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Foundation for the National Institutes of Health — Working Group on Malaria Gene Drive Testing Path

Award Date 
7/2016
Grant Amount 
$1,228,845
Purpose 
To support development of a consensus pathway for field testing modified mosquitoes with driving transgenes
Topic (focus area) 

Published: July 2016

We decided to write about this grant in order to share the rationale for our interest in gene drives. This page is a summary of the reasoning behind our decision to make the grant; it was not written by the grant investigator(s).

Foundation for the National Institutes of Health staff reviewed this page prior to publication.

The Open Philanthropy Project awarded a grant of $1,228,845 to the Foundation for the National Institutes of Health (FNIH) to form a working group to support development of a consensus pathway for field testing modified mosquitoes with driving transgenes.

The FNIH proposes to convene a working group of approximately twenty experts to recommend a consensus path for field testing gene drives to fight malaria. This recommendation will include guidelines on how to safely field test gene drives for population modification and population suppression of vector mosquitoes in order to determine whether they could safely and ethically be deployed widely. To date, the FNIH and the Bill & Melinda Gates Foundation (BMGF) have been key actors supporting the development of this new technology, including commissioning of prior independent studies to consider best practices, and we think the FNIH is well positioned to convene a working group to develop a field testing pathway that can be used to inform researchers and other stakeholders. Our hope is that developing consensus around a testing pathway will clarify the requirements and reduce the amount of time needed before a gene drive affecting malarial burdens could be released, if the technology is eventually determined to be feasible, safe, and ethical.

Background

The cause

As part of our work to investigate potential focus areas within the category of scientific research, we became aware of a relatively new technology called “gene drives” (see this New York Times article for an overview).

One important potential application of gene drives that has been discussed is to prevent the spread of malaria by significantly reducing the population of mosquitos that can carry it.1

According to the World Health Organization (WHO), 438,000 people died from malaria in 2015.2 Our interest in this technology is driven by the potential, if it can be deployed safely and effectively, to substantially reduce this figure.

Many questions about the potential development and deployment of gene drives sit at the intersection of science and policy. Accordingly, our investigation of the topic has explored it from both perspectives, led by staff members who focus on each of science and policy (including scientific advisors).

The organization

The Foundation for the National Institutes of Health (FNIH) was established by Congress in 1990 as a not-for-profit 501(c)(3) charitable organization to support the mission of the National Institutes of Health (NIH). The FNIH procures funding, manages inter-institutional relationships, works with partner institutions, and provides other support to help accelerate biomedical research.3

About the grant

Proposed activities

FNIH proposes to convene a working group of approximately twenty experts to develop a consensus recommendation on a pathway for field testing gene drives focused on population modification or population suppression of mosquitoes in an effort to significantly reduce the burden of malaria in Sub-Saharan Africa. The working group will aim to include experts in malaria research as well as insect containment/quarantine, mathematical modeling, epidemiology, clinical trial design, and regulatory science. The working group will also aim for geographic diversity and representation from the World Health Organization and the New Partnership for Africa’s Development (an African Union technical advisory body).

The FNIH plans to hold three meetings of the working group in different countries, then to conclude the process by publishing a set of recommendations in an open-access peer reviewed journal. The anticipated timeline for this work is around 18 months.

One specific question we expect the working group to address is whether the field testing pathway should, in addition to cage and other field trials, include a self-limiting release.4 We are interested in learning from the working group’s process what sorts of questions or risks a self-limiting release might address and whether they are sufficiently important to warrant the associated delay.

Budget and room for more funding

The FNIH’s proposed budget for this project is $1,228,845. Absent our funding we think it is fairly likely that BMGF would have funded the creation of the working group, but we do not consider this a strong reason not to make this grant because we would guess that the counterfactual use of their malaria funds is likely to be quite cost-effective.

Case for the grant

Our understanding is that there is not yet consensus on what a pathway for field testing gene drives focused on modifying or suppressing vector mosquito populations should look like. Our guess is that developing such a consensus path might help accelerate the identification and redress of technological, ethical, and regulatory issues, leading to a faster eventual timeline for deployment if it is determined to be appropriate. We also believe that supporting this project is likely to help us better understand the open questions and any disagreements between key parties.

