## Target Malaria — Gene Drives for Malaria Control

Published: May 2017

We decided to write about this grant in detail because it is a large grant that we find exciting. This page is a summary of the reasoning behind our decision to recommend the grant; it was reviewed but not written by the grant investigator(s).

The Open Philanthropy Project recommended a grant of $17,500,000 to Target Malaria over four years to help the project develop and prepare for the potential deployment of gene drive technologies to help eliminate malaria in Sub-Saharan Africa, if feasible, ethical, safe, approved by the regulatory authorities, and supported by the affected communities. Target Malaria is also a grantee of the Bill & Melinda Gates Foundation. This grant will support training and outreach programs, research into the potential ecological effects of releasing gene drives, operational development, regulatory support, and an unrestricted funding reserve. ## 1. Background #### 1.1 The cause Malaria is a leading cause of child mortality in the developing world, and the Institute for Health Metrics and Evaluation (IHME) estimates that the current mortality rate of malaria in Sub-Saharan Africa is roughly 1,700 people per day.1 It has been proposed that gene drives, a new scientific tool, could substantially contribute towards eliminating mosquito-borne diseases like malaria and dengue fever. Gene drives are tools for genetically altering an organism in a way that increases the proportion of offspring that inherit the altered trait. This allows the altered trait to spread rapidly through a population, even if the trait is not conducive to the fitness of the organism. (We recommend this report2 from the National Academies for a more detailed overview of gene drive technology.) In the last few years, improvements in DNA editing technology using the CRISPR/Cas9 system have made it possible to create gene drives much more easily. Researchers have recently demonstrated a mosquito gene drive capable of passing on desired traits to the next generation with over 99% efficiency.3 Two different kinds of strategies have been proposed for delivering traits that could help reduce malaria burdens. One approach would be to deliver traits that would render some species of mosquitoes incapable of carrying malaria; another approach would be to deliver traits that would greatly suppress the population of the main species of mosquitoes that carry malaria. #### 1.2 The grantee Target Malaria is an international collaboration aimed at developing gene drive technologies that could eventually be used to help eliminate malaria in Sub-Saharan Africa. It is led by Professor Austin Burt and housed legally at Imperial College London. It brings together over a hundred experts from 14 research institutions, including three institutions based in malaria-endemic countries (Institute de Recherche en Sciences de la Sante in Burkina Faso; the Malaria Research and Training Center at the University of Sciences, Techniques and Technologies of Bamako in Mali; and the Uganda Virus Research Institute in Uganda). Target Malaria is currently the largest research group working on gene drive technologies for malaria control, and we would guess that it is the one that is most likely to develop a fit-for-field construct first. This effort focuses on three interbreeding species of mosquito that account for the majority of the malarial disease burden in Sub-Saharan Africa. The project recently received a grant of$36 million over three-and-a-half years from the Bill & Melinda Gates Foundation (Gates Foundation). Target Malaria Principal Investigator Professor Austin Burt states that the organization’s main goal during this period is to create a gene drive construct that:

• Is robust against resistance (i.e. will continue working even if the mosquito genomes change under evolutionary pressure from the gene drive).
• Cuts the mosquito genome in unintended locations sufficiently rarely.
• Reduces the fitness of carriers sufficiently little.
• Can suppress a mosquito population in a large cage trial.
• Would be ready to be evaluated if it received regulatory approval.

Professor Burt is confident that the team will succeed in these goals over the given time period, and this assessment seems plausible to us.

#### 2.1 Budget and proposed activities

Target Malaria plans to spend this funding as follows:

• Training of graduate students and postdoctoral researchers in Burkina Faso, Mali, and Uganda to strengthen the number of people with relevant expertise who, in the future, could provide technical support for the potential development, testing, or release of gene drives.
• Designing materials for outreach events and three-day and two- to three-week courses and conduct these in Burkina Faso, Mali, Uganda, and elsewhere, with the aim of informing regulators and key technical experts about the technical details of gene drives.
• Recruiting additional support to focus on stakeholder engagement at the international level.
• Investigating the ecological role of the mosquito Anopheles gambiae s.l. using metagenomic analyses. This may involve sequencing the DNA of organisms in the digestive systems of organisms that eat mosquito adults and larvae and analyzing the results to understand the diets of organisms that eat An. gambiae, in order to help identify possible negative ecological outcomes of greatly reducing the population of An. gambiae. While people we consider well-informed on this issue have told us that they see no reason to expect such outcomes, we expect that learning more about potential ecological impacts will be necessary to answer the questions of regulators and concerned stakeholders.
• Developing methods that make it more feasible to rear and release modified mosquitoes, including work on cryopreservation and RNA interference (RNAi) (for sorting male from female mosquitoes), as well as work on mosquito population genomics, which will hopefully lead to an increase in Target Malaria’s precision in its understanding of how fast gene drives will spread in natural populations. The latter is important for planning any eventual release.
• Developing protocols for rearing, transporting, and releasing modified mosquitoes that aim to ensure that the gene drive constructs will be introduced into natural populations in an efficient manner. The ability to rear and release large numbers of mosquitoes would be necessary to conduct field trials.
• Recruiting additional regulatory support for the Target Malaria team, which would allow regulatory dossiers to be submitted to the appropriate agencies in an efficient and timely manner, potentially shortening timelines to testing. This will include funds to support the project’s regulatory affairs consultant for an additional nine days per month, as well as supporting a full-time regulatory science officer.
• Funding the work of a postdoctoral entomology researcher and an insectary technician to conduct experiments that are likely to be required for regulatory applications and that are not currently budgeted for. Their work will include:
• Temperature profiling studies.
• Protein expression studies.
• Validating tests for the presence of the gene drive construct using fluorescent markers and other methods.
• A 10% unrestricted reserve. Target Malaria currently has very limited unrestricted funding; it previously operated with 10% unrestricted funding and found this useful in covering expenses that can otherwise be difficult to fund.

