Indeed, legislation is still catching up to the rising availability of genetic information. The federal Genetic Information Nondiscrimination Act forbids discrimination based on genetic information with regard to health insurance or employment, but doesn't cover life, disability, or long-term care insurance.

Aside from privacy concerns, experts fret that a deluge of personal genetic data may create a class of "worried well" who engage in ultimately unnecessary diagnostic tests and treatments based on information that's still of questionable value.

"Until we develop the knowledge, I think we have to be 'buyer beware,' " Kohane says. "Just as critical as we should be of any test, the whole genome presents us with literally millions of tests and each will do something potentially helpful or harmful to you. If you're healthy, you have more to lose. If you're not healthy, you have less to lose."

Despite the current drawbacks of the technology for genome sequencing, Kohane and others in the field contend that the more healthy people who take part, the more valid the data will become, with widespread benefits to society. "There will be a day," says Kohane, "when we'll have sequenced thousands of individuals with a variety of diseases who were healthy for a very long time, and we'll understand the meaning of these variants."

Predisposition testing has arguably captured the most public attention, with Angelina Jolie Pitt becoming the poster child for how BRCA mutation testing can present wrenching but proactive choices to avoid disease. Jolie Pitt, whose mother died of ovarian cancer, had her breasts and ovaries removed in two separate surgeries over the past several years in an attempt to escape the same fate - a decision that generated national attention.

Pharmacogenomic testing to predict how patients will respond to specific medications depending on their genetic makeup is another way in which sequencing can be useful. Certain gene variants can indicate that a medication may be more effective for an individual, while others might increase the risk for severe side effects.

Of sequencing's uses, Topol and Khoury contend that pharmacogenomic data may be the most valuable to the average healthy person. But the ability to actually access this data - all of which isn't yet clinically useful - still lags.

"There are well over 100 drugs where the interaction between DNA and the drug [may determine] if there are serious side effects, if it will or won't work, or if the dose has to be adjusted from the norm," Topol says. "But that information is not really attainable by anyone today, because there's no good, widespread service to get that information."

Finally, whole genome sequencing can reliably determine a wide variety of traits that test subjects may find edifying, intriguing, or just plain odd. These include their blood type; whether they're lactose intolerant, with dairy consumption causing digestive distress; or how quickly or slowly they metabolize caffeine or alcohol.

While some feel drug-specific genomic data isn't yet, as Khoury puts it, "ready for prime time," the same is true of many common gene variants thus far identified by scientists for common diseases like diabetes, schizophrenia, and heart disease. These variants tend to increase a person's risk of disease only slightly, so knowing about them doesn't help a physician to treat or prevent illness. And geneticists don't yet know the best way to compile the subtle health risks posed by many variants predisposing people to everyday disorders in a way that accurately predicts a person's overall risk.

This is one of the reasons the Food and Drug Administration (FDA) shut down 23andMe's initial $99 kit that tested for hundreds of genetic markers. According to a letter the FDA sent to 23andMe in November 2013, the agency had serious concerns "if test results are not adequately understood by patients or if incorrect test results are reported." While the FDA approved 23andMe's new $199 test kit in October 2015, the new kit offers a fraction of the tests in the original kit.

The complexity of these diseases is brought on by a mysterious interplay of genetic, environmental, and lifestyle triggers, says Isaac Kohane, chair of the Department of Biomedical Informatics at Harvard Medical School in Boston. "For most common diseases, the measure of your risk due to heredity is about 50 percent," Kohane says. "Even with perfect omniscience about the genome, for common diseases like heart attacks, strokes, diabetes, Alzheimer's, and so on, a big chunk of risk is still determined by other factors."

Greater use of DNA sequencing tests is also serving to illuminate other increasingly glaring glitches in scientists' ability to correctly forecast rare disorders. Some genetic variants originally identified in people with rare diseases and thought to be highly penetrant - bestowing a high likelihood of developing the condition - are now being found in healthy people as well.

This means the variants aren't as accurate at predicting disease as once believed. "It turns out," Kohane observes, "that we are riddled with abnormalities that will not kill us."

Snyder experienced this shortcoming firsthand, when his WGS results indicated mutations suggesting he should have aplastic anemia, a rare and life-threatening condition in which the bone marrow shuts down blood cell production. Fortunately, however, that warning was wrong. "There's no single gene that's 100 percent predictive of getting something," Snyder says, though he adds that some results are more alarming than others.

To Sequence, Or Not to Sequence

Snyder is a self-described "believer in the whole enterprise" of genome sequencing. He doesn't share the deep worries of those who fear the potential psychological ramifications of learning what's encoded in their genes. Indeed, the technology can open a Pandora's box - both enlightening people about their genetic variations and spurring emotional distress as well as concerns about how others might use the information.

Michael Linderman, an assistant professor in the Department of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai in New York City, and a member of Genome's advisory board, led research published in June 2015 in the European Journal of Human Genetics. The research focused on the motivations, concerns, and preferences of 35 healthy people who chose to have their whole genomes sequenced. The majority expressed interest in learning personal disease risk or health-related information, with one-quarter mentioning concerns about the adverse psychological impact of potential results. Nearly 6 in 10 endorsed concerns related to potential privacy issues about their data, and an equal number gave permission for their data to be used by researchers elsewhere.

Indeed, legislation is still catching up to the rising availability of genetic information. The federal Genetic Information Nondiscrimination Act forbids discrimination based on genetic information with regard to health insurance or employment, but doesn't cover life, disability, or long-term care insurance.

Aside from privacy concerns, experts fret that a deluge of personal genetic data may create a class of "worried well" who engage in ultimately unnecessary diagnostic tests and treatments based on information that's still of questionable value.

"Until we develop the knowledge, I think we have to be 'buyer beware,' " Kohane says. "Just as critical as we should be of any test, the whole genome presents us with literally millions of tests and each will do something potentially helpful or harmful to you. If you're healthy, you have more to lose. If you're not healthy, you have less to lose."

Despite the current drawbacks of the technology for genome sequencing, Kohane and others in the field contend that the more healthy people who take part, the more valid the data will become, with widespread benefits to society. "There will be a day," says Kohane, "when we'll have sequenced thousands of individuals with a variety of diseases who were healthy for a very long time, and we'll understand the meaning of these variants."

# data[].attributes.attachment_link.description
Michael Snyder never saw it coming. Healthy, trim, and active at age 54, the Stanford geneticist decided to undergo whole genome sequencing (WGS) in 2010, when the technology was just being established at his university.

# data[].attributes.headline
Potential and risks of recent developments in biotechnology

# data[].attributes.subject
Potential and risks of recent developments in biotechnology

# data[].attributes.body
A speech by Venki Ramakrishnan,
President of the Royal Society
AAAS annual meeting 2017 (includes human genetic technologies)

# data[].attributes.headline
Reader: DNA testing could save lives; it did for me

# data[].attributes.subject
Reader: DNA testing could save lives; it did for me

# data[].attributes.body
A Letter to the Editor of USA Today from a DTC genetic testing customer

# data[].attributes.attachment_link.readable_text
Missing from all the coverage of the Food and Drug Administration authorization of the first-ever over-the-counter genetic cancer risk test for BRCA gene variants was any reaction from the people this decision impacts the most - people like me.

Almost eight years ago, during the short period when 23andMe first offered this report, one of these tests likely saved my life. Yet I've seen comments dismissing 23andMe's report as "meaningless."

It wasn't for my family or me. And I know I'm not alone. Only less than 40% of people who have one of these mutations qualify for cancer screening under current guidelines.

Almost nine years ago, my sister Sara was diagnosed with breast cancer. It was a frightening and humbling experience. After her diagnosis, both Sara and my mother had clinical genetic tests done that found no risk variants. I went to my doctor, who following standard protocol, advised against BRCA testing because both my mother and sister tested negative. I took her advice.

Then unrelated to any of this, my husband bought 23andMe kits. We didn't expect it, but I discovered that I had a BRCA mutation putting me at a much higher risk for breast and ovarian cancer. I went to my doctor, who did follow up screening confirming the 23andMe results. I likely inherited these mutations from my father. I talked to a genetic counselor and took action.

I am healthy now. I've become very involved with the Basser Center for BRCA, advocating for more research. I understand the caution around how this information is delivered, and the limits of 23andMe's test. But I also know that there are many people like me for whom a report like this could make all the difference.

If this test can save just one life, that's enough for me.

Jill Steinberg; New York
To join the conversations about topics on USA TODAY, email letters@usatoday.com, comment on Facebook, or use #tellusatoday on Twitter.
Read or Share this story: https://usat.ly/2pWGOGm

# data[].attributes.attachment_link.title
Reader: DNA testing could save lives; it did for me

# data[].attributes.attachment_link.description
Missing from all the coverage of the Food and Drug Administration authorization of the first-ever over-the-counter genetic cancer risk test for BRCA gene variants was any reaction from the people this decision impacts the most - people like me. Almost eight years ago, during the short period when 23andMe first offered this report, one of these tests likely saved my life.

# data[].attributes.body
A long-read about the limitations of genetic testing from The Globe and Mail.
(note- No need to read it all- the first few paragraphs are really interesting)

# data[].attributes.attachment_link.readable_text
Ever since DNA was first used in 1986 to catch a killer, it's swashbuckled its way through society as an almost infallible weapon of truth: convicting the guilty, freeing the innocent, revealing bloodlines, paternity and identity.

On the health front, even before it had a name, excitement over DNA's power straddled centuries. But only the 21st has cast it as the attainable key to "precision medicine" - enabling doctors and patients to practise pro-active care: pinpointing diseases before they strike, and fighting them with targeted therapies tailored to an individual's unique genome.

Yet, the more genomes researchers study, the more evidence mounts that using DNA to predict health risks is anything but precise - for now, at least. These days, nature's longest thread comes off a like a trickster, shape-shifting from person to person, written in a wily language no one fully understands, with at least three billion ways to misread it.

To try to bridge the chasm between reading and comprehension, scientists leading Canada's Personal Genome Project say they have taken the deepest dive possible into human DNA, conducting the most thorough analysis that current computing allows on the whole genome sequences of 56 Canadians who agreed to take part in the unusual and continuing experiment. Their report is published today in the Canadian Medical Association Journal.

Launched publicly in Canada in 2012, the PGP aims to build an open, online database of Canadian genomes for use by researchers anywhere and more than 1,100 Canadians have signed up so far. But by unravelling the entire codes of just the inaugural participants, what the project leaders have found is both promising and perplexing: medically relevant information in each volunteer, but also a vast trove of mysterious quirks and dramatic glitches that none of them expected to see in a cohort of healthy people.

Surprising, too, is that many of the volunteers carry mutated genes that suggest they should be sick, diseased or even near death - but aren't.

Participant No. 27 is another jolt. Missing from about 70 per cent of her blood cells is an entire chromosome, the X sex chromosome, of which women usually have two copies. On paper, No. 27 has mosaic Turner syndrome, a rare disorder that only affects females and can lead to impaired sexual development, short stature, a webbed neck and heart problems. In reality, she is a healthy 54-year-old who had no inkling her DNA harboured such a twist.

The report, compiled by 53 researchers at the Hospital for Sick Children and the University of Toronto, captures the staggering breadth of how much is left to learn before science can properly interpret humanity's operating code. It offers proof that most research to date has overlooked the different types of genetic glitches that can lead to health problems, while adding to the growing realization that many genes once thought to cause disease probably don't.

All of which implies that in these foggy days of the so-called genomic revolution, people can easily be led astray by test results that may bring false comfort, or needless stress and treatment - especially now, when the largely unregulated market of direct-to-consumer DNA tests is booming.

Just ask Participant No. 16 about the heart abnormalities his genes suggest.

"You can imagine someone getting this report back and saying, 'Oh my God, I'm gonna die of this! How do I check it out?' Then there will be echocardiograms and all these things being done on people who are perfectly healthy," says Doug Mowbray, who wasn't troubled by his vexing results because the participants had a genetic counsellor walk them through the fog. But also because he's a doctor himself - a radiologist, in fact, in Southwestern Ontario. He knew his heart was normal because he took a good look at it while calibrating a new imaging scanner a few years ago.

Unsurprisingly, the new report concludes that Whole Genome Sequencing (WGS) is not ready to become a standard feature of routine health care. But the researchers predict that "despite a considerable burden of uncertainty, and the possibility that false-positive findings may engender follow-up investigations and a 'worried well' population" - it will be: the plummeting cost of reading DNA is pushing it into mainstream medicine.

Study leader Stephen Scherer, director of both the McLaughlin Centre at U of T and the Centre for Applied Genomics at Sick Kids, says people send him e-mails almost daily asking if they should have their whole genomes sequenced. His answer: "At the current time, unless you have a medical query that can't be explained by traditional means ... don't. But when the price comes down, into the hundreds, or less, there's not going to be a question any more - it's just going to happen. There's going to be an onslaught of information, and society needs to figure out how to deal with that."

In less than two decades, the cost to sequence a human genome has dropped by billions of dollars. The first map of the genome, decoded in 2000, rang in at about $3-billion. Today, such a map costs roughly $1,000. Estimates are that in five years, both researchers and the curious will be able to see what they're made of for $100 - less than the cost of an X-ray.

At hospitals and medical labs across the country, the sequencing of whole genomes, or parts of them, is taking off, just as it is in the consumer market. While most of it remains in the research sphere, doctors are increasingly looking to whole genomes to diagnose disease, or to choose the best drugs for their patients - and it's making a difference: unearthing the roots of rare conditions for patients who have waited years for answers; pointing the way to effective medicines; and predicting if patients will tolerate them. In cancer care, especially, it's transforming treatments and early diagnosis.

So, filling the knowledge gap is urgent not only to counter the potential for misleading results, Dr. Scherer says, but because the chance increases all the time that you will find something helpful in your genome, something that might even save your life or the lives of your children.

In all, the study found that a quarter of the participants, or 14 people, carry genetic variants associated with heart disease, cancer and neurological conditions. Nearly a quarter were also found to be at risk of potentially life-threatening reactions to certain drugs. More than 94 per cent, or 53 of the 56 volunteers, were carriers of rare disease genes - such as cystic fibrosis - that give a one-in-four chance of having a child with that disease should a co-parent also be a carrier.

The researchers recommended further monitoring, tests and counselling for several participants, and noted the findings have health-management implications for their families and future generations. As. Dr. Scherer explains, decoding a whole genome may happen once, but individuals, and their descendants, may turn to it many times for answers and explanations.

From the get-go, the Personal Genome Project was unorthodox - in part because participants were not only asked to share their genomes online but also personal details about their lifestyles, traits and medical histories. Since DNA is a living language that responds to how we live, and even where we live - studies find it can change with the weather - the project has given researchers the capacity to break down the lifelong bossa nova that genes dance with the environment.

The philosophy behind the project sprouted at Harvard University, where the first PGP project began in 2005. But when Dr. Scherer started making plans in 2007 to launch a Canadian version, it was unclear how many Canadians would go in for that kind of molecular Full Monty, especially with no guarantees of privacy. At the time, Canada was the only Group of Eight country without a law to protect genetic information from use by a third party. Before signing on, participants had to pass an exam to demonstrate they understood the wide range of risks involved - that they could lose the ability to obtain life insurance or a job, discover they're not biologically related to their families or that someone could even make a synthetic copy of their DNA and plant it at a crime scene.

After the Canadian launch of PGP, the movement gathered global steam, with projects taking off in Britain, Austria and, last October, in China. But in Canada, with no dedicated funding at the start, the first 25 participants had to pay for themselves to be sequenced - which for most, in 2012, cost about $4,000. "These volunteers were the heroes," Dr. Scherer says.

But asking people to pay their own way also resulted in a fairly select group of early volunteers. Most are affluent, well educated and, the paper notes, "idealistic about the promise of genomic medicine" - and, it so happens, white. Apart from one participant from East Asia, one described as "white native" and three from the Middle East, all are Caucasian. The 25 women and 31 men ranged in age from 25 to 81 at enrolment, the median age being 51. The researchers are up front about the study's lack of diversity and say in the paper that they "explicitly aim to expand" it in the next rounds of analysis, with participation from Indigenous people and recent immigrants.

The initial selection process was also skewed deliberately, Dr. Scherer says, toward enrolling people "who are in a position to spread the word about the experience." Many of the participants also work in health care: doctors, professors, genetic counsellors; even more unusually, some are also co-authors on the paper.

Progress was slow going in the early years, but in 2016, after a new generation of sequencing machines arrived at Dr. Scherer's lab, and the McLaughlin Centre put up funding, the team decided to reread the genomes of the first participants at a level never before possible. Then, last March, Dr. Scherer decided to freeze the data at 56 samples, "knowing it would take about four good months to analyze."

He wasn't wrong. Trying to make sense of the various quirks that turned up in about a hundred billion units of code from the sequences of those 56 demanded a huge research team that included specialists in cardiology, biology pharmacology, epigenetics, paediatrics, metabolic disorders, bioinformatics and genetic counselling.

The PGP's deep dive into human DNA overturns the notion that the healthy inherit from their parents two matching sets of 23 tidy chromosomes that line up like soldiers. Indeed, it finds major structural differences not only between people, but between chromosomes in the same person. "People are walking around with these massive chunks of chromosomes missing, and [duplications] that affect multiple genes," Dr. Scherer says. "When I was a student, these things were associated with Down Syndrome, or DiGeorge Syndrome, so to see how structurally different we are, and how many examples there are in this [small, healthy] group - it amazes me."

Most research on DNA has focused on the single letter "typos" in genetic code as signposts of disease. But the PGP study concludes that further research should include places where whole "sentences" or "paragraphs" of code may be missing, or upside down, or, like a stutter, repeated - a quirk known as a copy-number variation, or a CNV.

Yet, without that information, there's a serious risk of missing a health issue: "It would be like going to your doctor's office to get checked out for skin cancer, and they're looking for moles of a certain size - but miss the great big gaping tumour on your back."

The study also examined changes in mitochondrial DNA, which people inherit only from their mothers. In one participant, this separate ring of genetic code, which cells use to convert food to energy, contained an abnormality researchers had previously predicted could lead to neurological disorders in childhood. But there was no evidence of it doing so.

While the study is small, and it can't be extrapolated to the general population, Dr. Bulman noted that it took nearly as many researchers as there were participants to sift through the data. It may come down to "the $10 genome, and the $100,000 analysis," he quipped.

The PGP identified variants in the study by comparing them with the third version of the very first human-genome map, which was compiled from the chromosomes of 13 people in Buffalo. Then, researchers checked to see whether those variants had been tagged as potentially harmful in various disease-gene databases. But there's a wide reckoning in the field that much of this database information is lopsided: Ever since the first disease gene was identified in Canada in 1989, researchers have generally hunted for disease mutations by looking at people who have a particular disorder, or affected family members.

That made for biased samples, says Heidi Rehm, an associate professor of pathology at Brigham and Women's Hospital and Harvard Medical School. "The significant challenge," Dr. Rehm says, "is to have a true estimate of the likelihood of a healthy person developing disease if they carry the variant, a true estimate of penetrance."

Ultimately, it comes down to a judgment call as to whether there's enough evidence in the disease-gene databases to flag a variant as dangerous - and it's a wide , wishy-washy spectrum of judgment that ranges from "likely benign" to "pathogenic" or, as is often the case, "a variant of unknown significance," which basically parks it in diagnostic limbo.

Dr. Rehm estimates there are more than 100 million variants that have been identified in public databases, while only about 330,000 of them have been interpreted, and "probably two-thirds of those are of uncertain significance."

In the United States, proof that the knowledge gap can lead to serious misinterpretations has already surfaced. In South Carolina, a wrongful-death lawsuit is under way against a private testing company for allegedly misclassifying a mutation that may have cost a two-year-old boy his life. The boy's mother, Amy Williams, claims that the company misinterpreted a mutation in her son, Christian, who suffered from epilepsy. As a result, Ms. Williams says he did not receive the effective treatment he could have, and was instead given medication that made him worse. Christian died following a severe seizure in 2008.

In 2016, doctors at the Mayo Clinic detailed the troubling case of two dozen family members who were wrongly informed by a testing company that they carried a heart-related mutation that could cause sudden death. The family had lost a 13-year-old boy to an unexplained heart condition, and after receiving the test results, had a heart defibrillator surgically implanted in the chest of the boy's brother. Only after further investigation at the Mayo did the family learn that the variant they carry is harmless. Mayo doctors concluded that the 13-year-old had died of an unrelated heart problem, and that the defibrillator - which twice delivered painful shocks to the surviving brother's heart - had been implanted needlessly.

In a video release from the Mayo, genetic cardiologist Michael Ackerman notes that "the fumbles that are occurring with genetic testing out there ... are starting to mount."

As are concerns around a consumer marketplace that waits for no one. Mail-order DNA tests, from companies such as 23 andMe and Ancestry.ca, have helped fuel a market that's tripled in size in the past four years. These firms only parse the genome for certain markers, to tell their customers if they're lactose intolerant, say, or hail from Viking stock. But over the next several years, as the cost of sequencing whole genomes falls to practically nothing, forecasts suggest that genetic testing will become a $10-billion global industry.

In the genomic era, people keen to dip into their DNA should be comfortable curling up with ambiguity. Chances are, as the PGP study participants found, you may well carry genes for conditions you don't have, while discovering that there's no explanations for those you do.

Logan Donaldson, a 49-year-old York University biology professor, had no idea when he joined the PGP that he would go on to develop early onset glaucoma in 2015. The condition requires him to take daily medication and to have his eye pressure maintained at normal levels by laser therapy. Some might chalk it up to bad luck, but, Prof. Donaldson says, "since I had my complete genome, I started scouring it for some explanation."

He discovered he carries a rare and serious mutation in one of the seven genes linked to glaucoma. Still, "as exciting as that might be," he says, there's not enough data to be confident it's the cause without further testing and investigation.

Nor can his genome currently offer him an explanation for the low cholesterol that runs in his family.

Prof. Donaldson's levels are two times lower than normal, which has no apparent effect on his life, beyond the jokes he gets to share about undergoing "intensive french-fry therapy."

Prof. Donaldson, who has far more genetic literacy than most, says his genome has left him with more questions than answers, but he feels that most people , "even if you only had high-school biology going into this," are not likely to overreact to what they find in their genetic closets: "I think people are smarter than that."

The American College of Medical Genetics advises that people should be informed of health risks uncovered in their genome only if such risks are medically actionable, which currently includes a fluctuating list of more than 50 conditions. By contrast, the very aim of the PGP study was to dig up every relevant health issue that could be gleaned from a genome and to gauge how participants react to the mountain of murky data.

To Dr. Mowbray, Participant No. 16, the real danger in the evolving field is among those who dive solo into their whole genomes: "If people are going to do this genetic decoding but don't have the proper genetic-counselling follow-up, they're going to be stirring up all kinds of dismay."

Dr. Mowbray sees his string of false positives as evidence that the research is important and necessary, which is why, as a man close to retirement, without any children, he joined the project. "They know that these defects cause genetic illness, because that's how it was first identified - in people who had the illness. But what they don't know is how many people have these defects that don't have the illness - and the question is why," he says. "Maybe the thing that's stopping it in me may point them in a direction for treating people who may have this in the future."

His results do have some utility. Dr. Mowbray learned about a medication he should avoid, and that he carries the variant for an irregular heartbeat disorder both his mother and grandmother had. He suspected he would eventually develop it, but since learning of his genetic risk, he takes a daily Aspirin.

Even Michael Szego, the project's lead ethicist, discovered something both leading and misleading in his genome. He's a carrier for Tay-Sachs disease, which may be relevant to his children when they reach child-bearing age. But his genes also suggest that they're children he shouldn't have: His DNA carries a variant tied to hypogonadism, a condition that impairs masculine development and leads to infertility. Dr. Szego is a healthy father of three.

Last summer, in a speech to science graduates at the University of Waterloo, Dr. Scherer described the high-speed progress he's seen in genetics in the past 30 years: how, as a student, it took him eight months to sequence one gene in a roundworm, a job that would now take eight hours. He told them the 10-year hunt for the cystic-fibrosis gene at Sick Kids would now take 10 weeks. "The most successful scientists of my generation were the ones who built the machines to generate massive novel data sets," he said, allowing researchers to read the language of DNA that has evolved to create human minds "capable of decoding our own instruction manual."

Yet, Dr. Scherer suspects that humans will never be able to truly translate that language. He predicts it will be the advent of artificial intelligence that will yield the next big genomic breakthroughs; in the meantime, humanity will have to rely on its machines to help it connect the dots.

The world seems determined to do so. The United States is building a one-million-genome-strong database under its Precision Medicine Initiative. With its brand new Big Data Nanjing Centre, China will be capable of decoding half a million genomes a year. In December, Finland announced FinnGen - a six-year project to combine the genomes and digital health records of 500,000 Finns. Britain is at work on the 100,000 Genomes Project; Turkey has launched its own project, and Israel's is in the works.

Canada has no other open-source effort to sequence its citizens beyond the Personal Genome Project, which remains a small, sideline operation for most of the researchers involved. But, Dr. Scherer says, the country should have something like "PGP on steroids."

The idea is not far-fetched. 23 andMe is selling access to the DNA in its customer database (which customers themselves pay to be part of) to several drug companies. One, Genentech, paid a reported US$10-million for a look at the genes of people with Parkinson's disease.

"I fully expect that, in the near future, sequencing genomes will fall to free," Mr. Hessel says, "and some people's genomes will even be worth paying for because they have some interesting feature, trait or flaw" - a rare disease, or are high achievers, or simply because they're celebrities. "We're going to see a completely new dynamic appear that could potentially bring in millions, tens of millions, potentially hundreds of millions of genomes over the next decade."

"It is a revolution," he says, "it just takes a while for a revolution to build up steam and change everyone's lives."
THE GENETIC FUTURE: MORE FROM THE GLOBE AND MAIL

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Cracks in the code: Why mapping your DNA may be less reliable than you think

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Ever since DNA was first used in 1986 to catch a killer, it's swashbuckled its way through society as an almost infallible weapon of truth: convicting the guilty, freeing the innocent, revealing bloodlines, paternity and identity. On the health front, even before it had a name, excitement over DNA's power straddled centuries.

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14min video from Nowgen about how genes affect health.

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This video from Nowgen, produced by Teachers TV, explores how modern genetic research is helping scientists to understand a rare life-threatening heart condition, as well as the more common skin condition, eczema. Susie Murray has a rare inherited heart condition called Long QT which, if left untreated, can lead to rapid heartbeats, blackouts and even sudden death.

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Article from Markkula Center for Applied Ethics

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Our genes contain information that scientists hope will help in the treatment of many diseases. Huntington's disease provides a window on the choices we face as medicine increases our ability to intervene in human genetics.
Stop pacing, Mom. It'll be all right." Meghan and her mother, Anne, fidget nervously in the waiting area of the genetic testing center.

Anne halts and faces her daughter. "I wish it wasn't this way, Meghan." Anne's family has been haunted by Huntington's since anyone can remember; those who get it always die from it. Her brother Harry was just fine until his mid- 40s-then came the depression, the twitching arms."I need to have this test, Mom," Meghan continues. "I want to know if I'm going to wind up like Uncle Harry. I want to know the chances that my children will inherit Huntington's disease." Meghan and her husband, Rick, want to start a family-a family untouched by Huntington's bizarre dances, frightening mood swings, and untimely death. "I'd rather not have children if it means sentencing them to a death like that," Meghan says.

"I would do anything to spare you," Anne says. "But, Meghan, please understand that I don't want to be tested. 'So far, so good' is my philosophy. I'm only 42. I want to live my life and make my decisions without a Huntington's diagnosis hanging over my head."

"But Mom, you're not the one being tested; I am."

Falling into the chair next to her daughter, Anne pleads, "Don't you see? If your test is positive, it means I've got the gene, too. And I don't want to know. I have a right not to know, don't I?"

Anne and Meghan face a tentative future. Members of families with a history of Huntington's disease have long known that this neurological disorder-with its loss of motor control, personality changes, depression, dementia, and death-might eventually be their fate.

Huntington's is a genetic disease, one that can be passed down from parents to children. The gene for Huntington's is dominant, which means that a single copy of the gene from either parent triggers the disease. Children of people afflicted with Huntington's disease have a 50/50 chance of also having the disease.

Until recently, these people had no way of knowing whether they were in the unlucky 50 percent until symptoms actually appeared, usually between the ages of 30 and 50. Then, in 1993, scientists identified the gene responsible for the disorder and made possible the test Meghan wants to take.

If Meghan is tested and found to carry the gene for Huntington's disease, her mother must also have the gene. Meghan, then, will know what Anne does not want to know. What should Meghan do?

The Human Genome Project

Meghan's problem foreshadows the dilemmas many people will face as scientists learn more about genetics. In 1990, an international effort was launched to decode the language of our genes-the Human Genome Project (HGP). The United States is investing $3 billion over 15 years in this endeavor to map the complete set of genes for humans-the human genome. The project will make it easier for researchers who want to identify the genetic components both of disease and of physical and intellectual traits.

Thus far, the most obvious result of the HGP is the rapid proliferation of genetic information. As the new information pours in, the traditional questions haunt us: What should we do with this information? What does this particular genetic alteration mean personally, medically, and socially? If we can, should we intervene to correct or enhance an individual's genome? And when we cannot intervene, how do we handle diagnostic information in the absence of a cure?

Genetic screening can provide new information, not only for potential Huntington's victims but also for sufferers of the more than 4,000 other diseases of genetic origin. Additional ailments are rooted in the interaction of genes with the environment. All told, genetic disorders are the fourth leading cause of death in the United States.

Discovering the location of a disease-causing gene on a chromosome permits diagnosis before the onset of symptoms. It also allows testing of entire populations to identify carriers as well as those who are affected.

The long-term hope is for a precise molecular correction of the defect so that genetic disease becomes as curable as infectious disease. Such therapy might also prevent genetic pathologies from moving from one generation to the next.

The Rift Between Diagnosis and Cure

Yet despite the progress of the HGP-and, indeed, primarily because of it-disease prediction continues to outpace medicine's ability to treat or cure. The test for Huntington's disease can confirm a mutation in the Huntington's gene, but it offers no treatment for the devastating symptoms. The result is a therapeutic rift between what we know and what we can do.

Meghan and Anne fearfully straddle this crevasse, hoping against hope that it will narrow. However, it seems likely that as information flows from the HGP, this therapeutic rift will continue to enlarge for the foreseeable future. This poses profound and puzzling questions about the limits of medical knowledge and human choice.

Consider the effects of genetic information on people who, like Anne and Meghan, confront Huntington's disease. If they discover they do, in fact, have the Huntington's gene, a shadow is cast over the rest of their lives. A slight misstep becomes an omen of uncontrollable muscle movements. Feeling blue is no longer part of everyday life but a precursor of mental collapse. The person's view of life is irreversibly changed by a set of prophecies about affliction and horrifying death.

In Mapping Fate, Alice Wexler describes what it's like to live with this knowledge:

A dancer with Huntington's disease, in her early forties, described how, long before there were any other symptoms, she began having difficulty learning dance sequences; whereas once she had no problem memorizing complicated routines, she gradually found it more and more difficult to master a series of different steps. Later on she found it increasingly difficult to organize a meal, coordinating the different dishes so that they would all come out together. Living at risk undermines confidence, for there is no way of separating the ordinary difficulties and setbacks of life from the early symptoms of the illness. It is not like any other physical illness, where consciousness can at least continue in the knowledge that one is still oneself, despite severe pain and physical limitation. Huntington's means a loss of identity.

But long before the loss of motor control and identity, those who carry the Huntington's gene may face the loss of jobs and health coverage. Many people from families with a history of genetic disorders fear that if they are tested, the results might become public and cause employers or insurers to exclude them. Laws to prohibit such discrimination are not yet completely in place. This is the prophecy of social and medical doom that Anne is resisting.

Responsibilities to the Next Generation

But her daughter Meghan has a different set of concerns. Genetic knowledge is apt to have its greatest impact not on the lives of those who, like the stumbling dancer, are currently stricken, but on the choices to be made by those who, like Meghan, are contemplating parenthood.

If Meghan does not have the gene, then her child will not have the disease. If she does have the gene, any child she conceives has a 50 percent chance of sharing her fate.

Assuming Meghan learns that she has the Huntington's gene, what should she and her husband do? Should they take their chances with genetic roulette? Should they remain genetically childless? Should they undergo prenatal diagnosis?

Prenatal screening and diagnosis can be accomplished through methods such as amniocentesis. Sometimes genetic testing is coupled with in vitro fertilization in a technique called preimplantation genetic diagnosis (PGD). PGD is currently offered in a limited number of research facilities.

In this method, after the egg is fertilized outside the womb, the embryo is allowed to reach the eight-cell stage of development before a cell is removed. This cell is then tested for genetic components that would predispose the child to a particular disease such as Huntington's. Then, only those embryos that do not contain the disease gene are transferred to the uterus, thereby eliminating the chance of having a child with Huntington's disease.

Whatever the promise of this technique, the cost is far from trivial. It includes the fee for IVF-averaging $8,000 per cycle-plus the cost of genetic testing, which adds an estimated $2,000. Even in the rare cases when IVF expenses are paid by health insurance, the genetic component is not covered.

Costs are also likely to be high in the even more advanced procedures now being proposed. In the future, PGD might identify candidates for emerging techniques such as constructive genetic surgery and embryonic cell cloning. Constructive genetic surgery involves removing the affected gene from an embryo and replacing it with normal genetic material. But this is risky business with a failure rate of 80 percent-far too perilous to perform on a single human embryo.

Through cell cloning, however, scientists could make multiple copies of the embryo they wish to modify, increasing the genetic surgical success rate. Indeed, cellular cloning seems to hold the key to the successful genetic engineering of humans. But to what end?

Is Meghan's wish to prune Huntington's disease from her family tree a justified use of this future technology? Suppose parents wish to eliminate the predisposition to alcoholism. What if they want to increase a child's physical stature or intellectual acumen? Would these be reasonable requests for embryonic genetic intervention?

After all, we send our children to soccer practice and tutoring after they are born; why not give them a genetic head start? Is there an ethically relevant difference between genetic therapy and genetic enhancement?

Questions and Guidelines

Reproductive and genetic technologies are opening new medical and moral frontiers, urging us to think in new ways. As the level of medical diagnosis and treatment shifts from bodies and bones to cells and chromosomes, the level of ethical consideration must do the same.

Reaching ethical conclusions about the new genetics is challenging for two reasons: First, it is inherently difficult to understand the subtleties of genetics and the wealth of data tumbling out of the HGP. Second, it is next to impossible to foresee accurately the implications and consequences-short-term, long-term, and unintended-of intervening in the genetic "stuff of life."

The following questions may help to clarify key issues as genetic medicine comes of age:
1. What is the purpose of taking a particular genetic test? Who is affected by the results?
Some people undergo genetic screening simply to know their predisposition to a particular disease. Others may hope to fix that predisposition. Currently, the diagnosis of numerous genetic diseases or predispositions is possible; in most cases, however, there is no treatment or cure. Care must be taken to ensure that patients understand this rift between diagnosis and treatment and that their expectations of the testing are realistic.

