Genome Editing 2020: Ethics and Human Rights in Germline Editing in Humans and Gene Drives in Mosquitoes

HUMAN GENOMIC GERMLINE EDITING

In the immediate aftermath of the Second International Summit on Human Genome Editing in Hong Kong (November 2018) I asked, rhetorically,

How is it consistent with either science or ethics to permit a conference on human genome editing to be hijacked by a rogue researcher who is unwilling (or unable) to present evidence that his experiment has actually been done, and to make his data available to scientists and the public? ¹

More than a year later, researcher He Jiankui (referred to in this article by the initials he uses to identify himself, “JK”) was convicted of “illegal medical practice,” sentenced to three years in jail, and fined $450,000. ² It is still a bit unclear exactly what crime JK has been convicted of, but it seems to involve three acts: fraud in falsification of ethics committee reviews, violation of law against embryo editing, and practicing medicine without a license (JK is a biophysicist and not licensed to practice medicine). ³ JK has yet to publish his research in any journal, let alone in a peer-reviewed journal, although the biophysicist did submit a paper that was rejected by both Nature and JAMA. ⁴ More significantly, copies of JK's manuscript were provided to the Associated Press (“AP”) (and by the AP to other scientists, including Kiran Musunuru) and his publicity team welcomed photographers into his lab. ⁵ All of this took place at least a week before the Hong Kong meeting, making it evident that JK was planning to use the meeting as a publicity vehicle to gain notoriety as the first person to genetically modify a human embryo and use it to produce a live birth (twin girls), not to make a scientific presentation of his work. ⁶

JK's wish for massive media coverage came true, but rather than being toasted as a pioneering scientist, JK has been consistently described as a “rogue” who engaged in wildly premature experimentation outside the norms of scientific and ethical standards. ⁷ At the meeting, JK announced not just the birth of twin girls, but also an additional pregnancy (the third baby has since been born). ⁸ JK almost immediately disappeared from public view, and it has been reported that his lab and data were seized by Chinese authorities shortly after the Hong Kong meeting. ⁹ Nor has anyone not involved in his criminal trial reported actually seeing either the twin girls, known as Lulu and Nana, or the third child, all of whom JK contends had their genomes edited, and have been described as “CRISPR babies.” ¹⁰ It may seem overly harsh, but I believe that The National Academy of Sciences (“the Academy”), the major sponsor of the meeting, was recklessly complicit in stoking the flames of publicity at the expense of science and ethics. I reach this conclusion at least in part because the organization is not innocent in providing a forum for less-than-serious scientists to exaggerate their work for fame. In 2001, in the middle of the great human cloning debate, the Academy invited three extremely fringy scientists to describe their cloning techniques at the Academy's headquarters in Washington, D.C. ¹¹ Perhaps needless to say, none of them were actually engaged in cloning humans (at best, they all cloned multiple press conferences), and had little to contribute to either the scientific or ethical debate over human cloning. ¹² Instead, their value was mostly entertainment. This was also true of JK, about whom I also wrote at the time: “Giving He [JK] a legitimate scientific forum was the equivalent of giving a clown the opening performance of a classical music orchestra.” ¹³ At the least, sponsoring JK's presentation was their second strike.

THE JK EXPERIMENT

In 2017, the National Academy of Sciences (“NAS”) issued their report on Human Genome Editing: Science, Ethics and Governance. It made a strong clinical moratorium recommendation that no clinical trials using heritable genome editing should be permitted until there was a robust and effective regulatory framework that encompasses:

the absence of reasonable alternatives;

restriction to preventing a serious disease or condition;

the availability of credible preclinical and/or clinical data on the risks and potential health benefits of the procedures;

ongoing, rigorous oversight during clinical trial of the effects of the procedure on the health and safety of the research participants;

comprehensive plans for long-term, multigenerational follow-up that still respect personal autonomy;

maximum transparency consistent with patient privacy;

continued reassessment of both health and societal benefits and risks, with broad ongoing participation and input by the public; and

reliable oversight mechanisms to prevent extension to uses other than preventing a serious disease or condition. ¹⁴

There was no transparency or oversight, no continuous reassessment, no long-term follow-up plan, and no restriction to serious diseases that could not be prevented with reasonable alternatives in JK's experiment. ¹⁵ Most of these provisions are either not mentioned at all in the JK consent form, or mentioned in an incomplete or misleading way. ¹⁶ Remarkably, the NAS committee makes no direct requirement for the informed consent of the couple involved in the experiment, nor did it address the inherent inadequacy of a germline genomic research project modeling its consent process on assisted reproduction forms. ¹⁷ Nevertheless, that is no excuse for the failure of the consent process or form used by JK. I also think it is striking that the NAS did not require the leader of any “clinical trial” to be a physician. Doing so would at least require the oversight of someone professionally familiar with health and safety issues in the doctor-patient relationship, and with a clear fiduciary duty to “do no harm” to the couple and their future child or children. ¹⁸ The experiment did underline, however, a major new “dual use” problem: all anyone capable of applying gene editing to an embryo needs to produce a child is a cooperative IVF clinic. ¹⁹ This will make CRISPR-editing embryos virtually impossible to regulate.

