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Benefits and Ethical Concerns of CRISPR – Pros and Cons

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Benefits and Ethical Concerns of CRISPR – Pros and Cons

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Main idea:
Benefits of using CRISPR

Arguments:
- Cancer Therapeutics: New immunotherapies can be developed using CRISPR to treat cancer. Scientists can genetically modify T-cells using CRISPR to locate and kill cancer cells.
- Curing Genetic Diseases: CRISPR technology can eliminate the genes that cause genetic diseases such as diabetes, cystic fibrosis.
Drug Research: Scientists are predicting that CRISPR could potentially speed up the drug discovery process.
- Pest Resilient Crops: According to Jennifer Doudna, a CRISPR pioneer, genome editing can address pest and nutrition challenges facing the agriculture, particularly in light of both climate change and rapid population growth.

Dialogue:
Some people are worried that their newborn can have any genetic diseases, but with CRISPR they already have a solution.

Summary:
It can treat cancer, and by only that a lot of people would be cured. It can also cure genetic diseases, making people trust more on this solution, and it can help a little as well in other aspects such as in agriculture.

APA style:
Gillan, S. (2018, September 2) Benefits and Ethical Concerns of CRISPR - Pros and Cons, Explore Biotech. Retrieved from: https://explorebiotech.com/crispr-pros-and-cons/

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CRISPR has become one of the most powerful gene-editing tools today. Unlike other genetic engineering tools, CRISPR is cheap, relatively easy to use and precise. Undoubtedly, its popularity has surged amongst scientists in the biotechnology industry.

Pros and Cons of CRISPR

While the benefits of CRISPR range from curing genetic conditions to organ transplants, ethicists fear its use in promoting desired traits rather than life-saving traits such as intelligence that could have long-term implications.

Benefits of CRISPR [Pros]

CRISPR technology has wide-ranging applications in various industries. Some of the benefits are discussed below.

Cancer Therapeutics: New immunotherapies can be developed using CRISPR to treat cancer. Scientists can genetically modify T-cells using CRISPR to locate and kill cancer cells.

Curing Genetic Diseases: CRISPR technology can eliminate the genes that cause genetic diseases such as diabetes, cystic fibrosis. Given that the scientific community has already mapped many genes that cause genetic disease, CRISPR could be used to cure faulty genes that cause genetic diseases.

Drug Research: Scientists are predicting that CRISPR could potentially speed up the drug discovery process, given the technology is relatively cheap, precise, and simple to use. Some of the drug makers in the world are already incorporating CRISPR technology into their drug research and discovery phase.

Pest Resilient Crops: According to Jennifer Doudna, CRISPR pioneer, genome editing could address pest and nutrition challenges facing agriculture, especially in light of climate change and rapid population growth. Earlier in 2018, USDA decided not to regulate about a dozen crops edited with CRISPR as GMOs partially due to the accuracy of the technology.

Ethical Concerns of CRISPR [Cons]

Changes to the Germ-line Cells: Genetically modifications to human embryos and reproductive cells such as eggs and sperms are called germline editing. Changes to the germline can be passed to the next generation. If the desired traits such as intelligence and strong muscles can be passed to the next generation, then how far are we from the designer babies?

Many countries have an outright ban on germline editing, whereas some countries do not have clear guidance. The United States and the United Kingdom are testing the water by considering exemptions in the case of monogenic hereditary disorders such as muscular dystrophy, cystic fibrosis, and Huntington's disease.

Bioweapons: The former U.S. director of national intelligence James Clapper listed "genome editing" among six threats in the section on weapons of mass destruction in 2016. Compared to other genetic engineering tools, CRISPR technology is relatively inexpensive and simple, which could make it attractive to terrorist organizations. The technology can be used to genetically modify bacteria or viruses to wage biological attacks against humans.

DARPA, US's secretive Defense Advanced Research Projects Agency, announced to invest US$65 million in 2017 over four years in seven teams that will investigate ways to make gene editing technologies safer and targeted. The program relates to both intentional and unintended consequences of gene editing technologies. Three main objectives of the program are

to develop processes that allow greater control of genome editing in living systems

to develop countermeasures that protect genome integrity in populations

and to investigate a way to remove engineered genes from living systems

Also Read - Pros and Cons of Having a Designer Baby

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Benefits and Ethical Concerns of CRISPR - Pros and Cons

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CRISPR has become one of the most powerful gene-editing tools today. Unlike other genetic engineering tools, CRISPR is cheap, relatively easy to use and precise. Undoubtedly, its popularity has surged amongst scientists in the biotechnology industry.

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11 Must-Know Advantages and Disadvantages of CRISPR

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11 Must-Know Advantages and Disadvantages of CRISPR

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Main idea:
To show what bad changes it can cause.
Arguments
- Time-consuming: Not all laboratories have an existing pipeline for genome editing. If you are in a laboratory without such a pipeline but have established CRISPR-Cas9 genome editing as the perfect technique to further your research, then chances are that your PI will appoint you to build and refine the protocol. Optimizing a protocol for CRISPR-Cas9 can be difficult and time-consuming.
- Off target effects: We may think we have taken all the correct steps, and that everything should turn out fine, but it can go very wrong as the CRISPR- Cas9 method is very precise, and it can cause mutations elsewhere in the gene.
- Not efficient: In any genome editing experiment, editing performance can be affected by multiple factors and can seriously hamper your efforts. Editing performance basically represents the number of cells in your culture vessel that have been successfully edited, so an editing efficiency of less than 100% basically means a failure.

Dialogue:
To succeed by using CRISPR, we have to make studies in other similar aspects, so we don't fail and can be sure it is gonna be a success.

Summary:
It is time consuming and very risky.
If because of CRISPR, it causes new problems, how are we going to make it a safe use?

APA style:
Tiwari, S. (2020, November 21) 11 Must-Know Advantages and Disadvantages of CRISPR, Honest Pros and Cons. Retrieved from: https://honestproscons.com/advantages-and-disadvantages-of-crispr/

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11 Must-Know Advantages and Disadvantages of CRISPR

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Genome editing is an immensely effective technique that can assist you with your study to address a multitude of concerns. Here is a discussion of the key advantages and disadvantages of CRISPR and the process involved with genome editing using CRISPR.

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Gene editing Pros and Cons - 8 Advantages and Disadvantages

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Gene editing Pros and Cons - 8 Advantages and Disadvantages

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Main idea:
Disadvantages of using CRISPR

Arguments:
- Ethical dilemma: If scientists remove all the diseases, the Earth can be overpopulated in no time
- Safety concerns: Even with the slightest change, it is possible we manage to wipe out a particular disease just to introduce an even more dangerous one.
- The gene therapy is costly, let's suppose that in the near future we could eliminate a child’s defected generic code. But if only the very rich and elite could afford it and let the child of poor ones die, this will obviously not bring justice.

Dialogue:
Even though it may help in many aspects, there can be a lot of problems coming in the way.

Summary:
The Earth can be an overpopulated really fast after ending all diseases. There can be risks of having other new diseases and lastly, not everyone has the money to use that and it can end up only a tool for the rich ones.

APA style:
Niglia, S. (2021). Gene editing Pros and Cons – 8 Advantages and Disadvantages. Retrieved from: https://explorebiotech.com/gene-editing-pros-and-cons/

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Just a decade back, Gene editing was not even a term. But with more scientific research and experiments being done with the technology at full swing, it's a matter of discussion everywhere. All over the world, scientists keep discussing the opportunities and risks involved in genome editing. While, plant geneticists are successful to breed resilient, high-yield plants to combat famine, critics warn against the unpredictable impact of it on human health.

In February 2018, the Human Fertilization and Embryology Authority in the UK approved a request by the Francis Crick Institute London, to modify human embryos by using the new gene-editing technique CRISPR-Cas9. CRISPR has become one of the most powerful gene-editing tools in this date, which can modify disease-causing genes in embryos brought to term- remove the faulty genetic code of that person's future descendants as well. This is the biggest revolution in gene editing till the date.

Recent advancements seen in gene editing have not only introduced a number of exciting possibilities for human advancement but raised difficult ethical questions about building a "designer humans". Today, let's break down the pros and cons of gene editing.

The Pros of Gene Editing

Firstly, here are the advantages of genome editing technology.

1. Tackling and Defeating Diseases:

Most deadly and severe diseases in the world have resisted destruction. A number of genetic mutations that humans suffer will end only after we actively intervene and genetically engineer the next generation.

Cancer Therapeutics: New immunotherapy can be developed using genetic editing that can treat cancer. Modification of T-cells using CRISPR can locate and kill cancer cells.

Drug Research: Genetic makeup can potentially speed up the drug discovery process. Some of the drug makers are already incorporating CRISPR technology in drug research and discovery phase.

Inherent diseases: With genetic editing, the scientist can prevent the inherent disease from flowing to the offspring. Diabetes and cystic fibrosis can also be eliminated.

Read More on The Diseases That Can Be Cure by CRISPR
2. Extend Lifespan

Genome editing could extend the human lifespan. The human lifespan has already shot up by a number of years, and we are already living longer and longer. Genetic engineering could make our time on Earth even long. There are specific, common illnesses and diseases that can take hold later in life and can end up killing us earlier than necessary. Genetic editing can reverse the most fundamental reasons for the body's natural decline on a cellular level. So it can drastically improve both the span and the quality of life later on.

3. Growth In Food Production and Its Quality:

Genetic engineering can design foods that can withstand harsh temperatures and are packed full of all the right nutrients. Additionally, it could also be the answer to meet the heavy food demands that are still not met in many countries. We may also increase the medicinal value of our food and introduce edible vaccines.

4. Pest Resilient Crops:

According to Jennifer Doudna, CRISPR pioneer, "genome editing can address pest and nutrition challenges facing agriculture". Instead of using tons of insecticides and pesticides, we can protect our plan in a healthier way.

The Cons of Gene Editing

While Genome editing has many benefits, it could also have many areas to be questioned. Such as,

1. Ethical Dilemma

Let's start with the major objection- modification is unnatural and amounts to playing God. This argument claims, "natural is inherently good, and diseases are natural". They believe that humans, by the millions falling ill and dying prematurely, are all perfectly natural. While living longer is already creating social problems today, what about the overpopulated earth after scientists remove all the disease in it?

2. Safety Concerns

Well, for a moment, let's ignore what society or ethics has to say. Is it even safe to make changes at the cellular level? Slight changes made at the smallest level may lead to unexpected results. What if we manage to wipe out particular disease only to introduce a brand new and even more dangerous one? Experimenting in little life still in the womb could lead to complications, including miscarriage, premature birth, or even stillbirth- all of which are unthinkable.

3. What About Diversity?

Diversity in all species of animals is a key to evolution on earth. Genetically engineering our species will have a detrimental effect on our genetic diversity- as in something like cloning would. Doesn't the future generation deserve to see the diversity on Earth as we did?

4. Rich people's tool or For Everyone?

A Well known fact, gene therapy is costly. Okay, let suppose in the near future we could eliminate a child's defected generic code. But what if only the very rich and elite could afford it and let the child of poor ones die. If this is going to happen, will genetic editing give "justice" to our society? Is the government going to pay for all the embryos of the poor family for genetic make-up?

In Conclusion

Genetic engineering's pros and cons give an idea of its results. Thus, many countries and laws have already been put forward to bring the best outcome. With proper laws and control over its usage, it will definitely be a huge gift for humankind.

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Gene Editing Pros and Cons - 8 Advantages and Disadvantages

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Just a decade back, Gene editing was not even a term. But with more scientific research and experiments being done with the technology at full swing, it's a matter of discussion everywhere. All over the world, scientists keep discussing the opportunities and risks involved in genome editing.

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Main idea: The PAM, which stands for the protospacer adjacent motif, is a specific sequence of nucleotides, around 2–6 base pairs, that follows the protospacer sequence in a viral genome.

Facts:
- PAM  prevents cleavage of the host CRISPR matrix, where PAM is not present.

- If scientists want to use Cas9 to cut human DNA or the DNA of any other organism, they first look for a PAM sequence within the target genome and then design an RNA to match the sequence next to it.

- PAM is required so that CRISPR–Cas systems wouldn't target their CRISPR arrays

Dialogue: PAM is extremelly important  because it is required for a Cas nuclease to cut and is generally found 3-4 nucleotides downstream from the cut site. Also, CRISPR–Cas systems would target their CRISPR arrays, leading to a potentially catastrophic autoimmune response. Virtually all CRISPR nucleases require a PAM in one form or another.

Summary: PAM is a short sequence that must be present next to a DNA sequence for Cas9 to bind and cut.

APA style: Innovative Genomics Institute -IGI (2017, Sep 7). What is the PAM? - A CRISPR Whiteboard Lesson. Retrievered from: https://www.youtube.com/watch?v=iSEEw4Vs_B4

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What is the PAM? - A CRISPR Whiteboard Lesson

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Main idea: On Nov 25th 2018 Dr. He Jiankui announced, via youtube, that he had decided to push humankind across a controversial threshold. This announcement was, of course, that his work had resulted in the birth of twins who had both been subject to genetic engineering using CRISPR.

Arguments:
- In 2015 two of the foremost journals in research,  BBC Science Focus and Nature, both made similar statements stating that modification of human germ cells, that is sperm and egg, should be avoided.

-The scientific community seemed to have come to an agreement not to experiment with this technology until we could agree how and when to apply it to humans. Obviously,  Dr. He Jiankui didn't follow the pre-established agreement, because of that, he received lots of criticism.

Dialogue: There is an urgent need to stop and ask what the outcomes of this work are for the individuals who have been subject to it, and also how the rest of society may be affected.

Summary: He Jiankui was heavily criticized for making a "medically unnecessary" edit, a genetic change that he hoped would make babies genetically resistant to HIV. Critics argued that there were easier and safer ways to prevent transmission of the virus.

APA style: Real Engineering (2019, Feb 22).

Designer Babies - The Problem With China's CRISPR Experiment.

Retrieved from: https://www.youtube.com/watch?v=kFFyeHJDI50

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Designer Babies - The Problem With China's CRISPR Experiment

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Gene editing Pros and Cons - 8 Advantages and Disadvantages

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Gene editing Pros and Cons - 8 Advantages and Disadvantages

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Main idea:
Advantages for using CRISPR

Arguments:

- It can defeat diseases:

Cancer Therapeutics: Modification of T-cells using CRISPR can locate and kill cancer cells.

Drug Research: It can speed up drug discovery process.

Inherent diseases: Inherent disease can be prevented from flowing to the offspring, such as Diabetes.

- It can extend lifespan:

Even though we are already living longer and longer, there are common illnesses and diseases that can take hold later in life and can end up killing us earlier. With genetic editing, it can reverse the most fundamental reasons for the body's natural decline on cellular level, so it can make a big improvement both the span and the quality of life later on.

- Food production:

Genetic engineering can design foods to withstand harsh temperatures and packed full of the right nutrients.

There are heavy food demands that are still not met in many countries, and this can be the answer to resolve that.

We may also increase the medicinal value of our food and introduce edible vaccines.

Dialogue:
How can they exactly design foods to withstand harsh temperatures and make sure that it is safe to eat?

Summary:
It can fefeat many diseases that are happening now and taking a big amount of lifes, it can make people live longer and it can help in food production.

APA style:
Niglia, S. (2021). Gene editing Pros and Cons – 8 Advantages and Disadvantages. Retrieved from: https://explorebiotech.com/gene-editing-pros-and-cons/

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Just a decade back, Gene editing was not even a term. But with more scientific research and experiments being done with the technology at full swing, it's a matter of discussion everywhere. All over the world, scientists keep discussing the opportunities and risks involved in genome editing. While, plant geneticists are successful to breed resilient, high-yield plants to combat famine, critics warn against the unpredictable impact of it on human health.

In February 2018, the Human Fertilization and Embryology Authority in the UK approved a request by the Francis Crick Institute London, to modify human embryos by using the new gene-editing technique CRISPR-Cas9. CRISPR has become one of the most powerful gene-editing tools in this date, which can modify disease-causing genes in embryos brought to term- remove the faulty genetic code of that person's future descendants as well. This is the biggest revolution in gene editing till the date.

Recent advancements seen in gene editing have not only introduced a number of exciting possibilities for human advancement but raised difficult ethical questions about building a "designer humans". Today, let's break down the pros and cons of gene editing.

The Pros of Gene Editing

Firstly, here are the advantages of genome editing technology.

1. Tackling and Defeating Diseases:

Most deadly and severe diseases in the world have resisted destruction. A number of genetic mutations that humans suffer will end only after we actively intervene and genetically engineer the next generation.

Cancer Therapeutics: New immunotherapy can be developed using genetic editing that can treat cancer. Modification of T-cells using CRISPR can locate and kill cancer cells.

Drug Research: Genetic makeup can potentially speed up the drug discovery process. Some of the drug makers are already incorporating CRISPR technology in drug research and discovery phase.

Inherent diseases: With genetic editing, the scientist can prevent the inherent disease from flowing to the offspring. Diabetes and cystic fibrosis can also be eliminated.

Read More on The Diseases That Can Be Cure by CRISPR
2. Extend Lifespan

Genome editing could extend the human lifespan. The human lifespan has already shot up by a number of years, and we are already living longer and longer. Genetic engineering could make our time on Earth even long. There are specific, common illnesses and diseases that can take hold later in life and can end up killing us earlier than necessary. Genetic editing can reverse the most fundamental reasons for the body's natural decline on a cellular level. So it can drastically improve both the span and the quality of life later on.

3. Growth In Food Production and Its Quality:

Genetic engineering can design foods that can withstand harsh temperatures and are packed full of all the right nutrients. Additionally, it could also be the answer to meet the heavy food demands that are still not met in many countries. We may also increase the medicinal value of our food and introduce edible vaccines.

4. Pest Resilient Crops:

According to Jennifer Doudna, CRISPR pioneer, "genome editing can address pest and nutrition challenges facing agriculture". Instead of using tons of insecticides and pesticides, we can protect our plan in a healthier way.

The Cons of Gene Editing

While Genome editing has many benefits, it could also have many areas to be questioned. Such as,

1. Ethical Dilemma

Let's start with the major objection- modification is unnatural and amounts to playing God. This argument claims, "natural is inherently good, and diseases are natural". They believe that humans, by the millions falling ill and dying prematurely, are all perfectly natural. While living longer is already creating social problems today, what about the overpopulated earth after scientists remove all the disease in it?

2. Safety Concerns

Well, for a moment, let's ignore what society or ethics has to say. Is it even safe to make changes at the cellular level? Slight changes made at the smallest level may lead to unexpected results. What if we manage to wipe out particular disease only to introduce a brand new and even more dangerous one? Experimenting in little life still in the womb could lead to complications, including miscarriage, premature birth, or even stillbirth- all of which are unthinkable.

3. What About Diversity?

Diversity in all species of animals is a key to evolution on earth. Genetically engineering our species will have a detrimental effect on our genetic diversity- as in something like cloning would. Doesn't the future generation deserve to see the diversity on Earth as we did?

4. Rich people's tool or For Everyone?

A Well known fact, gene therapy is costly. Okay, let suppose in the near future we could eliminate a child's defected generic code. But what if only the very rich and elite could afford it and let the child of poor ones die. If this is going to happen, will genetic editing give "justice" to our society? Is the government going to pay for all the embryos of the poor family for genetic make-up?

In Conclusion

Genetic engineering's pros and cons give an idea of its results. Thus, many countries and laws have already been put forward to bring the best outcome. With proper laws and control over its usage, it will definitely be a huge gift for humankind.

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Gene Editing Pros and Cons - 8 Advantages and Disadvantages

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Just a decade back, Gene editing was not even a term. But with more scientific research and experiments being done with the technology at full swing, it's a matter of discussion everywhere. All over the world, scientists keep discussing the opportunities and risks involved in genome editing.

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4 ways in which CRISPR is more than just gene editing

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4 ways in which CRISPR is more than just gene editing

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Main idea:
CRISPR can be used for many different purposes aside from just the basic treatment of diseases and enhancement.

Arguments:
- CRISPR can be used to create antibiotics. Over time, bacteria grow resistant to the antibiotics we use against them. But, CRISPR can be used to eradicate bacteria as well. Even though it is originally a defense system of these bacteria, scientists can install pieces of bacterial DNA in viruses that attack bacteria and CRISPR will be forced to destroy the DNA of that bacteria. This, of course, would kill the bacteria.
- CRISPR can be used for faster diagnosis of infections. When a sample is taken from a patient, doctors are able to find out if the infection is present if the DNA makes copies of itself. If not, nothing happens. Then they can add a CRISPR system with special Cas proteins that are especially aggressive (meaning that they do not only destroy the target gene, but also everything nearby). Finally, they add special pieces of DNA called reporter DNA that fluoresce when the gene is cut. Therefore, if they Cas proteins find their target DNA pieces, they will also cut the nearby reporter DNA, making the whole tube fluoresce. This can bring easier testing to areas that are far away from labs and may enable more testing to occur in general.
- CRISPR can allow us to grow human-like organs in animals. But, these organs might contain retroviruses that might have a negative effect on our health. Therefore, CRISPR could be used to chop these retroviruses in the DNA of pigs to completely eradicate them.
- Finally, CRISPR can also be used to tackle health problems on a larger scale. CRISPR can target vectors that transmit these diseases to humans rather than the bacteria themselves. For example, Lyme disease is spread by mice and by immunizing mice against this disease, we can prevent many humans from getting it as well.

Dialogue:
We may not be realising how many great uses there could be for this technology. As it evolves, we might find many other applications for it, meaning that there will be more and more improvements in areas we haven't even thought of before. CRISPR could also add to the benefits of other existing technologies, just like it can with antibiotics.

Summary:
CRISPR can be used to alter bacteria that are becoming increasingly more resistant to antibiotics. It could also make testing for diseases easier, meaning that they could be detected earlier and thus, treated more effectively. Moreover, CRISPR could solve the problem of the never-ending waiting line to get organs from a donor by growing these organs in animals. Finally, it could also tackle health problems on a larger scale by preventing them from their roots.

SciShow. (2020, December 20). 4 Ways CRISPR Is More Than Just Gene Editing. Retrieved from: https://youtu.be/Kh88cLtlclw

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4 Ways CRISPR Is More Than Just Gene Editing

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Bioethical issues in genome editing by CRISPR-Cas9 technology

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Bioethical issues in genome editing by CRISPR-Cas9 technology

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Main point:
CRISPR might cause some bioethical issues. Apart from that, it can alter all aspects of our life, ranging from security to healthcare quality.

Arguments:
- CRISPR technology might create some nontarget effects, and since changes will persist in the population, it may cause ecological imbalance. These genes could also be accidentally transferred to other species in the environment.
- The use of this technology is very difficult to control.
Another issue is patenting. Nowadays, transgenic organisms are used for industrial purposes, and also some human gene sequences have been patented. As the use of CRISPR technology will become more commonplace, there will be more issues with patenting.
- It is impossible to obtain informed consent from a person if the modifications are made while this person is an embryo.
Some genetically advanced societies may have more mental and physical privileges in comparison with other individuals.
- This technology can be used for the creation of new biological weapons.
- Richer countries may seek to use this technology to attack underdeveloped countries. They can take advantage of the fact that these countries would not be able to afford CRISPR and easily create an incredibly strong military to attack them.
- It allows us to create chimeric animals, which is controversial. This can disrupt the order of nature and the moral dilemma of whether this organism should be accepted as a human or as an animal. That is because chimeras contain human nerve and germ cells.
- Animal welfare is another huge concern. First of all, CRISPR might create off-target effects that would greatly affect the well-being of animals. The second issue is animal dignity. Some individuals state that using animals only as objects serving humans is immoral.
- Scientists found that unwanted mutations caused by CRISPR are much more likely to happen in embryos than in animals.
- This technology can also cause genetic mosaicism, which means that there are genetically different populations of somatic cells in one organism. This can lead to genetic diseases.
- Even though the problems caused by this type of genetic engineering may not arise instantaneously, they might affect the person later in life.
- When the technology will be accessible enough, humans may start using it for non-therapeutic reasons, such as changing their physical appearance. Since these characteristics will be defined by genome engineering rather than blood relations, the world will become a much more discriminatory and hostile place.

Dialogue:
CRISPR can have a massive impact on humanity, just like all the other important technological inventions did. However, we can't be totally sure that this impact will be positive. Things can unfold perfectly, such as CRISPR being used only for essential purposes like medical treatment. But, knowing the human nature, all the effort can end up being directed towards the creation of weapons.

