crispr-cas9: harbinger of human gene editing and its ethical turmoil
WASHINGTON UNIVERSITY IN ST. LOUIS
THE SUN YAT-SEN STUDY:
In April of 2015, a group of geneticists at Sun Yat-sen University in China attempted to alter the genomes of human embryos using CRISPR-Cas9, a powerful new gene-editing technology. The embryos possessed mutant copies of beta-globin, a gene that normally helps produce hemoglobin but, in its mutant form, causes beta-thalassemia, a troubling blood disorder.1 The study represented a major step in the scientific community—it was the first time CRISPR-Cas9 had been used on human cells. And though the embryos were not capable of developing into fully formed human beings due to complications of in vitro fertilization, the application of CRISPR-Cas9 on human genes alone sparked uproar and ethical backlash worldwide. Both Science and Nature, the most prominent scientific journals, refused to publish the results of the study.
These results were largely negative. Only four of eighty-six embryos successfully incorporated new copies of beta-globin, while CRISPR-Cas9 missed its target and inserted the gene at incorrect locations in other cases. However, the study showed that human gene editing is possible with this technology, and, instead of dissuading researchers, many think research and development will continue. In a National Geographic review, science journalist Carl Zimmer writes: “Just because this experiment turned out poorly doesn’t mean that future experiments will. There’s nothing in this study that’s a conceptual deal-breaker for CRISPR.”2
the mechanisms behind crispr-cas9:
Since the early 2000s, scientists have known about a key component of the bacterial immune system: clustered regularly interspaced short palindromic repeats (CRISPRs). When a virus invades a cell, these CRISPRs steal and house chunks of its DNA. When the same type of virus invades the cell or its offspring in the future, the CRISPRs recognize it and recruit a protein called Cas9 to cut up its viral DNA.3 In 2013, researchers at UC Berkeley figured out how to manipulate Cas9 to cut genes of their choosing. By inserting artificial CRISPRs into precise locations in the genome, one can direct a Cas9 protein to cut out harmful genes.4 Researchers can then bind a new gene to the ends of the severed DNA. Robert Blankenship, professor of biology and chemistry at Washington University in St. Louis (WUSTL), said that “what [CRISPR]’s become within just a couple of years is a technique in engineering cells—in particular eukaryotic cells—that permits a level of control and efficiency and a speed of modification … that’s much quicker and easier than any way that has been done before.”5 Previously, for example, in order to study a particular gene in an animal model, a lab would have had to insert a gene into a blastocyst, insert the blastocyst into a female uterus, wait for her to produce offspring, and study the offspring once they aged sufficiently. With CRISPR-Cas9, researchers no longer have to wait six months for their mice to breed. They can directly edit the animals’ genomes in mere weeks.
Professor Blankenship’s colleague, postdoctoral researcher Rafael Saer, added that, “with CRISPR, you control where the DNA gets cut at the sequence level, and that really is the power of the system. Before you weren’t able to do that. You had to engineer nucleases or proteins that would bind DNA and never be as specific.”6 Professor Blankenship and Dr. Saer, who both use CRISPR-Cas9 in their research on photosynthesis in bacteria, are among scientists worldwide who can now run more genetic engineering experiments and investigate causes of disease or processes such as photosynthesis with this technology.
USE IN HUMANS AND ETHICAL CONCERNS:
Despite the results of the Sun Yat-sen study, Professor Blankenship thinks it will not be long until CRISPR-Cas9 is ready to be used in humans. When considering its potential impact on our health, this seems wonderful. We could put in artificial DNA sequences that will tell Cas9 to go to a mutated gene that causes, say, Huntington's disease or cystic fibrosis, and correct or erase that harmful mutation. Imagine learning from a pregnancy screening that your child has a genetic precondition for Huntington’s disease and being able to cure him before he is born. With more time and research, this may very well be possible using CRISPR-Cas9.
What also may be possible, though, are blue eyes. Tall children. Above average intelligences. There is already a large and respectable crowd of scientists who believe that altering the human genome should never be done. With the possibility of editing traits that are not significantly life-threatening or harmful, or even creating “designer babies,” the use and regulation of CRISPR-Cas9 becomes an ethical mess.
There are divisions among the scientific community in this ethical debate: some believe CRISPR should not be used on human subjects at all, while others think we should proceed with research and development at full speed. The former camp includes heavyweights like the National Institute of Health (NIH), and journals like Science and Nature. In a recent statement denying funding to research using gene-editing technologies in human embryos, NIH president Francis Collins explains that throughout years of debate from many different perspectives, the idea of altering the human germline for clinical purposes has been viewed as a line that should never be crossed. He cites “serious and unquantifiable safety issues, ethical issues presented by altering the germline in a way that affects the next generation without their consent, and a current lack of compelling medical applications justifying the use of CRISPR-Cas9 in embryos” as reasons to withhold funding.7 Collins’ first two points are persuasive. In its current state, CRISPR-Cas9 poses serious safety concerns, as its inaccuracy in the Sun Yat-sen study shows. Not only would inaccurate insertion of a gene fail to cure an illness, but it would also likely create health problems of its own. Furthermore, we do not yet know what long term effects gene editing with CRISPR-Cas9 would have on humans. The more philosophical second point—preserving the autonomy of our offspring—seems like a necessary measure to guard against Big Brother. We would be making choices about their appearance and health that they, once mature, may not have made.
