Is It Ethical to Edit an Embryo's Genes?

Controversies Today, Implications for Tomorrow

Jennifer Leavitt, MS


November 15, 2017

Warning the world about the potential perils of genetic engineering, physician-novelist Robin Cook brought us his medical thriller Mutation in 1990. At the time, his foreboding tale about the perfect designer baby–turned–evil genius seemed like pure science fiction. A quarter century later, though, gene-editing tools are being perfected in labs throughout the world, and some fear that Cook's fantasy could someday be reality.

The first step in that scenario, human germline editing, is already a reality. Germline editing refers to genetically engineering a genome in ways that are heritable—as in, editing reproductive cells or embryos. And while gene therapy for ill, consenting adults is both promising and widely accepted as safe and ethical, in part because it involves nonheritable changes in somatic cell lines, editing the genes of embryos to create genetically modified human beings has raised significant concerns.

"The utility of germline genome editing is a topic of debate within the scientific community," Derek Scholes, PhD, told Medscape. Dr Scholes is a geneticist and director of science policy at the American Society of Human Genetics. There are several conundrums that have bubbled closer to the surface, given the recent breakthroughs in germline editing. While some believe that it is unethical under any circumstances—even to cure a devastating disease—a growing number of scientists and bioethicists are proponents of the technology. They do, though, advocate stringent guidelines in an effort to avoid unforeseen health and safety consequences and a potential slippery slope that could lead to designer babies.

Among those proponents is bioethicist and Medscape contributor Arthur Caplan, PhD, who serves as director of the Division of Medical Ethics at New York University Langone Medical Center and School of Medicine in New York City. "Our job is to ask the tough questions and move science forward," he told Medscape. "There are definitely serious considerations, though," he added. "We can't get ahead of ourselves."

Recent Breakthroughs

On the basis of gene editing that has already succeeded in the lab, scientists believe that germline editing will someday prevent a host of conditions and diseases, including sickle cell anemia, beta-thalassemia, and hemophilia. In one experiment, a mutation was introduced into a protein called CCR5, an approach that could help prevent infection with HIV.

There are many questions to be answered, and a lot of work to be done, but this could be an extremely useful therapy. We don't stop it at this level.

Just a few years ago, Dr Caplan, who also authors Medscape's Business of Medicine column on medical ethics, supported a moratorium on germline editing. "It made sense and still does in terms of clinical trials," he said. "But science must move forward." Today, he believes that the research needs to continue, though he stresses that regulation and strict protocols are essential. "There are many questions to be answered, and a lot of work to be done, but this could be an extremely useful therapy. We don't stop it at this level," he told Medscape.

Since 2015, the most promising gene-editing tool, CRISPR, has been used in several studies to remove or insert disease-modifying DNA, and all with unprecedented precision and affordability. Most notably, investigators with Oregon Health & Science University, the Salk Institute for Biological Studies in California, and Korea's Institute for Basic Science reported earlier in 2017 on their success in editing the DNA of numerous embryos to eliminate a mutation associated with hypertrophic cardiomyopathy. Mosaicism, in which some cells wound up with the introduced mutations and others didn’t, has been a significant hurdle in germline editing. This group, however, eliminated this confoudner by editing simultaneously with fertilization, before cell division begins.[1]

Once fertilized, an egg divides for approximately 7 days and then evolves into a blastocyst, a ball of about 200 cells. Niakan's team discovered that OCT4 is required by human embryos for a blastocyst to form. In its absence, normal development cannot take place.[2]
Image from iStock

Not long after that news, Kathy Niakan and her colleagues at the Francis Crick Institute in London reported that they had successfully used CRISPR to analyze the OCT4 gene, which plays a critical role in embryogenesis.[2] In the future, they hope to use their research to reduce miscarriage rates and improve in vitro fertilization results.

With these advances has come a fervent resurgence of the age-old debates about the status and rights of an embryo, whether interfering with "nature" is crossing a line, and whether scientists will doom us all by playing God.

