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.
The excitement and potential of CRISPR to treat severe genetic conditions by editing disease-causing DNA has taken an unexpected hit. A recent Wall Street Journal article highlighted the unexpected results from a CRISPR study in which attempts to edit a human gene responsible for blindness resulted in the loss of the entire chromosome from the cells in the embryos. These results echo another study conducted in human cell lines published earlier in 2019.
CRISPR is a targeted gene editing process that allows scientists to direct genetic modifications with far more precision than prior procedures. CRISPR has been touted as a gigantic leap in the ability to modify DNA by creating or repairing pinpoint DNA mutations without affecting other areas of the chromosome on which the gene resides. The recent study indicates that the technique might not be as straightforward in humans – and thus neither will be its use to fight disease.
CRISPR Technology – Promise and Problems
The value in CRISPR mediated genetic modification can be seen in a wide variety of biotechnology products, such as genetically modified crops and new biologics. But perhaps the most exciting and most controversial potential for CRISPR can be found in the desire to modify embryonic genomes to remove genetic abnormalities for which we currently have no cure.
This promise of embryonic gene editing is appealing not only because it would remove the condition from the child born from the gene-edited embryo, but also because the offspring of that child would also be free of the condition. CRISPR gene editing – because it is done at the embryonic stage – creates germline mutations that are passed to future generations. In a therapeutic use of CRISPR, those mutations would be cures for often untreatable diseases.
However, it is this very promise that raises many of the problems with CRISPR embryonic gene editing. Much debate has surrounded embryonic gene editing. Until this recent news, there were fears that CRISPR may make gene editing too easy. The technological development of CRISPR in embryonic gene editing is moving at a breakneck pace as scientists around the world are working on procedures. Biohackers work in their garages and livestream the use of CRISPR to edit their own genomes.
Many are debating which genes should be targeted and how fast the research into actual trials should proceed. Most agree that severe diseases would be the best place to start, but should the technology be deployed for cosmetic benefits such as eye color, or diseases for which a treatment exists? The dangers of CRISPR editing are unclear, and there has been an informal moratorium on the use of the technology to create children. Despite that, there has been at least one rogue scientist who has created genetically modified embryos and brought them to full term birth.
International Policy on Human Gene Editing
The scientific research is not occurring in a vacuum. Each country decides how CRISPR can be used in its medical system – both when the technique is safe enough and on which diseases it should be used.
An international commission recently pronounced that the technology is not ready for clinic implementation because scientists don’t understand the full safety issues surrounding its use in human embryos. The commission described some of the potential clinical uses in the future and outlined a basic safety protocol for approval.
One of the creators of CRISPR, Jennifer Doudna, has also spoken out against applying CRISPR too hastily to embryonic gene editing.
Based on the recent studies showing loss of chromosomes, the international commission and other scientists are correct to call for a moratorium on clinical embryonic gene editing.
CRISPR – The Path Forward
The setback in CRISPR gene editing does not mean that the technology and research should be discarded. The potential to change lives is too great; however, the dangers of use with our current understanding are even greater. So how do we move forward with CRISPR in embryonic gene editing? The answer must include balance – in research strategies and in voices.
While the technology is not ready for clinical use, and we have not yet determined which uses would be appropriate if it were available, the science should not stand still. The research surrounding CRISPR gene editing will yield insights into human biology that we cannot predict. For example, the loss of chromosome length in human embryonic cells undergoing CRISPR treatment seems to be different than the response of other species of embryonic cells. And debates about the appropriate use of the technology will allow us to discover more about ourselves as humans.
As we debate the best way to develop and deploy CRISPR technology, we should look to a variety of stakeholders. Scientists have a solid track record in understanding when recombinant DNA technology has potentially hazardous implications. In the 1970s, the Asilomar Conference allowed scientists to put together research guidelines that allowed the technology to be developed without harming public health. In fact, the international scientific consensus not to use the technology such as described above indicates that scientists are beginning that work. Such a moratorium on clinical uses gives us time to understand how to deploy the technology in the safest manner.
