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Beyond CRISPR babies: How human genome editing is moving on after scandal

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Beyond CRISPR babies: How human genome editing is moving on after scandal

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When researchers gather in London next week for the Third International Summit on Human Genome Editing, they will discuss the latest advances in deploying techniques such as CRISPR-Cas9 to treat genetic diseases, and will look ahead to the possible approval of the first genome-editing therapy later this year.

Despite that tantalizing future, it will be impossible to shake the shadow cast by the previous summit, in 2018. That meeting convened just a day after biophysicist He Jiankui announced that he had edited the genomes of three embryos that developed into living babies. The stunt ultimately earned him three years in prison for breaking China's laws on medical experiments.

Nearly five years later, researchers tell Nature that they do not expect a similar revelation at this year's summit - if only because He's experience will dissuade rogue researchers from going public with controversial genome-editing experiments. But that doesn't mean that such experiments aren't happening: "I wouldn't be surprised if there were other children that have been created with CRISPR-Cas9 in the years since 2018," says Eben Kirksey, a medical anthropologist at the University of Oxford, UK.

Since then, technological aspects of using genome editing to alter human embryos for reproductive purposes have not fundamentally changed, says Robin Lovell-Badge, a reproductive biologist at the Francis Crick Institute in London who is chairing the summit. "It's still an unsafe technique," he says, echoing a widespread scientific consensus that genome-editing technology is not ready for use in human embryos.

In the years since He's revelations, researchers have uncovered further concerns about the use of CRISPR-Cas9 in embryos, including that it can shuffle large segments of chromosomes. This adds to other potential problems with the technique, including the possibility of causing unwanted genetic changes, and of generating a fetus with a mosaic of edited and unedited cells.

Lacking regulation

From a regulatory standpoint, many countries - including the United States - still do not have mechanisms to ensure that edited embryos are not implanted, says Kirksey. In February, China released new guidelines on ethical conduct in biological and medical research. These address the need to inform study participants about potential risks, and provide a detailed description of how ethical review boards should run, says Joy Zhang, a sociologist at the University of Kent in Canterbury, UK. But they still rely on the conventional model of medical research based at hospitals, research institutes and universities, she says. "They ignore the fact that actually, increasingly, private ventures or even individuals can initiate a research project that could be quite damaging and quite cutting edge," she says. "We need to rethink how we govern."

That includes recognizing that restrictions on how government research funding can be spent might have decreasing influence on researchers' behaviour, says Zhang. Since his release from prison, He has been courting private investors to back a new project for a gene therapy for Duchenne's muscular dystrophy. "The bigger question that He Jiankui has raised was not so much creating designer babies per se, but the fact that there's an increasing number of scientific practices that are outside of conventional scientific institutions," says Zhang. "How do we track them?"

Furthermore, national regulations do not take into consideration the possible international scope of heritable genome editing, says María de Jesús Medina Arellano, a human-rights lawyer at the National Autonomous University of Mexico in Mexico City. "It's not that there are no laws. There are many laws," she says. "We need to change the approach to enforcement. This should be considered an international jurisdiction."

Affordability concerns

Researchers developing techniques for editing genomes in non-reproductive, or somatic, cells are also wrestling with an upcoming quandary: how to ensure that the therapies are broadly accessible. In 2018, there were very few trials of somatic genome-editing therapies; now there are well over 100, says Lovell-Badge. "Every week, it seems like there's a new one."

But prices for existing gene therapies are rocketing, which is making researchers worry that genome-editing therapies will be similarly unaffordable for much of the world. In November, the US Food and Drug Administration approved a gene therapy to treat haemophilia that has been priced at US$3.5 million per treatment. "There's a lot of hope, but the hope has to be balanced a bit with the way things are going," says Lovell-Badge.