Informed consent is a necessary, but not sufficient, condition for ethical and lawful experimentation. ²⁰ Better referred to as informed choice, it is (or should be) more than a form. Nonetheless, reading the consent form for a research project can be extremely telling. It certainly is in JK's case. The consent form is, I think, at best radically misleading, and at worst no consent form at all, but rather a combination waiver of liability and a nondisclosure agreement. The following are some major problems with the form. ²¹

The title of the document, which should identify the research project, is simply captioned: “Informed Consent.” ²² The first paragraph of the form reads, “[t]he research team is launching an AIDS vaccine development project … [and] the research team would like to invite you to participate.” ²³ At the end of the form, on the signature page, the project is given two slightly different titles: “AIDS Development Research Project” and “HIV Development Research Project.” ²⁴ Later, under “possible benefits” the form reads: “[t]his research project will likely help you produce HIV-resistant infants.” ²⁵ This is at best extraordinarily misleading, as the experiment is meant to test CRISPR/Cas9 modification of a human embryo and use it to initiate a pregnancy for the first time ever. ²⁶

Article 1 of the form does make an attempt to move from HIV research to assisted reproduction research, but still remains extremely misleading. It does roughly describe the experiment, but it is inherently confusing by stressing that it is “based on the human assisted reproductive technology” without disclosing that the CRISPR/Cas9 gene editing technique has never before been used in humans to produce a pregnancy. ²⁷ The form often cross-references “the contract between you and the medical institution” as a separate agreement without making it clear that the research project itself (genetically modifying the embryos by editing the embryos so that the CCR5 gene will be able to “prevent the newborn” from developing HIV) is entirely under the control of non-physicians, while procurement of the ova and using genetically modified embryos to initiate a pregnancy will be overseen by a physician who is not affiliated with the research. ²⁸ This is important because “in case of any disputes over rights and obligations during the project period between you and the medical institution, the contract signed shall prevail, and the project is not responsible for this.” ²⁹ In fact, the main theme of Article 3 of the form (possible risks and precautions) is that the research team “is not responsible” if anything goes wrong. ³⁰ All such waiver of liability clauses are simply impermissible in legitimate human research protocols. The form goes even further, purporting to grant the research team additional rights and removing basic rights from the research subjects. ³¹

One example is Subpart Seven, a provision I have never seen before. It grants the research team exclusive rights to characterize the project results:

Regarding the qualitative characterization of the project results, only the project team has the right of final interpretation and announcement to the public. Then you have NO right to explain and have NO right to announce the project or result without permission. Violation of this will [be] dealt with as breach of contract and the volunteers need [to] compensate for the damages. ³²

Another peculiar (and unethical) provision revokes the couple's right to unilaterally discontinue the research, noting that after the IVF pregnancy is begun (except for spontaneous abortion or genetic defects) “you will need to pay back all of the costs that the project team has paid for you.” ³³ There are also bizarre clauses relating to the baby, which are listed in Article 10, rights of the project team: “[a]fter the baby is born, it needs to cooperate with the project team … to conduct a series of routine tests.” ³⁴ “Baby's photo on the day of birth will be kept by the project team. The project team has the portrait right of the infant and can make it open to the public.” ³⁵

Further clauses relate specifically to “trade secrets” and suggest that the entire “consent form” is actually a nondisclosure form common in the commercial sphere, but not in the medical research with humans sphere. Article 11, for example, is labelled as a confidentiality clause. ³⁶ It states:

For the project team's trade secrets, you hereby agree:

What is not included in the consent form is as important as what is included. Perhaps the most noteworthy is the most obvious: there is no warning to the couple of the risk of twins. ³⁸ Twins is one of the most discussed risks of IVF in the therapeutic setting because it puts the twins at higher risks of premature birth, and puts the pregnant woman at higher physical risk during both the pregnancy and delivery (predictably, it has been reported that the twins were born two months premature). ³⁹ Additionally, of course, instead of just putting one baby at risk for this first-in-the-world experiment, it puts two at risk—in this case without any attempt to justify risking the health of two newborns rather than one. ⁴⁰ Perhaps even worse, there was no scientific reason to use the second embryo because a preimplantation analysis showed that it was not successfully edited. ⁴¹ Unlike the first embryo, which did contain two copies of the CCR5 gene (thought to protect against HIV infection), it contained only one, giving her very little, if any, gain from the embryo editing. ⁴² This is extraordinary.

The related question of who can consent on behalf of the planned child (or children) to genetically modifying the embryo used to produce the child will be taken up in the section of human rights. For now, it is worth emphasizing that, as illustrated at the November 2019 London meeting on Genome Editing, the third in the NAS series, genome researchers seem very anxious to adopt the ethics of the infertility industry as their own. ⁴³ This could be because there is almost no regulation of IVF clinics or physicians, and their own ethics is market driven and based on the fundamental belief that government should stay away from human reproduction (at least outside of China), and that whatever the competent couple and their physician agree to should be ethically acceptable if the result of the IVF intervention is likely to be a healthy child. ⁴⁴