Since it became possible to test for the Huntington's gene, fewer than 15 percent of those at risk have taken the test, even when it was offered free of charge. Most would rather not know. Anne, like many of us, is reluctant to find out about an inevitable future. Perhaps, out of respect for her mother's wishes, Meghan could wait to take the test, hoping that in a few more years, scientists may make progress toward a cure. Perhaps Meghan is particularly good at keeping secrets.

Traditional notions of confidentiality are profoundly challenged by medical tests that tell patients not only about themselves but also about family members. As genetic tests become readily available, respect must be given to those who, like Anne, claim a right to ignorance.
2. Who has control of genetic information?
In this era of rapid communication and data proliferation, absolute confidentiality of medical information no longer seems realistic. In a hospital, anywhere from 60 to 200 people have access to a patient's medical records. The information is also passed along to insurance carriers and health maintenance organizations. Given that complete privacy is not possible, it is important to consider who has access to genetic information and for what purpose.

People questioned about genetic testing worry that insurers will raise rates or refuse to insure them. They express concern that employers will not hire them. There is a general fear that friends and family will treat them differently or abandon them once they are "tarnished" by a deadly gene. Medicine's obligation to do no harm mandates that genetic information be used in ways that help people, not in ways that stigmatize and marginalize them.
3. What does it mean to offer genetic testing and/or therapy in the absence of universal access to health care?
This is a question of justice. What counts as a fair share of the health care pie for the poor or for those without health insurance? We live in an era of limited access to childhood immunizations and routine preventive care-both of which are relatively inexpensive and medically effective. As we pour health care dollars into genetic research and treatment, we must also seek to provide basic care to those who are most vulnerable to the ravages of disease: the poor and their children.
4. On what basis should someone undertake genetic intervention such as genetic constructive surgery if and when it becomes available?
Two approaches to this question are possible. One is therapeutic; that is, such techniques should be used to correct particular diseases. The other is eugenic; that is, genetic intervention is permissible to enhance specific characteristics (e.g., intellect) or to give individuals capacities they might not otherwise have had (e.g., playing piano).

The distinction between therapy and enhancement may turn on intention. Is the purpose of the intervention to bring a person to a state of health or to go beyond health in the design of someone new or better?

With the fledgling capacity to alter the human genome comes the responsibility to think carefully about what we consider a benefit for individuals and society. Test tube racks filled with "designer genes" hold not only the promise of molecular treatments but also the age-old mischief of discrimination and exclusion. We are not yet free of the specter of forced eugenicsÑwitness reports that up until the 1970s, an estimated 60,000 people had been sterilized in Sweden under government policies to weed out traits such as poor eyesight and "Gypsy features." What some consider desirable traits may not be a benefit in the eyes of either humanity as a whole or the affected individual.
5. For what kind of genetic future are we planning?
Genetics, by its very nature, embodies a concern for coming generations. Genetic diagnosis and intervention hold great promise. However, we need to consider carefully the power conferred on us by knowing our genetic identity and being able to alter it.

With great power comes greater responsibility, asking us to think carefully about the dramatic impact that genetic information and intervention might have on the future. We face not a red light but a flashing yellow as we enter the age of genetic medicine.
Margaret R. McLean is the director of biotechnology and health care ethics at the Markkula Center for Applied Ethics. This article was originally published in Issues in Ethics - V. 9, N. 2 Spring 1998.

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our genes contain information that scientists hope will help in the treatment of many diseases. huntington's disease provides a window on the choices we face as medicine increases our ability to intervene in human genetics.

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Our genes contain information that scientists hope will help in the treatment of many diseases. Huntington's disease provides a window on the choices we face as medicine increases our ability to intervene in human genetics. Stop pacing, Mom. It'll be all right." Meghan and her mother, Anne, fidget nervously in the waiting area of the genetic testing center.

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A book excerpt from Genetic Alliance with summaries of many ethical issues

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Over the past decade, many ethical, legal, and social issues (ELSI) associated with genetic testing and research have been raised. For genetic testing to be used safely and appropriately, these issues should be discussed with patients so they are aware of risks and benefits.

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Ethical Issues in Human Genetics and Genomics

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Ethical Issues in Human Genetics and Genomics

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Fact sheet from the Center for Genetics Education (click 'open in new window')

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It’s time to talk about who can access your digital genomic data

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It’s time to talk about who can access your digital genomic data

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Article from The Conversation about privacy of genetic information

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We are approaching a time when you might be too scared to have your genome sequenced.

Only last week, a US senator called for an investigation into the privacy policies of direct-to-consumer DNA companies. But this is only one piece of a puzzle that is about to get much more connected.

As with any kind of personal data there are a number of concerns regarding collection, transmission, storage and use. But unlike most other data, your genome reveals intimate information about not only you, but also the people to whom you are related.

It's time to talk about who can access that data, how, when and why.

Read more: Our healthcare records outlive us - it's time to decide what happens to the data once we're gone

The current situation

Genetic databases are not new. For a while we have had law enforcement DNA databases, medical genetic databases, and ancestry DNA databases, among others.

Historically there has been a natural separation between these databases, because they tend to contain different types of genetic data. Medical genetic databases, for example, have typically screened specific genes, and this data is usually not variable enough to be useful in law enforcement.

Additionally, some databases have been governed by specific rules, such as those that limit who can be included in law enforcement DNA databases.

This is changing. The unit of genetic "currency" is becoming the same thing: the sequence of the entire human genome.

The rise of the genomes

Sanger Institute, Genome Research Limited

The rate of genome sequencing is increasing rapidly. Massive genomics projects are set to emerge in the United Kingdom, Canada, France, and elsewhere.

The US National Institutes of Health has launched a Precision Medicine Initiative that aims to combine genetic and health data for one million people. China is investing more than US$9 billion in a similar initiative - the pilot stage alone includes one million human genomes.

It's not just governments. Private companies have also set their sights on massive human genome datasets. Craig Venter's Human Longevity Inc. is planning to sequence a million genomes by 2020 and has partnered with pharmaceutical giant AstraZeneca to work towards this goal.

The marketplace of corporate, direct-to-consumer genomics companies is also rapidly expanding. Amazon (which claimed 45% of online sales on a record-breaking Black Friday) reported the 23andMe DNA testing kit as one of its top 5 bestselling items.

Read more: Genetic home testing: why it's not such a great guide to your ancestry or disease risk

It's impossible to put a precise figure on the number of genomes that have been sequenced to date. Projects like BabySeq in the US point to a future in which genome sequencing may be a routine screen at birth.

Genome data is not anonymous

Keeping databases separate and anonymous may seem like a solution but this will be very difficult to accomplish. It is already possible, at least in some instances, to use information from a complete genome to locate the donor through searches of publicly available ancestry databases.

Gerd Altmann (geralt) @ pixabay

More recently, a controversial study claimed to be able to de-anonymise genomic data using facial reconstruction. In reality this isn't possible yet - but the application of AI will certainly accelerate our understanding of these links.

Read more: Google may get access to genomic patient data - here's why we should be concerned

Who wants your data, and why?

Your genetic data could be useful to three main groups in society.
1. Law enforcement
Law enforcement queries to commercial ancestry DNA databases have already begun to blur the lines that have typically kept these databases apart. The controversial process of familial searching shows how data may be used from ancestry databases to make inferences about a suspect. In the US, the existence of federally unregulated genetic databases may create further complication.

The establishment of mandatory DNA testing seems far-fetched, however that may not be the case everywhere. In 2015, Kuwait passed a law mandating DNA collections from all citizens and residents, although this was revoked earlier this year.

Closer to home, NSW Police Minister Michael Gallacher proposed that mandatory DNA collection from all newborns in Australia was " something that needs to happen". Australia is not averse to surveillance of its population, as we have discovered with the national facial recognition system. This system goes into effect in 2018, and both law enforcement and private companies are pushing for access.
2. Private industry
Commercial DNA test providers can be legally required to hand over customer data to law enforcement. The privacy policies that consumers agree to make it impossible to know who else will have access to the data.

What is clear is that a digitised genome has monetary value. Genetic data from direct-to-consumer companies has already reportedly been sold to pharmaceutical companies.
3. Insurance companies
Our digital genomes provide information about our predisposition to various medical conditions and this is attractive to insurance companies. The predictive power of the genome is only going to increase over time. Once a consumer has taken a genetic test, they may be required to disclose that fact to an insurer or risk fraud charges.

What's more, legislation protecting consumers from genetic discrimination is inadequate, and may be eroding in the US. Access to insurance is already being impacted in Australia.

Read more: Australians can be denied life insurance based on genetic test results, and there is little protection

Let's talk about the future

Australia just created its first National Health Genomics Policy Framework, for 2018-20, and this begins to create guidelines for genomic data. This policy is geared towards medical research, however, so would not apply to consumer DNA services, and does not make provisions for law enforcement access requests.

Blockchain and "genome cloaking" cryptography approaches are being explored as a way to give people control over their genomic data and who can access it. A new company claims to offer a commercial, decentralised, blockchain system based on buying genetic services and selling access to genetic information.

Perhaps these approaches are part of the technological solution. But the central issue is this: should we own our genetic data, and should we as individuals be able to decide who can access it?

What is absolutely clear is that the future of genomic databases is almost here, and now is the time to figure out how we are going to allow this information to be used.

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It's time to talk about who can access your digital genomic data

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We are approaching a time when you might be too scared to have your genome sequenced. Only last week, a US senator called for an investigation into the privacy policies of direct-to-consumer DNA companies. But this is only one piece of a puzzle that is about to get much more connected.

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A webcomic that gives insights into carrier screening

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* Correction: The text about the effects of cystic fibrosis has been changed to reflect the improved prognoses for babies born with CF, based on modern treatments. (The doctor originally predicted a likely lung transplant by age 5 instead of a possible lung transplant in childhood.) While the original text came from the author's personal memory of the conversation, we made the changes so that the comic gives a more current and accurate snapshot about an important medical question.

Lauren R. Weinstein is a cartoonist, cartooning teacher, and avid gardener who lives in scenic Maplewood, New Jersey. She is currently working on a teenage memoir entitled How to Draw a Nose.

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Carriers: A Webcomic on Health, Luck, and Life - Facts So Romantic - Nautilus

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Correction: The text about the effects of cystic fibrosis has been changed to reflect the improved prognoses for babies born with CF, based on modern treatments. (The doctor originally predicted a likely lung transplant by age 5 instead of a possible lung transplant in childhood.)

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Insurers discriminating against people who get genetic test results could hobble research, bioethicists warn

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Insurers discriminating against people who get genetic test results could hobble research, bioethicists warn

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Article from the Sydney Morning Herald about genetic tests and insurance

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Updated first published at

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Edwina Sawyer has been denied life insurance by half a dozen policyholders, but she's not sick.

She doesn't smoke or drink excessively, and has taken drastic preventative measures to guard against cancer.

Edwina Sawyer says a genetic test she had a decade ago is barring her family access to insurance. Credit:James Brickwood

But a genetic test she had a decade ago is barring the Sydney mother-of-two and her family access to insurance, she says.

Ms Sawyer and her brother both tested positive for Lynch syndrome, a mutation in one of their 'mismatch repair' genes that normally function to protect a person from cancer.

Not everyone with Lynch syndrome will develop cancer. A person with the mutation has an increased risk of bowel cancer of between 30 and 50 per cent.

Her mother died of bowel cancer when Ms Sawyer was 40, and her 12-year-old niece Margot died of brain cancer in February 2017.

"I wasn't a huge believer in taking out life insurance, but I wanted to take a look and have that option," Ms Sawyer said.

But she said she has been consistently denied cover.

"They classify my mutation as a pre-existing condition, when strictly speaking what it does is predisposes me to cancer."

People applying for life, disability, trauma, income and protection insurance must disclose any personal genetic test results they have received.

But her own children - who have a 50 per cent chance of inheriting the gene mutation - will "absolutely" get tested.

"It's hugely important that they are armed with the knowledge they need to protect their health," she said.

Insurers are able to discriminate against individuals who undergo genetic testing, and that threatens to hobble genomic research, bioethics and law experts have warned in a recent paper published in Public Health Genomics.

Anyone who receives their results of genetic testing as part of a research project needs to disclose them to insurers if asked, despite the Human Genetics Society of Australasia calling for research findings to be excluded.

Insurers can deny cover or hike up premiums for healthy individuals who discover they carry a mutation for a condition they may never develop based on the testing results, the authors warned.

"The policy is not intended to discourage anyone from taking a genetic test if they want to, and in practise most insurers do not ask this question," Mr Kirwan said.

Referring to the need for applicants to disclose if they were considering genetic testing, Mr Kirwan said "life insurance is a long-term agreement so the policy is worded this way to discourage people from taking out insurance immediately before they have a genetic test and then cancelling the policy as soon as they get the result".

"The FSC strongly believes that a flexible, self-regulatory policy response, which gathers evidence to inform future settings, is the right way forward given the fast-evolving nature of the science," he said.

The FSC had provided data regarding adverse selection to researchers at University of Sydney. The findings would be published in the European Journal of Human Genetics in the coming months, Mr Kirwan said.

Kate Aubusson is Health Editor of The Sydney Morning Herald.

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Insurers discriminating against people who get genetic test results could hobble research, bioethicists warn

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Updated first published at Normal text size Larger text size Very large text size Edwina Sawyer has been denied life insurance by half a dozen policyholders, but she's not sick. She doesn't smoke or drink excessively, and has taken drastic preventative measures to guard against cancer.

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We are all mutants now: The trouble with genetic testing

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We are all mutants now: The trouble with genetic testing

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Long read about limitations and legal issues associated with genetic testing. (note- No need to read it all- the first few paragraphs are really interesting)

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'We are all mutants now': the trouble with genetic testing

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The long read: With so many unknowns in our DNA, using genetics in medical testing doesn't always bring the answers - sometimes it brings only doubt

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Report from the Australian Law Reform Commission

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Population genetic screening programs | ALRC

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24.6 Population screening programs are established to offer individuals the opportunity to obtain more information about their current and future health. Armed with this information, they can make better-informed choices about health care, lifestyle and reproduction.

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Cardiovascular Cascade Genetic Testing: Exploring the Role of Direct Contact and Technology

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Cardiovascular Cascade Genetic Testing: Exploring the Role of Direct Contact and Technology

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An academic opinion paper about the ethics of contacting family members who may have a harmful variant

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Cascade screening is one of the more forceful demonstrations that molecular biology and genetics are not just a tool for researchers, but represent an important and by now essential component of good medical care.

Introduction

There is much attention and excitement in the current health care environment on the potential of precision medicine based on a patient's genomic data. Today, what arguably remains as one of the most valuable and informative genetic tests is that of predictive testing for a known familial pathogenic variant. Predictive genetic testing determines whether the pathogenic variant previously identified in an affected family member(s) is present or not in relatives at risk. Previous research has documented that affected individuals undergoing genetic testing cite obtaining genetic information for others as being the most important, if not the only, motivation for undergoing genetic testing ( 2). Predictive, cascade testing is able to separate at-risk relatives who require vigilant serial screening from those who do not. For those with the predisposition, clinical screening allows for early identification of the family's phenotype, which when present, may require lifelong medical therapy, implantation of devices, and/or other types of medical management. Relatives who test negative for the familial variant can typically be released from lifelong screening. In addition, it is also then known that their children are not at increased risk for the family's disease. This approach can save the health care system, and the family itself, thousands of dollars. Cascade screening is imperative with "high-stakes" cardiovascular conditions, such as familial hypercholesterolemia (FH), long QT syndrome (LQTS), and other inherited arrhythmias, as well as other heritable cardiovascular phenotypes, including cardiomyopathies and aneurysms, where there is an increased risk for sudden cardiac death and severe morbidities such as heart failure.

The value of cascade screening for highly penetrant cardiovascular (and cancer) phenotypes has been acknowledged by public health officials. The United States Centers for Disease Control Office of Public Health Genomics classifies cascade screening of at-risk relatives for certain conditions, FH being one, as a Tier 1 genomic application, meaning it meets the criteria for analytic and clinical validity and utility and therefore has evidence supporting its implementation into practice ( 3). Cascade screening may include targeted genetic testing as well as clinical screening (e.g., lipid panel) of at-risk relatives.

This opinion provides a brief summary of research in this area and poses questions to facilitate future discussion regarding the potential for direct contact of at-risk relatives. As a practicing genetic counselor in clinical genetic medicine for 14 years who has provided genetic counseling and testing to thousands of families with heritable cardiovascular and cancer conditions, it is my opinion that more could be done to provide assistance to probands for at-risk relative notification and that genetic counselors are in the ideal position to facilitate cascade testing and lead forward-thinking research in this area ( 4).

Cascade Screening: Where are We Now?

Cascade screening is a mechanism for identifying people at risk for a genetic condition by a process of systematic family tracing. It should begin with first-degree relatives (parents, siblings, and children) and then extend to second- and third-degree relatives in a stepwise, cascade fashion, moving through the pedigree in sequential steps as additional family members are diagnosed until all at-risk relatives have been screened ( 5). Cascade screening for FH is a cost-effective method for identifying new cases of FH ( 6- 8). Cascade screening in families with inherited arrhythmia syndromes has been shown to lead to immediate prophylactic treatment, including drug treatment or implantation of pacemakers or cardioverter defibrillators ( 9). However, cascade screening is not effective unless at-risk relatives are first notified of their risk, the health implications of the inherited condition in their family, the availability of testing, with subsequent uptake. However, uptake of genetic counseling and predictive genetic testing has been shown to be inadequate ( 10). While there is support from payers, public health, and health care providers (HCPs) regarding the importance of cascade testing, how best to inform relatives of their risk and systematically implement cascade testing has yet to be determined.

Psychological, educational, geographical, and other barriers exist to family communication of genetic risk information. Ethical factors and family dynamics, including maintenance of confidentiality and privacy, potential for psychological harm and genetic discrimination (i.e., life insurance), balancing the right "not to know" with "duty to warn," among others, must be considered ( 11). The currently recommended approach for FH, made by the International FH Foundation, includes the following: (1) the proband's HCP should construct a pedigree that facilitates identification of at-risk relatives who should be offered testing; (2) the HCP should discuss risk notification with the proband; and (3) the proband should be provided with written information that includes general information about the family's condition, the benefit, and availability of preventive therapies, emphasizes health consequences without testing, and be encouraged to share this with relatives ( 12). This approach should be taken with other highly penetrant autosomal dominant conditions. In one study specific to inherited arrhythmias and cardiomyopathies, probands were asked to distribute "family letters" containing information on risks, genetic and other screening tests, and preventive options to relatives at risk. In this study, 57% of informed relatives underwent screening (80% in arrhythmia families; 45% in cardiomyopathy families), and this was statistically significant when compared to the group where no family letter was provided (35%). While such "family letters" increased the number of relatives who presented for evaluation, over 50% in cardiomyopathy families and 43% overall of at-risk relatives had no documentation that they underwent cascade evaluation ( 13).

It has been suggested that it is not outrageous to expect that clinicians, once they have diagnosed a patient with a genetic arrhythmia, "track down" all at-risk family members and determine their genetic status ( 1). However, realistically, implementation of this approach is problematic since many health care systems do not support this type of family-centric care model. Specifically, a recent review presents health policy-related limitations faced in the United States to effective implementation of cascade screening and includes (1) a low rate of reimbursement for comprehensive genetic counseling services; (2) an individual, versus family-centric, approach to prevention and insurance coverage; (3) insufficient genetic risk assessment and knowledge by a majority of HCPs without genetics credentials; and (4) a shortage of genetics specialists (in rural areas especially) ( 14). In order to begin addressing and overcoming these challenges, research should be conducted demonstrating effectiveness of novel methods and tools that have the capacity to efficiently notify relatives of risk. These tools should provide education, offer support, and provide attainable next steps with calls to action so that probands can be assisted, and their relatives can understand their own risk and be supported to act on it.

Direct Contact in Cascade Screening: Should We Take a More Active Approach?

Different methods of informing relatives of risk exist including (1) proband, or family-mediated, contact; (2) proband, or family-mediated, contact with assistance (provision of materials, such as a family letter or other written information aids, by the HCP to the proband); and (3) direct contact of at-risk relatives by the clinical service itself.

Research suggests that clinical providers may take an active approach and directly contact relatives to notify them of their risk without compromising privacy or autonomy, with significantly higher numbers of relatives whose genetic status is clarified for greater efficiency, and with high levels of acceptability ( 15- 18). A thematic analysis of FH proband interviews found that probands believed they had insufficient authority or control to persuade family members to attend screening and that they welcomed greater assistance from the clinic for contact with relatives ( 19). Also in support of direct contact is increased accuracy, as errors may occur in proband-mediated transmission of genetic testing result information through families ( 20). However, a prior study found that FH patients who expressed a preference regarding cascading method favored indirect contact because they considered it less threatening to family members ( 21). A genetic counseling intervention study that offered direct contact to the index patient as a last option for assistance in informing at-risk relatives reported no uptake; only eight index patients were offered this service, however, and none of the patients in this study had cardiovascular phenotypes ( 22). A recent literature review concluded that most studies support direct contact of relatives via letter mailed from the provider and that provider-initiated communication more often resulted in relatives being tested compared to other methods of communication ( 16).

Regarding additional Tier 1 conditions, a prospective study of families with BRCA mutations associated with Hereditary Breast Ovarian Cancer syndrome compared proband-mediated contact to a direct contact intervention protocol that included a letter and subsequent phone call to at-risk relatives ( 17). This study concluded that the direct contact protocol nearly doubled the number of relatives tested and was also found to be psychologically safe. A direct contact study in families with Lynch syndrome, or hereditary non-polyposis colorectal cancer, demonstrated high approval in those who consented to participate, with a third of newly diagnosed mutation carriers having cancer identified in their first post-test colonoscopy. This type of data demonstrates acceptability of direct contact risk notification programs, as well as efficacy, feasibility, and also ethical responsibility.

From the perspective of those potentially at risk, a study conducted in Australia assessing community members' viewpoints showed that over 90% of respondents indicated their desire to be informed about a familial risk of FH and to be offered screening, with evidence of strong community support for direct contact by an FH clinic ( 23). The "right to know" must also be considered.

Future Directions

Research evaluating genetic counseling interventions focused on strengthening family communication, the number of relatives informed of risk, and the impact on uptake of genetics services is ongoing and will help inform future efforts ( 22, 24). A randomized controlled trial studying whether a specifically designed genetic counseling intervention that included telephone support up to three times post new genetic diagnosis showed no overall significant difference for the level of family communication between the intervention and control groups ( 25). In this study, the level of family communication was the highest for conditions with appropriate treatments or active surveillance, such as LQTS and hypertrophic cardiomyopathy. While promising, the level still only reached ~30%. These data again beg the question regarding the potential role for direct contact, especially in "high stakes" conditions.

Most, if not all, of the research conducted to date specific to direct contact has been done outside the United States. Therefore, there is a real need for research to determine whether direct contact methods would be acceptable to probands, at-risk relatives, and HCPs within the United States. How many probands might indeed welcome and appreciate this assistance and support and opt in to programs that work with and/or for them to assist in disclosure of risk information to relatives? This opinion piece does not propose that we break probands' confidentiality and throw privacy to the wind. Instead, it hopes to promote additional conversation and brainstorming that may lead to the development and testing of innovative models of care for probands with highly penetrant, yet manageable conditions. The ultimate goal is that we will have greater impact in our work with these families where there are clear risk-reducing interventions. Probands and family members should be engaged in shaping these models and the research testing them, starting now!

The next question becomes, what is feasible now in the landscape of our current health care system? Can we systematize the collection of informed consent from probands to directly share their protected health information with relatives for which they provide the clinic contact information? Can we offer probands active assistance in family communication of genetic risk information? In the pediatric setting, is there a role for standardized direct contact of HCPs caring for the at-risk children in our pedigrees with FH, other Tier One conditions, and beyond? This may be a service welcomed by the affected parent proband, who may appreciate greater assistance in coordination of care for their at-risk children and other pediatric members of their family.

Advances in web-based technologies and novel models for the delivery of genetic counseling may be able to bring cascade testing more effectively and efficiently to larger numbers of at-risk relatives. For example, home-based online genetic counseling sessions for cardiovascular genetic cascade screening can be effective ( 26), allowing at-risk individuals to access their genetic risk information at the time of their choosing and without having to travel to a hospital or clinic, a barrier mentioned previously. In addition, interactive e-learning and decisional support e-tools available via informative websites and mobile applications have been used in pre-test genetic counseling with high knowledge and satisfaction, leading toward the "e-informed" patient ( 27). Mobile health applications have been shown to result in more "activated" patients - defined as individuals who believe their roles are important, that they have the confidence and knowledge needed to take action, and that they can engage in health-promoting behaviors ( 28), such as predictive genetic testing. Probands with higher activation may lead toward more at-risk relatives notified of their risk. In turn, e-learning information, such as an informational video about the family's inherited cardiovascular disease, could then be delivered to relatives, who may then become activated themselves to pursue cascade testing.

The power of preventive genetic and genomic information is real - that is not the question. How to ensure this information gets into the hands of all that need it, including children, however, needs more active attention.

In conclusion, a powerful quote from Newson and Humphries ( 11): "Our biology does not stop: the risk of developing coronary heart disease as a consequence of FH will still be present, even if relatives live in ignorance."

Author Contributions

The author confirms being the sole contributor of this work and approved it for publication.

Conflict of Interest Statement

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

4. Sturm AC. The role of genetic counselors for patients with familial hypercholesterolemia. Curr Genet Med Rep (2014) 2(2):68-74.10.1007/s40142-014-0036-8

26. Otten E, Birnie E, Ranchor AV, van Langen IM. Online genetic counseling from the providers' perspective: counselors' evaluations and a time and cost analysis. Eur J Hum Genet (2016).10.1038/ejhg.2015.283 [ PMC free article]

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Cardiovascular Cascade Genetic Testing: Exploring the Role of Direct Contact and Technology

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Cascade screening is one of the more forceful demonstrations that molecular biology and genetics are not just a tool for researchers, but represent an important and by now essential component of good medical care. There is much attention and excitement in the current health care environment on the potential of precision medicine based on a patient's genomic data.

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Newborn Screening: Adapting to Advancements in Whole-Genome Sequencing

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Newborn Screening: Adapting to Advancements in Whole-Genome Sequencing

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A short (academic) opinion paper from the journal Genetic Testing and Molecular Biomarkers

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September is newborn screening awareness month. Since 1963, state public health programs have screened newborns for a number of life-altering health conditions. Many of these disorders are rare and genetic, and if caught in the first weeks of life they can be treated or managed to prevent death or a lifetime of disability. Early detection can also help families avoid the lengthy and stressful "diagnostic odyssey" involved in finding out what ails their child (Exe et al.). In 2013, the United States celebrated the 50th anniversary of newborn screening. From scientist Robert Guthrie's discovery of a test for phenylketonuria to development of state programs that screen every newborn for up to 56 conditions, newborn screening has saved and improved millions of lives. State-mandated screening gives newborns their best chance for typical development, in large part because of strong national guidelines and efficient state public health systems that have been evolving to support screening for the last 50 years.

As newborn screening success stories gained national notoriety in the early 1960s, scientists quickly discovered diagnostic tests for a host of genetic disorders that could be treated at birth. State public health officials then responded by developing mandatory screening programs with inclusion of increasing numbers of genetic and metabolic conditions. While testing every newborn at birth is a seemingly simple process, organizing the resources required for obtaining samples, analyzing results, diagnosing disorders, and providing follow-up care is a large undertaking for state public health systems.

Since its inception, the newborn screening program has seen continued improvement. Creation of the International Society for Neonatal Screening in 1988 and the signing of the Newborn Screening Saves Lives Act of 2008 are examples of initiatives to increase education and funding for newborn screening in an effort to adapt to new discoveries and methods for treating rare or genetic diseases. Recently, the cost of whole-genome and whole-exome sequencing has decreased dramatically, emphasizing the potential for genome sequencing to affect newborn screening programs. Newborn screening policymakers and stakeholders must respond to these advancements as they have responded to others in the past, recognizing that while some technological updates have a place in the newborn screening system, others may not. As public health officials work to come to a conclusion on whole-genome sequencing for newborns, it is important to keep the interests of families and children at the forefront of the discussion.

In June 2014, a geneticist sequenced his son's genome at birth, making the child one of just a few thousand healthy newborns in the United States who have undergone this type of testing (Regalado, 2014). Inova Translational Research Institute is also offering newborn genome sequencing as a part of their Childhood Longitudinal Cohort Study, which looks to learn about disease by tracking 2500 children in Fairfax County, Virginia, from pregnancy to age 2 years (Inova Translational Medical Institute, 2014). The press surrounding both the father's controversial decision and Inova's study highlights the evolving debate over whether whole-genome or -exome sequencing for healthy newborns has a place in public health screening programs. Currently in newborn screening programs across the country, whole-genome sequencing is used only as a secondary method to confirm positive test results for genetic disorders such as cystic fibrosis or sickle cell disease, but experts have suggested that in the next decade large-scale sequencing for all healthy babies at birth could be plausible (Knoppers et al., 2014). As of this writing, the American College of Medical Genetics and Genomics had not yet released an official position on genome sequencing for newborns, although they have presented preliminary guidelines for genome sequencing and its clinical application in adults and children.

It is important when discussing potential updates to newborn screening programs to keep the typical parent with minimal genetic testing experience in mind. Goldenberg and colleagues did just this in 2014, surveying parent opinion of whole-genome sequencing for newborns if it were offered by newborn screening programs or pediatrician services. In both scenarios, about 70% of parents expressed interest in whole-genome sequencing, citing test accuracy and the ability to protect a child from developing a disease as important factors in their decision-making process (Goldenberg et al., 2014). In addition to confirming preliminary parent interest in whole-genome sequencing, research has determined that genome sequencing may be less costly and faster than conventional newborn screening processes, with the ability to produce results in 50 hours rather than the typical 4-6 weeks (Saunders et al., 2012). Lower cost and shorter time to results could be beneficial in lessening public health costs and parent anxiety; however, the possibility of learning a child's susceptibility to more than 3000 diseases, some adult-onset and some without cures, presents a daunting ethical and public health concern to policymakers.

While genome sequencing has the potential to detect disease and improve health outcomes, an assessment of its impact on individuals, families, and overall health is needed before public health programs could ever implement official clinical whole-genome sequencing for newborns. Responding to this need for large-scale evaluation of newborn genome and exome sequencing, the National Institutes of Health awarded $25 million over 5 years under the Genomic Sequencing and Newborn Screening Disorders program to four grantees, with the goal of exploring the use of genomic sequencing in newborn healthcare, in the fall of 2013 (National Institutes of Health, 2013). The grantees for 2013 are implementing studies to explore best practices for delivering sequencing results to parents, as well as looking at the law, policy, and ethics of newborn exome and genome sequencing. Outcomes of these earliest large-scale assessments of the risks and benefits of genome sequencing for newborns will help to inform newborn screening policy for the future, but today the topic of newborn genome sequencing as a public health initiative remains contentious.

Is whole-genome sequencing of newborns best left to the private sector of health? Newborn screening is a highly successful public health program, and addition of whole-genome sequencing would require a complete overhaul of a system that has saved millions of lives. Private-sector whole-genome sequencing at birth instead puts the ethical and financial burden of interpreting results primarily on new parents, private practice genetic counselors, and nongovernment labs. Before whole-genome sequencing could ever be of value to newborn screening programs and families, public health initiatives would need to create an infrastructure that could properly support whole-genome sequencing outcomes. It may also be prudent while considering whole-genome sequencing of newborns to simultaneously improve prenatal screening and carrier testing protocols. Although generally not included in public health-based screening, prenatal testing for genetic disorders gives parents who choose any of the many tests available ample time to consider their options and prepare for a child who could be born with health challenges. Carrier screening identifies the likelihood of offspring having a genetic disorder before conception and during the prenatal period. For both, the ethical implications and clinical outcomes are more clearly defined than those for whole-genome sequencing. Increased public health initiatives for prenatal testing and carrier screening have the potential to drastically reduce the incidence of infants born with genetic disorders and also better prepare parents for the outcomes of their pregnancies.

Regardless of where newborn whole-genome sequencing ends up within the health sector, policymakers need to tackle challenges, such as storing vast amounts of sequence data securely, developing genetic counseling techniques to advise new parents, and establishing ethical standards for the practice as a whole. These challenges also apply to prenatal and carrier testing initiatives. The public health community must decide whether the benefits of adding whole-genome sequencing to well-established newborn screening programs outweigh the associated ethical pitfalls, while also preparing to educate families about the option of whole-genome sequencing for their newborn.

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Newborn Screening: Adapting to Advancements in Whole-Genome Sequencing

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September is newborn screening awareness month. Since 1963, state public health programs have screened newborns for a number of life-altering health conditions. Many of these disorders are rare and genetic, and if caught in the first weeks of life they can be treated or managed to prevent death or a lifetime of disability.

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Take it from a genetic counselor: 23andMe's health reports are dangerously incomplete

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Take it from a genetic counselor: 23andMe's health reports are dangerously incomplete

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Opinion piece from the LA Times

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Earlier this fall, I spat into a test tube and mailed off my DNA to be screened for disease risks by 23andMe, the genetic testing firm. Although millions do this to research their ethnic background and health conditions, my interest was more professional than personal.

I am in my final semester of graduate school to become a genetic counselor. When I see patients during clinical rotations, they often come bearing results from direct-to-consumer companies like 23andMe. But patients don't always realize what they are getting from these services.

Until last year, genetic testing firms like 23andMe were prevented from selling health risk reports to the public. The Food and Drug Administration imposed a moratorium on such tests in 2013 out of concerns that the results might be misleading.

Under the Trump administration, the FDA has allowed 23andMe to reintroduce the tests. The company now tests for variants related to nine diseases and carrier status for more than 40 conditions. But there is still no guarantee that its results provide adequate or complete information about a customer's profile or health risks.

Under the Trump administration, the FDA has allowed 23andMe to reintroduce the tests.

I had no reason to be anxious about my results. I had already received perhaps the most important genetic test results of my life.

Six years earlier, after receiving a diagnosis of bilateral breast cancer, I was referred to a genetic counselor by my oncologist. From a blood test the genetic counselor conducted, I learned that I have a pathogenic mutation in my BRCA2 gene.

This meant that my chance of a recurrence of breast cancer was substantially higher than for a woman without a BRCA mutation. It also meant my chance of having ovarian cancer and pancreatic cancer was higher.

In the months that followed, I underwent a double mastectomy rather than lumpectomies. I then had my ovaries and fallopian tubes removed, as recommended, plunging me into surgical menopause at the age of 41.

Throughout this period I was concerned and worried - about my own health, of course, but also that of my family members. My sisters and mother subsequently met with the same genetic counselor and learned they were negative for the mutation, and I found out that I likely inherited it from my father.

The sessions and follow-up discussions with my genetic counselor were essential to understanding the role of genetics in breast cancer.

A genetic counselor takes a family history of three generations, explains treatment guidelines and, if the patient chooses, tests her for thousands of mutations in several genes related to breast cancer and other cancers. The sessions are in-depth. A first visit with a cancer genetics specialist might take as long as 90 minutes. If the patient's results show an inherited mutation, a second visit is typically scheduled to discuss screening and management options as well as risk to other family members.