Several sessions at the meeting will look at ways to ensure access in low- and middle-income countries - a subject of particular concern this year as regulators in the United States, United Kingdom and European Union weigh up an application from Vertex Pharmaceuticals in Boston, Massachusetts, and CRISPR Therapeutics in Zug, Switzerland, to approve a CRISPR-Cas9 therapy for sickle-cell disease, a genetic condition that mainly affects people of African, Indian or Middle Eastern descent. The treatment could become the first genome-editing therapy to be approved, but researchers are watching anxiously to see how much it will cost.

Over the past year and a half, cardiologist Kiran Musunuru at the University of Pennsylvania in Philadelphia and his colleagues have been developing a genome-editing therapy for the genetic disease phenylketonuria. The team is harnessing variations on the original CRISPR-Cas9 system that, unlike CRISPR-Cas9, do not involve creating double-strand breaks in the DNA. It is hoped that these techniques, called base editing and prime editing, can yield safer genome-editing therapies. But Musunuru says it is important to tackle the affordability question early in development. "I see enormous potential for inequities," he says.

Genome-editing technologies must also be tailored to specific DNA sequences. The relative dearth of information on such sequences from individuals of non-European descent could leave regions of the world without access to genome editing therapies that will work for them.

One development that could facilitate access in low- and middle-income countries is the effort to expand vaccine-manufacturing capacity in the global south. Some mRNA vaccines against COVID-19 rely on a lipid nanoparticle to shield the mRNA strand and help it to penetrate cell membranes. It's possible that genome-editing therapies, which also use snippets of RNA, will involve similar delivery systems, says Musunuru, so could use the same fundamental technology. "If it hadn't been for the pandemic, we wouldn't be where we are," he says. "If you had asked me five years ago if we could do the things we could do now, I would have said, 'That would be amazing, but no.'"
doi: https://doi.org/10.1038/d41586-023-00625-w

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Beyond CRISPR babies: How human genome editing is moving on after scandal

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Researchers will discuss advances in genome-editing technologies - and the ethics of deploying them - at a major international summit. Researchers will discuss advances in genome-editing technologies - and the ethics of deploying them - at a major international summit.

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The human genome needs updating. But how do we make it fair?

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The human genome needs updating. But how do we make it fair?

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n June 2000, Bill Clinton, the then US president, stood smilingly next to the leaders of the Human Genome Project. "In genetic terms, all human beings, regardless of race, are more than 99.9% the same," he declared. That was the message when the first draft of the human genome sequence was revealed at the White House.

The single string of As, Ts, Cs and Gs eventually became the first human reference genome. Since its publication in 2003, the reference has revolutionised genome sequencing and helped scientists find thousands of disease-causing mutations. Yet at its core is a somewhat ironic problem: the code meant to represent the human species is mostly based on just one man from Buffalo, New York.

Though humans are very similar, "One person is not representative of the world," says Pui-Yan Kwok, a specialist in genome analysis based at University of California, San Francisco and Academia Sinica in Taiwan. As a result, most genome sequencing is fundamentally biased.

This bias limits the kind of genetic variation that can be detected, leaving some patients without diagnoses and potentially without proper treatment. What is more, people who share less ancestry with the man from Buffalo will probably benefit less from the incoming era of precision medicine, which promises to tailor healthcare to individuals.

To combat this, researchers have started to assemble reference genomes for specific countries, including South Korea, Japan, Sweden, Denmark and the United Arab Emirates. They hope this will serve their populations better, but critics worry it could turn migrants into second-class citizens in their healthcare systems. Now, a huge new project is offering a different solution with the aim to represent global diversity: a human pangenome.

recision medicine, also known as personalised medicine, has been a buzzword within the medical community for years and it undeniably sounds good. "Getting the right medicine to the right patient at the right time is the tagline," says Neil Hanchard, a physician scientist at the US National Human Genome Research Institute.

But standard genome sequencing misses a lot of variation that could be connected to disease. In most cases, it works by chopping DNA into small bits known as "short reads", before sequencing them and organising them into a genome using the reference as a guide.

