The Cusp of a New Era in Human History: Human Gene Editing with CRISPR-Cas9
Just 22 years after James Watson, Francis Crick, and Rosalind Franklin discovered the structure of DNA, 140 top genetic researchers gathered at the Asilomar Conference Grounds in California’s Monterey Peninsula to discuss the implications of the recently created “recombinant DNA” technology. It was 1975, and suddenly scientists had a newfound ability to decrypt and combine genes through recombinant DNA. It offered what seemed to be God-like powers in the field of biology — on one hand it could be used to develop new medicine and food, potentially saving millions of lives, but on the other hand it posed dangerous biohazards if used without oversight. At the conclusion of the conference, the scientists successfully established recommendations and guidelines to limit the risk in experiments with recombinant DNA, but that was the end of the discussion. A few scientists expressed concern over the idea of human gene editing, but given the complexity of engineering microbes, engineering human embryos seemed far off.
Fast forward 40 years to late 2015, and again experts from around the world gathered in Washington D.C. for the International Summit on Human Gene Editing — this time to discuss the scientific, ethical, and governance issues associated with unprecedented advancements in human gene editing research. But this wasn’t just another Asilomar Conference. The recent discovery of the CRISPR-Cas9 genome editing tool now allows practically anyone with basic lab skills and a few hundred dollars to precisely alter genetic sequences at significantly higher accuracy and efficiency than ever before. For the first time in the history of bioengineering, the prospects of accurate gene editing in humans is no longer an if, but simply a matter of when. While a full technical understanding of how CRISPR-Cas9 actually works is beyond the scope of this paper, it may be helpful to understand the basic science behind it in layman’s terms: Officially known as “clustered regularly interspaced short palindromic repeats,” CRISPR is actually a naturally-occurring defense mechanism found in bacteria immune systems . With CRISPR, bacteria can find and keep copies of invading viruses in order to identify and “kill” future invaders. Once an invading DNA is identified with CRISPR, the bacteria sends Cas9 enzymes to precisely snip and slice the invading DNA. If you think of bacteria’s immune system to be like the FBI, CRISPR would be the FBI’s most wanted list, and Cas9 would be the actual FBI agents who are sent to capture/kill those on the list. In the context of gene-editing, modified use of the CRISPR-Cas9 technology allows us to accurately identify and alter genetic sequences. For the sake of brevity, CRISPR-Cas9 will now be referred to as CRISPR.
All the big questions in the field of biology are now answerable with CRISPR: What does each gene do? What are the causes of various diseases? How do we pinpoint and find cures to them? As Amy Maxmen of WIRED magazine puts it, “Humankind’s ability to dial in genetic traits to suit our needs is nothing new. But CRISPR promises direct access to the source code of life.” The goal of this paper will be primarily to establish a line and boundaries for which future CRISPR research should not cross. That being said, it is impossible to draw a perfect universal line for the world to obey, as CRISPR is still in its early stages and there is much progress to be made. We establish laws and restrictions in society not because they are perfect, but because we think they work well enough. There will be no perfect regulatory scheme for CRISPR today, but there can be a good regulatory scheme. We’ll start by examining key events and advancements with CRISPR, then consider safety and germline editing, then develop the slippery slope argument, and finally use various ethical and religious considerations to attempt to establish a line for CRISPR.
The Current State of the CRISPR Debate
Comparisons between the accelerating research with CRISPR in the scientific community and the ethically dodgy research for the development of the atomic bomb present a potentially frightening view of the future. When asked whether the powerful new tool might do more harm than good, CRISPR pioneer Jennifer Doudna of the University of California, Berkeley responded uncomfortably: “I lie in bed almost every night and ask myself that question. When I’m ninety, will I look back and be glad about what we have accomplished with this technology? Or will I wish I’d never discovered how it works?” Perhaps the dystopian worlds filled with eugenics and designer babies we’ve become familiar with through science fiction may become a reality with CRISPR. But at the same time, precautionary development of CRISPR can potentially enable us to eventually eliminate disease, solve world hunger, provide unlimited clean energy, and much much more.
