Dangers of an Unscientific Policy Process: Why the UK’s legalization of “three-person babies” should not be the model for CRISPR

Dangers of an Unscientific Policy Process: Why the UK’s legalization of “three-person babies” should not be the model for CRISPR.

Several researchers around the world have now turned the CRISPR genome editing craze towards human embryos, reigniting questions around the feasibility, legality, and morality of creating genetically modified humans. Some have suggested that we look for guidance to the United Kingdom’s policy process for “mitochondrial replacement,” also known as “three-person IVF,” which culminated in the world’s first legalization of a procedure that is technically a form of heritable human genetic modification in 2015.

How did the UK come to enable techniques that arguably contradict a policy in force throughout Europe for more than 15 years?

Having followed the process for several years, I would argue that we can learn a great deal from its history, but more specifically in what not to do moving forward in the CRISPR policy debate. In this blog, I will try to explain why.

I am a UK citizen who generally respects Britain’s regulatory models. However, I believe this process failed to live up to its self-image of openness and transparency. The experience taught me that science and technology hold such ingrained cultural and economic capital that people often hear any concern raised – even when it comes from other scientists – as “anti-science” or “anti-technology.” Moreover, it taught me that simple stories can become so compelling and satisfying that they do not bend, even in the presence of critical new information.

In this case, a consequential law was altered on the basis of a group of scientific methods whose human health and safety consequences have not been vetted, and could end up harming those they were designed to help. For those of us paying attention, this was not a great surprise. There were readily apparent data suggesting this outcome all the way through. The question is, why was this not enough to have shifted the policy process when it mattered? And how can we protect the children now being created around the world by researchers recklessly racing to beat the UK at its own game?

First, some breaking news

On September 27, a US team of fertility doctors told New Scientist they had produced a child at a clinic in Mexico whose starting cells were engineered using what they described as “spindle nuclear transfer”, otherwise known as the maternal spindle transfer (MST) mitochondrial manipulation technique. The team was led by Dr. John Zhang (based in New York City; working in Mexico because “there are no rules there”) who performed the procedure for a Jordanian couple at risk of transmitting Leigh syndrome.

Two weeks later on October 10, New Scientist broke a second set of claims from Valery Zukin, a fertility doctor working in Kiev, Ukraine. Zukin claimed he had used the pronuclear transfer (PNT) technique and implanted the resulting embryos in two women currently pregnant in their third trimesters.  Unlike the Zhang team, Zukin claimed he was using mitochondrial manipulation techniques to address “embryo arrest,” a general infertility issue not directly related to mitochondrial DNA mutations.

On October 19,  Nature News reported on further commentary from Zhang and Zukin at recent fertility conferences, and also broke the news that a scientific journal was considering whether to publish a paper documenting the use of mitochondrial manipulation techniques to produce a live birth in China. The same day, Zhang published a brief report in Fertility and Sterility.

These developments are arguably not unpredictable in the wake of the reckless hype and minimization of the techniques’ unknowns that occurred in the UK.

Second, some background on UK law

According to the UNESCO International Bioethics Committee who considered these issues in its follow-up to the UN’s Universal Declaration on the Human Genome and Human Rights, and the Council of Europe’s Convention on Human Rights and Biomedicine (the “Oviedo Convention”), human germline modification is considered medically unnecessary human experimentation that is contrary to human dignity. UNESCO recommends a moratorium on human germline engineering, and 29 nations have ratified the legally binding Oviedo Convention prohibiting the same.

The United Kingdom, like every country that has considered regulation on the matter, has a legal prohibition against making genetic modifications to human sperm, eggs, or embryos because such changes alter the human germline and thus every human born thereafter (as opposed to somatic gene therapies, which only affect a single consenting individual.)

However, a group of researchers at Newcastle University working on somatic cell nuclear transfer (i.e. cloning to create embryonic stem cells for therapies) thought that they might be able to use the same mechanism for a more immediate human application. There are a small number of women – in the range of 1 in 5,000–10,000 – who have what is called mitochondrial disease. This covers a number of issues that impact the functioning of the mitochondria, leading to wildly divergent conditions and outcomes. In about 15% of these cases, the problem is caused by the mitochondrial genome (which has 37 genes of its own and makes up a small fraction of the estimated 20,000 genes present in every cell of our bodies.)

Mitochondrial DNA is passed on solely through the maternal line, so if a large proportion of a woman’s mitochondrial DNA carries mutations, she may be at risk of passing them on to her children. Researchers at Newcastle (as well as several others around the world) came up with the hypothesis that in these cases, women who wanted to have genetically related children, but avoid this risk of mitochondrial disease transmission, could use nuclear transfer.

