A Scientific Policy Process Gone Wrong: The Need for Agile Thinking

Should we use the UK policy process around legalizing mitochondrial replacement as a model for future human genetic modification policies? I think we can do better.

The scientific process, at its best, tends to be an agile one. A scientist starts off with a hypothesis or a question, designs an experiment to test exactly that thing, learns from the process, makes modifications, and tries again. However, knowledge for knowledge’s sake is increasingly a luxury in the scientific world. National funding can be hard to come by, and competition encourages researchers to put the answer in the question: to declare the solving of a problem, often before we know whether such an application is possible or desirable.

For three years, I followed the UK policy process around a particularly consequential new technology. What I learned from this experience is that science and technology (S&T) hold enormous cultural value; that people find compelling the story of a designated problem having a distinct solution. It is sexy, and it is satisfying. Unfortunately, policymaking has a rigidity that is not well-aligned with quickly changing S&T. And in this case, a consequential law was altered on the basis of science that has not come to bear, and could end up harming those it was designed to help.

The United Kingdom, like every country that has considered regulation on the matter, has a 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.) According to the UN’s Universal Declaration on the Human Genome and Human Rights, as well as the Council of Europe’s Convention on Human Rights and Biomedicine, human germline modification is considered unnecessary human experimentation that is contrary to human dignity.

However, a group of researchers at Newcastle University working on somatic cell nuclear transfer (i.e. therapeutic cloning to create embryonic stem cells) 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 conditions ranging from mild to severe. In a small proportion of these cases, the problem is caused solely by the mitochondrial genome (which has 37 genes of its own and makes up a small fraction of the DNA present in every cell of our bodies.)

Mitochondrial DNA is passed on solely through the maternal line, so if a woman has a large degree of mutations in her mitochondrial DNA, 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 women who wanted to have genetically related children, but avoid this risk of mitochondrial disease transmission, could use nuclear transfer. 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. Any resulting child would thus end up with DNA from three parents (leading to this technique being referred to as “three-person IVF” and to the creation of “three-person embryos.”) Scientists have tended to prefer the names “mitochondrial replacement” or “nuclear genome transfer.”

Does this sound complicated? It is. 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. So they did lobby, very intensely, for numerous years. As it turned out, there was some stretching of the truth and deceptive labeling involved. And, in February 2015, they succeeded in carving out an exception to the law for this specific purpose.

The only problem is, it now turns out that their technique doesn’t work. Mutated mitochondria can still carry over, and can lead to a host of problems. Thankfully, no child has yet been born.

Did the researchers and policymakers know this before the law was changed? It’s possible they did (other researchers certainly did.) If it was just about doing the best S&T, surely the researchers would have moved on, and iterated new and better means to try to solve the problem. But a policy process had been set in motion, a particularly pre-destined, non-agile policy process.

The Human Fetilisation and Embryology Authority (HFEA) is the UK’s regulatory body for UK fertility clinics and for research involving human embryos. It led the charge in enabling UK law to change in order to provide this technique. It’s process for “mitochondrial replacement” included three separate reviews of the scientific methods over four years, and one public consultation to gauge public sentiment. I’ll spare you the gory details, but each and every one on these documents did turn up concerns. For example, the first scientific methods 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 the 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.

The downfalls of this process seem to have stemmed from a commitment to a pre-determined end-goal, from sticking to a locked-in plan. While that goal surely began with helping women with a rare disease, it became about changing a law. Everything was done in order to see that law changed. The time, money, and resources spent throughout multiple sectors of society were enormous. And in the end, it is possible that not a single person will end up being helped. Cultural assumptions led many policymakers to hear all objections as theoretical religious concerns, and seemed to ignore the simultaneous scientific and efficacy concerns also being voiced. In the end, public trust has been compromised and patient’s hopes have been dashed. But this was not necessary.

Because policy tends to move so much slower than technological innovation, it can be tempting to push for policy changes before exact applications are determined or tested. But the goal in creating policy around consequential science and technology should be to make it as responsive to changes in the data 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. In this case, commitment to an agile learning process would have spotted failures of mitochondrial replacement 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 and adaptation 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 inheritable human genetic modification will always be a precedent; it will always be a part of history. And how that history is recorded could have profound implications for how the future unfolds. The global consequences for the UK’s breach of a scientific and ethical global consensus are only beginning to be felt.

As the world scrambles to determine how best to govern human applications of breakthrough of the year gene-editing technique CRISPR, people are seeking instructive precedents. A lot of people 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, renowned Professors of Brown Medical School and Harvard Law School respectively, provide just one of the recent arguments for why the debate over mitochondrial replacement should inform that of gene editing. They write, “Both 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, where we have no regulatory body for fertility clinics and embryo research, the mere existence of the HFEA and public consultations represent important improvements. But this process was not exemplary. Scientific and public concerns were routinely ignored. I believe we can, and must, do better. The creation of policy for the most consequential emerging technologies would benefit enormously from a commitment to ongoing learning and adaptation.

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