The FNIH seems to us to be well-positioned to lead the process of developing a consensus proposal. Our understanding is that the FNIH (working with funding from BMGF) has been instrumental in supporting gene drive research to date, and that it has experience convening groups of this nature. For instance, it co-organized with WHO a similar report on consensus standards for testing non-gene-drive genetically modified mosquitoes (GMMs) in the past.5 That report was opened for public comment in 2012, and was subsequently incorporated into a WHO guidance framework that was published and adopted in 2014.6 The FNIH also co-sponsored a recent report from the National Academies of Sciences on responsible conduct of gene drive research.7

As mentioned above, the main positive effect we hope this grant could have is reducing deaths from malaria, though we think the grant could also have a smaller positive impact by accelerating a regulatory rejection of gene drive technology (and thereby freeing up research funding and effort for other things) if that turned out to be appropriate. In terms of reducing deaths from malaria, we think a natural comparison point to use is a grant to the Against Malaria Foundation (AMF), the top recommended charity of our sister organization, GiveWell. Roughly speaking, we estimate that this $1.2 million grant would be more cost-effective than a similarly sized grant to AMF if it relieved two days worth of future malaria burden (more details on this estimate in the footnote).8

Though we see it as a bet worth taking, we think there is a very considerable likelihood that this grant never affects malaria burden at all, for any number of potential reasons, falling into two main buckets:

  • The working group doesn’t have any impact on gene drive development:
    • The working group fails to develop consensus.
    • The consensus recommendations are fairly obvious, and so don’t argue for any changes relative to current plans.
    • The consensus recommendations are never adopted by key regulatory bodies, and so projects have to follow the same path they would have had to otherwise.
  • Gene drives don’t affect malaria:
    • Gene drive technology turns out not to work or to be unsafe to deploy.
    • Authorization for gene drive deployment turns out to be impossible to achieve.
    • Another technology leads to malaria eradication prior to gene drive having any impact.

Though we think these risks jointly make it quite unlikely that this grant will have any impact on malaria, we see the possibility that it could have a significant impact by leading to faster field testing timelines as sufficient to justify the grant.

Risks and reservations about this grant

We find it plausible that this project could potentially cause an unnecessary delay in the deployment of gene drives to reduce the burden of malaria. If the working group consensus process produces a recommendation that commits researchers working on anti-malaria gene drives to a sub-optimal testing pathway, safe and ethical deployment could take place at a later date than would have been the case in the absence of the working group. We think this is unlikely and that the risk of our grant causing this outcome is mitigated by the likelihood that another funder would have supported it in our absence.

Plans for learning and follow-up

We do not expect to produce any updates on this grant until after the working group has completed its work, though we are hoping to attend its meetings if scheduling allows. Once the committee has completed its work, we plan on writing a public review of that work and an update about this grant.

Key questions we will follow up on include:

  • Did the working group reach a consensus on a plan that seems likely to reduce uncertainty about the field testing path for a malaria gene drive?
  • What, if any, disagreements arise during the working group’s convening?
  • What do we think about the consensus path recommended by the group?
  • Do other organizations (e.g., the WHO) ultimately support the consensus of the group?

Sources

Document Source
Esvelt et al. 2014 Source (archive)
FNIH, About Us Source (archive)
GiveWell, Against Malaria Foundation Source
MIT Technology Review, The Extinction Invention Source (archive)
National Academies of Sciences, Engineering, and Medicine, Gene Drives on the Horizon Source (archive)
New York Times, Gene Drives Offer New Hope Against Diseases and Crop Pests Source
Roll Back Malaria, About RBM Source (archive)
Sculpting Evolution, Gene Drive FAQ Source (archive)
Statista, Impact of mosquito-borne diseases worldwide in 2015 Source (archive)
Statista, Sustained Progress in the Worldwide Fight Against Malaria Source (archive)
WHO, 10 facts on malaria Source (archive)
WHO, Guidance Framework for testing of genetically modified mosquitoes Source (archive)
WHO, Progress and prospects for the use of genetically modified mosquitoes to inhibit disease transmission Source (archive)
WHO, World Malaria Report 2015 Source (archive)
  • 1.
    • “The ability to edit populations of sexual species would offer substantial benefits to humanity and the environment. For example, RNA-guided gene drives could potentially prevent the spread of disease, support agriculture by reversing pesticide and herbicide resistance in insects and weeds, and control damaging invasive species.” Esvelt et al. 2014
    • “Right now, we have very few ways of addressing ecological problems because we can’t alter the traits of wild populations. We can’t stop mosquitoes from carrying diseases like malaria, dengue, yellow fever, or West Nile. […]
      We might be able to alter the mosquitoes so they can’t carry disease or suppress their populations until the disease is permanently eradicated.” Sculpting Evolution, Gene Drive FAQ
  • 2.Malaria deaths in all ages. The number of malaria deaths globally fell from an estimated 839 000 in 2000 (range: 653 000–1.1 million), to 438 000 in 2015 (range: 236 000–635 000), a decline of 48%.” WHO, World Malaria Report 2015, pg. x.
  • 3. “The Foundation for the National Institutes of Health procures funding and manages alliances with public and private institutions in support of the mission of the National Institutes of Health (NIH), the premier medical research agency. The Foundation, also known as the FNIH, works with its partners to accelerate biomedical research and strategies to fight against diseases in the United States and across the world. The FNIH organizes and administers research programs; supports education and training of new researchers; organizes educational events and symposia; and administers a series of funds supporting a wide range of health challenges.

