Democratizing Collective Biotechnologies
We live in interesting times. Billions have risen from poverty to prosperity, though at a high cost to environmental sustainability. Habitat destruction, invasive species, and overharvesting are driving the toll of extinction ever higher; climate change exacerbates these problems and damages agricultural productivity just as we are running out of arable land. Meanwhile, billions remain remain impoverished and stricken with diseases for which we have few economical cures. There is widespread agreement that we must transition towards a sustainable 'green' future, but biotechnology is hampered by widespread public distrust of genetic engineering. More generally, the scientific consensus is questioned in areas as diverse as climate change, vaccines, and GMOs, numerous fields struggle with a crisis of reproducibility, and the life sciences remain mired in an outdated publication system that blocks the distribution of knowledge. Perhaps most ominously, rising risk aversion and increased social and political distance between citizens and ever more specialized scientist/engineers threaten our ability to deploy new technologies to solve urgent global problems.
Into this volatile mix, throw a disruptive spark: my colleagues and I recently described and then demonstrated how synthetic “gene drives” based on CRISPR/Cas9 genome engineering could spread virtually any genomic change made in the laboratory through populations of wild organisms. Even alterations that reduce the odds of survival and reproduction – as nearly all changes do – can be driven through populations by biasing inheritance in their favor.
The premise of a Cas9 gene drive is simple: in each generation, replace the wild-type gene with an edited version, thereby ensuring that all offspring will inherit the alteration. This can be done by encoding the molecular scissors we currently use to edit genes next to a particular alteration. When the resulting gene drive organism mates with a wild-type counterpart, all offspring will inherit one edited and one wild-type copy. The scissors cut the wild-type copy and the cell uses the edited version as a repair template, eventually producing sperm or eggs with two edited copies that are guaranteed to be transmitted to all offspring.
Biasing inheritance is an incredibly common strategy in nature; nearly every genome ever sequenced has some type of natural gene drive. Because Cas9 privileges design over evolution, we can harness this same strategy to drive nearly any altered trait through wild populations. The implications for our relationship with nature are profound.
Imagine a world where mosquitoes no longer spread malaria or dengue, chikungunya or yellow fever. Children can freely venture outdoors because ticks cannot transmit Lyme. Locusts no longer swarm and spark famines, agricultural pests have no taste for our crops, weeds are kept in check without toxic herbicides. The worst invasive species have been confined to their native habitats; freed of their destructive influence, ecosystems are returning to health.
We can make that world a reality. Many of the requisite advances are feasible within a decade; all are accessible within twenty years. On a technical level, we must study gene drives in large laboratory populations over many generations, develop candidate applications in target species, and carefully assess of the ecological effects of each candidate gene drive; I am pursuing each of these goals with a variety of collaborators (Technical Requirements).
But technology alone is not enough. Deciding whether, when, and how to use gene drives will require societal engagement and coordination. We began this process by publishing our technical analysis in eLife detailing how Cas9-based gene drives could be used to alter species and reverse alterations that turn out to be mistakes, provided safeguards to prevent accidental release, and called for transparency, engagement, and discussion – all before building gene drives in the laboratory. We also published a policy forum in Science on appropriate risk assessment, regulation, and necessary reforms, and an online article at Scientific American explaining the technology, the ethical issues, and the need for openness and humility. By many measures our efforts were successful; we received extensive media coverage and favorable reviews from both prominent bioethicists and longstanding critics of biotechnology. Yet the odds are that you have not previously heard of gene drives, so a great deal of work remains. And while our successes to date are gratifying, I remain more familiar with sculpting the evolution of biomolecules and ecosystems than the media landscape and popular opinion.
That opinion will matter more than ever, for gene drives are an inherently collective technology: each use reshapes the common environment shared by all. As strikingly demonstrated by the ongoing controversy over genetically modified organisms, public acceptance requires trust, and trust requires early two-way engagement and the acknowledgement of shared interests. How we approach gene drives and other collective biotechnologies will have ramifications far beyond human and environmental health.
By embracing full transparency and inviting public involvement with gene drive development in my own laboratory and those of my colleagues, I hope to set a precedent of early engagement, citizen science, and community ownership in this nascent field. Gene drives might thereby provide a model for the responsible development of other technological solutions and collective technologies such as geoengineering. And just as a driven gene spreads through a population, the practices of a single transparent field in which citizens are closely involved with research and development could spread throughout the life sciences, catalyzing a shift in the scientific ecosystem towards earlier sharing of results through preprints, greater engagement of citizen scientists, and improved cooperation between disciplines. In other words, successfully involving the public in the story of gene drives may represent a single coordinated solution to a remarkably diverse group of ecological and societal challenges.