Additionally, there is a role for the voices of the patients whose lives could be changed by the technology. Patients may not be in the best place to judge when the technology should be deemed safe enough to deploy, but they certainly will have input about which mutations cause hardships that merit the risk of germline editing. Many of these patients already work with scientists on potential treatments for their diseases. CRISPR discussions may open another avenue for many.
Finally, there is a role for legal regulation of the use of CRISPR. Governments should listen to the voices of scientists and potential patients in drafting these regulations. But as shown by the example of at least one rogue scientist, there needs to be teeth to the moratorium on CRISPR clinical use at this time. CRISPR and its use in human gene editing raise complicated issues and hold great promise as a powerful tool to defeat genetic diseases. The development of those technologies will not be straightforward or without risk and will require more basic science research to achieve clinical efficacy. But with proper planning, we may learn more about ourselves as humans on the path to a cure.
Jennifer Carter-Johnson, PhD, JD, is Associate Dean for Academic Affairs and Associate Professor of Law in the Michigan State University College of Law. Dr. Carter-Johnson is a member of the Michigan State Bar. She is registered to practice before the U.S. Patent and Trademark Office.
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In November of 2018, a Chinese scientist announced that he had edited the embryos of twin girls and that the twins had been born. The scientist, He Jiankui, used CRISPR, a revolutionary method of editing sequences of genes, to delete the gene CCR5 from the embryos’ sequences. The intention was to make the twins resistant to HIV. Editing human embryos and allowing those embryos to develop into living, breathing babies was widely condemned. However, now it appears possible, likely even, that the twins’ cognition was impacted, perhaps improved. This, however, was an off-target effect—it was unintended. On March 13, Nature published a comment from a group of scientists calling for a moratorium on clinical uses of human germline editing. This call is only for a moratorium on clinical uses, not on research on editing the human germline.
Despite the moratorium, I think a good argument can be made that tolerating the clinical use of human germline editing is morally permissible. Here is one such argument. The fact that He Jiankui edited the girls’ embryos suggests that it is inevitable that some scientists are going to engage in this behavior. Imposing a moratorium is unlikely to change this—the cat’s out of the bag. Given that the behavior is inevitable, we should ensure it is performed as safely as possible in order to reduce the risk of harm.
The Inevitability Argument
I’m claiming that because clinical use of human germline editing is now inevitable, we should tolerate and regulate it. Generally, arguments of this type don’t work. It isn’t generally true that just because something is going to happen anyway, we should not only tolerate that behavior, but also make sure that it is done safely. For example, it’s true that humans murdering other humans is inevitable (unless we can cognitively or morally enhance people through, for example, gene editing!). Despite prohibitions on murdering, it still happens and probably always will. But its inevitability doesn’t mean that we should tolerate it but ensure that it is done safely. We shouldn’t, obviously.
Sometimes the argument does work, though. Sometimes the inevitability of a behavior suggests that we should tolerate it under regulation. For example, people using IV drugs is, for the foreseeable future, inevitable. Given this inevitability, it is morally justifiable to tolerate the behavior and do what we can to ensure that it is done safely. One way we do this is through needle exchanges. More recently, similar arguments support the widespread availability of naloxone for overdoses. So, sometimes, but not generally, the inevitability of a behavior justifies the tolerance of the behavior in order to ensure it is performed safely.
Why does the Inevitability Argument work in the case of needle exchanges? Why does it fail in the case of murder? One difference is that we know murder is wrong. You can’t have the concept of murder without also having the concept of wrongness. To tolerate murder would be to tolerate something that is morally prohibited. But we should be more skeptical of the wrongness of IV drug use—it may not be wrong at all, to say nothing of policies that permit or prohibit it. Even if it is wrong, our confidence that it is so should be lower. Another difference is that in the case of needle exchanges with IV drug users, the tolerance and regulation is meant to reduce harm, not only to the users, but to society. On the face of it, it seems implausible that one could anticipate a parallel policy of tolerating and regulating murder to reduce harm. Rather, tolerating and regulating murder would increase harm.