Controversy Runs Deep

The United States is unique in that the right-to-life lobby has had a significant influence on laws that govern human embryo and fetal research, from stem cells to germline editing. For those who believe that life begins at conception, the idea of creating a human embryo, only to conduct research and then destroy it, is unacceptable. "This is nothing new, of course," said Dr Caplan. Research may ebb and flow in accordance with political climate and control in the country.

"While germline genome editing could theoretically be used to prevent a child being born with a genetic disease, its potential use also raises a multitude of scientific, ethical, and policy questions. These questions cannot all be answered by scientists alone, but also need to be debated by society," —Derek T. Scholes, PhD, ASHG Director of Science Policy; ASHG press release.
Image from iStock

In Europe, the prevailing concerns have been about medical and genetic safety. A number of European nations have long prohibited germline editing, and the Council of Europe placed a ban on the technology 20 years ago.[3] But this policy, which made sense when it was implemented, is now outdated, Dr Caplan insists. The European Union remains deeply concerned about the potential repercussions for humankind should attempts to alter evolution produce unexpected medical consequences. While the United Kingdom recently broke from the EU policy and the Union seemed briefly open to some discussion, the prevailing sentiment is still one of extreme caution and reluctance to lift a moratorium. In EMBO Reports, Dr Caplan recently published his opinion that "The Council of Europe should not reaffirm the ban on germline genome editing in humans." The science has advanced to a level where it is safe to continue to research in a laboratory setting, he explained.[4] "They won't stop it," he said. "There is virtually no regulation in Asia, and in the United States, government funding is banned, but private industry can fund these studies." Ideally, Dr Caplan reflected, there would be consensus, collaboration, and regulation that would allow for optimum quality control.

Even with its contentious history, the ethical debate had remained on the sidelines until April 2015, when Sun Yat-sen University investigators reported on their use of CRISPR to edit the genomes of human embryos.[5] Although the technology still faced many hurdles, the world stopped to listen and the controversy arose anew. With the 2017 advances, the stakes were raised even higher.

Irreversible Decisions for Future Generations

Indeed, altering the DNA of human embryos may result in the eradication of inherited diseases. That's monumental. But there is significant concern over the fact that germline editing of viable embryos will affect not only one person, but all future generations as well.

At the International Summit on Human Gene Editing in 2015, the national science academies of the United States, the United Kingdom, and China convened in large part to voice concerns about making irreversible alterations to the DNA of children-to-be and their descendants. Among those concerns were the possibilities of unintentional edits and mutations, undiscovered genetic and developmental mechanisms, and longer-term health and safety consequences that have yet to be imagined.

In early 2017, the National Academies of Sciences, Engineering, and Medicine released guidance that at this time it was not recommending the clinical application of human germline editing unless a broad public consensus could be reached on both its safety and merits. They believe that significant work has yet to be done before germline editing can be used for pregnancy. Similarly, the American Society of Human Genetics has, for now, opposed germline editing in embryos destined for human implantation. Less has been said about the interim research that might be conducted before we reach that point. For this reason, the Oregon researchers consulted an ethics committee, which endorsed the use of gene correction in research so long as "significant oversight and continued dialogue" is used, and "for the purpose of answering basic science questions needed to evaluate germline gene correction prior to the use in human models."[1]

Risks and Liability

The long-term safety of these germline changes may not be known until later in life, or even a next generation, but there are more immediate safety concerns as well. "The deleterious effects of egg donation, and all of the short-term risks involved, are well known," said Dr Caplan. When women need to produce a larger number of eggs, whether for fertility treatments or donation to science, they may face all of the issues that come with hormonal stimulation and egg retrieval, including nausea, stomach pain and vomiting, weight gain, dyspnea, and even potential damage to organs near the ovaries. "Super-ovulation can cause serious problems, and longer-term risks may present even more issues," said Dr Caplan.