Single nucleotide variants (SNVs) - a change from a C to a T in the code of a gene, say - are mostly easy to spot this way, but larger chunks of variation known as structural variants (SVs) are trickier. New sections, sometimes hundreds or thousands of base pairs long, can go undetected, as can sections that are missing, reversed or moved somewhere else. In those cases, short reads cannot easily be mapped to the reference and "a whole bunch", says Kwok, are thrown away.

Former US president Bill Clinton hosts the launch of the Human Genome project in June 2000. Photograph: Stephen Jaffe/AFP/Getty Images

This means that standard genome sequencing is biased towards the SVs already in the reference. If your SVs differ, you end up with a sequence that does not fully capture your personal variation. As it is these small differences between people that we hope will tell us, for example, why one person might respond well to a medicine but another person will not, that is bad news.

Kwok's work hints at the amount of SVs going undetected. In 2019, his team analysed samples from 154 people around the world and found 60m base pairs-worth of SV genome content missing from the reference, with much more still out there. A follow-up of 338 people that looked only for extra inserted DNA found nearly 130,000 new sequences.

But SVs also appear to show different frequency patterns in different populations. By extension, says Kwok, if a person "is from a population quite different from the person from which the genome reference is derived, there will be more misalignment" when their short reads are mapped to the reference. Consequently, he says: "We may miss risk variants in those regions not represented in the reference."

This lack of representation is a general problem in genomics. Even the more studied SNVs show large data gaps. Recently, for example, Hanchard and his colleagues sampled 426 individuals from 50 ethnolinguistic groups across Africa and found more than 3m new SNVs, mostly from populations that had never been sampled before. "We haven't even touched [SVs]," says Hanchard, "but our preliminary data suggests it's going to be more of the same."

Such data disparities directly affect medical outcomes. For example, if a person with a rare variant has a rare disease, there is a good chance the variant is responsible. But often we do not know whether variants are genuinely rare, or just common in understudied populations. In those cases, doctors cannot give a diagnosis. "For persons with non-European ancestry, that occurs a lot more," says Hanchard.

As we move into an era of precision medicine, that will only become more important. Kári Stefánsson, whose Reykjavik-based biotechnology company DeCode Genetics specialises in connecting the dots between genetic variants and disease, says that what keeps him up at night is that our understanding of diversity within populations of European descent is now so good that we can start to use it for precision medicine. But for other populations, "We do not have the same kind of data," he says. "[This] is going to increase healthcare disparities above and beyond what they are today."

hile there are no genetic underpinnings that meaningfully group people into different races, some believe it makes sense to create references to capture the variation within specific populations, such as ethnic groups and nation states. One country that now has its own reference is Denmark.

"What we see is that there's a lot of variation that [has only been detected in] the Danish population," says computational biologist Simon Rasmussen of Copenhagen University, who led the work. That is a strong argument for a local reference, and the appeal is obvious: a reference based on Danes is uniquely positioned to supercharge the Danish healthcare system.

Framing genomes in terms of nationality does inevitably lead to exclusion

Jenny Reardon, sociologist

But some criticise national genomes for focusing too much on differences between populations, rather than individuals. Medical anthropologist Emma Kowal of Deakin University in Victoria, Australia, worries that national genomes might "keep the idea of race alive". And framing genomes in terms of nationality does inevitably lead to exclusion, says Jenny Reardon, a sociologist of the life sciences based at the University of California, Santa Cruz. "We are deciding, in effect, who is Danish and who is not."

Rasmussen admits the reference would be less useful for the 15% of the Danish population who are migrants or their descendants. Samples from people with mixed ancestry were even removed during the selection for the reference. But because of consent problems the reference never made it to the clinic, so Rasmussen and his team want to create another. For that, he says: "We want to take a different [selection] approach." Exactly how is yet to be determined.

There is an alternative to the national genomes, though. Instead of zooming in on different populations, the Human Pangenome Reference Consortium wants to zoom out; overlaying many genomes to create a reference that has variation built into it - a pangenome. The consortium recently published the first draft of such a reference in a preprint.

