Breaking Genetic Technology Out of Regulatory Limbo
Government, unfortunately, is often susceptible to making policy on the back of a wave of emotion. Environmental disasters, national crises, and public health disasters have all produced an environment of high public emotions and led to major policy enactments. This can mean that policy is rushed, incomplete, and lacking rigorous debate.
Technology policy is especially subject to emotional lawmaking. The early days of Uber were full of quickly enacted bans. In vitro fertilization (IVF) procedures and genetic modification inspired fears that led to bans. And artificial intelligence is currently sparking panics that could lead to similar prohibitions.
Such hasty law making leads to unintended consequences that can harm Americans, especially in the case of new genetic technologies that possess life-saving potential. Congress ought to do away with the ban on these procedures in order to realize its incredible benefits.
A New Method
Last year, Dr. John Zhang, the medical director and founder of the New Hope Fertility Clinic, assisted a Jordanian couple with having a child, a baby boy. The child’s mother was a carrier for a rare genetic disease called Leigh syndrome, a disease that affects the body’s energy production and the brain.
Most of a person’s DNA is stored in the nucleus of the cell, but there is also some of our DNA that resides in our mitochondria, organelles in our cells that are mainly responsible for producing the energy that powers the cell. About 80% of Leigh syndrome cases are caused by mutations in nucleic DNA, while 20% are caused by mutations in mitochondrial DNA (mtDNA).
The mutated DNA of a Leigh syndrome sufferer interferes with the energy-producing process in the mitochondria likely leading to cell death. Organs that require a lot of energy, like the brain, are especially susceptible to widespread cell death. This leads to lesions in the brain, especially in areas that control movement and vital functions. These functions quickly deteriorate eventually killing the sufferer by the time they are two or three.
In the case of the Jordanian couple, the mother carried the mutation in her mtDNA and passed it down to her offspring. Because the egg cells contribute mitochondria to the developing embryo, the presence of the mutation in the mother’s mtDNA greatly increased the likelihood that the child would be affected. The couple had already suffered several miscarriages and lost two of their children to this horrible disease when the infants were about eight months before they asked for Dr. Zhang’s help.
Unfortunately, studies have shown that there is no reliable way of pre-selecting embryos with pre-implantation genetic diagnosis for most cases of mtDNA mutation, especially when there is a high number of mitochondria with mutated mtDNA, as was the case with this woman.
Dr. Zhang needed to take the woman’s mitochondria out of the reproductive equation altogether, thereby greatly reducing the chance that the child would suffer from a mitochondrial disorder. Citing the horrific cost in life wrought by this disorder and the chance to give a child a full and healthy life, he turned to an experimental procedure called mitochondrial replacement therapy that several groups, including his, had been working on for around two decades.
Mitochondrial replacement therapy is really an umbrella title for two procedures specifically: pronuclear transfer and metaphase II spindle transfer. After much counseling to help the mother and father understand the options, the couple chose to undergo the spindle transfer procedure based on religious objections to the destruction of unwanted embryos involved in pronuclear transfer.
To do the spindle transfer, Dr. Zhang removed the nucleus from both the mother’s egg cell and a female donor’s egg cell specifically chosen for the procedure. He then inserted the nucleus from the mother’s cell into the hollowed out cell of the donor, and then fertilized the hybrid egg cell with the father’s sperm. This formed an embryo that contained DNA from the mother and father, but also mtDNA from the donor cell. These three sets of DNA have led some to call this procedure “3 parent IVF.”
Dr. Zhang then implanted the properly formed embryo into the womb of the mother, who gave birth to a normal, healthy baby boy nine months later. The doctors continued to monitor the child and found none of the problems present in the woman’s other children. Several genetic tests confirmed that the child did not have enough mtDNA mutations to cause him to experience severe symptoms. It seems that he will indeed be able to live a full life and, since he is a male, will have no chance of passing the devastating disease on to his children.
Regulatory Landscape in the US
One of the challenges in undertaking the procedure was navigating the regulatory quagmire surrounding this novel and controversial technique. Dr. Zhang admits that “these techniques … have yet to be conducted clinically owing to regulatory constraints in countries in which reproductive techniques are subject to legal and regulatory oversight.” The United States has, in effect, completely banned procedures that genetically modify human embryos.
NIH Response
Policy conversations about the modification of genes in human embryos were sparked in earnest by the first study published in April 2015, claiming that Chinese researchers had done just that. Almost immediately after the Chinese study appeared in Protein & Cell, Francis Collins, the director of the National Institutes of Health (NIH), reiterated the agency’s refusal to fund similar research in the United States. He cited “serious” safety issues, ethical considerations, almost universal opposition from the scientific community, and a “lack of compelling” medical applications for this technology as reasons for retaining the ban.