#### 2.2 Case for the grant

We decided to recommend this grant for the following reasons:

• Gene drive technologies seem to us to be a credible method for substantially contributing to the elimination of malaria. Target Malaria’s work on this appears to us and our scientific advisors to be important and tractable.
• Target Malaria is leading the effort to develop gene drives for malaria control. While it has about \$10 million per year in funding from the Gates Foundation to develop gene drive technologies in mosquitoes, we believe it has room for more funding for work on public acceptance, regulatory considerations, and planning and preparing for the possible eventual release of gene drives, if they are determined to be feasible, ethical, and safe.
• Target Malaria currently has limited unrestricted funding, and has listed specific projects that seem important to us that it could be working on if it had more of this funding.
• We estimate that this project would likely have good cost-effectiveness if it speeds up Target Malaria’s work even by a few weeks, which seems plausible. It seems likely to us that the cost-effectiveness of this grant will be competitive with donations to the Against Malaria Foundation (though unlikely that it will be more than 10 times as cost-effective).4 Our rough estimate is that this grant will accelerate Target Malaria’s work by a few months and modestly improve the probability that deployment of a vector control tool using gene drive technology will eventually be approved and accepted if the technology turns out to be feasible, ethical, and safe. This estimate is based on the facts that a) our grant increases Target Malaria’s annual funding by about 50%, and b) the work that we are funding could be one of several bottlenecks on progress, and we believe likely would be if it did not receive funding in the next few years.

#### 2.3 Risks and reservations

We have discussed with researchers several remaining challenges in developing effective technologies using gene drive. Any of these may prove to be more scientifically difficult than expected and thereby delay Target Malaria’s work; we see this as a general concern for any work related to gene drive technologies. The main reservation we have specific to this grant is that, given that this seems like an exciting funding opportunity, it is possible that another funder would have funded this in our absence.

## 3. Plans for follow-up

We plan to follow up with Target Malaria twice annually for the duration of the grant, and to request both verbal and written updates on the project’s progress.

#### 3.1 Key questions for follow-up

We plan to consider the following questions when following up with Target Malaria:

• Scale-up and enabling experiments:
• Did the RNAi experiment enable cheap and easy sex sorting?
• Did the cryonics experiment enable cheap and easy preservation and reanimation of mosquito larvae?
• Did the population genetics project plan get fleshed out to an appropriate level of detail?
• Are the population genetics studies on track to provide a sufficient understanding of mosquito migration and behavior during the dry season to allow for substantially improved predictions of gene drive diffusion timelines?
• Training and outreach:
• Have students been recruited for the education and training programs?
• What proportion of students who complete their education during the program take on roles that are relevant to the Target Malaria project?
• Are the outreach sessions happening on track? Who is attending? What do we know about what attendees are taking away from the sessions?
• Ecology:
• Did the data gathered illuminate the ecological role of An. gambiae?
• Did Target Malaria gather the data and do the analysis necessary to answer the concerns of critics and regulators?
• Other:
• What did the regulatory affairs consultant, regulatory science officer, postdoc, and technician do? Does it seem like their involvement is speeding up the process?
• What did Target Malaria do with the contingency funds?
• Are projects proceeding in accordance with budgets and timelines?

## 4. Our process

Our process for deciding to recommend this grant involved conversations with Target Malaria, the Gates Foundation, Kevin Esvelt, Stephanie James, and several other people. Our work was reviewed by two of the Open Philanthropy Project’s scientific advisors, Chris Somerville and Daniel Martin-Alarcon.

## 5. Sources

DOCUMENT SOURCE
Hammond et al. 2016 Source (archive)
IHME, Global Burden of Disease Source
National Academies of Sciences, Engineering, and Medicine 2016 Source (archive)
Open Philanthropy, Rough Target Malaria Cost-effectiveness Calculation Source