Summary:
CRISPR can trigger certain issues, which range across completely different topics. It could create ecological imbalance, cause non-target mutations during the process of editing (which can have an effect on future generations), and simply pose a danger to the whole of humanity.

Ayanoglu, F. B., Elcin, A. E., Elcin, Y. M. (2020, April 2). Bioethical in genome editing by CRISPR-Cas9 technology. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7129066/

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Abstract

Genome editing technologies have led to fundamental changes in genetic science. Among them, CRISPR-Cas9 technology particularly stands out due to its advantages such as easy handling, high accuracy, and low cost. It has made a quick introduction in fields related to humans, animals, and the environment, while raising difficult questions, applications, concerns, and bioethical issues to be discussed. Most concerns stem from the use of CRISPR-Cas9 to genetically alter human germline cells and embryos (called germline genome editing). Germline genome editing leads to serial bioethical issues, such as the occurrence of undesirable changes in the genome, from whom and how informed consent is obtained, and the breeding of the human species (eugenics). However, the bioethical issues that CRISPR-Cas9 technology could cause in the environment, agriculture and livestock should also not be forgotten. In order for CRISPR-Cas9 to be used safely in all areas and to solve potential issues, worldwide legislation should be prepared, taking into account the opinions of both life and social scientists, policy makers, and all other stakeholders of the sectors, and CRISPR-Cas9 applications should be implemented according to such legislations. However, these controls should not restrict scientific freedom. Here, various applications of CRISPR-Cas9 technology, especially in medicine and agriculture, are described and ethical issues related to genome editing using CRISPR-Cas9 technology are discussed. The social and bioethical concerns in relation to human beings, other organisms, and the environment are addressed.

Keywords: Genome editing, CRISPR-Cas9 technology, bioethical issues, bioethics

1. Introduction

For many years, molecular biologists have sought ways to use cellular repair mechanisms to manipulate DNA through genome editing. In this way, they would have the power to change the genome by correcting a mutation or introducing a new function (Rodriguez, 2016). For this purpose, genome editing technologies were developed (Memi et al., 2018). In recent years, clustered regularly interspaced short palindromic repeats technology (CRISPR-Cas9) has become the most preferred method of gene editing. This technology has advantages such as high accuracy, easy handling, and relatively low cost compared to previous technologies, such as zinc-finger nuclease (ZFN) and transcription activator-like effector nuclease (TALEN). Thanks to these benefits, CRISPR-Cas9 technology can be easily applied in any molecular biology laboratory.

Genome editing technologies are used in the formation of human disease models in experimental animals and for the understanding of basic gene functions. They also have great therapeutic potential for future treatment of untreated diseases such as certain cancers, genetic disorders, and HIV/AIDS. Today, genome editing in somatic cells is one of the promising areas of therapeutic development (Otieno, 2015). However, various bioethical issues have arisen due to the potential impact of these technologies on the safety of food stocks and clinical applications (Hundleby and Harwood, 2018; Hirch et al., 2019). This review discusses the challenges, possible consequences, and bioethical issues of CRISPR-Cas9 in detail.

2. Biology and function of CRISPR-Cas9 technology

Genome editing technologies often work by creating fractures in chromosomal DNA. ZFN, TALEN, and CRISPR-Cas9 are all based solely on nucleases (Kim and Kim, 2014; Roh et al., 2018). The strength of these technologies stems from the ability to create fractures in the desired region of a specific target sequence as determined by the researcher. This allows researchers to modify the genome in practice in any region (Memi et al., 2018).

The creation of changes in the genome depends mainly on the DNA repair capacity of the cells (Lau et al., 2018). All cells have two basic mechanisms for the repair of double chain breaks on DNA. One of them is nonhomologous end joining (NHEJ) and the other is the homologous dependent repair (HDR) mechanism. In NHEJ, the ends of the fractures are quickly connected directly to each other, regardless of the sequence homology, while HDR requires homology to repair the damaged DNA site. In order to achieve homology, the undamaged sister chromatid is used as a template and DNA damage is repaired (Urnov, 2018).

CRISPR-Cas9 is a naturally occurring defense system in prokaryotic organisms that provides resistance to foreign genetic elements such as plasmids and bacteriophages (Barrangau et al., 2007; Marraffini and Sontheimer, 2008). When the virus or plasmid enters a bacterial cell, CRISPR-Cas9 allows the addition of short viral DNA molecules to the CRISPR site. CRISPR sequences (CRISPRs) are short DNA repeats of viral or plasmid origin found in the genomes of bacteria and are defined as clustered regularly interspaced short palindromic repeats. Cas genes (CRISPR-related) are genes that encode nuclease or helicase proteins associated with CRISPR repeat sequences that have the function of cutting or dissolving DNA (Jansen et al., 2002). Cas9, a member of the Cas gene family, was isolated from Streptococcus pyogenes and is an endonuclease capable of cutting DNA from two active cut regions at both ends of the DNA double helix (Doudna and Charpentier, 2014; Rodriguez, 2016). The CRISPR-Cas system recognizes the DNA of the invading virus or bacterium and directs the Cas protein to destroy foreign DNA (Otieno, 2015).

In the following years, it was discovered that the CRISPR-Cas system can be programmed to find and cut specific target DNA regions, thereby providing genome editing (Jinek et al., 2012; Hsu et al., 2013). As a result of understanding that the human genome can be edited by CRISPR-Cas9, it became clear that genome editing could also be used for therapeutic purposes, and a new era in genetic engineering began (Lau et al., 2018; Roh et al., 2018).

3. Application areas

3.1. Animal models

CRISPR-Cas9 can be used to create animal models to mimic human diseases and to understand disease development by mutating or silencing genes. A mouse model has been developed to determine the harmful effects of mutations in cancer by making mutations that cause the loss of function in tumor suppressor genes or give functions to protooncogenes (Chin, 2015).

Conventional genetically modified (GM) mouse models are produced by gene targeting in embryonic stem cells or transgenesis, which are time-consuming and highly expensive. With CRISPR-Cas9, GM mice can be efficiently produced in a much shorter time (Mei et al., 2016). It can be applied to nonhuman primates such as monkeys. Nonhuman primates are more similar to humans in anatomical, physiological, and genetic terms than rodents (Zhang et al., 2014). Therefore, they are more suitable models than rodents in understanding human biology and disease development (Xin et al., 2016). The first successful application of CRISPR-Cas9 in nonhuman primates, from which a knockout monkey was produced, was realized in 2014 (Niu et al., 2014). However, genome sequences of many nonhuman primates are not yet fully identified. This makes it difficult to design selected single-guide RNAs (sgRNAs) (Gou and Li, 2015; Lou et al., 2016). Therefore, the application of CRISPR-Cas9 in nonhuman primates is still at an early stage.

3.2. Genome editing in specific tissues

Researchers have been able to modify the genomes of specific tissues such as liver and brain tissues using hydrodynamic injection and adeno-associated virus (AAV) (Rodriguez et al., 2014; Senis et al., 2014). In a study, CRISPR-Cas9 has been successfully and effectively applied to the mammalian nervous system. A mixture of green fluorescent protein (GFP)-labeled AAV-spCas9 and AAV-spGuide plasmids was transferred in vivo to the hippocampal toothed brain folds of adult male mice (Swiech et al., 2015). It is thought that the number of such applications will grow in the fields of cancer and neuroscience in the following years (Mei et al., 2016).

3.3. Multiple gene mutations

CRISPR-Cas9 can be used to generate mutants for target genes. In the first such study by Li et al., six sgRNAs targeting Cas9 mRNA and six different genomic regions encoding the Tet1, Tet2, and Tet3 genes were transferred to the cytoplasm of rat embryos (Li et al., 2013). Findings showed that all three Tet genes carried the desired mutations in 59% of newborn rat pups. Successful results were also reported in studies with zebrafish embryos and Arabidopsis as well (Ota et al., 2014; Wang et al., 2015).

3.4. Epigenome studies

Epigenome studies can be performed in two different ways: genome or epigenome editing (Chen et al., 2014; Huisman et al., 2015). In genome editing, nuclease is used to modify the DNA sequence, whereas in epigenome editing, an effector domain is used and the DNA sequence is not changed. This function is achieved by catalytic inactivation of the Cas9-associated effector domain by replacing the Cas9 protein. Altered effector proteins are used to activate or suppress transcription (Lau and Davie, 2016). In epigenome editing, the epigenome can be modified by changing the proteins that maintain and protect the epigenome. Suppression of DNA methylation as a result of degradation of catalytic domains that accelerate the loss of spherical DNA methylation in human cells and lead to cell death is a good example of epigenome studies using CRISPR-Cas9 (Liao et al., 2015).

Another application is the editing of long nonencoded RNAs (lncRNAs) and enhancer RNAs (eRNAs) that can control gene expression and epigenome processes. In a study, eRNA-expression factors and IncRNA-expression enhancers were suppressed by stimulating deletion mutations in a lymphoma cell line using CRISPR-Cas9 (Pefanis et al., 2015). It is predicted that CRISPR-Cas9 may allow different levels of epigenome modification and facilitate further changes to humans (Liao et al., 2015; Mei et al., 2016).

3.5. Treatment of diseases

CRISPR-Cas9 can be applied to cells in vivo or ex vivo. In the in vivo approach, CRISPR-Cas9 is directly transferred to cells in the body using either viral or nonviral methods. In the ex vivo approach, first the cells are removed from the body; then CRISPR is applied to the cells and they are transferred back to the body (Roh et al., 2018). This approach has great potential to develop tissue-based therapies (Rath et al., 2015). Using CRISPR-Cas9, the mutation in the dystrophin protein responsible for the most common form of Duchenne muscular dystrophy was successfully removed (Amoasii et al., 2018; Duchêne et al., 2018; Koo et al., 2018; Long et al., 2018). There are studies to prevent and treat AIDS by inhibiting the entry of HIV into the cell or by removing the HIV genome integrated into the host genome using CRISPR-Cas9 (Saayman et al., 2015). Induced pluripotent stem cells (iPSCs) were successfully produced from cystic fibrosis patients with confirmed F508 deletion in the cystic fibrosis transmembrane regulator ( CFTR) gene by CRISPR-Cas9 (Firth et al., 2015). There are also studies for cataracts (Wu et al., 2015; Yang et al., 2016) and Parkinson's disease (Yang et al., 2016). However, recent studies have shown that CRISPR-Cas9 activates the type 1 interferon (INF) pathway, causing a type 1 INF-mediated immune response (Kim et al., 2018; Charleswort et al., 2019). These findings currently limit the use of CRISPR-Cas9 in treatment.

3.6. Industrial uses

CRISPR was first used for commercial purposes to make bacterial cultures used in cheese and yogurt production resistant to viral infections (van Erp et al., 2015). One of the applications in agriculture is to produce GM crops (Hundleby and Harwood, 2019). There are attempts to increase the yield in the livestock industry (van Erp et al., 2015). It can be used to control invasive pest species to reverse pesticide and herbicide resistance in insects and weeds or to prevent disease spread (Esvelt et al., 2014). Researchers have succeeded in preventing the spread of genes protecting mosquitoes from harmful malaria parasites (Gantz et al., 2015) and making female mosquitoes infertile in the laboratory (Hammond et al., 2016). Vaccine development is another significant area of interest. The smallpox virus vector (VACV) is used in the eradication and vaccination of smallpox. Using CRISPR-Cas9, the efficiency of marker-free VACV vectors has been increased (Yuan et al., 2015). Another example is the hepatitis B vaccine. In order to prevent viral gene expression and replication, specific regions of the hepatitis B genome were targeted and cut by CRISPR-Cas9 (Ramanan et al., 2015).

3.7. RNA editing

Single-stranded RNA (ssRNA) sequences can also be edited by CRISPR-Cas9. In RNA editing, CRISPR-Cas9 consists of a DNA oligonucleotide presenting the PAM (protospacer adjacent motif) region (PAMmer), ssRNA, guide RNA (gRNA), and Cas9 protein. PAMmer acts as a PAM region specifically recognized by Cas9 and directs Cas9 to bind and cut the target ssRNA. 5'-Elongated PAMmers containing bases paired with different ssRNAs and immediately in front of PAM are required for specific binding of target ssRNAs. Since RNA molecules have different functions than DNA, CRISPR-Cas9 can offer a much more flexible application than other genome editing methods (Mei et al., 2016).

3.8. Military applications

One of the lesser-discussed application areas of CRISPR-Cas9 technology is its use for military purposes. As is known, a substantial portion of genome editing studies are supported by the defense ministries of the countries. These studies are commonly focused on increasing the tolerance of soldiers against biological or chemical warfare. This technology has the potential to influence human performance optimization (Greene and Master, 2018). Studies are usually concentrated on discovering different genes that can be harnessed from other species (Gracheva et al., 2010) and identifying new genes that can be associated with posttraumatic stress disorder, which is frequently experienced by soldiers (Cornelis et al., 2010). In a study by Zou et al. (2015), researchers developed dog embryos with higher muscle mass using CRISPR-Cas9. Another interesting study showed that the CMG2 gene, known to cause low sensitivity to anthrax toxin when expressed in small amounts, could be silenced by this technology (Arévalo et al., 2014). However, it should be noted that far more research needs to be conducted for using CRISPR technology in humans as a defense tool against biological and chemical weapons (Greene and Master, 2018).

3.9. DNA replacement in human embryos (germline genome therapy)

The most controversial usage of CRISPR-Cas9 is the modification of human embryo DNA, or, in other words, its use for germline genome therapy. In 2015, a group of Chinese researchers led by Junjiu Huang applied CRISPR-Cas9 to remove a mutation that causes β-thalassemia, which is a fatal blood disease, from the human β-globulin ( HBB) gene in the germline of human embryos. In this research, six abnormal embryos not suitable for in vitro fertilization were used. The mutation could be corrected in only one of the embryos. Although the mutation could be corrected in two other embryos, nontarget effects occurred in other genes. In the other three embryos, the mutation could not be corrected. It has been reported that this technique is not ready for clinical use because of nontarget effects on different genes (Roh et al., 2018; Carroll, 2019). Modifications that occur in germline cells can be transferred to future generations. Scientists think that they can extract genes that cause diseases in the population using CRISPR-Cas9 (Cai et al., 2018; Memi et al., 2018).

4. Bioethical issues

The fact that CRISPR-Cas9 is among the important discoveries of the 21st century is widely accepted in the scientific community and related industries. However, the rapid rise of CRISPR-Cas9 has led to new bioethical, social, and legal issues in medicine, agriculture, livestock, and the environment. Possible risks and bioethical issues related to CRISPR-Cas9 are summarized in the Table.

Table

Organism

Risks

Bioethical issues

References

Bacteria

Nontarget mutationsGene drifts

Ecological imbalance

Rodriguez, 2016 Hundleby and Harwood, 2019 Esvelt et al., 2014

Plants

Nontarget mutationsGene drifts

Ecological imbalancePatenting

Shinwari et al., 2017 Hundleby and Harwood, 2019

Animals /chimeric animals

Nontarget mutations

Ecological imbalance Patenting Animal welfare and dignity Threatening of human dignity and identity

Rodriguez, 2016 Polcz and Lewis, 2016 Rodriguez, 2017 Eriksson et al., 2018 Koplin, 2019 Degrazia, 2019 de Graeff et al., 2019

Humans

Nontarget mutations Side effects Cost Genetic mosaicism

Eugenics Informed consent Enhancement Accessibility Patenting Safety Incomplete or over legislations

Otieno, 2015 Rodriguez, 2016 Duardo-Sánchez, 2017 Shinwari et al., 2017 Greene and Master, 2018 Sherkow, 2018 Cathomen et al., 2019 Hirsch et al., 2019

4.1. Ecological imbalance

In studies using RNA-targeted gene editing methods based on CRISPR-Cas9, nontarget effects should be examined in depth. Since gene drift will persist in a population, possible off-target mutations will continue in each generation. In addition, the number and effect of mutations may increase as generations progress (Rodriguez, 2016; Hundleby and Harwood, 2019). Another concern is the possibility that genes can be transferred to other species in the environment. Transferring the regulated sequences to other species may result in the transmission of negative characteristics to the associated organisms (Esvelt et al., 2014). The distribution of the properties of the entrained genes among the populations can make control very difficult.

4.2. Regulations for consumers

The use of CRISPR-Cas9 to obtain the desired genetic modifications makes it very difficult to identify and regulate genetically modified organisms (GMOs) in the market after they leave the laboratory. Therefore, regulatory agencies, such as the US Food and Drug Administration (FDA), European Medicines Agency (EMA), and others, should consider whether any GMOs are suitable for consumers. However, it is not known exactly how to evaluate the possibilities of a growing market with CRISPR-Cas9 (Ledford, 2015; Hundleby and Harwood, 2019).

One of the dilemmas of CRISPR-Cas9 that concerns all the humanity is patenting. As is known, transgenic organisms of industrial use and also some human gene sequences for clinical purposes have been patented (Rodriguez, 2016; Sherkow, 2018). As technologies such as CRISPR continue to evolve, patent-related issues in many areas of biotechnology will continue to increase in the upcoming years. Even today, there are many such cases of patenting. The best-known case is the patent right case between Zhang and Doudna and Charpentier for the therapeutic use of CRISPR-Cas9 in human cells. In the case concluded on 2 December 2016, it was decided to grant the patent to Caribou Biosciences, which Doudna was the founder of (Donohoue et al., 2018).

4.3. Genome editing for enhancement

The editing of human germline cells with CRISPR-Cas9, which will be discussed later in more detail, is prohibited for various safety reasons. However, the rate of application of CRISPR-Cas9 to somatic cells is gradually increasing in order to transfer the desired characteristics to our lives. Many phenotypic characteristics have a genetic component independent of the environment. By utilizing this feature, CRISPR-Cas9 can be used to improve the performance of athletes, to prevent violent behavior, or to reduce dependence (Rodriguez, 2016). Although gene therapy is often used to treat patients for their own benefit, the criminal justice system may require repeater or dangerous offenders to correct the genes associated with violence by genome editing technologies in the future. One of the biggest dilemmas here is to obtain informed consent for an underage person if the intervention is made during the development of the zygote. This will give parents or guardians the right to make decisions on behalf of minors for nonhealth reasons. Furthermore, when socially assessed, some genetically improved populations or individuals may have some advantages in comparison to others in terms of various features such as mental and physical capacity (Brokowski, 2018). Therefore, the use of CRISPR-Cas9 in genome enhancement should be seriously discussed both socially and morally.

4.4. Military research

The use of CRISPR technology for military purposes is generally considered within the scope of nontherapeutic enhancement and is covered similarly. From this point of view, related bioethical issues are commonly discussed in terms of concepts of benefit/risk, informed consent, and accessibility (Greene and Master, 2018). A notable bioethical problem is the off-target mutations that have been mentioned in relation to other topics. Off-target mutations can cause many undesirable changes in the genome or even lead to fatal diseases. Current information obtained from studies on off-target mutations caused by CRISPR on the genome is very limited. Therefore, the benefit/risk relationship needs to be evaluated carefully. In addition, the possibility that this technology can be used for the production of new biological weapons is frightening.

Another ambiguous issue that needs to be discussed in military enhancement applications is informed consent. It could be difficult to obtain informed consent forms independently without any interaction among individuals due to military training methods, strict norms, and chains of command. Additionally, some soldiers may have difficulty in understanding the concepts of gene therapy and genome editing, as well as the potential risks and benefits of the applications (Greene and Master, 2018).

One important ethical issue is that the use of such technologies will support ongoing inequalities among military parties (Amoroso and Wenger, 2003). CRISPR is currently an expensive technology. Some developed countries might think of using this technology to further strengthen their defenses and even attack underdeveloped or developing countries. This situation could cause a constant tension, making it difficult to provide an environment of peace and stability worldwide.

4.5. Generation of chimeric animals for organ transplantation

Organ transplantation is the replacement of an organ that cannot function in an individual's body with a healthy organ from a living donor or cadaver. The primary purpose is to save the life of the patient, who is in danger of organ failure, and to increase the lifespan and quality of life (Black et al., 2018). The development of chimeric animals may prevent patients from spending precious time waiting for an appropriate donor.

Bioethical issues in the generation of chimeric animals arise from the fact that chimeras contain human nerve and germ cells (Polcz and Lewis, 2016). The two main issues can be summarized as defining the order of nature and the moral disorders caused by how the organism is treated depending on whether the organism is accepted as human or animal. Some people think that chimeric embryos will affect human dignity and identity because they have the power to develop organisms with human-derived cells and tissues. The others state that chimeric organisms containing human cells cannot turn into humans and therefore will not affect human dignity. They also argue that the human-like features imparted to chimeras will neither affect the biological environment nor the moral status of animals and will never reach human consciousness (Koplin, 2019; Degrazia, 2019).

4.6. Animal welfare and dignity

Animal welfare is another bioethical concern encountered during the application of genome editing technologies on animals. First of all, the possibility of off-target mutations in the genome can lead to diseases or different side effects in animals (Ishii, 2017a; Schultz-Bergin, 2018; de Graeff et al., 2019). Such a situation will adversely affect animal welfare (Rodriguez, 2017).

The second bioethical issue to be discussed could be the concerns about "animal dignity" (Eriksson et al., 2018) and alterations in their natural environments and physiological needs (Manesh et al., 2014). Some studies have stated that the use of animals as objects only serving for humans is not ethically or morally acceptable (Martinelli et al., 2014; Fung and Kerridge, 2016; Greenfield, 2017), and such practices can lead to greater control over humans on animals (Ishii, 2017a; de Graeff et al., 2019). Some others think that animals are not bound by any moral law and therefore there is no need for a discussion regarding animal dignity (Heeger, 2015; Shriver and McConnachie, 2018). Schultz-Bergin (2017) stated that animal rights, welfare, and dignity will not be adversely affected since these animals will occur through genome editing technologies. The existence of contrary opinions on this matter indicates that the mentioned bioethical issues will be on the agenda for a long time.

4.7. CRISPR-Cas9 for human germline

The potential for using CRISPR-Cas9 for genome editing in the human germline has raised serious ethical debates. Until 2015, all therapeutic applications in humans were performed in somatic cells using genome editing technologies. However, in 2015, the editing of the human germline performed by Chinese scientist Huang and his team with CRISPR-Cas9 raised new social, moral, and bioethical issues (Liang et al., 2015; Ormond et al., 2017). Bioethical issues caused by genome editing in the germline can be classified into two main topics depending on the success and failure of genome editing technologies (Ormond et al., 2017; Greely, 2019).

4.7.1. Issues that may occur in the failure of germline genome editing

Some of the ethical dilemmas of genome editing in the germline arise from the fact that changes in the genome can be transferred to the next generations. Therapeutic genome editing in somatic cells generally does not cause significant concerns when assessing the risk/benefit balance and the use of informed consent. The application of CRISPR-Cas9 in the germline is considered more problematic because of the risk of causing various mutations and side effects and transferring undesirable changes to future generations (Cyranoski and Reardon, 2015; Brokowski, 2018; Cai et al., 2018; Halpern et al., 2019). In fact, Huang and his team found that nontarget mutations in the genome occurred and the study was terminated earlier than planned (Liang et al., 2015). Nontarget mutations are unintentional mutations in the genome and may have harmful effects on the organism as these mutations can lead to cell death or transformation (Zhang et al., 2014). Frighteningly, researchers have found that mutations caused by CRISPR-Cas9 in embryos are much more common than in mouse or human adult cells (Cyranoski and Reardon, 2015). In a study performed with human embryos, it was stated that nontarget mutations occur only in the exon regions and therefore the number of mutations may be much higher than expected (Liang et al., 2015). Due to the high risk of nontarget mutations, some scientists argue that genome editing studies in germline cells should be terminated and its future should be discussed (Cyranoski and Reardon, 2015). Some scientists state that newly developed CRISPR-Cas9 could reduce or even prevent the number of nontarget mutations. In this method, the efficiency of CRISPR-Cas9 was increased by using Cas9-regulated human iPSCs in region-specific gene targeting (Yumlu et al., 2019).

Another bioethical dilemma is the cost of germline genome editing. Genome editing is an expensive technology (Wilson and Carroll, 2019). While families in rich countries may have the power to cover this cost, families in developing countries may not. This situation may cause children born in developed countries to have an unfair advantage in terms of various characteristics such as intelligence and physical state compared to children in other countries (Otieno, 2015).