A key question is whether any of this can be accomplished in traditional academia, which struggles to embrace the idea of merging the fields of molecular biology and evolutionary ecology, much less adding engineering, ethics, and citizen science. Even interdisciplinary centers and institutes tend to interpret “transparency” and “engagement” as buzzwords invoked to secure NSF funding. Most importantly, they do not count successes in these areas as equivalent to laboratory advances, effectively handcuffing young scientists seeking nontraditional paths to changing the world. In such an institution, I might pursue the science in my own laboratory, even transparently, but time spent on community involvement would be time wasted with respect to tenure and advancement.
How might we encourage citizens to involve themselves in gene drive science? The end-stage goal is clear: a community of citizens interested in helping to answer the “whether, when, and how” of gene drive technology. This community should be diverse in age, educational and economic background, politics, country of origin, and level of trust in scientists, technology, and genetic modification. It must include a forum that welcomes concerns and criticism of all kinds, enabling respectful discussions that in time could be distilled into specific empirical questions, which in turn would direct gene drive research in my laboratory and those of both professional collaborators and citizen scientists. Scientifically inclined community members might contribute directly by performing experiments on their own or in collaboration. Others might analyze data or devise improved methods of presentation. Those skilled in composition might help critique, edit, or even write publications or grant proposals. Perhaps most valuable of all, those philosophically opposed to the very idea of gene drives might stretch their creativity to the limit in offering objections, and thereby ask every question that must be answered to ensure responsible use.
Channelling and discussing concerns, directing laboratory research, and participating technically shouldn't be the only ways to engage. People interested in communication and education could devote themselves to making exhibits for museums, or enter contests for the best explanatory animation targeted at people of a certain age or education level. Others might be competitive fans of a particular application and root for it to beat out others in a race to improve the world. Programmers might build games to help solve technical challenges in the field analogous to EteRNA and FoldIt, or devote their expertise to creating educational games that help players learn about gene drives while trying to solve simulated ecological problems. Others might contribute artistically by making explanatory animations targeted at different education levels, or original sketches to reward exceptional contributions. Creative writers might be inspired to write fan fiction detailing the quests and adventures of anthropomorphized gene drives, thereby telling the story in an entirely new way.
In coming together with respect and humility to make a better world, such a community would exemplify the best of humanity. I cannot imagine a better way to address difficult and controversial scientific and societal problems, especially those involving collective technologies, than with community direction, participation, and support.
How might we catalyze the formation of this community? We might convey an artistic vision of that imagined future, invent new ways of democratizing science through civic engagement, and seek to understand the social dynamics of involvement and rejection. We could devise creative ways of encouraging children to play with natural systems, build public interfaces with the laboratory science, encourage participants to shape the story of our collective efforts to speak with nature, and eventually scale these developments to diverse communities and other fields of science. Success could emerge from any combination of these, or from other creative approaches that haven't yet been invented.
These answers should emerge naturally if I pursue the technical and scientific questions within a community already devoted to issues spanning art and science, design and engineering, communication and democratization: the Media Lab. Whether through deliberate collaborations between project leaders or student ventures originating in idle speculation over lunch, the confluence of people working on these problems will catalyze solutions that could never otherwise appear. Perhaps one of these may prove crucial in tipping the balance towards our imagined future, for we have only one chance to get this right. The sensitivity of the subject is an amplifier in both directions: an early disaster could disgrace biotech and open science, an early success will open opportunities that multiply as they are seized.
What I might offer the Media Lab beyond the facts listed in my CV? A unique viewpoint on evolution, certainly, in both the biological and cultural realms. A creative compass that enjoys combining the metaphors of art and the elegance of nature with the utility of functional design, and placing all three in the service of science. A deep sense of obligation to forge a better world, regardless of the technical or regulatory hurdles, and to take responsibility for the outcome. A history of engaging with ethicists, political scientists, and regulators outside of traditional silo of science. The capacity to design and evolve new biomolecular tools that could aid efforts in neurobiology and molecular automation. A passion for playing with ideas that span disciplines. Perhaps most important of all, a record of conceiving, designing, and actualizing highly innovative technologies.