State-of-the-art gene-sequencing machines offer the possibility of medicine tailored to each patient. Photograph: Carolyn Fong/Carolyn Fong/NYT/ eyevine

Made up of 47 exquisitely detailed genomes, the draft represents the first chunk of the 350 genomes it is planning to sequence to include the most common variation across the world. "This is not a standard that has ever been performed before," says Karen Miga of the University of California, Santa Cruz, who is part of the consortium.

But the project is not just about sequencing more diverse data. "We need to come up with a better data structure to encode that information," says Miga's colleague Ting Wang of Washington University School of Medicine in St Louis, Missouri.

That data structure is called a genome graph. In contrast to the current reference, which is just a long string of letters, the genome graph shows variation between genomes as detours on an otherwise shared path. That will enable researchers and doctors to map short reads to the version of the path that best fits their sample.

The natural question is: how does one choose who gets to represent the world? The first genomes qualified because of their high technical quality, but the consortium will need to choose new samples in future. Since Africa is the cradle of humanity, Miga says: "The vast majority of the genomes that we are including are of African ancestry."

From Reardon's perspective, however, 350 people might do a better job of representing the world than one person, but "[the consortium] have made some choices about groups," she says. "Who did they sample? Who did they not sample?" As long as the reference contains only a subset, arguably someone will not make the cut.

Miga does not deny that. "[We are] really trying to capture common variation at a global level, so things you would see quite frequently," she says. Documenting common variation in this case leaves out uncommon variation. "If you're looking for something extremely rare," she says, "that is not our charge at the moment."

n an ideal world, individuals would have their genomes sequenced without the use of a reference. This has long been held up as the ultimate, problem-free solution, but hardly anyone believes that is on the cards. "It's not a trivial undertaking and I don't see it being non-trivial in 10 years' time," says Hanchard.

And rather than using a broad, global pangenome, countries might be swayed by a reference more tuned to their population, as well as maintained and controlled by themselves. "We don't really expect anyone other than the Danes to make a Danish reference genome," says Rasmussen, who hopes the next iteration will be run by Denmark's state-controlled National Genome Centre, potentially as part of the EU's Genome of Europe project.

Hanchard also sees the benefit of local or regional references. "[The pangenome] is not going to have all the variation represented," he says. He is part of the H3Africa consortium, which aims to bring the benefits of genomics to Africa and is considering an Africa-specific genome graph. At the same time, he expects all these references will probably eventually coalesce.

When asked about his hopes for the future of genomics, he speaks of knowing and understanding the variation as it relates to himself, or anyone else with Jamaican ancestry. "I would love to get to a point where everyone feels represented and that this is for them, as much as it is for any particular group," he says. "We are from one humanity, that's the important part."

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The human genome needs updating. But how do we make it fair?

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n June 2000, Bill Clinton, the then US president, stood smilingly next to the leaders of the Human Genome Project. "In genetic terms, all human beings, regardless of race, are more than 99.9% the same," he declared. That was the message when the first draft of the human genome sequence was revealed at the White House.

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Why the human genome was never completed

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Why the human genome was never completed

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https://www.bbc.com/future/article/20230210-the-man-whose-genome-you-can-read-end-to-end

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Why the human genome was never completed

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No human genome has ever been read in its entirety before. This year, scientists expect to pass that milestone for the first time.

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Artificial intelligence can improve efficiency of genome editing

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Artificial intelligence can improve efficiency of genome editing

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Artificial intelligence can improve efficiency of genome editing

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Researchers at the University of Zurich have developed a new tool that uses artificial intelligence to predict the efficacy of various genome-editing repair options. Unintentional errors in the correction of DNA mutations of genetic diseases can thus be reduced.

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NIH software assembles complete genome sequences on-demand

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NIH software assembles complete genome sequences on-demand

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National Institutes of Health researchers have developed and released an innovative software tool to assemble truly complete (i.e., gapless) genome sequences from a variety of species. This software, called Verkko, which means "network" in Finnish, makes the process of assembling complete genome sequences more affordable and accessible. A description of the new software was published today in Nature Biotechnology.