It should be noted that while the potential applications of CRISPR appear to be endless with more research and development, the current state that it is at is much less glamourising than portrayed in the media. CRISPR today does not enable us to start creating superman babies, or even in the next few years. The debate surrounding CRISPR today does not so much concern the sensationalist fears of designer babies/Gattaca-esque eugenics, nor is it regarding somatic gene editing (using CRISPR to change adult cells or tissues, which is basically the same as existing medical treatments and can be weighed ethically as such), but rather the ethicality of what is known as “human germline editing” — the manipulation of reproductive cells to spread gene changes to future generations/offspring (this can range from eradicating severe inherited diseases to changing cosmetic characteristics of in a hereditary line). Germline editing is much more realistic and technically feasible in the immediate future, which has led to scientists and researchers to call for a moratorium on all experiments involving gene modification in order to come together as a community to consider the safety, legality, and ethics of the prospects of tinkering with the human genome.
There are two key events that one should become familiar with regarding the CRISPR germline editing debate: first, a controversial study in April 2015 by Chinese scientists at the Sun Yat-sen University of CRISPR-based gene editing in human tripronuclear zygotes (basically human embryos that can never develop into actual humans). Many media outlets immediately expressed outrage with clickbait headlines after the Chinese “unethically” engineered human embryos — which simply was not what happened. With careful ethical considerations, the Chinese team wanted to see the viability of using CRISPR gene editing technologies to modify a gene responsible for a fatal blood disorder in human embryos. What many people fail to realize is that the embryos used in the study were embryos that could not birth into live humans, it was simply used to see whether or not CRISPR in human embryos was feasible. The results showed that CRISPR was not effective with human embryos — in fact, only 50% of embryos they tested were successful, and the rest were plagued with mutations and off-target effects. In this landmark study, the researchers provided direct evidence that CRISPR was currently unsafe for use in human embryos and the need for further ethical considerations and research. As part of the controversy, the paper was rejected by the well-known scientific journal Nature for ethical objections, but then was published by a relatively unknown journal, Protein & Cell. In the days after Protein & Cell published the paper, Xiaoxue Zhang responded to critics in an editorial for the journal: “In this unusual situation, the editorial decision to publish this study should not be viewed as an endorsement of this practice nor an encouragement of similar attempts, but rather the sounding of an alarm to draw immediate attention to the urgent need to rein in applications of gene-editing technologies, especially in the human germ cells or embryos.” The sounding of the alarm has indeed worked, which leads us to the second important event (mentioned earlier): the International Summit on Human Gene Editing in December 2015, organized in response to increasing demand for an international discussion on the ethicality of CRISPR based gene editing.
After three days of thoughtful discussion at the International Summit on Human Gene Editing, the organizing committee issued a statement on the conclusions reached by experts from leading institutions around the world. The statement offered four conclusions: first, intensive basic and preclinical research is clearly needed to further understand CRISPR technology in relation to the biology of human embryos and germline cells, and the potential risks and benefits of proposed uses. Second, using CRISPR to edit somatic cells that will not be passed onto future generations is fine as long as risks and benefits are properly weighed under existing regulatory frameworks. Third (the most important), human germline editing should not be used clinically until both relevant safety issues are resolved and there is “broad societal consensus about the appropriateness of the proposed application”. Regarding germline editing, the statement raises several issues, including the risks of inaccurate and incomplete editing, potential unknown harmful effects that genetic changes may have, the obligation to consider implications for both individuals and future generations, the irreversibility and extent of genetic alterations, genetic enhancements that exacerbate social inequality, and the moral considerations of altering human evolution. The statement acknowledges that as our knowledge about CRISPR and human biology improved and societal view evolves, the ethicality of germline editing should be revisited on a regular basis. Fourth, there is a need for an ongoing international forum to continue the discussion of CRISPR and germline editing. The organizing committee, which included representatives from the U.S. National Academy of Sciences and U.S. National Academy of Medicine, the Royal Society, and the Chinese Academy of Sciences, essentially called to continue the summit, recognizing the need to keep in close communication with all parties involved as CRISPR technology improves.
