Our ‘Second Chance’ Program for NIH Transformative Research Applicants

As part of getting started in science funding, we’ve explored several different methods of finding high-impact giving opportunities, including scanning published research, networking in fields of interest, and considering proposals sent to us by people we know. We recently announced four grants totalling $10.8 million that represent another approach: piggybacking on a government grant program designed to find transformative research.

The approach, in brief:

  • The National Institutes of Health has a program specifically for higher-risk, high-impact research.
  • The NIH has been able to fund only a small portion of proposals received through that program. Some projects considered worthy by peer review were ultimately rejected.
  • The NIH sent out a notice on our behalf to all unfunded 2016 applicants, and more than half re-submitted their applications to us. We received 120 proposals in three weeks.
  • We viewed this RFP as a way to both identify high-risk, high-reward projects and to test our hypothesis that high-risk, high-reward research is underfunded in general.

Background

The NIH launched the Transformative Research Award program in 2009 with an explicit goal to support “exceptionally innovative, high-risk, and/or unconventional research projects that have the potential to create or overturn fundamental paradigms or otherwise have unusually broad impact” in response to a perceived deficit of high-risk, high-reward funding opportunities.

According to our conversations with the NIH, the TRA program has generally funded 8-12 of approximately 150-300 proposals received each year, though more proposals were considered worthy by peer review. Grant amounts for selected projects have varied widely, ranging roughly from $250,000 to $3.5 million per project, and there is no cap to the funding for any one grant.

We decided to pursue this project because:

  • We are sympathetic to the idea that high-risk, high-reward research is underfunded and therefore found it plausible that this strategy would yield proposals we would be excited to fund.
  • Funding some work under this project would be likely to give us a sense of what to expect in the future if we had a call for high-risk, high-return proposals ourselves.
  • We knew of at least one Open Philanthropy Project grantee whose project had been funded by us but originally declined by the TRA program, and we were curious to see what the rest of the applicant pool looked like.
  • We wanted to learn about research projects from many domains, in addition to those that our scientific advisors have already investigated.

In addition to sharing their already-written proposals, applicants also shared the feedback they had received from the NIH peer reviewers with us, which helped accelerate our review process.

Grants

The projects we decided to fund through this process are:

  • $6.4M to Arizona State University to test a broad-spectrum cancer vaccine. A double-blinded trial led by Dr. Stephen Albert Johnston will involve 800 healthy, middle-aged pet dogs receiving either placebo or a preventative vaccine. The animals will receive regular exams over the following five years to see if the vaccine reduces the natural incidence of tumors. All dogs will receive normal standard of care. This will be the largest canine clinical trial ever conducted. If successful, this clinical trial would provide support for the concept of using frame-shift peptides to vaccinate against the very early stages of cancer, possibly lead to a canine cancer vaccine, and could eventually justify human clinical trials. However, even at this scale, the study is somewhat underpowered to find likely effects, so we think of this as mainly exploratory research. This project is high-risk because the underlying idea is novel and preventative vaccine trials for non-infectious disease are extremely rare and difficult to conduct. If this project leads to a successful vaccine, it could provide substantial health improvements worldwide.
  • $2.1 million to the University of Notre Dame for nanopore protein sequencing. Professor Gregory Timp and collaborators have made progress in developing an instrument that can read the amino acid sequence of single, unmodified protein molecules, allowing for faster, cheaper analysis with smaller samples than existing technologies. One potential application is rapid detection of pathogens, thereby improving the diagnosis and treatment of disease as well as potentially improving our ability to respond to pandemic threats. Technical challenges of reliable measurement at this scale give this project a high risk of failure. But if successful, we think that it could accelerate a wide range of basic biological research in the laboratory and eventually in the field. We also anticipate that lowering costs of protein analysis would enable scientists and clinicians with fewer financial resources.
  • $1.5 million to Rockefeller University for viral histone mimics. Professor Alexander Tarakhovsky and his team plan to explore a newly discovered mechanism in the life cycle of the yellow fever virus and to determine whether the mechanism occurs in other host-virus interactions. Understanding the structure and function of this mechanism may present a new target for development of antiviral compounds, which we believe is an important element of maximizing pandemic preparedness. The idea that pathogens are taking advantage of their hosts’ epigenetic machinery is quite new, and we think this represents an exciting and important new research area in immunology.
  • $825,000 to the University of California, San Francisco for organ regenerative surgery. Professor Tammy Chang is developing a novel stem cell treatment for repairing damaged human livers. Because it uses new techniques to selectively remove damaged cells while aiming to leave the structure of the tissue intact, allowing new stem cells to repopulate the organ, this project has a high risk of failure. However, if successful, we think this could potentially be high-impact because approximately 2 million people die of end-stage liver disease each year, and transplants are often not available and not always appropriate. We are particularly interested in whether the method could have broad applications for repairing or replacing other human organs.

Lessons learned

First, we found little correlation between our evaluations of the 120 proposals and the NIH peer review panel’s evaluation of these proposals. About half of the proposals we advanced to the second stage of our review failed to advance in the NIH peer review process, and the same can be said of proposals we declined to move forward. We think this might be because we evaluated proposals against a different set of criteria. Specifically, we were looking to support projects that could have the largest humanitarian impact, regardless of whether they “overturn fundamental paradigms,” as the NIH phrases it. (That said, when we went back and tried to evaluate the 12 projects ultimately funded by the NIH in 2016, the majority scored highly in our review process, which indicates some overlap on that subset.) There was some internal debate about how to rate specific proposals we reviewed, and we are confident that even after our process some deserving research projects were “left on the table” (though staff disagree on which ones).

Second, we thought many of the proposals we reviewed were similar to proposals in more typical RFPs in terms of their novelty and potential impact. In other words, we considered many of the submitted proposals to be a bit on the conventional side. This surprised us given the “transformative” premise and focus of the TRA program. We speculate that this may be due to the constraints within which applicants feel they must work to get through panel reviews.

Third, the process called attention to areas we hadn’t thought about yet, and we feel we learned a lot about underfunded areas of science. We believe this was a low-cost way to get a diverse set of good proposals into our pipeline, though we struggled at the end of the process with evaluating both the science and the humanitarian value of such wide-ranging proposals.

Ultimately, we found the overall RFP process to be a useful undertaking both for the lessons learned and diverse funding opportunities identified. We are still determining whether we will pursue a similar process in future years.

We’re grateful to Ravi Basavappa at the NIH, who provided information about the TRA program and helped us circulate our RFP to prior NIH applicants. We’re also grateful to all the applicants, who trusted us with their proposals and reviews, and our external reviewers, who provided valuable insights.

To learn more about our process for making these grants, read the full writeup here.

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