Gene Drives on the Horizon: Issues for Biosafety

Abstract

In June 2016, the National Academies of Sciences, Engineering, and Medicine published a 220-page report from its multidisciplinary Committee on Gene Drive Research in Non-Human Organisms, which addressed the state of the science of gene drive research and related governance, as well as an array of ethical, social, and legal considerations. Gene drive research is scientifically intriguing and ethically daunting because, unlike other applications of new gene-editing technologies, an effective gene drive is intended to cause the spread of a specific genetic modification through a population and potentially throughout an entire species. This technology holds promise for addressing complex and persistent challenges in public health and ecology but also raises the threat of unintended consequences. Biosafety specialists will have an important role in defining and meeting the need for effective containment, mitigation, and governance strategies for gene drive research. This article reviews the conclusions and recommendations of the committee and recent commentary from leading gene drive researchers, with emphasis on issues in biosafety.

In June 2016, the National Academies of Sciences, Engineering, and Medicine (NASEM) published a 220-page report on the scientifically intriguing and ethically daunting research on gene drives. Gene drive is a naturally occurring phenomenon that has generated considerable scientific interest as a result of new gene-editing techniques, particularly CRISPR-Cas9, that make targeted modifications possible in the genomes of an array of sexually reproducing species. Unlike other applications of gene-editing techniques to date, an effective gene drive could alter traditional Mendelian genetics in some sexually reproducing species, causing the spread of a specific genetic trait through a population and potentially throughout an entire species. This technology holds promise for new approaches to addressing an array of complex and persistent challenges in public health and ecology; it simultaneously raises the threat of unintended consequences and the need for effective containment, mitigation, and governance strategies.

Gene Drives on the Horizon was written in response to a 2015 request from the National Institutes of Health and the Foundation for the National Institutes of Health, which charged the NASEM’s Board on Life Sciences to do the following:

Review the state of the science of gene drive research and identify the key scientific techniques for reducing ecological and other risks, as well as the mitigation strategies that should be considered prior to field releases of organisms carrying gene drives

Examine oversight mechanisms and regulations for research with gene drive–modified organisms in laboratories and other contained or semicontained environments, in field trials within the United States, and in field trials in low- and middle-income countries

Discuss relevant legal, social, or ethical considerations in selecting sites for field trials

Provide general principles to guide investigators and their institutions, as well as funders and regulators, in responsible practices in gene drive research.

The 16 members of the committee appointed to address these questions represented a highly diverse assortment of disciplines, from biosafety and biosecurity to entomology and plant biology to population ecology to risk assessment to ethics, science policy, and the law. The committee’s final report ¹ promotes a broad definition of responsible gene drive research, as it addresses the challenges that face researchers and their institutions and communities, as well as those facing funders and regulators in the United States and around the world.

The Science of Gene Drives

Gene drive is a natural phenomenon of biased genetic inheritance in which mechanisms such as meiotic drive, homing endonucleases, and transposable elements cause certain traits to spread through a population at higher rates than the 50% seen in traditional Mendelian genetics. With the advent of CRISPR-Cas9, researchers have explored the creation of intentional gene drive mechanisms in several species. Proof of concept has been established in a gene drive–modified yeast, ² a gene drive–modified fruit fly, ³ and 2 species of gene drive–modified mosquito^4,5; work is also underway to develop a gene drive–modified rodent. ⁶ Gene drive modifications in sexually reproducing plants have also been proposed. ¹

The goal of developing a gene drive–modified organism is typically to spread a specific modification through a wild population, either to replace a perceived noxious trait in the species with a benign or beneficial one or to reduce or eliminate the target population itself. For example, the malaria-transmitting mosquitoes in which gene drives have been developed in the laboratory are from 2 of the 6 species of mosquito (out of 3000 species worldwide) that are vectors for human infectious disease.^4,5 One research trajectory has led to a gene drive–modified version of Anopheles stephensi that is unable to carry—and thus unable to transmit—the malaria-causing parasite Plasmodium. ⁴ The other line of research has developed a gene drive version of a sterile insect technique, rendering female Anopheles gambiae mosquitoes unable to reproduce. ⁵ Discussion of developing gene drive–modified mice includes plans for both disease control (reducing the incidence of Lyme disease by making the white-footed mouse either immune to the pathogen or resistant to the ticks that spread the disease) ⁷ and conservation (reduction or elimination of the nonindigenous house mouse Mus musculus to protect native biodiversity on islands). ¹ Although the potential for useful gene drive modifications in plants currently seems limited, proposed agricultural uses of gene drive–modified organisms include changing or suppressing organisms that transmit plant diseases or otherwise damage crops. ¹