This kind of education and care is not provided in a 23andMe spit kit. Though there is a lot of fine print, there is no counseling to speak of. (The company does provide contact information for the National Society of Genetic Counselors in its report.) Had I learned about my mutation via email, as 23andMe customers do, I would have had to find healthcare providers to help me navigate its meaning. I would have been terribly lost at an enormously vulnerable point in my life.

Not only does 23andMe not provide counseling, their results are incomplete. For instance, they report only on BRCA1 and BRCA2 and restrict their findings to the three mutations common among Jewish women. (They do explain this in their printed materials.)

While the most common three mutations in the BRCA1 and BRCA2 genes are typically found in women of Ashkenazi Jewish heritage, there are more than 1,000 other mutations that can be just as deadly. Women with Ashkenazi heritage can also have a mutation not associated with being Ashkenazi.

There are other genes that can have mutations that substantially increase one's risk for breast cancer, including PALB2, CHEK2, PTEN, CDH1, TP53 and STK11. 23andMe doesn't provide test results for any of these mutations.

It's because 23andMe's health data provide a limited picture that the FDA made the company stop. The agency was concerned, and reasonably so, that a negative result might lead a woman to think her risk was not high, when in fact she could still carry a different mutation than the three tested. Conversely, a woman might receive a positive test result and undergo a risk-reducing double mastectomy when a different option might have been more appropriate.

None of these risks have been addressed. Instead, the FDA simply allowed 23andMe to downgrade their kits from Class III devices, which receive the highest level of safety scrutiny, to Class II devices.

My 23andMe test results arrived during the evening crush of homework and dinner. I scanned the email quickly while my kids ate.

In the health information, it listed my likelihood for lactose intolerance, my inclination toward flushing when drinking alcohol and my "propensity to sleep deeply." Below all this, in a big bold box, it stated: "Zero variants identified in the BRCA1 and BRCA2 genes."

I felt a flicker of elation, until I remembered that it was incorrect.

Sarah C. Hopkins is a graduate student in genetic counseling. She holds a master's degree in health policy.

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Take it from a genetic counselor: 23andMe's health reports are dangerously incomplete

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Earlier this fall, I spat into a test tube and mailed off my DNA to be screened for disease risks by 23andMe, the genetic testing firm. Although millions do this to research their ethnic background and health conditions, my interest was more professional than personal.

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Genetics has learned a ton — mostly about white people. That’s a problem

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Genetics has learned a ton — mostly about white people. That’s a problem

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Article from Vox about lack of equity in genetics research

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In the future, it's possible that when you go in for a physical, your doctor will, along with the usual blood pressure test and bloodwork, analyze your genome for health risks lurking in the code of your DNA.

It's possible your genome will suggest you're at high risk of developing heart disease. If you are, your doctor may start you on cholesterol-lowering drugs early or could also, maybe, make predictions about what other medications are most likely to work to prevent the disease.

A treatment plan like this - tailored to an individual's genetic risk - is one of the great promises of " precision medicine." Whether genomic analysis will ever yield enough useful results to make it possible is a subject of heated debate. If it does pan out, it could be a game changer.

"If people aren't involved in the research, they may not benefit from the advances"

Though, as it stands, the game won't be changed for everyone: If you're not white, this new research may fail you.

If the new age of "precision medicine" is going to be equitable, we'll have to fix this.

There's an important lesson in diversity and genetics lurking here too. It's not that people of different ethnic backgrounds have wildly different biology. It's much more subtle, and fascinating, than that. We need to explore the vast range of human genetic variation: It could end up saving us all.

Genetic prediction works better for people of white, European ancestry for a simple reason

This is not a hypothetical problem: Last week, Color Genomics announced that next year, it will release a risk test for heart disease. When it debuts, MIT Technology Review reports, the product will only be useful for people of white European ancestry. Though, again, many scientists think genetic risk research is too preliminary for these risk tests to be sold to any consumer. (Color is also working on expanding its tests to cover more people.)

But the reason the test won't work for most of the world's population is simple: Most participants in the studies that yield predictive insights - genome-wide association studies (or GWAS for short) - are of white European ancestry. In all, white people of European ancestry make up 80 percent of the participants in all these studies, despite only representing a fraction of the world's population.

This is "a vast disparity, and it hasn't been getting a whole lot better," says Alicia Martin, a geneticist at the Broad Institute who has co-authored papers on racial disparities in genetics research.

You can see the disparity clearly in the following chart. It plots the number of individuals used in GWAS studies over time. While there's been some progress in recent years, the participants are still overwhelmingly white - despite the fact that white Europeans represent just a fraction of the world's population.

The disparity matters for a simple reason: We are developing genetic risk tools that people of color will not benefit from, unless we do genetic risk studies for them too. It's adding to the long-standing problem of people of color being excluded from medical research. And it could also end up increasing health care disparities in America - which are already stark and stubborn.

For instance, in the past few years, researchers have learned that the genetic variants that can contribute to asthma in white children aren't the same for African-American children. Imagine a (hypothetical) genetic test at infancy that could be used to start preventive asthma treatment on the first day of life. It would be a great tragedy if all of these tools were not useful for African-American children, who are disproportionately affected by asthma.

When minorities aren't included in scientific research, they can suffer. The cures derived from the research may not work as well for them. Diagnostic tests might fail them. Again, this isn't just a hypothetical: It has already happened in some cases.

Genetic risk, explained

You may recall from high school biology that a strand of DNA is made up of a string of nucleotides: adenine, guanine, cytosine, and thymine. These are the letters that spell out the recipe for our biology. You, me, Neil deGrasse Tyson, Kim Kardashian - indeed, all of humanity - share 99.9 percent of all the identical letters of DNA.

GWASs look for the sites on the genome where we commonly differ from one another. These sites are called single nucleotide polymorphisms - a.k.a. SNPs, or "snips" - and they're simply spots where you might have the nucleotide adenine and I'll have a cytosine.

Some of these SNPs are meaningful for our health, and activate the biological pathways that make some of us taller than others, smarter than others, or healthier than others. Others are just kind of randomly acquired through generations and don't tell us all that much besides for our geographic ancestry.

This is something people may misunderstand about evolution: Species survive because of diversity

To be very clear: African, Asian, Native American, Ashkenazi Jew, and European biology is not different from one another. None of this is evidence that race is a "biological construct" (which it isn't). What can be different among various ethnic groups is the patterns of genes we inherit from our families. "It's a difference in terms of disease, and what causes disease," says Emmanuel Peprah, a global health scientist at NYU.

Most humans will be at higher risk of heart attacks when there's more LDL cholesterol in their blood; that's the basic biology. The differences here are more about why LDL accumulates greatly in one person and not another.

There are some diseases and physical traits that are caused by a change in a single gene. Examples include sickle cell disease, which affects many African Americans, and Huntington's disease, which deteriorates nerve cells in the brain. Whether the bottom of your earlobes stick to the side of your face or hang free is the result of one gene.

But even more diseases and physical traits are polygenic. For instance, there are hundreds of locations in the genome that influence diabetes. And each of them changes the odds of developing diabetes minutely. Heart disease risk is polygenic; so is intelligence and height.

GWAS works to identify the constellation of genetic changes that make it slightly more or less likely you'll have a trait or a disease. And that's the basis of genetic risk prediction: Labs read your genome and essentially tally up your genetic variants that signal risk.

Why GWAS studies with Europeans don't generalize well to other groups

There are some legitimate reasons most GWASs to date have involved only Europeans. For one, most genetics research funding comes from white-majority countries. (One of the largest repositories of genetics data is the UK Biobank, which has nearly half a million participants of white European ancestry.)

For these studies to work - that is, for them to yield the genetic markers that most accurately predict biological outcomes - researchers have to limit subject pools to people of a common ancestry. This allows them to control for the SNPs that have nothing to do with the disease or trait they're studying.

For instance, if you did a GWAS for height that included both Southern and Northern Europeans, you'd find that the gene for lactose tolerance (the ability to drink milk without stomach problems) is associated with height. This gene has nothing to do with - or very little to do with - height. But it is picking up on the fact that Northern Europeans tend to be taller than Southern Europeans, and that they, coincidentally, are more likely to be lactose-tolerant.

The GWAS, in this case, isn't identifying biology of height; it's identifying gene variants that are "accidentally correlated with ancestry," says Graham Coop, a population geneticist at UC Davis, who walked me through this example.

If you're trying to predict disease risk in East Asians with insights derived from a European GWAS, "you do a little less than half as well in terms of prediction accuracy," Martin says. "And if you look at an African-American population, you do about a quarter as well."

Even controlling for ancestry, researchers don't always exactly know the biological purpose of SNPs uncovered by GWAS. (Much more on that here.)

And that's another problem with generalizing GWAS results from one population to another. The GWASs don't just pick up on the variants that contribute to a disease, they pick up on the variants that are just coincidentally correlated with the disease variants. (Yes, the way our genes works is extremely confusing.)

The patterns of these correlations differ from one ancestral group to the next and are part of the reason why the predictive power of GWAS diminishes from one group to the next.

Everyone loses when genetics research is not diverse

When we don't do genetics research on diverse populations, we not only risk widening health disparities - we risk missing out on new biology that will help us all.

When researchers only look at European DNA, they find genetic disease variants that are common among Europeans. "But if we were to study non-European populations, we'd start to find variants that contribute to diseases that are common in those populations, but are rarer in European populations," Martin says. "We'd actually learn new biology."

We could also find more cures. PCSK9 inhibitors are a new class of cholesterol-lowering drugs that show promise in lowering the chance of heart disease beyond what statin drugs can do alone. Doctors debate whether these new drugs will be worth the cost. Regardless, they're a breakthrough: a novel way to prevent heart disease. And these drugs were discovered because researchers noticed that some African Americans had mutations on their PCSK9 genes that led them to have very low LDL cholesterol in their bloodstream.

We need to explore human genetic diversity to make game-changing insights. This is something people may misunderstand about evolution: Species survive because of diversity. When change comes, there's someone, somewhere, who can help our species survive. Genetics is helping us find those beneficial adaptations and bring them to the broader world.

Here's what needs to change

It's not that individual GWAS studies need to include diverse participants. It's that these GWASs need to be redonepopulation by population to ensure their generalizability. Just as there is a GWAS study on hundreds of thousands of Europeans to assess genetic risk for heart attacks, there needs to be a study on many people of African origin, East Asian origin, and so on.

It is changing, but too slowly. In 2009, 96 percent of participants in GWAS studies were of European descent. In 2016, that number had dropped to 80 percent of participants.

There are projects in the works to diversify genetics research, which offer some reason for hope. Notably, the NIH is currently recruiting for a program called All of US. With it, the NIH aims to recruit 1 million people across the country to participate in a long-term study on the intersection of genetics, lifestyle, environment, and health. The goal: get 75 percent of the participants from groups who are typically underrepresented in biomedical research, with at least 500,000 participants from racial and ethnic minorities.

"You really can't have precision medicine for all of us if all of us don't participate and aren't reflected in the research and the studies," Dara Richardson-Heron, chief engagement officer for the All of Us program, says.

Richardson-Heron recognizes there's a long, earned historical mistrust of medical studies, particularly among African Americans. (Also concerning: how white supremacists are seizing on genetic science and distorting it for self-aggrandizing aims.)

But this data needs to be collected if health care is going to advance equitably. "There's a real chance if people aren't involved in the research, they may not benefit from the advances," she says. "And everyone, I think, wants better health for their families."

Further reading: the new science of genetic prediction
Correction: An earlier version of this piece stated the forthcoming Color Genomics test for heart disease risk will be available direct-to-consumer. A spokesperson for Color clarifies "all all of our tests are physician ordered."

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Genetics has learned a ton - mostly about white people. That's a problem.

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In the future, it's possible that when you go in for a physical, your doctor will, along with the usual blood pressure test and bloodwork, analyze your genome for health risks lurking in the code of your DNA. It's possible your genome will suggest you're at high risk of developing heart disease.

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What consumer DNA data can and can’t tell you about your risk for certain diseases

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What consumer DNA data can and can’t tell you about your risk for certain diseases

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Feature article from Science News

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R esults from Family Tree DNA, a genetic testing company, helped Lara Diamond find a branch of her family she thought had been lost in the Holocaust. Those 2012 results brought dozens of new people into her life.

Eager to find more relatives, Diamond, now 42, a professional genealogist in Baltimore, decided to try out all the companies that offer geneaological DNA testing to see what else she could learn. Results from one of them, 23andMe, hit her with an entirely different kind of life-changing knowledge: a high risk for breast cancer.

Browsing through the health and trait reports the company provides, Diamond reached the locked reports, which contain information about genetic variants that increase risk for developing breast cancer, Alzheimer's disease or Parkinson's. Customers have to choose to "unlock" that information since it can bring upsetting news.

Diamond considered her family history. "Because we have Alzheimer's and Parkinson's in my family, I said, 'OK, I'll think about those. But we don't have breast cancer, so I'll open this BRCA thing,' " she says, referring to the family of genes linked to breast cancer.

To her shock, Diamond learned she has a variant in her DNA that alters one amino acid in the BRCA2 protein, putting her at high risk for the disease. "One little stupid mutation. One amino acid. And it changes your whole life."

The next morning she called her doctor, who sent her to a genetic counselor. The counselor ordered a confirming DNA test from a lab certified to do medical diagnostic testing. Diamond also got a mammogram, an MRI, an ultrasound and blood work to screen for breast, ovarian and pancreatic cancers, because her variant boosts risk for all three. The MRI revealed a tiny spot of cancer deep in her breast, too small for the mammogram to detect. She decided to have a double mastectomy.

This feature is part of a multipart series on consumer genetic testing. See the whole series.

Her doctors are urging her to have her ovaries and fallopian tubes removed as well, to head off ovarian cancer. "I'm not ready to do that yet," Diamond says.

Diamond had been mostly interested in what her genes could reveal about her family history, not the health information they hold. But millions of genetic testing customers want to know their medical future. Even though most consumer genetic testing companies collect data on thousands of gene variants that may have an impact on health, companies such as 23andMe are allowed to give only limited information about genetic health risks. The companies' reports focus mainly on ancestry or basic physical traits ( SN: 5/26/18, p. 20).

So the marketplace has devised a work-around: Consumers who want to know about their risks for diabetes or several other diseases can turn to third-party services to analyze the raw DNA results generated by testing companies. New research suggests, however, that some of the answers people find through these third-party services are wrong and could prevent people from listening to their doctors or genetic counselors. That is, if the person bothers to go see one.

The market responds

Diamond got her health-related results in 2013, just before the U.S. Food and Drug Administration told 23andMe to stop giving consumers health information. The company had to demonstrate to the FDA that the information it provides is accurate and communicated in an easy-to-understand way. In 2017, 23andMe won approval to slowly add back reports for certain health conditions.

Most recently, in March, the FDA granted approval for the company to tell customers if they have one of three genetic variants in the BRCA1 and BRCA2 genes. Those three variants are responsible for about 74 percent of inherited breast cancers among people of Ashkenazi Jewish heritage. Less than 0.1 percent of people of other ethnicities carry these variants.

Offering information on only three variants, when there are thousands in the two genes that increase risk for breast and ovarian cancers - as well as melanoma, prostate and pancreatic cancers - is troublesome, say health care providers, breast cancer advocacy groups and others.

One little stupid mutation. One amino acid. And it changes your whole life.

- Lara Diamond

With only a partial list of variants called out, test takers who don't carry one of those variants may misinterpret the results, worries Lisa Schlager, vice president of community affairs and public policy for FORCE, a hereditary breast cancer information and support group.

People who don't carry one of the variants may say, "I don't have a genetic risk that predisposes me to cancer. I'm safe," Schlager says. "But that is absolutely not correct; you are only negative for three out of thousands of possible mutations. So our concern is that the public is not going to understand the limitations."

Yet Schlager and others admit that allowing companies like 23andMe to provide FDA-approved information and explain the results - however incomplete - may be the lesser of two evils.

"There's a sort of underworld that's been going on since the FDA stopped 23andMe from interpreting these results and giving them out to people," Schlager says. For a small fee, third-party analysis services stand eager to offer the interpretation that testing companies choose not to provide, or aren't allowed to provide under FDA rules. These services include Promethease, an early player in the consumer raw data analysis market, along with Genetic Genie, LiveWello and many, many others.

That's possible because customers of direct-to-consumer DNA testing services such as 23andMe, AncestryDNA and Family Tree DNA can download their raw DNA data to send to third-party analysis sites or apps. Those raw data consist of a list of spots, known as SNPs (pronounced "snips"), where customers' DNA varies. Some third-party analysis services will also look at a wider swath of information, data on protein-coding regions, called the exome. Genos is one testing company that provides raw data on the exome.

Helix, a testing company that provides "exome plus" data, has partner apps that customers can buy to analyze limited sets of their data. (Or, for $499, you can download all of your raw data). So far, very few of the third-party analysis services are set up to process data from the entire genetic instruction book, or genome.

To write their reports, Promethease and the others find scientific studies that mention the genetic variants a customer carries and make inferences about the health risks of carrying those variants. "That has been an absolute nightmare," Schlager says. Consumers don't understand the information and often overreact.

Devil in the data

In Facebook groups for people with BRCA mutations, Diamond, who volunteers with FORCE, often encounters people who got a scary result from a third-party analysis site. "I have to talk a lot of people off the ledge," she says. "They will upload their data and these services tell them, 'You're BRCA2 positive.' They understandably freak out." Many of those people would get an entirely different answer from medical diagnostic testing, she says.

Diamond makes a good point, says Stephany Tandy-Connor, a genetic counselor at Ambry Genetics in Aliso Viejo, Calif., the kind of clinical diagnostic company that doctors use for testing. She and colleagues examined test results of 49 people who received worrisome reports based on raw data generated by direct-to-consumer genetic testing companies between January 2014 and December 2016.

The people had gotten a doctor's order to get retested by Ambry. The company did comprehensive testing of the supposedly faulty genes. More than half of the harmful variants (60 percent) flagged by consumer tests were verified by Ambry's clinical test. The problem was, 40 percent of the harmful variants were false positives, the researchers reported March 22 in Genetics in Medicine. The results misstated that the people carried the variant when they actually didn't.

The fault doesn't lie with the third-party analysis service, Tandy-Connor says. Those companies simply analyze the raw data received from consumer testing companies. The errors were in the raw data. Often the testing companies are aware of the mistakes, but when they don't use that information themselves, they don't always bother clearing errors from the raw data, Tandy-Connor says.

Plus, the raw data don't contain a full draft of a patient's genome, as some consumers mistakenly think, Tandy-Connor says. Those data report only a few genetic spelling variations. Clinical testing labs, such as Ambry, use several methods to examine and reexamine disease-related genes to uncover all possible harmful variants. If each gene is a chapter in the body's instruction manual, clinical tests read every letter in that chapter hundreds to thousands of times, Tandy-Connor says.

Clinical labs also check to see if paragraphs or even pages have been ripped out or glued into the chapter. Such missing or added information, known as structural or copy number variants, might affect more than one gene ( SN: 4/25/09, p. 16).

Contrast that approach with the genotyping, or SNP testing, provided by 23andMe, AncestryDNA and many other direct-to-consumer companies. "Basically they don't read the whole chapter," Tandy-Connor says. "They just spot-check three or four letters and don't even look at the rest of it."

False alarm

A clinical lab checked worrisome results that people received from consumer DNA testing companies. Of the variants flagged as harmful, 40 percent were false positives. All but one of the bad calls were in cancer risk genes: BRCA1, BRCA2, TP53, CHEK2, MLH1 and ATM.

Source: S. Tandy-Connor et al/Genetics in Medicine 2018

Filling a gap

In 2006, even before 23andMe started offering consumer DNA tests, geneticist Greg Lennon and bioinformatician Mike Cariaso wanted to learn more about their own DNA. The two compiled SNPedia, a Wiki-style database of SNPs that are linked to diseases and traits in the scientific literature. Lennon and Cariaso's app, Promethease, uses SNPedia to compile reports about the genetic variants in a user's raw data.

The reports consist of long lists of variants with a description of what the scientific literature says about each variant. So even though 23andMe and other companies may not be allowed to give customers that information, Promethease can. Lennon says the difference is that his service doesn't generate any DNA data. He simply serves up scientific literature pertaining to the data.

"If the science is credible, we'll tell you about it," Lennon says. "We are not going to suppress information." It's then up to the customers, their doctors and genetic counselors to decide how to proceed. "The flip side is that it's easy for someone to misinterpret what they see in a Promethease report and panic over it," he admits.

Consumers shouldn't just assume that the information contained in their raw data is correct, or that third-party services have interpreted it correctly, Tandy-Connor says. In fact, genetic testing companies say buyers should beware of using raw data as medical information.

"Uninterpreted raw genotype data, including data that are not used in 23andMe reports, has undergone a general quality review. However only a subset of markers have been individually validated for accuracy," Dave Hinds, a statistical geneticist at 23andMe wrote on April 23 in an "Ask Me Anything" forum on the website Reddit.

Don't schedule any surgeries or screenings until you can talk it over with a professional.

- Stephany Tandy-Connor

Genetic results should be confirmed in a clinical lab, Tandy-Connor adds. And, importantly, the information needs to be evaluated in the context of a person's overall health and family history. "Take it to your doctor. Take it to a genetic counselor or some other genetic professional," she says. "Certainly don't act on it. Don't schedule any surgeries or screenings until you can talk it over with a professional."

Lennon doesn't quibble with that advice. "We are 100 percent in agreement that anything seen in a consumer test should be confirmed," he says.

But the message consumers take away from the Ambry study could have the opposite effect, he says: encouraging people to ignore the results of a consumer test.

"To say there are 40 percent false positives may dissuade people - people who are really carrying mutations - from having these things clinically checked out," Lennon says. These people might think their result is also a false positive. "That kind of blanket message is a huge disservice to people who might otherwise have actually gone in and gotten confirmatory screening."

Tandy-Connor disagrees. "I can see the angle he's coming from, but I don't share the same sentiment. I'm fairly confident most people would follow up. I mean, why else are they even doing this in the first place? If you're not going to do anything about it, what was the point? Just freak yourself out and walk away?" Not likely.

Risks explained

Customers of 23andMe who want to unlock information on their breast cancer risk must click through several screens of information before learning the result. This screen explains that risk goes beyond the three variants reported.

Matters in their hands

Consumers are using these third-party apps, but, according to a recent study, at least some people are taking their results to doctors and genetic counselors, says Catharine Wang, a behavioral scientist at Boston University School of Public Health. In an online survey on several social media sites, Wang and colleagues found that of 478 people who did a direct-to-consumer genetic test, 321, or more than two-thirds, used third-party analysis services to investigate ancestry or health information or both.

About 30 percent of those 321 people shared their results with a medical provider and 21 percent shared results with more than one provider, the researchers reported last year in Molecular Genetics & Genomic Medicine. Wang wasn't surprised that not everyone brought their results to their doctors. "If you don't find anything in your results, you're not going to show it to your doctor," she says. The study did not determine what percentage of people got a worrying result.

Those people who did tell their doctors about their results weren't always happy with the responses. Doctors were dismissive, weren't interested in the results or didn't know what to do with them, 23 percent of respondents reported. Other times, patients had to educate their physicians about DNA testing. Some consumers went straight to genetic counselors.

321

people
used third-party analysis services in a survey of 478 individuals who took consumer genetic tests
30

percent
of those 321 people shared their results with a medical provider

Source: C. Wang et al/ Molecular Genetics & Genomic Medicine 2017

In a separate online survey of 85 genetic counselors, about half said that they had been contacted by people who had used a third-party interpretation service, Wang and colleagues reported January 29 in Translational Behavioral Medicine. Counselors reported that patients turned to raw data analysis for several reasons: to get answers about mysterious symptoms, out of curiosity or to find out more about their health risks, including disease risks that the patients might pass on to their children.

According to the counselors, sessions didn't always go well. "They were encountering resistance from the patient," Wang says, as the counselors tried to correct misconceptions. Some consumers were overconfident about their knowledge, even when they were wrong. When counselors attempted to explain how DNA testing works and that raw data may contain errors, some people didn't want to hear it. "Consumers just don't know these nuances," Wang says. "Sometimes they're just not receptive to the information."

Some third-party interpretation services get into shady territory. LiveWello and Genetic Genie sometimes suggest clients take various vitamin supplements based on variants in certain genes. Some of the supplements are supposed to control DNA methylation, an important part of gene regulation, and reduce levels of a chemical called homocysteine in the blood. DNA methylation is a complex and delicately balanced system. Messing with it could cause problems.

Plus, methylation can't be gauged by looking at someone's DNA variants, says Preston Estep III, cofounder and chief scientific officer of Veritas Genetics. "SNPs cannot tell you - no amount of genetic information, actually, can tell you - what the state of your DNA methylation is," Estep says.

To be fair, the LiveWello website says it is not giving advice and people should talk to their doctors before taking supplements. But the disclaimer is easy to overlook.

Genetic tests are a whole other ball game in the womb. They offer unprecedented detail about fetal genomes. But whole-genome tests aren't ready for widespread use yet, doctors caution. See the companion story by Laura Sanders.

The tendency is to think that any change to DNA automatically means disease. But that's not the case, says Gail Jarvik, a clinical medical geneticist at the University of Washington in Seattle. Some genetic diseases affect a small subset of people who carry the variants. For instance, just 24.4 percent of men and 14 percent of women who have two copies of a variant in the HFE gene will develop hemochromatosis, an organ-damaging iron buildup, Jarvik and colleagues reported in 2015.

Even for DNA changes that are strongly linked to disease, like those in the breast cancer genes, disease is not definite, Jarvik says. About 72 percent of women who carry a cancer-associated variant in the BRCA1 gene and 69 percent of women with a harmful BRCA2 variant will develop breast cancer by age 80, researchers reported last year in JAMA. "But a bunch of these women will never get breast cancer, even if they live a long life," Jarvik says.

Because of the 23andMe test, Diamond knew her odds of getting breast cancer were high. But until her doctors found the cancer, she didn't know if she might escape genetic fate.

"During the time between getting the 23andMe results and the cancer results I did a lot of, 'Do I even want to know this?' " Diamond says. Ultimately, she is glad she knew. "They talk about early detection, but this was super early. Nothing on the mammogram. Nothing that you could feel. It's the best-case scenario for having cancer, I guess."

Diamond told her extended family that she carries a cancer-causing BRCA2 variant and suggested they get tested, too. Many more people in Diamond's family turned out to carry the variant than expected for a genetic change that has a 50/50 chance of being passed on to the next generation. "We just lose the coin flip a lot," she laments.

Diamond says she never would have known she was at risk for breast cancer if not for the consumer test. She's now grateful she and her family have the information, but says she's wary of getting similar information from a third party.

"There's goodness in being able to get your raw data," Diamond says. Uploading raw data from one ancestry site to another allows people to find more long-lost relatives. "But when you upload it to these other services to get medical information, that's what's more dangerous ... because people may interpret it for themselves incorrectly."

This article appears in the June 9, 2018 issue of Science News with the headline, "Risks and riddles: Health risk results from genetic testing have a lot riding on them."

S. Tandy-Connor et al. False positive results released by direct to consumer genetic tests highlight the importance of clinical confirmation testing for appropriate patient care. Genetics in Medicine. Published online March 22, 2018. doi:10.1038/gim.2018.38.

C. Wang et al. Consumer use and response to online third‐party raw DNA interpretation services. Molecular Genetics & Genomic Medicine. Vol. 6, November 2, 2017. doi: 10.1002/mgg3.340.

CG Allen et al. The impact of raw DNA availability and corresponding online interpretation services A mixed methods study. Translational Behavioral Medicine. Vol. 8, January 29, 2018, p. 105. doi: 10.1093/tbm/ibx009.

CJ Gallego et al. Penetrance of hemochromatosis in HFE genotypes resulting in p.Cys282Tyr and p.[Cys282Tyr];[His63Asp] in the eMERGE network. American Journal of Human Genetics. Vol. 95, October 1, 2015, p. 512. doi: 10.1016/j.ajhg.2015.08.008.

K. B. Kuchenbaecker et al. Risk of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA. Vol. 317, June 20, 2017, p. 2402. doi:10.1001/jama.2017.7112.

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What consumer DNA data can and can't tell you about your risk for certain diseases

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R esults from Family Tree DNA, a genetic testing company, helped Lara Diamond find a branch of her family she thought had been lost in the Holocaust. Those 2012 results brought dozens of new people into her life.

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DNA ancestry tests may look cheap. But your data is the price

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DNA ancestry tests may look cheap. But your data is the price

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Opinion piece from The Guardian

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DNA ancestry tests may look cheap. But your data is the price | Adam Rutherford

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Do customers realise that genetic genealogy companies profit by amassing huge biological datasets, asks geneticist and author Adam Rutherford

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They Thought Hemophilia Was a ‘Lifelong Thing.’ They May Be Wrong.

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They Thought Hemophilia Was a ‘Lifelong Thing.’ They May Be Wrong.

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Article about gene therapy from the NY Times

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Experimental gene therapies have yielded promising results in early trials. But the drugs have left some patients worried that success will not last.

Image

A colored scanning electron micrograph of a blood clot. Hemophilia is defined by an inability to form blood clots, leading to uncontrolled bleeds and chronic pain. Credit Credit Steve Gschmeissner/Science Source

Scientists are edging closer to defeating a longtime enemy of human health: hemophilia, the inability to form blood clots.

After trying for decades to develop a gene therapy to treat this disease, researchers are starting to succeed. In recent experiments, brief intravenous infusions of powerful new treatments have rid patients - for now, at least - of a condition that has shadowed them all their lives.

There have been setbacks - years of failed clinical trials and dashed hopes. Just last week, a biotech company reported that gene therapy mostly stopped working in two of 12 patients in one trial.

But the general trajectory has been forward, and new treatments are expected by many experts to be approved in a few years.

No one is saying yet that hemophilia will be cured. Currently the gene therapy - which uses a virus to deliver a new gene to cells - can only be used once. If it stops working, the patients lose the benefits.

For now, "we are anticipating that this is a once-in-a-lifetime treatment," said Dr. Steven Pipe, director of the hemophilia and coagulation disorders program at the University of Michigan and a lead investigator of a clinical trial conducted by the biotech company BioMarin.

The successful treatments are so recent it is hard to say how long they will last. But for the few patients who have been through the clinical trials successfully, life after treatment is so different that it's something of a shock.
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There are 20,000 hemophilia patients in the United States who lack one of two proteins needed for blood to clot. It's a genetic condition, and the gene for blood clotting sits on the X chromosome. Virtually all people with hemophilia are men.

Those most severely affected must inject themselves every couple of days with the missing proteins, clotting factor VIII or factor IX. The shots keep hemophiliacs alive, but levels of clotting proteins drop between injections.

Even with regular injections, people with hemophilia risk uncontrolled bleeding into a muscle or joint, or even the brain. They must be extremely careful. Once bleeding begins, a joint may bulge as the joint space fills with blood. When the bleeding stops, the joint may be damaged.

Even a routine flight is risky, said Mark Skinner, a 57-year-old attorney in Washington with hemophilia who is a past president of the World Federation of Hemophilia.

"Carrying luggage around, you can twist the wrong way and immediately trigger a bleed," he said. "Or you can get hit with a cart going down the aisle."

People with hemophilia often are taught as children to avoid most sports and to find professions that will not require much physical activity. Many move to cities to gain easier access to treatment.

They may change jobs to get insurance needed to cover medical bills for hospitalizations and surgeries that can reach $1 million a year, plus an average of $250,000 to $300,000 a year for the clotting proteins. (The shots alone can cost as much as $1 million per year.)

Despite their vigilance, most with severe disease eventually develop permanent joint damage from bleeds, often leading to surgery for ankle fusion or hip or knee replacements at an early age. Most live with chronic pain from past bleeds.

For older patients, there is an additional complication. The clotting proteins used in the 1980s were contaminated with H.I.V. and hepatitis C. Nearly everyone with hemophilia got infected.

Now, though, researchers see the start of a new era.

"It's a really optimistic time," said Dr. Lindsey A. George, a hematologist at the Children's Hospital of Philadelphia and a principal investigator for Spark Therapeutics, one of several companies developing gene therapies for hemophilia.

The goal of gene therapy is to reduce or eliminate patients' need for injections with clotting factor and to reduce the number of bleeds. The gene to be inserted depends on whether the patient has hemophilia A, caused by a mutation in the gene for factor VIII, or hemophilia B, caused by a mutation in the gene for clotting factor IX.

Although the symptoms are the same with both forms of the disease, hemophilia A is by far the most common.

A handful of biotech companies are now rushing to get their gene therapies to market. Spark, with gene therapy for hemophilia B, and BioMarin, another biotech company, with a similar treatment for hemophilia A, are starting large, final-phase clinical trials. (Pfizer is taking over the development of the Spark drug.)

Results from the two companies' preliminary trials were not perfect.

Patients in Biomarin's hemophilia A trial got, on average, normal or above normal levels of factor VIII in their blood, but in the second year, those levels dropped to a median of 46 percent. It's not clear why.

Patients in Spark's hemophilia B trial only reached on average 35 percent of normal blood levels of factor IX. But those levels have remained steady for the two years they have been followed.

The good news is that those levels are sufficient for blood to clot, because normal levels are more than people need. After dreaming of a cure for decades, some treated patients are trying to adjust to newfound freedom.

John Brissette, 39, a computer user interface designer in Hanover, Mass., said hemophilia A always dominated his life.

He spent childhood yearning to be active like other kids. But bleeds into his joints put him on crutches for days at a time or forced him to keep his arm in a sling.

He would be out of school for a week, then back, then out again with yet another bleed. He was embarrassed by nosebleeds that would not stop.

As an adult, he had to have his damaged ankle bones fused. His elbow, after numerous bleeds over the years, gives him chronic pain.

Foreseeing more pain and injuries in the years to come, Mr. Brissette began seeking out gene therapy clinical trials. Eventually, he enrolled in a Spark trial. (The company has an experimental hemophilia A drug, too.)

He received a single infusion on April 19. His blood levels of factor VIII rose from zero to as high as 30 percent of normal and so far have stayed there.

"I have not had a single bruise. I have not had a single bleed," Mr. Brissette said.

He has not given himself a shot of clotting factor since the procedure.

But he is still struggling to let go of a lifetime of wariness. As he tries to do work around the house or run around with his children, he is unable to shake the dread that he will bleed.

"I've become a very cautious person," Mr. Brissette said.

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Bill Konduros, left, and his brother, Jay, have lived with hemophilia most of their lives. Since receiving an experimental gene therapy, they have struggled to shed their wariness of what had been dangerous physical activity. Credit Ian Willms for The New York Times

At first, hemophilia seemed ideal for gene therapy.

Normal blood levels of clotting proteins range widely, from 50 percent to 150 percent of average. A gene therapy for the disease would not have to provide much to be effective for patients.

And researchers knew just which genes to insert into patients' liver cells. The genes for hemophilia A and B were isolated in the early 1980s.