Inevitability of Clinical Use of Human Germline Editing
Is the clinical use of human germline editing more like IV drug use, or more like murder? Supposing that whether the Inevitability Argument works depends on whether we know the behavior being tolerated is wrong, and whether tolerating it is intended to reduce harm, the clinical use of human germline editing seems much more similar to IV drug use than it does to murder. First, we don’t know whether the clinical use of human germline editing is wrong, unlike our knowledge that murder is wrong. Whether it is wrong or permissible or obligatory depends on a lot of factors, including on whether embryos have a moral status and whether we have a duty to future persons.
Second, what would tolerating the clinical use of human germline editing look like? It would require scientific and political oversight of methods, data, and follow-up clinical care. But more importantly, the tolerance and regulation of the clinical use of human germline editing would require that we know more about what the effects of it will be. The only way we can acquire this knowledge is by conducting research on the clinical consequences of editing the human germline. This is all to say that the intention of tolerating the clinical use of human germline editing is to reduce as much as possible any potential harms, both to the person whose embryo was edited as well as to society.
Tolerating and Regulating Clinical Use of Human Germline Editing
By these criteria, the clinical use of human germline editing looks much more like needle exchanges for IV drug use. If so, then the Inevitability Argument may work, suggesting that we should tolerate and regulate its practice. But this tolerance and regulation impose further requirements: we must closely monitor the behavior and support research on the effects of editing the human germline.
Scientists assert (without sufficient foundation, I think) that the behavior is wrong. Do we really know that the clinical use of editing the human germline is wrong? If so, what general principle grounds this knowledge? What are the consequences of this general principle for other lines of scientific research? Is the clinical use of human germline editing really inevitable?
Parker Crutchfield, PhD, is Associate Professor in the Program in Medical Ethics, Humanities, and Law at the Western Michigan University Homer Stryker M.D. School of Medicine, where he teaches medical ethics and provides ethics consultation. His research interests in bioethics include the epistemology of bioethics and the ethics of enhancement, gene editing, and research.
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What are the ethical implications of gene-editing human embryos? Do we risk stifling scientific advancement by banning such medical research?
Guests Dr. Leonard Fleck, Acting Director and Professor in the Center for Ethics and Humanities in the Life Sciences, and Dr. Marleen Eijkholt of Leiden University Medical Center in the Netherlands discuss the pros and cons, stemming from the recent news out of China of gene-edited babies. They share thoughts on the ethical implications of using such technology to alter human embryos, both now and in the future.
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—clinical ethics, evidence-based medicine, health policy, medical education, neuroethics, shared decision-making, and more. Episodes are hosted by H-Net: Humanities and Social Sciences Online.
Scientists have recently announced that they had used the new gene editing technique, CRISPR, to remove remnants of ancient viruses that had integrated into the pig genome. An amazing feat of genetic engineering to be sure—but the article is notable as a first step in “humanizing” pig organs for use in organ transplant by removing pig-specific viruses before they can infect human organ recipients. The idea of humanizing pigs should make us wonder—what does it mean to be human? How much genetic modification can pigs undergo and still be pigs? How do we define humanity for our neighbors and ourselves? How much genetic modification would it take to remove the label of humanity?
These questions are not asked in a vacuum nor is the research being conducted solely for philosophical inquiry. We need organs to save lives. There are over 116,000 people on the organ donor list and only 33,611 organ donations each year. About 20 people die every day in the U.S. waiting for a match so that they can receive a new heart, kidney or lung. Additionally, not everyone who actually receives a transplant has a successful outcome.
Transplant rejection occurs because each person has a fairly unique set of signal markers on their cells that allow the immune system to identify “self.” Bacterial or viral infections trigger immune responses in part because they change the infected cell’s signal markers from “self” to “foreign.” A transplanted organ also looks “foreign” to the recipient’s immune system due to the difference in signal markers, and this immune response leads to transplant rejection. For instance, identical twins would have very little risk of transplant rejection, while two unrelated people of different backgrounds would likely be unable to donate to each other. Thus, doctors search for the greatest amount of match between recipient and donor, and then suppress the recipient’s immune system to further decrease the risk of transplant rejection.