Preliminary evidence from studies published to date indicates that a gene drive–modified organism developed in the laboratory could be used to spread a trait through up to 100% of a wild population and that the trait would likely persist over generations. But much remains unknown about the science of gene drives and the behavior and impact of gene drive–modified organisms both in and outside the laboratory. While comprehensive biosafety systems are largely in place for other forms of gene-editing research, many of the most prominent gene drive investigators remain concerned that much more attention to biosafety is needed for gene drive research. In 2015, a group of the field’s most active researchers advocated using multiple stringent confinement strategies whenever possible. ⁸ They further urged that researchers who are intending to work with gene drives or potential gene drive systems have the relevant biosafety authorities conduct a thorough evaluation of the risk of unintended release of a modified organism from the laboratory. ⁸

However, understanding fully how gene drives work—at the molecular level, within a single population, and in the context of an ecosystem—will require extensive and complex research in the laboratory and in the field. Achieving the potential public health or ecological benefits of gene drives will ultimately require the open release of gene drive–modified organisms into the environment. The biosafety challenges posed by gene drives stem from the fact that they are intended to spread genetic modifications efficiently through populations; therefore, containment is ultimately undesirable. As gene drive research matures, biosafety specialists will need to look beyond containment to establish processes to recognize and prevent the potential unintended ecological consequences of releasing gene drive–modified organisms, whether intentional or accidental.

Moving from laboratory studies to field research also significantly increases the level of uncertainty about the safety of gene drives. The likely unintended consequences of introduced gene drives include off-target effects on the modified species, disruption of nontarget species, and the undesired response of the target species or the diseases they carry to continue with similar or even greater virulence. Moreover, the effects of a gene drive–modified organism on the ecosystem are likely to be irreversible. The committee concluded that anticipating and preventing unwanted ecological effects of gene drive–modified organisms will require in-depth multidisciplinary collaboration among researchers from molecular biology, population genetics, evolutionary biology, ecology, and the social sciences to establish best practice standards for specific kinds of gene drive research. Moreover, to prevent the unnecessary repetition of unsuccessful experiments or potentially dangerous procedures, the committee recommended that gene drive researchers share standard operating procedures and related information through open online databases.

Ecological Risk Assessment and Phased Testing

Anticipating the risks of new research is an essential component of responsible science. The committee concluded that gene drives’ potential to spread quickly throughout a population, persist in the environment, and have irreversible effects on ecosystems demands careful and comprehensive risk assessment before undertaking gene drive research. It deemed the established approaches of environmental assessment and environmental impact assessment, required under the National Environmental Policy Act, to be too limited to address the population dynamics and evolutionary processes that may be affected by the release of a gene drive–modified organism into a complex ecosystem. Instead, the committee recommended the multifaceted approach of ecological risk assessment. Ecological risk assessment examines the immediate and long-term harms and benefits of a given activity and its alternatives, through the use of dynamic multivariate statistical modeling. ⁹ While uncertainty can never be eliminated, ecological risk assessment allows researchers to trace cause-and-effect pathways, quantify the likelihood of specific outcomes of concern, and highlight sources of continued uncertainty.

Extrapolations from other kinds of genetic research may inform predictive models of a gene drive’s off-target and nontarget effects and may be useful in estimating other variables, such as gene flow, population change, trophic interactions, and community dynamics. Eventually, however, reducing uncertainty around gene drives will require data from actual gene drive research. In cases where ecological risk assessment demonstrates the anticipated benefits of gene drive research to outweigh the risks of perceived harm, expanded laboratory studies and confined field research (eg, greenhouse trials and large cage- or tank-based studies) will be needed to generate those data.

The committee recommended that, before any such trial begins, researchers, their institutions, and their funders engage in case-by-case evaluation with a structured decision-making process, such as the World Health Organization’s Guidance Framework for Testing of Genetically Modified Mosquitoes, to determine when it is safe to proceed. ¹⁰ Using this framework as a model, the committee recommended that gene drive researchers follow a 5-step phased testing pathway that starts with careful research design and preparation for research (phase 0) and moves to laboratory-based research (phase 1), field-based research (phase 2), staged environmental release (phase 3), and, as applicable, postrelease surveillance (phase 4). The pathway incorporates a number of feedback loops and predefined go/no-go decision points that require investigators to identify benchmarks and the data necessary to meet them and move safely to the next phase.