But the research proved difficult, and the first positive result was reported just a few years ago by scientists at University College London and St. Jude Children's Research Hospital. They treated ten patients with hemophilia B and managed to increase their blood levels of factor IX to between 2 percent to 6 percent of normal.

In those patients, clotting proteins have persisted at those levels ever since.

Then scientists stumbled upon an unexpected bonanza. They found a man in Padua, Italy, who had a genetic mutation that made cells churn out as much as 12 times the usual amounts of factor IX.

Investigators realized that they could put the mutated gene into a virus and use it to insert the mutated gene into the cells of patients with hemophilia B.

The advantage was that they would not have to use so much virus - and the lower the dose, the less likely the immune system would attack.

"We dropped the dose four-fold," said Dr. Kathy High, a hematologist who is president of Spark.

"Our first patient was a 23-year-old nurse. His level of factor IX rose to around 30 percent and has remained there for two years," she said. The nurse has not needed to inject factor IX and has had no bleeds, she added.

But hemophilia A has been more daunting.

The viruses used to carry modified genes into patient cells are called adeno-associated viruses. They cannot carry a large gene, and the gene for factor VIII, needed to treat hemophilia A, is enormous.

After 15 years of effort, investigators finally discovered they could reduce the gene to a manageable size by slicing out portions that turned out not to be needed.

No longer are scientists and patients dazzled by a treatment that raises blood clotting factor levels merely to 6 percent of average. "My thinking has evolved," said Mr. Skinner of the World Hemophilia Foundation.

The results that companies are reporting now "really seemed unimaginable" just a few years ago, he added.

Bill Konduros, 59, owner of a machine shop who lives in Mississauga, Ontario, and his brother, Jay Konduros, 54, a baker in Cambridge, Ontario, had assumed that constant vigilance and increasing disability was their lot in life.

Hemophilia would be "a lifelong thing," said Jay Konduros. Then the brothers joined Spark's gene therapy trial for hemophilia B.

The actual infusion of the experimental drug was anticlimactic, Jay Konduros recalled. He walked into a hospital in Philadelphia, sat in a chair and had an intravenous drip for half an hour. That was it.

Now levels of factor IX in Jay Konduros's blood are around 50 percent. Bill, who also joined the trial, has levels closer to 75 percent. Neither has required any factor IX since their gene therapy.

Both struggle to accept the fact that, for the moment, their lives are very different.

"When I hit myself or strain a muscle or twist, I immediately revert to thinking like a hemophiliac," Bill Konduros said. "You go on high alert. Is the ache spreading? Is it throbbing?"

One day in May, Jay fell, landing on his forearms. Both wrists hit hard on concrete, and he struck the left side of his thigh, already damaged from previous bleeds.

He took a few deep breaths and told himself, "You will be O.K., you will be O.K."

He worried, anticipating disaster. That night he stretched. He examined himself. Nothing seemed damaged. He woke up in wee hours of the morning and nervously examined himself again.

He was fine. He waited three days to call his brother and tell him: He was now a normal person who had a minor fall.

"You hear a lot of things described as miracles or miraculous," Bill said. "I guess I would say this truly is."

Gina Kolata writes about science and medicine. She has twice been a Pulitzer Prize finalist and is the author of six books, including "Mercies in Disguise: A Story of Hope, a Family's Genetic Destiny, and The Science That Saved Them." @ginakolata * Facebook

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They Thought Hemophilia Was a 'Lifelong Thing.' They May Be Wrong.

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Experimental gene therapies have yielded promising results in early trials. But the drugs have left some patients worried that success will not last. Scientists are edging closer to defeating a longtime enemy of human health: hemophilia, the inability to form blood clots.

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CRISPR/Cas9 gene editing scissors are less accurate than we thought, but there are fixes

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CRISPR/Cas9 gene editing scissors are less accurate than we thought, but there are fixes

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Article from The Conversation

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CRISPR gene editing technology is revolutionising medicine and biology. This technique allows scientists to edit DNA with more precision and greater ease than previous gene editing technology.

But a new study has called into question the precision of the technique.

The hope for gene editing is that it will be able to cure and correct diseases. To date, many successes have been reported, including curing deafness in mice, and in altering cells to cure cancer.

Some 17 clinical trials in human patients are registered testing gene editing on leukaemias, brain cancers and sickle cell anaemia (where red blood cells are misshaped, causing them to die). Before implementing CRISPR technology in clinics to treat cancer or congenital disorders, we must address whether the technique is safe and accurate.

How does CRISPR work again?

CRISPR technology utilises molecular scissors (a bacteria enzyme called "Cas9") to cut the DNA we want to target, and then we can paste DNA in to replace what we have removed. Cas9 recognises a specific segment of DNA among the entire human genome by utilising a guide, something like a map, that is linked to Cas9.

Read more: What is CRISPR gene editing, and how does it work?

Cas9 can persist in the body for several hours to several weeks. While it remains in the body, Cas9 can cut and paste other segments of DNA ("off targets") or the targeted segment of DNA over and over ("on target").

What the new study found

A study published today in Nature Biotechnology explores the accuracy of the Cas9 scissors. Scientists at the Sanger Institute at Cambridge, UK sought to determine whether Cas9's cut and paste process is accurate enough to be safely used in humans for treating disease.

To answer this important question, they examined in detail the DNA segments in mouse embryonic stem cells and human cells near the segment that was cut to see if they were affected.

They found that after the DNA was repaired (new DNA pasted into the "cut" segment), the scissors continued to cut the DNA over and over again. They found significant areas near the cut site where DNA had been removed, rearranged or inverted.

If a fragment of DNA is removed or inverted (the genes switched around), the gene modification could be dangerous, and even lead to disease. While this seems scary, this could potentially be overcome using new sequencing technologies.

Read more: Human embryo CRISPR advances science but let's focus on ethics, not world firsts

Can we use different scissors?

There are a few options for getting around this problem. One option is to isolate the cells we wish to edit from the body and reinject only the ones we know have been correctly edited.

For example, lymphocytes (white blood cells) that are crucial to killing cancer cells could be taken out of the body, then modified using CRISPR to heighten their cancer-killing properties. The DNA of these cells could be sequenced in detail, and only the cells accurately and specifically gene-modified would be selected and delivered back into the body to kill the cancer cells.

While this strategy is valid for cells we can isolate from the body, some cells, such as neurons and muscles, cannot be removed from the body. These types of cells might not be suitable for gene editing using Cas9 scissors.

Fortunately, researchers have discovered other forms of CRISPR systems that don't require the DNA to be cut. Some CRISPR systems only cut the RNA, not the DNA (DNA contains genetic instructions, RNA convey the instructions on how to synthesise proteins).

As RNA remains in our cells only for a specific period of time before being degraded, this would allow us to control the timing and duration of the CRISPR system delivery and reverse it (so the scissors are only functional for a short period of time).

This was found to be successful for dementia in mice. Similarly, some CRISPR systems simply change the letters of the DNA, rather than cutting them. This was successful for specific mutations causing diseases such as hereditary deafness in mice.

In short, before using CRISPR clinically, we still have a lot to learn about the effects of Cas9 scissors in the cells.

Read more: Debate on whether we should use gene-editing technology is far from black and white

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CRISPR/Cas9 gene editing scissors are less accurate than we thought, but there are fixes

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CRISPR gene editing technology is revolutionising medicine and biology. This technique allows scientists to edit DNA with more precision and greater ease than previous gene editing technology. But a new study has called into question the precision of the technique. The hope for gene editing is that it will be able to cure and correct diseases.

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Gene-Therapy Trials for Inherited Form of Blindness Could Start Soon

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Gene-Therapy Trials for Inherited Form of Blindness Could Start Soon

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Article from Frontline Genomics

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Frida Holme

Researchers from the University of Pennsylvania have developed a gene therapy that successfully treats a form of macular degeneration in a canine model.

The work, published in Proceedings of the National Academy of Sciences, sets stage for translating the findings into a human therapy for an inherited disease that results in a progressive loss of central vision and which is currently untreatable.

The research is part of a long-standing partnership between Penn Vet and Penn Medicine scientists to push forward gene and other novel therapies for blinding disorders. The study was led by Karina E. Guziewicz, research assistant professor in Penn's School of Veterinary Medicine, and Arthur V. Cideciyan, a research professor of ophthalmology at Penn's Perelman School of Medicine.

"In the eye, you have these who integral retinal cell layers that puzzle into one another, and, like a zipper, they interweave your vision cells and the support cells," Cideciyan says. "What this disease is doing is basically unzipping those layers, and what we've done is rezip them, bringing them together lightly."

With this research, Guziewicz continues, "we have demonstrated that there is a therapy that is working in a large animal model. Following safety studies, a human clinical trial could be less than two years away."

Best disease, or vitelliform macular degeneration, is an inherited blinding disorder caused by mutations in the BEST1 gene. It often manifests in children and young adults, gradually robbing them of their central vision.

Through a variety of studies during the last several years, the team has shown that dogs, too, develop a strikingly similar disease.

A 2014 study led by Beltran revealed that dogs, like humans, have a tiny region at the centre of their retina that is densely packed with cone photoreceptor cells-those responsible for reading, driving, and perceiving fine details-called a fovea. BEST1 mutations in both humans and dogs compromise the fovea, leading to vision loss.

Based on success treating other blinding diseases, the group has been developing a gene therapy to treat this condition.

Last year, working with the canine model, Guziewicz and colleagues reported the discovery of the underlying defect responsible for disease, the failure of a supporting structure known as the retinal pigment epithelium, or RPE, to tightly connect to the light-sensing photoreceptor cells. That finding gave the researchers the outcome measures they needed to determine with confidence whether a gene therapy would work.

In the newly published study, the researchers further probed the canine Best disease while also examining human patients with BEST1 mutations to see if analogous defects could be seen.

While Best disease and related conditions were known to affect central vision, it had long been known that the disorders involved dysfunctions all across the retina. Examining the retinas of dogs with disease mutations, the researchers found a retina-wide abnormality; the internal surface of the RPE, critical for communication with the light-sensing photoreceptor cells, failed to develop normally, preventing the photoreceptors from coming into close contact. This could be detected very early, when the affected dogs were only 6 weeks old.

"This was unexpected," says Aguirre, professor of medical genetics and ophthalmology, "and helps explain this puzzling finding in the disease that, while patients have lesions that are very local, when you do electrophysiological measurements you see that there is a retina-wide defect. Now that we can see this separation happening very early between the RPE and photoreceptors, we know that the disease involves a structural abnormality across the retina that precedes the loss of photoreceptor cells."

An additional finding that arose when the dogs were examined under light was that light exposure dramatically increased the severity of the RPE-photoreceptor separation. When dogs were returned to darkness, the separation decreased.

It's unknown whether this association with light is present in human patients. But the researchers did take steps to show that a similar separation between RPE and photoreceptors is affecting vision. By measuring the time it took for patients to adjust to darkness, or acquire "night vision," the researchers obtained a proxy for the time it takes for nutrients to diffuse between these two layers of cells, a process that enables dark adaptation. They showed that a longer distance was associated with much slower rates of nutrient transport.

"This flow of nutrients normally occurs over a very small distance," Cideciyan says. "So if you have a separation between these two layers, the recovery rate to get night vision slows down. The implication is that, if we could correct the apposition of these two tissues, we would correct the visual defect as well."

That is what the researchers set out to do in testing the gene therapy construct. Using a harmless viral vector, they injected a healthy copy of the BEST1 gene, using either the canine or human version of the gene, into the dogs with the canine version of Best disease, at early- and middle-disease stages.

Remarkably, they were able to correct both mild and more severe lesions. Close examination of the eyes of treated dogs revealed that the gene therapy restored the "zipper" structure between RPE and photoreceptor cells. To ensure their therapy was functioning to correct this RPE-photoreceptor interface, they exposed to light the eyes of dogs that had been previously injected with gene therapy and saw that the triggered RPE-photoreceptor cell separation did not occur in the area of the retinas that had been treated.

"Since we understand the mechanism of disease better than before," says Guziewicz, "it also allows us to understand the mechanism of rescue. We can visualize these projections extending from the RPE that never existed before; it's incredible. That restored the proper apposition between those two cell layers."

The therapy appears to be lasting, as the treated dogs' eyes remained disease-free for as long as five years.

Work remains to be done before embarking on human clinical trials, including identifying which patients might benefit, assessing how far advanced a disease could be and still be effectively treated, and ensuring safety so as not to compromise vision that the patients still have. But, given the closeness with which dogs recapitulate the human disease, the researchers are hopeful that the findings will translate.

"On a human level, there are a lot of families who know that previous generations have had this disease, and the young people can live in fear of whether it is going to affect them," Jacobson says. "This is the unveiling of a mechanism and a treatment for a previously untreatable form of juvenile or inherited macular degeneration, and that's a major step forward."

Materials provided by University of Pennsylvania. Note: Content may be edited for style and length.

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Gene-Therapy Trials for Inherited Form of Blindness Could Start Soon

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Frida Holme Researchers from the University of Pennsylvania have developed a gene therapy that successfully treats a form of macular degeneration in a canine model. The work, published in Proceedings of the National Academy of Sciences , sets stage for translating the findings into a human therapy for an inherited disease that results in a progressive loss of central vision and which is currently untreatable.

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Ethics of embryo editing divides scientists

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Ethics of embryo editing divides scientists

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Article from Nature News

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MOLEKUUL/SPL

Research that uses powerful gene-editing techniques on human embryos needs to be restricted, scientists agree - but they are split over why.

Some say that if safety fears can be allayed, such applications could have a bright future, and could help to eradicate devastating diseases. Others say that modifying the DNA of embryos, which means that the changes could be passed on to future generations, is an ethical line that should not be crossed.

The concerns are laid out in an article published in Nature on 12 March and in one expected to appear in Science, amid suspicions that scientists have already edited the genes of human embryos.

Gene-editing techniques use enzymes called nucleases to snip DNA at specific points and then delete or rewrite the genetic information at those locations. Most recently, excitement has focused on a technique called CRISPR/Cas9, which is particularly easy to use. Current applications of the technology are in non-reproductive, or somatic, cells: for example, Sangamo BioSciences of Richmond, California, has used zinc-finger nucleases, an older gene-editing technology, to remove a gene from white-blood cells that encodes the receptor to which HIV binds to enter the cells.

But concerns focus on the use of gene editing to modify the genomes of eggs and fertilized eggs - a process known as germline modification.

Edward Lanphier, president of Sangamo and chairman of the Alliance for Regenerative Medicine in Washington DC, together with colleagues from both organizations, wrote the Comment article in Nature calling on scientists not to modify human embryos, even in research. The authors warn that such work could be exploited for "non-therapeutic modifications" - to change a child's eye colour, for example - and that a public outcry about such an "ethical breach" could hinder the use of gene editing in somatic cells.

They also have more basic objections. "We are humans, not transgenic rats," says Lanphier. "We believe there is a fundamental ethical issue in crossing the boundary to modifying the human germ line."

George Church, a geneticist at Harvard Medical School in Boston, Massachusetts, agrees that there should be a moratorium on embryo editing, but only "until safety issues are cleared up and there is general consensus that it is OK". Church, along with a group of scientists who met in Napa, California, in January to discuss the ethics and potential of the procedure, authored the piece for publication in Science detailing their concerns.

One concern is that nucleases could make mutations at locations other than those targeted, potentially causing disease. Church says that gene editing in animals is likely to reveal how to understand and avoid this complication. In one application, his group is editing genes related to the immune system in pig embryos to 'humanize' them, potentially allowing the pig's organs to be transplanted into people.

Other indications of safety will come from trials on somatic cells. Sangamo has already demonstrated the safety of its modified white-blood cells in a clinical trial of people with HIV.

Church sees no fundamental problem with editing the germ line - he notes that even the somatic-cell therapies are still a form of artificial modification. He compares gene editing in embryos to in vitro fertilization, which people objected to until it was shown to be safe.

"In the distant future, I could imagine that altered germ lines would protect humans against cancer, diabetes and other age-related problems," says Nobel-prizewinning geneticist Craig Mello of the University of Massachusetts in Worcester. In the nearer term, "there could be good reason to experiment with discarded embryos or embryonic stem cells for research purposes", he says.

But Lanphier says that for most cases in which parents carry disease-causing genes, not all of a couple's embryos will carry the faulty gene. Existing technology can be used to genetically screen and select healthy embryos before transplantation into the uterus, negating the need for permanent germline repair. "There are almost always alternatives," he says.

Church, however, says that for the growing number of known cases in which several genes are involved in a disease, most embryos need to be discarded. Editing would greatly increase the odds of getting a healthy embryo.

Dana Carroll, a geneticist at the University of Utah in Salt Lake City who was at the Napa meeting, says that a national agency such as the US National Academy of Sciences should convene a conference that includes medical professionals and the interested public to weigh up the positive and negative aspects of germline editing. They had better hurry: several researchers who do not want to be named told Nature 's news team that papers describing such work are currently being considered for publication in journals.

Carroll also cites the importance of educating the next generation of physicians about gene editing. "They should be learning now what the technology is able to do and what the social, as well as clinical, concerns are."

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Ethics of embryo editing divides scientists

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MOLEKUUL/SPL Research that uses powerful gene-editing techniques on human embryos needs to be restricted, scientists agree - but they are split over why. Some say that if safety fears can be allayed, such applications could have a bright future, and could help to eradicate devastating diseases.

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Designer babies aren’t futuristic. They’re already here.

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Designer babies aren’t futuristic. They’re already here.

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This article about preimplantation genetic diagnosis asks the question "Are we designing inequality into our genes?"

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Benedikt Luft

At first, Matthew assumed the weakness in his knee was the sort of orthopedic nuisance that happens when you turn 30. It was weeks before he consulted a doctor, and months before it occurred to him that there could be a connection between his worsening limp and a cousin's shoulder problem when they were kids. DNA testing confirmed it: Matthew, like his cousin, had a genetic form of dystonia, a condition where muscles contract uncontrollably. Their grandfather most likely had dystonia as well.

I'd met Matthew only a few months earlier, when he'd married my friend's daughter, Olivia, in one of those hip old New York hotels with an elegant downtown vibe. Since I was the only genetic counselor of their acquaintance, they brought their questions to me. With their permission, I am sharing their story. I have changed their names to preserve their privacy.

Matthew was lucky. His was a mild version of DYT1 dystonia, and injections of Botox in his knee helped. But the genetic mutation can cause severe symptoms: contractures in joints or deformities in the spine. Many patients are put on psychoactive medications, and some require surgery for deep brain stimulation.

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Their kids, Matthew and Olivia were told, might not be as lucky. They would have a 50-50 chance of inheriting the gene variant that causes dystonia and, if they did, a 30% chance of developing the disease. The risk of a severely affected child was fairly small, but not insignificant.

My friends learned there was an alternative. They could undergo in vitro fertilization and have their embryos genetically tested while still in a laboratory dish. Using a technology called pre-implantation genetic testing, they could pick the embryos that had not inherited the DYT1 mutation.

It would be expensive-costs for IVF in the US average over $20,000 for each try, and testing can add $10,000 or more. And it would require an unpleasant two-week process of ovarian stimulation and egg harvesting. "It wasn't the way I saw myself making a baby," Olivia told me. But they wanted what the procedure could offer them: a guarantee that dystonia was eliminated for the next generation, and beyond.

Matthew and Olivia don't think of themselves as having a "designer baby." That term has negative associations, suggesting something trivial, discretionary, or unethical. They weren't choosing eye color or trying to boost their kid's SAT score. They were looking out for the health and well-being of their future child, as parents should.

We risk creating a society where some groups, because of culture or geography or poverty, bear a greater burden of genetic disease.

Public opinion on the use of assisted reproductive technology consistently draws a distinction between preventing disease and picking traits. The Johns Hopkins Genetics and Public Policy Center, which contacted over 6,000 people through surveys and focus groups from 2002 to 2004, summed up its findings this way: "In general, Americans approve of using reproductive genetic tests to prevent fatal childhood disease, but do not approve of using the same tests to identify or select for traits like intelligence or strength." The dystonia gene is in a gray zone-some people born with it live perfectly healthy lives-yet presumably few parents would criticize Matthew and Olivia's choice to weed it out.

All embryo testing does fit the "designer" label in one important way, however: it is not available to everybody.

Matthew and Olivia opted in to what is a quiet but significant trend. Although the number of couples using this technology remains small, it is growing rapidly. According to the Society for Assisted Reproductive Technology, the number of US IVF attempts with single-gene testing rose from 1,941 in 2014 to 3,271 in 2016, an increase of almost 70%.

This is only the beginning. As the price of genetic testing of all kinds drops, more adults are learning about their genetic makeup as part of routine medical care and discovering specific genetic risks before pregnancy. But these people are still most likely to be affluent and educated, like Olivia and Matthew. While they consulted with IVF clinics, Olivia's own brother and his wife got news of a gene that increased risk for cancer in their kids. "If you could get rid of it, why wouldn't you?" he asked.

Cost was not a concern for these couples, but it is an obstacle for many Americans. The Centers for Disease Control and Prevention (CDC) estimates that 1.7% of babies born in the US today are conceived using IVF. It's much higher in countries that publicly fund assisted reproductive technology: 4% in Belgium, 5.9% in Denmark. A 2009 study found that 76% of the medical need for assisted reproduction in the US is unmet.

Insurance doesn't normally cover IVF in the US, except for a handful of states where coverage is mandated. Even policies that cover fertility treatment are inconsistent in what they reimburse. Coverage for pre-implantation genetic testing is downright Kafkaesque. Under many policies, testing the embryos is covered, but the IVF procedure itself is not, because the couples are not infertile.

"The analogy I like to use," says James Grifo, director of the Division of Reproductive Endocrinology and Infertility at NYU Langone Health, "is if you were having coronary bypass surgery and they didn't pay for cracking the chest."

At least part of the reason the IVF industry is growing is not that more people can afford it but that those who can are paying for new kinds of services. Egg banking, for example, is now aggressively marketed to younger women as an insurance policy against age-related infertility. In 2011, egg banking did not even exist as a category in the CDC's annual report on IVF; by 2016, storing eggs or embryos was the purpose of 25% of all IVF cycles. Elite companies like Facebook offer egg freezing as a perk, but for most people it remains a luxury.

Cost isn't the only barrier. Reproductive technology is less acceptable in racial, ethnic, and religious groups where being seen as infertile carries a stigma. Language barriers can reduce awareness and referrals. Geography also plays a role, since IVF clinics cluster in areas of greatest demand.

Presumably, many people would make the same decision as Matthew and Olivia if given the option, but many don't have that choice. Our discomfort around designer babies has always had to do with the fact that it makes the playing field less level-taking existing inequities and turning them into something inborn. If the use of pre-implantation testing grows and we don't address these disparities, we risk creating a society where some groups, because of culture or geography or poverty, bear a greater burden of genetic disease.

What could change society more profoundly than to take genetic disease-something that has always epitomized our shared humanity-and turn it into something that only happens to some people?

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Designer babies aren't futuristic. They're already here.

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Benedikt Luft At first, Matthew assumed the weakness in his knee was the sort of orthopedic nuisance that happens when you turn 30. It was weeks before he consulted a doctor, and months before it occurred to him that there could be a connection between his worsening limp and a cousin's shoulder problem when they were kids.

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17min documentary about gene therapy for inherited blindness

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Genes as Medicine | HHMI BioInteractive video

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Gene testing exposes us all to discrimination

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Gene testing exposes us all to discrimination

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Article from the Sydney Morning Herald (2010)

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Gene testing exposes us all to discrimination

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Loss of privacy and risk of penalties can outweigh benefits.

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Research Ethics Recommendations for Whole-Genome Research: Consensus Statement

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Research Ethics Recommendations for Whole-Genome Research: Consensus Statement

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Paper from journal PLOS Biology

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Timothy Caulfield ,

Amy L McGuire,

Mildred Cho,

Janet A Buchanan,

Michael M Burgess,

Ursula Danilczyk,

Christina M Diaz,

Kelly Fryer-Edwards,

Shane K Green,

Marc A Hodosh,

Eric T Juengst,

Jane Kaye,

Laurence Kedes,

Bartha Maria Knoppers,

Trudo Lemmens,

Eric M Meslin,

Juli Murphy,

Robert L Nussbaum,

Margaret Otlowski,

Daryl Pullman,

Peter N Ray,

Jeremy Sugarman,

[ ... ],

Michael Timmons

[ view all ]

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Timothy Caulfield,

Amy L McGuire,

Mildred Cho,

Janet A Buchanan,

Michael M Burgess,

Ursula Danilczyk,

Christina M Diaz,

Kelly Fryer-Edwards,

Shane K Green,

Marc A Hodosh

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Citation: Caulfield T, McGuire AL, Cho M, Buchanan JA, Burgess MM, Danilczyk U, et al. (2008) Research Ethics Recommendations for Whole-Genome Research: Consensus Statement. PLoS Biol 6(3): e73. https://doi.org/10.1371/journal.pbio.0060073

Published: March 25, 2008

Copyright: © 2008 Caulfield et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Advances in technology have made it possible to sequence a whole human genome [ 1, 2]. National and international funding initiatives have stimulated whole-genome research activities [ 3, 4], and media coverage of both the science [ 5, 6] and the emerging commercial offerings [ 7, 8] related to genome research has heightened public awareness and interest in personal genomics. As technology continues to advance, whole-genome research activities seem likely to intensify and expand, necessitating carefully considered consensus guidelines for ethical research practice.

To date, there has been only minimal consideration of the research ethics issues associated with this work [ 9-12]. We therefore convened an interdisciplinary consensus workshop to develop ethically rigorous and practical guidance for investigators and research ethics boards. What follows are recommendations on the four topics that were the focus of the workshop. These topics-consent, withdrawal from research, return of research results, and public data release-were selected because they were viewed as being among the most pressing research ethics issues and as representing areas where whole-genome analysis creates unique challenges. They are not, of course, the only policy issues that need to be considered; commercialization, patenting, benefit sharing, and the possibility of genetic discrimination are among other topics that warrant reflection. Regardless, the four topics covered in this paper are current issues worthy of immediate attention.

The paper starts with initial considerations, including general recommendations about governance and the characterization of the research activities related to the whole genome. It is important to note that while there was consensus on all recommendations, there was a good deal of debate about the degree to which they satisfy existing ethical and legal norms [ 13]. All participants believed that we need both empirical research and continued conceptual analysis ( Box 1). These are early days in the field of whole-genome research. Research ethics guidance is needed immediately, but we should continue to explore the ethical, legal, and social implications of this rapidly evolving field ( Box 2). Indeed, the door must remain open for further reflection on these and other social concerns.

Box 1. Ethical Questions for the Future

The following is a list of research ethics questions that warrant future investigation and analysis. It is not an exhaustive list of the research ethics questions associated with whole-genome research.

1. Duty to Recontact: Given the numerous disciplines and health care providers potentially involved in whole-genome research, further analysis of the legal and ethical obligations of each (particularly in the context of return of results) seems warranted. Who has what obligations? Who, if anyone, has the duty to return results? Is there a "chain of obligation" that runs through the various members of a research team?

2. Right to Withdraw: Because of the potential for the rapid dissemination of research results, the right to withdraw can quickly become impractical. This raises the issue of the degree to which there is an ethical requirement to structure the research and dissemination of results in a manner that will allow the right to withdraw to endure as long as possible. As such, this issue should be investigated with consideration of existing and evolving legal and ethical norms, emerging information technology tools that may facilitate withdrawal, and governance structures that can be implemented.

3. Risk/Benefit Analysis: There is a need for a comprehensive risk/benefit analysis of public data sharing. Studies that explore the impact on research of restricted access versus open access would be useful, and should include a consideration of costs and actual risk of harm.

4. Governance Structures: There is a need to systematically evaluate existing and emerging governance structures. This should include a consideration of the ways in which new information technologies can be utilized to facilitate, inter alia: continued communication with participants; the continued right to withdraw; and, when appropriate, community engagement.

Box 2. Personal Genome Research: What Are the Possible Risks?

By Timothy Caulfield, Mildred Cho, and Amy McGuire

The ability to sequence an individual's entire genome will allow for the production of an unprecedented amount of detailed genetic information, helping researchers to explore the relationship of genes and environment in the development of a wide variety of human diseases.

But imagine being a research participant in this exciting new field. Researchers would be seeking to produce a record of all your genetic information. As a result, all known genetic predispositions will be available and, depending on the data sharing policy, accessible to a wide range of researchers and, possibly, the public at large-this, at a time when we are still seeking to understand the social, clinical, and personal implications of genetic information.

These uncertainties can create unique ethical challenges. What do you tell potential participants during the consent process about risks when we still don't have a clear sense of their nature? Also, it is difficult to know, at the time of recruitment, exactly how the genetic information will be used, and by whom.

While most of the risks remain speculative, and we imagine that much of this research will be conducted by highly respected researchers at leading academic centers, one can imagine a number of controversial scenarios. Some of these may seem far-fetched, and we do not intend to be alarmist, but it is important to recognize that just one breach similar to those described below, or even the threat of such a breach, could hurt public trust and significantly hamper the ability to conduct genetic research.

Imagine you are watching the news and learn about a study linking race to IQ, which you find offensive. You later learn that they used your DNA for this study. You donated your DNA five years ago for use in a genetic association study of cancer and heart disease. At the time, you were told that other researchers might want to use your DNA for other types of research. You want to withdraw your consent, but it is too late. Your genetic information has been analyzed by many researchers and is now integrated in databanks throughout the world.

Imagine that you are sitting home, minding your own business, and the police show up at your door with a search warrant. They are looking for the suspect from a crime scene 2,000 miles away in Des Moines, Iowa. It turns out that some DNA that was left at the crime scene matched a sample from a publicly accessible scientific database that contained DNA from one of your brothers.

Imagine that at the time you first donated your sample for genetic research, it was explained as part of the consent process that no information about your genetics would be returned to you. Years later, you develop a heritable form of cancer and learn that the research team must have known you were genetically predisposed to the disease. To complicate matters further, you have a large number of siblings, none of whom want to know about their genetic predispositions. This information is now available to all.

Imagine you just opened your own electronics recycling business and are trying to find private health insurance. Your friend recommends that you contact a specific company. As part of the enrollment process, the company finds out that you participated in a genetic study and that your genetic information has been released into a publicly accessible database. By accessing the database, the company finds out that you are at increased risk of early-onset Alzheimer disease and are highly susceptible to cancer from the chemicals encountered in your recycling process. They also find that you are at greatly increased risk of colon cancer, which alerts you to now take early screening and preventive measures.

This is, no doubt, an exciting time for genetic research. And it cannot move forward without research participants. As such, it is important to note that the risks associated with this kind of research may be limited and controversial events rare. But history has told us that they do occur and can have a devastating impact on public trust and the research environment. It is therefore critical that as this research moves forward, there are guidelines in place, such as those outlined by this paper, to promote ethical research conduct and to help avoid, as much as possible, scenarios like those described above.

Initial Considerations, Governance, and Oversight

Whole-genome research can be utilized in a wide variety of contexts, including as a mode to advance sequencing technology, to develop a research resource platform, and to do disease-specific investigations. Regardless of the purpose of the activity, whole-genome research may implicate issues and ethics norms associated with population health (particularly when used in conjunction with biobanks and cohort studies), the provision of health care, and research. Recognizing that the characterization and resolution of ethical challenges will vary depending on which domain is used as the lens of analysis, we explicitly chose to consider the following issues from the perspective of research ethics. This lens was chosen because most of the current work seems to be research activities and, for the purpose of governance and regulation, should be characterized as such. In addition, given the preliminary nature of the technology, it was felt that it was prudent to frame whole-genome sequencing as a biomedical research enterprise, and more specifically as research involving human subjects.

As with other emerging areas of research (e.g., biobanking initiatives) [ 14, 15], whole-genome sequencing tests traditional clinical trials ethics paradigms, particularly in the areas discussed below. For example, the vast amount of data produced, the uncertain future research uses of the data, the implications of the data for family members, and the technological ability (and expectations) to publicly release the data are realities that challenge existing research ethics norms. While these issues have emerged in other contexts [ 16, 17], they seem particularly acute in the context of whole-genome research. For example, this research will produce an amount of genetic information about an individual well beyond what is currently done in most genetic research protocols. Also, given the recent rapid advances and intense interest in whole-genome research, it seems worthwhile to consider how existing research ethics norms apply.

This area of research invites a move beyond reliance on the usual informed consent strategies [ 18], to the utilization of robust governance and oversight mechanisms [ 19]. Ideally, the governance scheme should have a mandate to ensure research integrity and the protection of the interests of all stakeholders, including the public, participants, family members, communities, and the research community at large. Governance structures should reflect the nature and scope of the particular whole-genome research protocol ( Figure 1). A project involving a single research participant would have a more modest governance framework than an initiative engaging a large number of individuals or a particular population or community. Also, in designing governance structures, investigators should draw on existing ethics resources (e.g., local committees and experts). Attention has to be paid to concerns that research ethics review structures may not always be sufficiently independent and that improvements to the system are needed to promote their accountability [ 20]. Regardless, as will be discussed, appropriate governance schemes seem essential to the ethical conduct of whole-genome investigations-in part because the unique challenges associated with the research make it impractical to satisfy the norms, tools, and processes usually utilized to respect autonomy (e.g., specific informed consent). Also, the ethical issues often move beyond autonomy challenges alone [ 21].

The following governance structure is similar to other policies [ 22]. It is only an example and should be modified to meet the needs and scope of each research initiative. The mandate and scope of the entity's responsibilities, obligations, and powers should be clear and should be reconciled with roles and requirements of existing ethics review committees. The membership of the entity, their criteria and process for making decisions, and the review and appeal system should be publicly available in order to ensure transparency and accountability.

Consent

Whole-genome research involves the collection of a biological sample, the sequencing of the genome, various levels of data analysis, and, possibly, the use of the sample and/or data for a wide variety of future research projects that are likely unknown at the time that the sample is taken. In addition, the data may be released into scientific databases that are publicly accessible in order to facilitate research (to be discussed below). These activities create tremendous consent challenges.

First, the implications and potential social risks associated with the sequencing of an entire genome remain unknown. While most of the data will have limited immediate clinical significance, the massive volume of the data triggers challenges to protecting privacy and respecting autonomy. In addition, as will be discussed below, whole-genome research creates complex ethics challenges associated with the repercussions of data release and return of results, all of which must be covered in the initial informed consent process. The involvement of commercial entities and the potential commercialization of research results complicate the process even more. Given the uncertainty and complexity of the activity, ensuring fully informed consent will be difficult.

Second, the fact that there will likely be many unspecified future uses for the data raises the question of whether reconsent is required. Given that numerous investigators may be using the data over an extended period, reconsenting all individuals who participate in whole-genome research for all uses of the data seems impractical-a challenge that has been encountered in other areas of research, such as biobanking [ 13, 22].

Finally, when individuals provide consent for whole-genome scanning of their own biological material, this also has implications for family members and community members with whom they share some genetic information. Traditional individually based informed consent procedures do not deal well with this aspect of genetic research.

Informed consent is a foundational principle in research ethics [ 23, 24]. It is meant to respect individual autonomy. While it is recognized that consent remains essential, in the context of whole-genome research it is not likely that it can be fully satisfied nor do all the work. As such, the consent process must be supplemented with a governance structure that can respond to the particular ethics issues associated with whole-genome research.

