Ethical, legal, and social implications (ELSI) research was an integral part of the Human Genome Project (HGP) from the outset.1 In 1993, Congress required the National Institutes of Health (NIH) to allocate “not less than 5%” of its HGP budget for ELSI research. By 2014, the NIH had provided almost $317 million of ELSI research support.2 These developments coincided with a flowering of the field of bioethics. The percentage of hospitals with an ethics committee rose from around 1 percent in the early 1980s to over 90 percent by the early twenty-first century,3 and academic bioethics programs, once a rarity, are now a common fixture on many college campuses.
September 01, 2016
The Evolving Ethics Challenge in Genomic Science
It is growing clear that the HGP, which focused on reading the content of the human genome, was merely the first HGP. A similarly large, globally coordinated effort may be needed in order to read with comprehension—in other words, to be able to interpret the clinical significance of the gene variants that today’s genomic tests efficiently detect. A person’s genome typically contains on the order of three million variants, or small deviations from an idealized human reference genome.4 As of 2014, fewer than 200 variants were sufficiently well understood to warrant a follow-up medical analysis if a patient has those variants.5 The first HGP taught us to read, but at the skill level of a small child who has mastered phonetics and can sound out the words without grasping what they mean.
Still another large, coordinated effort may grow up around the challenge of learning to edit and write the genome—that is, repairing variants in the naturally occurring genomes that all creatures possess, or synthesizing large segments or even entire genomes from scratch. It may seem hasty to attempt to write while still learning to read, yet the analogy to learning a first or foreign language is strong: reading and writing skills are interdependent—each skill is essential to mastering the other one. Synthesizing a genome that lacks a particular variant may help clarify what that variant does.
Rapid advances in gene editing and synthesis are fueling fresh interest in ELSI questions. In December 2015, the U.S. National Academy of Sciences, the U.S. National Academy of Medicine, the Chinese Academy of Sciences, and the U.K. Royal Society convened an International Summit on Human Gene Editing in Washington, D.C., to discuss appropriate ethical limits and regulatory approaches for gene editing.6 On May 10, 2016, an allegedly top-secret meeting (videotapes of which are freely available on YouTube7) discussed HGP-write,8 a proposed effort to synthesize genomes in cells. This latter meeting featured two ethics panels,9 even though the proposal only contemplated basic scientific research with no plan to insert synthesized genomes into living or embryonic human beings. On May 26, the Oxford Union Society at Oxford University hosted a formal English parliamentary debate10 about whether the potential of these technologies to improve human lives and eliminate disease is so profound that there is an ethical necessity to manipulate human DNA.
Having had the opportunity to participate in these three discussions, I was asked to share a few personal impressions about the ELSI challenges that lie ahead. One observation is that the future of ELSI research may not mirror the past. There tends to be a presumption that future ELSI research will look a lot like the studies that accompanied the first HGP. It is important to query that presumption. As the first HGP discovered how to read the genome, a major ethical concern was that learning its content could harm patients and research subjects who were perceived as vulnerable, scientifically naïve, and potentially unable to cope with unpleasant truths that genetic testing might reveal. Regular people were seen as needing top-down protection from professional ethics experts, who would receive large public funding to enunciate standards of protection from on high. The scientific effort focused on reading genomes, but the ethics work often was directed at writing ethics: normative ethical standards and related policies and regulations.
As scientists begin to write the genome, the ethics problems seem qualitatively different. Much of the work of the next five to 15 years will involve basic laboratory studies to learn how to synthesize very large molecules, such as the human genome, reliably and efficiently. Despite the hyperbolic claims one sometimes reads, scientists are not yet close to cloning copies of Albert Einstein or repopulating the world with dinosaurs. Much of the work in coming years will not be human-subjects research. For studies that do use human subjects, well-developed human research protections are in place and presumably can be adapted to ensure appropriate risk disclosures and consent procedures.
Does the mere act of manipulating genomes in a laboratory merit special ethical and regulatory restrictions? Gene synthesis is “writing” not only in a metaphorical sense but, potentially, in a First Amendment sense. Scientists will, in effect, be making “artistic renderings” of human beings and their genomes, and there are constitutional boundaries on how far the government can go in regulating “art” or subjecting it to prior ethical and regulatory constraints. Basic research, when there are no plans to introduce the resulting products into research subjects or patients, arguably deserves First Amendment protection insofar as it amounts to assembling microscopic “sculptures” of the human genome. Synthesized genomes may be pure speech or commercial speech, depending on who is doing it.
During early phases of gene synthesis/editing research, the ELSI challenge may not lie in enunciating top-down ethical standards to be translated into laws and regulations. Rather, the major ELSI concern may be moral acceptability to the public. It may be less effective to engage ethics experts to tell the people what is right, than to ask the people to tell us. Ethics reading—reading the public’s concerns and appetite for innovation and risk—may turn out to be more important than expert-led ethics writing. The principal ethical challenge will be to read the public’s sentiments about the developing science and to try to stay aligned with those sentiments.
Another area of concern is the potential risks, such as biosafety hazards or environmental impacts, if a laboratory’s containment system fails. Risks to the public can materialize even when human subjects and patients are not directly placed at risk. Managing these risks will be a matter of scientific risk assessment and legal jurisdiction: which regulations attach to the specific research activities that create potential risks, and how effective are the regulations at addressing those risks?