“While each nation ultimately has the authority to regulate activities under its jurisdiction, the human genome is shared among all nations. The international community should strive to establish norms concerning acceptable uses of human germline editing and to harmonize regulations, in order to discourage unacceptable activities while advancing human health and welfare.”
That basically leaves us at the current state of the CRISPR debate. With a newly formed international body leading the conversation, the standard for CRISPR research and procedures is largely set for now. But the conclusions offered by the group isn’t very conclusive and doesn’t bring any closure — rather, it brings even more discussion and debate to what is becoming increasingly relevant. Just this past February, Britain gave scientists official approval to conduct gene editing experiments on human embryos. Unlike the previous Chinese study, the embryos to be used in this study are human embryos that can eventually birth into real humans, although it was explicitly noted that the researchers would destroy all embryos after 7 days. Additionally, this was the first time a study of this nature passed a country’s full regulatory process. We don’t know the results of the study yet, but this only shows the speed at which this debate is moving at. Say the study finds an improvement with CRISPR and edits genes with close to perfect accuracy. What would be next?
Safety and Germline Editing
Before we get into the core of the issue, let’s establish that there is absolute ethical consensus that none of this should be done if it cannot be shown to be safe for everybody involved. As shown with the Chinese study, CRISPR isn’t safe yet for use in human embryos. Morally, safety is a precondition. But as CRISPR technology is improved, the question still remains — just because germline editing is safe doesn’t mean that it should be done. We cannot collapse ethics to just safety; the ethical concerns do not vanish once it is determined that CRISPR is safe for gene editing in human embryos. While we may think “safe” means that 100% of all procedure with CRISPR are successful, safety is always relative. Our human biological reproductive system isn’t 100% perfect (autism, genetic disorders), but we still consider it a good enough process. Like with any therapeutic treatments, we need to weigh safety in the context of benefits. If you had a drug that instantly cured half of people with metastatic pancreatic cancer — one of the worst diagnoses you can get — and instantly and painlessly killed the other half, that’s a wonderfully safe and effective drug in the context of the disease. On the other hand, if you had a drug that did the same (cure half, kill half) for the common cold, it isn’t such a safe drug anymore. Generally speaking, higher risks can be compensated by high rewards of success, but such risks also require higher confidence in its efficacy. Whether or not CRISPR is widely considered “safe” at times in the future is impossible to predict now. With this in mind, all discussion in the rest of this paper assumes a time when CRISPR is considered to be safe by scientists and the general public.
It’s important to really understand what human germline editing is. All of us are the result to some extent of unintended germline modification; none of us is born with the same DNA sequence as our parents. Every time a cell divides there are some changes in our “germline”. The germline does not stay the same throughout generations — it changes. It doesn’t stay inviolate. When we talk about germline modification in embryos under the context of CRISPR, we are referring to the process of taking an allele that is known to be disease causing, and replacing it with the average non-diseased version of the allele. By doing this, the embryo and all future offspring will not have the genetic disease. You are changing the germline of that embryo, but are you changing the human species germline? In the short run, not really. In the long run, possibly, but it only eradicates genetic diseases from humans altogether. Doesn’t sound too bad. Additionally, we have changed the prevalence of certain alleles throughout human history: agriculture leads to some genetic variations being favored, certain diseases do the same, and the invention of insulin meant that there are more people alive today who are genetically predisposed to have type 1 diabetes that otherwise would be the case, since now they can survive long enough to reproduce. One way to look at it is that under current proposed practices, we are changing the relative frequencies of certain alleles, not necessarily the human species germline.