How do the techniques work?

A specialist would remove eggs from the intending mother’s body, and obtain eggs from another healthy woman, then combine them to use the nucleus from the first with the mitochondria and cytoplasm from the second. At some point sperm would be directly injected. Any resulting child would thus end up with DNA from three people (leading to this technique being referred to as “three-person IVF” or to the creation of “three-person embryos”). Scientists have tended to prefer the terms “mitochondrial replacement” or “nuclear genome transfer.”

Does this sound complicated? It is. Technically, legally, socially, and morally. But complicated doesn’t get laws changed. And, given that these techniques result in a genetically modified embryo, which is illegal in the UK, these scientists had to lobby for a change in the law in order to continue their work clinically. So they did lobby, for numerous years. And, in February 2015, they succeeded in carving out an exception to the law for this specific purpose.

It now turns out that their “pronuclear transfer” technique doesn’t work as expected. Mutated mitochondria can still carry over, and can lead to a host of problems. No child has yet been born using the PNT technique, but Valery Zukin claims two such children are expected in Ukraine in early 2017 (see breaking news above). The same cannot be said for the similarly under-researched MST technique which was reportedly used by John Zhang (using the term “spindle nuclear transfer”) to bring the child born on April 6, 2016 into existence. Even as these cases were being reported, researchers were searching for new variations that might avoid the numerous safety concerns surfacing in animal model research using these two techniques.

What kinds of problems emerged before the UK decision, and who knew about them?

The Human Fertilisation and Embryology Authority (HFEA) is the UK’s regulatory body for UK fertility clinics and for research involving human embryos. It led the charge to change UK law in order to enable embryo engineering licenses. Its process for assessing “mitochondrial replacement” included three separate reviews of the scientific methods over four years, and one public consultation to gauge public sentiment. Were members of the HFEA aware of any concerns?

The short answer is yes. A number of civil society groups, including the Center for Genetics and Society, raised concerns with them on numerous occasions, as did many scientists and researchers.

For example, in March 2014, David Keefe, The Stanley H. Kaplan Professor and Chair of the Department of Obstetrics and Gynecology at NYU Langone Medical Center, wrote to the HFEA to inform them of his concerns. He told them that his own lab, which was the first to report using mitochondrial manipulation techniques in mammals, had determined it to be unsafe for use in humans. He wrote:

Our own group moved away from this research because PGD [preimplantation genetic diagnosis] provides a relatively safe alternative to MR [mitochondrial replacement] for the majority of patients, and because vexing concerns linger about the safety of MR, including the safety of reagents employed during MR, carryover of mutant mtDNA during MR and disruption of interactions between mtDNA and nuclear DNA (nDNA).

For more information on the kinds of concerns raised by scientists around the world, see this compilation from the Center for Genetics and Society.

The HFEA’s own scientific reports also turned up some issues. For example, the first scientific review determined primate testing to be a necessary pre-requisite to human testing. A subsequent review found that a group of US researchers had tried PNT technique in primates and that it didn’t work. Instead of heeding this red flag, the HFEA simply dropped the primate requirement altogether.

Moreover, the HFEA defined their public consultation as highlighting “broad support” for the techniques in question. However, independent analysis of the consultation found that the majority of people who responded to the only open segment were actually against the law being changed at that time for a range of scientific and ethical concerns. That did not stop the HFEA from claiming the opposite, or from pushing forward.

So, how was the law changed?

The problems with the UK policy process seem to stem from a number of factors. For one thing, it apparently involved a commitment to the story that had taken hold, to a pre-determined end goal. While that goal surely began with the desire to help women with a rare disease, it seemed to become primarily a question of changing the pre-existing law. Everything was done in order to see that law changed. The time, money, and resources spent throughout multiple sectors of society were enormous.

As a particularly telling case in point, there was the sustained effort to control the language used in the public debate. The common term “mitochondrial replacement” is itself a euphemism because it is not the mitochondria, but the nucleus containing more than 20,000 genes, that is transferred. One scientist commented early on that such “scientifically inaccurate descriptions have been instrumental in easing the way to public acceptance of these manipulations.”

Perhaps even more brazenly, the Government’s Department of Health later came out with the position that the technique did not constitute “genetic modification”. This led to other scientists straight-out accusing the Government of dishonesty in its efforts to gain support for these techniques.

