Inspired by the Nobel Prize in Chemistry awarded to Dr. Jennifer Doudna and Dr. Emmanuelle Charpentier in 2020 for the development of CRISPR-Cas9 gene editing, I wrote this research paper about the risks and rewards which accompany the novel technology. With every new innovation comes the fears of abuse and questions about regulation, and I hoped to shine light upon both the incredible potential of this technology to revolutionize healthcare and the societal responsibilities as we harness this potential.
When humans can play God with the very genotypes of those around them, are we entering a new era of scientific discovery or writing the plot of a dystopian novel? CRISPR-Cas9 has developed specificity and efficiency in modifying genetic code incomparable to that of preceding technologies, opening the door to gene editing projects which were once unfeasible. CRISPR-Cas9 uses the Cas9 enzyme to cut the DNA, and this enzyme is escorted by a guide RNA that leads it to the selected region to be edited. Scientists create or purchase guide RNA with sequences of nucleic acids complementary to that of the DNA section which they are targeting, directing the Cas9 complex to the correct area with high precision. However, along with such advanced gene editing capabilities comes the responsibility to define who has access to such powerful technology and to set thoughtful limits to its implementation. Although the risks of using CRISPR-Cas9 may be far outweighed by the potential it has to revolutionize the field of healthcare, its utilization within the scientific community should not be allowed until appropriate regulatory committees have established a set of guidelines for the application of CRISPR in order to prevent dire societal and health outcomes.
The great promise of CRISPR lies in its potential to create therapies for illnesses that were previously without effective treatments or cures. In fact, CRISPR-Cas9 is being applied to the most pressing health challenge of the 21st century, COVID-19. Even though vaccines have already been made accessible for most healthy citizens, there are very few effective treatment options for patients hospitalized with severe illness aside from supportive care. Researchers from the Peter Doherty Institute for Infection and Immunity are using CRISPR to create an inexpensive oral antiviral medication that would be taken immediately after the patient receives a positive COVID test. As new and dangerous COVID variants become more prevalent, it is all the more exciting that CRISPR has successfully demonstrated its ability to prevent viral reproduction of such variants (AFP, 2021). Other widespread illnesses that CRISPR is being tested on are mosquito-borne illnesses such as dengue fever and malaria which can result in severe bleeding, shock, and death. Mosquitoes have begun to adapt by becoming resistant to various antimalarial efforts, including developing immunity to previously effective drugs. Two approaches have been formulated in order to combat this growing immunity. With the first approach, scientists introduce genes through a mechanism which forces their transmission to the next generation, ultimately ensuring the extinction of the entire mosquito population. The other approach uses the same mechanism to introduce genes which instead render the mosquitoes incapable of transmitting disease, an alternate solution which would cause less harm to the ecosystems of which mosquitoes are an essential part (Caplan et al., 2015). Having access to the genomes of such pathogen-carrying organisms gives one direct control not only over the first generation of mosquitoes’ ability to reproduce and infect, but the ability of subsequent generations as well. Although humans may identify alternate means of preventing the spread of a mosquito-borne pathogen, the only method in which the trait would be modified within the entire species is by directly editing the genome itself. CRISPR is the only technology that would affect the gametes as the mosquitos reproduce. Recently, scientists have also begun to explore the groundbreaking potential of combining CRISPR-Cas9 with chimeric antigen receptor T cells, also known as CAR-T cells, a novel form of cancer treatment. Once genetically engineered to express chimeric antigen receptors, CAR-T cells circulate in the bloodstream and recognize proteins on the surfaces of tumors. However, CAR-T cells have many limitations, including their lengthy production time, their inability to treat solid tumors, the difficulty of manufacturing them successfully, and their variable efficacy. Scientists now have the ability to address each of these problems by using CRISPR-Cas9 to edit CAR-T cells, allowing them to attack solid tumors and evade the immune system. Specifically, by using gene editing to eliminate certain surface proteins on the CAR-T cells, the immune system will not be able to recognize them as unfamiliar, allowing them to enhance the body’s cancer-fighting response without interference (CRISPR Therapeutics). CAR-T therapy is often the only treatment available to patients who experience a relapse after chemotherapy or stem cell transplant, so continuing to improve CAR-T technology is essential in order to care for those with no other treatment options. CAR-T therapy is already being tested within B cell malignancies such as multiple myeloma, holding out the promise of less toxic treatments than those currently used to fight cancers. The application of CRISPR-Cas9 in treating or even eradicating currently incurable infections or malignant diseases is central to the advancement of medical science.