There are essentially two possible types of human germline editing: one for the purpose of restoring a normal state of health (e.g. avoiding/healing cystic fibrosis or other genetic disorders), and one for the purpose of enhancing non-disease traits in humans (e.g. increasing intelligence, stopping aging). Today, we can draw the line in between these two types of germline editing — that is, we should be using germline editing for health purposes only, and treatments should be limited to restoring a normal state of health. Where we draw this distinction can get blurrier and blurrier with various applications of CRISPR. What was before for the purpose of restoring a normal state of health now becomes relieving suffering from disease. For example, notable geneticist George Church is currently researching ways to install genes that offer lifelong protection against infection, Alzheimer’s, and maybe even the effects of aging. There is no human genetically immune from aging. This destroys the moral line because George Church can argue that such a treatment is an enhancement in the name of relieving disease. We end up in moral no man’s land — the slippery slope.
The Slippery Slope and Curing “Disease” with CRISPR
The main argument in the CRISPR debate is that of the slippery slope — that starting to allow certain gene editing will eventually lead to something worse, which will then lead to an undesirable state like designer babies. There are ultimately good and bad slippery slope arguments. The bad arguments are the ones that claim inevitability, that once you step allow some gene editing, in ten, twenty years time we will end up at the bottom of the slope. This line of thought is flawed because it assumes throughout the time on the slope, nobody has any decision making authority for regulation or oversight. The good slippery slope argument is probabilistic — they give good guesses on what society will be like and what will change as CRISPR develops. Imagine that California approves a law for assisted suicide for patients who are terminally ill. Then say in 10 years, after people get used to this idea of terminally ill patients committing suicide, people may be asking why not extend it to people who are just “suffering” in some sort of other way. Then 10 years after that, when people get used to that idea, before we know it we may be euthanizing people who aren’t useful in society. This argument only works if you can explain the sociological mechanism as we go. To have a slippery slope argument you have to have a “bottom” that is undesirable. The bottom that we are trying to avoid with CRISPR is situations where we have genetic enhancements for things like intelligence, which leads to a society with the genetic haves and have nots — like that portrayed in the science fiction movie Gattaca. Most people don’t want to end up in a state like that portrayed in Gattaca, but most people also don’t want people to suffer from diseases like sickle cell anemia. It’s interesting to note that as of today, 15 of 22 countries in Western Europe have decided not to get on the slope at all, outlawing any germline modification for disease.
Those against germline editing are also generally not against the practice of germline editing itself, rather they are just concerned about ending up at the bottom of the slippery slope to a Gattaca-society. If it was guaranteed that germline editing be strictly limited to curing hereditary diseases and never fall down the slope, then we wouldn’t be having this conversation. But this is something that is impossibly hard to guarantee, as once we start mastering the technique of using CRISPR for germline editing, the risk of the slippery slope is too strong. Once we can safely and accurately cure something like deafness, it seems highly likely that the definition of “disease” will be expanded. Given the history of how our government handles controversial consumer-facing technologies, it isn’t hard to imagine an entire industry of lobbyists to back up companies who want to provide genetic enhancements. We need to also look at the social dynamics that introducing germline editing would set. In the worst case scenario, it may trigger a sort of genetic arms race between nations. Or in another possibility, affluent parents would purchase “upgrades” for their children. The line between medical/therapeutical and enhancement cosmetic traits may eventually become blurry, leaving us with no way to define a meaningful line between purposes.
Take this hypothetical example: You and your spouse have already invested in genetic upgrades to give your child immunity to AIDS, so why not throw in a few dozen genetic variants that you think might boost her IQ at no additional risk? Then say the child grows up and she gets high SAT scores — we don’t know whether it’s from that gene or from hard work and “talent”. Eventually, there would be competitive forces and commercial dynamics that would make affluent parents think they are irresponsible to deny their children the once in lifetime opportunity to add upgrades. This will result in two unequal populations of humans, exacerbating the problem of inequality today. In principle, poor people in today’s society can get rich. Of course, intergenerational mobility of wealth has gotten a lot harder, but at least it’s still possible. This argument rests on the assumption that germline editing will be used for purposes outside of disease prevention. Modifying an embryo’s germline to not have Tay Sachs disease doesn’t give them any advantage, it just makes them “normal” — equal to the rest of the human population. On the other hand, modifying an embryo’s germline to make them resistant to ageing does provide them benefit and therefore makes them unequal to the rest of the human population. Moreover, it is most likely that it is wealthy parents who will buy these treatments. Already, wealthy parents go to great lengths to provide the best for their children — tennis lessons, piano lessons, private tutors, et cetera. Some people would become biologically superior to others, as portrayed in Gattaca. Of course, this is all beyond technical reach at this point, but should be considered in our development of a regulatory line. How do we make sure there is a clear distinction between medical/therapeutic and cosmetic/enhancement treatments? We have to decide what a disease is, and if at one point someone like Hitler decided what a disease was, there would be disastrous consequences.