CRISPR-Cas9 is based on the use of nuclease enzymes. The nuclease enzymes used may not be as effective as desired and not be able to cut all copies of the target gene, or the cell may begin to divide before genome editing is completed. As a result, a condition called genetic mosaicism can occur (Lanphier et al., 2015). Genetic mosaicism is the presence of genetically different somatic cell populations in an organism and is often masked. Mosaicism can also lead to major phenotypic changes, the formation of fatal genetic mutations (Capalbo and Rienzi, 2017), and some genetic diseases such as Down, Klinefelter, and Turner Syndromes (Otieno, 2015). Therefore, the nuclease cleavage sites should be exactly confirmed and the possibility of mosaicism should be completely eliminated.

One of the important bioethical issues is side effects in embryos. It is pointed out that the possible side effects cannot be predicted before birth and the consequences are not clearly known (Otieno, 2015; Brokowski, 2018). Controls can only be performed in a small group of cells. This limitation causes the effects of genome editing on embryos to be unknown and unprevented until birth. In fact, it should be considered that it may take years for many potential problems to emerge (Lanphier et al., 2015; Halpern et al., 2019).

4.7.2. Issues that may occur in the successful application of germline genome editing

The first of the bioethical issues of successful germline genome editing is the use for nontherapeutic changes (Lanphier et al., 2015; Greely, 2019). Such uses will lead to new questions about breeding (eugenics) of the human species and its position in the universe (Yang, 2015). In one study, the fur color of rats was successfully changed by genome editing (Yoshimi et al., 2014). It is possible that the skin color of people could be changed in the future. Since the characteristics of individuals can be determined by genome editing rather than blood relations, the possibility that children with similar physical and mental health can be born in the same way should be considered (Ishi, 2015).

The second bioethical issue is what the fate of children born using genome editing will be. From whom or where informed consent will be obtained in the case of undesirable effects on behalf of genome-edited children and whether informed consent will give detailed information are important questions (Beriain and del Cano, 2018; Neuhaus and Zacharias, 2018; Sykora, 2018; Knoppers and Kleiderman, 2019). While clear informed consent can be given for genome-edited somatic cells to be used in clinical trials, it is an enigma to whom and how to give precise information about the potential risks involved in germline editing (Lanphier et al., 2015; Neuhaus and Zacharias, 2018; Knoppers and Kleiderman, 2019).

In December 2015, the International Summit on Human Gene Editing was convened to discuss the social, moral, and bioethical issues caused by genome editing in the human germline. The results of the summit concluded that basic and clinical investigations should be continued in accordance with the appropriate legal and ethical regulations; however, genome editing on gametocytes and embryos that would cause hereditary changes in humans was found to be irresponsible. It was therefore emphasized that the use of CRISPR-Cas9 on the human germline should be postponed until a solution is found for existing bioethical, social, legal, and technical concerns and issues (Baltimore et al., 2015). In addition, it was agreed to establish an international forum where such concerns could be addressed continuously and the studies in different countries could be organized together (Baltimore et al., 2015; Lanphier et al., 2015; Olson, 2015). The NIH announced that genome editing studies in human embryos will not be financially supported (Collins, 2015). In spite of the joint decisions that were made, in February 2016, British scientists were allowed to use CRISPR-Cas9 and similar technologies in human embryos for research purposes only (https://www.bbc.com/news/health-35459054). In March 2017, the US National Academy of Sciences and the American Society of Human Genetics published a position statement stating that they should be aware of the scientific and bioethical issues that can be caused by germline genome editing, but, on the other hand, research should continue (Ormond et al., 2017). As of January 2020, 24 countries have forbidden genome editing in human embryos by law and 9 countries have banned it by guidelines. However, there are countries that do not impose strict prohibitions on germline genome editing (Ishii, 2017b; Lau et al., 2018; Macintosh, 2019).

5. Discussion and future directions

Thanks to its high accuracy, ease of use, and relatively low cost, CRISPR-Cas9 offers a wide range of applications for many people in the medical, agricultural, livestock, and environmental sectors. Furthermore, its precision and accuracy are much higher compared to older technologies such as ZFN and TALEN (Mittal, 2019). The powerful effects of CRISPR-Cas9 have raised many social, moral, and bioethical issues.

Discussions have generally focused on the social, bioethical, and legal consequences of using genome editing technology in human germline cells. Scientists generally agree that CRISPR-Cas9 should be allowed for use in the creation of human disease models, and in understanding the development and molecular mechanisms of diseases; however, it should be prohibited for the purposes of eugenics or enhancement. When ethical issues, safety concerns, and application difficulties are considered together, it is predicted that therapeutic genome editing in human embryos will not be possible in the near future. Thus, the risk of hereditary nontarget genetic mutation is higher than the possible treatment benefits and it affects the principle of intentional harm. Nevertheless, it is clear that scientists will apply CRISPR-Cas9 in germline cells in the future if solutions are found to the issues mentioned here (Duardo-Sánchez, 2017; Hirsch et al., 2019). CRISPR-Cas9 must be fully reliable for therapeutic use in germline cells. Social, legal, and bioethical issues should be discussed in detail once genome editing technologies have reached the permissible level of safety for clinical applications in the prevention of genetic diseases (Rossant, 2018; Cathomen et al., 2019). Subsequently, regulatory laws that may eliminate breaches of germline genome editing will need to be reassessed (Rodriguez, 2016; Duardo-Sánchez, 2017; Cathomen et al., 2019; Macintosh, 2019). The therapeutic use of CRISPR-Cas9 and its rapid rise in the medical field are expected to continue. While studies on the use of CRISPR-Cas9 for clinical purposes are continuing, the necessary legal, social, and ethical legislation should be put into practice as soon as possible and the public conscience should not be ignored.

On the other hand, the potential effects of CRISPR-Cas9 in other areas should not be forgotten. CRISPR-Cas9 is not just about social and bioethical issues related to people. Interactions with other organisms and the environment, such as the consideration of the principle of intentional harm in risk assessment, safety measures to prevent ecological degradation, or potential use in genetic enhancement of animals and agriculture products should also be discussed (Rodriguez, 2016; Hirsch et al., 2019). There are serious concerns about changes in the natural ecosystem that may occur if the GMOs produced with CRISPR-Cas9 are released to the ecosystem in a controlled or uncontrolled manner. Considering the applications of CRISPR-Cas9 that protect mosquitoes from malaria parasites (Gantz et al., 2015) or make female mosquitoes infertile (Hammond et al., 2016), the effect of GM mosquitoes on other organisms with which they are associated in their ecosystems cannot be predicted. It is clear that small-scale research in the laboratory does not fully reflect possible changes in the natural ecosystem (Carroll, 2017). In agriculture, another concern about GMOs produced with CRISPR-Cas9 is whether they will be accepted by the public. GMOs that were produced using different technologies in the past faced harsh public reactions (Carroll, 2017). Furthermore, the fact that GMOs produced with CRISPR-Cas9 are difficult to identify outside the laboratory raises safety concerns (Shinwari et al., 2017). Before the launch of such products, the necessary explanations and declarations should be made by the authorities in a transparent and clear manner in order to prevent misjudgments and questions that may occur in the public, and precautions and arrangements should be established to ensure the safety of the public.

Another issue to consider about CRISPR-Cas9 is patenting. Patenting can considerably limit the application of such technologies. Unilateral patenting can significantly increase the profitability of biotechnology companies, which may lead to a rise of bioethical issues. There is disagreement in the scientific community regarding the patenting or nonpatenting of GMOs to be used specifically for therapeutic purposes (Shinwari et al., 2017; Sherkow, 2018). However, there are some who think that patenting will help to eliminate and regulate the deficiencies in the field (Rodriguez, 2016; Shinwari et al., 2017). It should not be forgotten that the most important of these debates about patenting is commercialization and the release of only reliable products.

In recent years, deals between the scientific community and the pharmaceutical and biotechnology sectors for the therapeutic use of CRISPR-Cas9 have raised public safety concerns (Shinwari et al., 2017; Carroll, 2019) The guidelines and legislations that will regulate the content and application of these deals should be prepared as quickly as possible and shared with the public. Due to the challenges and bioethical issues of CRISPR-Cas9, the scientific community and other interested bioethical, social, legal, and governmental parties should be provided with a detailed guide for future processing and use of this technology (Otieno, 2015; Shinwari et al., 2017; Cathomen et al., 2019). In this way, a long-term policy can be developed that will support the scientific development of CRISPR-Cas9 technology together with the discussion of the possible problems in advance and preparation of solution plans.

References

Gene editing in human embryos. A comment on the ethical issues involved. The Ethics of Reproductive Genetics. Cham. 2018. p. 173.

The human genome editing race: loosening regulatory standards for commercial advantage? Trends in Biotechnology 37 (2. 2019. p. 120. [PubMed]

CRISPR-Cas9 Therapeutics: A Technology Overview 2015.

Statement on NIH Funding of Research Using Gene-Editing Technologies in Human Embryos 2015.

Dignity only for humans? A controversy. The Cambridge Handbook of Human Dignity: Interdisciplinary Perspectives. 2015. p. 541.

International Summit on Human Gene Editing: A Global Discussion 2016. [PubMed]

Germline gene therapy in the era of precise genome editing: how far should we go? In: Soniewicka M (editor. The Ethics of Reproductive Genetics. Cham. 2018. p. 157.

Thinking Towards the Future of CRISPR/Cas9 2015.

Efficient gene editing of human induced pluripotent stem cells using CRISPR/Cas9. CRISPR Gene Editing. 2019. p. 137. [PubMed]

Articles from Turkish Journal of Biology are provided here courtesy of The Scientific and Technological Research Council of Turkey

# data[].attributes.attachment_link.title
Bioethical issues in genome editing by CRISPR-Cas9 technology

# data[].attributes.attachment_link.description
Genome editing technologies have led to fundamental changes in genetic science. Among them, CRISPR-Cas9 technology particularly stands out due to its advantages such as easy handling, high accuracy, and low cost. It has made a quick introduction in fields ...

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Bioethical issues in genome editing by CRISPR-Cas9 technology

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Bioethical issues in genome editing by CRISPR-Cas9 technology

# data[].attributes.body
Main point:
There are many potentially beneficial uses for the CRISPR technology.

Arguments:
- CRISPR can be used to create animal models for mimicking diseases and understanding different diseases.
- It can be used to edit certain human tissues, such as the liver and the brain. This can help eradicate cancer.
- It can be used to treat numerous diseases, such as muscular dystrophy, AIDS, cataracts, and Parkinson's disease.
- It could also be used for industrial purposes like making the bacterial cultures used in yogurt and cheese production resistant to viruses. Also, it could make crops resistant to plagues and control the invasive species. It can also protect mosquitoes from harmful malaria parasites and make female mosquitoes infertile.
- It could even be used in vaccine development.
- An unusual use could be made for military purposes. CRISPR could be used to make soldiers resistant to biological and chemical warfare. This technology can optimize human performance and prevent soldiers from developing PTSD.
- It can improve the performance of athletes, prevent violent behaviour, or reduce dependence.
- The criminal justice system may require to edit the genes related to violence in dangerous criminals.
- It can be used to create animals that could develop organs suitable for transplantation to humans.

Dialogue:
CRISPR could be a solution to a variety of diseases that are nowadays considered incurable. It could also promote further scientific research, which may be beneficial in many ways. That means that CRISPR can also influence areas beyond its own applications by providing the necessary base for development.

Summary:
The most widely recognised and beneficial usage of this technology is definitely the cure of deadly diseases such as cancer and HIV. Apart from that, CRISPR can be used to create test subjects for experiments, making the task easier for the scientists. Finally, it could also be used for a variety of other purposes, such as producing yogurts with genetically engineered bacteria and even reducing crime rates.

Ayanoglu, F. B., Elcin, A. E., Elcin, Y. M. (2020, April 2). Bioethical in genome editing by CRISPR-Cas9 technology. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7129066/

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Abstract

Genome editing technologies have led to fundamental changes in genetic science. Among them, CRISPR-Cas9 technology particularly stands out due to its advantages such as easy handling, high accuracy, and low cost. It has made a quick introduction in fields related to humans, animals, and the environment, while raising difficult questions, applications, concerns, and bioethical issues to be discussed. Most concerns stem from the use of CRISPR-Cas9 to genetically alter human germline cells and embryos (called germline genome editing). Germline genome editing leads to serial bioethical issues, such as the occurrence of undesirable changes in the genome, from whom and how informed consent is obtained, and the breeding of the human species (eugenics). However, the bioethical issues that CRISPR-Cas9 technology could cause in the environment, agriculture and livestock should also not be forgotten. In order for CRISPR-Cas9 to be used safely in all areas and to solve potential issues, worldwide legislation should be prepared, taking into account the opinions of both life and social scientists, policy makers, and all other stakeholders of the sectors, and CRISPR-Cas9 applications should be implemented according to such legislations. However, these controls should not restrict scientific freedom. Here, various applications of CRISPR-Cas9 technology, especially in medicine and agriculture, are described and ethical issues related to genome editing using CRISPR-Cas9 technology are discussed. The social and bioethical concerns in relation to human beings, other organisms, and the environment are addressed.

Keywords: Genome editing, CRISPR-Cas9 technology, bioethical issues, bioethics

1. Introduction

For many years, molecular biologists have sought ways to use cellular repair mechanisms to manipulate DNA through genome editing. In this way, they would have the power to change the genome by correcting a mutation or introducing a new function (Rodriguez, 2016). For this purpose, genome editing technologies were developed (Memi et al., 2018). In recent years, clustered regularly interspaced short palindromic repeats technology (CRISPR-Cas9) has become the most preferred method of gene editing. This technology has advantages such as high accuracy, easy handling, and relatively low cost compared to previous technologies, such as zinc-finger nuclease (ZFN) and transcription activator-like effector nuclease (TALEN). Thanks to these benefits, CRISPR-Cas9 technology can be easily applied in any molecular biology laboratory.

Genome editing technologies are used in the formation of human disease models in experimental animals and for the understanding of basic gene functions. They also have great therapeutic potential for future treatment of untreated diseases such as certain cancers, genetic disorders, and HIV/AIDS. Today, genome editing in somatic cells is one of the promising areas of therapeutic development (Otieno, 2015). However, various bioethical issues have arisen due to the potential impact of these technologies on the safety of food stocks and clinical applications (Hundleby and Harwood, 2018; Hirch et al., 2019). This review discusses the challenges, possible consequences, and bioethical issues of CRISPR-Cas9 in detail.

2. Biology and function of CRISPR-Cas9 technology

Genome editing technologies often work by creating fractures in chromosomal DNA. ZFN, TALEN, and CRISPR-Cas9 are all based solely on nucleases (Kim and Kim, 2014; Roh et al., 2018). The strength of these technologies stems from the ability to create fractures in the desired region of a specific target sequence as determined by the researcher. This allows researchers to modify the genome in practice in any region (Memi et al., 2018).

The creation of changes in the genome depends mainly on the DNA repair capacity of the cells (Lau et al., 2018). All cells have two basic mechanisms for the repair of double chain breaks on DNA. One of them is nonhomologous end joining (NHEJ) and the other is the homologous dependent repair (HDR) mechanism. In NHEJ, the ends of the fractures are quickly connected directly to each other, regardless of the sequence homology, while HDR requires homology to repair the damaged DNA site. In order to achieve homology, the undamaged sister chromatid is used as a template and DNA damage is repaired (Urnov, 2018).

CRISPR-Cas9 is a naturally occurring defense system in prokaryotic organisms that provides resistance to foreign genetic elements such as plasmids and bacteriophages (Barrangau et al., 2007; Marraffini and Sontheimer, 2008). When the virus or plasmid enters a bacterial cell, CRISPR-Cas9 allows the addition of short viral DNA molecules to the CRISPR site. CRISPR sequences (CRISPRs) are short DNA repeats of viral or plasmid origin found in the genomes of bacteria and are defined as clustered regularly interspaced short palindromic repeats. Cas genes (CRISPR-related) are genes that encode nuclease or helicase proteins associated with CRISPR repeat sequences that have the function of cutting or dissolving DNA (Jansen et al., 2002). Cas9, a member of the Cas gene family, was isolated from Streptococcus pyogenes and is an endonuclease capable of cutting DNA from two active cut regions at both ends of the DNA double helix (Doudna and Charpentier, 2014; Rodriguez, 2016). The CRISPR-Cas system recognizes the DNA of the invading virus or bacterium and directs the Cas protein to destroy foreign DNA (Otieno, 2015).

In the following years, it was discovered that the CRISPR-Cas system can be programmed to find and cut specific target DNA regions, thereby providing genome editing (Jinek et al., 2012; Hsu et al., 2013). As a result of understanding that the human genome can be edited by CRISPR-Cas9, it became clear that genome editing could also be used for therapeutic purposes, and a new era in genetic engineering began (Lau et al., 2018; Roh et al., 2018).

3. Application areas

3.1. Animal models

CRISPR-Cas9 can be used to create animal models to mimic human diseases and to understand disease development by mutating or silencing genes. A mouse model has been developed to determine the harmful effects of mutations in cancer by making mutations that cause the loss of function in tumor suppressor genes or give functions to protooncogenes (Chin, 2015).

Conventional genetically modified (GM) mouse models are produced by gene targeting in embryonic stem cells or transgenesis, which are time-consuming and highly expensive. With CRISPR-Cas9, GM mice can be efficiently produced in a much shorter time (Mei et al., 2016). It can be applied to nonhuman primates such as monkeys. Nonhuman primates are more similar to humans in anatomical, physiological, and genetic terms than rodents (Zhang et al., 2014). Therefore, they are more suitable models than rodents in understanding human biology and disease development (Xin et al., 2016). The first successful application of CRISPR-Cas9 in nonhuman primates, from which a knockout monkey was produced, was realized in 2014 (Niu et al., 2014). However, genome sequences of many nonhuman primates are not yet fully identified. This makes it difficult to design selected single-guide RNAs (sgRNAs) (Gou and Li, 2015; Lou et al., 2016). Therefore, the application of CRISPR-Cas9 in nonhuman primates is still at an early stage.

3.2. Genome editing in specific tissues

Researchers have been able to modify the genomes of specific tissues such as liver and brain tissues using hydrodynamic injection and adeno-associated virus (AAV) (Rodriguez et al., 2014; Senis et al., 2014). In a study, CRISPR-Cas9 has been successfully and effectively applied to the mammalian nervous system. A mixture of green fluorescent protein (GFP)-labeled AAV-spCas9 and AAV-spGuide plasmids was transferred in vivo to the hippocampal toothed brain folds of adult male mice (Swiech et al., 2015). It is thought that the number of such applications will grow in the fields of cancer and neuroscience in the following years (Mei et al., 2016).

3.3. Multiple gene mutations

CRISPR-Cas9 can be used to generate mutants for target genes. In the first such study by Li et al., six sgRNAs targeting Cas9 mRNA and six different genomic regions encoding the Tet1, Tet2, and Tet3 genes were transferred to the cytoplasm of rat embryos (Li et al., 2013). Findings showed that all three Tet genes carried the desired mutations in 59% of newborn rat pups. Successful results were also reported in studies with zebrafish embryos and Arabidopsis as well (Ota et al., 2014; Wang et al., 2015).

3.4. Epigenome studies

Epigenome studies can be performed in two different ways: genome or epigenome editing (Chen et al., 2014; Huisman et al., 2015). In genome editing, nuclease is used to modify the DNA sequence, whereas in epigenome editing, an effector domain is used and the DNA sequence is not changed. This function is achieved by catalytic inactivation of the Cas9-associated effector domain by replacing the Cas9 protein. Altered effector proteins are used to activate or suppress transcription (Lau and Davie, 2016). In epigenome editing, the epigenome can be modified by changing the proteins that maintain and protect the epigenome. Suppression of DNA methylation as a result of degradation of catalytic domains that accelerate the loss of spherical DNA methylation in human cells and lead to cell death is a good example of epigenome studies using CRISPR-Cas9 (Liao et al., 2015).

Another application is the editing of long nonencoded RNAs (lncRNAs) and enhancer RNAs (eRNAs) that can control gene expression and epigenome processes. In a study, eRNA-expression factors and IncRNA-expression enhancers were suppressed by stimulating deletion mutations in a lymphoma cell line using CRISPR-Cas9 (Pefanis et al., 2015). It is predicted that CRISPR-Cas9 may allow different levels of epigenome modification and facilitate further changes to humans (Liao et al., 2015; Mei et al., 2016).

3.5. Treatment of diseases

CRISPR-Cas9 can be applied to cells in vivo or ex vivo. In the in vivo approach, CRISPR-Cas9 is directly transferred to cells in the body using either viral or nonviral methods. In the ex vivo approach, first the cells are removed from the body; then CRISPR is applied to the cells and they are transferred back to the body (Roh et al., 2018). This approach has great potential to develop tissue-based therapies (Rath et al., 2015). Using CRISPR-Cas9, the mutation in the dystrophin protein responsible for the most common form of Duchenne muscular dystrophy was successfully removed (Amoasii et al., 2018; Duchêne et al., 2018; Koo et al., 2018; Long et al., 2018). There are studies to prevent and treat AIDS by inhibiting the entry of HIV into the cell or by removing the HIV genome integrated into the host genome using CRISPR-Cas9 (Saayman et al., 2015). Induced pluripotent stem cells (iPSCs) were successfully produced from cystic fibrosis patients with confirmed F508 deletion in the cystic fibrosis transmembrane regulator ( CFTR) gene by CRISPR-Cas9 (Firth et al., 2015). There are also studies for cataracts (Wu et al., 2015; Yang et al., 2016) and Parkinson's disease (Yang et al., 2016). However, recent studies have shown that CRISPR-Cas9 activates the type 1 interferon (INF) pathway, causing a type 1 INF-mediated immune response (Kim et al., 2018; Charleswort et al., 2019). These findings currently limit the use of CRISPR-Cas9 in treatment.

3.6. Industrial uses

CRISPR was first used for commercial purposes to make bacterial cultures used in cheese and yogurt production resistant to viral infections (van Erp et al., 2015). One of the applications in agriculture is to produce GM crops (Hundleby and Harwood, 2019). There are attempts to increase the yield in the livestock industry (van Erp et al., 2015). It can be used to control invasive pest species to reverse pesticide and herbicide resistance in insects and weeds or to prevent disease spread (Esvelt et al., 2014). Researchers have succeeded in preventing the spread of genes protecting mosquitoes from harmful malaria parasites (Gantz et al., 2015) and making female mosquitoes infertile in the laboratory (Hammond et al., 2016). Vaccine development is another significant area of interest. The smallpox virus vector (VACV) is used in the eradication and vaccination of smallpox. Using CRISPR-Cas9, the efficiency of marker-free VACV vectors has been increased (Yuan et al., 2015). Another example is the hepatitis B vaccine. In order to prevent viral gene expression and replication, specific regions of the hepatitis B genome were targeted and cut by CRISPR-Cas9 (Ramanan et al., 2015).

3.7. RNA editing

Single-stranded RNA (ssRNA) sequences can also be edited by CRISPR-Cas9. In RNA editing, CRISPR-Cas9 consists of a DNA oligonucleotide presenting the PAM (protospacer adjacent motif) region (PAMmer), ssRNA, guide RNA (gRNA), and Cas9 protein. PAMmer acts as a PAM region specifically recognized by Cas9 and directs Cas9 to bind and cut the target ssRNA. 5'-Elongated PAMmers containing bases paired with different ssRNAs and immediately in front of PAM are required for specific binding of target ssRNAs. Since RNA molecules have different functions than DNA, CRISPR-Cas9 can offer a much more flexible application than other genome editing methods (Mei et al., 2016).

3.8. Military applications

One of the lesser-discussed application areas of CRISPR-Cas9 technology is its use for military purposes. As is known, a substantial portion of genome editing studies are supported by the defense ministries of the countries. These studies are commonly focused on increasing the tolerance of soldiers against biological or chemical warfare. This technology has the potential to influence human performance optimization (Greene and Master, 2018). Studies are usually concentrated on discovering different genes that can be harnessed from other species (Gracheva et al., 2010) and identifying new genes that can be associated with posttraumatic stress disorder, which is frequently experienced by soldiers (Cornelis et al., 2010). In a study by Zou et al. (2015), researchers developed dog embryos with higher muscle mass using CRISPR-Cas9. Another interesting study showed that the CMG2 gene, known to cause low sensitivity to anthrax toxin when expressed in small amounts, could be silenced by this technology (Arévalo et al., 2014). However, it should be noted that far more research needs to be conducted for using CRISPR technology in humans as a defense tool against biological and chemical weapons (Greene and Master, 2018).