Although virtually all language in the research consent form is singular when referring to “the baby” the following language does appear at the end of Article 2: “[i]n case of three or more fetuses, the fetus reduction treatment may be needed according to the guidelines of the State Family Planning Commission and the consideration of serious harm of multiple births to mothers and infants.” ⁴⁵ This is not further explained, and by itself is not informative. No mention is made of the possibility of twins. ⁴⁶

No legitimate Institutional Review Board (“IRB”) could approve this “consent form,” and based on reports from China, none did. ⁴⁷ To the extent that one observer of the consent process, JK's former biophysics supervisor, says he thinks the subjects understood—he needs to be asked, understood what? ⁴⁸ The trade secrets they were not to disclose? The reason for a separate agreement with the hospital and IVF physicians? The obsession with controlling the newborn's photograph as well as all revenue derived from selling it? ⁴⁹

SCIENCE FICTION, VALUES, AND CODES

Articles about CRISPR commonly allude to Aldous Huxley's Brave New World when suggesting how things might go wrong when engineering embryos (a technique not used in the novel) becomes widespread. ⁵⁰ Derek So has published an article on this subject. ⁵¹ So identifies 500 academic articles about CRISPR that allude to Brave New World, and concludes that most, if not all, are not directly relevant, and that other novels could be better deployed for ethical depth. ⁵² So has a point. In particular, when using fiction to anticipate ethical and societal problems with new technologies, there are many other candidates. A much better choice for commentary on JK's first of its kind experiment is Mary Shelly's Frankenstein. ⁵³ At the beginning of 2018, for the 200th anniversary of the publication of Frankenstein, Science devoted a major portion of an issue (and used it on the cover) to the relevance of the novel to today's scientists. ⁵⁴ It is not surprising, therefore, that shortly after JK's Hong Kong display, he was being referred to as the “Chinese Frankenstein.” ⁵⁵ Just what people meant to imply by that label requires some discussion. Frankenstein and his monster have often been confused, and we should be especially careful in not tainting the twin girls, who are blameless, hardly monstrous, and fully human, with the sins of the experimenter, who is himself the Chinese Frankenstein.

Philosopher Hank van den Belt wrote the Science editorial entitled Frankenstein Lives On, noting that while it is “repeatedly invoked in debates about emerging technologies like biotech, nanotech, synthetic biology, and artificial intelligence” the theme of “scientific hubris” and the dangers of “playing God” is only “one possible interpretation.” ⁵⁶ Van den Belt suggests the more important theme is one of scientific responsibility—and that Frankenstein's real sin was that he “ran away from his creature and left him without any parental care …. Researchers, especially in the life sciences, are understandably anxious about being tainted with the ‘F-word.’” ⁵⁷ In this regard, he mentions the approach of Kevin Esvelt with approval:

Kevin Esvelt, co-inventor of CRISPR-based gene drives, aligns with the proponents of responsible innovation in his pleas for openness and public engagement. For him, it is really hubris when researchers work in secret like Frankenstein and fail to seek advice from others. ⁵⁸

Another Science author, Kai Kupferschmidt, notes that the book “has inspired technophobes and scientists alike. ‘Franken-’ has become a passe-partout prefix for anything deemed unnatural or monstrous.” ⁵⁹

Our experience with cloning may be the closest to germline genetic engineering. In commenting on Dolly's birth at the time, I suggested that while there were parallels with Frankenstein, Wilmut was able to readily distinguish his work from that of Frankenstein. ⁶⁰ Like Dolly, for example, the “spark of life” was infused into the creature by electric current. Unlike Dolly (or the Chinese twins), the creature was fully grown (not a cloning possibility, but what many Americans fantasized and feared), and wanted more than creature-hood. He wanted a mate of his “own kind” with whom to live and reproduce. Frankenstein reluctantly agreed, but ultimately recognized his responsibilities to humanity to destroy his creation, and Shelley's great novel explores virtually all of the noncommercial elements of today's germline genomic editing debate.

The naming of the world's first cloned mammal also had great significance. As the sole survivor of 277 cloned embryos, the clone could have been named after its sequence in this group (e.g., C-137), but this would have only emphasized its character as a produced product. ⁶¹ In stark contrast, the name Dolly suggests a unique individual, and even at the manufactured level, a doll evokes joy in our children and is itself harmless. Victor Frankenstein, of course, never named his creature, thereby repudiating any parental responsibility. ⁶² Naming the world's first mammal-clone Dolly is meant to distance her from the Frankenstein myth both by making her something she is not (a doll) and by accepting parental responsibility for her.

Perhaps the only thing JK did right was to name the twins (even if just to use for his press releases). After that, he seems to have made no provisions to see to their welfare or their privacy. ⁶³ In fact, in the consent form they were to be treated more like pets than persons. The twins are not required to spend their lives in confinement—but their mother was under contract to spend both the last month of her pregnancy and the first month after childbirth confined to a hospital ward. ⁶⁴ The Frankenstein myth gives us a window on the question of scientific responsibility—new buzz words in science. But what do we mean by “scientific responsibility,” and how does it relate to other values that should guide genomic researchers, especially when engaged in first-of-a-kind human experiments?