Many argue that it would be easier to perform preimplantation genetic diagnosis to identify embryos without a disease-causing variant than it would be to fix that disease-causing variant by editing the genome of an embryo.

"Many argue that it would be easier to perform preimplantation genetic diagnosis to identify embryos without a disease-causing variant than it would be to fix that disease-causing variant by editing the genome of an embryo," Dr Scholes told Medscape.

But as Dr Caplan points out, it may be more palatable to repair an existing embryo than to throw embryos out. Harvesting eggs is physically taxing, risky, and expensive. "Repair is a far more elegant solution," he said.

Dr Caplan pointed out that the issues go beyond medical concerns. "Before this is used in a clinical setting, we will need to figure out who is responsible. Who pays for the procedure? Who pays for the healthcare of the child if something goes wrong? There will need to be some very clear agreements in place," he said.

Designer Babies?

Although research into germline editing is still in its early days, and some scoff at the notion that parents will someday choose their children's genes Chinese-menu style, others are not so quick to dismiss the possibility. Eugenics has an ugly past and, in the wrong hands, is subject to myriad abuses.

Oxford bioethicist Julian Savulescu argues that we have a moral obligation to eugenically engineer our children.
Image from iStock

This science was first developed, in all likelihood, with a small number of couples in mind—those who, because of their shared genetics, will not be able to produce viable embryos. "One can imagine scenarios where all of the embryos harbor genetic variants that will give rise to disease, such as if both parents have two defective copies of the same gene," said Dr Scholes. "But this would be a rare circumstance, and the scientific community has not come to a consensus on other uses. ASHG believes that this needs to be explored further before germline genome editing is ever performed."

When germline editing becomes clinically applicable, will these rare couples be the only people who should be allowed access to embryo gene editing? Who will make that determination, and who will decide which traits are worthy of editing and which are not? What about high cholesterol? What about stature? Should we permit germline gene editing only for desperate cases, or are all health concerns valid? How do we draw the line between a desire and a need? Parents might someday be able to cherry-pick their children's traits—hair and eye color, intelligence, athletic skill. This science is known as eugenics, the process of creating superior human beings by weeding out undesirable traits.

"I can imagine certain enhancements that would make sense," Dr Caplan said, "such as removing a gene associated with high cholesterol."

As soon as one kind of germline editing comes into practice, though, the door will be open. Just as FDA-approved drugs are prescribed off-label, it will be difficult to distinguish between uses and monitor who is doing what and why. Once a perceived benefit exists, it may be hard for people to resist. There was a time when the general public believed that few people would ever fly through the sky in a tube of metal, but today, of course, millions of people travel on airplanes without a second thought.

Eventually, some ethicists argue, medical needs may expand until they become enhancements, and an entire lucrative eugenics market is born—one that puts the 1% at an even greater advantage, increasing the divide between those with privilege and those without. Some groups question whether eugenics will corrupt society's view of human dignity and equality.

Would It Be Unethical Not to Do This Research?

As CRISPR research moves forward around the world, legal and funding limitations could further undermine the US position as a world leader in science and technology. If the US government refuses to fund similar research, American scientists will be forced into the private sector if they want to compete. Once there, they could be beholden to corporate interests, Dr Caplan points out. At that point, the slippery slope becomes far more plausible.

"We need government cooperation and full transparency," Dr Caplan said. "We need clear data and methods, clear regulations. Children produced this way will need to be followed for many, many years—for life, not just for 6 months.

"Even if eugenic applications such as gene enhancements should remain off limits," Caplan wrote in EMBO, "it is unethical to hold hostage patients with severe genetic diseases to fears of a distant dystopian future."[4]

Arthur L. Caplan, PhD, serves on Johnson & Johnson's Panel for Compassionate Drug Use (an unpaid position). Derek Scholes, PhD, has disclosed no relevant conflicts of interest.


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