Institutional biosafety committees (IBCs) and biosafety professionals have a vital role to play in this evaluation process and the stepwise decisions to develop a gene drive–modified organism. IBCs have provided a robust system of oversight and safeguards for genetic research for the past 40 years. Nonetheless, the NASEM committee found that due to the novel characteristics of gene drives, few regulatory standards apply directly to gene drive research. Moreover, the committee concluded that many IBCs are unlikely to have the expertise or resources to assess the safety of gene drive research or to advise investigators’ practice and that even fewer are prepared to address issues of biosecurity or the intentional misuse of gene drives. Nonetheless, current leaders in gene drive research report working closely with their IBCs, and they offer important potential lessons for policy and practice at other institutions. ⁸

Values and Public Engagement in Considerations of Biosafety

A key feature of the NASEM committee’s recommendations and overall approach was its observation that questions about the responsible conduct of gene drive research depend on values at every step. Widely held ethical commitments to preventing disease, promoting human welfare, and protecting the environment imply that society must take the promise of gene drive research seriously. But those same values may simultaneously argue for restrictions—even prohibitions—against gene drive research if it poses risks of harm that outweigh the probability of meaningful benefit. What constitutes a meaningful benefit and an unbearable harm is not a strictly scientific calculation. The committee argued that researchers, institutional officials, funders, and regulators cannot truly assess the potential benefits and harms of gene drive research and the possible release of gene drive–modified organisms into the environment without the informed input of the individuals, communities, and publics who will be affected by them. Public engagement must be an integral part of planning, assessment, and regulation of gene drive research, including considerations of biosafety. This point was more forcefully stressed by gene drive researchers concerned about not only field trials but also the potential impact of a single laboratory accident on surrounding communities and ecosystems. ¹¹

Some structures exist for public engagement in the assessment of biosafety and the regulation of biotechnology in the United States, but there is generally little clarity on how the public’s values should shape governance generally or gene drive research specifically. IBCs typically have provisions for public access to records, but there are few opportunities for public education about biosafety or public participation in deliberation or agenda setting. The committee recommended that research institutions, funders, and regulators with responsibility for oversight of gene drive research develop and maintain clear policies and mechanisms for how public engagement will factor into research, ecological risk assessments, and public policy decisions about gene drives.

As noted by participants in a recent workshop hosted by the J. Craig Venter Institute on gene drive research in insects, guidance on community engagement for researchers and product developers is a foremost priority, especially regarding how to work with communities in developing and testing new approaches to the control of insect-borne infectious diseases and agricultural pests. ¹² Prior NASEM panels have addressed the complex process of public participation in environmental assessment and policy making, ¹³ but the gene drive committee noted that much more work is necessary to understand how best to conduct public engagement on the many levels relevant for gene drive research.

Challenges in the Governance of Gene Drive Research

The committee found that the regulation of gene drive research does not fit well within either the purview of any of the US agencies involved in the coordinated framework for the regulation of biotechnology (eg, the Food and Drug Administration, the Environmental Protection Agency, and the US Department of Agriculture) or the international regulatory framework provided by the Convention on Biological Diversity and its Cartagena Protocol. In this context, where the regulation of biosafety lags behind unpredictably rapid developments in research, the committee recognized the fundamental contribution that scientists must make to governance in defining best practices and articulating safety standards. It called on researchers, IBCs and institutional administrators, and those who fund research to work with policy makers to define and formalize flexible and rapidly adaptable governance policies on the safe conduct and oversight of gene drive research.

Because gene drive research offers particular promise for the control of previously intractable vector-borne diseases in low-resource countries and because gene drive–modified organisms released into the environment are likely to spread across national borders, international collaboration in research and policy making will be essential. The committee called on international biosafety experts to reconcile the preventative and permissive regulatory schemes adopted by various nations, especially where differences create gaps in the ability to protect human health and the environment. Moreover, professional capacity building related to biosafety in gene drive research will be particularly important in countries that do not have the resources needed to enforce international standards through regulation and formal oversight.

Conclusion

Responsible conduct and systems of governance for biosafety in gene drive research will need to incorporate clear mechanisms for international dialogue among researchers, research institutions, funders, and governing authorities and, perhaps, formal or informal agreements about the use of potential gene drive–modified organisms. Professional journals such as Applied Biosafety are integral to the discourse on best practices in biosafety for gene drives and evolving perspectives on their potential benefits and harms. Barbara Johnson’s Animal Bytes column in the previous issue was a welcome introduction to the many biosafety challenges posed by new gene-editing techniques, and we look forward to the future contributions of Applied Biosafety’s readers.