3.9. DNA replacement in human embryos (germline genome therapy)

The most controversial usage of CRISPR-Cas9 is the modification of human embryo DNA, or, in other words, its use for germline genome therapy. In 2015, a group of Chinese researchers led by Junjiu Huang applied CRISPR-Cas9 to remove a mutation that causes β-thalassemia, which is a fatal blood disease, from the human β-globulin ( HBB) gene in the germline of human embryos. In this research, six abnormal embryos not suitable for in vitro fertilization were used. The mutation could be corrected in only one of the embryos. Although the mutation could be corrected in two other embryos, nontarget effects occurred in other genes. In the other three embryos, the mutation could not be corrected. It has been reported that this technique is not ready for clinical use because of nontarget effects on different genes (Roh et al., 2018; Carroll, 2019). Modifications that occur in germline cells can be transferred to future generations. Scientists think that they can extract genes that cause diseases in the population using CRISPR-Cas9 (Cai et al., 2018; Memi et al., 2018).

4. Bioethical issues

The fact that CRISPR-Cas9 is among the important discoveries of the 21st century is widely accepted in the scientific community and related industries. However, the rapid rise of CRISPR-Cas9 has led to new bioethical, social, and legal issues in medicine, agriculture, livestock, and the environment. Possible risks and bioethical issues related to CRISPR-Cas9 are summarized in the Table.

Table

Organism

Risks

Bioethical issues

References

Bacteria

Nontarget mutationsGene drifts

Ecological imbalance

Rodriguez, 2016 Hundleby and Harwood, 2019 Esvelt et al., 2014

Plants

Nontarget mutationsGene drifts

Ecological imbalancePatenting

Shinwari et al., 2017 Hundleby and Harwood, 2019

Animals /chimeric animals

Nontarget mutations

Ecological imbalance Patenting Animal welfare and dignity Threatening of human dignity and identity

Rodriguez, 2016 Polcz and Lewis, 2016 Rodriguez, 2017 Eriksson et al., 2018 Koplin, 2019 Degrazia, 2019 de Graeff et al., 2019

Humans

Nontarget mutations Side effects Cost Genetic mosaicism

Eugenics Informed consent Enhancement Accessibility Patenting Safety Incomplete or over legislations

Otieno, 2015 Rodriguez, 2016 Duardo-Sánchez, 2017 Shinwari et al., 2017 Greene and Master, 2018 Sherkow, 2018 Cathomen et al., 2019 Hirsch et al., 2019

4.1. Ecological imbalance

In studies using RNA-targeted gene editing methods based on CRISPR-Cas9, nontarget effects should be examined in depth. Since gene drift will persist in a population, possible off-target mutations will continue in each generation. In addition, the number and effect of mutations may increase as generations progress (Rodriguez, 2016; Hundleby and Harwood, 2019). Another concern is the possibility that genes can be transferred to other species in the environment. Transferring the regulated sequences to other species may result in the transmission of negative characteristics to the associated organisms (Esvelt et al., 2014). The distribution of the properties of the entrained genes among the populations can make control very difficult.

4.2. Regulations for consumers

The use of CRISPR-Cas9 to obtain the desired genetic modifications makes it very difficult to identify and regulate genetically modified organisms (GMOs) in the market after they leave the laboratory. Therefore, regulatory agencies, such as the US Food and Drug Administration (FDA), European Medicines Agency (EMA), and others, should consider whether any GMOs are suitable for consumers. However, it is not known exactly how to evaluate the possibilities of a growing market with CRISPR-Cas9 (Ledford, 2015; Hundleby and Harwood, 2019).

One of the dilemmas of CRISPR-Cas9 that concerns all the humanity is patenting. As is known, transgenic organisms of industrial use and also some human gene sequences for clinical purposes have been patented (Rodriguez, 2016; Sherkow, 2018). As technologies such as CRISPR continue to evolve, patent-related issues in many areas of biotechnology will continue to increase in the upcoming years. Even today, there are many such cases of patenting. The best-known case is the patent right case between Zhang and Doudna and Charpentier for the therapeutic use of CRISPR-Cas9 in human cells. In the case concluded on 2 December 2016, it was decided to grant the patent to Caribou Biosciences, which Doudna was the founder of (Donohoue et al., 2018).

4.3. Genome editing for enhancement

The editing of human germline cells with CRISPR-Cas9, which will be discussed later in more detail, is prohibited for various safety reasons. However, the rate of application of CRISPR-Cas9 to somatic cells is gradually increasing in order to transfer the desired characteristics to our lives. Many phenotypic characteristics have a genetic component independent of the environment. By utilizing this feature, CRISPR-Cas9 can be used to improve the performance of athletes, to prevent violent behavior, or to reduce dependence (Rodriguez, 2016). Although gene therapy is often used to treat patients for their own benefit, the criminal justice system may require repeater or dangerous offenders to correct the genes associated with violence by genome editing technologies in the future. One of the biggest dilemmas here is to obtain informed consent for an underage person if the intervention is made during the development of the zygote. This will give parents or guardians the right to make decisions on behalf of minors for nonhealth reasons. Furthermore, when socially assessed, some genetically improved populations or individuals may have some advantages in comparison to others in terms of various features such as mental and physical capacity (Brokowski, 2018). Therefore, the use of CRISPR-Cas9 in genome enhancement should be seriously discussed both socially and morally.

4.4. Military research

The use of CRISPR technology for military purposes is generally considered within the scope of nontherapeutic enhancement and is covered similarly. From this point of view, related bioethical issues are commonly discussed in terms of concepts of benefit/risk, informed consent, and accessibility (Greene and Master, 2018). A notable bioethical problem is the off-target mutations that have been mentioned in relation to other topics. Off-target mutations can cause many undesirable changes in the genome or even lead to fatal diseases. Current information obtained from studies on off-target mutations caused by CRISPR on the genome is very limited. Therefore, the benefit/risk relationship needs to be evaluated carefully. In addition, the possibility that this technology can be used for the production of new biological weapons is frightening.

Another ambiguous issue that needs to be discussed in military enhancement applications is informed consent. It could be difficult to obtain informed consent forms independently without any interaction among individuals due to military training methods, strict norms, and chains of command. Additionally, some soldiers may have difficulty in understanding the concepts of gene therapy and genome editing, as well as the potential risks and benefits of the applications (Greene and Master, 2018).

One important ethical issue is that the use of such technologies will support ongoing inequalities among military parties (Amoroso and Wenger, 2003). CRISPR is currently an expensive technology. Some developed countries might think of using this technology to further strengthen their defenses and even attack underdeveloped or developing countries. This situation could cause a constant tension, making it difficult to provide an environment of peace and stability worldwide.

4.5. Generation of chimeric animals for organ transplantation

Organ transplantation is the replacement of an organ that cannot function in an individual's body with a healthy organ from a living donor or cadaver. The primary purpose is to save the life of the patient, who is in danger of organ failure, and to increase the lifespan and quality of life (Black et al., 2018). The development of chimeric animals may prevent patients from spending precious time waiting for an appropriate donor.

Bioethical issues in the generation of chimeric animals arise from the fact that chimeras contain human nerve and germ cells (Polcz and Lewis, 2016). The two main issues can be summarized as defining the order of nature and the moral disorders caused by how the organism is treated depending on whether the organism is accepted as human or animal. Some people think that chimeric embryos will affect human dignity and identity because they have the power to develop organisms with human-derived cells and tissues. The others state that chimeric organisms containing human cells cannot turn into humans and therefore will not affect human dignity. They also argue that the human-like features imparted to chimeras will neither affect the biological environment nor the moral status of animals and will never reach human consciousness (Koplin, 2019; Degrazia, 2019).

4.6. Animal welfare and dignity

Animal welfare is another bioethical concern encountered during the application of genome editing technologies on animals. First of all, the possibility of off-target mutations in the genome can lead to diseases or different side effects in animals (Ishii, 2017a; Schultz-Bergin, 2018; de Graeff et al., 2019). Such a situation will adversely affect animal welfare (Rodriguez, 2017).

The second bioethical issue to be discussed could be the concerns about "animal dignity" (Eriksson et al., 2018) and alterations in their natural environments and physiological needs (Manesh et al., 2014). Some studies have stated that the use of animals as objects only serving for humans is not ethically or morally acceptable (Martinelli et al., 2014; Fung and Kerridge, 2016; Greenfield, 2017), and such practices can lead to greater control over humans on animals (Ishii, 2017a; de Graeff et al., 2019). Some others think that animals are not bound by any moral law and therefore there is no need for a discussion regarding animal dignity (Heeger, 2015; Shriver and McConnachie, 2018). Schultz-Bergin (2017) stated that animal rights, welfare, and dignity will not be adversely affected since these animals will occur through genome editing technologies. The existence of contrary opinions on this matter indicates that the mentioned bioethical issues will be on the agenda for a long time.

4.7. CRISPR-Cas9 for human germline

The potential for using CRISPR-Cas9 for genome editing in the human germline has raised serious ethical debates. Until 2015, all therapeutic applications in humans were performed in somatic cells using genome editing technologies. However, in 2015, the editing of the human germline performed by Chinese scientist Huang and his team with CRISPR-Cas9 raised new social, moral, and bioethical issues (Liang et al., 2015; Ormond et al., 2017). Bioethical issues caused by genome editing in the germline can be classified into two main topics depending on the success and failure of genome editing technologies (Ormond et al., 2017; Greely, 2019).

4.7.1. Issues that may occur in the failure of germline genome editing

Some of the ethical dilemmas of genome editing in the germline arise from the fact that changes in the genome can be transferred to the next generations. Therapeutic genome editing in somatic cells generally does not cause significant concerns when assessing the risk/benefit balance and the use of informed consent. The application of CRISPR-Cas9 in the germline is considered more problematic because of the risk of causing various mutations and side effects and transferring undesirable changes to future generations (Cyranoski and Reardon, 2015; Brokowski, 2018; Cai et al., 2018; Halpern et al., 2019). In fact, Huang and his team found that nontarget mutations in the genome occurred and the study was terminated earlier than planned (Liang et al., 2015). Nontarget mutations are unintentional mutations in the genome and may have harmful effects on the organism as these mutations can lead to cell death or transformation (Zhang et al., 2014). Frighteningly, researchers have found that mutations caused by CRISPR-Cas9 in embryos are much more common than in mouse or human adult cells (Cyranoski and Reardon, 2015). In a study performed with human embryos, it was stated that nontarget mutations occur only in the exon regions and therefore the number of mutations may be much higher than expected (Liang et al., 2015). Due to the high risk of nontarget mutations, some scientists argue that genome editing studies in germline cells should be terminated and its future should be discussed (Cyranoski and Reardon, 2015). Some scientists state that newly developed CRISPR-Cas9 could reduce or even prevent the number of nontarget mutations. In this method, the efficiency of CRISPR-Cas9 was increased by using Cas9-regulated human iPSCs in region-specific gene targeting (Yumlu et al., 2019).

Another bioethical dilemma is the cost of germline genome editing. Genome editing is an expensive technology (Wilson and Carroll, 2019). While families in rich countries may have the power to cover this cost, families in developing countries may not. This situation may cause children born in developed countries to have an unfair advantage in terms of various characteristics such as intelligence and physical state compared to children in other countries (Otieno, 2015).

CRISPR-Cas9 is based on the use of nuclease enzymes. The nuclease enzymes used may not be as effective as desired and not be able to cut all copies of the target gene, or the cell may begin to divide before genome editing is completed. As a result, a condition called genetic mosaicism can occur (Lanphier et al., 2015). Genetic mosaicism is the presence of genetically different somatic cell populations in an organism and is often masked. Mosaicism can also lead to major phenotypic changes, the formation of fatal genetic mutations (Capalbo and Rienzi, 2017), and some genetic diseases such as Down, Klinefelter, and Turner Syndromes (Otieno, 2015). Therefore, the nuclease cleavage sites should be exactly confirmed and the possibility of mosaicism should be completely eliminated.

One of the important bioethical issues is side effects in embryos. It is pointed out that the possible side effects cannot be predicted before birth and the consequences are not clearly known (Otieno, 2015; Brokowski, 2018). Controls can only be performed in a small group of cells. This limitation causes the effects of genome editing on embryos to be unknown and unprevented until birth. In fact, it should be considered that it may take years for many potential problems to emerge (Lanphier et al., 2015; Halpern et al., 2019).

4.7.2. Issues that may occur in the successful application of germline genome editing

The first of the bioethical issues of successful germline genome editing is the use for nontherapeutic changes (Lanphier et al., 2015; Greely, 2019). Such uses will lead to new questions about breeding (eugenics) of the human species and its position in the universe (Yang, 2015). In one study, the fur color of rats was successfully changed by genome editing (Yoshimi et al., 2014). It is possible that the skin color of people could be changed in the future. Since the characteristics of individuals can be determined by genome editing rather than blood relations, the possibility that children with similar physical and mental health can be born in the same way should be considered (Ishi, 2015).

The second bioethical issue is what the fate of children born using genome editing will be. From whom or where informed consent will be obtained in the case of undesirable effects on behalf of genome-edited children and whether informed consent will give detailed information are important questions (Beriain and del Cano, 2018; Neuhaus and Zacharias, 2018; Sykora, 2018; Knoppers and Kleiderman, 2019). While clear informed consent can be given for genome-edited somatic cells to be used in clinical trials, it is an enigma to whom and how to give precise information about the potential risks involved in germline editing (Lanphier et al., 2015; Neuhaus and Zacharias, 2018; Knoppers and Kleiderman, 2019).

In December 2015, the International Summit on Human Gene Editing was convened to discuss the social, moral, and bioethical issues caused by genome editing in the human germline. The results of the summit concluded that basic and clinical investigations should be continued in accordance with the appropriate legal and ethical regulations; however, genome editing on gametocytes and embryos that would cause hereditary changes in humans was found to be irresponsible. It was therefore emphasized that the use of CRISPR-Cas9 on the human germline should be postponed until a solution is found for existing bioethical, social, legal, and technical concerns and issues (Baltimore et al., 2015). In addition, it was agreed to establish an international forum where such concerns could be addressed continuously and the studies in different countries could be organized together (Baltimore et al., 2015; Lanphier et al., 2015; Olson, 2015). The NIH announced that genome editing studies in human embryos will not be financially supported (Collins, 2015). In spite of the joint decisions that were made, in February 2016, British scientists were allowed to use CRISPR-Cas9 and similar technologies in human embryos for research purposes only (https://www.bbc.com/news/health-35459054). In March 2017, the US National Academy of Sciences and the American Society of Human Genetics published a position statement stating that they should be aware of the scientific and bioethical issues that can be caused by germline genome editing, but, on the other hand, research should continue (Ormond et al., 2017). As of January 2020, 24 countries have forbidden genome editing in human embryos by law and 9 countries have banned it by guidelines. However, there are countries that do not impose strict prohibitions on germline genome editing (Ishii, 2017b; Lau et al., 2018; Macintosh, 2019).

5. Discussion and future directions

Thanks to its high accuracy, ease of use, and relatively low cost, CRISPR-Cas9 offers a wide range of applications for many people in the medical, agricultural, livestock, and environmental sectors. Furthermore, its precision and accuracy are much higher compared to older technologies such as ZFN and TALEN (Mittal, 2019). The powerful effects of CRISPR-Cas9 have raised many social, moral, and bioethical issues.

Discussions have generally focused on the social, bioethical, and legal consequences of using genome editing technology in human germline cells. Scientists generally agree that CRISPR-Cas9 should be allowed for use in the creation of human disease models, and in understanding the development and molecular mechanisms of diseases; however, it should be prohibited for the purposes of eugenics or enhancement. When ethical issues, safety concerns, and application difficulties are considered together, it is predicted that therapeutic genome editing in human embryos will not be possible in the near future. Thus, the risk of hereditary nontarget genetic mutation is higher than the possible treatment benefits and it affects the principle of intentional harm. Nevertheless, it is clear that scientists will apply CRISPR-Cas9 in germline cells in the future if solutions are found to the issues mentioned here (Duardo-Sánchez, 2017; Hirsch et al., 2019). CRISPR-Cas9 must be fully reliable for therapeutic use in germline cells. Social, legal, and bioethical issues should be discussed in detail once genome editing technologies have reached the permissible level of safety for clinical applications in the prevention of genetic diseases (Rossant, 2018; Cathomen et al., 2019). Subsequently, regulatory laws that may eliminate breaches of germline genome editing will need to be reassessed (Rodriguez, 2016; Duardo-Sánchez, 2017; Cathomen et al., 2019; Macintosh, 2019). The therapeutic use of CRISPR-Cas9 and its rapid rise in the medical field are expected to continue. While studies on the use of CRISPR-Cas9 for clinical purposes are continuing, the necessary legal, social, and ethical legislation should be put into practice as soon as possible and the public conscience should not be ignored.

On the other hand, the potential effects of CRISPR-Cas9 in other areas should not be forgotten. CRISPR-Cas9 is not just about social and bioethical issues related to people. Interactions with other organisms and the environment, such as the consideration of the principle of intentional harm in risk assessment, safety measures to prevent ecological degradation, or potential use in genetic enhancement of animals and agriculture products should also be discussed (Rodriguez, 2016; Hirsch et al., 2019). There are serious concerns about changes in the natural ecosystem that may occur if the GMOs produced with CRISPR-Cas9 are released to the ecosystem in a controlled or uncontrolled manner. Considering the applications of CRISPR-Cas9 that protect mosquitoes from malaria parasites (Gantz et al., 2015) or make female mosquitoes infertile (Hammond et al., 2016), the effect of GM mosquitoes on other organisms with which they are associated in their ecosystems cannot be predicted. It is clear that small-scale research in the laboratory does not fully reflect possible changes in the natural ecosystem (Carroll, 2017). In agriculture, another concern about GMOs produced with CRISPR-Cas9 is whether they will be accepted by the public. GMOs that were produced using different technologies in the past faced harsh public reactions (Carroll, 2017). Furthermore, the fact that GMOs produced with CRISPR-Cas9 are difficult to identify outside the laboratory raises safety concerns (Shinwari et al., 2017). Before the launch of such products, the necessary explanations and declarations should be made by the authorities in a transparent and clear manner in order to prevent misjudgments and questions that may occur in the public, and precautions and arrangements should be established to ensure the safety of the public.

Another issue to consider about CRISPR-Cas9 is patenting. Patenting can considerably limit the application of such technologies. Unilateral patenting can significantly increase the profitability of biotechnology companies, which may lead to a rise of bioethical issues. There is disagreement in the scientific community regarding the patenting or nonpatenting of GMOs to be used specifically for therapeutic purposes (Shinwari et al., 2017; Sherkow, 2018). However, there are some who think that patenting will help to eliminate and regulate the deficiencies in the field (Rodriguez, 2016; Shinwari et al., 2017). It should not be forgotten that the most important of these debates about patenting is commercialization and the release of only reliable products.

In recent years, deals between the scientific community and the pharmaceutical and biotechnology sectors for the therapeutic use of CRISPR-Cas9 have raised public safety concerns (Shinwari et al., 2017; Carroll, 2019) The guidelines and legislations that will regulate the content and application of these deals should be prepared as quickly as possible and shared with the public. Due to the challenges and bioethical issues of CRISPR-Cas9, the scientific community and other interested bioethical, social, legal, and governmental parties should be provided with a detailed guide for future processing and use of this technology (Otieno, 2015; Shinwari et al., 2017; Cathomen et al., 2019). In this way, a long-term policy can be developed that will support the scientific development of CRISPR-Cas9 technology together with the discussion of the possible problems in advance and preparation of solution plans.

References

Gene editing in human embryos. A comment on the ethical issues involved. The Ethics of Reproductive Genetics. Cham. 2018. p. 173.

The human genome editing race: loosening regulatory standards for commercial advantage? Trends in Biotechnology 37 (2. 2019. p. 120. [PubMed]

CRISPR-Cas9 Therapeutics: A Technology Overview 2015.

Statement on NIH Funding of Research Using Gene-Editing Technologies in Human Embryos 2015.

Dignity only for humans? A controversy. The Cambridge Handbook of Human Dignity: Interdisciplinary Perspectives. 2015. p. 541.

International Summit on Human Gene Editing: A Global Discussion 2016. [PubMed]

Germline gene therapy in the era of precise genome editing: how far should we go? In: Soniewicka M (editor. The Ethics of Reproductive Genetics. Cham. 2018. p. 157.

Thinking Towards the Future of CRISPR/Cas9 2015.

Efficient gene editing of human induced pluripotent stem cells using CRISPR/Cas9. CRISPR Gene Editing. 2019. p. 137. [PubMed]

Articles from Turkish Journal of Biology are provided here courtesy of The Scientific and Technological Research Council of Turkey

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Bioethical issues in genome editing by CRISPR-Cas9 technology

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Genome editing technologies have led to fundamental changes in genetic science. Among them, CRISPR-Cas9 technology particularly stands out due to its advantages such as easy handling, high accuracy, and low cost. It has made a quick introduction in fields ...

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Genetic Engineering Will Change Everything Forever – CRISPR

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Genetic Engineering Will Change Everything Forever – CRISPR

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Main idea: until recently, gene editing was extremely expensive, complicated and took a long time to do. This has now changed with a revolutionary new technology: CRISPR. Overnight, the costs of engineering have shrunk by 99%

instead of a year.

Facts:
- The earliest genetically modified animal was born in 1974,

making mice a standard tool for research, saving millions of lives.

- In the 1990s, there was also a brief foray into human engineering. To treat maternal infertility, babies were made to carry genetic information from three humans, making them the first humans ever to have three genetic parents.
-In 2016, scientists carried out a larger scale project with rats that had the HIV virus in basically all of their body cells. By simply injecting CRISPR into the rats tails, they were able to remove more than 50% of the virus from cells all over the body.

- CRISPR is a kind of repeating DNA structure that was first discovered accidentally in bacterial DNA by the Japanese scientist Yoshizumi Ishino in 1987

Dialogue:  Modified humans could alter the genome of our entire species because their engineered traits will be passed on to that children and could spread over generations, slowly modifying the whole gene pool of humanity.

Summary:  The video talks about where CRISPR came from, what humanity is doing right now related to genetic engineering, and about a recent breakthrough that will change how we live and what we perceive as “normal” forever.

APA style: Kurzgesagt-In a nutshell (2016, August). Genetic Engineering Will Change Everything Forever – CRISPR
from: youtube.com/watch?v=jAhjPd4uNFY&t=730s

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Genetic Engineering Will Change Everything Forever – CRISPR

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Explanation about the CRISPR tool to edit genes

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Explanation about the CRISPR tool to edit genes

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Main idea: CRISPR allows researchers to cut-and-paste DNA sequences. First, scientists compose a set of genetic letters or “guide RNA” that, like the original pieces of viral code, recognize a specific stretch of DNA among the millions of A, T, G and C letters in the genome.

They then introduce this guide sequence together with a Cas9-like enzyme into the target cell, which recognizes the corresponding text and opens it. Scientists use this mechanism to delete, mutate, insert, or repair genomic DNA sequences in cells, animals, and humans.

Facts:
- CRISPR stands for “Clustered Regularly Interspaced Short Palindromic Repeats”.
- The technology was developed in 2012, and since then, more than 8,000 scientific papers mentioning CRISPR have been published. Today, this technology is used in research laboratories in more than 80 countries to study the molecular basis of disease and create new treatments.
- The possible applications of CRISPR technology are limitless. In petri dishes and animal models, researchers have used CRISPR to fix large genetic errors, such as those that cause muscular dystrophy, cystic fibrosis, and fragile X syndrome. They have also harnessed technology to manipulate pigs to obtain organs for people in need of transplants. Other work is underway to eliminate HIV infections, create smarter microbial antagonists and control disease-carrying mosquitoes.

Dialogue:   CRISPR could be used in many good ways,  But what if CRISPR was used to manipulate genes related to characteristics such as height, eye color or IQ, in order to generate aesthetic improvements? Could it be that efforts to improve the genome will inevitably lead to the generation of configured babies?

Summary: This article explains what is CRISPR, how does it work and how CRISPR could change every people's lives. It also raises potential questions and misuses of CRISPR.

APA style:
Broadfoot, M. V. (2018, August) Explicación sobre la herramienta CRISPR para editar genes. Retrieved from:
https://discoverysedge.mayo.edu/2019/05/29/explicacion-sobre-la-herramienta-crispr-para-editar-genes/#:~:text=%C2%BFQu%C3%A9%20es%3F,defenderse%20de%20los%20virus%20invasores.

