Center for Ethics professor Dr. Leonard M. Fleck is among a group of seventeen international co-authors of “Heritable Human Genome Editing: The Public Engagement Imperative,” published in the December 2020 issue of The CRISPR Journal.
Abstract: In the view of many, heritable human genome editing (HHGE) harbors the remedial potential of ridding the world of deadly genetic diseases. A Hippocratic obligation, if there ever was one, HHGE is widely viewed as a life-sustaining proposition. The national go/no-go decision regarding the implementation of HHGE, however, must not, in the collective view of the authors, proceed absent thorough public engagement. A comparable call for an “extensive societal dialogue” was recently issued by the International Commission on the Clinical Use of Human Germline Genome Editing. In this communication, the authors lay out the foundational principles undergirding the formation, modification, and evaluation of public opinion. It is against this backdrop that the societal decision to warrant or enjoin the clinical conduct of HHGE will doubtlessly transpire.
The full text is available with free access on the publisher’s website.
Delighted to post our latest contribution on the public engagement imperative re: remedial germline genome editing. Published in the The CRISPR Journal with @CohenProf & 16 contributors from around the world, the paper delineates the ways by which public opinion is formed. pic.twitter.com/whTP3ezVUf
We can look at an individual’s DNA and know what their hair color is, but what about their behavioral traits? This episode features Center for Ethics Assistant Professor Dr. Laura Cabrera, and Dr. Mark Reimers, Associate Professor in the Neuroscience Program in MSU’s College of Natural Science. Drawing from their expertise as neuroscience researchers, they discuss what we know about how our DNA affects our behavior—from IQ scores to mental illness. They also explore possible ethical issues that may arise in the near future related to the study of behavioral genetics and gene expression.
This episode was produced and edited by Liz McDaniel in the Center for Ethics. Music: “While We Walk (2004)” by Antony Raijekov via Free Music Archive, licensed under a Attribution-NonCommercial-ShareAlike License. Full episode transcript available.
About: No Easy Answers in Bioethics is a podcast series from the Center for Ethics and Humanities in the Life Sciences in the Michigan State University College of Human Medicine. Each month Center for Ethics faculty and their collaborators discuss their ongoing work and research across many areas of bioethics. Episodes are hosted by H-Net: Humanities and Social Sciences Online.
It was good news to learn last month that the “Golden State Killer” had at last been identified and apprehended. A very evil man gets what he deserves, and his victims and their families get some justice.
The story of how he was found, however, raised concerns in some quarters. The police had a good DNA sample from the crime scenes, which with other evidence supported the conclusion that the crimes were committed by the same person. But whose DNA was that? Answering that question took some clever detective work. Police uploaded the DNA files to a public genealogy website, GEDmatch, which soon reported other users of GEDmatch who were probably related to the killer. More ordinary police work did the rest.
Most of the concern was over the fact that the police submitted the DNA under a pseudonym, in order to make investigative use of a database whose members had signed up and provided their DNA only for genealogical purposes.
Image description: a black and white photo of the panopticon inside of Kilmainham Gaol in Dublin, Ireland. Image source: Craig Sefton/Flickr Creative Commons.
My interest in this story, however, is the way it both feeds and undermines a common narrative about our DNA—that it is uniquely identifying, and that therefore any uses of our DNA pose special threats to our privacy. As The New York Times expressed this idea, “it is beginning to dawn on consumers that even their most intimate digital data—their genetic profiles—may be passed around in ways they never intended.”
It’s true that a sample of DNA belongs uniquely to a particular individual. But the same is true of a fingerprint, a Social Security number, or an iris. More importantly, by themselves none of these pieces of information reveals who that unique individual is.
As the Golden State Killer story illustrates, it’s only when put in the context of other information that any of these admittedly unique markers becomes identifying. If the GEDmatch database contained nothing but genetic profiles, you could determine which genomes the killer was related to. But you’d have no idea who those genomes belonged to, and you’d be no closer to finding the killer.
Although an individual genome can’t by itself be identifying, it can provide a link that ties together different information sources which include that genome. It can then be that collection that points to an individual, or narrows the list of possibilities to increase the odds of identification, and the threats to privacy. Imagine the state police maintains a database of forensic DNA linked to records of criminal convictions, and provides that database to criminologists, stripped of any names or other direct identifiers. Imagine as well that one of the hospitals provides researchers with DNA from their patients along with their de-identified medical records (which can include patients’ age, race, first 3 ZIP numbers, and other demographic information).
If we put those together we can do some interesting research: use the DNA link to identify those who both committed various crimes and had a psychiatric history, so we can compare them to convicted felons without a psychiatric history.
