3-Person IVF: Putting the First Legal Genetic Modification of Babies in Context

Jerry Lai / Flickr

By: Jessica Cussins

The UK has a prohibition on the genetic engineering of embryos for the purpose of reproduction. But in February 2015, the prohibition was altered to allow one exception: so-called mitochondrial replacement, or 3-person IVF. This was the world’s first legalization of human germline genetic engineering. In March 2017, Newcastle University was awarded a license to begin offering this technique clinically.

This blog will look back at some of the history that led to this point, discuss global policy developments, and provide a rough framework for thinking about the ethical considerations.

What? Who? Why?

We first started hearing about these techniques back in 2012. At the time, a small number of scientists in New York and Oregon in the US, and in Newcastle in the UK, started putting out papers describing their efforts. Looking back, it’s safe to say that nobody knew what to make of it. Some of the papers acknowledged that this was the same technique used for somatic cell nuclear transfer, otherwise known as cloning. Some acknowledged that it would create permanent changes to the genome of any resulting children as well as their descendants. People weren’t sure whether to categorize it with IVF or with cloning, or whether it should be treated like other forms of germline modification that would permanently alter the human gene pool.

The Center for Genetics and Society (CGS) was one of the few organizations that started reporting at this early stage that 3-person IVF did, in fact, constitute inheritable human genetic modification, and that it was not just a minimal, additional technique added onto the IVF process. Rather, it was a biologically unprecedented intervention, and part of a much larger conversation about the extent of experimentation and control ethically acceptable to exert on a future person. CGS helped position 3-person IVF on the international policy landscape and suggested that many of the dominant frames being used to discuss it were misleading.

Misconceptions and Metaphors

There were many common misconceptions that started circulating in 2013. These included the following notions:

  • That this would “save lives”
  • That it would “eliminate disease”
  • That it was the only option available to women who wanted a healthy child
  • That it would help large numbers of people
  • That the techniques were proven to work in animals
  • That there was broad public support
  • That the biological contribution of the mitochondrial DNA was inconsequential
  • That the slippery slope concerns about it were overstated

In fact, none of these things turned out to be true.

Only a small percentage of women with mitochondrial disorders are candidates for the use of this technique, since in 85% of mitochondrial disease, nuclear DNA as well as mitochondrial DNA is involved. In addition, studies show it can actually be pretty dangerous for women affected by mitochondrial DNA conditions to carry a pregnancy. Moreover, advances in the genetic sequencing of embryos were already showing promise for the prevention of mitochondrial diseases in a significantly safer way. Despite the repeated notion that we should “introduce this life-saving treatment as soon as we can,” the medical rationale for 3-person IVF was always pretty flimsy.

Another misleading aspect of 3-person IVF was the way scientists framed the technique using the common metaphor that mitochondrial replacement was like changing a battery in a flashlight. It’s true that mitochondria are typically understood as the source providing a cell’s energy. But this metaphor far oversimplifies the process, creating the illusion that alterations created through 3-person IVF wouldn’t change anything meaningful about an organism.

Research has found that mitochondria actually play a key role in determining many of our traits. This led to a September 2014 editorial in New Scientist in which the editors admitted that 3-person IVF was much more challenging ethically than they had previously realized because a resulting child would genuinely inherit traits from three people.

What is happening in the UK?

The UK is the only country to date that has an explicit legal exception to allow 3-person IVF. The policy process that led to this decision was fascinating, and did have a number of commendable aspects. Unlike the US, which has little explicit regulation of the fertility industry, the UK has a regulatory agency that deals with assisted reproductive technologies, called the Human Fertilisation and Embryology Authority, or HFEA. The HFEA led multiple scientific reviews of 3-person IVF techniques, and also conducted a public consultation. On the surface, these reviews represented a measured, thoughtful approach. Many people have even congratulated the UK for its “well-respected regulatory regime.”

However, as I dug deeper into the reports and meetings, I found that there were actually many warning signs along the way that were simply ignored. Scientists from around the world who worked on similar techniques wrote to the HFEA on multiple occasions to explain why they thought these methods were too dangerous to ever be ethical. Additionally, the HFEA originally required the Newcastle researchers to try out their method in macaques to prove that it might work in humans. Buried deep within one of their science reviews, researchers explained that these experiments did not work. Yet, instead of shifting gears and trying to figure out why, the HFEA just dropped the requirement for a primate model.

Finally, the HFEA claimed to have found broad public support in its public consultations, and this was widely reported. But in fact the majority of respondents said that they did not support the techniques in the only portion of the consultation that was open to the public. An independent poll also found that the majority of UK women opposed legalization. However, in many of the meetings, this public dissent was overlooked and dismissed by scientists and Members of Parliament as being either “religious” or “theoretical.” I would suggest that it was actually something close to blind faith in technological progress that was enabling this work to move forward all along.

