Potential Risks of Advanced Gene Editing Technologies
Open Philanthropy Cause Area Exploration
Note: Open Philanthropy already supports efforts to solve important global issues using gene editing under “Scientific Research.” This proposal is complementary to but omitted from Open Philanthropy’s portfolio. This cause area emphasizes prevention, mitigation, and adaptation concerning the risks of advanced gene editing.
Gene editing technologies have incredible potential to benefit healthcare, conservation, and agriculture. Because of its potential, gene editing will reasonably occur on a transformative scale within the next 50 years.
Like any high-potential technology, gene editing has the potential to be misused in ways that undermine science, humanity, and equality. If gene editing is not clearly regulated, there are risks to humans and wildlife that range from mild to severe. Risks include harm to humans through poor science and regulatory efforts; inequitable access to gene editing technologies and therapy; conservation issues; and political instability through the use of gene editing in governance.
I would choose to give the overall topic a label of “high” importance due to the potential for risks to occur on a broad and severe scale.
As a field, tractability is moderate. There are many theoretical opportunities to fund ventures that would encourage communication, collaboration, education, research, new legislation, and equitable access. Yet, based on my research, there are not many risk-based initiatives off the ground and actively seeking funding.
Within the field, however, there are specific solutions and categories that seem particularly promising. These include the formation of a global observatory on gene editing (which has already been proposed), and many projects that seek to help or improve accessibility for underserved populations. I would label these solutions as highly tractable.
Lastly, I think it’s reasonable to expect outreach and communication initiatives to proliferate, as many scientists are advocating for more forums of discussion and public education. Because of this, I would label public outreach as moderately tractable for now, with potential to become highly tractable.
Overall, the field is highly neglected. Most of the funding in the field is dedicated to the highly tractable “Improving Accessibility” sect. The Gates Foundation is a generous funder of many projects in this area. OP is also familiar with this field- through their Scientific Research cause area, OP is a collaborator with the Gates Foundation on Target Malaria.
There are also some smaller endowments and projects that various other nonprofits dedicated to education and outreach efforts. Communication and consensus-making between scientists is primarily facilitated by WHO, with the Nuffield Foundation and ARRIGE participating on a smaller and more independent scale.
There remains a high demand for grants in improving accessibility, with the Gates Foundation being one of the only organizations that is broadly invested in the field. Other initiatives and funds are mostly small or region-specific.
Major Sources of Uncertainty
After writing this review, my major sources of uncertainty are:
- The tractability of educational, research, and consensus initiatives. There are few grants and little funding for educational programs, risk-related research, and collaborative efforts. I’m not sure if this is because of a lack of demand/importance, or if a lack of supply of grants decreases demand.
- The timeline and severity of risk development. Funding long-term risks depends on the likelihood of that risk developing into a severe danger. To confirm estimations with reasonable significance would require a much more in-depth analysis of each of the risks detailed.
Gene editing as we know it has been around for about 50 years, but really took off in the last 20. Since 2000, the potential to edit the genome has grown with new technologies like CRISPR-cas9 and prime editing. The ability to edit the human genome increased with the capacity to do fast and accurate sequencing using Illumina technologies. Seven gene therapies using a variety of techniques (AAV, CAR T, Oncolytic virus) have been jointly approved by the FDA and EMA for clinical use. Projects to bring back extinct species have begun, and gene drive mosquitoes have been released into the environment to prevent disease.
With the speed at which ideas and technologies have been developed, regulations have not been able to keep up. There are few efforts to address risks inherent in advanced gene editing and a lack of resources dedicated to novel initiatives. Furthermore, governments are rushing to compete with each other in a gene editing arms race, which could lead to underdeveloped experimentation. The following shallow review looks at the justification of funding towards this field, where funding is needed, and what nonprofits and agents are already involved.
Risks & Rationale (Importance)
I. Health Risks of Unregulated Human Genome Editing
In 2018, Chinese scientist He Jiankui announced that he had performed the world’s first germline edits on two twin girls. He had injected a human embryo with a CRISPR construct designed to immunize the girls from HIV. Not only did Jiankui go against a global consensus not to perform germline edits- the editing was done poorly and his protocol did not ensure cause-and-effect results. In response to widespread backlash, Jiankui stated, “The world has moved onto the stage for embryo genetic editing. There will be someone, somewhere who is doing this. If it’s not me, it will be someone else.”