But it is Collins’ final point denying the existence of “compelling medical applications” for CRISPR-Cas9 use in human embryos that draws sharp opposition from the second camp—the believers, the optimists. Among these, renowned cognitive scientist, author, and Harvard psychology professor Steven Pinker leads the charge. In an opinion piece for the Boston Globe, Pinker stresses that the cost of disease is felt by every human being and that biomedical research produces concrete reductions of that problem. He then forcefully concludes, “The primary moral goal for today’s bioethics can be summed up in a single sentence. Get out of the way.” He also points out that while some find it prudent to pause and consider the long-term implications of research before trying to change the human condition, slowing down research in this manner has a massive human cost. For every year that new, effective treatments are delayed, millions of people will face death, suffering, and disability. Thus, those in the optimist camp, like Pinker, think we should continue developing CRISPR-Cas9 so we can cure as many people as possible as soon as possible and focus on the ethical issues as they arise. After all, “biomedical research in particular is definitely unpredictable,” Pinker notes.8
However, in between the arguments of these giants, there lies a middle ground where people are understandably torn over what they think the limits of human gene editing should be. On one hand, it seems that if we possess the means to cure a disease like Huntington’s or cystic fibrosis, and we learn that a child will be born with such a condition, then we should use a technology like CRISPR-Cas9 to cure that child. Some may even consider this a moral obligation. On the other, most people have no problem dismissing alterations like blue eyes or dark hair as highly unnecessary, unfair enhancements. Though, what if we learn our child will experience severely stunted growth? Or that she will be born with Down syndrome? Or that he will be significantly less intelligent than his peers and have trouble getting into college? These unfortunate cases all have the potential to severely decrease quality of life. We are tempted to fix them—but we think longer about whether doing so is absolutely necessary. If we eradicate every disadvantage one could experience, worlds like those presented in GATTACA (the sci-fi film) enter the realm of possibility.
Charlie Kurth, a professor of bioethics at WUSTL, offers a helpful framework for thinking about CRISPR-Cas9 regulation. “One way to get a handle on this question is to think about what the point of healthcare is as a whole … If you think the point of healthcare is to extend life, then you will think using [CRISPR-Cas9] will be legitimate only to the extent that it will extend life. So blonde hair, blue eyes—no—but life threatening diseases—yes,” he commented. “Alternatively, you might think the point of health care is to ensure that individuals can function effectively as members of society … That suggests the treatment should be used not just for life threatening diseases, but anything that undermines your ability to participate as a citizen.”9 Under this second conception of health care, he explained, conditions like severe stunted growth or mental retardation would be ethical to treat.
The best way to clarify the line separating ethical and unethical applications of CRISPR-Cas9 may be to examine the fundamental purpose of healthcare. Unfortunately, the nature of healthcare is another intensely debated topic in America, so this approach may help individuals decide their stance on gene editing regulations, but might not bring national authorities any closer to a resolution on CRISPR-Cas9 (as Kurth himself admitted).9
If there exist cases where genetic modification is necessary and cases where genetic modification seems highly unnecessary, presumably there is a line somewhere denoting which conditions are acceptable to modify, a line that tells us whether or not we should bring our child’s intelligence or height up to the national average. But, where is this line? How do we define it? While the answer to these questions may vary for each individual, the ethics as they apply to the entire public eye may take a long time to understand.
Though it is not the first of its kind, the development of CRISPR-Cas9 has brought the ethics of altering the human genome to international attention. The National Academy of Sciences will hold a summit this fall for researchers and experts to discuss the ethical and policy issues associated with CRISPR-Cas9 and recommend guidelines for gene-editing technologies. While some of the most important minds worldwide attempt to figure out the ethics of genetic engineering, we would be wise to ponder the topic ourselves, because—for better or worse—human gene editing will likely end up touching all of our lives in the years to come.
 Liang, P. et al. Prot. & Cell 2015, 6, 362-372.
 Zimmer, C. Editing Human Embryos: So This Happened. National Geographic [Online], Apr. 22, 2015. http://phenomena.nationalgeographic.com/2015/04/22/editing-human-embryos-so-this-happened (accessed Sep. 24, 2015).
 Horvath, P. and Barrangou, R. Science 2010, 327, 167-170.
 Doudna, J. et al. Science 2012, 337, 816-821.
 Blankenship, R. Biology and Chemistry Departments, Washington University, St. Louis, MO. Personal communication, Sep. 2015.
 Saer, R. Biology Department, Washington University, St. Louis, MO. Personal communication, Sep. 2015.
 Collins, F. Statement on NIH Funding of Research Using Gene-editing Technologies in Human Embryos. National Institutes of Health [Online], Apr. 29, 2015. http://www.nih.gov/about-nih/who-we-are/nih-director/statements/statement-nih-funding-research-using-gene-editing-technologies-human-embryos (accessed Sep. 24, 2015).
 Pinker, S. The Moral Imperative for Bioethics. Boston Globe [Online], Aug. 1, 2015. https://www.bostonglobe.com/opinion/2015/07/31/the-moral-imperative-for-bioethics/JmEkoyzlTAu9oQV76JrK9N/story.html (accessed Sep. 25, 2015).
 Kurth, C. Philosophy Department, Washington University, St. Louis, MO. Personal communication, Sep. 2015.