But now it may take very little additional information to identify someone in that combined database and invade their privacy. If I’m a researcher (or hacker) who knows that my 56-year-old neighbor was convicted of assault, I can now also find out whether he has a record of psychiatric illness—and a lot more besides. What he had thought private, is no longer so.
The point of this somewhat fanciful example is that as more information is collected about us, from more sources, the threats to our privacy will increase, even if what’s contained in individual sources offers little or no chance of identification.
For this reason, the prospect of merging various data sources for “big data” health research will challenge the current research regulatory framework. Under both the current and the new rules (which haven’t yet gone into effect), the distinction between identifiable and non-identifiable research subjects is critical. Research using information that can be linked to an individual’s identity requires that person’s consent. To avoid this requirement, research data must be “de-identified”. De-identification is the regulatory backbone on which much of the current “big data” research relies, allowing the appropriation of patient medical records and specimens for use in research without consent; and it provides the regulatory basis for uploading the data collected in NIH-supported research into a large NIH-sponsored database, the database of Genotypes and Phenotypes (dbGaP), which most NIH-supported genomic studies are required to do. Data from dbGaP can then be used by other researchers to address other research questions.
The possibilities of merging such “de-identified” databases together for research purposes will only increase, including facial recognition databases being collected online and on the street. As the mergers increase, it will become more difficult to claim that the people represented in those databases remain non-identifiable. As Lynch and Meyer point out in the Hastings Center Report, at this point there will be two choices. We can require that all such research will need at least broad consent, which will have to be reaffirmed every time a person’s data is used in new contexts that make identification possible. Or we will have to fundamentally reassess whether privacy can play any role at all in our research ethics, as the very idea of “privacy” evaporates in the panopticon of everyday surveillance.
Tom Tomlinson, PhD, is Director and Professor in the Center for Ethics and Humanities in the Life Sciences in the College of Human Medicine, and Professor in the Department of Philosophy at Michigan State University.
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Give God a rest; do your own gene editing (and thinking). On August 2, 2017 the New York Times headline read, “In Breakthrough, Scientists Edit a Dangerous Mutation from Genes in a Human Embryo.” The mutation was of a gene called MYBPC3, and the result of that mutation is a disease called hypertrophic cardiomyopathy. This disease affects 1 in 500 people. Its victims are typically young athletes. CRISPR-cas9 is the technology used to accomplish the gene editing. More precisely, a synthetic healthy DNA sequence was injected into an egg cell fertilized by a sperm cell with the mutated gene. This healthy DNA sequence was supposed to be copied into the newly created embryo. In fact, however, the maternal DNA was copied, thereby correcting the paternal mutation in 72% of the resulting embryos. A total of 54 embryos were created, later destroyed, after genetic analysis had been done. The remaining embryos were genetically mosaic. This research received worldwide attention.
Image description: a black and white image of an 8-cell human embryo, day 3. Image source: Wikimedia Commons.
I want to raise two questions. How should we assess this research and its future possible uses from an ethical perspective? How should we assess public policies designed to regulate this research now and in the future? I am going to give more attention to this latter question in the context of a liberal, pluralistic, democratic political culture because many people would demand that the research itself be outlawed, not just regulated. The relevant question to ask is this: What sort of justification must be given for regulating or banning gene-editing technologies used to create or modify human embryos? The short answer I will defend in response to that question is that regulations must satisfy public reason and public interest requirements (as explained below).
From an ethical perspective, gene-editing technology represents considerable potential benefit, as the example of hypertrophic cardiomyopathy above suggests. At least 200 single-gene disorders could be corrected at the embryonic or pre-embryonic level, thereby preventing premature death or substantial diminishment of quality of life in these future possible children (as well as potential descendants of those children). To be clear, no gene-editing technology is ready for clinical application. Off-target effects remain a problem. From an ethical perspective, the risk-benefit ratio of such interventions today weighs too heavily on the risk side. Researchers, however, are confident that these risks can be overcome.
Assuming that the safety issues can be effectively managed, another ethical objection is that these future possible children (maybe for several generations) would not have consented to such fundamental interventions. I do not see this as a compelling objection. Parents today must consent to very risky surgery or other medical interventions in a two-year old child that could result in the death of that child or substantial lifelong impairment. We have to trust the judgment of parents and physicians in such circumstances. We have to believe they are all acting in the best interests of that child (absent compelling evidence to the contrary). This seems perfectly analogous to what would be occurring with gene-editing of an embryo. (For a broad overview of relevant ethical principles, see Wolpe et al., 2017.)