Recommendation 1.

Prior to participation in a whole-genome project, participants should be asked to provide consent for future use that includes as much detail as possible, including information about the sampling and sequencing process, associated commercialization activities, possible risks, and the nature of likely future research initiatives. The consent process should also include information about data security and the governance structure and, in particular, the mechanism for considering future research protocols ( Figure 1). When deemed appropriate by the governance scheme, reconsent for specific research projects may be required (e.g., when the proposal deviates significantly from what was stated in the initial consent).

Withdrawal from Research

The right of research participants to withdraw consent at any time, for any reason and without repercussions is a central component of existing research ethics statements [ 23-25]. In general, this right extends to research on identifiable health information and tissue samples [ 26]. In the context of whole-genome research, this right endures and must be respected. Indeed, any minimization of the right to withdraw could pose a threat to public trust. However, because whole-genome research results in the production of data that, when used for research, are likely to be disseminated rapidly and widely (depending on the relevant data release policy), there will inevitably be profound practical limitations to the right to withdraw. Indeed, once whole-genome research data are released, it will be very difficult, if not impossible, to retrieve or destroy the data in response to a withdrawal request.

So, while research participants retain the right to withdraw their consent whenever possible (e.g., they could request the destruction of the relevant tissue sample or the severance of ongoing linkages to personal information), it will often be impossible to destroy data that have already been released. As part of the ethics review process, there should be a careful consideration of how far along the research process withdrawal can (and should) be possible. This should also be done in order to inform the consent process and to ascertain the proper balance between research goals and the right to withdraw.

Return of Results

Even if the purpose of some whole-genome research is not to provide results about individual participants, the work may generate such results, ranging on a continuum from clinically significant information to information relevant to ancestry and genealogy to information that is merely of recreational interest.

On this continuum, there may be situations in which the research generates genetic information that the researcher has a moral (but not necessarily legal) obligation to offer to individual participants [ 27, 28]. Such research may also generate results that could be detrimental or that a research participant has specifically asked not to be returned. Due to the unknown clinical value of much of the genomic data, the amount of information that a researcher might have a duty to disclose will likely be small at the current time. However, it is expected to grow with increased knowledge about the clinical significance of the genome. In addition, some associations will be found by other research teams, warranting review and tough decisions about whether to invest time in confirming results for one's own study population and informing subjects about those secondary findings [ 29].

The duty to offer results is, in part, related to the relationship between researchers and participants. It may also be based on expectations founded on institutional or cultural assumptions. Because results may be generated by researchers who did not collect the samples and who may not know the identity of the research participants, there are interesting questions about who may have a duty to offer results. Do researchers who provide samples or data to other researchers for secondary analyses retain responsibility to support return of appropriate results?

Recommendation 4.

Personal genome research projects should have an established process, approved by a research ethics review entity, for evaluating whether findings (incidental or otherwise) meet criteria for offering to individual participants ( Figure 1). This process should be highlighted in the initial consent and should acknowledge the participants' right not to know certain results.

Public Data Release

International policies call for the rapid public release of all sequence data [ 30-32]. The benefit of public data access is that it provides significant scientific utility by enabling immediate international research use of the data. However, policies that advocate unrestricted data sharing have been challenged because of the privacy risks associated with public access to genomic information [ 33, 34]. Whole-genome research increases these privacy concerns, particularly the uncertainties surrounding the implications of the data. As a result, a cautious approach seems warranted. Investigators and research ethics boards need to carefully consider whether public data release is warranted.

As noted above, once data are released into a publicly accessible database, it becomes impossible to withdraw the data from the public domain. The finality of public data sharing needs to be clearly articulated in the informed consent process. A balanced approach should be adopted when explaining the risks and benefits of data sharing. In the consent and review process, neither the benefits of research nor the potential privacy risks should be minimized or exaggerated. In this regard, several potential privacy issues should be discussed: the data security mechanisms put in place; the primary concern of identifiability; the practical limits on an individual's right to control access to their personal information; and the secondary concern about genetic profiling and an individual's right to control their "ascribed social identity" [ 35]. Given the complexity of these privacy challenges, it is essential that the relevant ethics review entity have appropriate ethics expertise.

More research and policy analysis on the issues associated with data release is clearly needed, including an analysis of the actual harms and benefits resulting from publicly accessible data; the implications for family members and relevant communities; the appropriate balance between public access and individual privacy interests; and considerations regarding compensation for research-related injury resulting from participation in personal genome research. While the likelihood of injury is small, compensating individuals for harm or loss associated with research participation would promote reciprocity for participation in research with no direct benefit to the individual.

It may be more appropriate to release genome data into databases with restricted access. Restricted access databases typically require some authentication so that only bona fide researchers can access the information. Most restricted access databases provide some phenotypic information linked to the genotypic data, increasing the scientific utility of the data. Restricted access provides enhanced privacy protection, but the level of restriction and stringency of oversight vary significantly depending on the database (e.g., the degree to which the database contains sensitive or identifying information). Regardless, appropriate security, oversight, and access policies are essential for the protection of human subjects.

Acknowledgments

We would like to thank the Institute of Genetics (Canadian Institutes of Health Research), the Archon X Prize, and the Ontario Genomics Institute for funding and administrative support, and Alethea Adair and Genome Alberta for additional editing and research assistance. We would also like to thank Adam L. Felsenfeld, National Human Genome Research Institute, National Institutes of Health, for his helpful insight. Competing interests. Marc A. Hodosh and Michael Timmons are employed by the X Prize Foundation. Eric Meslin is consultant to Eli Lilly and Company.

References

1. 18. Kahn JP, Mastroianni AM, Sugarman J, editors. (1998) Beyond consent: Seeking justice in research. New York: Oxford University Press. editors.

2. 20. Lemmens T, Waring D, editors. (2006) Law and ethics in biomedical research: Regulation, conflict of interest, and liability. Toronto: University of Toronto Press. editors.

3. 26. Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, Social Sciences and Humanities Research Council of Canada (1998) Tri-Council policy statement: Ethical conduct for research involving humans. Ottawa: Public Works and Government Services Canada.

# data[].attributes.attachment_link.title
Research Ethics Recommendations for Whole-Genome Research: Consensus Statement

# data[].attributes.attachment_link.description
Timothy Caulfield , Amy L McGuire, Mildred Cho, Janet A Buchanan, Michael M Burgess, Ursula Danilczyk, Christina M Diaz, Kelly Fryer-Edwards, Shane K Green, Marc A Hodosh, Eric T Juengst, Jane Kaye, Laurence Kedes, Bartha Maria Knoppers, Trudo Lemmens, Eric M Meslin, Juli Murphy, Robert L Nussbaum, Margaret Otlowski, Daryl Pullman, Peter N Ray, Jeremy Sugarman, [ ...

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Two articles from The Guardian that highlight opposing views on embryo editing

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Two articles from The Guardian that highlight opposing views on embryo editing

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"Genetically modified babies given go ahead by UK ethics body"

https://www.theguardian.com/science/2018/jul/17/genetically-modified-babies-given-go-ahead-by-uk-ethics-body
AND
"Genetically modifying future children isn’t just wrong. It would harm all of us"

https://www.theguardian.com/commentisfree/2018/jul/17/genetically-modifying-future-children-embryos-nuffield-council-bioethics

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Briefing Note: Whole genome sequencing of babies

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Briefing Note: Whole genome sequencing of babies

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PDF from the Nuffield Council of Bioethics

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Educational Materials — Genetic Testing: Current Approaches

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Educational Materials — Genetic Testing: Current Approaches

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A comparison of using gene panels and genome sequencing. Designed for doctors but with helpful introductory information and pros/cons.

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What Types of Genetic Alterations Cannot Be Reliably Identified by Exome Sequencing?

Exome sequencing requires sequence enrichment to target exons and sequence each exon. Genetic alterations that cannot reliably be detected by exome sequencing include alterations that:

Disrupt probe binding during the enrichment process; thus, the exon is not sequenced and not included in the analysis;

Are present in a highly repetitive region of DNA that is difficult to sequence (e.g., nucleotide repeat expansions and contractions);

Are present in a deep intronic (noncoding) region;

Are present in mitochondrial DNA, not nuclear DNA;

Are somatic mosaic changes (i.e., the genetic change is present in a small percentage of cells and not present in the germline, i.e., all cells); thus, either base calls do not pass quality thresholds or the genetic change was not present in the cells from which the DNA was extracted;

Result from large copy number variants (i.e., insertions or deletions >50 bp). Although copy number variants may be identified on exome sequencing by comparing actual read depth to expected read depth through intra- and inter-sample comparisons, variations in read depth (e.g., due to guanine-cytosine [GC] content of a region) can lead to false positive results.

Result from structural chromosome rearrangements (e.g., inversions, translocations). Note that chromosome rearrangements may be identified by using paired-end and mate-pair mapping to identify malalignment of sequences to a reference genome.

What Types of Disorders Are Not Reliably Identified by Exome Sequencing?

Disorders resulting from genetic alterations that are not reliably identified by exome sequencing because of technical limitations:

Genetic disorders that may not be recognized during analysis of exome sequencing due to unexpected inheritance pattern:

Disorders with incomplete penetrance or variable age of onset (e.g., variant present in an unaffected parent)

Disorders for which associated genes and/or pathogenic variants have not been reported:

Mendelian disorders associated with multiple unidentified genes

Disorders caused by pathogenic variants that are not described as disease-associated in the literature or HGMD ®

Disorders that are not known to be genetic:

Conditions with a non-genetic etiology (e.g., fetal alcohol syndrome)

Conditions for which there is no known genetic etiology

What Variables Affect the Sensitivity of Exome Sequencing?

Laboratory-dependent variables. Read depth (sometimes called exome coverage) and accuracy of base calling

"Read" refers to the nucleotide sequence generated from the laboratory process of sequencing a segment of DNA or RNA. Read depth refers to the number of times each nucleotide is sequenced. Read depth of an exome can vary significantly because some exons are easier to capture with probes and sequence than others. Read depth can refer to a single nucleotide, but is typically reported as the percentage of nucleotides that are sequenced either an average or minimum number of times (e.g., 30x average read depth for 95% of the exome).

Exome coverage refers to the number of times each nucleotide is sequenced or the percentage of the exome sequenced an average or minimum number of times (e.g., 95% of exome at ≥20x coverage).

Accuracy of base calling, the reported nucleotide sequence compared to the actual nucleotide sequence, is measured by the Phred quality score. Phred scores are logarithmically related to nucleotide identification error probability. A Phred score of 10 indicates a one-in-ten chance of an inaccurate nucleotide determination. A Phred score of 20 indicates a one-in-100 chance of an inaccurate nucleotide determination, or a 99% likelihood of correct nucleotide assignment.

Additional laboratory-dependent variables. Sequence enrichment method used to target exons, sequencing technique, and length of sequence generated

Sequence enrichment method used to target exons: fixed array-based probes versus solution-based probes. Fixed array-based probes were the first method used to capture exons; while newer solution-based probes require less sample DNA, they may not capture regions with low GC content as well as array-based probes.

Laboratories select probes that will target well-annotated genes associated with genetic conditions, thereby increasing the read depth of these genes. Laboratories frequently update the number of probes used in an assay to include noncoding regions of the genome (e.g., promoters, highly conserved regulatory sequences). Solution-based methods are more adaptable for updates than array-based methods.

Sequencing technique: paired-end reads (both ends of each DNA fragment are sequenced) versus single-end reads (only one end of a DNA fragment is sequenced). Paired-end reads are better than single-end reads at unambiguously determining alignment of a sequence to the reference exome, particularly in repetitive regions. However, sequencing of paired-end reads requires more laboratory time and is more expensive.

Length of sequence generated: longer reads reduce false positives that result from mapping ambiguity better than shorter reads.

Laboratory-dependent variables introduced by analysis of data. Application of filters and analysis of remaining unfiltered variants

Variant classification guidelines updated by the American College of Medical Genetics and Genomics set forth objective variant classification methods [ Richards et al 2015]. Nonetheless, to determine the pathogenicity of every variant identified, molecular and/or clinical geneticists in each laboratory develop their own approach to variant classification, often using the following:

Because the expertise of the molecular geneticist(s) and the data available vary, variant classification, and therefore clinical sensitivity, are laboratory dependent to some degree.

Laboratory-independent variables. Source of the DNA; GC (guanine-cytosine) content of the region

The source of DNA (e.g., blood, skin, saliva) affects the quantity and quality of DNA. For example, saliva samples have a lower quantity of DNA and higher contamination rates (e.g., bacterial DNA) than blood and skin samples. Lower DNA quantity will decrease achievable read depth. Higher contamination rates will decrease the accuracy of base calling.

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Educational Materials - Genetic Testing: Current Approaches

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Note: This information, provided by the editors of GeneReviews, is intended both for individuals who have limited experience with comprehensive genetic testing (see Introductory Information) and for clinicians who routinely order comprehensive genetic testing (see Detailed Information). - The Editors

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Fact sheet from the Centre for genomics education (click 'open in new window)

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Article from Nature News asks people with genetic diseases what they think about embryo editing.

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Preston Gannaway

Ruthie Weiss's basketball team seemed to be minutes away from its fourth straight loss. But even as she stood on the sidelines for a brief rest, the nine-year-old had not given up. She convinced the coach to put her back in the game. Then, she charged out onto the court, caught a pass from a teammate and drove straight to the basket. Swish! Ruthie scored a quick two points, putting her team in the lead. As the game clock wound down, she scored again, clinching the victory. The team had earned its first win of the season, and celebrated as if it had just taken the national championship. A couple of parents from the opposing team even stopped by to congratulate Ruthie, who had scored all of her team's 13 points: "Wow, she's unbelievable!" they told her mum and dad.

What makes Ruthie's performance even more extraordinary is her DNA. Because of a misspelling in one of her genes, she has albinism: her body produces very little of the pigment melanin, which means that her skin and hair are fair, and that she is legally blind. Her visual acuity is ten times worse than average. She is still learning to read and will probably never be able to drive a car, but she can make out the basket and her teammates well enough to shoot, pass and play.

In January, Ruthie's dad Ethan asked her whether she wished that her parents had corrected the gene responsible for her blindness before she was born. Ruthie didn't hesitate before answering - no. Would she ever consider editing the genes of her own future children to help them to see? Again, Ruthie didn't blink - no.

The answer made Ethan Weiss, a physician-scientist at the University of California, San Francisco, think. Weiss is well aware of the rapid developments in gene-editing technologies - techniques that could, theoretically, prevent children from being born with deadly disorders or with disabilities such as Ruthie's. And he believes that if he had had the option to edit blindness out of Ruthie's genes before she was born, he and his wife would have jumped at the chance. But now he thinks that would have been a mistake: doing so might have erased some of the things that make Ruthie special - her determination, for instance. Last season, when Ruthie had been the worst player on her basketball team, she had decided on her own to improve, and unbeknownst to her parents had been practising at every opportunity. Changing her disability, he suspects, "would have made us and her different in a way that we would have regretted", he says. "That's scary."

Ethan and Ruthie are not the only people pondering these kinds of questions. The emergence of a powerful gene-editing technology, known as CRISPR-Cas9, has elicited furious debate about whether and how it might be used to modify the genomes of human embryos. The changes to their genomes would almost certainly be passed down to subsequent generations, breaching an ethical line that has typically been considered uncrossable.

But emerging technologies are already testing the margins of what people deem acceptable. Parents today have unprecedented control over what they pass on to their children: they can use prenatal genetic screening to check for conditions such as Down's syndrome, and choose whether or not to carry a fetus to term. Preimplantation genetic diagnosis allows couples undergoing in vitro fertilization to select embryos that do not have certain disease-causing mutations. Even altering the heritable genome - as might be done if CRISPR were used to edit embryos - is acceptable to some. Mitochondrial replacement therapy, which replaces a very small number of genes that a mother passes on with those from a donor, was approved last year in the United Kingdom for people who are at risk of certain genetic disorders.

Many safety, technical and legal barriers still stand in the way of editing DNA in human embryos. But some scientists and ethicists say that it is important to think through the implications of embryo editing now - before these practical hurdles are overcome. What sort of world would these procedures create for those currently living with disease and for future generations?

So far, little has been heard from the people who could be first affected by the technology - but speaking with these communities reveals a diverse set of views. Some are impatient, and say that there is a duty to use genome editing quickly to eliminate serious, potentially fatal conditions. Some doubt that society will embrace it to the degree that many have feared, or hoped. Above all, people such as Ethan Weiss caution that if policymakers do not consult people with disabilities and their families, the technology could be used unthinkingly, in ways that harm patients and society, today and in the future.

"Hearing the voices of people who live with these conditions is really important," says Tom Shakespeare, a medical sociologist at the University of East Anglia in Norwich, UK.

The cases for

John Sabine, now 60, was once described as one of the brightest legal minds of his generation in England. Now, he is in the advanced stages of Huntington's disease: he cannot walk or talk, is incontinent and requires constant care. Charles Sabine, his younger brother, carries the same genetic glitch that causes Huntington's disease, and therefore knows that, like his brother and his father before him, he is destined to undergo the same deterioration of brain and body.

Charles and his brother have five children between them, each of whom as a 50% chance of having inherited the mutation that causes Huntington's disease. To Charles - and to many others who live with the mutation that causes Huntington's - there is no legitimate ethical argument about whether gene editing should be used, either to treat people living with the condition now or to spare their children from it.

"Anyone who has to actually face the reality of one of these diseases is not going to have a remote compunction about thinking that there is any moral issue at all," Sabine says. "If there was a room somewhere where someone said, 'Look, you can go in there and have your DNA changed,' I would be there breaking the door down."

Matt Wilsey, a technology entrepreneur in San Francisco, would be there too. His daughter Grace was one of the first people in the world to be diagnosed with a disease caused by a mutation in the gene NGLY1, which makes it difficult for her cells to get rid of misshapen proteins. Grace, now six years old, has severe movement and developmental disabilities. She can barely walk and cannot talk. Because her condition is new to medicine, doctors cannot even predict how long she might live.

Wilsey is bullish on CRISPR. He says that if he had had the chance to detect and fix the mutation in Grace's genome before she was born, he would have. But he is frustrated that the debate over editing embryos seems to have monopolized discussions about the technology. He is hopeful that a gene-therapy-like approach using CRISPR, which would be free of the ethical concerns about altering the genes she passes on, could help Grace within several years. And he wonders whether a temporary moratorium on embryo editing might allow the field to focus on such approaches sooner.

"As a parent with an incredibly sick child, what are we supposed to do - sit by on the sidelines while my child dies? There's zero chance of that," Wilsey says. "CRISPR is a bullet train that has left the station - there's no stopping it, so how can we harness it for good?"

A meeting convened in December 2015 by the US national academies of sciences and medicine, the Chinese Academy of Sciences and the Royal Society of London recommended such a moratorium in light of multiple safety and ethical concerns. Still, many bioethicists and scientists have argued that if defects in single genes causing fatal and debilitating conditions could be corrected in an embryo, then they should be. Shakespeare notes that embryo editing for conditions that cause major disability and death are likely to raise less concern and criticism in the long term. But, he says: "As soon as you get away from the archetypal terrible condition, then you've got a debate about whether a condition makes life unbearably hard."

Social consequences

Many people are concerned about where that line would be drawn. Although it may seem now that only a few, very severe conditions should be subject to gene editing, disability activists point out that the list of conditions considered as illnesses, and possibly subject to medical treatment, is expanding. "More and more, people think of obesity or predisposition to alcoholism as disease," says Carol Padden, a linguist at the University of California, San Diego. She herself is deaf, and points out that many deaf people do not consider it a disability. This stance has led to controversy when, for instance, deaf parents decline technologies such as cochlear implants for their children, or even go so far as to select, through processes such as preimplantation genetic diagnosis, children who will be deaf.

Like Padden, some disability-studies researchers do not oppose the idea of gene editing, but do think that society needs to understand that it is not possible to eliminate all disability, and that humans might lose something important if they try to do so.

"These kinds of interactions significantly change our attitudes about what kinds of people matter in the world."

Padden points out that accommodations originally intended for people with disabilities often end up benefiting everyone. For example, the development of closed captioning - subtitles for the hearing-impaired on television - required major advocacy from the deaf community and legislative action to get off the ground in the United States in the 1970s. Today, people rely on it in ways that no one could have foreseen, such as in noisy airports and sports bars. Some people use it to learn to read or to learn a language.

Rosemarie Garland-Thomson, a literature scholar and co-director of the Disability Studies Initiative at Emory University in Atlanta, Georgia, adds that legislative mandates, such as the 1990 Americans with Disabilities Act in the United States, have helped to integrate people with disabilities into society - in workplaces, schools and other public spaces. As a result, the world is much more humane for everyone, says Garland-Thomson. "These kinds of interactions significantly change our attitudes about what kinds of people matter in the world."

The idea that parents should edit out characteristics that are considered debilitating goes against this drive towards inclusion, Garland-Thomson warns, and could create a harsher social climate for everyone. The experience of disability, she adds, is universal; all people inevitably experience sickness, accidents and age-related decline. "At our peril, we are right now trying to decide what ways of being in the world ought to be eliminated," she says.

Padden says that ethicists, patients and disabilities-studies researchers must work urgently to make a broad societal case in favour of greater acceptance of diversity. This has been a long-fought battle, and many see evidence of progress - for instance, in the 'neurodiversity' movement, which champions the idea that medical conditions such as autism are part of the spectrum of human variation. "We do have to start coming up with more arguments for diversity, and quickly, because CRISPR is coming upon us faster than some of us are thinking about this issue," she says.

Making choices

The prospect of editing the genome of a human embryo is still in its early stages, but the ability to prevent the inheritance of some conditions already exists. Prenatal screening, which has advanced to the point that doctors can sample a developing fetus's DNA through its mother's blood, has given parents the option to terminate pregnancies when a disease or disability is diagnosed. This has already started to show limited effects on the population.

In Europe, for example, the prevalence of a Down's syndrome diagnosis during pregnancy has risen from 20 cases per 10,000 in 1990 to 23 cases per 10,000 today, as the average age of women having babies has increased. But the number of children born with the syndrome has stayed level at about 11 per 10,000, because many women whose fetuses are diagnosed with the condition terminate their pregnancies. In the United States, pregnancies in which a Down's syndrome diagnosis is made are terminated in 67-85% of cases.

By surveying women whose fetuses and babies are diagnosed with Down's syndrome, and by compiling similar surveys from around the world, medical geneticist Brian Skotko of the Massachusetts General Hospital in Boston has found that doctors sometimes advise women to terminate or give up for adoption babies diagnosed prenatally with Down's syndrome. They can influence the decision by using phrases such as "I'm sorry", or "I have some bad news to share". For instance, 34% of 71 Dutch women who terminated their pregnancy after a Down's syndrome diagnosis said that their doctors did not even mention the possibility of carrying the pregnancy to term when discussing their options.

Mark Leach, a lawyer in Louisville, Kentucky, whose 11-year-old daughter has Down's syndrome, says that he and his wife have been asked many times - especially when his wife was pregnant with their second child - whether they "knew beforehand" that Juliet would be born with Down's. (They didn't.) Some people are simply curious, Leach says, but for others, there's judgement in that question. "The ability to do something beforehand imposes a sense of, 'You should do not only what's right for you, but what's right for society'," Leach says. It bothers him, he says, that although government and private health insurers routinely pay for prenatal diagnosis, he recently learned that his school system is discontinuing support for the learning specialist who had been helping Juliet to thrive in mathematics and reading.

Dorothy Roberts, a professor of law and sociology at the University of Pennsylvania in Philadelphia, says that this kind of pressure is troubling and that it could get worse if embryo editing were to become readily available. "Women should not be given the responsibility of ensuring the genetic fitness of their children based on lack of support for children with disabilities."

Leach knows that children with disabilities can live rich lives. Juliet likes ballet dancing and horse-riding, and she is especially attuned to the names of people and animals whom she knows. And Leach says that she helps to remind other people how to care for others. "The main thing that would be lost if Down's syndrome continues to diminish is a diminishment in the amount of compassion that is shown in this world," he says.

Even among people who already have life-threatening conditions, many choose not to interfere with the way the genetic cards are dealt. Edward Wild, a neurologist who cares for people with Huntington's disease at University College London, estimates that fewer than 5% of patients in the United Kingdom use preimplantation genetic screening to select embryos that lack the disease-causing mutation and so avoid passing it to their children. Some people do not know that they have the mutation; some decide against screening because of the costs or risks involved; some have personal or moral objections to the technique; and some just have a sense that 50-50 odds of passing down the disease are not so bad.

"Having kids the fun way is still much more popular than having kids the science way, even though the latter is how you guarantee the kid is free of Huntington's disease," Wild says.

"Prediction: my grandchildren will be embryo-screened, germline-edited. Won't 'change what it means to be human'. It'll be like vaccination."

Even if gene editing were safe, effective and everyone opted to use it, it would not eliminate genetic diseases, because researchers still have a long way to go to understand the genes involved. Even Huntington's, which is fairly well characterized, is no easy target. The glitch that causes it is a repeat of a particular genetic sequence; the more repeats, the more severe the symptoms, and repeats are added with each successive generation. New families are diagnosed with Huntington's all the time, either because the disease is misdiagnosed in older generations or because symptoms worsen, and become recognizable, in subsequent generations. Although he is working on genetic techniques to treat Huntingon's, Wild doesn't hold out high hopes for a future free of the disease. "Although it's nice to think about, it's little more than a dream," he says.

Human biology can complicate things in other ways. Padden notes, for instance, that some mutations that predispose to genetic disease, such as the sickle-cell mutation, confer population-level benefits, such as resistance to malaria. So editing out one disease could backfire by increasing the risk of another. She argues that very little is known about the potential benefits of other mutations associated with disease, and applying genome editing too freely could have unintended consequences.

And if it were adopted, the technology would almost certainly be applied unevenly around the world. Aleksa Owen, a sociologist at the University of Illinois at Chicago, predicts that genome editing would be used first in countries that approve of and support assisted reproductive technologies, such as the United Kingdom, some other European Union countries, China and Israel. But it would probably be too expensive for many people in developing countries.

Uneven access

Still, some scientists predict that editing human embryos could have transformative effects. During the National Academies' summit on gene editing in December, Harvard University geneticist Dan MacArthur tweeted, "Prediction: my grandchildren will be embryo-screened, germline-edited. Won't 'change what it means to be human'. It'll be like vaccination."

Sandy Sufian, a historian of medicine and disability at the University of Illinois, agrees with MacArthur that CRISPR has the potential to become widely adopted, both because of the perception that it would save money that would otherwise be spent caring for disabled people and because of people's fear of disability. But she questions the idea that eliminating such conditions will necessarily improve human life. Sufian has cystic fibrosis, a disease caused by mutations that render her lung cells more vulnerable to infection and disease. She spends 40 hours a week inhaling medicine to clear her lungs of mucus, exercising and undergoing physical therapy; others have to quit their jobs to make sufficient time for treatments. Yet given the option to edit cystic fibrosis out of her bloodline, Sufian wouldn't do it. "There are some great things that come from having a genetic illness," she says.

Garland-Thomson echoes that sentiment; she has one and a half arms and six fingers because of a condition called limb-reduction disorder. She says that she values traits in herself that she may have developed as adaptations to the condition: she is very sociable and wonders if that is because she's had to learn to work hard to make others feel comfortable around her. "Any kinds of restrictions or limitations have created the opportunity for me to develop work-arounds," Garland-Thomson says.

Shakespeare, who has achondroplasia, a genetic condition that causes shorter than average stature, says that people with disabilities are just as able to attain life satisfaction as others. "I have achieved everything I hoped for in life, despite having restricted growth: career, children, friendship and love." He wouldn't want to have altered his own genes to be taller, he says.

Disability rights

People without disabilities consistently underestimate the life satisfaction of those with them. Although people with disabilities report a slightly lower overall quality of life than those without, the difference is small. One study found that half of people with serious disabilities ranked their quality of life as 'good' or 'excellent'.

People also overestimate how severely health affects their happiness compared with other factors, such as economic or social support. One 1978 study, for instance, compared people who had recently become paralysed as a result of accidents with people who had recently won between US$50,000 and $1 million in a state lottery. Although people who had had accidents ranked their happiness lower than lottery winners, both groups predicted that their future happiness would be roughly equal, and people who had accidents derived more pleasure from everyday activities, such as eating breakfast or talking to a friend.

"A lot of this terrific science and technology has to take into account that the assumption of what life is like for people who are different is based on prejudice against disability," says Lennard Davis, a disability-studies researcher at the University of Illinois, who was raised by two deaf parents.

There is a common saying among people in the disability-rights community: "Nothing about us without us." People with disabilities argue that scientists, policymakers and bioethicists should take steps to ensure that the CRISPR debate reflects what is best for patients and their families, to ensure its most humane use now and for future generations.

At a minimum, they say, the investment in developing CRISPR should be matched by investments in innovations to help people who are already living with conditions that cause disability. And it is essential that people with the conditions that are up for consideration as possible CRISPR targets should be included in the decision-making processes.

For their part, Ruthie Weiss and her dad have already made up their minds. Ruthie must work harder than her classmates to do some routine activities. But when she is dominating the basketball court, or practising the piano, or skiing down a mountain, Ethan Weiss doesn't see a child with a disability. He sees his daughter making the most of her life, given all her strengths and challenges. And he knows that he wouldn't change a thing.

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Preston Gannaway Ruthie Weiss's basketball team seemed to be minutes away from its fourth straight loss. But even as she stood on the sidelines for a brief rest, the nine-year-old had not given up. She convinced the coach to put her back in the game.

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Meta-analysis of the diagnostic and clinical utility of genome and exome sequencing and chromosomal microarray in children with suspected genetic diseases

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Meta-analysis of the diagnostic and clinical utility of genome and exome sequencing and chromosomal microarray in children with suspected genetic diseases

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This academic paper reviews many studies to evaluate the effectiveness of genomic sequencing for diagnosis in children (advanced)

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Abstract

Genetic diseases are leading causes of childhood mortality. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) are relatively new methods for diagnosing genetic diseases, whereas chromosomal microarray (CMA) is well established. Here we compared the diagnostic utility (rate of causative, pathogenic, or likely pathogenic genotypes in known disease genes) and clinical utility (proportion in whom medical or surgical management was changed by diagnosis) of WGS, WES, and CMA in children with suspected genetic diseases by systematic review of the literature (January 2011-August 2017) and meta-analysis, following MOOSE/PRISMA guidelines. In 37 studies, comprising 20,068 children, diagnostic utility of WGS (0.41, 95% CI 0.34-0.48, I ² = 44%) and WES (0.36, 95% CI 0.33-0.40, I ² = 83%) were qualitatively greater than CMA (0.10, 95% CI 0.08-0.12, I ² = 81%). Among studies published in 2017, the diagnostic utility of WGS was significantly greater than CMA ( P < 0.0001, I ² = 13% and I ² = 40%, respectively). Among studies featuring within-cohort comparisons, the diagnostic utility of WES was significantly greater than CMA ( P < 0.001, I ² = 36%). The diagnostic utility of WGS and WES were not significantly different. In studies featuring within-cohort comparisons of WGS/WES, the likelihood of diagnosis was significantly greater for trios than singletons (odds ratio 2.04, 95% CI 1.62-2.56, I ² = 12%; P < 0.0001). Diagnostic utility of WGS/WES with hospital-based interpretation (0.42, 95% CI 0.38-0.45, I ² = 48%) was qualitatively higher than that of reference laboratories (0.29, 95% CI 0.27-0.31, I ² = 49%); this difference was significant among studies published in 2017 ( P < .0001, I ² = 22% and I ² = 26%, respectively). The clinical utility of WGS (0.27, 95% CI 0.17-0.40, I ² = 54%) and WES (0.17, 95% CI 0.12-0.24, I ² = 76%) were higher than CMA (0.06, 95% CI 0.05-0.07, I ² = 42%); this difference was significant for WGS vs CMA ( P  < 0.0001). In conclusion, in children with suspected genetic diseases, the diagnostic and clinical utility of WGS/WES were greater than CMA. Subgroups with higher WGS/WES diagnostic utility were trios and those receiving hospital-based interpretation. WGS/WES should be considered a first-line genomic test for children with suspected genetic diseases.

Introduction

Genetic diseases (single-gene disorders, genomic structural defects, and copy number variants) are a leading cause of death in children less than ten years of age.1,2,3,4,5,6,7,8 Establishing an etiologic diagnosis in children with suspected genetic diseases is important for timely implementation of precision medicine and optimal outcomes, particularly to guide weighty clinical decisions such as surgeries, extracorporeal membrane oxygenation, therapeutic selection, and palliative care.9 With the exception of a few genetic diseases with pathognomonic findings at birth, such as chromosomal aneuploidies, etiologic diagnosis requires identification of the causative molecular basis. In practice, this is remarkably difficult for several reasons: firstly, genetic heterogeneity-there are over 5200 genetic disorders for which the molecular basis has been established.10 Secondly, clinical heterogeneity-genetic disease presentations in infants are frequently formes frustes of classic descriptions in older children (see, for example Inoue et al.11). Thirdly, comorbidity is frequent in infants with genetic diseases-including prematurity, birth trauma, and sepsis-obfuscating clinical presentations.2 Fourthly, approximately four percent of children have more than one genetic diagnosis.12 Finally, disease progression is faster in children, switching the diagnostic odyssey to a race against time.9,13,14

Traditionally, establishment of molecular diagnoses was by serial testing guided by the differential diagnosis. CMA is the recommended first-line genomic test for children with several types of genetic diseases.15,16 Serial testing employs many other tests-including newborn screening panels, metabolic testing, cytogenetics, chromosomal fluorescence in situ hybridization, single-gene sequencing, and sequencing of panels of genes associated with specific disease types (such as sensorineural deafness, cardiac dysrhythmias, or epilepsy).15 Iterative inquiry of differential diagnoses, however, frequently incurs a diagnostic odyssey and rarely allows etiologic diagnosis in time to influence acute management. Thus, inpatient management of children with suspected genetic diseases largely remains empiric, based on clinical diagnoses.9

Over the past five years, WGS and WES have started to gain broad use for etiologic diagnosis of infants and children with suspected genetic diseases. By allowing concomitant examination of all or most genes in the differential diagnosis, WGS and WES have the potential to permit comprehensive and timely ascertainment of genetic diseases. Timely molecular diagnosis, in turn, has the potential to institute a new era of precision medicine for genetic diseases in children. During this period, WGS and WES methods have improved substantially. While numerous studies have been published, there are not yet guidelines for their use by clinicians. Here we report a literature review and meta-analysis of the diagnostic and clinical utility of WGS and WES, compared with CMA, in children (age 0-18 years) with any suspected genetic disease.