Asilomar II, where in 1975 a group of scientists decided to adopt a temporary moratorium on recombinant DNA research until safety could be assured, is sometimes held up as the model adopted by the NAS in its first International Meeting on Human Genome editing, ⁶⁵ although more nonscientists were invited to the first NAS meeting than to Asilomar II. ⁶⁶ This frame, nonetheless, is based on the premise that scientists are capable of self-regulation and should be trusted to only develop new products and procedures that benefit humankind. ⁶⁷ Medical research is the classic story, with scientists discovering or developing cures for diseases, like smallpox, that had previously ravaged the human population. ⁶⁸ Nonetheless, at least since World War II, we have been well aware that physicians and scientists unrestrained by ethics can commit war crimes and crimes against humanity. ⁶⁹ We also know that medical technologies that are developed for “good” purposes can be misused (or accidently used) in multiple ways to harm, including bioterrorism. ⁷⁰ For example, development and use of gene drives—probably the closet current analogy to the recombinant DNA regulatory debate—holds significant potential to do good, but also potential for misuse or accidents (bioterror and “bio-error”) that could cause serious harm. ⁷¹

CRISPR can be used in multiple ways (many more than just “dual uses”), and the challenge to scientists is to try to restrict its use to beneficial projects. To this end, a set of ethical principles or guidelines could help ensure that the good uses of the technology are maximized, and the less desirable or dangerous, are minimized. A code of ethics for gene drive research is not magic, but if developed with public input and with the backing of scientists, has the potential of highlighting major ethical issues before research projects that raise them are conducted. What would a “CRISPR code” look like, could it have prevented the JK experiment, and would it make serious ethical discussion of a gene drive release experiment more likely?

CRISPR RESEARCH CODES

Rules for research oversight have been suggested by various national and international science panels, and ethics, law, and social implications (“ELSI”) work has also influenced the continuing public discourse over prenatal screening, abortion, and use of fetal tissue for research. In the case of human experimentation, work that entails risks to human research subjects has, at least since the 1970s, been scrutinized to ensure that the autonomy of the human subject is protected by requiring informed consent and prior IRB review (safeguards more relevant to the Chinese twins than gene-drive research). ⁷² Justice is promoted by attempting to fairly distribute the burdens and benefits of research. Sometimes referred to as the “Georgetown mantra,” the principles of autonomy, beneficence, non-maleficence, and justice have been widely accepted as providing an ethical framework for examining human experimentation. ⁷³ Nonetheless, there is no agreement in the field of bioethics as to how many ethical principles should be employed (three seems a pretty standard number, but there are single-value statements as well, such as the non-maleficence rule of the Hippocratic ethic: “do no harm”). ⁷⁴ Nor is there wide agreement of which values should have priority over others when they conflict. ⁷⁵ In this historical context, it seems reasonable to begin an exploration of relevant values for researchers with an examination of values that leading national commissions and committees have identified, determine where they agree with each other, and use these overlapping lists as a first approximation of critical values that may be most relevant to gene editing research. ⁷⁶

Two general reports are relevant to genome editing research. The first is the report of the Presidential Commission for the Study of Bioethical Issues on Synthetic Biology entitled New Directions: The Ethics of Synthetic Biology and Emerging Technologies. ⁷⁷ The members of the Commission were charged by President Barack Obama to be “forward looking instead of reactive” and to be “transparent, to monitor risks, to support (through a peer-review process) the most publicly beneficial research, and to educate and engage with the public as [synthetic biology] progresses.” ⁷⁸ The Commission identified five “basic ethical principles for assessing emerging technologies”: (1) Public Beneficence, (2) Responsible Stewardship, (3) Intellectual Freedom and Responsibility, (4) Democratic Deliberation, and (5) Justice and Fairness. ⁷⁹

The Commission defined public beneficence as maximizing public benefits and minimizing public harm. ⁸⁰ Responsible stewardship focused on “prudent vigilance” to protect people (especially children and future generations) who are not able to protect themselves. ⁸¹ Intellectual freedom promotes “regulatory parsimony,” while recognizing that clear guidelines are needed to protect biosecurity and biosafety. ⁸² The principle of democratic deliberation encourages “respectful debate” of opposing views and active participation by citizens. ⁸³ Finally, justice and fairness relate to the distribution of benefits and burdens across society. ⁸⁴

Similarly, the NAS's report, Human Genome Editing: Science, Ethics and Governance identified seven principles “for the governance of human genome editing”: (1) Promoting Wellbeing, (2) Transparency, (3) Due Care, (4) Responsible Science, (5) Respect for Persons, (6) Fairness, and (7) Transnational Cooperation. ⁸⁵

Following the President's Commission, the Committee defined promoting well-being as “providing benefit and preventing harm to those affected.” Transparency is openness, which is necessary for accountability. ⁸⁶ Due care involves protecting patients (research subjects) by proceeding “carefully and deliberately.” ⁸⁷ Responsible science suggests “adherence to the highest standards of research.” ⁸⁸ Respect for persons requires recognition of the dignity of all persons, and respecting their individual decisions. ⁸⁹ Fairness requires that all be treated equitably, and transnational cooperation encourages respect for differing national policies, and cooperating and collaborating with them, especially in regulatory rules and data sharing. ⁹⁰ Respect for persons is obviously central to human experimentation, but has no direct application to gene-drive research and so it is not included.