Jiankiu’s actions alerted the scientific and ethics community to the seriousness of unregulated gene editing, particularly germline. The human gene pool has been forever altered starting with the edits on those two girls, and it happened without the consensus of the rest of humanity. Just as importantly, the scientific community is not sure what impacts the edits will have on the girls’ health.
At the end of the International Summit on Human Gene Editing of 2018 (where Jiankui made his announcement), WHO released a statement that condemned Jiankui’s actions and stated, “While we, the organizing committee of the second summit, applaud the rapid advance of somatic gene editing into clinical trials, we continue to believe that proceeding with any clinical use of germline editing remains irresponsible at this time.” WHO also has plans to expand their current Human Genome Editing Registry to include germline editing experiments, and establish an assessment mechanism to identify concerning experiments.
Despite these advances, pressing problems remain. In the ensuing investigation, it was discovered that a handful of scientists knew about Jiankiu’s experiment but did not report it, which brings up the problem that there is no reliable reporting method for such experiments. Additionally, there are questions of how to obtain a global consensus, develop and enforce ethical regulations, deter illegal or unethical experiments, oversee the accuracy of gene therapies, and develop a translational pathway for clinical germline editing.
Adjacent to poor science and regulatory efforts is the potential for gene editing medical tourism. Medical tourism isn’t innately unethical; sometimes it means a search for a treatment that is less costly elsewhere, or not yet approved in a home country. However, it often indicates the presence of rogue clinics and services that mislead or misinform patients. We saw a similar phenomenon with stem cell therapies, which have become increasingly popular in the last decade due to their potential to treat diseases. With the emergence of gene editing technologies, there are worries that dangerous and unproven treatments will begin to spring up in the same fashion.
These concerns have already been somewhat validated by the development of DIY Gene Editing Kits and Youtubers who do at-home biohacking experiments. A powerful example manifested in October 2017 when Dr. Josiah Zayner, NASA scientist turned biohacker, injected his bicep with a self-engineered CRISPR product that was allegedly designed for muscle enhancement. Four months later, in February 2018, Aaron Traywick, founder of Ascendance Bio, dropped his pants on live stream in order to personally undergo a test of a CRISPR product targeting Herpes.
There are concerns that these DIY investigations undermine the complexity and risks of gene therapy, and encourage dangerous experimentation. In an interview with the Atlantic in February 2018, shortly following Traywick’s presentation, Zayner said about his biohacking activism, “What it’s turned into now, people view it as a way to get press and get publicity and get famous… There’s no doubt in my mind that somebody is going to end up hurt eventually.”
What is lacking in the field is clarity on what counts as valid citizen science, and who should be able to do CRISPR at home. Furthermore, a lack of public awareness on the matter puts people at risk.
Lastly, we still do not understand systems-wide biology well enough to predict what could happen with germline editing- genetic engineering is even difficult for professionally trained scientists, producing off-target effects. Given how difficult it actually is to genetically engineer human cells, the potential for unregulated gene editing to get out of hand is high, and the risks could be severe.
II. Inequitable Access to Gene Editing Procedures
Gene editing procedures are expensive. I created a table below of all jointly FDA- and EMA- approved cell and gene therapies currently on the market. Out of the 7 therapies, the lowest price tag is $65,000, while the highest is $2.1 million. The high cost correlates to the price of R&D that biotechnology companies pay in order to develop gene therapy products. Many of these therapies treat rare diseases, and some are one-time treatments. This means that recouping on R&D costs requires a high list price.
The price tag on gene therapies is not likely to go down for a long time, at least while they are patented. What results is a disparity between those who can pay- typically richer people and richer countries- and those who cannot.
Leading organizations are pushing for gene therapies to be more accessible. WHO Director-General Dr. Tedros Ghebreyesus addressed potential inequality in July 2021: “Human genome editing has the potential to advance our ability to treat and cure disease, but the full impact will only be realized if we deploy it for the benefit of all people, instead of fueling more health inequity between and within countries.” How we will ensure health equity is not clear and requires supplementary research. Furthermore, initiatives to grant access to underserved populations would benefit from additional resources.