Verkko grew from assembling the first gapless human genome sequence, which was finished last year by the Telomere-to-Telomere (T2T) consortium, a collaborative project funded by the National Human Genome Research Institute (NHGRI), part of NIH.

"We took everything we learned in the T2T project and automated the process," said NHGRI associate investigator Sergey Koren, Ph.D., who led the creation of Verkko and is senior author on the paper. "Now with Verkko, we can essentially push a button and automatically get a complete genome sequence."

The T2T consortium used new DNA sequencing technologies and analytical methods to generate and assemble the remaining 8-10% of the human genome sequence. However, the researchers assembled those fragments manually - a process that took this massive and highly skilled team several years to complete. Verkko can finish the same task in a couple of days.

We took everything we learned in the T2T project and automated the process. Now with Verkko, we can essentially push a button and automatically get a complete genome sequence.

Assembling a genome sequence is like putting together a jigsaw puzzle, and different DNA sequencing technologies generate different types of genomic puzzle pieces. Some are small and highly detailed, while others are much bigger though the image is blurry. Verkko compares and assembles both types of pieces to generate a complete and accurate picture.

Verkko starts by putting together the small, detailed pieces, creating many partially assembled but disconnected segments of sequence. Then, Verkko compares the assembled regions with the larger, less precise pieces. These larger pieces serve as a framework to order the more detailed regions. The final product is an accurate and complete genome sequence.

The researchers tested Verkko with human and non-human genome sequencing data. The software quickly and precisely assembled the sequences of whole chromosomes, which was once a painstaking feat.

As Verkko leads to more complete human genome sequences, researchers can better assess human genomic diversity. With only one gapless human genome sequence, scientists currently lack knowledge about the diversity of many portions of the genome, such as regions of highly repetitive DNA, across the human population.

Verkko will also accelerate efforts to generate gapless genome sequences of species commonly used in research, such as mice, fruit flies and zebrafish, improving their usefulness to scientists. Additionally, generating gapless genome sequences from a variety of plants, animals and other organisms will aid in comparative genomics, the study of the differences and similarities among the genomes of diverse species.

"Verkko can democratize generating gapless genome sequences," said Adam Phillippy, Ph.D., an NHGRI senior investigator who worked on the T2T project and the development of Verkko. "This new software will make assembling complete genome sequences as affordable and routine as possible."

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NIH software assembles complete genome sequences on-demand

# data[].attributes.attachment_link.description
National Institutes of Health researchers have developed and released an innovative software tool to assemble truly complete (i.e., gapless) genome sequences from a variety of species. This software, called Verkko, which means "network" in Finnish, makes the process of assembling complete genome sequences more affordable and accessible.

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Gene therapy is not a new field; it has been evolving for decades. Despite the best efforts of researchers around the world, however, gene therapy has seen only limited success. Why?

Gene therapy poses one of the greatest technical challenges in modern medicine. It is very hard to introduce new genes into cells of the body and keep them working. And there are financial concerns: Can a company profit from developing a gene therapy to treat a rare disorder? If not, who will develop and pay for these life-saving treatments?

Let's look at some of the main challenges in gene therapy.

Gene delivery and activation

For some disorders, gene therapy will work only if we can deliver a normal gene to a large number of cells-say several million-in a tissue. And they have to the correct cells, in the correct tissue. Once the gene reaches its destination, it must be activated, or turned on, to make the protein it encodes. And once it's turned on, it must remain on; cells have a habit of shutting down genes that are too active or exhibiting other unusual behaviors.

Introducing changes into the wrong cells Targeting a gene to the correct cells is crucial to the success of any gene therapy treatment. Just as important, though, is making sure that the gene is not incorporated into the wrong cells. Delivering a gene to the wrong tissue would be inefficient, and it could cause health problems for the patient.

For example, improper targeting could incorporate the therapeutic gene into a patient's germline, or reproductive cells, which ultimately produce sperm and eggs. Should this happen, the patient would pass the introduced gene to his or her children. The consequences would vary, depending on the gene.