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Explicación sobre la herramienta CRISPR para editar genesDiscovery’s EdgeDiscovery’s Edge

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Con una nueva herramienta para editar genes, llamada CRISPR, los científicos son capaces de modificar los genomas de las plantas, [...]

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Main point:
Disorders are not necessarily something bad, meaning that some people would rather choose not to change them.

Arguments:
- If we strive to eliminate disabilities from our children, this can go against the drive towards inclusion. If there is diversity among the population, the world is much more humane for everyone.
- Accommodations originally intended for disabled people often benefit everyone, as is the case with closed captions.

Dialogue:
Eliminating disabilities with CRISPR might be a benefit for some, but it can also cause a lot of harm to others. For example, some disabilities may not be changeable, so these people would be even more left out from society. As fewer and fewer people will have disabilities, some commodities made just for disabled people may disappear, leaving the ones with disabilities in trouble.

Summary:
Even though some people are glad that disabilities can be reduced with technologies such as CRISPR, others are pointing out the possible risks of such practices. Some families confessed that if they had the opportunity to change their child's genes at the moment of birth, they would not. They think that disability is an irreplaceable part of their child and they do not want to get rid of it.

Hayden, E. C. (2016, February 23). Should you edit your children's genes?. Retrieved from: https://www.nature.com/articles/530402a

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In the fierce debate about CRISPR gene editing, it's time to give patients a voice.

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.

LISTEN

Your browser does not support the audio element.

How do those with disabilities feel about the possibility of editing the genomes of future generations?

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.

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."

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.

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.

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.

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.

About this article

Further reading

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Should you edit your children's genes? - Nature

# data[].attributes.attachment_link.description
In the fierce debate about CRISPR gene editing, it's time to give patients a voice. 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.

# data[].attributes.body
Main point:
CRISPR can reduce the struggles endured by certain people who suffer from disabilities related to genes.

Arguments:
- CRISPR could end with Huntington's disease, which deteriorates the brain and the body. This would also prevent it from passing on in the family, leaving the future generations free from it.

Dialogue:
This technology can drastically improve the quality of life of many individuals who suffer from diseases such as this one. Moreover, they can enjoy a happier rest of their lives, not burdened by mental and physical deterioration.

Summary:
Many people are glad that Huntington's disease will be cured soon. A family that carries this disease in its genes can already be considered doomed because it passes from generation to generation, decreasing the chances of having a healthy retirement.

Hayden, E. C. (2016, February 23). Should you edit your children's genes?. Retrieved from: https://www.nature.com/articles/530402a

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In the fierce debate about CRISPR gene editing, it's time to give patients a voice.

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.

LISTEN

Your browser does not support the audio element.

How do those with disabilities feel about the possibility of editing the genomes of future generations?

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.

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."

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.

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.

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.

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.

About this article

Further reading

# data[].attributes.attachment_link.title
Should you edit your children's genes? - Nature

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In the fierce debate about CRISPR gene editing, it's time to give patients a voice. 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.

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Main point:
DNA is the hereditary material that all the organisms have.

Facts:
- DNA is stored as a code made up of four chemical bases: adenine (A), guanine (G), cytosine (C) and thymine (T). The order, or sequence, of these bases determines the information for building and maintaining the organism.
- DNA can replicate, meaning it can make copies of itself.

Dialogue:
It is crucial to understand how DNA is formed in order to understand how CRISPR technology works. The position of the bases that make up the DNA is what CRISPR is aimed to rearrange.

Summary:
DNA is what determines all the characteristics of the organism, meaning that it plays a crucial role in every form of life. It has four bases that are attached to the double helix, which is twisted throughout the whole sequence. DNA also has the impressive ability to duplicate itself, creating new copies of itself constantly. Also, most of the cells in an organism have more or less the exact same DNA.

Medline Plus. (n.d.). What is DNA?. Retrieved on 2022, January 23, from: https://medlineplus.gov/genetics/understanding/basics/dna/

# data[].attributes.attachment_link.readable_text
DNA, or deoxyribonucleic acid, is the hereditary material in humans and almost all other organisms. Nearly every cell in a person's body has the same DNA. Most DNA is located in the cell nucleus (where it is called nuclear DNA), but a small amount of DNA can also be found in the mitochondria (where it is called mitochondrial DNA or mtDNA). Mitochondria are structures within cells that convert the energy from food into a form that cells can use.

The information in DNA is stored as a code made up of four chemical bases: adenine (A), guanine (G), cytosine (C), and thymine (T). Human DNA consists of about 3 billion bases, and more than 99 percent of those bases are the same in all people. The order, or sequence, of these bases determines the information available for building and maintaining an organism, similar to the way in which letters of the alphabet appear in a certain order to form words and sentences.

DNA bases pair up with each other, A with T and C with G, to form units called base pairs. Each base is also attached to a sugar molecule and a phosphate molecule. Together, a base, sugar, and phosphate are called a nucleotide. Nucleotides are arranged in two long strands that form a spiral called a double helix. The structure of the double helix is somewhat like a ladder, with the base pairs forming the ladder's rungs and the sugar and phosphate molecules forming the vertical sidepieces of the ladder.

An important property of DNA is that it can replicate, or make copies of itself. Each strand of DNA in the double helix can serve as a pattern for duplicating the sequence of bases. This is critical when cells divide because each new cell needs to have an exact copy of the DNA present in the old cell.

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DNA is the hereditary material in humans and almost all other organisms. Genes are made up of DNA.

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Main idea:
CRISPR engineering might disrupt the natural order of things.

Arguments:
- CRISPR could wipe out any species.
- Scientists will have to investigate if these mutations can pass onto other species. For example, they might want to change the genes of one species of mosquitoes, but of the rest of them.
- CRISPR might destroy food chains, as some species of animals disappear.
- CRISPR experiments should only be performed in areas where the animals aren't native species, meaning that if they escape, they will be less likely to take root.
- If the biologists don't resolve the ethical problems of gene engineering, the taxpayers who fund the research might.

Dialogue:
If engineering is not regulated, it might get out of hand and might actually cause a Butterfly effect. If just one species disappears, this might have irreversible consecuences on all the other species.

Summary:
Humans have been trying to change some traits of plants and animals in order to make them more beneficial for a long period of time. But, these processes were very time-consuming and expensive. So, when CRISPR was discovered, everybody became very eager to make new discoveries using it, which raised some worries about the safety and ethics of this method.

Maxmen, A. (2015, August). Easy DNA Editing Will Remake the World. Buckle Up. Retrieved from: https://www.wired.com/2015/07/crispr-dna-editing-2/

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Spiny grass and scraggly pines creep amid the arts-and-crafts buildings of the Asilomar Conference Grounds, 100 acres of dune where California's Monterey Peninsula hammerheads into the Pacific. It's a rugged landscape, designed to inspire people to contemplate their evolving place on Earth. So it was natural that 140 scientists gathered here in 1975 for an unprecedented conference.

They were worried about what people called "recombinant DNA," the manipulation of the source code of life. It had been just 22 years since James Watson, Francis Crick, and Rosalind Franklin described what DNA was-deoxyribonucleic acid, four different structures called bases stuck to a backbone of sugar and phosphate, in sequences thousands of bases long. DNA is what genes are made of, and genes are the basis of heredity.

Preeminent genetic researchers like David Baltimore, then at MIT, went to Asilomar to grapple with the implications of being able to decrypt and reorder genes. It was a God-like power-to plug genes from one living thing into another. Used wisely, it had the potential to save millions of lives. But the scientists also knew their creations might slip out of their control. They wanted to consider what ought to be off-limits.

By 1975, other fields of science-like physics-were subject to broad restrictions. Hardly anyone was allowed to work on atomic bombs, say. But biology was different. Biologists still let the winding road of research guide their steps. On occasion, regulatory bodies had acted retrospectively-after Nuremberg, Tuskegee, and the human radiation experiments, external enforcement entities had told biologists they weren't allowed to do that bad thing again. Asilomar, though, was about establishing prospective guidelines, a remarkably open and forward-thinking move.

At the end of the meeting, Baltimore and four other molecular biologists stayed up all night writing a consensus statement. They laid out ways to isolate potentially dangerous experiments and determined that cloning or otherwise messing with dangerous pathogens should be off-limits. A few attendees fretted about the idea of modifications of the human "germ line"-changes that would be passed on from one generation to the next-but most thought that was so far off as to be unrealistic. Engineering microbes was hard enough. The rules the Asilomar scientists hoped biology would follow didn't look much further ahead than ideas and proposals already on their desks.

Earlier this year, Baltimore joined 17 other researchers for another California conference, this one at the Carneros Inn in Napa Valley. "It was a feeling of déjà vu," Baltimore says. There he was again, gathered with some of the smartest scientists on earth to talk about the implications of genome engineering.

The stakes, however, have changed. Everyone at the Napa meeting had access to a gene-editing technique called Crispr-Cas9. The first term is an acronym for "clustered regularly interspaced short palindromic repeats," a description of the genetic basis of the method; Cas9 is the name of a protein that makes it work. Technical details aside, Crispr-Cas9 makes it easy, cheap, and fast to move genes around-any genes, in any living thing, from bacteria to people. "These are monumental moments in the history of biomedical research," Baltimore says. "They don't happen every day."

Using the three-year-old technique, researchers have already reversed mutations that cause blindness, stopped cancer cells from multiplying, and made cells impervious to the virus that causes AIDS. Agronomists have rendered wheat invulnerable to killer fungi like powdery mildew, hinting at engineered staple crops that can feed a population of 9 billion on an ever-warmer planet. Bioengineers have used Crispr to alter the DNA of yeast so that it consumes plant matter and excretes ethanol, promising an end to reliance on petrochemicals. Startups devoted to Crispr have launched. International pharmaceutical and agricultural companies have spun up Crispr R&D. Two of the most powerful universities in the US are engaged in a vicious war over the basic patent. Depending on what kind of person you are, Crispr makes you see a gleaming world of the future, a Nobel medallion, or dollar signs.

The technique is revolutionary, and like all revolutions, it's perilous. Crispr goes well beyond anything the Asilomar conference discussed. It could at last allow genetics researchers to conjure everything anyone has ever worried they would-designer babies, invasive mutants, species-specific bioweapons, and a dozen other apocalyptic sci-fi tropes. It brings with it all-new rules for the practice of research in the life sciences. But no one knows what the rules are-or who will be the first to break them.

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In a way, humans were genetic engineers long before anyone knew what a gene was. They could give living things new traits-sweeter kernels of corn, flatter bulldog faces-through selective breeding. But it took time, and it didn't always pan out. By the 1930s refining nature got faster. Scientists bombarded seeds and insect eggs with x-rays, causing mutations to scatter through genomes like shrapnel. If one of hundreds of irradiated plants or insects grew up with the traits scientists desired, they bred it and tossed the rest. That's where red grapefruits came from, and most barley for modern beer.

Genome modification has become less of a crapshoot. In 2002, molecular biologists learned to delete or replace specific genes using enzymes called zinc-finger nucleases; the next-generation technique used enzymes named TALENs.

Yet the procedures were expensive and complicated. They only worked on organisms whose molecular innards had been thoroughly dissected-like mice or fruit flies. Genome engineers went on the hunt for something better.

Scientists have used it to render wheat invulnerable to killer fungi. Such crops could feed billions of people.

As it happened, the people who found it weren't genome engineers at all. They were basic researchers, trying to unravel the origin of life by sequencing the genomes of ancient bacteria and microbes called Archaea (as in archaic), descendants of the first life on Earth. Deep amid the bases, the As, Ts, Gs, and Cs that made up those DNA sequences, microbiologists noticed recurring segments that were the same back to front and front to back-palindromes. The researchers didn't know what these segments did, but they knew they were weird. In a branding exercise only scientists could love, they named these clusters of repeating palindromes Crispr.

Then, in 2005, a microbiologist named Rodolphe Barrangou, working at a Danish food company called Danisco, spotted some of those same palindromic repeats in Streptococcus thermophilus, the bacteria that the company uses to make yogurt and cheese. Barrangou and his colleagues discovered that the unidentified stretches of DNA between Crispr's palindromes matched sequences from viruses that had infected their S. thermophilus colonies. Like most living things, bacteria get attacked by viruses-in this case they're called bacteriophages, or phages for short. Barrangou's team went on to show that the segments served an important role in the bacteria's defense against the phages, a sort of immunological memory. If a phage infected a microbe whose Crispr carried its fingerprint, the bacteria could recognize the phage and fight back. Barrangou and his colleagues realized they could save their company some money by selecting S. thermophilus species with Crispr sequences that resisted common dairy viruses.

As more researchers sequenced more bacteria, they found Crisprs again and again-half of all bacteria had them. Most Archaea did too. And even stranger, some of Crispr's sequences didn't encode the eventual manufacture of a protein, as is typical of a gene, but instead led to RNA-single-stranded genetic material. (DNA, of course, is double-stranded.)

That pointed to a new hypothesis. Most present-day animals and plants defend themselves against viruses with structures made out of RNA. So a few researchers started to wonder if Crispr was a primordial immune system. Among the people working on that idea was Jill Banfield, a geomicrobiologist at UC Berkeley, who had found Crispr sequences in microbes she collected from acidic, 110-degree water from the defunct Iron Mountain Mine in Shasta County, California. But to figure out if she was right, she needed help.

Luckily, one of the country's best-known RNA experts, a biochemist named Jennifer Doudna, worked on the other side of campus in an office with a view of the Bay and San Francisco's skyline. It certainly wasn't what Doudna had imagined for herself as a girl growing up on the Big Island of Hawaii. She simply liked math and chemistry-an affinity that took her to Harvard and then to a postdoc at the University of Colorado. That's where she made her initial important discoveries, revealing the three-dimensional structure of complex RNA molecules that could, like enzymes, catalyze chemical reactions.

The mine bacteria piqued Doudna's curiosity, but when Doudna pried Crispr apart, she didn't see anything to suggest the bacterial immune system was related to the one plants and animals use. Still, she thought the system might be adapted for diagnostic tests.

Banfield wasn't the only person to ask Doudna for help with a Crispr project. In 2011, Doudna was at an American Society for Microbiology meeting in San Juan, Puerto Rico, when an intense, dark-haired French scientist asked her if she wouldn't mind stepping outside the conference hall for a chat. This was Emmanuelle Charpentier, a microbiologist at Ume˚a University in Sweden.

As they wandered through the alleyways of old San Juan, Charpentier explained that one of Crispr's associated proteins, named Csn1, appeared to be extraordinary. It seemed to search for specific DNA sequences in viruses and cut them apart like a microscopic multitool. Charpentier asked Doudna to help her figure out how it worked. "Somehow the way she said it, I literally-I can almost feel it now-I had this chill down my back," Doudna says. "When she said 'the mysterious Csn1' I just had this feeling, there is going to be something good here."

Back in Sweden, Charpentier kept a colony of Streptococcus pyogenes in a biohazard chamber. Few people want S. pyogenes anywhere near them. It can cause strep throat and necrotizing fasciitis-flesh-eating disease. But it was the bug Charpentier worked with, and it was in S. pyogenes that she had found that mysterious yet mighty protein, now renamed Cas9. Charpentier swabbed her colony, purified its DNA, and FedExed a sample to Doudna.

Working together, Charpentier's and Doudna's teams found that Crispr made two short strands of RNA and that Cas9 latched onto them. The sequence of the RNA strands corresponded to stretches of viral DNA and could home in on those segments like a genetic GPS. And when the Crispr-Cas9 complex arrives at its destination, Cas9 does something almost magical: It changes shape, grasping the DNA and slicing it with a precise molecular scalpel.

Here's what's important: Once they'd taken that mechanism apart, Doudna's postdoc, Martin Jinek, combined the two strands of RNA into one fragment-"guide RNA"-that Jinek could program. He could make guide RNA with whatever genetic letters he wanted; not just from viruses but from, as far as they could tell, anything. In test tubes, the combination of Jinek's guide RNA and the Cas9 protein proved to be a programmable machine for DNA cutting. Compared to TALENs and zinc-finger nucleases, this was like trading in rusty scissors for a computer-controlled laser cutter. "I remember running into a few of my colleagues at Berkeley and saying we have this fantastic result, and I think it's going to be really exciting for genome engineering. But I don't think they quite got it," Doudna says. "They kind of humored me, saying, 'Oh, yeah, that's nice.'"

On June 28, 2012, Doudna's team published its results in Science. In the paper and in an earlier corresponding patent application, they suggest their technology could be a tool for genome engineering. It was elegant and cheap. A grad student could do it.

The finding got noticed. In the 10 years preceding 2012, 200 papers mentioned Crispr. By 2014 that number had more than tripled. Doudna and Charpentier were each recently awarded the $3 million 2015 Breakthrough Prize. Time magazine listed the duo among the 100 most influential people in the world. Nobody was just humoring Doudna anymore.

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Most Wednesday afternoons, Feng Zhang, a molecular biologist at the Broad Institute of MIT and Harvard, scans the contents of Science as soon as they are posted online. In 2012, he was working with Crispr-Cas9 too. So when he saw Doudna and Charpentier's paper, did he think he'd been scooped? Not at all. "I didn't feel anything," Zhang says. "Our goal was to do genome editing, and this paper didn't do it." Doudna's team had cut DNA floating in a test tube, but to Zhang, if you weren't working with human cells, you were just screwing around.

That kind of seriousness is typical for Zhang. At 11, he moved from China to Des Moines, Iowa, with his parents, who are engineers-one computer, one electrical. When he was 16, he got an internship at the gene therapy research institute at Iowa Methodist hospital. By the time he graduated high school he'd won multiple science awards, including third place in the Intel Science Talent Search.

When Doudna talks about her career, she dwells on her mentors; Zhang lists his personal accomplishments, starting with those high school prizes. Doudna seems intuitive and has a hands-off management style. Zhang ... pushes. We scheduled a video chat at 9:15 pm, and he warned me that we'd be talking data for a couple of hours. "Power-nap first," he said.

If new genes that wipe out malaria also make mosquitoes go extinct, what will bats eat?

Zhang got his job at the Broad in 2011, when he was 29. Soon after starting there, he heard a speaker at a scientific advisory board meeting mention Crispr. "I was bored," Zhang says, "so as the researcher spoke, I just Googled it." Then he went to Miami for an epigenetics conference, but he hardly left his hotel room. Instead Zhang spent his time reading papers on Crispr and filling his notebook with sketches on ways to get Crispr and Cas9 into the human genome. "That was an extremely exciting weekend," he says, smiling.

Just before Doudna's team published its discovery in Science, Zhang applied for a federal grant to study Crispr-Cas9 as a tool for genome editing. Doudna's publication shifted him into hyperspeed. He knew it would prompt others to test Crispr on genomes. And Zhang wanted to be first.

Even Doudna, for all of her equanimity, had rushed to report her finding, though she hadn't shown the system working in human cells. "Frankly, when you have a result that is exciting," she says, "one does not wait to publish it."

In January 2013, Zhang's team published a paper in Science showing how Crispr-Cas9 edits genes in human and mouse cells. In the same issue, Harvard geneticist George Church edited human cells with Crispr too. Doudna's team reported success in human cells that month as well, though Zhang is quick to assert that his approach cuts and repairs DNA better.

That detail matters because Zhang had asked the Broad Institute and MIT, where he holds a joint appointment, to file for a patent on his behalf. Doudna had filed her patent application-which was public information-seven months earlier. But the attorney filing for Zhang checked a box on the application marked "accelerate" and paid a fee, usually somewhere between $2,000 and $4,000. A series of emails followed between agents at the US Patent and Trademark Office and the Broad's patent attorneys, who argued that their claim was distinct.

A little more than a year after those human-cell papers came out, Doudna was on her way to work when she got an email telling her that Zhang, the Broad Institute, and MIT had indeed been awarded the patent on Crispr-Cas9 as a method to edit genomes. "I was quite surprised," she says, "because we had filed our paperwork several months before he had."

The Broad win started a firefight. The University of California amended Doudna's original claim to overlap Zhang's and sent the patent office a 114-page application for an interference proceeding-a hearing to determine who owns Crispr-this past April. In Europe, several parties are contesting Zhang's patent on the grounds that it lacks novelty. Zhang points to his grant application as proof that he independently came across the idea. He says he could have done what Doudna's team did in 2012, but he wanted to prove that Crispr worked within human cells. The USPTO may make its decision as soon as the end of the year.

The stakes here are high. Any company that wants to work with anything other than microbes will have to license Zhang's patent; royalties could be worth billions of dollars, and the resulting products could be worth billions more. Just by way of example: In 1983 Columbia University scientists patented a method for introducing foreign DNA into cells, called cotransformation. By the time the patents expired in 2000, they had brought in $790 million in revenue.

It's a testament to Crispr's value that despite the uncertainty over ownership, companies based on the technique keep launching. In 2011 Doudna and a student founded a company, Caribou, based on earlier Crispr patents; the University of California offered Caribou an exclusive license on the patent Doudna expected to get. Caribou uses Crispr to create industrial and research materials, potentially enzymes in laundry detergent and laboratory reagents. To focus on disease-where the long-term financial gain of Crispr-Cas9 will undoubtedly lie-Caribou spun off another biotech company called Intellia Therapeutics and sublicensed the Crispr-Cas9 rights. Pharma giant Novartis has invested in both startups. In Switzerland, Charpentier cofounded Crispr Therapeutics. And in Cambridge, Massachusetts, Zhang, George Church, and several others founded Editas Medicine, based on licenses on the patent Zhang eventually received.

Thus far the four companies have raised at least $158 million in venture capital.

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Any gene typically has just a 50-50 chance of getting passed on. Either the offspring gets a copy from Mom or a copy from Dad. But in 1957 biologists found exceptions to that rule, genes that literally manipulated cell division and forced themselves into a larger number of offspring than chance alone would have allowed.

A decade ago, an evolutionary geneticist named Austin Burt proposed a sneaky way to use these "selfish genes." He suggested tethering one to a separate gene-one that you wanted to propagate through an entire population. If it worked, you'd be able to drive the gene into every individual in a given area. Your gene of interest graduates from public transit to a limousine in a motorcade, speeding through a population in flagrant disregard of heredity's traffic laws. Burt suggested using this "gene drive" to alter mosquitoes that spread malaria, which kills around a million people every year. It's a good idea. In fact, other researchers are already using other methods to modify mosquitoes to resist the Plasmodium parasite that causes malaria and to be less fertile, reducing their numbers in the wild. But engineered mosquitoes are expensive. If researchers don't keep topping up the mutants, the normals soon recapture control of the ecosystem.

Push those modifications through with a gene drive and the normal mosquitoes wouldn't stand a chance. The problem is, inserting the gene drive into the mosquitoes was impossible. Until Crispr-Cas9 came along.

Today, behind a set of four locked and sealed doors in a lab at the Harvard School of Public Health, a special set of mosquito larvae of the African species Anopheles gambiae wriggle near the surface of shallow tubs of water. These aren't normal Anopheles, though. The lab is working on using Crispr to insert malaria-resistant gene drives into their genomes. It hasn't worked yet, but if it does ... well, consider this from the mosquitoes' point of view. This project isn't about reengineering one of them. It's about reengineering them all.

Kevin Esvelt, the evolutionary engineer who initiated the project, knows how serious this work is. The basic process could wipe out any species. Scientists will have to study the mosquitoes for years to make sure that the gene drives can't be passed on to other species of mosquitoes. And they want to know what happens to bats and other insect-eating predators if the drives make mosquitoes extinct. "I am responsible for opening a can of worms when it comes to gene drives," Esvelt says, "and that is why I try to ensure that scientists are taking precautions and showing themselves to be worthy of the public's trust-maybe we're not, but I want to do my damnedest to try."

Esvelt talked all this over with his adviser-Church, who also worked with Zhang. Together they decided to publish their gene-drive idea before it was actually successful. They wanted to lay out their precautionary measures, way beyond five nested doors. Gene drive research, they wrote, should take place in locations where the species of study isn't native, making it less likely that escapees would take root. And they also proposed a way to turn the gene drive off when an engineered individual mated with a wild counterpart-a genetic sunset clause. Esvelt filed for a patent on Crispr gene drives, partly, he says, to block companies that might not take the same precautions.

Within a year, and without seeing Esvelt's papers, biologists at UC San Diego had used Crispr to insert gene drives into fruit flies-they called them "mutagenic chain reactions." They had done their research in a chamber behind five doors, but the other precautions weren't there.Church said the San Diego researchers had gone "a step too far"-big talk from a scientist who says he plans to use Crispr to bring back an extinct woolly mammoth by deriving genes from frozen corpses and injecting them into elephant embryos. (Church says tinkering with one woolly mammoth is way less scary than messing with whole populations of rapidly reproducing insects. "I'm afraid of everything," he says. "I encourage people to be as creative in thinking about the unintended consequences of their work as the intended.")