Mastering the art of writing the genome will be a long process, and the legal concept of ripeness may be worth incorporating into future ethical analyses. There is a proper time when an issue is ripe to be litigated or debated. The point when scientists first begin to synthesize large DNA molecules in the laboratory may not be the point when it is timely to debate hypothetical risks and ethical quandaries that may arise in the future, if such a molecule were ever introduced into a human research subject or into a patient seeking clinical care. It may make sense to defer human-subject protection issues until human-subject research is actually contemplated. In the past I have used the analogy that the point when scribes in ancient Mesopotamia were first developing cuneiform script was not the right time to debate the ethical implications of the possibility that someone, someday might use written script to write pornography.
In return for deferring the consideration of ethical issues until they are ripe for review, scientists must be clear and transparent about what they plan to do and must remain true to the boundaries they set. Will the research manipulate DNA in silico as a computer simulation, or in cell lines, plants, animals, humans, or human embryos? Depending on where the boundaries are set, specific questions may or may not be ripe for ethical review.
It is time to insist on evidence-based bioethics. Many bioethicists support the concept of evidence-based medicine, but are reluctant to impose similar evidentiary standards on bioethical work. For example, considerable ELSI funding has been spent elaborating paternalistic bioethical doctrines to protect patients and research subjects from suffering psychosocial harms that might occur if they were granted access to their own genetic test results. It was speculated that people might go all to pieces if they learned they had a disease-associated gene. The little empirical work that has been done casts doubt on whether the alleged psychosocial harms are real.11
The NIH, in addition to funding normative ethical studies, also funds empirical studies and research into public engagement. These latter types of studies may do more to resolve future ELSI issues than will studies of the ethically appropriate response to speculative harms. Crowdfunding, rather than public funding, may be the superior mechanism for financing normative ethical studies that seek to tell people what is right to do.
It is indeed difficult to forecast benefits and risks, whether in the bioethical context or in drug development. A possible solution would be “postmarketing surveillance” of ethical claims: require analyses of the ethical implications of genome science to report their assumptions about risks into a registry and track them to see which claims prove true. In time, a more evidence-based discourse about benefits and risks could emerge.
A final point is that we need to resist our very natural human-centrism when assessing the risks of genetic manipulation. Editing the human genome tends to strike people as more profound, perilous, and grave than editing the genomes of plants or other animal species. Yet the risk of widespread, catastrophic harm may actually be greater when manipulating plant, animal, or microbial genomes than when manipulating human genomes. Humans have long generations and limited fecundity, which narrows the potential for human gene manipulation errors to have broad, global impacts. Many plants, animal species, and microbes reproduce promiscuously and rapidly, meaning that any misadventures of gene editing could propagate widely and produce global impacts, such as the loss of an important food crop or the introduction of a pestilential species. This is not to discount the potential for human gene editing and gene synthesis to create serious harms if done without proper oversight. Rather, it is merely to say that all gene editing and gene synthesis activities merit careful, evidence-based ELSI analysis, and it would be a mistake to let our human-centrism blind us to the need for equal care in assessing all forms of DNA manipulation.
Endnotes
1. For a history of the NIH ELSI research program, see generally Jean E. McEwen et al., The Ethical, Legal, and Social Implications Program of the National Human Genome Research Institute: Reflections on an Ongoing Experiment, 15 Ann. Rev. Genomics & Hum. Genetics 481 (2014).
2. Id.; see also National Institutes of Health Revitalization Act of 1993, Pub. L. No. 103-43, § 1521, 107 Stat. 122, 181.
3. Glenn McGee et al., A National Study of Ethics Committees, 1 Am. J. Bioethics 60 (2001).
4. Isaac S. Kohane et al., Taxonomizing, Sizing, and Overcoming the Incidentalome, 14 Genetics in Med. 399 (2012); see also FDA, Optimizing FDA’s Regulatory Oversight of Next Generation Sequencing Diagnostic Tests—Preliminary Discussion Paper (Dec. 29, 2014), available at http://www.fda.gov/downloads/medical devices/newsevents/workshopsconferences/ucm427869.pdf.
5. Frederick E. Dewey et al., Clinical Interpretation and Implications of Whole-Genome Sequencing, 311 JAMA 1035 (2014).
6. Video recordings of the summit are available at http://www.nationalacademies.org/gene-editing/Gene-Edit-Summit/index.htm.
7. See, e.g., Ctr. of Excellence for Eng’g Biology, HGP-write: Testing Large Genomes in Cells, YouTube (June 2, 2016), https://www.youtube.com/watch?v=GAuQ7Fs3WMU&list=PLHpV_30XFQ8R2Kpcc1pwwXsFnJOCQVndt.
8. Introducing GP-write: A Grand Challenge, Center of Excellence for Engineering Biology, http://engineeringbiologycenter.org/ (last visited Jan. 6, 2017).
9. Ctr. of Excellence for Eng’g Biology, Is “HGP-write: Testing Large Genomes in Cells” a Wise Choice?, YouTube (Aug. 5, 2016), https://www.youtube.com/watch?v=yvxk2tE9dQs; see also Ctr. of Excellence for Eng’g Biology, Regulatory and Bioethical Implications of the 1% Pilot Projects (June 2, 2016), https://www. youtube.com/watch?v=9xgm4U6E-CU& index=9&list=PLHpV_30XFQ8R2Kpcc1pwwXsFnJOCQVndt.
10. Oxford Union Soc’y, DNA Manipulation Debate, YouTube (July 8, 2016), https://www.youtube.com/watch?v=5AfiyzRLCow&list=PLOAFgXcJkZ2wU2oFwftqcAgdup3U4_HmN.
11. See, e.g., Effy Vayena & Barbara Prainsack, Regulating Genomics: Time for a Broader Vision, 5 Sci. Translational Med. 198 (2013).