Our immune systems are very good at fighting off intruders such as bacteria and viruses. Gene-delivery vectors must be able to avoid the body's natural surveillance system. An unwelcome immune response could cause serious illness or even death.

The story of Jesse Gelsinger illustrates this challenge. Gelsinger, who had a rare liver disorder, participated in a 1999 gene therapy trial. He died of complications from an inflammatory response shortly after receiving a dose of experimental adenovirus vector. His death halted all gene therapy trials in the United States for a time, sparking a much-needed discussion on how best to regulate experimental trials and report health problems in volunteer patients.

One way researchers avoid triggering an immune response is by delivering viruses to cells outside of the patient's body. Another is to give patients drugs to temporarily suppress the immune system during treatment. Researchers use the lowest dose of virus that is effective, and whenever possible, they use vectors that are less likely to trigger an immune response.

Disrupting important genes in target cells

A good gene therapy is one that will last. Ideally, an introduced gene will continue working for the rest of the patient's life. For this to happen, the introduced gene must become a permanent part of the target cell's genome, usually by integrating, or "stitching" itself, into the cell's own DNA. But what happens if the gene stitches itself into an inappropriate location, disrupting another gene?

This happened in two gene therapy trials aimed at treating children with X-linked Severe Combined Immune Deficiency (SCID). People with this disorder have virtually no immune protection against bacteria and viruses. To escape infections and illness, they must live in a completely germ-free environment.

Between 1999 and 2006, researchers tested a gene therapy treatment that would restore the function of a crucial gene, gamma c, in cells of the immune system. The treatment appeared very successful, restoring immune function to most of the children who received it.

But later, 5 of the children developed leukemia, a blood cancer. Researchers found that the newly transferred gamma c gene had stitched itself into a gene that normally helps regulate the rate at which cells divide. As a result, the cells began to divide out of control, causing leukemia. Doctors treated 4 of the patients successfully with chemotherapy, but the fifth died.

This unfortunate incident raised important safety concerns, and researchers have since developed safer ways to introduce genes. Some newer vectors have features that target DNA integration to specific "safe" places in the genome where it won't cause problems. And genes introduced to cells outside of the patient can be tested to see where they integrated, before they are returned to the patient.

Many genetic disorders that can potentially be treated with gene therapy are extremely rare, some affecting just one person out of a million. Gene therapy could be life-saving for these patients, but the high cost of developing a treatment makes it an unappealing prospect for pharmaceutical companies.

Developing a new therapy-including taking it through the clinical trials necessary for government approval- is very expensive. With a limited number of patients to recover those expenses from, developers may never earn money from treating such rare genetic disorders. And some patients may never be able to afford them.

Some diseases that can be treated with gene therapy, such as cancer, are much more common. However, many promising gene therapy approaches are individualized to each patient. For example, a patient's own cells may be taken out, modified with a therapeutic gene, and returned to the patient. This individualized approach may prove to be very effective, but it's also costly. It comes at a much higher price than drugs that can be manufactured in bulk, which can quickly recover the cost of their development.

If drug companies find a gene therapy treatment too unprofitable, who will develop it? Is it right to make expensive therapies available only to the wealthy? How can we bring gene therapy to everyone who needs it?

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Gene therapy is not a new field; it has been evolving for decades. Despite the best efforts of researchers around the world, however, gene therapy has seen only limited success. Why? Gene therapy poses one of the greatest technical challenges in modern medicine.

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In the most straightforward cases, gene therapy adds a functional copy of a gene to cells that have only non-functional copies. Gene Delivery: Tools of the Trade summarizes the viral and non-viral vectors most commonly used for this type of gene delivery.

But there are times when simply adding a working copy of the gene won't solve the problem. In these cases, scientists have had to think outside the box to come up other approaches.

To address the below situations, you could prevent the cell from making the protein the gene encodes, repair the gene, or find a work-around aimed at blocking or eliminating the protein.