That said, if unregulated, CRISPR threatens to wreak havoc in all aspects of society. One might question the harm of using genome editing to change small, seemingly insignificant physical traits such as hair color, height, or eye color, yet statistics demonstrate that these traits correlate with social and financial success. By acquiring traits considered “desirable” by society, newborns can be endowed with competitive advantages before they are out of the womb. Independent of skill level or qualifications, both men and women who are considered to be less physically attractive earn less than those deemed more attractive. Indeed, nearly every Fortune 500 CEO is taller than six feet. If the wealthy are afforded preferential access to CRISPR-Cas9, the wealth gap will inevitably widen. The wealthy who can afford such technology will be able to purchase advantages that favor their offspring, perpetuating their elevated position in the hierarchy. This cycle of genetic advantages leading to economic advantages which in turn afford further genetic advantages looms in the future if CRISPR is utilized before the proper regulatory bodies are formed. Not only will CRISPR worsen social and financial hierarchies within the boundaries of the countries that utilize it, but CRISPR’s unprecedented precision may also be harnessed as a form of bioterrorism between countries by amplifying the destructive effects of existing pathogens. Genome editing is arguably equally, if not more, dangerous than nuclear weapons due to its ability to stay largely invisible until its effects become evident. In recognition of the ease with which it could be harnessed for biological warfare, genome editing was classified as a potential weapon of mass destruction by the U.S. director of national intelligence in 2016. Whereas conventional and nuclear weapons are challenging to conceal, biological weapons created by genetic editing can be employed surreptitiously. The possibility that this technology could be used to wreak havoc in a population through exposure to modified infectious pathogens makes it potentially irresistible for terrorist organizations, raising the specter that, if not regulated, enemies of the country will have access to an even more destructive vehicle of warfare (Gillan). An equally grave threat might result from the unexpected effects of modifying the genome. CRISPR’s guide RNA is notorious for “recognizing” parts of the DNA that have similar - but not identical - sequences to the target DNA, resulting in splicing an incorrect region of the genome. Not only can CRISPR target the wrong DNA, but as its DNA repair mechanisms attempt to anneal the cuts it makes, it can create deletions of a large number of genes or reconnect non adjacent genes in random sequences. The repair mechanism does not “know” exactly which pieces of DNA lie adjacent to one another, potentially leading to errors and unexpected gene edits (Ledford, 2018). Scientists are not even certain of the function of 20% of human genes; by editing the function of even one gene, a nearby gene with an unknown function may be dangerously mutated. There is risk of causing mutations that result in serious illness or dysfunction, including germline mutations which will continue to affect the future generations of the family. Researchers estimate that anywhere from one to ten mutations are required to cause cancer, underscoring how dramatic the impact of a single mutation may have on an individual’s health. Given the risk of widening the wealth gap, its potential role in bioterrorism, and its occasional targeting of the wrong DNA, CRISPR-Cas9 has the power to thrust society into a period of unprecedented social, economic, and continental upheaval.
In order to reap the benefits of this novel technology without harming more people than are helped, both regulatory committees and material inspection facilities must be put in place to oversee who is given the privilege of receiving and administering this new treatment. However optimistic one may be that policies set by regulatory committees will be followed diligently by the scientific community, the worrisome fact is that such guidelines will never be enough to restrict everyone from performing unlawful experiments, as demonstrated by He Jiankui’s violation of Chinese law in 2018 in genetically editing twin zygotes to confer HIV resistance. In order to reduce the risk of CRISPR technology from being used in potentially dangerous ways, the scientific community is obligated to form an international clearinghouse through which all registered parties would be monitored to ensure the necessary credentials and training, stipulate the approved uses, and contain any potential biohazards (Caplan et al., 2015). While there is no perfect regulatory system, the vast majority of incidents could be prevented with thorough mandatory background checks. In He Jiankui’s experiments, it is of special concern that his colleagues knew the details of his application of CRISPR, but did not take action to prevent them (Bergman, 2019). No matter how much society would like to place its trust in the ethics of scientists, this incident demonstrates that multiple lines of regulation must stand between the scientific community and the procurement of CRISPR-Cas9 materials. Multiple regulatory and monitoring boards must be put in place with the authority and power to decide the legal and moral limits of such gene editing. These institutions would be in a position to restrict off-label uses of CRISPR-Cas9, and it is within the jurisdiction of the U.S. Congress to create legislation that further limits its applications. These committees function by balancing the risks posed by drugs and technologies against the benefits they provide to individuals, the scientific community, and society as a whole. When technological progress reaches the point at which the risk of utilizing CRISPR-Cas9 is low, if the same system of balancing the risk against the reward is kept, the application will almost always be deemed acceptable. As the risk lessens, the threshold for projects in which the use of CRISPR is permitted will become progressively lower, making it almost inevitable that society will approve projects that inch closer and closer to genetic enhancement and eugenics. Regulatory committees will then be forced to utilize other metrics to enforce a system of checks and balances (National Academy of Sciences, 2017). There must be unchanging guidelines established from the start, updating “soft law” such as UNESCO’s Universal Declaration on the Human Genome and Human Rights and its sequel, the Universal Declaration on Bioethics and Human rights, with more up-to-date proclamations. Until strict guidelines leave no room for interpretation regarding who is afforded access to CRISPR and its accepted applications, its utilization poses too much risk.
The only scenario in which CRISPR will provide a net benefit to society is one in which every aspect of its implementation is strictly controlled and enforced by regulatory boards and an international clearinghouse. When used ethically, CRISPR-Cas9 has the potential to cure a myriad of previously incurable diseases. But as the sophistication of the technology develops and our understanding of its potential grows, the risk of its use for personal genetic advantage or bioterrorism purposes only increases. When the affluent can purchase procedures to ensure their family and offspring maintain their privilege, “what you get is social inequality written into DNA” (Dr. David King). Considering our limited knowledge of the genomic building blocks which make up all living organisms, using this technology to shed light upon the capabilities of our DNA shepherds in the possibility of even more scientific advancements that are made possible by such information. The largest obstacle that stands between civilization and the hope of saving many lives is human nature itself, and through regulating the usages of CRISPR-Cas9, our knowledge of how human bodies work and how to treat them will increase exponentially. As society continues to make era-defining advancements, however, the real question becomes how much we are willing to risk in order to feel that we are the masters of global evolution.
Works Referenced
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