Gene Drives

For many years now, scientists have been able to alter genes inside microbial, plant, and animal cells to change organisms’ traits, creating, for example, plants that produce their own protective insecticides and fish that grow to maturity almost twice as fast as normal. But while it has become practically routine for scientists to genetically alter individual organisms, a new set of advances promises something much more ambitious: the ability to propagate new genetic traits* into entire populations over just a few generations. Rapid, population-wide dissemination of new traits is challenging because in most sexually reproducing species, only half of an individual’s offspring will inherit any given version of a gene. 

An emerging technology called a “gene drive” could solve this problem by overriding standard molecular mechanisms of inheritance and ensuring that virtually all offspring inherit a newly engineered trait, instead of just half. The prospect of accelerating the pace at which traits spread through a population from generation to generation is enticing. Imagine a few mosquitos, engineered so they can’t transmit malaria, passing that trait to every one of their many offspring until, over the course of just a few months, virtually no mosquitos in the area pose a risk of spreading malaria. But gene drives also present risks and ethical quandaries.…

What does gene-drive technology do?

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  • Sexually reproducing individuals typically have two copies of every gene—one inherited from each parent—and only one of those versions is passed on to each offspring. That means if a parent’s genome includes version A and version B of a given gene, each version has a 50 percent chance of getting passed along to a given offspring. Put differently, on average, half of one’s progeny are likely to end up with version A, and half will inherit version B. Gene drive technology changes those odds, so that a selected gene version has a near-100 percent chance of being passed down to all offspring.

How does a gene drive work?

  •  In effect, it changes one version of a gene—inherited from one parent—into a duplicate of the version inherited from the other parent. As a simple example, now there are two copies of version A and no version B, so the odds of passing A along to any individual offspring double to about 100 percent (“about” because biology is complex and many factors affect outcomes).

  • To start a gene drive, scientists introduce the desired gene into an organism or edit an existing gene to confer a new trait or to disable an unwanted trait. They also add a specialized set of molecular instructions—the recently developed gene-drive elements—which effectively duplicate that genetic change and ensure that not just half but virtually all offspring inherit it. (These gene-drive elements are themselves passed to offspring along with the altered gene, so the prevalence of that altered gene grows quickly with every generation.)

    • In a mosquito, for example, this change might block the insect’s ability to transmit malaria to people. Within a few generations–which can mean less than six months, since mosquitoes reproduce about every two weeks—a large proportion of mosquitos in a given area might be expected to now carry this new trait.

    • Results will depend a lot on such things as whether there are geographic or other barriers to the altered insects spreading out or getting diluted. But as an approximation, release of one gene-drive-altered mosquito for every 100 in a wild population would result in nearly all members carrying the gene within 10 generations.

    • Without a gene drive, the new trait would in most cases remain rare or disappear over time (especially if it offered no particular advantage to the mosquito), diluted in every generation by the far more prevalent, normal, “wild-type” genes found in everyday mosquitos.

In which organisms have scientists experimented with gene drives?

  • Primarily mosquitoes, fruit flies, and sexually reproducing yeast, whose short generation times make them excellent test subjects for this technique, as well as some studies in mice—in all cases in enclosed, specially protected laboratories to prevent escape. Bacteria and viruses, which reproduce asexually, are not candidates because gene drives work only on sexually reproducing species.

Could gene drives work in people?

  • In theory, yes. But gene drives have their most notable impact on species with very large numbers of offspring and very short generation times—not decades, as with humans.

What are the potential benefits of gene drives?

  • By significantly accelerating the propagation of a new trait in a population, gene drives could:

    • reduce or eliminate species’ ability to spread human diseases, greatly reducing the toll of some longstanding human scourges;

    • suppress plant pests that can otherwise decimate agricultural production; and 

    • help restore disturbed ecologies by weakening invasive species.

  • So powerful is a gene drive’s “finger on the scale” of inheritance, it can even increase the prevalence of genetic traits that evolution would normally cull over time, such as reduced fertility. With gene-drive technology, organisms would persistently pass this trait to virtually all offspring, despite the toll it was taking on them.

  • Gene drives could help tackle major public health issues without expensive and difficult-to-implement strategies that rely on personal behavior changes and high degrees of compliance, such as taking medications every day, buying and using bednets correctly, or trying to eliminate the countless places where mosquitos breed.

What are the potential risks of gene drives?

  • Because of the complexity and interconnectedness of the Earth’s web of life, seemingly desirable genetic changes in one species may turn out to have unanticipated, disruptive effects on others. Taken together with models suggesting that once a gene drive becomes established in a population it could be difficult or even impossible to stop, that means a gene drive could inadvertently cause long-lasting harm to the environment, the economy, or human health.
    • Case by case, such risks would need to be balanced against the risk of pursuing less effective strategies or of doing nothing.
  • There is also a risk of intentional misuse; a gene drive released by terrorists or a rogue state against, say, an agricultural target might cause significant damage and be difficult to counter.

Is there a way to limit, turn off, or reverse a gene drive?

  • Maybe. Scientists are studying whether:
    • molecular toolsets could be embedded within altered organisms to limit or even halt the spread of a gene drive to nearby populations outside the desired impact area; or
    • a new gene drive, using the original unaltered gene, could revert things to normal.
  • Experiments also suggest that gene-drive efficacy may sometimes naturally dissipate over time, whether scientists want it to or not, through the development of genetic “resistance” within the altered organisms that gradually suppresses the gene-drive elements.