Dominant negative
Some mutations in genes lead to the production of a dominant-negative protein. A dominant-negative protein may block a normal protein from doing its job (for an example, see Pachyonychia congenita). In this case, adding a functional copy of the gene won't help, because the dominant-negative protein will still be there causing problems.

Gain-of-function
A gain-of-function mutation makes a protein that acts abnormally, causing problems all on its own. For example, let's say a signal activates protein X, which then tells the cell to start growing and dividing. A gain-of-function mutation may make protein X activate cell growth even when there's no signal, leading to cancer.

Improper regulation
Sometimes a disorder can involve a protein that is functioning as it should-but there's a problem with where, when, or how much protein is being made. These are problems of gene regulation: genes need to be turned "on" in the right place, at the right time, and to the right level.

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In the most straightforward cases, gene therapy adds a functional copy of a gene to cells that have only non-functional copies. Gene Delivery: Tools of the Trade summarizes the viral and non-viral vectors most commonly used for this type of gene delivery.

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Researchers have been working for decades to bring gene therapy to the clinic, yet very few patients have received any effective gene-therapy treatments. But that doesn't mean gene therapy is an impossible dream. Even though gene therapy has been slow to reach patients, its future is very encouraging. Decades of research have taught us a lot about designing safe and effective vectors, targeting different types of cells, and managing and minimizing immune responses in patients. We've also learned a lot about the disease genes themselves. Today, many clinical trials are underway, where researchers are carefully testing treatments to ensure that any gene therapy brought into the clinic is both safe and effective.

Below are some gene therapy success stories. Successes represent a variety of approaches-different vectors, different target cell populations, and both in vivo and ex vivo approaches-to treating a variety of disorders.

Sebastian Misztal was a patient in a hemophilia gene therapy trial in 2011. Following the treatment, Misztal no longer had spontaneous bleeding episodes.
Credit: UCLH/UCL NIHR Biomedical Research Centre

Several inherited immune deficiencies have been treated successfully with gene therapy. Most commonly, blood stem cells are removed from patients, and retroviruses are used to deliver working copies of the defective genes. After the genes have been delivered, the stem cells are returned to the patient. Because the cells are treated outside the patient's body, the virus will infect and transfer the gene to only the desired target cells.

Severe Combined Immune Deficiency (SCID) was one of the first genetic disorders to be treated successfully with gene therapy, proving that the approach could work. However, the first clinical trials ended when the viral vector triggered leukemia (a type of blood cancer) in some patients. Since then, researchers have begun trials with new, safer viral vectors that are much less likely to cause cancer.

Adenosine deaminase (ADA) deficiency is another inherited immune disorder that has been successfully treated with gene therapy. In multiple small trials, patients' blood stem cells were removed, treated with a retroviral vector to deliver a functional copy of the ADA gene, and then returned to the patients. For the majority of patients in these trials, immune function improved to the point that they no longer needed injections of ADA enzyme. Importantly, none of them developed leukemia.

Gene therapies are being developed to treat several different types of inherited blindness-especially degenerative forms, where patients gradually lose the light-sensing cells in their eyes. Encouraging results from animal models (especially mouse, rat, and dog) show that gene therapy has the potential to slow or even reverse vision loss.

The eye turns out to be a convenient compartment for gene therapy. The retina, on the inside of the eye, is both easy to access and partially protected from the immune system. And viruses can't move from the eye to other places in the body. Most gene-therapy vectors used in the eye are based on AAV (adeno-associated virus).

In one small trial of patients with a form of degenerative blindness called LCA (Leber congenital amaurosis), gene therapy greatly improved vision for at least a few years. However, the treatment did not stop the retina from continuing to degenerate. In another trial, 6 out of 9 patients with the degenerative disease choroideremia had improved vision after a virus was used to deliver a functional REP1 gene.

Credit: Jean Bennett, MD, PhD, Perelman School of Medicine, University of Pennsylvania; Manzar Ashtari, Ph.D., of The Children's Hospital of Philadelphia, Science Translational Medicine.