I wasn’t the only one who noticed this. Scientist Ted Morrow, who was at one of the scientific meetings led by the UK Parliament’s Science and Technology Committee in October 2014, tweeted after the fact asking, “[W]hat’s the point of funding, performing, publishing and requesting scientific evidence if it’s then ignored?” Nonetheless, in February 2015, the UK did write into law an exception to its prohibition on human germline modification to enable 3-person IVF for the purpose of preventing the reproductive transmission of mitochondrial disease.

Amazingly, the Newcastle researchers who pushed for this policy shift did not publish their scientific paper until more than a year after the law was changed. And what they reported was that their technique did not work. Instead, they said they were trying a new version called early Pronuclear Transfer, or ePNT. The Newcastle researchers said ePNT might reduce the risk of transmission, but still could not guarantee it. Nonetheless, just last week, the HFEA granted a license to Newcastle to start using the technique on qualifying women. Of course, this comes after reports of births have already come from other countries that do not have explicit regulations on the matter.

These stories from the UK policy process are important to remember because this will always be the first example of legalization of genetic engineering of human embryos for the purpose of reproduction. It will be looked to as a model for how to enable additional experiments. But, in my opinion, the willingness to listen and adapt was in appearance only. As we face policy challenges for more kinds of human genetic engineering, we should recognize that in this case, finding out the technique did not work as intended and finding out that many people opposed it were not enough to even slow it down.

What about the US?

In the US, the policy framework has looked quite different. In early 2014, the FDA held a public meeting to discuss the scientific and technological issues related to 3-person IVF. What was most striking about the meeting was how many unknowns were raised. Not one member of the public spoke in favor of the techniques. A woman who herself had mitochondrial disease spoke about her wish for attention to people who actually have these diseases instead of encouraging them to have children they may struggle to care for. The Chair of the Committee concluded the meeting by saying that the many concerns discussed involved both preclinical data and the basic science, and that more animal studies of larger sample sizes would be critical before moving forward. He also acknowledged that many of the concerns were not about safety and efficacy, but about ethics, and that it was not within the purview of the FDA to address these issues.

Following this realization, the FDA requested the Institute of Medicine to conduct a series of subsequent meetings to consider the ethical and social policy issues raised by what they termed “genetic modification of eggs and zygotes to prevent transmission of mitochondrial disease.” They came up with some different notions from the UK, including a recommendation that only boys should be born. This is an attempt to prevent intergenerational risk, since mitochondria are passed along the maternal line. Clinical use of these techniques is not currently moving ahead in the US, partly due to a rider in a Congressional spending bill that prohibits federal funding of genetic engineering of embryos.

Is it Ethical?

There are profound ethical considerations at stake as we consider the prospect of human genetic engineering for reproduction. Here are six “buckets” one might think about:

  1. Limits of human experimentation: What is an acceptable level of risk given that this isn’t about saving a life, but creating one? What protections will be available for harm caused to resulting children?
  2. Exploitation of women: Many women will need to provide their eggs in order to enable these procedures. Additionally, women who may be sick themselves will need to carry these pregnancies. How much potential harm should be normalized in the quest for biologically related children?
  3. Informed consent: The actual person affected will not be able to provide consent. But even assuming that parents are entitled to make this decision on behalf of their future child, how can they be properly “informed” about experimental techniques that involve trans-generational impacts and under-studied biological components?
  4. Human autonomy vs. control over others: What are the limits on control exerted over another person’s body? Is the germline a kind of human commons? Who decides?
  5. Identity concerns: Will people think of themselves differently for having three genetic parents? In the UK, it was determined that children born from 3-person IVF are not allowed to know the identity of their “donor” — is that OK?
  6. Discrimination and equality: Whose values decide what is an acceptable life to bring into this world? Will this result in less care for people that don’t fit that mold today? Will it lead to greater inequality between those with means to access these technologies and those without?

These concerns are not the sort that can be easily overcome, but they nonetheless require a swift response. 3-person IVF is already being applied to non-disease purposes, as we have seen in Mexico and Ukraine where it was used for infertility. Some researchers have also suggested it could improve athleticism, longevity, or intelligence in future offspring.

The prevalence of misinformation throughout the discussion of 3-person IVF has led most people to treat it as less consequential both technically and ethically than CRISPR gene editing for reproduction. But evidence from the past five years suggests this reassurance isn’t entirely warranted. And now that the UK allows a technique that alters 37 genes in a resulting person, what rationale could possibly prevent future techniques that only seek to alter a single gene?