A report specifically on gene drive research, the NAS's Gene Drives on the Horizon, lists five values to incorporate in gene drive research: (1) Responsible Science, (2) Ecological Risk Assessment, (3) Open Data Access, (4) Public Engagement, and (5) [Good] Governance. ⁹¹

Like the first two reports, Gene Drives on the Horizon focuses on defining “the potential benefits and harms of gene drive research to people,” but significantly adds “the potential impact of gene-drive modified organisms on the environment.” ⁹² Under possible harms, the committee also directly refers to the dual use problem in the biosecurity realm (the intentional creation of a bioweapon), and in the biosafety realm (primarily unintended and unforeseen consequences). ⁹³ The committee also endorses international cooperation by, for example, following the provisions of the Convention on Biological Diversity and its two protocols, the Cartagena Protocol on Biosafety (which focuses on genetically modified crops) and the Nagoya Protocol on Access to Genetic Resources. ⁹⁴ These instruments are directed at countries. ⁹⁵ It is widely recognized (even well before the Hong Kong meeting) that international governance mechanisms are drastically underdeveloped and rely on voluntary compliance. ⁹⁶ Taking just public engagement seriously would have prevented the Chinese genome editing experiment—although the entire field of human genome editing, like gene drive research, merits, I think, its own code of ethics. As the committee noted, “[c]urrently, institutions, funders, and professional societies work in concert to encourage professional best practices in research. Such cooperation will be the key to maintaining high standards in gene drive research.” ⁹⁷ From these lists, it can be tentatively concluded that the most relevant consensus-based ethical principles for conducting gene drive research are: Responsible Science, (Ecological) Stewardship, and Public Engagement. ⁹⁸

Responsible Science in general can be contrasted to “irresponsible, Frankenstein-like,” secret science that is not peer reviewed and which can be predictably (and negligently, or even intentionally) dangerous. In the medical profession, responsibility has a shorthand code, “do no harm,” which is very popular with both the medical profession and the public. ⁹⁹ Agreeing to “do no harm” is a direct way for a physician to pledge to always act in the best interest of her patient, and take risks only when justified by reasonably expected health benefits. It is also a powerful reason for requiring that the principle investigator on any gene editing of a human embryo destined to be implanted be a physician. In this context, it also seems reasonable to adopt the precautionary principle, which amounts to adapting the “do no harm” principle for research that might adversely affect the environment or the human species. This principle puts the burden of proof on researchers to demonstrate that a proposed research project is “safe” before it can be undertaken. On the other hand, it can also be seen as simply arguing that a reasonable environmental risk/benefit analysis that shows that the likely risks of a project are outweighed by its likely benefits must be conducted prior to a research project being launched—especially one that could involve either intentional or unintentional release of gene drive modified mosquitoes.

(Ecological) Stewardship is generally seen as a recognition that we are all responsible for the long-term health of the planet, and that our actions should not damage the ecology in a way that cannot be remediated. ¹⁰⁰ Irreversible interventions that can cause significant damage to the environment should simply not be permitted. It can also be seen as a “do no harm” or precautionary approach to research involving the environment, including the release of genetically modified mosquitoes. In this respect it complements the principles of responsible science. It also seems reasonable to include the protection of endangered species under this principle.

Public Engagement is one of the most discussed and least understood of the ethical principles. It is easier to describe what it is not, than what it is. At the extremes, for example, it is not individual informed consent to modified life-form release, nor is it a democratic vote of a relevant population on whether or not to permit a release in their town, state, or country (although such a rule could be proposed). ¹⁰¹ Among the questions still to be determined in the context of modified life-form release are: what is the relevant public or community; who speaks for the public; what, if any, educational programs need to be implemented as part of public engagement; and what is the proper forum for such engagement? It is also worth considering whether transparency is inherently a part of public engagement, and whether genetic modification of insects is inherently an international concern (since containing modified insects in any one country may not be possible). Likewise, it seems reasonable to conclude that inheritable genome modification in humans is inherently a species-wide concern, since changes in the nature of human characteristics, including evolution, are of direct concern to all members of the species. ¹⁰² It is also reasonable to conclude that if JK had adopted the principles of scientific responsibility and public engagement, he could not have ethically done his CRISPR experiments on humans.

These values can usefully be supplemented by others that recur in the genetic literature focused on plants. For example, the Convention on Biological Diversity (the only international document in this group), and its two protocols, the Cartagena Protocol and the Nagoya Protocol, include: Conservation of Biological Diversity, Sustainability, and Fair and Equitable Sharing of Benefits. ¹⁰³

These objectives were originally developed primarily in the context of genetically modified crops, but have more recently been broadened to include animals. ¹⁰⁴ It also seems reasonable to conclude that “Conservation of Biological Diversity” is a more precise goal than “Ecological Stewardship,” although both could be defined to cover substantially the same ethical territory. The same could be said of “Sustainability,” even though here it refers directly to agricultural sustainability.