Using animal organs introduces yet more foreign signals to the organ recipient, leading to the desire to humanize those organs with markers that signal “human” and “self” to the recipient. In fact, doctors have been using pig heart valves in transplants since the 1970s. These hearts valves are extracted and then stripped of live cells to decrease the risk of rejection. This preparation procedure limits types of transplants that can be performed, and even with preparation, rejection issues may eventually arise.
Therefore, today’s scientists are working to use genetic engineering to modify pig organs to express the same cell markers that signal “self” to a human recipient. The referenced article described the development of pigs without endogenous retroviruses that some fear could infect recipients. From that basis, scientists could use several different techniques to develop pigs with humanized organs. One technique would be to genetically modify an embryo such that the pig’s cells express more “human” markers and less “pig” markers. Another technique that has been pioneered recently would be to inject human cells into a pig embryo such that the resulting chimeric pig would grow a genetically human organ.
Both of these techniques raise the question of what it means to be human. Merriam-Webster defines the noun human as “a bipedal primate mammal (Homo sapiens) : a person.” Furthermore, the adjective definition of the word human, “having human form or attributes,” broadens that definition in an ambiguous way that leaves us no closer to an answer than before. After all, the point of humanizing cells is to give them human attributes for organ transplantation. Surely, that isn’t enough to make the pig a human? Pigs with genomes edited to have organs that look more “human” will likely still act like pigs. But we don’t truly know how multiple genetic changes will present. Looking to the chimera technique, would a chimeric pig with the heart and kidneys of a human still be a pig? What if some of those human cells colonized the brain and some percentage of neurons were human? How do we answer the question of humanity? Do we ask what percentage of the body is human? Do we see if the animal still acts like a pig or test its skills on the SAT?
In contrast, does a person who receives a pig heart transplant cease to be human and become a pig? Humans do not have a great track record of recognizing humanity in others. Perhaps in recent times, we in the United States have not had to consider what qualifies as human. A baby born from a human mother is a human. But this concept has not always been so straightforward. Constitutional definition of a slave as 3/5 of a person and the idea of blood quantum to limit Native American rights go back to the beginning of our country. More broadly, Hitler wanted to develop a master race and viewed Jews as subhuman – leading to horrific abuses and mass murder. Today, some countries still view women as property rather than humans with rights.
Genetic technologies will challenge how we view ourselves, our neighbors, and the next generation. Genetic testing has revealed Neanderthal genetic code in many of us due to interbreeding thousands of years ago. CRISPR-based tools will eventually allow parents using artificial reproductive technologies to select genetic traits for their children. How many modifications would it take for a child to cease to be human? Perhaps super strength or gills to breathe under water sound like fantastic science fiction now, but so too did the tablets and communicators of Star Trek in the 1960s and the watch phone/TV from Dick Tracy in the 1940s. Returning to the idea of organ transplants, would a skin bag full of organs derived from a human’s cells but with no brain be considered a human? Would your answer differ if there was a brain but no higher order brain function? Such an option could reduce organ rejection to nil if a person’s cells could be used to create their own replacement organs.
The dangers of relegating a population to second tier status because they are genetically different from the norm have been explored across fiction from Animal Farm to the X-Men. Humanity’s history suggests that those stories are rooted in our inability to see humanity in those we deem as other. Advances in science mean that we need to define what it means to be human in order to avoid abuses equal to slavery or Nuremberg. Our world is changing and so too will humanity – whether or not we are prepared.
Jennifer Carter-Johnson, JD, PhD, is an Associate Professor of Law in the College of Law at Michigan State University. Dr. Carter-Johnson is a member of the Michigan State Bar and the Washington State Bar. She is registered to practice before the U.S. Patent and Trademark Office.
Join the discussion! Your comments and responses to this commentary are welcomed. The author will respond to all comments made by Thursday, November 9, 2017. With your participation, we hope to create discussions rich with insights from diverse perspectives.
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