Collins also pointed to “multiple existing legislative and regulatory prohibitions,” including the Dickey-Wicker Amendment which was included in the Health and Human Services appropriations bill passed in 1996 and signed by former President Bill Clinton. The amendment stipulates that no federal funds will be used for the “creation” of human embryos for research purposes, or for research in which embryos are “destroyed, discarded, or knowingly subjected to risk of injury or death.” The language from this amendment has been included in each subsequent appropriations package, including the current funding bill passed in May 2017[1]. Collins and the NIH held that this statute barred the agency from supporting research modifying human embryos.
National Academies Response
Only one month later, the National Academy of Sciences and the National Academy of Medicine announced a major initiative on human gene editing. The goal of the venture was to “guide decision making about controversial new research involving human gene editing.” The effort would include the best experts on the legal, scientific, and ethical issues involved in the new technologies as well as an international summit to discuss difficult questions. The announcement promised “standards, guidelines, and practices” to help foster and promote safe growth.
Congressional Response
Instead of waiting for the recommendations from the expert team assembled by the National Academies initiative, Congress panicked and included language in the omnibus appropriation bill, passed in December 2015, clearly prohibiting the Food and Drug Administration (FDA) from acknowledging “receipt of a submission for an exemption for investigational use of a drug or biological product … in research in which a human embryo is intentionally created or modified to include a heritable genetic modification.” This completely shut off any path for new gene modification technology to eventually make its way into clinical trials and thereby help suffering patients. Similar prohibitions have been included in each appropriations bill since 2015.
The move was likely motivated by fear and is an example of what scholar Adam Thierer has called a “technopanic.” Stanford Law Professor Hank Greely called the provision “ill-advised” and speculated that the Republican majority at the time was “trying to throw a (cheap) bone to some of its supporters.” Dr. Arthur Caplan, a professor of bioethics at NYU School of Medicine, agreed that fear of the relatively new and quickly developing technology likely motivated Congress. He also stated that it was irresponsible to halt something that has incredible potential to cure disease, as demonstrated by Dr. Zhang’s procedure.
Regulatory Moves in the United Kingdom
The UK’s approach to mitochondrial replacement therapy starkly contrasts with that of the US. In February 2015, before the Chinese experiments were published, Parliament voted to change British law to allow a pathway for approval of the therapy by the Human Fertilization and Embryology Authority (HFEA), the main regulator in the space. HFEA convened a panel of scientists to conduct further research into the procedure and make recommendations on the safety and ethical issues involved. After several years of debate and work, the panel advocated allowing the therapy to moving into clinical trials. HFEA decided in December 2016 to follow the recommendations and allowed clinics in the country to apply for licenses to offer the therapy.
Instead of allowing a moment of fear to preclude any future medical benefits that prospective mothers at risk of giving their children crippling genetic conditions, UK officials weighed the associated benefits and risks and allowed these new therapies to develop, with sufficient controls to ensure safe and ethical use, when it was clear that the benefits far outnumbered the risks. Additionally, both Parliament and HFEA waited on sufficient research to be completed and followed the measured advice of the experts they had asked to investigate the issues.
These actions contrast in almost every way the with rushed, over-the-top response from Congress. Not only did lawmakers push the measure through in response to a panic over the Chinese studies, but they failed to even wait for the recommendations of two expert bodies: one examining human gene modification in general, and the other specifically looking at mitochondrial replacement therapy.
Innovation Arbitrage
The actions of the British Parliament highlight an issue in technology policy that Thierer has called “innovation arbitrage.” This is the idea that innovators will move their research to jurisdictions that will welcome them rather than hinder them. Dr. Zhang demonstrated the potency of this idea when he traveled to Mexico in order to perform part of the replacement therapy, for the sole reason that regulation in Mexico was not an impediment in the way it was in the US. Similarly, Dr. Shoukhrat Mitalipov, the lead researcher of the recent experiment to genetically modify human embryos, flatly stated that because of the prohibitive regulatory landscape in the US, “There is a long road ahead … It’s unclear at this point when we would be able to move on. We would be supportive [of] moving this technology to other countries.”
While the fact that innovation arbitrage exists and influences the decisions of life science researchers does not in itself mean that American regulators ought to immediately deregulate and allow scientists to do whatever they desire, it does mean that regulators must take this phenomenon into account when issuing rules and guidance, or employing their enforcement powers against particular companies.
However, when an advanced, responsible country like the UK examines and approves a cutting-edge procedure after months of deliberation, American regulators ought to have an enormously exceptional reason for coming to a different conclusion.
Scientists like Zhang and Mitalipov will likely continue pushing the boundaries of science and ethics in their drive to improve medicine; and, true to their word, they will likely seek friendlier jurisdictions if the regulatory outlook in the US remains murky to grim. Policymakers in the United States should consider if allowing other countries like the UK to take the lead on next generation medicine is worth retaining outdated laws and regulations that do not seem to be in the public’s interest any longer.