Results

WGS and WES are relatively new methods for diagnosis of childhood genetic diseases. We compared the diagnostic utility of WGS and WES with that of CMA, the recommended first-line genomic test for genetic diseases in children with intellectual disability, developmental delay, autism spectrum disorder, and multiple congenital anomalies.15,16 A total of 2093 records were identified by searches for studies of the diagnostic utility of WGS, WES, and CMA in affected children with a broad range of suspected genetic diseases (Figure S1). Thirty seven of these, featuring 20,068 children, met eligibility criteria and were included in qualitative analyses (Tables 1 and 2). Thirty-six were case studies; one was a randomized controlled trial.26 In these, the pooled diagnostic utility of WGS was 0.41 (95% CI 0.34-0.48, seven studies, 374 children, I ² = 44%), which was qualitatively greater than WES (0.36, 95% CI 0.33-0.40, 26 studies, n = 9014, I ² = 83%) or CMA (0.10, 95% CI 0.08-0.12, 13 studies, n = 11,429, I ² = 81%, Fig. 1a). Severe heterogeneity ( I ²  > 75%) within the WES and CMA groups precluded statistical comparisons.

Table 1 Characteristics of studies reporting diagnostic or clinical utility of WES or WGS

Table 2 Characteristics of studies reporting diagnostic or clinical utility of chromosomal microarray

Fig. 1

Comparison of diagnostic (Dx) utility of WGS, WES and CMA. a The pooled diagnostic utility of WGS and WES were both greater than of CMA. However, severe heterogeneity precluded quantitative analysis. b The subset of studies published in 2017 showed reduced heterogeneity for all subgroups. The pooled diagnostic utility with WGS was significantly higher than with CMA ( P < 0.0001). c Among manuscripts that provided complete data for the frequency of diagnoses made by WES and CMA, the pooled odds of diagnosis was 8.3 times greater for WGS ( P  < 0.0001)

Analysis of heterogeneity of diagnostic utility in studies of WGS, WES, and CMA

We used meta-regression to model heterogeneity in the diagnostic utility of WGS, WES, and CMA. Studies of WES and WGS varied in size from 22 to 1745 probands; Meta-regression showed a modest relationship between study size and diagnostic utility: on average, an increase of 1000 subjects decreased the odds of diagnosis by 28% (Fig. 2a, P = 0.01). Studies were published between 2013 and 2017; meta-regression showed that the odds of diagnosis by WES or WGS increased by 16% each year (Fig. 2c, P = 0.01) while the odds of diagnosis by CMA decreased by 14% (Fig. 2c, P < 0.001). The rate of consanguinity varied between 0% and 100%. It was not significantly associated with the odds of diagnosis ( P > 0.05). The proportion of diagnoses in which causal variants occurred de novo (rather than inherited) ranged from 0.18-0.70; meta-regression showed that a 10% increase in the rate of consanguinity in studies of WES and WGS decreased the odds of de novo variant diagnoses by 21% ( P < 0.001; Fig. 2d). Heterogeneity of diagnostic utility in disease type and proband age subgroups precluded quantitative analysis (Figure S2).

Fig. 2

Exploration of heterogeneity of diagnostic utility in WGS and WES studies. a Meta-regression scatterplot for study size. On average, an increase of 1000 subjects decreased the odds of diagnosis by 28% ( P = 0.01). Size of data point corresponds to the study's inverse-variance weight. b Meta-regression scatterplot for diagnostic utility of WGS/WES vs year of study publication. On average, the odds of diagnosis increased by 16% per annum since 2013 ( P = 0.01). c Meta-regression scatterplot for the diagnostic utility of CMA vs year of study publication. The odds of diagnosis decreased by an average of 14% per year between 2013 and 2017 ( P < 0.001). d The rate of diagnosis associated with de novo variation varied inversely with consanguinity. On average, increasing the rate of consanguinity by 10% decreased the odds of de novo variant diagnoses by 21% ( P  < 0.001)

Subgroup comparisons of diagnostic utility of WGS, WES, and CMA

Heterogeneity within WGS and CMA groups was mild following removal of variance associated with year of publication. In eleven studies of 1962 children published in 2017, the pooled diagnostic utility of WGS (0.42, 95% CI 0.34-0.51, I ² = 13%) was significantly greater than CMA (0.05, 95% CI 0.03-0.09, I ² = 40%; P < 0.0001, Fig. 1b).23,25,26,33,35,36,38,40,41,42,44

Only two studies, featuring 138 children, compared WES and WGS within cohorts. The diagnostic utility of WES (0.29 and 0.37) did not differ significantly from that of WGS (0.34 and 0.50, respectively; P > 0.05).24,36 Since the diagnostic utility of WES and WGS was not significantly different, we pooled WGS and WES studies in remaining subgroup analyses. Seven studies directly compared the proportion diagnosed by WGS or WES and CMA in 697 children; in each study, the diagnostic utility of WGS/WES was at least three-fold higher than CMA.23,26,33,34,36,38,46 Four of these manuscripts contained enough information to estimate the marginal odds ratios of receiving a diagnosis among subjects that received both WGS/WES and CMA.26,33,34,46 In them, the odds of a diagnosis by WGS/WES was 8.3 times greater than CMA (95% CI, 4.7-14.9, I ² = 36%; P < 0.0001, Fig. 1c).

Comparison of singleton and trio genomic sequencing and effect of site of testing

WGS/WES tests were either of affected probands or trios (proband, mother, father). In eighteen studies, comprising 3935 probands, the heterogeneity of diagnostic utility of singleton and trio WGS/WES was too great to permit quantitative analysis (Figure S3). Meta-analysis was performed in five studies (3613 children) that compared the diagnostic utility of WGS/WES by singleton and trio testing within cohorts.18,21,22,28,33 In these studies, the odds of diagnosis using trios was double that using singletons (95% CI 1.62-2.56; I ² = 12%, P < 0.0001, Fig. 3).

Fig. 3

Comparison of diagnostic (Dx) utility of singleton and trio WGS/WES in studies where both analyses were performed. In five studies that conducted within-cohort comparisons of singleton and trio genomic sequencing, the pooled odds of diagnosis for trios was twice that of singletons ( P  < 0.0001)

Studies were performed in three settings: (i) Research studies of novel methods or disease gene discovery; (ii) Clinical testing with hospital-based interpretation, where a deep phenotype was ascertained from the medical record at interpretation, and clinicopathologic correlation was facilitated by communication between clinicians and interpreters; and (iii) Clinical testing and interpretation in reference laboratories, where phenotype information was limited to that provided in test orders, and communication between clinicians and interpreters was not possible. In nineteen studies, comprising 1597 probands, the diagnostic utility of hospital-based genomic sequencing was 0.42 (95% CI 0.38-0.45, I ² = 48%), and by reference laboratory-based genomic sequencing was 0.29 (95% CI 0.27-0.31, I ² = 49%, eleven studies, 6140 probands, Fig. 4a). Both hospital and reference laboratory subgroups demonstrated significant heterogeneity. However, heterogeneity was reduced in ten studies published in 2017 ( I ² = 22%, P = 0.25, and I ² = 26%, P = 0.26, respectively).23,25,26,33,35,36,38,40,41,44 In these, the diagnostic utility of hospital genomic sequencing was 0.42 (95% CI 0.38-0.46, I ² = 22%), which was significantly higher than reference laboratories (0.31, 95% CI 0.27-0.34, I ² = 26%; P < 0.0001, Fig. 4b). Of note, hospital studies had an average of 84 subjects, while reference laboratory studies had an average of 558 subjects, providing a possible explanation for the inverse relationship between-study size and rate of diagnosis (Fig. 1a).

Fig. 4

Comparison of diagnostic (Dx) utility of WGS/WES in hospital laboratories and reference laboratories. a The pooled diagnostic utility of hospital-based testing was greater than reference laboratory testing. However, substantial heterogeneity was observed. b The subset of studies published in 2017 showed reduced heterogeneity for both subgroups. The pooled diagnostic utility was significantly greater in hospitals than in reference laboratories ( P  = 0.004)

Clinical Utility of WGS, WES, and CMA

To decrease the heterogeneity in definitions of clinical utility between studies, we excluded cases in which the only change in clinical management was genetic counseling or reproductive planning.55 The proportion of children receiving a change in clinical management by WGS results was 0.27 (95% CI 0.17-0.40, I ² = 54%, four studies of 136 children), compared with 0.17 (95% CI 0.12-0.24, I ² = 76%, twelve studies of 992 children) by WES, and 0.06 (95% CI 0.05-0.07, I ² = 42%, eight studies of 4271 children) by CMA (Fig. 5). Meta-analysis of WGS and CMA groups, for which heterogeneity was not significant ( P = 0.09 and P = 0.10, respectively), demonstrated that the rate of clinical utility of WGS was higher than CMA ( P < 0.0001).26,33,35,36,38,46,51,52,53

Fig. 5

Comparison of the rate of clinical utility of WGS, WES, and CMA. The rate of clinical utility was the proportion of children tested who received a change in medical or surgical management as a result of genetic disease diagnosis. The pooled rate of clinical utility of WGS and WES were both greater than of CMA. However, there was severe heterogeneity in the WES subgroup. Testing for subgroup differences amongst groups with low to moderate heterogeneity, we found that WGS diagnoses lead to an improved rate of clinical utility over CMA diagnoses

Discussion

Current guidelines state that CMA is the first-line genomic test for children with intellectual disability, developmental delay, autism spectrum disorder, and congenital anomalies.15,49,50,51,52,53,54,56,57,58 Since 2011, WGS and WES have gained relatively broad use for etiologic diagnosis of genetic diseases, but guidelines do not yet exist for their use. A systematic review identified 37 publications in the period January 2011-August 2017, comprising 20,068 affected children, which reported the diagnostic utility of WGS, WES, and/or CMA. Since only thirteen (35%) of these reported results of a comparator test, pooling made comparisons susceptible to confounding from factors including clinical setting, patient factors, eligibility criteria, study quality, clinical expertise, and testing procedures. Meta-regression showed that the odds of diagnosis by WES or WGS increased by 16% each year, while the odds of diagnosis by CMA decreased by 14% each year between 2013 and 2017. For WES and WGS, which are evolving technologies, this likely was due to methodologic improvements; for CMA, which is a mature technology, this was likely due to broader use with time following allowance of reimbursement. Meta-analysis of studies published in 2017, which removed variance associated with year of publication, showed that the diagnostic utility of WGS (0.42, 95% CI 0.34-0.51, I ² = 13%) was significantly greater than CMA (0.05, 95% CI 0.03-0.09, I ² = 40%; P < 0.0001).23,25,26,33,35,36,38,40,41,42,44 Similarly, meta-analysis of studies featuring within-cohort comparisons showed that the odds of a diagnosis by WGS or WES was 8.3 times greater than CMA (95% CI, 4.7-14.9, I ² = 36%; P < 0.0001).26,33,34,46 These results suggest that CMA should no longer be considered the test with highest diagnostic utility for childhood genetic diseases. Rather, WGS or WES should be considered a first-line genomic test for etiologic diagnosis of children with suspected genetic diseases.

While diagnostic utility is an important measure of the value of a clinical test, the relative clinical utility of WGS, WES, and CMA are more relevant for clinicians seeking to improve outcomes of rare childhood genetic diseases through implementation of targeted treatments (precision medicine).9 Given the genetic and clinical heterogeneity of genetic disease10 and consequent myriad potential therapeutic interventions, it has been difficult to nominate meaningful, generally applicable measures of clinical utility. A previous approach was to collapse all interventions that were temporally and causally related to a molecular diagnosis into an overall "actionability" rate.26,36,38,46,51,52,53,55 Such interventions were either based on practice guidelines endorsed by a professional society or peer-reviewed publications making medical management recommendations. While this has been applied in seven WGS and WES studies to date, definitions of actionability have varied. Furthermore, the evidence base for efficacy of ultra-rare genetic disease treatments is often qualitative rather than quantitative. Nevertheless, after excluding cases in which the only changes were ending the diagnostic odyssey or reproductive planning, WGS and WES had a higher actionability rates than CMA (0.27 [95% CI 0.17-0.40], 0.17 [95% CI 0.12-0.24], and 0.06 [95% CI 0.05-0.07], respectively). This difference was significant for WGS and CMA ( P  < 0.0001), in which within-group heterogeneity was not significant. One caveat was that children tested by CMA in these studies more frequently had multiple congenital anomalies, developmental delay, intellectual disability, or autism spectrum disorders, which were a subset of the presentations of children tested by WGS. Unfortunately, no study has yet reported the relationship between clinical utility of WGS, WES, or CMA and outcomes in children with genetic diseases.

Since WGS is about twice as expensive as WES, which is about twice as expensive as CMA, it is important to identify factors associated with high diagnostic utility. One such factor was the test setting: Hospital laboratory testing had a higher diagnostic utility (0.42, 95% CI 0.38-0.45) than reference laboratory testing (0.29, 95% CI 0.27-0.31). This difference was statistically significant ( P < 0.0001) among studies published in 2017, in which within-subgroup heterogeneity was not significant. This difference was supported by a study of double interpretation of WES of 115 children, first at a reference laboratory and second at the hospital caring for the children; the diagnostic utility of reference laboratory interpretation was 0.33, and rate of false positive diagnoses was 0.03. The diagnostic utility of hospital interpretation was 0.43, and there were no false positives.40 The major difference between hospital and reference laboratory interpretation is the quality and quantity of phenotype information available at time of interpretation. In hospital testing, phenotypic features are ascertained from the medical record, include findings by subspecialist consultants, results of other concomitantly ordered tests, negative findings, and, in difficult cases, are supplemented by discussion with clinicians to ascertain material negative findings or clarify conflicting findings. In reference laboratories, the available phenotypic features are those provided in test orders. They tend to be fewer in number and have less information content. One reference laboratory study found an association between the number of phenotypes available at interpretation and diagnostic yield: the diagnostic utility was 0.26 with one to five phenotype terms, 0.33 with six to fifteen terms, and 0.39 with more than fifteen terms.25 This was observed for all phenotypes, family structures, and inheritance patterns. Additional studies are needed to evaluate the reason for the apparent difference in diagnostic utility of hospital and reference laboratory WES/WGS. In the interim, it is suggested that "send out" WES and WGS tests should be accompanied by as much phenotypic information as possible, and open discussion should be encouraged between the laboratory and referring clinician after the results are available to provide a better diagnosis.

De novo variants accounted for the majority of genetic disease diagnoses, except in studies with high rates of consanguinity. Consanguinity is known to increase the population incidence of homozygous recessive genetic diseases. Herein, consanguinity was associated with decreased likelihood of attribution of diagnosis to de novo variants: Meta-regression of 29 studies found the rate of consanguinity to be inversely related to the odds of diagnoses attributed to de novo variants ( P < 0.001). Consanguinity is thought to increase the diagnostic utility of WGS and WES: In one study, the diagnostic utility of WES was 0.35 in 453 consanguineous families, and 0.27 in 443 non-consanguineous families.25 However, meta-analysis failed to show a significant association between the rate of consanguinity and diagnostic utility. Unfortunately, most studies did not report the proportion of probands with a family history of a similar illness, which was also anticipated to increase diagnostic utility.

Testing of parent-child trios is considered superior to singleton (proband) testing for genetic disease diagnosis, since trios facilitate detection of de novo variants and allow phasing of compound heterozygous variants during interpretation (rather than during confirmatory testing). However, trio testing is about twice as costly as singleton testing. Meta-analysis of five studies that compared the diagnostic utility of singleton and trio testing within cohorts showed trio testing to have twice the odds of diagnosis than singleton testing (95% CI 1.62-2.56, P < 0.0001).18,21,22,28,33 This result was supported by a study in which 36% of unsolved singleton WES cases were diagnosed when re-analyzed as trios.19,20,42 Additional studies are needed to guide clinicians with regard to the choice of initial trio or singleton testing. Factors to be considered include cost, time-to-result, and presence of consanguinity or family history of a similar condition.

Clinical WES has been much more broadly used than clinical WGS, since WGS was very expensive until recently, and remains ~$6000 per proband. WES examines almost all known exons and several hundred intronic nucleotides at ends of exons, or approximately two percent of the genome. WGS examines all exons and 90% of the genome. Only seven studies have reported the diagnostic utility of clinical WGS in 374 children.24,26,34,35,36,38,46 Meta-analysis did not show the difference in the diagnostic utility of WGS and WES to be significant. Subsequent to the meta-analysis, one very recent study directly compared the diagnostic utility of clinical WGS and WES in 108 subjects. Three patients (3%) received diagnoses by WGS that were completely unidentified by WES.59 Additional studies are needed since the diagnostic utility of WGS and WES are increasing disparately as a result of improved identification of disease-causing copy number and structural variations, repeat expansions, and non-exonic regulatory and splicing variations.34,36,42,57,58,60,61,62,63,64 In one recent study, these increased diagnostic utility by 36%.42 Recent research has shown WGS to have higher analytic sensitivity for copy number and structural variations than CMA, particularly small structural variations (less than 10,000 nucleotides34,36,64), suggesting that WGS may become the single first-line genomic test for etiologic diagnosis of most children suspected to have a genetic disease. However, the published data do not yet support superiority of WGS over WES.

This meta-analysis had several limitations. We used published diagnostic rates at face value; we did not reclassify diagnoses according to the strength of evidence of gene-disease relationships.65 Comparisons should be interpreted with caution due to heterogeneity of pooled averages of the published data. We were unable to control for heterogeneity in diagnostic utility associated with different types of clinical presentations or "cherry picking" (enrichment for children considered a priori to have high likelihood of a genetic etiology of disease. The highest level of evidence for clinical interventions is meta-analyses of randomized controlled trials (Level I).66 For WGS and WES, only one such study has yet been published.26 Published studies constitute Level II evidence (controlled studies or quasi-experimental studies) and Level III evidence (non-experimental descriptive studies, such as comparative studies, correlation studies, and case-control studies). The meta-analysis did not include diagnostic specificity (which has only been directly examined in one manuscript),40 nor the relative cost-effectiveness of WGS, WES, and CMA, either in terms of the cost of the diagnostic odyssey or long-term impact on healthcare utilization. It excluded next-generation sequencing-based panel tests, which are frequently used for specific presentations, such as epilepsy. It did not include subgroup analysis of the diagnostic utility or clinical utility by affected organ system, which might have identified subgroups of children who are most likely to benefit from testing. While, on average, the CMA studies were one or two years older than the WGS/WES studies, the diagnostic utility of CMA did not increase with time. In several of the WGS/WES studies, patients had previously received negative CMA tests, diminishing the relative diagnostic utility of WGS/WES.

Conclusions

In meta-analyses of 37 studies of children with suspected genetic diseases, the diagnostic utility of WGS (0.41, 95% CI 0.34-0.48) and WES (0.36, 95% CI 0.33-0.40) were higher greater than CMA (0.10, 95% CI 0.08-0.12), the current first-line genomic test for certain childhood genetic disorders. The same was true for the rate of clinical utility (WGS 0.27, 95% CI 0.17-0.40; WES 0.17, 95% CI 0.12-0.24; CMA 0.06, 95% CI 0.05-0.07). Additional randomized controlled studies are needed, particularly studies that examine the diagnostic determinants of optimal outcomes for children with rare genetic diseases.67

Methods

Data sources and record identification

We searched PubMed from 1 January 2011, to 4 August 2017 with the terms ("exome sequencing" or "whole-genome sequencing" or "chromosomal microarray"), and ("diagnosis" or "clinical"), and "genetic disease" (Figure S1). We manually searched journals not indexed by PubMed that published articles related to clinical genomic testing. There were no language restrictions.

Study screening and eligibility

Studies that evaluated the diagnostic utility (proportion of patients tested who received genetic diagnoses) or clinical utility (proportion of patients tested in whom the diagnosis changed medical or surgical management) of WGS, WES, and/or CMA were eligible. We limited eligibility to studies of cohorts with a broad range of genetic diseases, rather than one or a few disease types or clinical presentations, and in which the majority of probands were less than 18 years old. The systematic review and meta-analysis were performed according to the MOOSE and PRISMA guidelines (Table S1 and Figure S1).

Inclusion criteria and data extraction

Data extraction was manual. Data were reviewed for completeness and accuracy by at least two expert investigators and disparities were reconciled by consensus. The QUADAS-2 tool was used to assess the quality of the included studies (Table S2). The PICOTS typology of the criteria for inclusion of studies in quantitative analyses was:

Patients: Data extraction was limited to affected children (age less than 18 years) with suspected genetic disease.

Intervention: WGS, WES, and/or CMA for etiologic diagnosis of a suspected genetic disease.

Comparator: The groups compared were subjects tested by WGS, WES, and CMA. CMA was treated as the Reference Standard. Subgroups were patients tested with WGS, WES, or CMA as singletons (proband) and trios (parents and child). Trios did not include the use of parental DNA for confirmatory phasing by Sanger sequencing.

Outcomes: Diagnostic utility, rate of clinical utility. Molecular diagnoses were defined as pathogenic or likely pathogenic diplotypes (pairs of haplotypes) affecting genes or genomic variations with definitive, strong, or moderate associations with phenotypes that overlapped at least part of the clinical features of the affected patient, and that were reported to the patient's clinician.65 Variants of uncertain significance and secondary findings were not extracted. The definition of clinical utility conformed to a position statement of the American College of Medical Genetics and Genomics, but was limited to changes in management for individual patients.55

Timing: Where more than one publication reported results from a cohort, we included the most recent value for diagnostic utility. Clinical utility was assessed acutely (typically within six months of enrollment of the last patient).

Settings: Testing was performed clinically in hospital laboratories and reference laboratories, and experimentally in research laboratories. Hospital and reference laboratory clinical tests were defined primarily by the site of testing and, as disclosed in the methods, and, secondarily, by the affiliations of the authors. Clinical testing was defined as testing under fixed protocols that were attested to comply with state or national regulatory guidelines for in vitro diagnostic testing. Experimental research tests were those that explored the utility of novel or bespoke methods of testing or analysis.

Study Design: There were no study design restrictions.

Statistical Analysis

Between-study heterogeneity was explored by univariate analysis. Potential sources of heterogeneity included year of publication, number of probands, genetic disease tested, and consanguinity. The variable for genetic disease tested was treated as having four categories in the publications examined: any genetic disease, genetic diseases that included neurodevelopmental and metabolic disorders, neurodevelopmental disabilities alone, and infants (average proband age less than one year at testing). The effect of disease tested on heterogeneity was explored with a random-effects model as described below. We used meta-regression to study associations of continuous variables (year, study size, and the rate of consanguinity) and heterogeneity.

When comparing rates between studies, raw proportions (i.e., molecular diagnostic and clinical utility rates) for individual studies were logit transformed due to small sample sizes and low event rates.68 For each comparison, only the relevant subsets of patients reported in each relevant study were retained. Pooled subgroup proportions and their variances were obtained by fitting an inverse-variance weighted logistic-normal random-effects model to the data. 95% confidence intervals (CIs) for individual studies were derived using the Clopper-Pearson exact method.69 Pooled proportions and CIs were back-transformed for interpretation. For studies which conducted within-cohort comparisons, an inverse-weighted random-effects model was used to estimate pooled odds ratios (ORs). Due to the paired nature of the data, the marginal cross-over OR estimator of Becker and Balagtas70,71 was used for the meta-analysis of studies that conducted within-cohort comparisons of WES and CMA diagnostic rates. For all analyses, between-study heterogeneity was assessed using between-study variance (τ ²), the I ² statistic72 and Cochran's Q test.73 I ² values of 25, 50, and 75% indicate mild, moderate, and severe heterogeneity, respectively.72 Subgroup analyses were conducted to minimize severe heterogeneity between studies. Subgroup differences in rates and ORs were tested when there was not significant evidence of within-group heterogeneity. Forest plots were used to summarize individual study and pooled group meta-analysis statistics. Two-tailed P ≤ 0.05 were considered statistically significant. All statistical analyses were conducted using the 'meta' (version 4.8.1) and 'metafor' (version 2.0.0) packages in R (version 3.3.3).74,75,76

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Download references

Acknowledgements

We thank the many investigators who have built the evidence base for genomic medicine in children with genetic diseases. This work was supported by NICHD/NHGRI grant U19HD077693 to S.F.K. and by the Melbourne Genomics Health Alliance.

Author information

Affiliations

1. Rady Children's Institute for Genomic Medicine, San Diego, CA, USA

Michelle M. Clark

, Lauge Farnaes

, David Dimmock

& Stephen F. Kingsmore

2. Murdoch Children's Research Institute, Melbourne, Australia

Zornitza Stark

, Tiong Y. Tan

& Susan M. White

3. Department of Pediatrics, University of California San Diego, San Diego, CA, USA

4. Department of Paediatrics, University of Melbourne, Melbourne, Australia

Tiong Y. Tan

& Susan M. White

Contributions

S.F.K. conceived the study, performed the literature searches, analyzed the data, and wrote the first draft of the manuscript. M.M.C. checked accuracy of the data, performed the statistical analyses, prepared the figures, and helped write and revise the manuscript. L.F. and D.D. helped write and revise the manuscript and assisted in data collection. Z.S. helped conceive the study and helped write and revise the manuscript. T.T. and S.W. helped write and revise the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Stephen F. Kingsmore.

Electronic supplementary material

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Meta-analysis of the diagnostic and clinical utility of genome and exome sequencing and chromosomal microarray in children with suspected genetic diseases

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Gene therapy: advances, challenges and perspectives

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Gene therapy: advances, challenges and perspectives

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Academic review article about gene therapy

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INTRODUCTION

In 1991, James Watson declared that "many people say they are worried about the changes in our genetic instructions. But these (genetic instructions) are merely a product of evolution, shaped so we can adapt to certain conditions which might no longer exist. We all know how imperfect we are. Why not become a little better apt to survive?".⁽ 1 ⁾ Since the beginning, humans understand that the peculiar characteristics of the parents can be transmitted to their descendents. The first speculation originated from the ancient Greek students, and some of these theories continued for many centuries. Genetic-scientific studies initiated in the early 1850s, when the Austrian monk, Gregor Mendel, in a series of experiments with green peas, described the inheritance pattern by observing the traces that were inherited as separate units, which we know today as genes. Up until 1950, little was known as to the physical nature of genes, which was when the American biochemist, James Watson, and the British biophysicist, Francis Crick, developed the revolutionary model of the double strand DNA. In 1970, researchers discovered a series of enzymes that enabled the separation of the genes in predetermined sites along the DNA molecule and their reinsertion in a reproducible manner. These genetic advances prepared the scenario for the emergence of genetic engineering with the production of new drugs and antibodies, and as of 1980, gene therapy has been incorporated by scientists.⁽ 2 , 3 ⁾

In this review, we cover gene therapy, the different methodologies of genetic engineering used for this technique, its limitations, applications, and perspectives.

Gene therapy

Currently, gene therapy is an area that exists predominantly in research laboratories, and its application is still experimental.⁽ 5 ⁾ Most trials are conducted in the United States, Europe, and Australia. The approach is broad, with potential treatment of diseases caused by recessive gene disorders (cystic fibrosis, hemophilia, muscular dystrophy, and sickle cell anemia), acquired genetic diseases such as cancer, and certain viral infections, such as AIDS.⁽ 3 , 6 ⁾

One of the most often used techniques consists of recombinant DNA technology, in which the gene of interest or healthy gene is inserted into a vector, which can be a plasmidial, nanoestrutured, or viral; the latter is the most often used due to its efficiency in invading cells and introducing its genetic material. On , a few gene therapy protocols are summarized, approved and published for clinical use, exemplifying the disease, the target, and the type of vector used.⁽ 3 ⁾

Table 1

Although several protocols have been successful, the gene therapy process remains complex, and many techniques need new developments. The specific body cells that need treatment should be identified and accessible. A way to effectively distribute the gene copies to the cells must be available, and the diseases and their strict genetic bonds need to be completely understood.⁽ 3 ⁾ There is also the important issue of the target cell type of gene therapy that currently is subdivided into two large groups: gene therapy of the germline⁽ 7 ⁾ and gene therapy of somatic cells.⁽ 8 ⁾ In germline gene therapy, the stem cells, e.g., with the sperm and egg, are modified by the introduction of functional genes, which are integrated into the genome. The modifications are hereditary and pass on to subsequent generations. In theory, this approach should be highly effective in the fight against genetic and hereditary diseases. Somatic cell gene therapy is when therapeutic genes are transferred to a patient's somatic cells. Any modification and any effects are restricted only to that patient and are not inherited by future generations.

Gene therapy process: release of the gene

In gene therapy, a normal gene is inserted into the genome to replace an abnormal gene responsible for causing a certain disease. Of the various challenges involved in the process, one of the most significant is the difficulty in releasing the gene into the stem cell. Thus, a molecular carrier called a "vector" is used to release the gene, which needs to be very specific, display efficiency in the release of one or more genes of the sizes necessary for clinical applications, not be recognized by the immune system, and be purified in large quantities and high concentrations so that it can be produced and made available on a large scale. Once the vector is inserted into the patient, it cannot induce allergic reactions or inflammatory process; it should increase the normal functions, correct deficiencies, or inhibit deleterious activities. Furthermore, it should be safe not only for the patient, but also for the environment and for the professionals who manipulate it. Finally, the vector should be capable to express the gene, in general, for the patient's entire life.⁽ 3 , 9 ⁾

Although the efficacy of viral vectors is confirmed, recently some studies demonstrated that the use of these carriers presented with several limitations. The presence of viral genetic material in the plasmid is a strong aggravating factor, since it can induce an acute immune response, besides a possible oncogenic transformation. Currently, there are two main approaches for genetic modifications of the cells, namely: virus-mediated () and via physical mechanisms, from preparations obtained by advanced nanotechnology techniques.⁽ 5 ⁾ Within this context, included are polymers that form networks that capture a gene and release its load when they penetrate the cells, such as DNA microinjections,⁽ 10 ⁾ cationic polymers,⁽ 11 ⁾ cationic liposomes,⁽ 12 , 13 ⁾ and particle bombardment.⁽ 14 ⁾

Table 2

Gene therapy and hematopoietic stem cells

Hematopoietic stem cells have become ideal targets for gene transfer due to the high potential for longevity and the capacity for self-renovation. One example of this combination of gene therapy and stem cells would be the production of gene transfer vectors for the creation of induced pluripotent stem cells (iPS), in order to generate the differentiation of the iPS and afford an additional phenotype from this differentiated derived cell. Patients with chronic liver disease and infection by the hepatitis virus ( e.g., hepatitis B virus and hepatitis C virus), which require a liver transplant, may be likely to undergo the hepatic transplantation of mature hepatocytes or those derived from iPS.⁽ 15 ⁾ Not only the transfer of genes might be needed to convert stem cells into hepatocytes; since the transplanted cells are susceptible to reinfection by the hepatitis virus, the transfer of a vector that encodes a short hairpin RNA directed against the virus would provide the transferred cells with resistance or 'immunity' to reinfection. Resistant cells can repopulate the liver over time and restore normal hepatic function ().⁽ 15 ⁾

Therapy with T cells of the recipient of a chimeric antigen

Chimeric antigen recipient T (CAR-T) cell therapy is a type of immunotherapy that involves manipulation/reprogramming of immune cells (T lymphocytes) of the patients themselves, in order to recognize and attack the tumor T cells. Initial advancement in the design of the first CAR generation, by Eshhar et al.,⁽ 16 ⁾ was marked by the fusion of a single chain fragment variable (scFv) to a transmembrane domain and an intracellular signaling unit: chain CD3 zeta.⁽ 17 , 18 ⁾ This design combined the active element of a well-characterized monoclonal antibody with a signaling domain, increasing the recognition of the tumor-specific epitope and the activation of T cells, without depending on molecules from the histocompatibility complex.

The most critical point of the adverse effects of CAR-T therapy is the identification of non-tumor cells that express the target epitope by CAR. Tumor antigens are molecules highly expressed in the tumor cells, but are not exclusive of these cells. For example, the CD19 antigen can be found in normal or malignant B cells, and the CAR design for the CD19 target in not capable of distinguishing them.⁽ 20 , 22 ⁾ Other common toxicity for CAR-T therapy (and many other types of immunotherapy for cancer) is the cytokine release syndrome (CRS). Activation of the immune system after CAR-T infusion can induce a rapid increase in the levels of inflammatory cytokines.⁽ 20 , 23 ⁾

New developments in the design of vectors and trials with CAR-T provide balance and reinforcement in safety for amplification of the clinical application. The progressive improvement in the CAR trials has already advanced, as was observed from the first to the third generation. Knowledge and experience acquired in the assessment of CAR-T toxicity will increase the success of the progressive improvements for future trials.

CRISPR-Cas9

During the 1980's, in the genome of Escherichia coli, a region was identified with an uncommon pattern, in which a highly variable sequence was intercalated by a repeated sequence with no known function. In 2005, it was assumed that the variable sequences were of extra-chromosomal origin, acting as an immune memory against phages and plasmids, starting the then unknown CRISPR system (Clustered Regularly Interspaced Short Palindromic Repeats) and Cas (Associated Proteins), that shines since 2012 as one of the primary biotechnological tools for gene edition.⁽ 24 ⁾ Originating in the immune-adaptive system of procaryontes, this mechanism recognizes the invading genetic mateiral, cleaves it into small fragments, and integrates it into its own DNA. In a second infection by the same agent, the following sequence occurs: transcription of the CRISPR locus, RNAm processing, and creation of small fragments of RNA (crRNAs) that form complexes with the Cas proteins, and these recognize the alien nucleic acids and finally destroy them.⁽ 24 ⁾

Based on this natural mechanism, the CRIPSR technique was developed enabling editing of the target-specific DNA sequences of the genome of any organism by means of basically three molecules: nuclease (Cas9), responsible for cleavage of the double-strand DNA; an RNA guide, which guides the complex to the target; and the target DNA, as is shown in .⁽ 25 , 26 ⁾

Due to its simplicity and its precision when compared to other techniques (Zinc-Finger Nucleases, TALENs, and Gene Targeting), the CRISPR system arrives as a versitile tool that promotes the genetic editing by means of inactivation (knockout gene − KO), integration of exogenous sequences (knock-in), and allele substitution, among others.⁽ 27 , 28 ⁾

The guide RNA hybridizes with the target DNA. Cas-9 recognizes this complex and should mediate cleavage of the DNA double strand and reparation in the presence of a (homologous) donor DNA. The result of this process is the integration of an exogenous sequence into the genome (knock-in) or allele substitution.

The rapid advancement of this new technology allowed the performance of translational trials in human somatic cells, using genetic editing by CRISPR. The first applications with a therapeutic focus already stood out in describing even the optimization steps of the delivery systems and specificity for the safety and efectiveness of the system.⁽ 28 , 29 ⁾

Ethical issues

The possibility of genetically modifying germlines has been the object of heated discussion in the field of science for a long time. Bioethics is always present when new techniques are created, in order to assess the risks of the procedure and the moral implications involved.

A large part of the scientific community approves genetic therapy in somatic cells, especially in cases of severe disorders, such as cystic fibrosis and Duchenne muscular dystrophy.

In 2015, however, Chinese researchers went beyond the moral issues and announced, for the first time, the genetic modification of embryonic cells using the CRISPR-Cas9 technique. Next, another Chinese group also reported the conduction of the same process done with the intention of conferring resistance to HIV by insertion of the CCR5 gene mutation. The genetic analysis showed that 4 of the 26 embryos were successfully modified. The result clearly reveals the need for improving the technique, alerting that, possibly, such trials could be previously tested in animal models.⁽ 4 , 30 ⁾

COMMENT

Since the declaration of James Watson in 1991, in reference to the likely optimization of human genetics, gene therapy has advanced throughout the decades, whether by optimization of the types of vectors, by the introduction of new techniques, such as induced pluripotent stem cells in combination with current models of genetic editing (CRISPR-Cas9), and even by trials in germ cells, bringing with it the contradictory ethical and moral aspects that accompany the technique.