Finally, “fair and equitable sharing of benefits” is an additional value, suggested in other reports by the terms “fairness” and “beneficence.” A guidance document on mosquitoes for the Cartagena Protocol notes, for example, that “[i]n cases where living modified mosquitoes are modified with gene drives, containment may not be possible even when efforts are made to reduce long-distance dispersal due to anthropogenic activities.” ¹⁰⁵

Adopting a code is, I think, important, but it is also important to acknowledge the limitations of codes. The Gene Drives on the Horizon committee put it this way: “[p]rofessional codes of conduct that address technical and ethical considerations in research are an important source of governance that helps both to promote awareness among researchers and encourage them to take responsibility for their science.” ¹⁰⁶ On the other hand, a World Health Organization (“WHO”) report on “dual use” research noted:

[While] oversight mechanisms are essential, and codes of conduct are important in ensuring awareness and building commitment to an ethically aware, legitimate research enterprise … [codes] would likely have minimal impact on those who operate outside the system and are intent on causing harm. ¹⁰⁷

Scientific codes of conduct are not, of course, made to deter outlaws, but to help enshrine universal ethical principles as an integral part of legitimate science. Codes have historically been adopted by professional groups to (1) respond to scandals by promising to try to do better; (2) to establish the “moral credibility” of a field; and (3) to provide a profession with a “moral compass” by setting forth its ideals. ¹⁰⁸ Until the Hong Kong meeting, it could be argued that there is no scandal we are responding to. Now there is. Any code must be at least relevant to the threat of a repetition of the Chinese twins experiment. ¹⁰⁹ But, it should be more than that. It seems reasonable, for example, that we also view our quest for a code as providing a “moral compass” for gene drive researchers. Scientists can constructively affirm their beliefs in relevant standards of research conduct by affirming their acceptance of a code of conduct (sometimes referred to as an ethical code) that summarizes them. ¹¹⁰ For example, the notion of responsible science can be compared to responsible physicians who accept non-maleficence by pledging the Hippocratic principle, “first, do no harm.”

Although the “do no harm” model may seem only to apply to physicians caring for individual patients in a health care setting (or physicians doing research on human subjects), many commentators have suggested the Hippocratic “do no harm” principle can usefully be adopted by scientists, especially in the context of “dual use,” bioterrorism, bio-error, and even the environment. For example, in the aftermath of 9/11, a new “Code of Ethics for the Life Sciences” was suggested by Somerville and Atlas, ¹¹¹ the first principle of which is:

All persons and institutions engaged in any aspect of the life sciences must:

Work to ensure that their discoveries and knowledge do no harm (i) by refusing to engage in any research that is intended to facilitate or that has a high probability of being used to facilitate bioterrorism or biowarfare; and (ii) by never knowingly or recklessly contributing to development, production, or acquisition of microbial or other biological agents or toxins, whatever their origin or method of production, of types or quantities that cannot be justified on the basis that they are necessary for prophylactic, protective, therapeutic, or other peaceful purposes. ¹¹²

Other parts of the code pledged scientists to “work for ethical and beneficent advancement, development, and use of scientific knowledge” and to “subject research activities to ethics and safety reviews and monitoring.” ¹¹³

The World Medical Association has also updated its 1948 Declaration of Geneva to read in part:

As a member of the medical profession I solemnly pledge to dedicate my life to the service of humanity. The health and wellbeing of my patient will be my first consideration. I will respect the autonomy and dignity of my patient … I will not use my medical knowledge to violate human rights and civil liberties, even under threat. ¹¹⁴

The most recent code of ethics for scientists is a one paragraph, “Statement of Scientific Freedom and Responsibility,” published by American Association for the Advancement of Sciences in November 2017:

Scientific freedom and scientific responsibility are essential to the advancement of human knowledge for the benefit of all. Scientific freedom is the freedom to engage in scientific inquiry, pursue and apply knowledge, and communicate openly. This freedom is inextricably linked to and must be exercised in accordance with scientific responsibility. Scientific responsibility is the duty to conduct and apply science with integrity, in the interest of humanity, in a spirit of stewardship for the environment, and with respect for human rights. ¹¹⁵

Putting all of these inputs together, a group of scientists working with me developed this model code for gene drive research: ¹¹⁶

Code of Ethics for Gene Drive Research

I will conduct and apply my work in genetics consistent with the needs and interests of humanity, with respect for human dignity and human rights, and holding paramount public health, public safety, and ecological stewardship. I am committed to the fair distribution of risks and benefits of gene drive research, and to practicing science that is transparent and reproducible.

Scientific Responsibility

I will work to ensure that my research, discoveries, and knowledge do no harm by (a) taking steps to minimize the risk of my research being misappropriated by others who might use it to cause harm, including refusing to engage in research that is intended to facilitate or that has a high probability of being used to facilitate bioterrorism or biowarfare; (b) never knowingly or recklessly contributing to the development, production, or acquisition of biological agents or toxins; and (c) continuously assessing risks throughout the research process, from gauging risks prior to release of any gene modified organism to monitoring effects after release, and disclosing promptly factors that might endanger individuals, society, or the environment.

Ecological Stewardship

I will work to identify, minimize, and justify any adverse effect my work may have on the public's health, animal and plant life, and the natural environment. This may include partnering with experts necessary to carry out this duty.