I now want to switch to concerns in the context of public policy. What sort of political justification would be needed to legitimize the complete banning of gene-editing research on human embryos? Here are two answers that are entirely “out of bounds” in a liberal, pluralistic society: (1) doing gene-editing of embryos is “playing God,” and (2) destroying embryos should never be regarded as an acceptable part of medical research.
The phrase “playing God” invokes amorphous religious associations, deliberately and arrogantly engaging in some life-or-death activity that is the exclusive prerogative of God. However, if this is supposed to be a compelling argument for public policy purposes, then large areas of medical practice would have to be outlawed as well. It might well be the will of God that I die from my heart attack, but I still want my surgeon to be agnostic and do the bypass surgery needed to save my life. God is typically described as being omnipotent, though millions of embryos are created annually with thousands of serious genetic disorders. Allowing those future possible children to suffer the awful consequences of those disorders by forbidding the development of the technology that could correct those disorders looks like willful social negligence, not impiety.
Critics of gene-editing rail against the possible, speculative harms this technology could unleash on future generations of children, all the while ignoring the very real harms current actual children are having to suffer as a consequence of these genetic disorders. This is not just shortsighted; it is ethically and politically perverse. Virtually everyone agrees that it would be premature today to do embryonic gene-editing with the intent of bringing that future possible child to birth. However, nothing would justify laws that would forbid going forward with the research until such time as it would be safe to introduce into the clinic.
Some religious critics will object to the destruction of embryos that will be integral to the development of this technology. We noted above that 54 embryos were created and destroyed in connection with the hypertrophic cardiomyopathy research. Some religious critics will see those embryos as having the moral status of persons with the same rights as you and I. However, this is where public reason must be invoked as the appropriate basis for formulating policy in a liberal, pluralistic society.
Public reason (Rawls, 1996) must be neutral or agnostic with respect to all religious belief systems or other comprehensive worldviews. From an objective, scientific perspective embryos have no capacity to feel pain, no consciousness, no interests, and no personal identity. Embryos are not mini-persons. Some religious adherents may believe otherwise. They are free to affirm that belief in the private social space of their religious community. However, they may not seek to create laws that would effectively impose that belief on citizens who did not share that belief. This would be an illegitimate, illiberal use of the coercive powers of government unless they were able to justify such laws through an appeal to public reasons and related public interests.
Public reasons are reasons that all free and equal reasonable citizens as citizens can accept as reasonable, as consistent with the best science and fair terms of cooperation in a just society. Public reasons are the currency of rational democratic deliberation. Public interests are interests that all citizens have, and that could not be adequately protected or enhanced without the use of the coercive powers of government to control those who would threaten those interests. Protecting air and water quality would be a clear example of a public interest.
A liberal, pluralistic society recognizes and respects many reasonable ways of living a good life. Individuals are free to order their lives in accord with many different reasonable values that do not represent a threat to the rights of others or to various public interests. Consequently, such a society will accept that some people will refuse to use gene-editing technology in the future to alter the genetic endowment of their future possible children. This is political respect for procreative liberty.
It would be illiberal and illegitimate for some political group to use the coercive powers of the state to force religious individuals to use gene-editing technology, contrary to their religious beliefs. Likewise, these religious individuals must be mutually respectful of the procreative liberty rights of others to use gene-editing technology to alter the genetic endowments of their future possible children. This would include paying taxes to support the medical and scientific research needed to develop safe and effective versions of embryonic gene-editing, keeping in mind the taxes needed to pay for the health care needs of children born with cystic fibrosis or muscular dystrophy or any number of other medical problems that could have been avoided with judicious gene-editing.
In conclusion, there can be reasonable disagreement regarding various uses of embryonic gene-editing technology. However, that disagreement will have to invoke public reasons and public interests. God’s will and God’s won’t are not public interests.
Leonard M. Fleck, PhD, is a Professor in the Center for Ethics and Humanities in the Life Sciences and the Department of Philosophy at Michigan State University.
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This post is a part of our Bioethics in the News series. For more information, click here.
By Leonard Fleck, PhD
In his State of the Union Address President Obama announced that he wished to set aside $215 million for his “Precision Medicine” initiative. Given the cantankerous nature of Congress of late, this would strike many as needed political palliation. Who could be opposed to precision medicine? What member of Congress would stand up and defend “slipshod medicine” or “best guess medicine”? Fortunately, I am not running for any political office. I am not opposed to precision medicine, but there might be some ethical challenges that deserve serious consideration before the political lovefest begins.