FDA- and EMA- approved Cell & Gene Therapies
|Yescarta||10/17||08/18||Kite Pharma Inc. (USA)||Relapsing or Refractory Large B-cell Lymphoma||CAR T|
|Imlygic||12/21||12/15||Amgen Inc. (Netherlands)||Spreading melanoma that cannot be surgically removed||Oncolytic virus||~$65,000|
|Luxturna||12/17||11/18||Spark Therapeutics Inc. (USA)||Inherited Retinal Dystrophy with a mutation in RPE65||AAV||$850,000|
|Tecartus||07/20||12/20||Kite Pharma Inc. (USA)||Mantle Cell Lymphoma||CAR T||~$373,000|
|Zolgensma||05/19||05/20||Novartis (Swiss-American)||Spinal Muscular Atrophy with mutations in SMN1|
|Abecma||03/21||08/21||Celgene Corporation||Relapsing or Refractory Multiple Myeloma||CAR T||$441,000|
|Kymriah||08/17||08/18||Novartis (Swiss-American)||Relapsing or Refractory Follicular/ B-Cell Lymphoma||CAR T||$475,000|
III. Genetically Modified Wildlife
In 2021, Colossal Biosciences was founded by George Church, “the father of synthetic biology.” Colossal fundraised money for a project fitting of their name: bring back the mammoth. Or something akin to it, at least. At Colossal, scientists are using CRISPR-cas9 to genetically engineer mammoth genes (extracted from mammoths cryopreserved in permafrost) into Asian elephants, with the goal of making a cold-tolerant Asian elephant. The plan is to reintroduce these mammoth-elephant hybrids into the Arctic, where they once existed thousands of years ago, in hopes that they will perform the same ecological functions they did then. One of these functions would be to slow the thaw of the Arctic permafrost, a looming threat to climate change.
Colossal is not the only company working to revive de-extinct species- Revive and Restore is famous for their efforts to bring back the passenger pigeon. De-extinction is controversial, however- there are worries about ecological re-integration, human-animal interactions, animal welfare, and governance methods. For the wooly mammoth in particular, there are concerns about how populations of a new megafauna would affect indigenous peoples in the Arctic.
One study from UCSB addressed the ecological standpoint of reintroducing extinct species- “...from the vantage point of many ecologists, the viability of de-extinction as a conservation tool will hinge upon the success of bringing function back from the dead…Ecologists are likely to be a demanding audience: a resurrected mammoth counts as mammoth only if it looks like a mammoth and consumes, defecates, tramples and migrates like a mammoth.”
De-extinction has great potential for conservation efforts and is now more possible than ever. However, like many other parts of the gene editing field, there is a lack of legislation and global consensus on the best ways to re-introduce cloned or hybrid organisms back into the environment.
IV. Gene Editing as a Method of Governance
Gene editing as a method of governance is the use of gene editing technologies to advance a political agenda. The most dramatic scenarios feature a dystopian world with classes of people that are physically distinct. Brave New World and Red Rising hold examples of governments that depend on bioengineered classes. In these scenarios, there is a hierarchical nature of society which prevents each sector of people from revolting against policymakers and overseers.
Advanced gene editing makes these scenarios more realistic, but societies like that take a long time to build. This is why it is vital to research and watch for the precursors of such societies.
One of the most relevant arguments here concerns the development of genetically enhanced soldiers, which could realistically occur within the next 100 years given the rate at which technology is progressing. A 2020 report by the U.S. Defense Technical Information Center investigated the likelihood of the U.S. and Russia genetically enhancing their soldiers. The report concluded that both would very likely do so, although Russia would do so first.
Aside from issues of free will, genetically enhancing soldiers breeds issues of inequality between nations. It’s unlikely that developing nations will be able to maintain a pace of genetic enhancement that richer, more militaristic countries do. Militaristic genetic enhancement could lead to an increase in global political instability and further inequality between developing and developed nations.
Addressing the usage of genetic enhancement in war is complicated, but could be done with global lobbying efforts in the same way that The Treaty on the Non-Proliferation of Nuclear Weapons was forged.
- Timeline- Based on my research, I strongly believe gene editing technology will be transformative within at least 50 years, its use widespread for a number of purposes. However, the timeline of some of these risks is highly uncertain. For example, very few people in the field can predict when we will begin clinical germline edits. Will it be 10 years? 20? It depends on how quickly the field moves and the risks we are willing to take to progress.
- Severity- Some of these problems exist on a small and manageable scale right now, but could become severe in the future. My uncertainty lies in evaluating how likely they are to become severe. For example, if a country decides to genetically enhance its soldiers, will it also decide to enhance its police officers? With the way human nature guides power dynamics, this could become an extremely severe human rights problem within the region. Determining the likelihood and severity of long-term risks plays an important role in how much funding should be dedicated to it in the now.