Public Engagement and Benefit Sharing

I will ensure that my work proactively incorporates ecological risk assessment and informs a structured decision-making process regarding gene-drive modified organisms and any proposed field test or environmental releases. This process will include wide-ranging public discussions, especially with the populations most likely to be directly affected, which should incorporate likely scenarios, the potential for unforeseeable risks, and methods to contain or reverse genetic modifications and the likelihood of their effectiveness. Public engagement will include a consultation process that honestly and transparently identifies the burdens and benefits to the community. ¹¹⁷

HUMAN RIGHTS AND GENOMIC RESEARCH

Considerable discussion has been devoted to the issue of global governance of genomic research in the wake of JK's announcement in Hong Kong. Another researcher, this one from Russia, has announced his intention to repeat the experiment with a different disorder—most recently deafness. ¹¹⁸ The immediate reaction to this announcement by leaders in the field was that there is currently no international mechanism to stop him. ¹¹⁹ The Russian scientist, also a non-physician, seems, however, much more intent on generating publicity—like the would-be human cloners—than generating science, and we should spend little time taking him seriously. ¹²⁰ But, what should society (and scientists) do now?

Groups of scientists have made post-Hong Kong proposals for diverse types of moratoria on genetically modifying human embryos to produce a better baby, or a healthier baby, or a baby with or without a specific mutation. ¹²¹ These proposals include multiple forms of moratoria, from voluntary to mandatory, from time-limited to permanent, from universal to country-specific. ¹²² In addition, since the human cloning debate of the mid-1990s, dozens of countries have enacted their own prohibitions on genetically modifying human embryos. ¹²³ The first attempt to adopt an international treaty to outlaw germline genetic engineering failed, however, and led to a nonbinding declaration adopted by the United Nations in 2005. ¹²⁴ The declaration did, however, continue the debate by including the following language: “Member States are called upon to adopt measures necessary to prohibit the application of genetic engineering techniques that may be contrary to human dignity.” ¹²⁵ This language is too vague to be of much practical guidance.

I have described elsewhere why I believe the treaty still merits adoption, as it would (or should) prevent unaccountable individuals and corporations from going ahead with these experiments without having to seek consultation or approval from any internationally representative body. ¹²⁶ It may also be worthwhile to establish an international IRB whose job it would be to review and comment (and perhaps approve or disapprove of) any and all proposals to attempt human germline genomic modifications. In 2001, I wrote that the attempts at human cloning provided the world with an opportunity to debate and adopt a treaty outlawing cloning and germline genetic manipulation. ¹²⁷ The Hong Kong scandal provides another opportunity for international action. I continue to believe that the human rights framework, and more precisely the health and human rights framework, provides a way forward. ¹²⁸ Bioethics has been called on to provide the voluntary regulatory framework for germline genomics, but as the Chinese example has demonstrated, it is far too weak and unaccountable to fulfill a regulatory mission. ¹²⁹ Nor can scientists simply set their own guidelines.

Even the human rights framework cannot provide the necessary oversight without at least some modifications, including a new binding treaty, rather than a hortatory declaration. In this regard, there is some relevant international movement in the form of an expert committee convened by WHO. The committee has the charge of making suggestions to the Secretary General of what steps WHO should take to regulate both somatic cell and germ cell gene editing. ¹³⁰ The organization itself is, of course, an international one, with 194 nations as its members. ¹³¹ It was founded on human rights, like the United Nations, and has dedicated itself more recently to fostering the health and human rights movement. ¹³² It should come as no surprise that the WHO expert committee adopted values from the same sources discussed in this article: transparency, inclusivity, fairness, responsible scientific stewardship, and social justice. ¹³³ There is some reason to hope that at the very least, this committee will inject the language of human rights into the genome editing debate. Here are some human rights issues the expert panel should consider.

Most centrally, human rights are constructively and intuitively described as “birth rights,” becoming an inherent characteristic of all human beings upon birth. ¹³⁴ The Convention on the Rights of the Child, for example, begins its protections of the child at birth. ¹³⁵ Prior to birth, the human rights protections focus on the pregnant woman herself. ¹³⁶ This certainly seems reasonable because, for example, one cannot provide adequate prenatal care to the developing fetus without the consent and cooperation of the pregnant woman. Likewise, it seems altogether reasonable to conclude that sperm, eggs, and even extracorporeal embryos have no rights at all, including no right to life, or even to have an attempt at life by being implanted in a human uterus. Governments should not have (I don't believe) any role in supervising a woman's pregnancy. ¹³⁷ But there is, or should be, no objection to regulating or even prohibiting altogether the manipulation of extracorporeal embryos which in no way interferes with a woman's life, health, or body.

It also needs to be emphasized that the embryos used by JK did not exist at all before his experiment, and were created as means to his ends: simply for his experiment. ¹³⁸ They were not sick or dying, they were in no way benefited by adding a novel gene: they simply would not have existed but for this experiment. ¹³⁹ This does not mean, however, that would-be parents have no obligations to the welfare or well-being of their future child, or that the state has no obligation to protect future children, including those extracorporeal embryos slated to be used in experiments, and the health of pregnant women (both for their sake and the sake of the children they plan to have). For example, it would seem contrary to human dignity to implant a human embryo in a pig for gestation, and governments could rightly prohibit this—or even prohibit human gestation in an artificial uterus. Also, exposing the fetus to toxic chemicals during gestation, for example, is simply wrong—whether or not we think the fetus should be able to sue its mother or the chemical plant after birth. It is, I think, reasonable to conclude that parents have no “right” to place the welfare of their future children at significant risk by subjecting them to unsafe experiments. In this regard, positing that genome editing will not be done on human embryos unless its safety is proven simply begs the question: will it ever be ethical to subject an embryo to editing to determine whether or not it can be done “safely”? Or, are we more likely to conclude that this is an experiment that will always be unlawful to do because of its high risk (and no benefit) to the resulting child?