Phage-assisted continuous evolution (PACE) is a synthetic ecosystem that harnesses parallel populations of a hundred billion bacteriophages to evolve useful biomolecules at >30 generations per day without human intervention. It's currently being used to evolve a truly safe method of gene therapy, among many other applications. CRISPR/Cas9 has revolutionized genome engineering and regulation in dozens of species. Less obviously, targeting multiple sequences with Cas9 can render evolutionary escape arbitrarily difficult, a rare example of a technology that privileges design over evolution. Based on this principle, my colleagues and I have developed ways of stably immunizing cells against hundreds if not thousands of target sequences at once. Targeting predatory bacteriophages can provide a fitness advantage not found in nature, enabling engineered bacteria to outcompete natives. In individuals, this technology could immunize our internal microbial communities against genes promoting pathogenic behavior and antibiotic resistance and confer resistance to invasion by external pathogens. If spread via horizontal gene transfer through populations of wild bacteria, such an element could prevent its hosts from acquiring genes that encodes toxins such as the one responsible for cholera, potentially driving them extinct in the wild; it is another example of a collective technology. And of course, RNA-guided gene drives based on Cas9 will permit us to reliably and reversibly engineer most populations of sexually reproducing wild organisms.
Some of these technologies can be used freely, others will be tightly regulated, and still more are morally complex, but none will reach their full potential without a radical shift in how science engages society and vice versa. By democratizing the pursuit of collective biotechnologies in a spirit of openness and humility, we have a unique opportunity to earn the faith and goodwill of our fellow citizens. Only in coming together can we gift our children's children with the story of how humanity collectively sculpted a better world.
References and quotes:
1. “For years, researchers have tinkered with genomes to try to produce a fuel, drug, or crop with a specific quality, but the new technology is not nearly so limited in scope. It is conceived of as a way to alter the world outside the lab or beyond the boundaries of a farm field.” - The Boston Globe
2. “This is one of the most exciting confluences of different theoretical approaches in science I’ve ever seen. It merges population genetics, genetic engineering, molecular genetics, into an unbelievably powerful tool.”
- Arthur Caplan, New York University
3. “The scientists involved (with gene drives) deserve to be commended for raising the issue of appropriate regulation, and we should note that one of the safety proposals is a plan to reverse such interventions should there develop a problem.”
- Pete Shanks, Biopolitical Times, Center for Genetics and Society
4. (The gene drive work was developed in the spirit of) “anticipatory governance, an argument that we as a society ought to be thinking about the ethical implications, legal implications, and societal implications of technology before it is developed.”
- James P. Collins, Arizona State University
5. “The thing that really slows things down is making a big mistake.” - George Church, Harvard University
6. “We recommend that all future research involving gene drives and other technologies capable of altering populations and ecosystems be conducted in full public view, with all empirical data and predictive models freely and openly shared with the global community in a transparent and understandable format. Only through broadly inclusive and well-informed public discussions can we as a society decide how best to manage our shared environment.” - Kevin Esvelt, George Church, and Jeantine Lunshof
Technical RequirementsFirst, we must understand the long-term effects of gene drives on populations and their evolution. This entails studying gene drives in large populations of fast-reproducing model organisms over many generations. We must use these systems to test and optimize different types of gene drives and quantify their potential to spread beyond the target population. The best model organism for this purpose is the nematode worm, which reproduces every 3 days, can be readily grown in the tens of millions, and computationally counted and distinguished by the color in which they fluoresce from microscope images. I am currently building gene drives in nematodes for just this purpose.
Second, we must identify begin constructing gene drives intended for candidate real-world applications, many of which will require working with organisms such as malarial mosquitoes that are currently difficult to engineer. I am collaborating with several laboratories working in different kinds of mosquitoes (to eliminate malaria, dengue, chikungunya, and yellow fever) and laying the groundwork for desert locusts and ticks.
Third, we'll need to carefully measure the potential ecological consequences of each candidate gene drive in order to accurately assess risks. That means cataloguing which species interact with the target population, studying what happens when we release organisms that have the proposed set of alterations but lack a functional gene drive to spread them, and combining this information with laboratory studies of gene drive fitness and evolution to model the likely outcomes. All of this information must be submitted to the National Academy of Sciences, the best truly neutral scientific body, to produce a risk assessment, which will be submitted to the FDA or corresponding international regulatory body for approval. According to authorities at the FDA, the National Academy assessment will determine whether or not approval is granted for a given gene drive.
Finally, all laboratory research must be performed without risking an accidental release into the wild. We outlined several containment methods that are proof against human error in our original eLife publication. I am currently promoting universal adoption of these safeguards and regulatory standards in the scientific community.