Funding Opportunities (Tractability)
Prevention, Mitigation, and Adaptation Research
Philanthropists can fund research that investigates preventing, mitigating, and adapting to situations where risks become reality.
- Programs and studies that monitor biohacker activity and track unauthorized cases
- Best ways to deter rogue scientists from performing unauthorized or unethical research
- Likelihood of nations using gene editing for governance purposes
- How to educate the public about risks without encouraging fear-mongering (especially important in countries with a lot of misinformation campaigns)
- Looking at the ethics and safety of research in conservation (e.g. providing funding that looks into how genetically mutated animals would affect their environment)
- Identifying where regulations are unclear or omitted; e.g. There are protocols on how to reintroduce extirpated animals back into an environment, but what about introducing genetically-engineered- novel- animals into an environment (re: mammoth hybrids)?
- Establishing criteria for preclinical evidence of gene modification in moving forward with clinical germline editing
Educational initiatives include grants towards curriculum development, ethics training, and public initiatives.
- Funding outreach efforts for the public, particularly in underserved populations
- Developing a curriculum on bioethics for trainees, or funding training programs (Example of a similar grant through NIH)
- Developing a curriculum on gene editing for high-schoolers or college students
- Funding gene editing science experiments or internships for high-schoolers or college students (so that they have a chance to experiment with it under the guidance of mentors)
Consensus & Collaboration
Grants in “consensus and collaboration” would go towards promoting professional forums, collecting opinions and statements from stakeholders around the world, and other efforts that allow for a globalized progression of gene editing research.
- Formation of a global observatory on gene editing
- Surveys to collect national or international public opinion on gene editing practices
- Initiatives and groups that inform politicians about best practices
- Nonprofits that independently promote the discussion of bioethics in gene editing, host forums, or otherwise foster communication in the field (such as ARRIGE)
- Lobbying efforts to encourage agreements on the usage of gene editing and enhancement in war settings
Fund Gene Editing Projects that Target Underserved Populations
Grants under this topic fund gene editing projects that specifically aim to help underserved populations.
- Nonprofits that help people pay for gene therapies that might otherwise be unattainable
- Producing affordable therapies for underserved populations, particularly in developing nations
- Funding gene editing projects within developing countries, by local scientists
- Funding gene editing projects that seek to help underserved populations in some way (e.g. Target Malaria)
Life Quality and Economic Impact
This is such a huge field that it is difficult to realistically calculate an overall return on investment. However, I believe that out of the above solutions, the most tractable are those with a large breadth that are challenging but would have a high long-term reward. This includes the following:
- Funding a major outreach program for the global public, particularly in underserved populations. In an era when misinformation is prolific, fact-based education is vital to policy making and scientific investigation. Particularly in the US and UK, politicizing gene editing- especially germline- will likely occur in the same vein that it did with stem cell technologies. I believe educating the public would allow safe gene editing to progress at an efficient pace, allowing us to create treatments that save many people and increase the overall global lifespan. It might also prevent DIY biohacking accidents, and pursuit of unproven therapies.
- Formation of a global observatory on gene editing. A global observatory would serve a similar purpose to the International Panel on Climate Change, being a central forum for interested stakeholders. The authors who proposed the observatory envision it tracking and analyzing feelings of consensus or tension, being a clearinghouse for literature and position statements, and serving as an origin point for forums that encourage communication and collaboration. Despite the push for one, there does not seem to be a project underway. I believe philanthropists could fund the development of such a global observatory, with a very high return on investment in the form of vastly improving global communications about gene editing. The potential for groundbreaking publications and novel collaborations is apparent, but there needs to be kickstarters to fund such a project.
- Fund Gene Editing Projects that Target Underserved Populations. I believe projects under this category show the highest promise for short-term and long-term investment. It promotes equality between and within nations, brings up the GDP of all nations, and has the potential to greatly increase life quality and length for the populations they serve. This is where I would prioritize the majority of the funding as a philanthropist. In fact, this could be a cause area entirely on its own.
I think the biggest fault in the justification for these solutions is the lack of quantitative data. Since modern gene editing is still such a novel technology, many of the solutions listed are based on assumptions, predictions, and history of similar technologies, rather than direct data. It makes estimating DALY and economic impacts difficult, and I’m afraid if I tried the result would be redundant. However, I read through the logic that Open Philanthropy used for their other emerging technology-“Risks of A.I.”- it seems similar to what I’ve written about gene editing, in that it is mostly based in concept and a reasonable assumption that the technology will generate moderate to severe risks in the future.