An additional factor enabling this process was a mistaken cultural assumption held by some policymakers, that helped them to hear all objections as “theoretical religious concerns.” This allowed them to diminish the myriad technical, social, and ethical concerns being voiced. One evolutionary biologist at an evidence hearing held by the UK Parliament’s Science and Technology Committee in October 2014 tried to raise his concerns about the techniques’ safety and efficacy at the meeting. He tweeted afterwards:

Thought on @CommonsSTC meeting: what's the point of funding, performing, publishing and requesting scientific evidence if it's then ignored?
— Ted Morrow (@ted_morrow) October 22, 2014

I described my own frustrations about this meeting in a blog at the time here.

A third factor that enabled the law to be changed seems to have stemmed from pride in seeing the UK as an innovation hub in the biomedical sciences, and in embryology in particular. At the evidence hearing, for example, Conservative MP Jane Ellison stated that she is “extremely proud” that Britain is a “pathfinder” and “innovator” with a “well-respected regulatory regime.” Similar sentiments were frequently voiced as part of the argument for proceeding.

What can we learn from this?

In the end, public trust has been compromised and patient’s hopes were repeatedly raised and then dashed, and now are being stoked again with the recent birth announcements – despite a startling lack of safety evidence about the health consequences for the resulting children. In my mind, this is exactly the kind of thing that threatens one’s position as a “respected” “pathfinder.”

But this turn of events was not necessary, and we can learn from the experience.

Because policy tends to move so much slower than technological innovation, it can be tempting to push for policy changes before important specifics are determined or tested. But the goal in creating policy around consequential science and technology must be to make it as responsive to changes in the data (both technical and social) as possible. If a new drug for Zika shows promise, its approval should be sped up; if it turns out that an alternative method for preventing transmission of disease is preferable, then that alternative should be pursued instead. When the technology is particularly risky or ethically problematic, its use should be especially carefully considered, and any potential alternatives taken very seriously.

We must continuously work to make sure we are driven by real, human needs. The push for technology for its own sake (or for the general sake of research or innovation) can be powerful, but it must not be the primary driver of public policy.

In this case, commitment to a thorough and adaptive learning process would have spotted failures and inefficiencies of the mitochondrial manipulation techniques much earlier on, and probably pivoted resources towards improved preimplantation genetic diagnosis as the safer and more efficacious method to prevent the transmission of mitochondrial disease. This kind of continuous learning may seem like more work up front, but it will save money, time, and maybe even lives in the long run.

The way we tell stories matters. The world’s first legalization of a form of heritable human genetic modification will always be a precedent. And how that history is recorded could have profound implications for how the future unfolds. The global consequences of the UK’s breach of a scientific and ethical global consensus are only beginning to be felt.

What should we do about CRISPR?

As the world scrambles to determine how best to govern human applications of genome editing, people are seeking instructive precedents. Many are looking to the UK’s “mitochondrial replacement” policy process as a prime model.

In a Cell report titled, “Going Germline: Mitochondrial Replacement as a Guide to Genome Editing,” Eli Y. Adashi and I. Glenn Cohen, professors of Brown Medical School and Harvard Law School respectively, provide just one example. They write:

Both [techniques] must contend with breaching the germline barrier. Both entail the manipulation of a human embryo. Both must address significant safety concerns. Both must engage a skeptical public… Applying the principles relied upon in the regulatory evaluation of [mitochondrial replacement] will go a long way toward assuring that the prospect of therapeutic genome editing in the human is the subject of a thorough, inclusive, ethical, safety-minded, and confidence-inspiring process.

Compared to the US context of piecemeal efforts by the FDA, but no explicit regulatory body for fertility clinics and embryo research, the existence in the UK of the HFEA and public consultations represent important improvements. But this process was far from exemplary. The creation of policy for the most consequential emerging technologies would benefit enormously from a commitment to scientific rigor, openness to a diversity of views, and adaptability.

Although the UK’s process for legalizing “mitochondrial replacement” may seem robust on its surface, the reality was that all dissenting views and unfavorable scientific results were sidelined, if not ignored. A façade of “rigor” that enables those in power to cherry-pick data and orchestrate public opinion may in fact be the most dangerous option of all. This is particularly true when the hype engineered to support legislative change is exported by forum-shopping doctors who seek to work in countries where “there are no rules”. When it comes to crafting policies for CRISPR germline genome editing, we must do better to put first the health, safety, and ethical treatment of women and children. We will need greater transparency and respect for inclusive debate to guide us towards responsible innovation in the life sciences.

Previously on Biopolitical Times:

• The Case Against Public Investment in Reproductive Genetic Modification
• UK Researchers Now Say Three-Person Embryo Technique Doesn't Work; Propose New Method
• Eight Misconceptions about “Three-Parent Babies”
• With World Watching, UK Allows Experiments to Genetically Alter Babies
• Key Questions About the Social and Ethical Implications of Nuclear Genome Transfer or “3-Person IVF” Techniques

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