The argument that parents can't hurt their future children by manipulating the embryos because without the manipulation the child would not have been born at all, may be the argument that sold the father of the Chinese twins on JK's experiment. ¹⁴⁰ But, the argument at best ignores the consequences of parental action (including agreeing to a radical experiment on an embryo that would have been child abuse if done on a child) and arguably rests on an unpersuasive and imaginary “philosophy of souls” to identify specific children. ¹⁴¹ It seems to accept, for example, the reductionist argument that children (and embryos) are properly identified by their DNA, and not by their souls (which are posited either not to exist, or not to matter). ¹⁴²

Would-be parents should be obligated to take all reasonable steps to protect the health of their future children. I also believe, contrary to current practice, that fertility physicians should have the same obligations to future children. That they now almost exclusively see their obligations solely to the would-be parents is a major problem for resulting children, including twins, triplets, and even higher order multiples, for example. That the unnamed IVF physician involved in JK's experiment went along with it in view of the defective consent form, the marginal rationale, and the results that showed both of the implanted embryos were mosaics, is disgraceful and a stain on the entire IVF industry. There was no scientific rationale to use two embryos and risk twins in this experiment, and of all the questionable actions, this may be the most horrific, as it doubled the number of humans at risk for no benefit to either of them. Of course, there was also no justification for beginning yet another pregnancy (child three) before learning the outcome of the first experiment. If Chinese authorities have concluded that what JK did is criminal, it is difficult to see why the IVF physician is not at least a coconspirator. Future children won't have human rights until they are actually born, but their parents (and IVF physicians) do have obligations to them based on the future—and highly predictable—membership in the human species. ¹⁴³

One reasonable step for governments to aid in protecting the health of the next generation is to prohibit parents from volunteering their future children (in the form of embryos) for dangerous experiments: those dangerous to society as a whole, as well as to individual children that are planned to be born. There was, for example, a reason the “Chinese Frankenstein” was also called “Dr. Mengele,” the notorious Nazi doctor who conducted lethal experiments on twins in the concentration camps of World War II. ¹⁴⁴ What Mengele did is easily classified as a war crime and a crime against humanity. Of course, his experiments were planned to end in death. ¹⁴⁵ Germline genomic experimentation is different: it is designed to end in life. ¹⁴⁶ To the extent that the resulting life is seen as radically different from existing human life, however, and the genetically altered child as either post-human or so different from existing humans as to put in question its human rights, alteration can be seen as a “type II crime against humanity”: altering an essential characteristic of the human species in a way that is “species endangering.” ¹⁴⁷

The rights claims in reproduction are legend, but not all of them are persuasive. ¹⁴⁸ There is, for example, no “right” to a genetically-related child in any existing human rights doctrine, any more than there is a right to a fertile spouse or a right to have grandchildren. ¹⁴⁹ The right at stake is more akin to the right to a habitable planet to live in and to the right to access and share the fruits of scientific research to live a dignified life. As the Universal Declaration of Human Rights articulates, there is a human right to live in a society devoted to human rights and human dignity, founded on the principle of equality and nondiscrimination, that all of us have a role in safeguarding. ¹⁵⁰

The question that merits more discussion than it has gotten to date is, if germline genomic editing is a question of species-wide concern (and if gene drive release experiments could imperil the health of our environment), where does any one researcher or any one set of parents, get the moral warrant to decide (informed or not) for the entire species? There does seem to be wide agreement that something akin to “species consultation” (if not species consensus) is required, although precisely what this should entail remains a work in progress. ¹⁵¹

Alternatively, we could follow a path I suggested more than forty years ago, which we might be left with should we fail to stop our planet's decay: “embark on a genetic engineering task aimed at adapting man to this changing environment by developing a pollution-breathing, cancer-resistant, grass–eating human.” ¹⁵²

CONCLUSION

The birth of the CRISPR-edited Chinese twins, and the future prospect of releasing gene drive enabled mosquitoes provides the world with an opportunity to have an international conversation about the future of the human species. Such conversation would include our commitment to human rights and how to use them to promote dignity and equality, our expectations of the obligations of parents to their children, and physicians to their patients—including their patients' planned future children, the meaning of “human progress,” and the future of our planet. Scientists are an integral part of this discussion, but as the meetings at Asilomar and Hong Kong illustrate, without transparency and accountability, their participation will not be particularly helpful. Adopting a code of ethics centered on genetics research could help make this discussion deeper, and would also bring non-physician genetic scientists into the bioethics sphere. Adopting a new treaty prohibiting germline genomic experimentation on humans until a set of conditions are certified by an international oversight agency, perhaps as recommended or endorsed by the WHO expert committee, could help more.