Organizations and Agents (Neglectedness)
World Health Organization (WHO)- The World Health Organization is the leading voice on ethics and regulatory recommendations in the field. They also host the International Summit on Human Gene Editing every 3 years, beginning in 2015. During the Second summit in 2018, they dedicated a panel specifically to Regulations. At the end of this summit, they called for an Expert Advisory Committee to discuss bioethics and recommendations for proceeding with human genome editing experiments.
Nuffield Foundation- The Nuffield Council on Bioethics is a UK-based council whose purpose is to identify ethical questions in biology, perform independent examinations of said questions, and use the results to inform policy making. They have a current project, “Genomics healthcare and research,” that looks to inform an ethical framework on genome editing for the UK. They are collecting case studies examining how people in the UK are addressing and overcoming ethical issues raised by advanced gene editing technologies.
ARRIGE- The Association for Responsible Research and Innovation in Genome Editing (ARRIGE) is a France-based nonprofit and international consortium of scientists. They were founded in 2018 with a mission geared towards fostering communication among stakeholders and scientists. Specifically, they are concerned about creating guidelines for gene editing. So far, they have released a few statements on ethical gene editing guidelines, hosted multiple meetings, and posted various newsletters (with the most recent being July 2022).
Gates Foundation- The Gates Foundation is the most involved philanthropic foundation involved in the field. Primarily, they are interested in promoting equitable access for gene therapies and procedures. In 2019, the Gates Foundation pledged $200 million to produce affordable therapies for patients in Africa. Grants on the Gates website include $2.5 million to the UW Foundation towards developing accessible gene therapies for sickle-cell and HIV. They also pledged $2.5 million to Emerging Ag Inc. in order to educate international policymakers about the potential uses of gene drive applications. Lastly, in partnership with Open Philanthropy, the Gates Foundation helped fund Target Malaria.
Alliance for Cancer Gene Therapy (ACGT)- ACGT is a nonprofit that funds research that targets cancer using gene therapy. Since 2001, they have awarded $30 million in grants. They also participate in advocacy efforts and host annual meetings.
American Society of Gene and Cell Therapy (ASGCT)- ASGCT is a nonprofit that hosts a gene and cell therapy patient education program, online portal for patient resources, and workshops in an effort to increase public outreach/education.
John Templeton Foundation- The John Templeton Foundation’s Genetics program funds “educational programs that increase public awareness”. Total giving for the foundation is $1.95 billion. Current grant endowments could not be identified, but the average grant amount for the foundation is $1.39 million.
Briefly, I wanted to list the reasons why I chose this cause area for OP.
- OP is interested in emerging technologies, given its current dedication to the Risks of A.I.
- OP invested in Target Malaria, indicating an interest in gene editing technologies and helping underserved populations.
- B/c of the above two points, I believe it would be a natural next step for OP to develop a more dedicated cause area to gene editing that includes risk prevention and mitigation.
Secondly, I omitted two risks from this review and wanted to explain why:
- Bioengineered pandemic- Open Philanthropy already has a cause area for “Biosecurity and Pandemic Preparedness.” Many of the solutions/actions for bioengineered pandemics are the same for “natural” pandemics.
- Gene Drive organisms- OP helps fund Target Malaria, which uses gene drive mosquitoes to drive down rates of mosquito-borne diseases. Considering that Target Malaria has an independent ethics committee, and the justification detailed in OP’s Target Malaria grant, I believe they are well aware of the risks and took the proper steps to ensure the project minimized them. Discussing the risks in this review would be redundant. However, there are additional ways that gene drive organisms could be investigated- for example, looking at the safety of gene drive usage in rats. I think it’s important that altruistic foundations have a hand in these projects, since they are the most likely to evaluate the risks carefully.
- Where to prioritize funding in order to maximize equitable access?
- What specific projects are looking for funding within underserved populations that would allow an expansion of gene editing research in that region?
- The next WHO International Summit on Human Gene Editing is in 2023. What collaborations and funding opportunities will arise out of that?
- Are the authors who wrote about forming a Gene Editing Observatory working to get the idea off the ground? What is their plan and timeline?
- What welfare issues arise with genetically editing highly complex animals? Is this a tractable risk area?
- What are the social and ethical issues of editing the genomes of farmed animals? Is this a tractable risk area?