Ethan Bier, who worked on the San Diego fly study, agrees that gene drives come with risks. But he points out that Esvelt's mosquitoes don't have the genetic barrier Esvelt himself advocates. (To be fair, that would defeat the purpose of a gene drive.) And the ecological barrier, he says, is nonsense. "In Boston you have hot and humid summers, so sure, tropical mosquitoes may not be native, but they can certainly survive," Bier says. "If a pregnant female got out, she and her progeny could reproduce in a puddle, fly to ships in the Boston Harbor, and get on a boat to Brazil."

These problems don't end with mosquitoes. One of Crispr's strengths is that it works on every living thing. That kind of power makes Doudna feel like she opened Pandora's box. Use Crispr to treat, say, Huntington's disease-a debilitating neurological disorder-in the womb, when an embryo is just a ball of cells? Perhaps. But the same method could also possibly alter less medically relevant genes, like the ones that make skin wrinkle. "We haven't had the time, as a community, to discuss the ethics and safety," Doudna says, "and, frankly, whether there is any real clinical benefit of this versus other ways of dealing with genetic disease."

Researchers in China announced they had used Crispr to edit human embryos.

That's why she convened the meeting in Napa. All the same problems of recombinant DNA that the Asilomar attendees tried to grapple with are still there-more pressing now than ever. And if the scientists don't figure out how to handle them, some other regulatory body might. Few researchers, Baltimore included, want to see Congress making laws about science. "Legislation is unforgiving," he says. "Once you pass it, it is very hard to undo."

In other words, if biologists don't start thinking about ethics, the taxpayers who fund their research might do the thinking for them.

All of that only matters if every scientist is on board. A month after the Napa conference, researchers at Sun Yat-sen University in Guangzhou, China, announced they had used Crispr to edit human embryos. Specifically they were looking to correct mutations in the gene that causes beta thalassemia, a disorder that interferes with a person's ability to make healthy red blood cells.

The work wasn't successful-Crispr, it turns out, didn't target genes as well in embryos as it does in isolated cells. The Chinese researchers tried to skirt the ethical implications of their work by using nonviable embryos, which is to say they could never have been brought to term. But the work attracted attention. A month later, the US National Academy of Sciences announced that it would create a set of recommendations for scientists, policymakers, and regulatory agencies on when, if ever, embryonic engineering might be permissible. Another National Academy report will focus on gene drives. Though those recommendations don't carry the weight of law, federal funding in part determines what science gets done, and agencies that fund research around the world often abide by the academy's guidelines.

The truth is, most of what scientists want to do with Crispr is not controversial. For example, researchers once had no way to figure out why spiders have the same gene that determines the pattern of veins in the wings of flies. You could sequence the spider and see that the "wing gene" was in its genome, but all you'd know was that it certainly wasn't designing wings. Now, with less than $100, an ordinary arachnologist can snip the wing gene out of a spider embryo and see what happens when that spider matures. If it's obvious-maybe its claws fail to form-you've learned that the wing gene must have served a different purpose before insects branched off, evolutionarily, from the ancestor they shared with spiders. Pick your creature, pick your gene, and you can bet someone somewhere is giving it a go.

Academic and pharmaceutical company labs have begun to develop Crispr-based research tools, such as cancerous mice-perfect for testing new chemotherapies. A team at MIT, working with Zhang, used Crispr-Cas9 to create, in just weeks, mice that inevitably get liver cancer. That kind of thing used to take more than a year. Other groups are working on ways to test drugs on cells with single-gene variations to understand why the drugs work in some cases and fail in others. Zhang's lab used the technique to learn which genetic variations make people resistant to a melanoma drug called Vemurafenib. The genes he identified may provide research targets for drug developers.

The real money is in human therapeutics. For example, labs are working on the genetics of so-called elite controllers, people who can be HIV-positive but never develop AIDS. Using Crispr, researchers can knock out a gene called CCR5, which makes a protein that helps usher HIV into cells. You'd essentially make someone an elite controller. Or you could use Crispr to target HIV directly; that begins to look a lot like a cure.

Or-and this idea is decades away from execution-you could figure out which genes make humans susceptible to HIV overall. Make sure they don't serve other, more vital purposes, and then "fix" them in an embryo. It'd grow into a person immune to the virus.

But straight-out editing of a human embryo sets off all sorts of alarms, both in terms of ethics and legality. It contravenes the policies of the US National Institutes of Health, and in spirit at least runs counter to the United Nations' Universal Declaration on the Human Genome and Human Rights. (Of course, when the US government said it wouldn't fund research on human embryonic stem cells, private entities raised millions of dollars to do it themselves.) Engineered humans are a ways off-but nobody thinks they're science fiction anymore.

Even if scientists never try to design a baby, the worries those Asilomar attendees had four decades ago now seem even more prescient. The world has changed. "Genome editing started with just a few big labs putting in lots of effort, trying something 1,000 times for one or two successes," says Hank Greely, a bioethicist at Stanford. "Now it's something that someone with a BS and a couple thousand dollars' worth of equipment can do. What was impractical is now almost everyday. That's a big deal."

In 1975 no one was asking whether a genetically modified vegetable should be welcome in the produce aisle. No one was able to test the genes of an unborn baby, or sequence them all. Today swarms of investors are racing to bring genetically engineered creations to market. The idea of Crispr slides almost frictionlessly into modern culture.

In an odd reversal, it's the scientists who are showing more fear than the civilians. When I ask Church for his most nightmarish Crispr scenario, he mutters something about weapons and then stops short. He says he hopes to take the specifics of the idea, whatever it is, to his grave. But thousands of other scientists are working on Crispr. Not all of them will be as cautious. "You can't stop science from progressing," Jinek says. "Science is what it is." He's right. Science gives people power. And power is unpredictable.

Amy Maxmen (@amymaxmen) writes about science for National Geographic, Newsweek, and other publications. This is her first article for WIRED.
This article appears in the August 2015 issue.
Animation by Anthony Zazzi; Illustrations by Ben Wiseman

# data[].attributes.attachment_link.description
Spiny grass and scraggly pines creep amid the arts-and-crafts buildings of the Asilomar Conference Grounds, 100 acres of dune where California's Monterey Peninsula hammerheads into the Pacific. It's a rugged landscape, designed to inspire people to contemplate their evolving place on Earth. So it was natural that 140 scientists gathered here in 1975 for an unprecedented conference.

# data[].attributes.body
Main idea:
CRISPR could be used for beneficial purposes, such as getting rid of deadly diseases.

Arguments:
- Gene editing could help us eradicate diseases in animals, like for example, malaria in mosquitoes.
- CRISPR allows scientists to create research tools, like cancerous mice, which are perfect for testing chemotherapies. It can also allow us to test drugs on cells that have single-gene variations to figure out why drugs don't work in some cases.
- Using CRISPR, scientists can knock out the protein that helps introduce HIV into cells, making the person an elite controller (who can be positive for HIV but never develop AIDS). Or it can be used to target HIV directly. Moreover, scientists could figure out which genes make humans susceptible to HIV, and if they don't serve any other vital purposes, fix them.

Dialogue:
Some of the biggest problems of humanity can be solved using CRISPR. Moreover, it won't be that expensive nor hard, because technically, everyone who has a molecular lab could engineer a gene.

Summary:
Humans have been trying to change some traits of plants and animals in order to make them more beneficial for a long period of time. But, these processes were very time-consuming and expensive. So, when CRISPR was discovered, everybody became very eager to make new discoveries using it, which raised some worries about the safety and ethics of this method.

Maxmen, A. (2015, August). Easy DNA Editing Will Remake the World. Buckle Up. Retrieved from: https://www.wired.com/2015/07/crispr-dna-editing-2/

# data[].attributes.attachment_link.readable_text
Spiny grass and scraggly pines creep amid the arts-and-crafts buildings of the Asilomar Conference Grounds, 100 acres of dune where California's Monterey Peninsula hammerheads into the Pacific. It's a rugged landscape, designed to inspire people to contemplate their evolving place on Earth. So it was natural that 140 scientists gathered here in 1975 for an unprecedented conference.

They were worried about what people called "recombinant DNA," the manipulation of the source code of life. It had been just 22 years since James Watson, Francis Crick, and Rosalind Franklin described what DNA was-deoxyribonucleic acid, four different structures called bases stuck to a backbone of sugar and phosphate, in sequences thousands of bases long. DNA is what genes are made of, and genes are the basis of heredity.

Preeminent genetic researchers like David Baltimore, then at MIT, went to Asilomar to grapple with the implications of being able to decrypt and reorder genes. It was a God-like power-to plug genes from one living thing into another. Used wisely, it had the potential to save millions of lives. But the scientists also knew their creations might slip out of their control. They wanted to consider what ought to be off-limits.

By 1975, other fields of science-like physics-were subject to broad restrictions. Hardly anyone was allowed to work on atomic bombs, say. But biology was different. Biologists still let the winding road of research guide their steps. On occasion, regulatory bodies had acted retrospectively-after Nuremberg, Tuskegee, and the human radiation experiments, external enforcement entities had told biologists they weren't allowed to do that bad thing again. Asilomar, though, was about establishing prospective guidelines, a remarkably open and forward-thinking move.

At the end of the meeting, Baltimore and four other molecular biologists stayed up all night writing a consensus statement. They laid out ways to isolate potentially dangerous experiments and determined that cloning or otherwise messing with dangerous pathogens should be off-limits. A few attendees fretted about the idea of modifications of the human "germ line"-changes that would be passed on from one generation to the next-but most thought that was so far off as to be unrealistic. Engineering microbes was hard enough. The rules the Asilomar scientists hoped biology would follow didn't look much further ahead than ideas and proposals already on their desks.

Earlier this year, Baltimore joined 17 other researchers for another California conference, this one at the Carneros Inn in Napa Valley. "It was a feeling of déjà vu," Baltimore says. There he was again, gathered with some of the smartest scientists on earth to talk about the implications of genome engineering.

The stakes, however, have changed. Everyone at the Napa meeting had access to a gene-editing technique called Crispr-Cas9. The first term is an acronym for "clustered regularly interspaced short palindromic repeats," a description of the genetic basis of the method; Cas9 is the name of a protein that makes it work. Technical details aside, Crispr-Cas9 makes it easy, cheap, and fast to move genes around-any genes, in any living thing, from bacteria to people. "These are monumental moments in the history of biomedical research," Baltimore says. "They don't happen every day."

Using the three-year-old technique, researchers have already reversed mutations that cause blindness, stopped cancer cells from multiplying, and made cells impervious to the virus that causes AIDS. Agronomists have rendered wheat invulnerable to killer fungi like powdery mildew, hinting at engineered staple crops that can feed a population of 9 billion on an ever-warmer planet. Bioengineers have used Crispr to alter the DNA of yeast so that it consumes plant matter and excretes ethanol, promising an end to reliance on petrochemicals. Startups devoted to Crispr have launched. International pharmaceutical and agricultural companies have spun up Crispr R&D. Two of the most powerful universities in the US are engaged in a vicious war over the basic patent. Depending on what kind of person you are, Crispr makes you see a gleaming world of the future, a Nobel medallion, or dollar signs.

The technique is revolutionary, and like all revolutions, it's perilous. Crispr goes well beyond anything the Asilomar conference discussed. It could at last allow genetics researchers to conjure everything anyone has ever worried they would-designer babies, invasive mutants, species-specific bioweapons, and a dozen other apocalyptic sci-fi tropes. It brings with it all-new rules for the practice of research in the life sciences. But no one knows what the rules are-or who will be the first to break them.

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In a way, humans were genetic engineers long before anyone knew what a gene was. They could give living things new traits-sweeter kernels of corn, flatter bulldog faces-through selective breeding. But it took time, and it didn't always pan out. By the 1930s refining nature got faster. Scientists bombarded seeds and insect eggs with x-rays, causing mutations to scatter through genomes like shrapnel. If one of hundreds of irradiated plants or insects grew up with the traits scientists desired, they bred it and tossed the rest. That's where red grapefruits came from, and most barley for modern beer.

Genome modification has become less of a crapshoot. In 2002, molecular biologists learned to delete or replace specific genes using enzymes called zinc-finger nucleases; the next-generation technique used enzymes named TALENs.

Yet the procedures were expensive and complicated. They only worked on organisms whose molecular innards had been thoroughly dissected-like mice or fruit flies. Genome engineers went on the hunt for something better.

Scientists have used it to render wheat invulnerable to killer fungi. Such crops could feed billions of people.

As it happened, the people who found it weren't genome engineers at all. They were basic researchers, trying to unravel the origin of life by sequencing the genomes of ancient bacteria and microbes called Archaea (as in archaic), descendants of the first life on Earth. Deep amid the bases, the As, Ts, Gs, and Cs that made up those DNA sequences, microbiologists noticed recurring segments that were the same back to front and front to back-palindromes. The researchers didn't know what these segments did, but they knew they were weird. In a branding exercise only scientists could love, they named these clusters of repeating palindromes Crispr.

Then, in 2005, a microbiologist named Rodolphe Barrangou, working at a Danish food company called Danisco, spotted some of those same palindromic repeats in Streptococcus thermophilus, the bacteria that the company uses to make yogurt and cheese. Barrangou and his colleagues discovered that the unidentified stretches of DNA between Crispr's palindromes matched sequences from viruses that had infected their S. thermophilus colonies. Like most living things, bacteria get attacked by viruses-in this case they're called bacteriophages, or phages for short. Barrangou's team went on to show that the segments served an important role in the bacteria's defense against the phages, a sort of immunological memory. If a phage infected a microbe whose Crispr carried its fingerprint, the bacteria could recognize the phage and fight back. Barrangou and his colleagues realized they could save their company some money by selecting S. thermophilus species with Crispr sequences that resisted common dairy viruses.

As more researchers sequenced more bacteria, they found Crisprs again and again-half of all bacteria had them. Most Archaea did too. And even stranger, some of Crispr's sequences didn't encode the eventual manufacture of a protein, as is typical of a gene, but instead led to RNA-single-stranded genetic material. (DNA, of course, is double-stranded.)

That pointed to a new hypothesis. Most present-day animals and plants defend themselves against viruses with structures made out of RNA. So a few researchers started to wonder if Crispr was a primordial immune system. Among the people working on that idea was Jill Banfield, a geomicrobiologist at UC Berkeley, who had found Crispr sequences in microbes she collected from acidic, 110-degree water from the defunct Iron Mountain Mine in Shasta County, California. But to figure out if she was right, she needed help.

Luckily, one of the country's best-known RNA experts, a biochemist named Jennifer Doudna, worked on the other side of campus in an office with a view of the Bay and San Francisco's skyline. It certainly wasn't what Doudna had imagined for herself as a girl growing up on the Big Island of Hawaii. She simply liked math and chemistry-an affinity that took her to Harvard and then to a postdoc at the University of Colorado. That's where she made her initial important discoveries, revealing the three-dimensional structure of complex RNA molecules that could, like enzymes, catalyze chemical reactions.

The mine bacteria piqued Doudna's curiosity, but when Doudna pried Crispr apart, she didn't see anything to suggest the bacterial immune system was related to the one plants and animals use. Still, she thought the system might be adapted for diagnostic tests.

Banfield wasn't the only person to ask Doudna for help with a Crispr project. In 2011, Doudna was at an American Society for Microbiology meeting in San Juan, Puerto Rico, when an intense, dark-haired French scientist asked her if she wouldn't mind stepping outside the conference hall for a chat. This was Emmanuelle Charpentier, a microbiologist at Ume˚a University in Sweden.

As they wandered through the alleyways of old San Juan, Charpentier explained that one of Crispr's associated proteins, named Csn1, appeared to be extraordinary. It seemed to search for specific DNA sequences in viruses and cut them apart like a microscopic multitool. Charpentier asked Doudna to help her figure out how it worked. "Somehow the way she said it, I literally-I can almost feel it now-I had this chill down my back," Doudna says. "When she said 'the mysterious Csn1' I just had this feeling, there is going to be something good here."

Back in Sweden, Charpentier kept a colony of Streptococcus pyogenes in a biohazard chamber. Few people want S. pyogenes anywhere near them. It can cause strep throat and necrotizing fasciitis-flesh-eating disease. But it was the bug Charpentier worked with, and it was in S. pyogenes that she had found that mysterious yet mighty protein, now renamed Cas9. Charpentier swabbed her colony, purified its DNA, and FedExed a sample to Doudna.

Working together, Charpentier's and Doudna's teams found that Crispr made two short strands of RNA and that Cas9 latched onto them. The sequence of the RNA strands corresponded to stretches of viral DNA and could home in on those segments like a genetic GPS. And when the Crispr-Cas9 complex arrives at its destination, Cas9 does something almost magical: It changes shape, grasping the DNA and slicing it with a precise molecular scalpel.

Here's what's important: Once they'd taken that mechanism apart, Doudna's postdoc, Martin Jinek, combined the two strands of RNA into one fragment-"guide RNA"-that Jinek could program. He could make guide RNA with whatever genetic letters he wanted; not just from viruses but from, as far as they could tell, anything. In test tubes, the combination of Jinek's guide RNA and the Cas9 protein proved to be a programmable machine for DNA cutting. Compared to TALENs and zinc-finger nucleases, this was like trading in rusty scissors for a computer-controlled laser cutter. "I remember running into a few of my colleagues at Berkeley and saying we have this fantastic result, and I think it's going to be really exciting for genome engineering. But I don't think they quite got it," Doudna says. "They kind of humored me, saying, 'Oh, yeah, that's nice.'"

On June 28, 2012, Doudna's team published its results in Science. In the paper and in an earlier corresponding patent application, they suggest their technology could be a tool for genome engineering. It was elegant and cheap. A grad student could do it.

The finding got noticed. In the 10 years preceding 2012, 200 papers mentioned Crispr. By 2014 that number had more than tripled. Doudna and Charpentier were each recently awarded the $3 million 2015 Breakthrough Prize. Time magazine listed the duo among the 100 most influential people in the world. Nobody was just humoring Doudna anymore.

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Most Wednesday afternoons, Feng Zhang, a molecular biologist at the Broad Institute of MIT and Harvard, scans the contents of Science as soon as they are posted online. In 2012, he was working with Crispr-Cas9 too. So when he saw Doudna and Charpentier's paper, did he think he'd been scooped? Not at all. "I didn't feel anything," Zhang says. "Our goal was to do genome editing, and this paper didn't do it." Doudna's team had cut DNA floating in a test tube, but to Zhang, if you weren't working with human cells, you were just screwing around.

That kind of seriousness is typical for Zhang. At 11, he moved from China to Des Moines, Iowa, with his parents, who are engineers-one computer, one electrical. When he was 16, he got an internship at the gene therapy research institute at Iowa Methodist hospital. By the time he graduated high school he'd won multiple science awards, including third place in the Intel Science Talent Search.

When Doudna talks about her career, she dwells on her mentors; Zhang lists his personal accomplishments, starting with those high school prizes. Doudna seems intuitive and has a hands-off management style. Zhang ... pushes. We scheduled a video chat at 9:15 pm, and he warned me that we'd be talking data for a couple of hours. "Power-nap first," he said.

If new genes that wipe out malaria also make mosquitoes go extinct, what will bats eat?

Zhang got his job at the Broad in 2011, when he was 29. Soon after starting there, he heard a speaker at a scientific advisory board meeting mention Crispr. "I was bored," Zhang says, "so as the researcher spoke, I just Googled it." Then he went to Miami for an epigenetics conference, but he hardly left his hotel room. Instead Zhang spent his time reading papers on Crispr and filling his notebook with sketches on ways to get Crispr and Cas9 into the human genome. "That was an extremely exciting weekend," he says, smiling.

Just before Doudna's team published its discovery in Science, Zhang applied for a federal grant to study Crispr-Cas9 as a tool for genome editing. Doudna's publication shifted him into hyperspeed. He knew it would prompt others to test Crispr on genomes. And Zhang wanted to be first.

Even Doudna, for all of her equanimity, had rushed to report her finding, though she hadn't shown the system working in human cells. "Frankly, when you have a result that is exciting," she says, "one does not wait to publish it."

In January 2013, Zhang's team published a paper in Science showing how Crispr-Cas9 edits genes in human and mouse cells. In the same issue, Harvard geneticist George Church edited human cells with Crispr too. Doudna's team reported success in human cells that month as well, though Zhang is quick to assert that his approach cuts and repairs DNA better.

That detail matters because Zhang had asked the Broad Institute and MIT, where he holds a joint appointment, to file for a patent on his behalf. Doudna had filed her patent application-which was public information-seven months earlier. But the attorney filing for Zhang checked a box on the application marked "accelerate" and paid a fee, usually somewhere between $2,000 and $4,000. A series of emails followed between agents at the US Patent and Trademark Office and the Broad's patent attorneys, who argued that their claim was distinct.

A little more than a year after those human-cell papers came out, Doudna was on her way to work when she got an email telling her that Zhang, the Broad Institute, and MIT had indeed been awarded the patent on Crispr-Cas9 as a method to edit genomes. "I was quite surprised," she says, "because we had filed our paperwork several months before he had."

The Broad win started a firefight. The University of California amended Doudna's original claim to overlap Zhang's and sent the patent office a 114-page application for an interference proceeding-a hearing to determine who owns Crispr-this past April. In Europe, several parties are contesting Zhang's patent on the grounds that it lacks novelty. Zhang points to his grant application as proof that he independently came across the idea. He says he could have done what Doudna's team did in 2012, but he wanted to prove that Crispr worked within human cells. The USPTO may make its decision as soon as the end of the year.

The stakes here are high. Any company that wants to work with anything other than microbes will have to license Zhang's patent; royalties could be worth billions of dollars, and the resulting products could be worth billions more. Just by way of example: In 1983 Columbia University scientists patented a method for introducing foreign DNA into cells, called cotransformation. By the time the patents expired in 2000, they had brought in $790 million in revenue.

It's a testament to Crispr's value that despite the uncertainty over ownership, companies based on the technique keep launching. In 2011 Doudna and a student founded a company, Caribou, based on earlier Crispr patents; the University of California offered Caribou an exclusive license on the patent Doudna expected to get. Caribou uses Crispr to create industrial and research materials, potentially enzymes in laundry detergent and laboratory reagents. To focus on disease-where the long-term financial gain of Crispr-Cas9 will undoubtedly lie-Caribou spun off another biotech company called Intellia Therapeutics and sublicensed the Crispr-Cas9 rights. Pharma giant Novartis has invested in both startups. In Switzerland, Charpentier cofounded Crispr Therapeutics. And in Cambridge, Massachusetts, Zhang, George Church, and several others founded Editas Medicine, based on licenses on the patent Zhang eventually received.

Thus far the four companies have raised at least $158 million in venture capital.

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Any gene typically has just a 50-50 chance of getting passed on. Either the offspring gets a copy from Mom or a copy from Dad. But in 1957 biologists found exceptions to that rule, genes that literally manipulated cell division and forced themselves into a larger number of offspring than chance alone would have allowed.

A decade ago, an evolutionary geneticist named Austin Burt proposed a sneaky way to use these "selfish genes." He suggested tethering one to a separate gene-one that you wanted to propagate through an entire population. If it worked, you'd be able to drive the gene into every individual in a given area. Your gene of interest graduates from public transit to a limousine in a motorcade, speeding through a population in flagrant disregard of heredity's traffic laws. Burt suggested using this "gene drive" to alter mosquitoes that spread malaria, which kills around a million people every year. It's a good idea. In fact, other researchers are already using other methods to modify mosquitoes to resist the Plasmodium parasite that causes malaria and to be less fertile, reducing their numbers in the wild. But engineered mosquitoes are expensive. If researchers don't keep topping up the mutants, the normals soon recapture control of the ecosystem.

Push those modifications through with a gene drive and the normal mosquitoes wouldn't stand a chance. The problem is, inserting the gene drive into the mosquitoes was impossible. Until Crispr-Cas9 came along.

Today, behind a set of four locked and sealed doors in a lab at the Harvard School of Public Health, a special set of mosquito larvae of the African species Anopheles gambiae wriggle near the surface of shallow tubs of water. These aren't normal Anopheles, though. The lab is working on using Crispr to insert malaria-resistant gene drives into their genomes. It hasn't worked yet, but if it does ... well, consider this from the mosquitoes' point of view. This project isn't about reengineering one of them. It's about reengineering them all.