People with hemophilia are missing proteins that help their blood form clots. Those with the most-severe forms of the disease can lose large amounts of blood through internal bleeding or even a minor cut.

In a small trial, researchers successfully used an adeno-associated viral vector to deliver a gene for Factor IX, the missing clotting protein, to liver cells. After treatment, most of the patients made at least some Factor IX, and they had fewer bleeding incidents.

Patients with beta-Thalassemia have a defect in the beta-globin gene, which codes for an oxygen-carrying protein in red blood cells. Because of the defective gene, patients don't have enough red blood cells to carry oxygen to all the body's tissues. Many who have this disorder depend on blood transfusions for survival.

In 2007, a patient received gene therapy for severe beta-Thalassemia. Blood stem cells were taken from his bone marrow and treated with a retrovirus to transfer a working copy of the beta-globin gene. The modified stem cells were returned to his body, where they gave rise to healthy red blood cells. Seven years after the procedure, he was still doing well without blood transfusions.

A similar approach could be used to treat patients with sickle cell disease.

In 2012, Glybera became the first viral gene-therapy treatment to be approved in Europe. The treatment uses an adeno-associated virus to deliver a working copy of the LPL (lipoprotein lipase) gene to muscle cells. The LPL gene codes for a protein that helps break down fats in the blood, preventing fat concentrations from rising to toxic levels.

Several promising gene-therapy treatments are under development for cancer. One, a modified version of the herpes simplex 1 virus (which normally causes cold sores) has been shown to be effective against melanoma (a skin cancer) that has spread throughout the body. The treatment, called T-VEC, uses a virus that has been modified so that it will (1) not cause cold sores; (2) kill only cancer cells, not healthy ones; and (3) make signals that attract the patient's own immune cells, helping them learn to recognize and fight cancer cells throughout the body. The virus is injected directly into the patient's tumors. It replicates (makes more of itself) inside the cancer cells until they burst, releasing more viruses that can infect additional cancer cells.

A completely different approach was used in a trial to treat 59 patients with leukemia, a type of blood cancer. The patients' own immune cells were removed and treated with a virus that genetically altered them to recognize a protein that sits on the surface of the cancer cells. After the immune cells were returned to the patients, 26 experienced complete remission.

Patients with Parkinson's disease gradually lose cells in the brain that produce the signaling molecule dopamine. As the disease advances, patients lose the ability to control their movements.

A small group of patients with advanced Parkinson's disease were treated with a retroviral vector to introduce three genes into cells in a small area of the brain. These genes gave cells that don't normally make dopamine the ability to do so. After treatment, all of the patients in the trial had improved muscle control.

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Researchers have been working for decades to bring gene therapy to the clinic, yet very few patients have received any effective gene-therapy treatments. But that doesn't mean gene therapy is an impossible dream. Even though gene therapy has been slow to reach patients, its future is very encouraging.

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What were the goals of the Human Genome Project?

A special committee of the U.S. National Academy of Sciences outlined the original goals for the Human Genome Project in 1988, which included sequencing the entire human genome in addition to the genomes of several carefully selected non-human organisms.

Eventually the list of organisms came to include the bacterium E. coli, baker's yeast, fruit fly, nematode and mouse. The project's architects and participants hoped the resulting information would usher in a new era for biomedical research, and its goals and related strategic plans were updated periodically throughout the project.

In part due to a deliberate focus on technology development, the Human Genome Project ultimately exceeded its initial set of goals, doing so by 2003, two years ahead of its originally projected 2005 completion. Many of the project's achievements were beyond what scientists thought possible in 1988.
President Bill Clinton and Francis Collins, M.D., Ph.D., (NHGRI Director) at a June 2000 event at the White House celebrating the draft human genome sequence generated by the Human Genome Project. Dr. Collins served as the de facto leader of the International Human Genome Sequencing Consortium, the group that sequenced the human genome during the Human Genome Project. (NHGRI Photo Archive)

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A fact sheet detailing how the project began and how it shaped the future of research and technology.