FDA Response
The regulatory response to Dr. Zhang’s procedure came in early August 2017, several months after his study was published and more than a year after the child had actually been born[2]. The FDA posted a letter online addressed to Dr. Zhang informing him that the procedure detailed in the study is under the regulatory jurisdiction of the FDA, that it was not approved, that he did not have the proper licenses for the procedure, that he illegally exported an embryo, and that he continues to illegally market the procedure.
The letter acknowledges that Dr. Zhang requested a pre-investigational new drug meeting to explore clinical trials for his mitochondrial replacement therapy technique in April 2016, soon after the child was born. These formal meetings take place early in a product’s life, even before clinical trials. Their purpose is for the applicant to receive feedback from FDA officials on the design and rationale of the planned, human clinical trials. This advice can save time and money for the applicant in the long run by reducing waste on trials that do not provide information the agency desires.
The FDA declined Dr. Zhang’s meeting request, citing the Congressional ban on acknowledging applications that involve genetically modifying a human embryo. The agency considers the embryo created by the therapy to be genetically modified and is therefore prohibited from approving clinical trials to develop the procedure. Additionally, the FDA also considers the therapy a “drug” as defined in the Food, Drug, and Cosmetic Act, and no drug can be marketed without FDA approval.
Hence, the combination of these laws creates a regulatory limbo out of which no treatment that involves a modified human embryo, no matter how potentially beneficial, can escape.
Congressional Ban Preempts Significant Potential Benefits
Each year since the ban was enacted, it becomes more and more counter-productive. The rapid development of therapies utilizing genetically modified embryos that has taken place since the first Chinese study was published means that safe and ethical procedures to modify human embryos are not that far away. In Dr. Zhang’s case, assuming that the child continues to develop normally as the study noted was the case in the first several months, such safe procedures were successfully demonstrated. The benefits that accompany this demonstration are enormous: a child can expect to live a full life instead of dying by the age of three.
Benefits of this magnitude, literally life and death, demand exploration. Clinical trials ought to be pursued in order to bring these benefits to more patients. The clinical setting, with all of its oversight mechanisms including institutional review boards and additional FDA oversight, has demonstrated that it is equipped to handle difficult and ethically fraught procedures.
Adam Thierer and I briefly recounted the history of IVF in our essay “Will Genetic Editing Advance Faster Than Our Ability to Regulate It?” to make the point that what started as a controversial procedure quickly became safe and standard, largely due to the careful treatment of IVF in the clinical setting. Genetic modification could follow the same trajectory if clinical experiments are allowed to move forward.
Not only does history indicate that there is a path toward safe and ethical uses of gene modification technology, but also Thierer and I also recently pointed out that a majority of the public is open to the therapeutic uses of this technology. The original fear that motivated Congress to enact the ban has been replaced by better knowledge of these procedures and a realization of the enormous benefits they could bring.
Policy Response
In order for American patients to realize the potentially life-saving benefits offered by gene modification technology, Congress must allow the FDA to review applications involving the procedures. This year’s appropriations round, due at the end of this month, gives government the immediate opportunity to change or drop the language that prohibits the FDA from moving these procedures forward. This step would significantly advance these new technologies and provide a path for them to be developed safely.
Conclusion
Historically, policy surrounding cutting-edge, life-science advancements has been dominated by fear and hasty decision making. This has stalled a field that could, given the right balance between oversight and freedom to innovate, break the cycle of genetic disease and allow parents who desperately want biological children to raise them without wondering whether they will live to see adulthood.
Such promises also come with serious issues of safety and ethics. But history also shows us that humans are surprisingly good at solving those difficult issues and moving forward, especially when we acknowledge that those issues do indeed exist. This what Joel Garreau has called “muddling through” in his book on the future of technology and our response to it.
We have structures that are equipped to deal with incredibly difficult issues. They can guide these new technologies to benefit humanity and to reduce harms. Allowing those mechanisms to operate will open the door to best-case scenarios while still providing the oversight that has protected patients in the past.
In light of the potential benefits, trusting these institutions and taking a calculated risk constitute far better policy than allowing fear to dominate the discussion and slam the door.
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Additional Reading:
“Will Genetic Editing Advance Faster Than Our Ability to Regulate It?”
“Ignoring the Future Won’t Forestall It”
“Might We Avoid a CRISPR Technopanic Altogether?”
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End notes
[1] In subsequent legal action, the US Court of Appeals in the District of Columbia Circuit clarified that the Dickey-Wicker Amendment does not ban all research on human embryos (in this case it was embryonic stem cells). Instead, the court accepted the narrow definition of “research” that the NIH had endorsed: “research” refers to the “discrete project” that was separate from the original act that involved destroying the embryos. It seems that this could be applied in the opposite direction: that “research” could also be separate from the act of creating a human embryo.
[2] The study was published on April 3, 2017. The child who was conceived and born using the procedure was born sometime in April 2016.