Kevin Esvelt, the evolutionary engineer who initiated the project, knows how serious this work is. The basic process could wipe out any species. Scientists will have to study the mosquitoes for years to make sure that the gene drives can't be passed on to other species of mosquitoes. And they want to know what happens to bats and other insect-eating predators if the drives make mosquitoes extinct. "I am responsible for opening a can of worms when it comes to gene drives," Esvelt says, "and that is why I try to ensure that scientists are taking precautions and showing themselves to be worthy of the public's trust-maybe we're not, but I want to do my damnedest to try."

Esvelt talked all this over with his adviser-Church, who also worked with Zhang. Together they decided to publish their gene-drive idea before it was actually successful. They wanted to lay out their precautionary measures, way beyond five nested doors. Gene drive research, they wrote, should take place in locations where the species of study isn't native, making it less likely that escapees would take root. And they also proposed a way to turn the gene drive off when an engineered individual mated with a wild counterpart-a genetic sunset clause. Esvelt filed for a patent on Crispr gene drives, partly, he says, to block companies that might not take the same precautions.

Within a year, and without seeing Esvelt's papers, biologists at UC San Diego had used Crispr to insert gene drives into fruit flies-they called them "mutagenic chain reactions." They had done their research in a chamber behind five doors, but the other precautions weren't there.Church said the San Diego researchers had gone "a step too far"-big talk from a scientist who says he plans to use Crispr to bring back an extinct woolly mammoth by deriving genes from frozen corpses and injecting them into elephant embryos. (Church says tinkering with one woolly mammoth is way less scary than messing with whole populations of rapidly reproducing insects. "I'm afraid of everything," he says. "I encourage people to be as creative in thinking about the unintended consequences of their work as the intended.")

Ethan Bier, who worked on the San Diego fly study, agrees that gene drives come with risks. But he points out that Esvelt's mosquitoes don't have the genetic barrier Esvelt himself advocates. (To be fair, that would defeat the purpose of a gene drive.) And the ecological barrier, he says, is nonsense. "In Boston you have hot and humid summers, so sure, tropical mosquitoes may not be native, but they can certainly survive," Bier says. "If a pregnant female got out, she and her progeny could reproduce in a puddle, fly to ships in the Boston Harbor, and get on a boat to Brazil."

These problems don't end with mosquitoes. One of Crispr's strengths is that it works on every living thing. That kind of power makes Doudna feel like she opened Pandora's box. Use Crispr to treat, say, Huntington's disease-a debilitating neurological disorder-in the womb, when an embryo is just a ball of cells? Perhaps. But the same method could also possibly alter less medically relevant genes, like the ones that make skin wrinkle. "We haven't had the time, as a community, to discuss the ethics and safety," Doudna says, "and, frankly, whether there is any real clinical benefit of this versus other ways of dealing with genetic disease."

Researchers in China announced they had used Crispr to edit human embryos.

That's why she convened the meeting in Napa. All the same problems of recombinant DNA that the Asilomar attendees tried to grapple with are still there-more pressing now than ever. And if the scientists don't figure out how to handle them, some other regulatory body might. Few researchers, Baltimore included, want to see Congress making laws about science. "Legislation is unforgiving," he says. "Once you pass it, it is very hard to undo."

In other words, if biologists don't start thinking about ethics, the taxpayers who fund their research might do the thinking for them.

All of that only matters if every scientist is on board. A month after the Napa conference, researchers at Sun Yat-sen University in Guangzhou, China, announced they had used Crispr to edit human embryos. Specifically they were looking to correct mutations in the gene that causes beta thalassemia, a disorder that interferes with a person's ability to make healthy red blood cells.

The work wasn't successful-Crispr, it turns out, didn't target genes as well in embryos as it does in isolated cells. The Chinese researchers tried to skirt the ethical implications of their work by using nonviable embryos, which is to say they could never have been brought to term. But the work attracted attention. A month later, the US National Academy of Sciences announced that it would create a set of recommendations for scientists, policymakers, and regulatory agencies on when, if ever, embryonic engineering might be permissible. Another National Academy report will focus on gene drives. Though those recommendations don't carry the weight of law, federal funding in part determines what science gets done, and agencies that fund research around the world often abide by the academy's guidelines.

The truth is, most of what scientists want to do with Crispr is not controversial. For example, researchers once had no way to figure out why spiders have the same gene that determines the pattern of veins in the wings of flies. You could sequence the spider and see that the "wing gene" was in its genome, but all you'd know was that it certainly wasn't designing wings. Now, with less than $100, an ordinary arachnologist can snip the wing gene out of a spider embryo and see what happens when that spider matures. If it's obvious-maybe its claws fail to form-you've learned that the wing gene must have served a different purpose before insects branched off, evolutionarily, from the ancestor they shared with spiders. Pick your creature, pick your gene, and you can bet someone somewhere is giving it a go.

Academic and pharmaceutical company labs have begun to develop Crispr-based research tools, such as cancerous mice-perfect for testing new chemotherapies. A team at MIT, working with Zhang, used Crispr-Cas9 to create, in just weeks, mice that inevitably get liver cancer. That kind of thing used to take more than a year. Other groups are working on ways to test drugs on cells with single-gene variations to understand why the drugs work in some cases and fail in others. Zhang's lab used the technique to learn which genetic variations make people resistant to a melanoma drug called Vemurafenib. The genes he identified may provide research targets for drug developers.

The real money is in human therapeutics. For example, labs are working on the genetics of so-called elite controllers, people who can be HIV-positive but never develop AIDS. Using Crispr, researchers can knock out a gene called CCR5, which makes a protein that helps usher HIV into cells. You'd essentially make someone an elite controller. Or you could use Crispr to target HIV directly; that begins to look a lot like a cure.

Or-and this idea is decades away from execution-you could figure out which genes make humans susceptible to HIV overall. Make sure they don't serve other, more vital purposes, and then "fix" them in an embryo. It'd grow into a person immune to the virus.

But straight-out editing of a human embryo sets off all sorts of alarms, both in terms of ethics and legality. It contravenes the policies of the US National Institutes of Health, and in spirit at least runs counter to the United Nations' Universal Declaration on the Human Genome and Human Rights. (Of course, when the US government said it wouldn't fund research on human embryonic stem cells, private entities raised millions of dollars to do it themselves.) Engineered humans are a ways off-but nobody thinks they're science fiction anymore.

Even if scientists never try to design a baby, the worries those Asilomar attendees had four decades ago now seem even more prescient. The world has changed. "Genome editing started with just a few big labs putting in lots of effort, trying something 1,000 times for one or two successes," says Hank Greely, a bioethicist at Stanford. "Now it's something that someone with a BS and a couple thousand dollars' worth of equipment can do. What was impractical is now almost everyday. That's a big deal."

In 1975 no one was asking whether a genetically modified vegetable should be welcome in the produce aisle. No one was able to test the genes of an unborn baby, or sequence them all. Today swarms of investors are racing to bring genetically engineered creations to market. The idea of Crispr slides almost frictionlessly into modern culture.

In an odd reversal, it's the scientists who are showing more fear than the civilians. When I ask Church for his most nightmarish Crispr scenario, he mutters something about weapons and then stops short. He says he hopes to take the specifics of the idea, whatever it is, to his grave. But thousands of other scientists are working on Crispr. Not all of them will be as cautious. "You can't stop science from progressing," Jinek says. "Science is what it is." He's right. Science gives people power. And power is unpredictable.

Amy Maxmen (@amymaxmen) writes about science for National Geographic, Newsweek, and other publications. This is her first article for WIRED.
This article appears in the August 2015 issue.
Animation by Anthony Zazzi; Illustrations by Ben Wiseman

# data[].attributes.attachment_link.description
Spiny grass and scraggly pines creep amid the arts-and-crafts buildings of the Asilomar Conference Grounds, 100 acres of dune where California's Monterey Peninsula hammerheads into the Pacific. It's a rugged landscape, designed to inspire people to contemplate their evolving place on Earth. So it was natural that 140 scientists gathered here in 1975 for an unprecedented conference.

# data[].attributes.body
Main idea:
Ever since DNA was first discovered, there was a competition between scientists to make more discoveries in this field. However, when genetic engineering became easily available, it turned into a race.

Facts:
- CRISPR is an acronym for "clustered regularly interspaced short palindromic repeats" and Cas9 is a protein that makes it work.
- Humans were actually genetic engineers long before they knew what a gene was. They could give living things new traits by selective breeding.
- Some researchers noticed segments in the DNA of Archaea microbes that were the same from front to back and from back to front - palindromic.
- A microbiologist working for a Danish yogurt company found these same repeated segments in the DNA of the bacteria that the company used to make yogurt and cheese. - The unidentified stretches of DNA between the palindromes matched the sequences from viruses that had invaded these bacteria. These segments play a vital role in the defence of bacteria against the viruses that attack them.
- Moreover, some of the CRISPR's sequences didn't encode the manufacture of a protein, but instead led to RNA. That means that most animals and plants defend themselves against viruses with structure made out of RNA.

Dialogue:
CRISPR is kind of a natural protection that has been present in all life forms since the beginning of all life forms on Earth. However, know we can use this super powerful tool for our own benefit, protecting us and making us immune against diseases that have threatened humanity for many years.

Summary:
Humans have been trying to change some traits of plants and animals in order to make them more beneficial for a long period of time. But, these processes were very time-consuming and expensive. So, when CRISPR was discovered, everybody became very eager to make new discoveries using it, which raised some worries about the safety and ethics of this method.

Maxmen, A. (2015, August). Easy DNA Editing Will Remake the World. Buckle Up. Retrieved from: https://www.wired.com/2015/07/crispr-dna-editing-2/

# data[].attributes.attachment_link.readable_text
Spiny grass and scraggly pines creep amid the arts-and-crafts buildings of the Asilomar Conference Grounds, 100 acres of dune where California's Monterey Peninsula hammerheads into the Pacific. It's a rugged landscape, designed to inspire people to contemplate their evolving place on Earth. So it was natural that 140 scientists gathered here in 1975 for an unprecedented conference.

They were worried about what people called "recombinant DNA," the manipulation of the source code of life. It had been just 22 years since James Watson, Francis Crick, and Rosalind Franklin described what DNA was-deoxyribonucleic acid, four different structures called bases stuck to a backbone of sugar and phosphate, in sequences thousands of bases long. DNA is what genes are made of, and genes are the basis of heredity.

Preeminent genetic researchers like David Baltimore, then at MIT, went to Asilomar to grapple with the implications of being able to decrypt and reorder genes. It was a God-like power-to plug genes from one living thing into another. Used wisely, it had the potential to save millions of lives. But the scientists also knew their creations might slip out of their control. They wanted to consider what ought to be off-limits.

By 1975, other fields of science-like physics-were subject to broad restrictions. Hardly anyone was allowed to work on atomic bombs, say. But biology was different. Biologists still let the winding road of research guide their steps. On occasion, regulatory bodies had acted retrospectively-after Nuremberg, Tuskegee, and the human radiation experiments, external enforcement entities had told biologists they weren't allowed to do that bad thing again. Asilomar, though, was about establishing prospective guidelines, a remarkably open and forward-thinking move.

At the end of the meeting, Baltimore and four other molecular biologists stayed up all night writing a consensus statement. They laid out ways to isolate potentially dangerous experiments and determined that cloning or otherwise messing with dangerous pathogens should be off-limits. A few attendees fretted about the idea of modifications of the human "germ line"-changes that would be passed on from one generation to the next-but most thought that was so far off as to be unrealistic. Engineering microbes was hard enough. The rules the Asilomar scientists hoped biology would follow didn't look much further ahead than ideas and proposals already on their desks.

Earlier this year, Baltimore joined 17 other researchers for another California conference, this one at the Carneros Inn in Napa Valley. "It was a feeling of déjà vu," Baltimore says. There he was again, gathered with some of the smartest scientists on earth to talk about the implications of genome engineering.

The stakes, however, have changed. Everyone at the Napa meeting had access to a gene-editing technique called Crispr-Cas9. The first term is an acronym for "clustered regularly interspaced short palindromic repeats," a description of the genetic basis of the method; Cas9 is the name of a protein that makes it work. Technical details aside, Crispr-Cas9 makes it easy, cheap, and fast to move genes around-any genes, in any living thing, from bacteria to people. "These are monumental moments in the history of biomedical research," Baltimore says. "They don't happen every day."

Using the three-year-old technique, researchers have already reversed mutations that cause blindness, stopped cancer cells from multiplying, and made cells impervious to the virus that causes AIDS. Agronomists have rendered wheat invulnerable to killer fungi like powdery mildew, hinting at engineered staple crops that can feed a population of 9 billion on an ever-warmer planet. Bioengineers have used Crispr to alter the DNA of yeast so that it consumes plant matter and excretes ethanol, promising an end to reliance on petrochemicals. Startups devoted to Crispr have launched. International pharmaceutical and agricultural companies have spun up Crispr R&D. Two of the most powerful universities in the US are engaged in a vicious war over the basic patent. Depending on what kind of person you are, Crispr makes you see a gleaming world of the future, a Nobel medallion, or dollar signs.

The technique is revolutionary, and like all revolutions, it's perilous. Crispr goes well beyond anything the Asilomar conference discussed. It could at last allow genetics researchers to conjure everything anyone has ever worried they would-designer babies, invasive mutants, species-specific bioweapons, and a dozen other apocalyptic sci-fi tropes. It brings with it all-new rules for the practice of research in the life sciences. But no one knows what the rules are-or who will be the first to break them.

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In a way, humans were genetic engineers long before anyone knew what a gene was. They could give living things new traits-sweeter kernels of corn, flatter bulldog faces-through selective breeding. But it took time, and it didn't always pan out. By the 1930s refining nature got faster. Scientists bombarded seeds and insect eggs with x-rays, causing mutations to scatter through genomes like shrapnel. If one of hundreds of irradiated plants or insects grew up with the traits scientists desired, they bred it and tossed the rest. That's where red grapefruits came from, and most barley for modern beer.

Genome modification has become less of a crapshoot. In 2002, molecular biologists learned to delete or replace specific genes using enzymes called zinc-finger nucleases; the next-generation technique used enzymes named TALENs.

Yet the procedures were expensive and complicated. They only worked on organisms whose molecular innards had been thoroughly dissected-like mice or fruit flies. Genome engineers went on the hunt for something better.

Scientists have used it to render wheat invulnerable to killer fungi. Such crops could feed billions of people.

As it happened, the people who found it weren't genome engineers at all. They were basic researchers, trying to unravel the origin of life by sequencing the genomes of ancient bacteria and microbes called Archaea (as in archaic), descendants of the first life on Earth. Deep amid the bases, the As, Ts, Gs, and Cs that made up those DNA sequences, microbiologists noticed recurring segments that were the same back to front and front to back-palindromes. The researchers didn't know what these segments did, but they knew they were weird. In a branding exercise only scientists could love, they named these clusters of repeating palindromes Crispr.

Then, in 2005, a microbiologist named Rodolphe Barrangou, working at a Danish food company called Danisco, spotted some of those same palindromic repeats in Streptococcus thermophilus, the bacteria that the company uses to make yogurt and cheese. Barrangou and his colleagues discovered that the unidentified stretches of DNA between Crispr's palindromes matched sequences from viruses that had infected their S. thermophilus colonies. Like most living things, bacteria get attacked by viruses-in this case they're called bacteriophages, or phages for short. Barrangou's team went on to show that the segments served an important role in the bacteria's defense against the phages, a sort of immunological memory. If a phage infected a microbe whose Crispr carried its fingerprint, the bacteria could recognize the phage and fight back. Barrangou and his colleagues realized they could save their company some money by selecting S. thermophilus species with Crispr sequences that resisted common dairy viruses.

As more researchers sequenced more bacteria, they found Crisprs again and again-half of all bacteria had them. Most Archaea did too. And even stranger, some of Crispr's sequences didn't encode the eventual manufacture of a protein, as is typical of a gene, but instead led to RNA-single-stranded genetic material. (DNA, of course, is double-stranded.)

That pointed to a new hypothesis. Most present-day animals and plants defend themselves against viruses with structures made out of RNA. So a few researchers started to wonder if Crispr was a primordial immune system. Among the people working on that idea was Jill Banfield, a geomicrobiologist at UC Berkeley, who had found Crispr sequences in microbes she collected from acidic, 110-degree water from the defunct Iron Mountain Mine in Shasta County, California. But to figure out if she was right, she needed help.

Luckily, one of the country's best-known RNA experts, a biochemist named Jennifer Doudna, worked on the other side of campus in an office with a view of the Bay and San Francisco's skyline. It certainly wasn't what Doudna had imagined for herself as a girl growing up on the Big Island of Hawaii. She simply liked math and chemistry-an affinity that took her to Harvard and then to a postdoc at the University of Colorado. That's where she made her initial important discoveries, revealing the three-dimensional structure of complex RNA molecules that could, like enzymes, catalyze chemical reactions.

The mine bacteria piqued Doudna's curiosity, but when Doudna pried Crispr apart, she didn't see anything to suggest the bacterial immune system was related to the one plants and animals use. Still, she thought the system might be adapted for diagnostic tests.

Banfield wasn't the only person to ask Doudna for help with a Crispr project. In 2011, Doudna was at an American Society for Microbiology meeting in San Juan, Puerto Rico, when an intense, dark-haired French scientist asked her if she wouldn't mind stepping outside the conference hall for a chat. This was Emmanuelle Charpentier, a microbiologist at Ume˚a University in Sweden.

As they wandered through the alleyways of old San Juan, Charpentier explained that one of Crispr's associated proteins, named Csn1, appeared to be extraordinary. It seemed to search for specific DNA sequences in viruses and cut them apart like a microscopic multitool. Charpentier asked Doudna to help her figure out how it worked. "Somehow the way she said it, I literally-I can almost feel it now-I had this chill down my back," Doudna says. "When she said 'the mysterious Csn1' I just had this feeling, there is going to be something good here."

Back in Sweden, Charpentier kept a colony of Streptococcus pyogenes in a biohazard chamber. Few people want S. pyogenes anywhere near them. It can cause strep throat and necrotizing fasciitis-flesh-eating disease. But it was the bug Charpentier worked with, and it was in S. pyogenes that she had found that mysterious yet mighty protein, now renamed Cas9. Charpentier swabbed her colony, purified its DNA, and FedExed a sample to Doudna.

Working together, Charpentier's and Doudna's teams found that Crispr made two short strands of RNA and that Cas9 latched onto them. The sequence of the RNA strands corresponded to stretches of viral DNA and could home in on those segments like a genetic GPS. And when the Crispr-Cas9 complex arrives at its destination, Cas9 does something almost magical: It changes shape, grasping the DNA and slicing it with a precise molecular scalpel.

Here's what's important: Once they'd taken that mechanism apart, Doudna's postdoc, Martin Jinek, combined the two strands of RNA into one fragment-"guide RNA"-that Jinek could program. He could make guide RNA with whatever genetic letters he wanted; not just from viruses but from, as far as they could tell, anything. In test tubes, the combination of Jinek's guide RNA and the Cas9 protein proved to be a programmable machine for DNA cutting. Compared to TALENs and zinc-finger nucleases, this was like trading in rusty scissors for a computer-controlled laser cutter. "I remember running into a few of my colleagues at Berkeley and saying we have this fantastic result, and I think it's going to be really exciting for genome engineering. But I don't think they quite got it," Doudna says. "They kind of humored me, saying, 'Oh, yeah, that's nice.'"

On June 28, 2012, Doudna's team published its results in Science. In the paper and in an earlier corresponding patent application, they suggest their technology could be a tool for genome engineering. It was elegant and cheap. A grad student could do it.

The finding got noticed. In the 10 years preceding 2012, 200 papers mentioned Crispr. By 2014 that number had more than tripled. Doudna and Charpentier were each recently awarded the $3 million 2015 Breakthrough Prize. Time magazine listed the duo among the 100 most influential people in the world. Nobody was just humoring Doudna anymore.

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Most Wednesday afternoons, Feng Zhang, a molecular biologist at the Broad Institute of MIT and Harvard, scans the contents of Science as soon as they are posted online. In 2012, he was working with Crispr-Cas9 too. So when he saw Doudna and Charpentier's paper, did he think he'd been scooped? Not at all. "I didn't feel anything," Zhang says. "Our goal was to do genome editing, and this paper didn't do it." Doudna's team had cut DNA floating in a test tube, but to Zhang, if you weren't working with human cells, you were just screwing around.

That kind of seriousness is typical for Zhang. At 11, he moved from China to Des Moines, Iowa, with his parents, who are engineers-one computer, one electrical. When he was 16, he got an internship at the gene therapy research institute at Iowa Methodist hospital. By the time he graduated high school he'd won multiple science awards, including third place in the Intel Science Talent Search.

When Doudna talks about her career, she dwells on her mentors; Zhang lists his personal accomplishments, starting with those high school prizes. Doudna seems intuitive and has a hands-off management style. Zhang ... pushes. We scheduled a video chat at 9:15 pm, and he warned me that we'd be talking data for a couple of hours. "Power-nap first," he said.

If new genes that wipe out malaria also make mosquitoes go extinct, what will bats eat?

Zhang got his job at the Broad in 2011, when he was 29. Soon after starting there, he heard a speaker at a scientific advisory board meeting mention Crispr. "I was bored," Zhang says, "so as the researcher spoke, I just Googled it." Then he went to Miami for an epigenetics conference, but he hardly left his hotel room. Instead Zhang spent his time reading papers on Crispr and filling his notebook with sketches on ways to get Crispr and Cas9 into the human genome. "That was an extremely exciting weekend," he says, smiling.

Just before Doudna's team published its discovery in Science, Zhang applied for a federal grant to study Crispr-Cas9 as a tool for genome editing. Doudna's publication shifted him into hyperspeed. He knew it would prompt others to test Crispr on genomes. And Zhang wanted to be first.

Even Doudna, for all of her equanimity, had rushed to report her finding, though she hadn't shown the system working in human cells. "Frankly, when you have a result that is exciting," she says, "one does not wait to publish it."

In January 2013, Zhang's team published a paper in Science showing how Crispr-Cas9 edits genes in human and mouse cells. In the same issue, Harvard geneticist George Church edited human cells with Crispr too. Doudna's team reported success in human cells that month as well, though Zhang is quick to assert that his approach cuts and repairs DNA better.

That detail matters because Zhang had asked the Broad Institute and MIT, where he holds a joint appointment, to file for a patent on his behalf. Doudna had filed her patent application-which was public information-seven months earlier. But the attorney filing for Zhang checked a box on the application marked "accelerate" and paid a fee, usually somewhere between $2,000 and $4,000. A series of emails followed between agents at the US Patent and Trademark Office and the Broad's patent attorneys, who argued that their claim was distinct.

A little more than a year after those human-cell papers came out, Doudna was on her way to work when she got an email telling her that Zhang, the Broad Institute, and MIT had indeed been awarded the patent on Crispr-Cas9 as a method to edit genomes. "I was quite surprised," she says, "because we had filed our paperwork several months before he had."

The Broad win started a firefight. The University of California amended Doudna's original claim to overlap Zhang's and sent the patent office a 114-page application for an interference proceeding-a hearing to determine who owns Crispr-this past April. In Europe, several parties are contesting Zhang's patent on the grounds that it lacks novelty. Zhang points to his grant application as proof that he independently came across the idea. He says he could have done what Doudna's team did in 2012, but he wanted to prove that Crispr worked within human cells. The USPTO may make its decision as soon as the end of the year.

The stakes here are high. Any company that wants to work with anything other than microbes will have to license Zhang's patent; royalties could be worth billions of dollars, and the resulting products could be worth billions more. Just by way of example: In 1983 Columbia University scientists patented a method for introducing foreign DNA into cells, called cotransformation. By the time the patents expired in 2000, they had brought in $790 million in revenue.

It's a testament to Crispr's value that despite the uncertainty over ownership, companies based on the technique keep launching. In 2011 Doudna and a student founded a company, Caribou, based on earlier Crispr patents; the University of California offered Caribou an exclusive license on the patent Doudna expected to get. Caribou uses Crispr to create industrial and research materials, potentially enzymes in laundry detergent and laboratory reagents. To focus on disease-where the long-term financial gain of Crispr-Cas9 will undoubtedly lie-Caribou spun off another biotech company called Intellia Therapeutics and sublicensed the Crispr-Cas9 rights. Pharma giant Novartis has invested in both startups. In Switzerland, Charpentier cofounded Crispr Therapeutics. And in Cambridge, Massachusetts, Zhang, George Church, and several others founded Editas Medicine, based on licenses on the patent Zhang eventually received.