Local successes have already solidified the viability of treatments using gene therapy in clinical practice, as an alternative form for patients with congenital diseases or monogenic disorders and cancer, especially when the pharmacological or surgical interventions do not show good results.

The design of new experimental vectors, the increase in efficiency, the specificity of the delivery systems, and the greater understanding of the inflammatory response induction may balance the improvement of safety with the expansion of techniques in clinical applications. Yet the knowledge and experience acquired with the careful assessment of toxicity of these technologies also allow significant advances in the application of these methods.

Therefore, historically, gene therapy and the discovery of antibiotics and chemotherapy agents, or any new technology, need more clarifying preclinical studies. In the future, there is the promise of applying these techniques in several fields of Medicine and a greater percentage of clinical trials.

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Gene therapy: advances, challenges and perspectives

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The ability to make site-specific modifications to the human genome has been an objective in medicine since the recognition of the gene as the basic unit of heredity. Thus, gene therapy is understood as the ability of genetic improvement through the correction ...

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Links for reading and research into medical applications of genetic technologies.

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Links for reading and research into medical applications of genetic technologies.

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These links have been compiled by the Kinghorn Centre for Clinical Genomics to support student inquiry in HSC Biology. They may be helpful for anyone interested the benefits, limitations and ethical considerations surrounding genomics or genetic medicine.

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Created October 2018
Last updated February 2019

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Embryo Screening and the Ethics of Human Genetic Engineering

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Embryo Screening and the Ethics of Human Genetic Engineering

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A 2008 article from Scitable

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embryo screening and the ethics of human genetic engineering

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Embryo Screening and the Ethics of Human Genetic Engineering | Learn Science at Scitable

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Scientists have coined the term "reprogenetics" to describe the combined use of reproductive and genetic technologies to select, and someday even genetically modify, embryos before implantation - not for health reasons, but for the sake of "improvement." The benefits and dangers of reprogenetics - including embryo screening and human genetic engineering - are strongly debated around the world.

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Please notify us of broken links at kccgeducation@garvan.org.au

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Everything you wanted to know about ‘3-parent’ babies

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Everything you wanted to know about ‘3-parent’ babies

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Article from New Scientist

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Stephanie Uhlenbrock/Plainpicture

A baby boy has been born using DNA from three people - the first ever birth resulting from a new technique that helps people with rare genetic diseases have healthy children. The achievement is being hailed as a milestone in fertility medicine, up there with the first IVF baby. But why is it such a big deal? How controversial is the technique? And is it safe? New Scientist answers your burning questions.

Who are the boy's three "parents"?
The boy's mother and father are a Jordanian couple who have already lost two children to a genetic disease called Leigh syndrome. The mother carries genes for this disease in her mitochondrial DNA, which is found in the cell's energy-generating mitochondria. While we inherit the bulk of our DNA from both parents, mitochondrial DNA is only passed down from our mothers. To avoid passing on the disease-causing mitochondrial DNA, John Zhang and his colleagues at the New Hope Fertility Center in New York City used mitochondria from an egg belonging to another woman - an anonymous donor.

How much DNA comes from each person?
Almost all of the boy's DNA will come from his mother and father. That's because most of our genes - around 20,000 in total - are found in the cell's nucleus; just 37 are found in the mitochondria. In the new procedure, Zhang's team removed the nucleus from one of the mother's eggs and inserted it into a donor egg, which had its own nucleus removed. This egg was then fertilised with the father's sperm. The resulting embryo therefore had nuclear DNA from its parents and mitochondrial DNA from the donor.

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What do these 37 mitochondrial genes do?
These mainly code for enzymes that keep the mitochondria themselves functioning. While a malfunction can trigger a devastating disease, the genes are unlikely to code for the more obvious traits people inherit from their parents.

But because they power cells, mitochondria could indirectly affect other things by altering the way cells function. A few studies have suggested that mitochondrial DNA might influence a person's athletic ability, how long they will live and even their IQ. The exact mechanisms aren't clear.

Haven't "three parent" babies been born before?
Yes, although using a different technique. Back in the 1990s, Jacques Cohen and his colleagues at the Institute for Reproductive Medicine and Science at Saint Barnabas in New Jersey were the first to inject fluid from healthy eggs - including their mitochondria - into eggs from women who had been through several rounds of failed IVF. The hope was that the donated mitochondria would boost the flagging eggs.

The team tried their technique 30 times in 27 people, and 17 babies were born. But two fetuses developed a genetic disorder, in which they lacked an X chromosome. One of these pregnancies resulted in a miscarriage, the other was aborted. This led to safety concerns. In 2001, the US Food and Drug Administration wrote to fertility clinics in the US, asking them to stop using the method, and to instead apply for approval from the FDA itself in all cases. The method, called ooplasmic transfer, fell out of favour at that point.

Is the new method safe?
As far as safety is concerned, it is too soon to know. The baby boy is the first to be born with the new method, so we have too few births to draw conclusions from. For now, though, it seems that the boy - now 5 months old - is healthy.

The primary concerns are that some faulty mitochondria could have slipped through the net. It is virtually impossible to leave behind all the mitochondria from the mother's egg when removing the nucleus, even with the steadiest hand. And the level of mutated mitochondria that can cause symptoms varies by disease. One concern is that "bad" mitochondria, even in tiny amounts, could be better at replicating than "good" mitochondria - eventually tipping the balance and causing disease further down the line.

A second concern is that having mitochondria from two sources could disturb the normal relationship between the nucleus and mitochondria, although it is unclear if this is the case. It is a good sign that the boy is healthy, but he will need to be carefully monitored over the coming years.

Is the procedure legal?
It depends on where you want to do it. A similar technique was approved in the UK last year, although, as far as we know, no one in the country has tried it yet. Embryologists who want to carry out the procedure in the UK first have to apply for a licence, and then must follow a legal and ethical framework. They must also closely follow the development of any babies that are born.

In the US, it is up to the FDA to approve the procedure before it can be legally carried out. The country's Institute of Medicine recommended that they do this back in February, at least for sons, who won't be able to pass on any of the mitochondrial DNA they receive from the donor. The FDA has yet to make a decision. Zhang says that he tried to apply for FDA approval, but that the organisation told him there was no department set up that could review his application. So he performed the treatment in Mexico, where, as he puts it "there are no rules". He hopes to continue his work in Mexico, China and the UK.

Why is it so controversial?
Some people don't like the idea of a baby having three biological parents, and argue that mitochondrial DNA goes some way to shaping important characteristics, such as personality. But the scientific consensus is that swapping mitochondria is similar to changing a battery - it's unlikely to have much, if any, influence over a person's behaviour.

Others have argued that the technique is unnecessary. After all, it won't help those who have already been born with mitochondrial diseases. Parents often don't find out they are carriers of these diseases until they give birth to sick children. And those who do know they could pass on a disease have other options, such as using a donor egg. The technique is specifically for people who carry genes for the disease, but want to have a child genetically related to them.

Another concern is that, by creating a new mix of genetic material, embryologists are creating lasting genetic changes that will be passed down through generations, before we have a chance to find out if they are dangerous. Some argue that this starts us on a slippery slope of germ-line editing - one that could eventually lead to "designer babies".

Could it have other uses?
Potentially. Some embryologists believe that ineffective mitochondria could be the cause of age-related infertility, and that eggs of older women fail to form viable embryos because they essentially lack energy. That's the idea behind Augment - a treatment that uses mitochondria from a woman's own ovarian stem cells to rejuvenate her egg cells. The team behind this project announced their first birth last year. However, many in the field remain sceptical - doubting that ovarian stem cells actually exist.

If ovarian stem cells don't exist, but the theory behind the rejuvenation idea stacks up, then mitochondria taken from the eggs of young women could be used as an alternative.

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Everything you wanted to know about '3-parent' babies

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Why is it such a big deal? How controversial is the technique? Is it safe? We have all your questions answered

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Fact sheet from the Australian Mitochondrial Disease Foundation

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Fact sheet from the Centre for Genetics Education (click 'open in new window)

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Summary article from Your Genome

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Gene therapy uses sections of DNA (usually genes) to treat or prevent disease.

The DNA is carefully selected to correct the effect of a mutated gene that is causing disease.

The technique was first developed in 1972 but has, so far, had limited success in treating human diseases.

Gene therapy may be a promising treatment option for some genetic diseases, including muscular dystrophy and cystic fibrosis.

There are two different types of gene therapy depending on which types of cells are treated:

Somatic gene therapy: transfer of a section of DNA to any cell of the body that doesn't produce sperm or eggs. Effects of gene therapy will not be passed onto the patient's children.

Germline gene therapy: transfer of a section of DNA to cells that produce eggs or sperm. Effects of gene therapy will be passed onto the patient's children and subsequent generations.

Gene therapy techniques

There are several techniques for carrying out gene therapy. These include:
Gene augmentation therapy

This is used to treat diseases caused by a mutation that stops a gene from producing a functioning product, such as a protein.

This therapy adds DNA containing a functional version of the lost gene back into the cell.

The new gene produces a functioning product at sufficient levels to replace the protein that was originally missing.

This is only successful if the effects of the disease are reversible or have not resulted in lasting damage to the body.

For example, this can be used to treat loss of function disorders such as cystic fibrosis by introducing a functional copy of the gene to correct the disease (see illustration below).

Gene inhibition therapy

Suitable for the treatment of infectious diseases, cancer and inherited disease caused by inappropriate gene activity.

The aim is to introduce a gene whose product either:

inhibits the expression of another gene

interferes with the activity of the product of another gene.

The basis of this therapy is to eliminate the activity of a gene that encourages the growth of disease-related cells.

For example, cancer is sometimes the result of the over-activation of an oncogene (gene which stimulates cell growth). So, by eliminating the activity of that oncogene through gene inhibition therapy, it is possible to prevent further cell growth and stop the cancer in its tracks.

Killing of specific cells

Suitable for diseases such as cancer that can be treated by destroying certain groups of cells.

The aim is to insert DNA into a diseased cell that causes that cell to die.

This can be achieved in one of two ways:

the inserted DNA contains a "suicide" gene that produces a highly toxic product which kills the diseased cell

the inserted DNA causes expression of a protein that marks the cells so that the diseased cells are attacked by the body's natural immune system.

It is essential with this method that the inserted DNA is targeted appropriately to avoid the death of cells that are functioning normally.

How is DNA transfer done?

A section of DNA/gene containing instructions for making a useful protein is packaged within a vector, usually a virus, bacterium or plasmid.

The vector acts as a vehicle to carry the new DNA into the cells of a patient with a genetic disease.

Once inside the cells of the patient, the DNA/gene is expressed by the cell's normal machinery leading to production of the therapeutic protein and treatment of the patient's disease.

Challenges of gene therapy

Delivering the gene to the right place and switching it on:

it is crucial that the new gene reaches the right cell

delivering a gene into the wrong cell would be inefficient and could also cause health problems for the patient

even once the right cell has been targeted the gene has to be turned on

cells sometimes obstruct this process by shutting down genes that are showing unusual activity.

Avoiding the immune response:

The role of the immune system is to fight off intruders.

Sometimes new genes introduced by gene therapy are considered potentially-harmful intruders.

This can spark an immune response in the patient, that could be harmful to them.

Scientists therefore have the challenge of finding a way to deliver genes without the immune system 'noticing'.

This is usually by using vectors that are less likely to trigger an immune response.

Making sure the new gene doesn't disrupt the function of other genes:

Ideally, a new gene introduced by gene therapy will integrate itself into the genome of the patient and continue working for the rest of their lives.

There is a risk that the new gene will insert itself into the path of another gene, disrupting its activity.

This could have damaging effects, for example, if it interferes with an important gene involved in regulating cell division, it could result in cancer.

The cost of gene therapy:

Many genetic disorders that can be targeted with gene therapy are extremely rare.

Gene therapy therefore often requires an individual, case-by-case approach. This may be effective, but may also be very expensive.

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Gene therapy uses sections of DNA (usually genes) to treat or prevent disease. The DNA is carefully selected to correct the effect of a mutated gene that is causing disease. The technique was first developed in 1972 but has, so far, had limited success in treating human diseases.

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CAR-T therapy works for some blood cancers, but can we make it work for brain tumours?

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CAR-T therapy works for some blood cancers, but can we make it work for brain tumours?

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Article from The Conversation

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A powerful new anti-cancer therapy, called CAR-T, has shown great promise in treating blood cancers. Last year, the Food and Drug Administration approved the treatment for acute lymphoblastic leukaemia, and the results have been very promising, with remission rates of up to 83% for the very worst case patients, whose disease had returned following conventional treatments.

CAR-T (chimeric antigen receptor T-cell) therapy uses the body's immune system to destroy cancer cells. It involves taking a patient's T-cells (a type of immune cell) and genetically altering them so they attack cancer cells rather than invading organisms, such as bacteria. Large numbers of these CAR-T cells are grown in the lab before being infused into the patient.

With the recent success in mind, it is tempting to consider whether this approach would work in other cancers, particularly cancers that are notoriously difficult to treat, such as brain tumours. Unfortunately, this has not happened yet, and the reason is to do with the nature of cancer itself.

Cancer is not just one disease but many, each requiring a different treatment, and brain tumour treatment has a dismal history, with high-grade glioblastoma patients having an average survival rate of one year after diagnosis.

Why so difficult?

So what is the problem with treating solid tumours and brain tumours in particular? The answer lies in the nature of the disease and the treatment. In leukaemia, there is a single, identifiable target: a molecule on the surface of the tumour cell called CD19. It's a relatively straightforward task to engineer a CAR-T cell to attack that target and destroy the tumour.

In high-grade brain cancers (where cancer cells spread and grow more quickly), the tumour is heterogeneous, which means the target molecules on the tumour cells are constantly changing over the course of the disease. In different areas of the same tumour you will have different target molecules, so creating a CAR-T cell to attack the tumour becomes an impossible task.

Also, high-grade brain tumours build a network of blood vessels to support and feed the tumour as it grows and spreads to other areas of the brain, in a process known as "angiogenesis". Understandably, this makes some brain tumours very difficult to treat and remove.

O_Akira/Shutterstock.com

Another feature of brain tumours involves another type of immune cell called the regulatory T-cell. These are the cells that stop our immune system from attacking our own bodies. (When they go wrong they cause autoimmune diseases such as rheumatoid arthritis.) Brain tumours can hijack these cells to create an immunosuppressive micro-environment for the tumour to live in. Even if immune cells could get to the site of the tumour, they would be "switched off" by the actions of these regulatory T-cells, and the tumour would be safely protected from the attack.

Dismantling safe spaces

The outlook for using immunotherapy to treat brain cancer looks poor with several barriers to be overcome, but let's look again at CAR-T therapy.

We can create a specific immune cell to attack a specific target and fourth-generation CAR-T cells can be produced to attack two or more specific targets - but this isn't enough. So instead of focusing on the moving target of the tumour cell, perhaps we should look at other targets.

The processes of angiogenesis (the development of new blood vessels) and immuno-suppression are driven by cells that have their own unique molecular characteristics, so let's target these areas. Let's take away the "safe space" the tumour has created for itself by destroying the micro-environment of the tumour, allowing our immune cells to do their job of destroying it.

There is a major problem that would need to be overcome for this to work, which is systemic toxicity - the result of the engineered CAR-T cells attacking the wrong healthy target cells. The last thing we need is for our CAR-T cells to destroy new blood vessels or all regulatory T cells.

What we need are tumour-specific targets for the newly created blood vessels and the immune-suppressing T-cells. Finding these will be the focus of my future research.

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CAR-T therapy works for some blood cancers, but can we make it work for brain tumours?

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CAR-T is a powerful new immunotherapy for treating leukaemia. We need to build on it to attack other, harder-to-treat cancers.

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from the Broad Institute

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Discovery of CRISPR and its function
1993 - 2005 - Francisco Mojica, University of Alicante, Spain

Francisco Mojica was the first researcher to characterize what is now called a CRISPR locus, reported in 1993. He worked on them throughout the 1990s, and in 2000, he recognized that what had been reported as disparate repeat sequences actually shared a common set of features, now known to be hallmarks of CRISPR sequences (he coined the term CRISPR through correspondence with Ruud Jansen, who first used the term in print in 2002). In 2005 he reported that these sequences matched snippets from the genomes of bacteriophage (Mojica et al., 2005). This finding led him to hypothesize, correctly, that CRISPR is an adaptive immune system. Another group, working independently, published similar findings around this same time (Pourcel et al., 2005)

Bolotin was studying the bacteria Streptococcus thermophilus, which had just been sequenced, revealing an unusual CRISPR locus (Bolotin et al., 2005). Although the CRISPR array was similar to previously reported systems, it lacked some of the known cas genes and instead contained novel cas genes, including one encoding a large protein they predicted to have nuclease activity, which is now known as Cas9. Furthermore, they noted that the spacers, which have homology to viral genes, all share a common sequence at one end. This sequence, the protospacer adjacent motif (PAM), is required for target recognition.

Koonin was studying clusters of orthologous groups of proteins by computational analysis and proposed a hypothetical scheme for CRISPR cascades as bacterial immune system based on inserts homologous to phage DNA in the natural spacer array, abandoning previous hypothesis that the Cas proteins might comprise a novel DNA repair system. (Makarova et al., 2006)

S. thermophilus is widely used in the dairy industry to make yogurt and cheese, and scientists at Danisco wanted to explore how it responds to phage attack, a common problem in industrial yogurt making. Horvath and colleagues showed experimentally that CRISPR systems are indeed an adaptive immune system: they integrate new phage DNA into the CRISPR array, which allows them to fight off the next wave of attacking phage (Barrangou et al., 2007). Furthermore, they showed that Cas9 is likely the only protein required for interference, the process by which the CRISPR system inactivates invading phage, details of which were not yet known.

Scientists soon began to fill in some of the details on exactly how CRISPR-Cas systems "interfere" with invading phage. The first piece of critical information came from John van der Oost and colleagues who showed that in E-scherichia coli, spacer sequences, which are derived from phage, are transcribed into small RNAs, termed CRISPR RNAs (crRNAs), that guide Cas proteins to the target DNA (Brouns et al., 2008).

The next key piece in understanding the mechanism of interference came from Marraffini and Sontheimer, who elegantly demonstrated that the target molecule is DNA, not RNA (Marraffini and Sontheimer, 2008). This was somewhat surprising, as many people had considered CRISPR to be a parallel to eukaryotic RNAi silencing mechanisms, which target RNA. Marraffini and Sontheimer explicitly noted in their paper that this system could be a powerful tool if it could be transferred to non-bacterial systems. (It should be noted, however, that a different type of CRISPR system can target RNA (Hale et al., 2009)).

Moineau and colleagues demonstrated that CRISPR-Cas9 creates double-stranded breaks in target DNA at precise positions, 3 nucleotides upstream of the PAM (Garneau et al., 2010). They also confirmed that Cas9 is the only protein required for cleavage in the CRISPR-Cas9 system. This is a distinguishing feature of Type II CRISPR systems, in which interference is mediated by a single large protein (here Cas9) in conjunction with crRNAs.

The final piece to the puzzle in the mechanism of natural CRISPR-Cas9-guided interference came from the group of Emmanuelle Charpentier. They performed small RNA sequencing on Streptococcus pyogenes, which has a Cas9-containing CRISPR-Cas system. They discovered that in addition to the crRNA, a second small RNA exists, which they called trans-activating CRISPR RNA (tracrRNA) (Deltcheva et al., 2011). They showed that tracrRNA forms a duplex with crRNA, and that it is this duplex that guides Cas9 to its targets.

Siksnys and colleagues cloned the entire CRISPR-Cas locus from S. thermophilus (a Type II system) and expressed it in E. coli (which does not contain a Type II system), where they demonstrated that it was capable of providing plasmid resistance (Sapranauskas et al., 2011). This suggested that CRISPR systems are self-contained units and verified that all of the required components of the Type II system were known.

Taking advantage of their heterologous system, Siksnys and his team purified Cas9 in complex with crRNA from the E. coli strain engineered to carry the S. thermophilus CRISPR locus and undertook a series of biochemical experiments to mechanistically characterize Cas9's mode of action (Gasiunas et al., 2012).They verified the cleavage site and the requirement for the PAM, and using point mutations, they showed that the RuvC domain cleaves the non-complementary strand while the HNH domain cleaves the complementary site. They also noted that the crRNA could be trimmed down to a 20-nt stretch sufficient for efficient cleavage. Most impressively, they showed that they could reprogram Cas9 to target a site of their choosing by changing the sequence of the crRNA.

June, 2012 - Charpentier and Jennifer Doudna, University of California, Berkeley

Similar findings as those in Gasiunas et al. were reported at almost the same time by Emmanuelle Charpentier in collaboration with Jennifer Doudna at the University of California, Berkeley (Jinek et al., 2012). Charpentier and Doudna also reported that the crRNA and the tracrRNA could be fused together to create a single, synthetic guide, further simplifying the system. (Although published in June 2012, this paper was submitted after Gasiunas et al.)

Zhang, who had previously worked on other genome editing systems such as TALENs, was first to successfully adapt CRISPR-Cas9 for genome editing in eukaryotic cells (Cong et al., 2013). Zhang and his team engineered two different Cas9 orthologs (from S. thermophilus and S. pyogenes) and demonstrated targeted genome cleavage in human and mouse cells. They also showed that the system (i) could be programmed to target multiple genomic loci, and (ii) could drive homology-directed repair. Researchers from George Church's lab at Harvard University reported similar findings in the same issue of Science (Mali et al., 2013).

Barrangou, R., Fremaux, C., Deveau, H., Richards, M., Boyaval, P., Moineau, S., Romero, D.A., and Horvath, P. (2007). CRISPR provides acquired resistance against viruses in prokaryotes. Science 315, 1709-1712.

Bolotin, A., Quinquis, B., Sorokin, A.,and Ehrlich, S.D. (2005). Clustered regularly interspaced short palindrome repeats (CRISPRs) have spacers of extrachromosomal origin. Microbiology 151, 2551-2561.

Brouns, S.J., Jore, M.M., Lundgren, M., Westra, E.R., Slijkhuis, R.J., Snijders, A.P., Dickman, M.J., Makarova, K.S., Koonin, E.V., van der Oost, J. (2008) Small CRISPR RNAs guide antiviral defense in prokaryotes. Science 321, 960-964.

Cong, L., Ran, F.A., Cox, D., Lin, S., Barretto, R., Habib, N., Hsu, P.D., Wu, X., Jiang, W., Marraffini, L.A., et al. (2013). Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819-823.

Deltcheva, E., Chylinski, K., Sharma, C.M., Gonzales, K., Chao, Y., Pirzada, Z.A., Eckert, M.R., Vogel, J., and Charpentier, E. (2011). CRISPR RNA maturation by trans-encoded small RNA and host factor RNase III. Nature 471, 602-607.

Gasiunas, G., Barrangou, R., Horvath, P., and Siksnys, V. (2012). Cas9-crRNA ribonucleoprotein complex mediates specific DNA cleavage for adaptive immunity in bacteria. Pnas 109, E2579-E2586.

Hale, C.R., Zhao, P., Olson, S., Duff, M.O., Graveley, B.R., Wells, L., Terns, R.M., and Terns, M.P. (2009). RNA-Guided RNA Cleavage by a CRISPR RNA-Cas Protein Complex. Cell 139, 945-956.

Jinek, M., Chylinski, K., Fonfara, I., Hauer, M., Doudna, J.A., and Charpentier, E. (2012). A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337, 816-821.

Makarova, K.S., Grishin, N.V., Shabalina, S.A., Wolf, Y.I., Koonin, E.V. (2006). A putative RNA-interference-based immune system in prokaryotes: computational analysis of the predicted enzymatic machinery, functional analogies with eukaryotic RNAi, and hypothetical mechanisms of action. Biology Direct 2006, 1:7.

Mali, P., Yang, L., Esvelt, K.M., Aach, J., Guell, M., DiCarlo, J.E., Norville, J.E., and Church, G.M. (2013). RNA-guided human genome engineering via Cas9. Science 339, 823-826.

Marraffini, L.A., and Sontheimer, E.J. (2008). CRISPR interference limits horizontal gene transfer in staphylococci by targeting DNA. Science 322, 1843-1845.

Mojica, F.J.M., D ez-Villase or, C.S., Garc a-Mart nez, J.S., and Soria, E. (2005). Intervening Sequences of Regularly Spaced Prokaryotic Repeats Derive from Foreign Genetic Elements. J Mol Evol 60, 174-182.

Pourcel, C., Salvignol, G., and Vergnaud, G. (2005). CRISPR elements in Yersinia pestis acquire new repeats by preferential uptake of bacteriophage DNA, and provide additional tools for evolutionary studies. Microbiology 151, 653-663.

Sapranauskas, R., Gasiunas, G., Fremaux, C., Barrangou, R., Horvath, P., and Siksnys, V. (2011). The Streptococcus thermophilus CRISPR/Cas system provides immunity in Escherichia coli. Nucl. Acids Res. 39, gkr606-gkr9282.

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Discovery of CRISPR and its function 1993 - 2005 - Francisco Mojica, University of Alicante, Spain Francisco Mojica was the first researcher to characterize what is now called a CRISPR locus, reported in 1993.

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What are genome editing and CRISPR-Cas9?

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What are genome editing and CRISPR-Cas9?

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From the 'Help Me Understand Genetics' primer form the GHR

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What are genome editing and CRISPR-Cas9?: MedlinePlus Genetics

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Gene editing occurs when scientists change the DNA of an organism. Learn more about this process and the different ways it can be done.

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Scientists edit human embryos to safely remove disease for the first time – here’s how they did it

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Scientists edit human embryos to safely remove disease for the first time – here’s how they did it

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Article from The Conversation

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Human eight cell embryo for IVF selection. K. Hardy, Wellcome Images , CC BY-SA

Scientists in the US have released a paper showing that they have successfully edited human embryos to correct a mutation that causes an inheritable heart condition. The findings are hugely important as they demonstrate for the first time that the technology may one day be used safely to edit out many devastating diseases.

But how close to curing genetic diseases does the new study actually take us? And how concerned should we be about the ethical implications of the technology?

The genome editing tool used, CRISPR-Cas9, has transformed the field of biology in the short time since its discovery in that it not only promises, but delivers. CRISPR has surpassed all previous efforts to engineer cells and alter genomes at a fraction of the time and cost.

The technology, which works like molecular scissors to cut and paste DNA, is a natural defence system that bacteria use to fend off harmful infections. This system has the ability to recognise invading virus DNA, cut it and integrate this cut sequence into its own genome - allowing the bacterium to render itself immune to future infections of viruses with similar DNA. It is this ability to recognise and cut DNA that has allowed scientists to use it to target and edit specific DNA regions.

When this technology is applied to "germ cells" - the sperm and eggs - or embryos, it changes the germline. That means that any alterations made would be permanent and passed down to future generations. This makes it more ethically complex, but there are strict regulations around human germline genome editing, which is predominantly illegal. The UK received a licence in 2016 to carry out CRISPR on human embryos for research into early development. But edited embryos are not allowed to be inserted into the uterus and develop into a fetus in any country.

Stockce/Shutterstock

Germline genome editing came into the global spotlight when Chinese scientists announced in 2015 that they had used CRISPR to edit non-viable human embryos - cells that could never result in a live birth. They did this to modify the gene responsible for the blood disorder β-thalassaemia. While it was met with some success, it received a lot of criticism because of the premature use of this technology in human embryos. The results showed a high number of potentially dangerous, off-target mutations created in the procedure.

Impressive results

The new study, published in Nature, is different because it deals with viable human embryos and shows that the genome editing can be carried out safely - without creating harmful mutations. The team used CRISPR to correct a mutation in the gene MYBPC3, which accounts for approximately 40% of the myocardial disease hypertrophic cardiomyopathy. This is a dominant disease, so an affected individual only needs one abnormal copy of the gene to be affected.

The researchers used sperm from a patient carrying one copy of the MYBPC3 mutation to create 54 embryos. They edited them using CRISPR-Cas9 to correct the mutation. Without genome editing, approximately 50% of the embryos would carry the patients' normal gene and 50% would carry his abnormal gene.

After genome editing, the aim would be for 100% of embryos to be normal. In the first round of the experiments, they found that 66.7% of embryos - 36 out of 54 - were normal after being injected with CRIPSR. Of the remaining 18 embryos, five had remained unchanged, suggesting editing had not worked. In 13 embryos, only a portion of cells had been edited.

The level of efficiency is affected by the type of CRISPR machinery used and, critically, the timing in which it is put into the embryo. The researchers therefore also tried injecting the sperm and the CRISPR-Cas9 complex into the egg at the same time, which resulted in more promising results. This was done for 75 mature donated human eggs using a common IVF technique called intracytoplasmic sperm injection. This time, impressively, 72.4% of embryos were normal as a result. The approach also lowered the number of embryos containing a mixture of edited and unedited cells (these embryos are called mosaics).

Sebastian Kaulitzk/Shutterstock

Finally, the team injected a further 22 embryos which were grown into blastocyst - a later stage of embryo development. These were sequenced and the researchers found that the editing had indeed worked. Importantly, they could show that the level of off-target mutations was low.

A brave new world?

So does this mean we finally have a cure for debilitating, heritable diseases? It's important to remember that the study did not achieve a 100% success rate. Even the researchers themselves stress that further research is needed in order to fully understand the potential and limitations of the technique.

In our view, it is unlikely that genome editing would be used to treat the majority of inherited conditions anytime soon. We still can't be sure how a child with a genetically altered genome will develop over a lifetime, so it seems unlikely that couples carrying a genetic disease would embark on gene editing rather than undergoing already available tests - such as preimplantation genetic diagnosis or prenatal diagnosis - where the embryos or fetus are tested for genetic faults.

Many people worry about where the line will be drawn between altering and ameliorating human embryos. If there is a risk that a person will have short stature because of an abnormality of growth hormone, would editing their genome to make them taller be considered a treatment or an enhancement? It is easy to see how the line could get blurred.

Most countries are debating the clinical, ethical and social significance of being able to genetically modify human embryos. It may be that some countries will never permit germline genome editing because of moral and ethical concerns. And even if the law in the UK was changed to allow genome editing, it would be highly regulated by the Human Fertilisation and Embryology Authority to ensure it is only used for medical reasons.

That doesn't mean that we shouldn't have a public debate about the ethical implications - it is hugely important that we do. But it is important to remember to celebrate the amazing advances of this field of research, which could one day help eradicate many devastating diseases, before jumping to conclusions about a brave new world.

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Scientists edit human embryos to safely remove disease for the first time - here's how they did it

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Two researchers are impressed with a pioneering study showing that it may be both safe and effective to edit out diseases in human embryos.

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Explainer: CRISPR technology brings precise genetic editing – and raises ethical questions

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Explainer: CRISPR technology brings precise genetic editing – and raises ethical questions

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Article from The Conversation

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A powerful new genetic engineering technique allows scientists to precisely cut out and replace DNA in genes. Jennifer Doudna/University of California Berkeley

A group of leading biologists earlier this month called for a halt to the use of a powerful new gene editing technique on humans. Known by the acronym CRISPR, the method allows precise editing of genes for targeted traits, which can be passed down to future generations.

With this explainer, we'll look at where this technique came from, its potential and some of the issues it raises.

Surgical precision

CRISPR stands for clustered regularly interspaced short palindromic repeats, which is the name for a natural defense system that bacteria use to fend off harmful infections.

Bacteria are infected by other microorganisms, called bacteriophages, or phages. The intricate details of the mechanism were elucidated around 2010 by two research groups led by Dr Doudna of the University of California Berkeley and Dr Charpentier of Umeå University in Sweden.

The CRISPR system recognizes specific patterns of DNA from the foreign invaders and decapacitates them by cutting the invader's DNA into pieces. The way that the bacteria target specific DNA and cleave it gave scientists a hint of its potential in other applications.

In 2013, two research groups, one lead by Dr Zhang of Massachusetts of Institute of Technology and the other by Dr Church of Harvard University, successfully modified this basic mechanism and turned it into a powerful tool that can now cut human genomic DNA at any desired location.

The ability to cut DNA or genes at specific locations is the basic requirement to modify the genome structure. Changes can be made in the DNA around the cleavage site which alter the biological features of the resulting cells or organisms. It is the equivalent of a surgical laser knife, which allows a surgeon to cut out precisely defective body parts and replace them with new or repaired ones.

Tool for gene discovery

Scientists have long sought after this sort of genome editing tools for living cells. Two other technologies, called zinc-finger nucleases and TALEN (transcription activator-like effector nuclease) are available to achieve the same result. However, the CRISPR technology is much easier to generate and manipulate. This means that most biological research laboratories can carry out the CRISPR experiments.

As a result, CRISPR technology has been quickly adopted by scientists all over the world and put it into various tests. It has been demonstrated to be effective in genome editing of most experimental organisms, including cells derived from insects, plants, fish, mice, monkeys and humans.

Such broad successes in a short period of time imply we've arrived at a new genome editing era, promising fast-paced development in biomedical research that will bring about new therapeutic treatments for various human diseases.

US Department of Energy

The CRISPR technology offers a novel tool for scientists to address some of the most fundamental questions that were difficult, if not impossible, to address before.

For instance, the whole human genomic DNA sequence had been deciphered many years ago, but the majority of information embedded on the DNA fragments are largely unknown. Now, the CRISPR technology is enabling scientists to study those gene functions. By eliminating or replacing specific DNA fragments and observing the consequences in the resulting cells, we can now link particular DNA fragments to their biological functions.

Recently, cells and even whole animals with desired genome alterations have successfully been generated using the CRISPR technology. This has proven highly valuable in various biomedical research studies, such as understanding the cause and effect relationship between specific DNA changes and human diseases. Studying DNA in this way also sheds light on the mechanisms underlying how diseases develop and provides insights for developing new drugs that eliminate specific disease symptoms.

With such profound implications in medical sciences, many biotech and pharmaceutical companies have now licensed the CRISPR technology to develop commercial products.

For example, a biotech company, Editas Medicine, was founded in 2013 with the specific goal of creating treatments for hereditary human diseases employing the CRISPR technology.

However, products derived from the use of CRISPR technology are yet to hit the market with FDA approval.

Call for ethical guidelines

With the CRISPR technology, scientists can now alter the genome composition of whole organisms, including humans, through manipulating reproductive cells and fertilized eggs or embryos. Those particular genetic traits are then passed down through generations. This brings hope to cure genetic defects that cause various hereditary human diseases, such as cystic fibrosis, haemophilia, sickle-cell anemia, Down syndrome and so on.

Unlike the current approaches of gene therapy which temporarily fix defective cells or organs through the introduction of corrected or functional genes, the CRISPR technology promises to correct the defect in the reproductive cells, producing progenies that are free of the defective gene. In other words, it can eliminate the root causes of hereditary human diseases.