Establishing the Line
For decades of the extended genetic engineering debate, the so-called “line” on the slippery slope that no one was supposed to cross was germline editing. But now we’re debating that line, and it’s likely that whatever new line we set for the future will be debated eventually too as times change. There seems to a fundamental difference in how some people view controversial new technologies in the world — absolutism and relativism. Most people would agree that there should be a line drawn as to what extent CRISPR can be used for. While it’s easy to say that CRISPR should be limited to important medical needs to relieve human suffering and areas like appearance or intelligence should be left untouched, there really is no way to draw a perfect universal line for the world to obey. Here, an absolutist might reason that because there is no way to establish perfect, agreed upon boundaries, we should just outlaw CRISPR as a whole to avoid any possible consequences. On the other hand, a relativist would encourage the use of this new technology under regulations, like banning use for cosmetic enhancement or non-genetic disorders. The line we reasonably establish today with consideration for future advancements in CRISPR is to only allow germline editing for the purpose of eliminating genetic disorders that are passed on between generations. Because there is an absolute list of known genetic disorders, drawing such a line gives individuals suffering from known hereditary diseases closure without any risk to a potential slippery slope — yet.
It’s impossible to draw a perfect universal line for the world to obey today, just as there is no perfect line to determine when one is old enough to vote or drink. We establish lines like 18 or 21 not because they are perfect, but because we think they work well enough. This line established today may work well enough for now, but in the end we have to know what’s actually possible with CRISPR as further research is done. It would be foolish to expect that this line established today will be able to keep with the rapid and exponential advancements in society. This isn’t a bad thing; if anything, genomics with CRISPR and the advent of artificial intelligence reveals how exciting it is to be a human alive today.
There is one last thing to note regarding CRISPR that doesn’t have anything to do with science or ethics — the potential of CRISPR ending up with the “Monsanto problem”. The Monsanto problem is a sociological problem that arises when any growing technology is too rapidly adopted by scientists, leaving the public confused, anxious, and suspicious. When Monsanto first introduced GMOs in the 1990s, the public had no idea what it was and doubted the safety of seeds created in a lab. The result was suspicion and controversy that has lingered with the public perception of GMOs, even long after it has been proven safe and useful. The disconnect between the science community and the public has already caused great harm; unjustified public and federal fear of GMOs has prevented many potentially ground-breaking crops from even being tested. A couple decades ago, scientists thought GMOs were the secret to curing world hunger. Today, CRISPR faces similar circumstances. In order to avoid the Monsanto problem, we ought to make sure the scientific community, lay audience, and federal regulators come together to consider the ethicality of editing our very own heredity.
As David Baltimore of the California Institute of Technology said in the opening remarks of the International Summit on Human Gene Editing, “We could be on the cusp of a new era in human history. Today, we sense that we are close to being able to alter human heredity. Now we must face the questions that arise. How, if at all, do we as a society want to use this capability? This is the question that has motivated this meeting.” As we learn more about the technicalities and feasibilities behind CRISPR in the future, we’ll have this debate once again. Maybe we’ll establish a new line, maybe we won’t. Regardless, the important part is that the topic continues to gain public trust with ongoing transparent and open discussion. The conversation doesn’t end here — in fact, it’s just starting.