Thus far the four companies have raised at least $158 million in venture capital.

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Any gene typically has just a 50-50 chance of getting passed on. Either the offspring gets a copy from Mom or a copy from Dad. But in 1957 biologists found exceptions to that rule, genes that literally manipulated cell division and forced themselves into a larger number of offspring than chance alone would have allowed.

A decade ago, an evolutionary geneticist named Austin Burt proposed a sneaky way to use these "selfish genes." He suggested tethering one to a separate gene-one that you wanted to propagate through an entire population. If it worked, you'd be able to drive the gene into every individual in a given area. Your gene of interest graduates from public transit to a limousine in a motorcade, speeding through a population in flagrant disregard of heredity's traffic laws. Burt suggested using this "gene drive" to alter mosquitoes that spread malaria, which kills around a million people every year. It's a good idea. In fact, other researchers are already using other methods to modify mosquitoes to resist the Plasmodium parasite that causes malaria and to be less fertile, reducing their numbers in the wild. But engineered mosquitoes are expensive. If researchers don't keep topping up the mutants, the normals soon recapture control of the ecosystem.

Push those modifications through with a gene drive and the normal mosquitoes wouldn't stand a chance. The problem is, inserting the gene drive into the mosquitoes was impossible. Until Crispr-Cas9 came along.

Today, behind a set of four locked and sealed doors in a lab at the Harvard School of Public Health, a special set of mosquito larvae of the African species Anopheles gambiae wriggle near the surface of shallow tubs of water. These aren't normal Anopheles, though. The lab is working on using Crispr to insert malaria-resistant gene drives into their genomes. It hasn't worked yet, but if it does ... well, consider this from the mosquitoes' point of view. This project isn't about reengineering one of them. It's about reengineering them all.

Kevin Esvelt, the evolutionary engineer who initiated the project, knows how serious this work is. The basic process could wipe out any species. Scientists will have to study the mosquitoes for years to make sure that the gene drives can't be passed on to other species of mosquitoes. And they want to know what happens to bats and other insect-eating predators if the drives make mosquitoes extinct. "I am responsible for opening a can of worms when it comes to gene drives," Esvelt says, "and that is why I try to ensure that scientists are taking precautions and showing themselves to be worthy of the public's trust-maybe we're not, but I want to do my damnedest to try."

Esvelt talked all this over with his adviser-Church, who also worked with Zhang. Together they decided to publish their gene-drive idea before it was actually successful. They wanted to lay out their precautionary measures, way beyond five nested doors. Gene drive research, they wrote, should take place in locations where the species of study isn't native, making it less likely that escapees would take root. And they also proposed a way to turn the gene drive off when an engineered individual mated with a wild counterpart-a genetic sunset clause. Esvelt filed for a patent on Crispr gene drives, partly, he says, to block companies that might not take the same precautions.

Within a year, and without seeing Esvelt's papers, biologists at UC San Diego had used Crispr to insert gene drives into fruit flies-they called them "mutagenic chain reactions." They had done their research in a chamber behind five doors, but the other precautions weren't there.Church said the San Diego researchers had gone "a step too far"-big talk from a scientist who says he plans to use Crispr to bring back an extinct woolly mammoth by deriving genes from frozen corpses and injecting them into elephant embryos. (Church says tinkering with one woolly mammoth is way less scary than messing with whole populations of rapidly reproducing insects. "I'm afraid of everything," he says. "I encourage people to be as creative in thinking about the unintended consequences of their work as the intended.")

Ethan Bier, who worked on the San Diego fly study, agrees that gene drives come with risks. But he points out that Esvelt's mosquitoes don't have the genetic barrier Esvelt himself advocates. (To be fair, that would defeat the purpose of a gene drive.) And the ecological barrier, he says, is nonsense. "In Boston you have hot and humid summers, so sure, tropical mosquitoes may not be native, but they can certainly survive," Bier says. "If a pregnant female got out, she and her progeny could reproduce in a puddle, fly to ships in the Boston Harbor, and get on a boat to Brazil."

These problems don't end with mosquitoes. One of Crispr's strengths is that it works on every living thing. That kind of power makes Doudna feel like she opened Pandora's box. Use Crispr to treat, say, Huntington's disease-a debilitating neurological disorder-in the womb, when an embryo is just a ball of cells? Perhaps. But the same method could also possibly alter less medically relevant genes, like the ones that make skin wrinkle. "We haven't had the time, as a community, to discuss the ethics and safety," Doudna says, "and, frankly, whether there is any real clinical benefit of this versus other ways of dealing with genetic disease."

Researchers in China announced they had used Crispr to edit human embryos.

That's why she convened the meeting in Napa. All the same problems of recombinant DNA that the Asilomar attendees tried to grapple with are still there-more pressing now than ever. And if the scientists don't figure out how to handle them, some other regulatory body might. Few researchers, Baltimore included, want to see Congress making laws about science. "Legislation is unforgiving," he says. "Once you pass it, it is very hard to undo."

In other words, if biologists don't start thinking about ethics, the taxpayers who fund their research might do the thinking for them.

All of that only matters if every scientist is on board. A month after the Napa conference, researchers at Sun Yat-sen University in Guangzhou, China, announced they had used Crispr to edit human embryos. Specifically they were looking to correct mutations in the gene that causes beta thalassemia, a disorder that interferes with a person's ability to make healthy red blood cells.

The work wasn't successful-Crispr, it turns out, didn't target genes as well in embryos as it does in isolated cells. The Chinese researchers tried to skirt the ethical implications of their work by using nonviable embryos, which is to say they could never have been brought to term. But the work attracted attention. A month later, the US National Academy of Sciences announced that it would create a set of recommendations for scientists, policymakers, and regulatory agencies on when, if ever, embryonic engineering might be permissible. Another National Academy report will focus on gene drives. Though those recommendations don't carry the weight of law, federal funding in part determines what science gets done, and agencies that fund research around the world often abide by the academy's guidelines.

The truth is, most of what scientists want to do with Crispr is not controversial. For example, researchers once had no way to figure out why spiders have the same gene that determines the pattern of veins in the wings of flies. You could sequence the spider and see that the "wing gene" was in its genome, but all you'd know was that it certainly wasn't designing wings. Now, with less than $100, an ordinary arachnologist can snip the wing gene out of a spider embryo and see what happens when that spider matures. If it's obvious-maybe its claws fail to form-you've learned that the wing gene must have served a different purpose before insects branched off, evolutionarily, from the ancestor they shared with spiders. Pick your creature, pick your gene, and you can bet someone somewhere is giving it a go.

Academic and pharmaceutical company labs have begun to develop Crispr-based research tools, such as cancerous mice-perfect for testing new chemotherapies. A team at MIT, working with Zhang, used Crispr-Cas9 to create, in just weeks, mice that inevitably get liver cancer. That kind of thing used to take more than a year. Other groups are working on ways to test drugs on cells with single-gene variations to understand why the drugs work in some cases and fail in others. Zhang's lab used the technique to learn which genetic variations make people resistant to a melanoma drug called Vemurafenib. The genes he identified may provide research targets for drug developers.

The real money is in human therapeutics. For example, labs are working on the genetics of so-called elite controllers, people who can be HIV-positive but never develop AIDS. Using Crispr, researchers can knock out a gene called CCR5, which makes a protein that helps usher HIV into cells. You'd essentially make someone an elite controller. Or you could use Crispr to target HIV directly; that begins to look a lot like a cure.

Or-and this idea is decades away from execution-you could figure out which genes make humans susceptible to HIV overall. Make sure they don't serve other, more vital purposes, and then "fix" them in an embryo. It'd grow into a person immune to the virus.

But straight-out editing of a human embryo sets off all sorts of alarms, both in terms of ethics and legality. It contravenes the policies of the US National Institutes of Health, and in spirit at least runs counter to the United Nations' Universal Declaration on the Human Genome and Human Rights. (Of course, when the US government said it wouldn't fund research on human embryonic stem cells, private entities raised millions of dollars to do it themselves.) Engineered humans are a ways off-but nobody thinks they're science fiction anymore.

Even if scientists never try to design a baby, the worries those Asilomar attendees had four decades ago now seem even more prescient. The world has changed. "Genome editing started with just a few big labs putting in lots of effort, trying something 1,000 times for one or two successes," says Hank Greely, a bioethicist at Stanford. "Now it's something that someone with a BS and a couple thousand dollars' worth of equipment can do. What was impractical is now almost everyday. That's a big deal."

In 1975 no one was asking whether a genetically modified vegetable should be welcome in the produce aisle. No one was able to test the genes of an unborn baby, or sequence them all. Today swarms of investors are racing to bring genetically engineered creations to market. The idea of Crispr slides almost frictionlessly into modern culture.

In an odd reversal, it's the scientists who are showing more fear than the civilians. When I ask Church for his most nightmarish Crispr scenario, he mutters something about weapons and then stops short. He says he hopes to take the specifics of the idea, whatever it is, to his grave. But thousands of other scientists are working on Crispr. Not all of them will be as cautious. "You can't stop science from progressing," Jinek says. "Science is what it is." He's right. Science gives people power. And power is unpredictable.

Amy Maxmen (@amymaxmen) writes about science for National Geographic, Newsweek, and other publications. This is her first article for WIRED.
This article appears in the August 2015 issue.
Animation by Anthony Zazzi; Illustrations by Ben Wiseman

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Spiny grass and scraggly pines creep amid the arts-and-crafts buildings of the Asilomar Conference Grounds, 100 acres of dune where California's Monterey Peninsula hammerheads into the Pacific. It's a rugged landscape, designed to inspire people to contemplate their evolving place on Earth. So it was natural that 140 scientists gathered here in 1975 for an unprecedented conference.

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There are really good reasons why we should — and shouldn't — genetically engineer human embryos 

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There are really good reasons why we should — and shouldn't — genetically engineer human embryos 

# data[].attributes.body
Main idea:
At an international summit in Washington, D.C. Scientists, bioethicists, and other stakeholders made a debate, they discussed how this technique can cure many diseases as well as the risks.

Arguments/facts: (Why we should allow it)

Firstly, by using CRISPR to edit the human embryos, we can prevent genetic diseases such as cystic fibrosis or Huntington's disease. Which are done by mutations in an only gene, so if that gene could be fixed the baby would be born healthier.

Chinese researchers announced they cured a fatal blood disorder, beta thalassemia, by using CRISPR to modify human embryos. Even thought the embryos could not survive birth, for many parents whose children suffer from genetic diseases or germline editing, it is a convincing cure.

Last but not least, it can also be used to understanding of our basic biology, for example to study how fertilized egg develops into a baby (reported by STAT)

Dialog:
It can help with many diseases, avoiding less death

Summary:
Even though the CRISPR may have risks, it can be of a lot of help to children who suffer diseases, or prevent diseases for human embryos, so they can be born healthier or lastly to get better understanding.

APA:
Lewis, T. (2015, December 4). There are really good reasons why we should - and shouldn't - genetically engineer human embryos. Retrieved from: https://www.businessinsider.com/arguments-for-and-against-editing-human-embryos-2015-12

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A powerful tool that lets scientists modify DNA with extreme precision could be used to genetically engineer the human species.

For the past three days, scientists, bioethicists, and other stakeholders at an international summit in Washington, D.C. have been debating some tough questions related to the gene-editing technology known as CRISPR/Cas9.

They discussed the technique's enormous potential to cure genetic diseases and expand our understanding of human biology, as well as the safety risks and ethical hazards of modifying the human "germline" - the genetic blueprint that will be passed on to future generations.

At the conclusion of the summit, Committee Chair David Baltimore of the California Institute of Technology read a statement summarizing the committee's position on the use of gene editing in humans, which said the following:

1. Basic and preclinical research should proceed. But if human embryos are edited, they should not be used to establish a pregnancy.

2. Gene editing of somatic cells, whose DNA is not passed on to the next generation, falls under existing regulations for gene therapy, an experimental treatment for genetic diseases that involves transplanting normal genes into cells with defective ones.

3. It would be "irresponsible" to edit the human germline, which is passed on to future generations, unless 1) the relevant safety and efficacy issues have been resolved and 2) there is "broad societal consensus" about a use of the technology.

4. We need an ongoing international forum to discuss potential medical uses of gene editing, help steer policymakers, make recommendations and guidelines, and encourage coordination between countries.

Here are some of the main arguments that were made for and against human germline editing:

Why we should allow it

One of the most tantalizing reasons for using CRISPR to edit human embryos is the potential to prevent devastating genetic diseases like cystic fibrosis or Huntington's disease. These are caused by mutations in a single gene, so if you could fix that gene, the baby would be born healthy.

In April, Chinese researchers announced they had used CRISPR to modify human embryos in order to cure a fatal blood disorder known as beta thalassemia. The embryos were not viable, meaning they could not survive to birth, but it could be a preview of what's to come.

For many parents whose children suffer from genetic diseases, germline editing is a compelling prospect.

Sarah Gray of the American Association of Tissue Banks was one of those who spoke up at the meeting. Her son died of a fatal genetic disease six days after he was born, after suffering terrible seizures. As Sharon Begley reported in STAT, Gray told the attendees, "If you have the skills and the knowledge to eliminate these diseases, then frickin' do it!"

In addition to diseases with a relatively straightforward cause, gene editing could also be used, in principle, to modify genes that lower the risk of contracting or developing diseases like HIV/AIDS. However, it's not that easy - the same gene that makes people resistant to HIV also makes them more likely to die of West Nile virus, as Ed Yong reported in The Atlantic.

Finally, beyond preventing diseases, the ability to edit embryos opens up an exciting new means for understanding our basic biology. For example, it could be used to study how a fertilized egg develops into a baby, as STAT reported.

Why we shouldn't allow it

However, like any new medical therapy, CRISPR poses safety and ethical concerns.

Although the Chinese experiment showed the technique could be used in human embryos, it also caused a number of unintended, "off-target" effects on some parts of the genome. These changes could lead to other genetic complications, some of which could be fatal.

"In my opinion, the data is not there to say [the use of CRISPR in humans] is safe or reliable," Joy Larsen Haidle, president of the National Society of Genetic Counselors, told Business Insider previously. Furthermore, "do we risk causing a different problem we didn't anticipate?"

The technology is improving, but scientists will need to do many more studies before it can be proven safe. After all, the broader field of gene therapy suffered some high-profile tragedies including the deaths of several patients.

Safety aside, many experts argue the use of CRISPR to correct congenital genetic defects is unnecessary. Doctors can already screen out many of these diseases before a pregnancy, thanks to in vitro fertilization and pre-implantation genetic screening.

New York Times columnist and science writer Carl Zimmer told Business Insider previously, "I haven't seen anybody give a legitimate medical reason [for using CRISPR in human embryos] that couldn't be achieved through other means."

If we do allow germline editing, some worry that it could lead to the creation of "designer babies" whose DNA has been carefully selected to enhance their appearance, intelligence, or other traits that are not medically necessary.

These enhancements may also be unevenly distributed among the population, leading to a society of genetic haves and have-nots.

This also opens the door to another potentially scary idea, spectre of eugenics, the racist practice of trying to "improve" the human race by controlling genetics and reproduction.

"Eugenics was not unique to the Nazis," Daniel Kevles, a historian of science at New York University, reminded the audience at the gene editing summit on Tuesday. "It could - and did - happen everywhere."

Given all of these concerns, many people at the summit or following along on social media advocated the "precautionary principle" - the idea that a new product or process which could have controversial or unknown effects should be avoided.

"When an activity raises threats of harm to human health or the environment, precautionary measures should be taken even if some cause and effect relationships are not fully established scientifically," according to a statement made at the Wingspread Conference in 1998.

The summit in D.C. only scratched the surface of these questions. Given the pace at which this technology has been developing, we are likely to be having many more these discussions in the years to come.

# data[].attributes.attachment_link.title
There are really good reasons why we should - and shouldn't - genetically engineer human embryos

# data[].attributes.attachment_link.description
A powerful tool that lets scientists modify DNA with extreme precision could be used to genetically engineer the human species. For the past three days, scientists, bioethicists, and other stakeholders at an international summit in Washington, D.C. have been debating some tough questions related to the gene-editing technology known as CRISPR/Cas9.

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What are the ethical concerns of genome engineering?

# data[].attributes.subject
What are the ethical concerns of genome engineering?

# data[].attributes.body
Main point:
Genetic engineering can sometimes go not according to plan and even get out of hand.

Arguments:
- There is a possibility of edits in the wrong place and mosaicism (some cells have the edit while others do not).
- Any genome editing can start us on a slippery slope towards using it for non-therapeutic and enhancement purposes.
- It is impossible to get informed consent for gremlin therapy because the ones affected by the edits are the embryos and the future generations.
- CRISPR would probably be available for the wealthy and would increase the existing disparities in access to health care.
- It could create classes defined by the quality of their engineered genome.

Dialogue:
Should CRISPR be used if it creates so many class divisions?  As for now, our aspect doesn't fully depend on us, but once CRISPR starts being used for enhancement, people who will not be able to afford it will be looked down on for their appearance. Moreover, it would just increase the toxicity and, most likely, the rates of mental illnesses throughout the globe.
If can alter the genetic code of the generations to come, meaning that what we decide to do now can have incredible impacts on the future.

Summary:
CRISPR could be used for non-medical purposes, meaning that all the benefits would be directed towards improving the physical appearance of humans or upgrading their capabilities. This could create class divisions, as these enhancements will most likely be costly and inaccessible for those in the lower classes. This could also be reflected in the accessibility of health care. What's more, by editing the DNA of some individuals now, we would probably be making great changes to future generations.

NIH. (2017, August 3). What are the Ethical Concerns of Genome Engineering?. Retrieved from: https://www.genome.gov/about-genomics/policy-issues/Genome-Editing/ethical-concerns

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Most of the ethical discussions related to genome editing center around human germline because editing changes made in the germline would be passed down to future generations.

The debate about genome editing is not a new one but has regained attention following the discovery that CRISPR has the potential to make such editing more accurate and even "easy" in comparison to older technologies.

Bioethicists and researchers generally believe that human genome editing for reproductive purposes should not be attempted at this time, but that studies that would make gene therapy safe and effective should continue. 1, 2 Most stakeholders agree that it is important to have continuing public deliberation and debate to allow the public to decide whether or not germline editing should be permissible. As of 2014, there were about 40 countries that discouraged or banned research on germline editing, including 15 nations in Western Europe, because of ethical and safety concerns. 3 There is also an international effort led by the US, UK, and China to harmonize regulation of the application of genome editing technologies. This effort officially launched in December 2015 with the International Summit on Human Gene Editing in Washington, DC. For more information on this summit, see What's happening right now?

NHGRI uses the term "genome editing" to describe techniques used to modify DNA in the genome. Other groups also use the term "gene editing." In general, these terms are used interchangeably.

Ethical Considerations

Safety

Due to the possibility of off-target effects (edits in the wrong place) and mosaicism (when some cells carry the edit but others do not), safety is of primary concern. Researchers and ethicists who have written and spoken about genome editing, such as those present at the International Summit on Human Gene Editing, generally agree that until germline genome editing is deemed safe through research, it should not be used for clinical reproductive purposes; the risk cannot be justified by the potential benefit. Some researchers argue that there may never be a time when genome editing in embryos will offer a benefit greater than that of existing technologies, such as preimplantation genetic diagnosis (PGD) and in-vitro fertilization (IVF). 4

However, scientists and bioethicists acknowledge that in some cases, germline editing can address needs not met by PGD. This includes when both prospective parents are homozygous for a disease-causing variant (they both have two copies of the variant, so all of their children would be expected to have the disease); cases of polygenic disorders, which are influenced by more than one gene; and for families who object to some elements of the PGD process. 5, 6

Some researchers and bioethicists are concerned that any genome editing, even for therapeutic uses, will start us on a slippery slope to using it for non-therapeutic and enhancement purposes, which many view as controversial. Others argue that genome editing, once proved safe and effective, should be allowed to cure genetic disease (and indeed, that it is a moral imperative). 6 They believe that concerns about enhancement should be managed through policy and regulation.

Lastly, commenters on the issue are concerned that the use of genome editing for reproductive purposes will be regulated differently inside and outside of the U.S., leading to uses considered objectionable to the American public. These arguments cite the largely self-regulated environments of the reproductive clinics that offer PGD and IVF 7, 8 and the existing differences in regulations among different countries. 9

Informed Consent

Some people worry that it is impossible to obtain informed consent for germline therapy because the patients affected by the edits are the embryo and future generations. The counterargument is that parents already make many decisions that affect their future children, including similarly complicated decisions such as PGD with IVF. Researchers and bioethicists also worry about the possibility of obtaining truly informed consent from prospective parents as long as the risks of germline therapy are unknown. 10

Justice and Equity

As with many new technologies, there is concern that genome editing will only be accessible to the wealthy and will increase existing disparities in access to health care and other interventions. Some worry that taken to its extreme, germline editing could create classes of individuals defined by the quality of their engineered genome.

Genome-Editing Research Involving Embryos

Many people have moral and religious objections to the use of human embryos for research. Federal funds cannot be used for any research that creates or destroys embryos. In addition, NIH does not fund any use of gene editing in human embryos. (See: U.S. and NIH regulations and perspective)

While NIH will not fund gene editing in human embryos at this time, many bioethical and research groups believe that research using gene editing in embryos is important for myriad reasons, including to address scientific questions about human biology, as long as it is not used for reproductive purposes at this time. 11, 12 Some countries have already allowed genome-editing research on nonviable embryos (those that could not result in a live birth), and others have approved genome-editing research studies with viable embryos. 13, 14 In general, research that is conducted in embryos could use viable or nonviable embryos leftover from IVF, or embryos created expressly for research. Each case has its own moral considerations.

References

[1] National Academies of Sciences, E., Medicine,. (2017). Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press.

[2] The Hinxton Group. (2015). Statement on Genome Editing Technologies and Human Germline Genetic Modification. Retrieved from http://www.hinxtongroup.org/Hinxton2015_Statement.pdf

[3] Araki, M., & Ishii, T. (2014). International regulatory landscape and integration of corrective genome editing into in vitro fertilization. Reprod Biol Endocrinol, 12, 108. doi:10.1186/1477-7827-12-108

[4] Lanphier, E., Urnov, F., Haecker, S. E., Werner, M., & Smolenski, J. (2015). Don't edit the human germ line. Nature News, 519(7544), 410. doi:10.1038/519410a

[5] Hampton, T. (2016). Ethical and Societal Questions Loom Large as Gene Editing Moves Closer to the Clinic. JAMA, 315(6), 546-548. doi:10.1001/jama.2015.19150

[6] Savulescu, J., Pugh, J., Douglas, T., & Gyngell, C. (2015). The moral imperative to continue gene editing research on human embryos. Protein Cell, 6(7), 476-479. doi:10.1007/s13238-015-0184-y

[7] Ishii, T. (2017). Germ line genome editing in clinics: the approaches, objectives and global society. Brief Funct Genomics, 16(1), 46-56. doi:10.1093/bfgp/elv053

[8] Park, A. (2016). UK Approves First Studies Using New Gene Editing Technique. Time Health.

[9] Araki, M., & Ishii, T. (2014). International regulatory landscape and integration of corrective genome editing into in vitro fertilization. Reprod Biol Endocrinol, 12, 108. doi:10.1186/1477-7827-12-108

[10] Lanphier, E., Urnov, F., Haecker, S. E., Werner, M., & Smolenski, J. (2015). Don't edit the human germ line. Nature News, 519(7544), 410. doi:doi:10.1038/519410a

[11] The Hinxton Group. (2015). Statement on Genome Editing Technologies and Human Germline Genetic Modification. Retrieved from http://www.hinxtongroup.org/Hinxton2015_Statement.pdf

[12] National Academies of Sciences, E., Medicine,. (2017). Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press.

[13] Callaway, E. (2016). UK scientists gain licence to edit genes in human embryos. Nature News, 530(7588), 18. doi:doi:10.1038/nature.2016.19270

[14] Cyranoski, D., & Reardon, S. (2017). Chinese scientists genetically modify human embryos. Nature News. doi:doi:10.1038/nature.2015.17378

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What are the Ethical Concerns of Genome Editing?

# data[].attributes.attachment_link.description
Most ethical discussions about genome editing center on human germline editing because changes are passed down to future generations.