DNA helix via www.shutterstock.com

In theory,then, hereditary features that people consider advantageous, such as higher intelligence, better body appearance and longevity, can be introduced into an individual's genome through CRISPR mediated reproductive cell modifications as well.

However, scientists do not yet fully understand all the possible side effects of editing human genomes. It is also the case, that there is no clear law to regulate such attempts.

That's why groups of prominent scientists in the field have recently initiated calls for ethical guidelines for doing such modifications of reproductive cells. The fear being that uncontrolled practice might bring about unforeseen disastrous outcomes in long run.

The guidelines call for a strong discouragement of any attempts at genome modification of reproductive cells for clinical application in humans, until the social, environmental, and ethical implications of such operations are broadly discussed among scientific and governmental organizations.

There is no doubt that the exciting and revolutionary CRISPR technology, under the guidance of carefully drafted and broadly accepted rules, will serve well for the well-being of human kind.

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Explainer: CRISPR technology brings precise genetic editing - and raises ethical questions

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Leading researchers have called for a ban on using a precise gene-editing technology on humans. How can CRISPR advance science and why is it raising concerns?

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Newborns and genome sequencing: Do we sacrifice privacy in the name of health?

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Newborns and genome sequencing: Do we sacrifice privacy in the name of health?

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An article from the Genetic Literacy project about a study that performed whole genome sequencing on healthy and sick newborns

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The day is coming when every newborn will have her or his genome sequenced, providing a personal health database for life. But will this ability to stay ahead of sickness compromise genetic privacy?

Initial findings of the ongoing BabySeq pilot project reported in January 2019 in The American Journal of Human Genetics demonstrate the power of genomics in predicting and preventing illness.

The National Institutes of Health unveiled BabySeq in 2013 with a news release, "NIH Seeks Proposals to Study Genomic Sequencing in Newborn Period." Using "genomic" instead of "genome" allows wiggle room to count kids who've had only their exomes sequenced, the 2 percent or so of the genome that encodes proteins - the parts most often implicated in disease. (The consumer DNA testing companies use far less information, typically a smattering of 750,000 or so SNP markers across the genome.)

The BabySeq "initiative will help us better understand how we can appropriately use this information to improve health and prevent disease in infants and children," said Eric Green, director of the National Human Genome Research Institute at the beginning.

The project is off to a great start. But if history provides a lesson, routine newborn genomic sequencing won't come without a fight, or at least objections.

Déjà vu all over again?

Genomic sequencing of newborns has a clinical precedent at the single-gene level: the screening for a few dozen "actionable" conditions that new parents sign off on. The tests are done a day or two after birth on a few drops of blood from a heel prick.

Newborn screening has been ongoing for half a century. The first test was for PKU (phenylketonuria), chosen because a restrictive medical diet from birth can prevent the intellectual disability that would otherwise ensue.

Despite the enormous success of newborn screening (see Baby's First Test), some people have protested. "The Government Has Your Baby's DNA" from CNN is a typical headline, omitting the fact that the testing is for the baby's own good. What to do with the info on stored blood spots has been the subject of much academic debate, but is moot considering that the sequences of A, C, T and G can be digitized, persisting even if the samples are tossed, like for the findings of any genetic test.

Another successful population-wide genetic testing effort is deCODE Genetics, which Wired dubbed "The World's Greatest Genetic Laboratory."

deCODE was the brainchild of Harvard neuropathology professor Kari Stefansson, who founded the "population-based genomics company" in 1996 with $12 million from seven US venture capitalist organizations. It was reborn as NextCODE Health after Amgen bought it in late 2012; a Chinese company took over in 2015.

Whatever the name, over the years deCODE's scientists have discovered many health-related gene variants by delving into the genomes of the Icelandic population, descended from just 20,000 or so Viking founders, with little immigration. Against such a uniform gene pool disease-causing mutations stand out, and researchers harvested forests of intertwined family trees. It's interesting to return to the initial objections to deCODE; I wrote about them two decades ago in The Scientist.

The anti-vaccination campaign that has lead to the return of measles illustrates the danger of distrusting government-sanctioned health tests. Opting out of newborn screening, in contrast, would only affect the particular child, perhaps delaying or missing a diagnosis of a treatable condition.

A clever experimental design

BabySeq was masterminded to maximize information, to test potential value of population-wide implementation. The protocol for the pilot study is described in BMC Pediatrics.

Two Boston area hospitals enrolled 127 healthy newborns and 32 sick babies in the neonatal intensive care unit (NICU). Half of the children in each group had their exomes or genomes sequenced. The parents of all of the participants gave a family history, and since all the babies had the standard heelprick for newborn screening, nobody knew which infants had their DNA sequenced.

For this trial run, the researchers tested the DNA for recessive variants of 310 genes that cause diseases (that is, they detected carriers as well as kids with the associated conditions). They also tested for five genes that elevate the risk of cancer: the two BRCA genes and three for Lynch syndrome (colon and other cancers).

A trove of data

Detailed tables of the recessive diseases festoon the paper, but what's important overall is the demonstrated value of newborn genomic sequencing.

The sequencing detected childhood-onset diseases that hadn't yet caused symptoms in fifteen (9.4 percent) of the babies. Ten of them were from the healthy group and five from the NICU group, but none of the discovered mutations were the reasons that the children were in the NICU.

And the findings are indeed actionable.

Detecting a mutation in a gene that causes hearing loss in teens alerted the care team to direct the parents to treatment that could preserve more hearing.

A child had a kidney condition that might not have been detected unless a physician knew to look for it.

The parents of six babies found to have heart muscle conditions were advised to track them with frequent EKGs and echocardiograms, avoid certain stimulants, choose certain sports, and follow a heart-healthy diet.

Two other conditions found in BabySeq are already detected with newborn screening - biotinidase deficiency and congenital adrenal hyperplasia - but the fuller sequencing picked up rare variants that screening would miss.

Perhaps the most useful information was pharmacogenetic, alerting parents and eventually their offspring to drugs that could be toxic. Eight of the 159 babies had mutations that would affect drug metabolism: four for fluoropyrimidine cancer drugs, three for thiopurine anti-inflammatories, and one for G6PD deficiency, a common disease worldwide that causes hemolytic anemia under certain conditions, like taking drugs to treat malaria or eating fava beans. (Hannibal Lecter refers to it in The Silence of the Lambs, explained here as involving his witnessing Russian soldiers during World War 2 eating his little sister.)

BabySeq found 2 babies with a BRCA2 mutation (elevated risk of breast, ovarian, prostate, and pancreatic cancer) and one with a mutation in the MSH2 gene, one of several behind Lynch syndrome (associated with colorectal, endometrial, gastric, and ovarian cancers).

All but one of the predictions was a surprise - no one in the extended family had the condition, although with extra digging a few relatives were found with the cancers or a heart condition.

In addition, 140 of the 159 infants had at least one recessive gene variant that would cause a disease if present in two copies. The median number was two, the most, seven. When these kids grow up, they need only compare these findings, listed on their smartphones or whatever data storage device we have in two or three decades, with their partners' to predict the risks to their potential children.

Further testing of the parents of newborns with errant genes revealed whether the mutation was inherited from them or originated in the children. That's important because a mutation in a parent would alert relatives to increased risk, but a child with a " de novo" (new) mutation could only pass it on to offspring. Ten of the 15 babies with mutations had de novo events - that is, a mutation in the egg or sperm, but not a parent. Testing parent-child trios is routine in rare disease diagnosis.

TMI?

A test that reveals actionable findings in nearly a tenth of a newborn population is clearly a positive, promising to shorten or prevent the "diagnostic odyssey" that many families with rare genetic diseases follow. And a genomic profile would provide a resource for medical situations beyond genetic diseases, with information on the physiology of all organ systems perhaps predicting how an individual would cope with other types of diseases.

But like the objections to newborn screening for the few dozen diseases, cataloging so much personal information has downsides.

How will we protect privacy? The use of genetic genealogy to find a suspect in the case of the Golden State Killer was obviously a good thing. But also it illustrated how DNA sequencing facilitates deducing identity. With a name and DNA profile from GEDmatch and Facebook, it's not that difficult to find people who might not want to be found.

Could genomic information stored at birth be accessed to process an application for preschool? College? A job? To select mates, much as the decades-old program Dor Yeshorim does to weed out recessive diseases in the Jewish community?

Could finding gene variants that hike testosterone production or increase risk for psychosis or narcissism be used against a candidate for political office?

If parents opt out of newborn genomic sequencing and a child develops preventable symptoms, would health insurers deny coverage?

When should the children of BabySeq have access to their data?

The challenge of what to do with genetic information is hardly new, but now it's no longer a hypothetical. The problem, I think, is that it's easier to predict applications in precision medicine than it is to imagine how DNA data, from birth, might be misused or abused.
Ricki Lewis is the GLP's senior contributing writer focusing on gene therapy and gene editing. She has a PhD in genetics and is a genetic counselor, science writer and author of The Forever Fix: Gene Therapy and the Boy Who Saved It, the only popular book about gene therapy. BIO. Follow her at her website or Twitter @rickilewis

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Newborns and genome sequencing: Do we sacrifice privacy in the name of health?

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The day is coming when every newborn will have her or his genome sequenced, providing a personal health database for life. But will this ability to stay ahead of sickness compromise genetic privacy? Initial findings of the ongoing BabySeq pilot project reported in January 2019 in The American Journal of Human Genetics demonstrate the power of genomics in predicting and preventing illness.

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Gene editing still has a few bugs in the system

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Gene editing still has a few bugs in the system

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Feb 2019 article about limitations of gene editing

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Gene editing has been in the news lately due to an ethically reckless experiment in which human embryos were subjected to an inefficient form of gene editing. The subjects, now born, gained uncertain protection from HIV in exchange for a big collection of potential risks. A large number of ethicists and scientists agreed that this isn't the sort of thing we should be using gene editing for.

That response contains an implicit corollary: there are some things that might justify the use of gene editing in humans. Now, a series of papers looks at some reasonable use cases in mice and collectively finds that the technology really isn't ready for use yet.

Use cases

Gene editing will likely always come with a bit of risk; when you're cutting and pasting DNA in millions of cells, extremely rare events can't be avoided. So the ethical questions come down to how we can minimize those risks and what conditions make them worth taking.

In the new work, spread across three papers, researchers tackle two genetic diseases that seem to tick most of the boxes for "worth the risk." The disease are Duchenne muscular dystrophy (DMD) and Hutchinson-Gilford progeria syndrome (HGPS). There are no effective treatments for either disease, and affected individuals die in their 20s or teens. Neither can be screened for effectively. For DMD, a third of the cases are due to new mutations; for HGPS, all of them are.

Both can be addressed by gene editing in mature cells rather than by editing in germ-line cells or early embryos. And the editing that is needed to return a cell to normal is relatively simple. So all in all, a fatal disease that is difficult to screen for and has no treatments can be addressed by relatively simple gene editing. These are exactly the use cases that many would consider ethical.

If these are the sorts of disorders we could treat with gene editing, how close are we to doing so? To find out, researchers decided to test out the systems in mice that had been engineered to carry mutations that cause these diseases in humans.

Tackling progeria

HGPS is caused by a mutation in a gene that encodes two proteins that help structure the cell's nucleus and the DNA it contains. The damaged form of one of those protein gets stuck immediately after it's sent into the nucleus, distorting the structure and altering gene activity. The result is a set of symptoms that resemble early and accelerated aging.

It's possible to delete a stretch of DNA that's specific to the damaged protein, while leaving the other protein untouched. So, two different research teams made CRISPR/Cas-9 constructs that would target this stretch of DNA and engineered them into a virus that can infect cells but can't duplicate once it's inside. These were tested in both human and mouse cells and found to work. So the researchers turned to actual mice.

It's unrealistic to think these viruses would infect every cell in the body. But past research found that mice with a mix of healthy and mutant cells could develop normally-the problems are apparently dependent in part on interactions among cells. The question is whether the virus can infect enough cells to make a difference. The answer is... sort of?

After a systemic infection, editing varied based on tissue. Over 13 percent of liver cells were edited, while only one percent of lung cells were; heart and muscle were somewhere in between. And these levels were somewhat helpful. The mice saw a slight improvement in body weight, and they lived a bit longer. As a percentage change, the difference was pretty large (over 25% in one study, even longer in the other), but that's in part because the life span was pretty dramatically shortened by the mutation.

Somewhat disturbingly, one of the two papers suggest that the mice die due to severe constipation.

Restoring muscle

DMD is another great candidate because the disease-causing mutations tend to occur in one of a large series of repeated units that encode an extended structure of the protein. It's possible to delete the damaged repeat and make a slightly shorter but still functional protein. Which is what the authors of the new research did. This wasn't the first time it had been tried, but this was the first report that followed the mice for a year after the gene editing took place.

That year turned out to be significant because editing continued to happen in the background at low levels throughout the year, meaning that the percentage of edited cells gradually went up. This happened even though the gene-editing virus didn't infect new cells, which suggests that it remained in place for long periods.

While the researchers also used a systemic infection of the virus, they tried to restrict the gene editing to muscles by engineering the virus with a stretch of DNA that ensured the editing genes were only active there. Except that didn't work, as some level of editing was found in many other organs. This included the testes, suggesting that a gene-edited version of the DNA might accidentally be passed on to the next generation.

Other potential problems included an immune response to both the virus that carried the editing constructs, and to the protein that did the editing. Either of these could prevent us from using multiple rounds of infections to make up for cases like HGPS, where editing in more cells appears to be important. The other thing is that a small fraction of the cells had large stretches near the targeted site that were deleted entirely. While this happened in far less than one percent of the infected cells, the number of cells we'll want to infect is extremely large.

Overall, the three papers present a consistent picture. The technology works, it's possible to fix genetic defects through gene editing, and the fixes can have an effect on health. But the editing isn't currently efficient enough to provide anything more than some partial help for people with these diseases. And that help comes with some significant risks: errors in editing, activity in the wrong cells, and an immune response that limits future interventions. We've got a lot of work ahead of us before this is ready for the clinic.

Nature Medicine, 2019. DOI: 10.1038/s41591-018-0338-6, 10.1038/s41591-019-0343-4, 10.1038/s41591-019-0344-3 ( About DOIs).

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Gene editing still has a few bugs in the system

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Gene editing has been in the news lately due to an ethically reckless experiment in which human embryos were subjected to an inefficient form of gene editing. The subjects, now born, gained uncertain protection from HIV in exchange for a big collection of potential risks.

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An explainer from the Duke University's Initiative for Science and Society

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What It Is

Facilitates precise, inexpensive, and easily programmable editing of genomic DNA.

Synopsis

CRISPR-Cas9, often abbreviated CRISPR (clustered, regularly interspersed short palindromic repeats), is a molecular tool that can edit DNA. CRISPR-Cas9 is naturally found in bacteria and other microbes, but scientists recently discovered that they could insert it into the cells of other organisms (like plants and animals) to edit their genomes (the collective DNA of a cell). This genome editing (sometimes called genome engineering) is akin to the more established field of genetic engineering (GE), wherein scientists alter the physical properties of an organism at the cellular level through manipulation of DNA. CRISPR-Cas9 is a significant improvement over other genome editing technologies, which are more challenging to design, more expensive, or less precise.

A cell's genome contains instructions that tell the cell how to function and how to interact with other cells. These instructions are encoded by a linear sequence of basic building blocks, called nucleotides, strung end-to-end. The basic unit of instruction is called a gene: each gene encodes information used for the production of other molecules, such as RNA and proteins, which operate and structure the cell.

Sometimes a cell is manipulated by foreign genetic instructions, like DNA injected into the cell by invading viruses. This is also true for bacteria, which are engaged in their own perpetual struggle against viruses. To fight back, bacteria (and other prokaryotes) have developed an antiviral defense - the CRISPR system. CRISPR (clustered, regularly interspersed short palindromic repeats) is a term that refers to copies of viral DNA that bacteria collect in the wake of viral infections. These viral DNA copies are used to remember the virus from which they are derived, allowing the bacteria to quickly attack and neutralize any subsequent infections.

The CRISPR system is mediated by Cas (CRISPR-associated) proteins, like the DNA-cutting Cas9. Cas9 is targeted at a specific sequence of DNA by a guide RNA molecule, which matches the target DNA sequence. Once Cas9 is guided to a target, it completely severs the DNA at a precise location.

Scientists recently found that CRISPR-Cas9 could function in non-prokaryotic cells, such as human cells, and could be used to precisely edit DNA. Specifically, they found that:

By changing the sequence of the guide RNA, CRISPR-Cas9 can be reprogrammed to target almost any location across a genome. For example, it can be used to cut and inactivate specific genes that researchers are interested in studying.

After Cas9 cuts the target DNA, the cut can be rejoined by a cell's DNA repair system. This repair process, called non-homologous end joining, is often imperfect, resulting in a random change (or mutation) in the DNA sequence such as an insertion, deletion, or substitution of nucleotides.

Going a step further, scientists can control this repair by inserting into the cell a short piece of synthetic (lab-manufactured) DNA that is largely identical to the target DNA, except for those modifications the scientists want to make to the target DNA. After the target DNA is cut, the synthetic DNA (with the desired changes) can serve as a template for the repair and be copied into the target DNA.

CRISPR-Cas9 can be targeted at multiple locations in the same genome (multiplex genome editing) with greater ease than other current genome editing systems.

Context

CRISPR-Cas9 is having a revolutionary impact. Since 2012, it has spread across the globe to be used by thousands of researchers, many of whom did not previously conduct genome editing or engineering. Recent patent trials in the US and Europe have highlighted the importance of CRISPR-Cas9 as a commercial technology. Because of its ease and simplicity, CRISPR-Cas9 is crossing over into the under-regulated world of do-it-yourself biology, or biohacking. This widespread use promises to drive a significant increase in the number and scope of new genome-edited products.

The majority of US biotechnology products, such as those involving genome editing, are regulated by the Environmental Protection Agency (EPA), Food and Drug Administration (FDA), and the US Department of Agriculture (USDA) under the Coordinated Framework for the Regulation of Biotechnology, a system of regulations created in 1986.

The Coordinated Framework sought to balance protecting health and environment with enabling innovation, and focused on the safety of the end product rather than the process by which that product was created. Thus, it is unclear if limited changes to an organism's DNA by genome editing (especially when the editing removes DNA rather than adds it) would be regulated by the current Coordinated Framework ( genetic engineering). This has been the case for a number of plants made with genome-editing techniques, like mushrooms edited with CRISPR-Cas9; the USDA said these were not to be regulated.

In July 2015 the Obama White House initiated an effort to overhaul this system, which led to the 2017 Update to the Coordinated Framework. The goal of the update was to "clarify the current roles and responsibilities of the EPA, FDA, and USDA in the regulatory process" for products of biotechnology. Another part of the 2015 Obama White House initiative was the development of an "expert analysis of the future landscape of biotechnology products," which was conducted by the National Academies of Sciences, Engineering, and Medicine (NASEM). The NASEM report was released shortly after the Coordinated Framework update. While it considered the update to be a good "starting point", it stated that "the profusion of biotechnology products over the next 5-10 years has the potential to overwhelm the US regulatory system."

The report went on to indicate that the relevant agencies responsible for the regulatory system should enhance their risk assessment mechanisms to account for new biotechnologies like CRISPR-Cas9 and their associated risks. For instance:

Genetic changes, especially in animals, might have unintended negative effects on the organism or environment that are not immediately discernable, perhaps requiring more extensive risk assessment modeling and monitoring.

Multiplex genome editing, as enabled by CRISPR-Cas9, might have unintended complications due to synergistic effects (the edits might interact in an unexpected way).

One potential risk of releasing genome edited organisms into the wild, e.g., via gene drives, is the possibility that the genetic change (or the CRISPR-Cas9 system itself) might unintentionally jump to another species (a horizontal gene transfer) or become unstable and nonfunctional.

Biohacker communities, which are usually small and decentralized, represent a unique challenge to government oversight agencies, which often rely on other parties (like companies) to work towards compliance.

Genome editing in humans, especially in relation to heritable, germline DNA, raises significant ethical questions about the boundaries of intervention.

Future Directions

This technology is accelerating the development of a number of GE projects, such as:

Gene drives, which are projects that seek to alter the genomes of wild populations of organisms by breeding them with GE organisms. These GE organisms are designed to spread, or "drive", a desired change into the wild population using "selfish" DNA (i.e., DNA that is inherited at higher rates than normal). For instance, a gene drive could be used to sterilize disease-carrying mosquitos or decrease the population of invasive rodents.

Other genome-edited animals, engineered for a food source, research, transplantable organs, disease control, or even hypoallergenic and novelty pets.

De-extinction efforts, like the proposal to resurrect the woolly mammoth.

Genome-edited bacteria, algae, and other microbes engineered for health, consumer, or environmental purposes.

Human gene therapy used to correct genetic disorders. The most immediate applications will be in adult disorders where the affected cells are easy to extract and treat, (e.g., sickle cell disease). In the future, CRISPR-Cas9 might be delivered directly into the body to alter the DNA in a particular cell type. CRISPR-Cas9 also opens the door for making changes to germline DNA (DNA that is heritable) to prevent the passage of genetic disorders to future generations. Such changes would be accomplished by editing DNA in eggs, sperm, or early embryos.

Recommended Citation

Duke SciPol, "CRISPR-Cas9 and Genome Editing" available at https://scipol.org/learn/science-library/crispr-cas9-and-genome-editing (05/17/2017).

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What It Is Facilitates precise, inexpensive, and easily programmable editing of genomic DNA. Synopsis CRISPR-Cas9, often abbreviated CRISPR (clustered, regularly interspersed short palindromic repeats), is a molecular tool that can edit DNA.

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Human genome editing and the identity politics of genetic disability

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Human genome editing and the identity politics of genetic disability

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An editorial on some ethical considerations of germline genome editing.

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As highlighted by Kleiderman and Kellner Stedman's ( 2019) recent article, the case for the use of genomic technologies, such as CRISPR/cas9 to undertake germline editing of human embryos, has been gaining momentum in recent years. In the UK, for example, a licence was granted to researchers in 2016 to allow CRISPR research using human embryos-although such embryos would not be permitted to develop past 14 days (HFEA 2016).

Monogenetic rare conditions are amongst those most frequently targeted by those developing human genome editing technologies, with recent claims of curative editing techniques being achieved for Duchenne Muscular Dystrophy (Nelson et al. 2019), Fragile X Syndrome (Yrigollen and Davidson 2019) and Cystic Fibrosis (Brothers et al. 2019), despite continued highly restrictive global governance of the practice, ongoing concerns about its future biological impacts and evolving debates regarding its social and ethical implications (Daley et al. 2019; Ormond et al. 2019).

Unlike other forms of reproductive genetic disease prevention, such as pre-conception or prenatal genetic screening, or the use of pre-implantation genetic diagnosis (techniques used to effectively filter out and eradicate embryos and foetuses affected by genetic conditions, or prevent their conception in the first place), germline genome editing techniques differ substantially in their approach to genetic disease prevention. As Cavaliere ( 2018) has argued, such technologies are targeted towards the correction or removal of disabling genetic traits, rather than the so-called seek and destroy approach of currently used technologies (Rothstein 2001). Through preservation of the life of the embryo (that would otherwise be disabled), and eradication only of the disabling trait, germline genome editing indeed appears to neatly sidestep one of the most critical social and ethical concerns levelled at current methods of genetic disease amelioration: that the disabling trait is considered more significant than the life of the embryo or foetus.

Parens and Asch ( 2000) have been amongst those who have most prominently developed this critique, initially in relation to prenatal testing and selective termination although more recently towards other technologies and practices. Parens and Asch argue that such technological intervention involves otherwise wanted embryos/foetuses being eradicated on the grounds of a single genetic difference: a genetic trait that is assigned such negative value as to render all other characteristics and traits of that (would-be) person irrelevant (Parens and Asch 2000). Given the nature of this critique, it does not take a large intellectual leap to arrive at the second most commonly cited disability rights critique of selective reprogenetic practices, known as the 'expressivist objection' (Buchanan 1996). This objection holds that selective reprogenetic practices not only prevent disabled people from coming into existence, but that their very availability-and the associated, and often clandestine, social pressures to use them (Clarke 1991; Markens et al. 2010)-both convey and perpetuate negative views about the particular disabling conditions they are targeted towards, and, by extension, people who currently live with those conditions (Asch and Wasserman 2015). Moreover, these negative appraisals of disability are seen as reverberating throughout wider society, affirming and reinforcing negative appraisals of the lives and worth not only of people who screened/tested for conditions, but of disabled people as a whole (Peterson 2012).

Recent empirical research by myself and other researchers clearly demonstrate the existence, ethical dilemmas and the ambivalence towards genetic technologies that emerge directly from these two concerns about reprogenetic technologies in the accounts of both genetically and non-genetically disabled people (Boardman 2014). My research has revealed, for example, that the majority of people with genetic disabilities feel that it would be a loss to society to have fewer people with their particular condition coming into the world (Boardman and Hale 2018) and the majority (90%) of family members of people with genetic disabilities such as haemophilia, for example, feel uncomfortable with the idea of pregnancy termination for the condition in their family (Boardman et al. 2019).

Despite this burgeoning body of research (e.g. Roadhouse et al. 2018; Barter et al. 2017; Stern et al. 2002; Tanjeja et al. 2004; Maxwell et al. 2011; Potrata et al. 2014; Gollust et al. 2003), however, the voices of the disability community remain largely under-represented in dialogue around the future development of reproductive genomic medicine such as genome editing (Wolbring and Diep 2016), and an ongoing and challenging relationship of mistrust and suspicion has been observed between the disability and genetics communities (Madeo et al. 2011).

The development of human germline genome editing is particularly significant; however, because unlike current practice, it directly challenges the first of the disability rights critiques of selective reproduction outlined above. By retaining-as an alternative to destroying-the (would-be) disabled embryo, and instead removing only the disabling trait, genome editing marks a significant departure in the way in which genetically selective reproduction operates. Whilst, as Kleiderman and Kellner Stedman ( 2019) outline, for many people with genetic conditions, this possibility suggests clear benefits for the embryo in question, their family and wider society; the assumption that this development is of universal benefit to the disability community may be challenged when expressivist objections and the identity politics of disability and personhood are taken into account.

As Shakespeare ( 2006) and others outline, research that explores the relationship between disabled people and the concept of cure, or other modes of disability removal (e.g. reprogenetics), is complex and multi-faceted, with disabled people experiencing particular forms of impairment (typically those involving pain, deterioration and shortened-life span) more likely to welcome the notion of disability removal than others (e.g. those with static impairments since birth). For example, recent research on adults with spinal muscular atrophy has highlighted a degree of ambivalence towards the first, and only recently licenced, drug therapy for the condition, nusinersen (Pacione et al. 2019). Some adults with SMA, particularly those with the static form of impairment (type II), regard their condition as an integral part of their personhood and identity and as a mediator of their interactions with the world. This deep cleft in the responses between genetically disabled people with contrasting experiences of their impairment and of disability and also the role of identity politics in their lives has also been mirrored in studies that explore attitudes towards genetic screening (Roadhouse et al. 2018; Boardman et al. 2017; Gollust et al. 2003). A recognition of the emerging literature that explores the role of impairment experiences and identity politics, therefore, is critical to understanding the broad spectrum of responses that are currently being observed amongst genetically disabled people to technologies that ameliorate genetic disability, of which genome editing is but one.

It is not yet possible to explore the new forms of personhood, identity and genetic relatedness that will inevitably emerge amongst individuals subject to embryonic germline genome editing in the future. The argument espoused by many prominent ethicists that life without disability is unequivocally preferable to one with disability would render genome editing a technology of undeniable benefit to the embryo in question (Savulescu et al. 2015; Savulescu and Singer 2019). However, such a focus on the benefit to individual embryos is to overlook the broader societal changes that genome editing will signal, as well as the potential negative impacts on existing persons with genetic conditions (Coller 2019). Indeed, unlike currently used forms of reprogenetic selection, genome editing, by treating germ cells, not only eliminates genetic variation in the treated embryo, but also makes permanent and heritable changes to the germline that will invariably be transferred to offspring, consequently reducing the incidence of the genetic condition in the human gene pool in ways that currently used technologies are not capable of.

People with lived experience of genetic conditions have much to offer our current understanding of the social, personal and ethical implications this technology will have. Expressivist concerns around genome editing, and the potential negative impacts on people with unedited genomes or spontaneous mutations are important considerations as we move towards genomic futures where genome editing is normalised (and non-use socially penalised) along with the inevitable changes to the demographic characteristics of society that will follow (Nuffield Council on Bioethics 2018: 78).

Whilst the technologies and methods of implementation of genomic medicine are likely to transform and shift overtime, the core ethical and social issues that genetic disability eradication and/or minimisation present will invariably remain the same. It is critical, therefore, that the literature exploring the views of people with the most vivid and visceral insights into the lived realities of genetic disability is included and valued in the processes of development and evaluation of new technologies such as genome editing (Petersen 2006). This is not only so that the potential impacts on them can be explored, but also so that informed decisions regarding which conditions are the appropriate targets of genome editing can be made. Indeed, given the inherent potential of germline genome editing, this inclusion is now of paramount importance, when it is considered that such voices and experiences could eventually become a resource of increasing inaccessibility in the future.

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Human genome editing and the identity politics of genetic disability

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As highlighted by Kleiderman and Kellner Stedman's ( 2019) recent article, the case for the use of genomic technologies, such as CRISPR/cas9 to undertake germline editing of human embryos, has been gaining momentum in recent years.

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Can we—should we—use CRISPR to edit human embryos, sperm or eggs to cure diseases?

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Can we—should we—use CRISPR to edit human embryos, sperm or eggs to cure diseases?

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A summary of a bioethics paper by its author, hosted on geneticliteracyproject.org

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he startling announcement by He Jiankui [two years] ago that he had created the first genetically modified human beings unleashed a torrent of criticism. It also brought to the surface common misunderstandings - even among scientists and ethicists - that reproductive uses of this genome-modifying tool have therapeutic value, will treat people with genetic disorders, will save lives, and will eradicate disease. None of those are true.

The twin girls that He helped create are publicly known as Lulu and Nana. Their father is HIV-positive. The scientist said he used CRISPR-Cas9 genome editing technology to disable a gene called CCR5 to mimic a naturally occurring gene deletion that appears to confer immunity against HIV.

A major criticism from the scientific community, which has otherwise been generally supportive of advancing gene technologies, was that He did not use the technology to address a serious medical need. That criterion stems from a 2017 report by the U.S. National Academy of Sciences and the National Academy of Medicine recommending that, once the technology is ready and safe, genetic modification of embryos could be allowed when there is a "serious disease or condition" to be addressed and no "reasonable alternatives" exist.

This scientific criticism of He's experiment was on target: Although HIV infection is a serious disease, there are proven ways to prevent transmission of the virus from an infected father to his offspring, and later in life to prevent or treat the infection.

That said, scientists criticizing He on the grounds that he did not treat a serious condition with no alternatives imply that other applications of CRISPR to modify eggs, sperm, or embryos could meet this standard. Indeed, many scientists hail reproductive applications of CRISPR (what I call rCRISPR) as potentially lifesaving and curative.

As I argued recently in the journal Bioethics, that claim for rCRISPR is mistaken and misleading. rCRISPR does not save lives or cure diseases that would otherwise exist. It merely aids in creating a person without a particular genetic disease who would otherwise not exist. The value here in creating healthy people - as opposed to healing people who would otherwise be sick - is nominal to none. If you are a genetically healthy person, you have a high chance of creating a healthy person right now. But nobody thinks you have an urgent moral reason to do so.

Let me be clear: I believe there are applications of CRISPR that do correctly purport to cure diseases in people who would otherwise have them. CRISPR-based gene therapies known as somatic applications, which are used in the bodies of people who have genetic diseases, have great curative potential. These aren't the target of my critique. In fact, it would be much better if we invested the money spent on reproductive CRISPR applications on somatic ones instead.

Here's why I say that using rCRISPR to modify eggs, sperm, and embryos does not cure disease.

Imagine an individual or couple at high risk for creating a child with a serious genetic disease. They have the following simplified range of options:

1. Create a genetically related child in the time-honored fashion who will be at high risk for the genetic disease.

2. Create a genetically related child using CRISPR who will be at very low risk for the genetic disease.

3. Create no genetically related child.

The existence of option C undermines the claim that rCRISPR applications are lifesaving or curative. If the prospective parent did not have option B available to them, option A would not inevitably happen, meaning they would not inevitably have a sick child. Individuals have a choice in the matter of creating children at high risk of genetic disease: They can choose option C.

Here is a different way of seeing the point that rCRISPR is not morally urgent because it does not involve a child whose existence, or illness, is inevitable. Compare the following scenarios: A doctor creates a cure for a serious and debilitating disease and administers it to a seriously sick child, thus healing her. This doctor saved a life, a morally commendable action. Now imagine that the doctor first injected the disease into the child that he cured. Now his action in its totality could hardly be called curative, for he first created the harm. His seemingly heroic act of healing now has dubious moral value.

This is similar to what occurs with rCRISPR. A clinician first creates an embryo with genetic defects, and then "rescues" it using rCRISPR. Calling this a cure or a therapy is a nonstandard use of those concepts, one that warrants a distinction from standard cures that save lives and prevent otherwise probable harms.

The analogy shows that an otherwise good act or cure can have its moral value undermined if it is part of a greater act that caused the disease in the first place.

Saying that people at risk for passing on serious genetic disease to their offspring can simply not have genetic children at all may seem harsh. But there are several options available to such individuals for becoming parents. They could adopt a child, an often-overlooked opportunity to become a parent that also helps an existing child in need of a family. They could use the egg or sperm of a healthy donor to create a child. Both of these options are expensive, but not more so than rCRISPR.

Reproductive applications of CRISPR simply cannot meet the criteria laid out by the U.S. national academies. They will not address a serious condition, because rCRISPR is used in the creation of a person who does not have to exist at all. Nonexistence is no condition, and thus not a serious one.

The real value of rCRISPR is not to the individual who is created but to the people who choose to use it to create a child. It helps individuals achieve their reproductive preferences by having genetically related children free of genetic diseases. But this preference, although perhaps deeply held by many, is not a medical need or an urgent one. And pre-implantation genetic diagnosis already enables people to meet this preference.

We should object to the investment of precious medical resources in bringing rCRISPR to market when there are serious and urgent medical needs that could be met elsewhere, including investing in somatic gene therapies that actually treat diseases.
Tina Rulli, Ph.D., is an assistant professor of philosophy at the University of California, Davis, and a member of the UC Davis Ethics Commons. A version of this article was originally posted at STAT News and has been reposted here with permission. STAT News can be found on Twitter @statnews

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Gattaca or life-saving? Can we-should we-use CRISPR to edit human embryos, sperm or eggs to cure diseases? | Genetic Literacy Project

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he startling announcement by He Jiankui [two years] ago that he had created the first genetically modified human beings unleashed a torrent of criticism. It also brought to the surface common misunderstandings - even among scientists and ethicists - that reproductive uses of this genome-modifying tool have therapeutic value, will treat people with genetic disorders, will save lives, and will eradicate disease.