    The FNIH was established by Congress in 1990 as a not-for-profit 501(c)(3) charitable organization. The Foundation began its work in 1996 to facilitate groundbreaking research at the NIH and worldwide. As an independent organization, it raises private funds and creates public private partnerships to support the mission of the NIH—making important discoveries that improve health and save lives.” FNIH, About Us

  • 4.
    • The WHO defines self-limiting as “GMM approaches where the genetic modification will not pass on indefinitely through subsequent generations.” WHO, Guidance Framework for testing of genetically modified mosquitoes, p. xi
    • “Ongoing releases of self-limiting GMMs will be required to maintain effectiveness. Self-limiting approaches may be attractive from an environmental safety perspective since they are not expected to persist in the environment or to spread far beyond the release site. However, self-sustaining approaches ultimately could provide more durable and cost-effective public health solutions. A phased testing pathway is recommended, in which new GMM strategies move from the laboratory, to testing in more natural environments under confined conditions, and finally to open release trials, with each transition dependent upon satisfactory demonstration of efficacy and safety. When GMM are incorporated into national or regional vector control programmes, the need for ongoing case-specific monitoring of effectiveness and safety should be considered to ensure acceptable quality and performance standards and to inform any necessary management responses.” WHO, Guidance Framework for testing of genetically modified mosquitoes, p. 1
  • 5. WHO, Progress and prospects for the use of genetically modified mosquitoes to inhibit disease transmission
  • 6. “WHO-TDR and the Foundation for the National Institutes of Health (FNIH) co-sponsored a technical consultation meeting in 2009 to assess current progress and future development of genetically modified mosquito technologies. The meeting was attended by participants from around the world with expertise in molecular biology, medical entomology, ecology, regulatory requirements, ethical, social and cultural issues, as well as staff from WHO, FNIH and other research funders WHO-TDR, 2010). Participants recommended the establishment by WHO and FNIH of a working group to develop a comprehensive guidance framework to provide quality standards for assessing the safety and efficacy of genetically modified xv mosquitoes and addressing legal, ethical, social and cultural issues that arise during their development and deployment. A multidisciplinary effort was subsequently commissioned and over 40 experts recruited to contribute at various stages of development. In accordance with the recommendations, the group included many members who possessed a broad knowledge in their topic areas but were not involved directly in research on GMMs. A draft guidance framework was produced and opened for public comment in late 2012. Responses to public comment have been incorporated into this current version.” WHO, Guidance Framework for testing of genetically modified mosquitoes, pp. xiv-xv.
  • 7. National Academies of Sciences, Engineering, and Medicine, Gene Drives on the Horizon
  • 8.

    Assuming that AMF’s work prevents a death due to malaria for approximately every $3000 donated (GiveWell, Against Malaria Foundation), a $1.2 million grant to AMF would be expected to prevent roughly 400 deaths. According to the WHO (WHO, 10 facts on malaria), more than 1000 people died each day from malaria-related causes in 2015 (around 438,000 per year), so $1.2M to prevent a day’s worth of malaria deaths this year would more than double the expected value of a similar contribution to AMF.

    However, the potential impact of accelerating gene drive field testing does not come this year. Roughly, we would guess that it will take around 10 years of development and testing before gene drives are deployed (if they are), and it would likely be many years after that date before malaria is fully eradicated. We think this makes the necessary expected impact larger for two reasons:

    • The time value of money. For example, using a 3% annual discount rate and assuming the impact of the grant on malaria burden is felt in 10 years, the present expected value would be 75% (1/1.03^10 ~= .75) of the value of eradication today. As a more conservative example, with a 5% annual discount rate and assuming the impact is felt in 17 years, present expected value would be approximately 44% (1/1.05^17 ~= .44) of the value of eradication today.
    • Declining malaria mortality. In 10 years, malaria is likely to be less prevalent than it is today regardless of the deployment of gene drives to suppress malaria transmission. According to a WHO estimate, between 2005 and 2015 the number of deaths from malaria fell from approximately 850,000 per year (Statista, Sustained Progress in the Worldwide Fight Against Malaria) to 438,000 per year (Statista, Impact of mosquito-borne diseases worldwide in 2015). Similarly, Roll Back Malaria Partnership is targeting a 75% reduction in global malaria mortality, relative to 2015, by 2025 (Roll Back Malaria, About RBM). For these reasons, we think it is reasonable to believe that malaria will cause substantially fewer deaths in 10 years than it does today regardless of the potential impact of gene drives.

    If we combine these factors to discount the impact of future malaria burden reductions by 5X, we would expect this grant to be roughly as cost effective as the same amount of money donated to AMF if it relieved two days worth of future malaria burden (1000 deaths/day * 1/5 discount * 2 days = 400 deaths).

    We find this kind of estimate helpful to give us a sense of scale and to expose some of our key assumptions, but are hesitant to place too much weight on it given that we are highly uncertain about many of the inputs.