What are some of the ethical questions to consider related to gene drives?

  • Is it acceptable to start a self-propagating change in the natural ecosystem without having a sure way to stop it or reverse it?
  • Who gets to decide whether to launch a gene drive given the possibility that impacts could cross political or geographic boundaries, and recognizing that each case may be different?
  • Should gene drives aim merely to reduce pest species’ numbers or their damaging behavior, or in some cases might it be appropriate to engineer a species to extinction?

Has anyone ever released a gene drive into the environment?

  • No team has reported releasing a gene drive into the environment or is even known to have formally asked permission to do so. Some researchers have proposed approaches for how to conduct such an experiment responsibly and with full transparency, for discussion purposes.

Who has oversight over gene drives?

  • In the United States, environmental release of gene-altered organisms falls under the shared regulatory jurisdiction the Environmental Protection Agency, the U.S. Department of Agriculture, and the Food and Drug Administration.
  • Internationally, in December 2016, member nations of the United Nations Convention on Biological Diversity rejected calls by 170 environmental groups to declare a moratorium on the development and release of gene-drive technology and instead released a statement urging caution if gene-drive experiments were to be attempted in the field.
    • Nearly 200 nations—including all United Nations member states except for the United States—are parties to that Convention.
    • Gene-drive technology is expected to be on the agenda again when those nations meet in November 2018 in Egypt.

Is gene-drive science ready for testing in the open?

  • In June 2016, the U.S. National Academies of Sciences, Engineering, and Medicine released a report, “Gene Drives on the Horizon,” prepared by a committee of experts in the natural and social sciences, ethics, and the law. The report:
    • referred to the “breathtaking” pace of change in the gene-drive field in recent years as “both encouraging and concerning”.
    • concluded that “There is insufficient evidence available at this time to support the release of gene-drive modified organisms into the environment. However, the potential benefits of gene drives for basic and applied research are significant and justify proceeding with laboratory research and highly controlled field trials.
    • called for improvements in the ability to model, or predict, the effects of a proposed gene drive, by better understanding such key factors as the affected species’ role in the environment; whether other species would fill a similar ecological niche if the affected species were to disappear; the likely impact on other species that have co-evolved with the affected species; and whether mechanisms of resistance would naturally emerge, which could slow or stop a gene drive, for better or worse.
    • called for a “precautionary, step-by-step” sequence of contained experiments to gain knowledge about potential benefits and risks, to provide time for public engagement, and to resolve issues of governance, but it does not preclude moving ahead with field tests under some conditions.

*The relationship between “genes” and “traits” is complicated. Some individual genes can result in a trait all by themselves. Other genes may only do so in conjunction with other genes, or with other limits. For simplicity, we limit our discussion here to simple traits that can be programmed with a single gene.

 

LAST UPDATED APRIL 18, 2018

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Sources

Key references for those who want to dig deeper

1.  Gene Drives on the Horizon, 2016, National Academies of Sciences, Engineering, and Medicine, is a comprehensive, 230-page assessment outlining the state of knowledge about the science of gene drives and related issues including ethics, public engagement, risk assessment, and research oversight and governance.

2. The mutagenic chain reaction: A method for converting heterozygous to homozygous mutations, 2015 (Science) is the first published, peer-reviewed scientific report showing evidence that gene drive technology could successfully increase the inheritance of a given gene, in this case in fruit flies.

3.  Highly efficient Cas9-mediated gene drive for population modification of the malaria vector mosquito Anopheles stephensi, 2015, (Proceedings of the National Academy of Sciences) is a seminal research report describing the creation of mosquitos with gene-drive elements to suppress malaria transmission, and raising some of the ethical and public policy issues that would need to be addressed before such insects were released into the wild.

4.  Safeguarding gene drive experiments in the laboratory, 2015, (Science) is an early commentary by several leading scientists in the gene-drive field addressing the need for agreed-upon confinement strategies to ensure that experimental organisms do not escape into the wild.

5.  Rules of the road for insect gene drive research and testing, (2017), (Nature Biotechnology) is a letter to the editor from 20 researchers involved in gene-drive research, proposing approaches to oversight and governance of the field.

6. US Defense agencies grapple with gene drives, 2017, (Nature) describes interest in gene drives by the US Department of Defense and among scientists focused on national security issues.

7.  Gene drives thwarted by emergence of resistant organisms, 2017, (Nature) is a science-journal news article describing emerging evidence that in some cases organisms altered by gene drives might naturally become resistant to the engineered change and no longer pass those changes to their offspring.

8. The creation and selection of mutations resistant to a gene drive over multiple generations in the malarial mosquito, 2017, (PLoS Genetics) describes experimental evidence for the emergence of gene-drive resistance and offers some approaches to overcoming it should researchers want a gene drive to persist.

9. Current CRISPR gene drive systems are likely to be highly invasive in wild populations, 2017, (bioRxiv) is a non-peer-reviewed report warning that, under some conditions, gene drives may prove “even more invasive” than anticipated. One of the authors of this report offers additional perspective in a piece he co-authored, Conservation demands safe gene drive 2017, (PLoS Biology).

10. Roadmap to Gene Drives: Research and Governance Needs in Social, Political, and Ecological Context, Dec. 2017/Jan. 2018, (Journal of Responsible Innovation), is a diverse set of articles stemming from a 2015 workshop held at North Carolina State’s Genetic Engineering and Society Center focused on the scientific and societal issues currently in play in the gene drive research world.