There were two main parts to the President’s proposed initiative. One part would fund building a cohort of one million American volunteers who would agree both to have their entire genome sequenced and to provide their complete medical records to researchers. The other part would fund efforts to understand the genomes of cancer cells, the goal being to identify vulnerable features of those cells and then develop drugs that would target those vulnerable features. This yields the mantra most often invoked to describe precision medicine, namely, finding the right treatments, at the right dose, at the right time for the right person, every time. This is intended to contrast with much of contemporary medicine where many drugs have damaging and debilitating side effects, some worse than the disease they were intended to treat.
The cover story for Time Magazine (May 28, 2001) was headlined “There is New Ammunition in the War Against Cancer: These are the Bullets.” The “bullets” being referred to was the drug Gleevec (imatinib), which was used to treat chronic myeloid leukemia [CML]. The root cause of CML is a “fusion gene” known as ABL-BCR. Research had shown that if the activity of that gene could be halted the disease process could be contained as well. Imatinib was the magic bullet that did just that. Prior to imatinib, patients diagnosed with CML had about a 30% chance of surviving five years. After being treated with imatinib 60% of these patients could expect to be alive after five years. This is the beginning of “precision” medicine. No one should doubt that these were immediately recognized as astounding results.
In all the excitement no one seems to have paid much attention to the other 40% who failed to achieve five year survival. Why was imatinib not just as effective for them? The short answer was “resistance,” the ability of cancer to mutate around these drugs and begin again a deadly progression. The biological reason why cancers become resistant to these precision therapies is the genetic heterogeneity of most cancers. What this means, biologically, is that there might be one main driver for the proliferation of a tumor and numerous other potential drivers either of that tumor or of other tumors. This is what is described as either intratumor heterogeneity or inter-tumor heterogeneity.
Presently there are more than sixty cancer drugs that would be considered instances of precision medicine. That is, they are designed to target one or another of these drivers of proliferation. In general, the vast majority are only marginally effective, typically yielding extra weeks to extra months of progression-free survival at a cost of $100,000 or more for a course of treatment. The problem is that these drugs do “turn off” the main driver in some or most of the tumors that might define a cancer, thereby allowing other drivers to emerge in Darwinian fashion. This is the phenomenon known as resistance. The take home message is that most cancers are enormously more complex than researchers imagined twenty years ago.
The medical response proposed over the past three years is to follow the AIDs strategy, i.e., use multiple precision drugs, either in combination or sequentially, the goal being to make cancer for most people a managed chronic condition rather than a deadly condition. This might well be a medically appropriate goal but it is ethically problematic. About 600,000 Americans die of cancer annually; another 1.3 million are diagnosed with a cancer. If those 600,000 individuals can be given one extra year of life with the help of a $100,000 precision cancer drug, that would add $60 billion to the cost of health care in the US. If we were to use multiple drugs over five years to “manage” drug resistance, then the annual cost of these drugs for those five cumulative cohorts would be $300 billion.
Should we, as a just and caring society, be committed to achieving this goal? Is this something that we are morally obligated to do? If so, are we equally obligated to put just as much money and research effort into finding comparably effective life-prolonging interventions for all the other life-threatening medical problems individuals in our society face? Would anyone have a right to object to the additional taxes or insurance premiums that would be necessary to fight a “war on cancer” or a global war on all deadly diseases? And if we were unwilling to raise taxes or insurance premiums, then what current health care therapies would be defunded in order to underwrite precision medicine and the war on cancer?
Cancer is largely a disease of older individuals. So it seems inapt to talk about “premature deaths” in those cases. In order to control the social costs of cancer, should access to these precision drugs be limited to one course of precision therapy for those above age 75? Would that be an ethically defensible choice? This may sound ethically dangerous, but status quo options are even more ethically problematic. Individuals with very complete health insurance coverage would have very low-cost access to five years of precision medicine. But individuals with more modest (affordable) health insurance with high co-pays (30% or more for these Tier 4 drugs) would find it impossible to pay their share of the cost of these interventions, which means “ability to pay” would determine who had access to these drugs (though all Americans would have paid taxes for the basic research that made these drugs possible). Should that outcome be regarded as ethically acceptable because the implicit rationing is hidden from public view (no death panels making these choices)?
There are no easy answers to these questions. But there is no moral excuse for embracing precision medicine while ignoring the ethical ambiguity it generates.
Michael Joyner, “’Moonshot’ Medicine Will Let us Down,” New York Times (Jan. 29, 2015). Last accessed Jan. 31, 2015. http://nyti.ms/1wDjJSR
Leonard Fleck, PhD, is a Professor in the Center for Ethics and Humanities in the Life Sciences and the Department of Philosophy at Michigan State University.
Join the discussion! Your comments and responses to this commentary are welcomed. The author will respond to all comments made by Thursday, March 5, 2015. With your participation, we hope to create discussions rich with insights from diverse perspectives.
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