Scientist's Efforts to Transform NIH Funding Process Spurs Scientific Risk-Taking

By Robin Hindery

Over the past two decades, UCSF molecular biologist Keith Yamamoto, PhD, has been a driving force behind efforts to transform the way the National Institutes of Health (NIH) issues grants that foster greater innovation and scientific risk-taking.

Keith Yamamoto

After serving on more than a dozen NIH committees, task forces and panels since 1986, Yamamoto’s activism has led to the development of a series of awards aimed at promoting ideas that have the potential to revolutionize their fields and spur medical advances. On Sept. 24, the NIH announced a total of 115 High-Risk Research Awards for 2009, including six grants for seven UCSF scientists. One of those funding mechanisms, the NIH Transformative R01 (T-R01) grant, was offered for the first time this year and supports unusually inventive, high-risk or unconventional research projects with potentially huge scientific implications. Yamamoto first introduced the idea of the T-R01 grants at a meeting of the NIH Peer Review Advisory Committee in 2006. He and other advocates hope the adoption of that proposal signifies a slow-but-steady paradigm shift within the NIH. “The T-R01 mechanism seeks to counter the fact that peer review is intrinsically conservative,” said Yamamoto, who serves as executive vice dean of the UCSF School of Medicine. “Most scientists will tend to be supportive of proposals that advance current prevailing views, rather than those that are disruptive and force us to start over and rethink. The T-R01 application and review process attempt to open the door to such transformative thinking.” In addition to the T-R01 grants, the High-Risk Research Awards include the New Innovator Awards, which were launched in 2007, and the Pioneer Awards, which were first conferred in 2004. Yamamoto called such mechanisms “encouraging” and said their success would be measured not only in the scientific breakthroughs they produce, but also in their ability to inspire more widespread change in the federal funding process. “It is true that an element of ‘grantsmanship’ is to write grants conservatively, and then to carry out research boldly,” Yamamoto said. “We will do much better, however, if our funding policies are explicit in encouraging scientists to be creative in their research plans and challenge existing paradigms.”

UCSF Scientists Benefit

UCSF scientists are already reaping the benefits of the new NIH funding opportunities, to the tune of more than $10 million in 2009 alone. This year, three investigators — Long-Cheng Li, MD; Hao Li, PhD; and Wallace Marshall, PhD — received T-R01 grants, one scientist, Nirao Shah, MD, PhD, received a Pioneer Award, and three others — Daniel Lim, MD, PhD; Stavros Lomvardas, PhD; and Erik Ullian, PhD — received New Innovator Awards. “I think it is spectacular that the NIH has these new funding mechanisms because science progresses by innovative jumps, not by conservative steps that add very little to our knowledge,” said Lomvardas, an assistant professor of anatomy whose research will explore the processes behind brain plasticity. “Suddenly, there is a window of hope that there will be funding for ideas that are out of the box.” The new funding mechanisms “really permit you to chase the ideas and questions that fascinate you. And if it works, the benefits could be huge,” added Shah, an assistant professor of anatomy who will study the circuits in the brain that enable animals to form long-lasting social attachments — research that could provide insight into mental disorders such as autism.

Studies Chart New Territory

Lim, an assistant professor and director of restorative neurosurgery in the Department of Neurological Surgery and a member of the Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, said his New Innovator Award will allow him to challenge certain scientific assumptions and therapeutic strategies — namely, the belief that stem cell transplantation is needed to treat neurological diseases. “I have always gravitated toward the fields in which we know the least and have the most controversy,” said Lim, who will study the gene expression “switches” that control the specialization of neural stem cells into the brain’s various cell types. For Lim’s fellow New Innovator Award recipient Ullian, the gaps in knowledge within his field have both motivated and impeded his research efforts. In his lab, Ullian, an assistant professor of ophthalmology and physiology, has demonstrated that a common neural cell type, the astrocyte, plays a key role in regulating plasticity in the developing brain. His award-funded study will examine whether neurological disorders stem from changes in this regulatory ability. Ullian is among the first to ask such questions, so finding NIH grant reviewers who are experts in his field of study is extremely difficult, he said. As a result, studies like his are perfect candidates for funding mechanisms that encourage researchers to chart new territory, he said.

Labor of Love

While all three types of High-Risk Research Awards support unconventional research undertakings, the T-R01 grants also pave the way for collaborations that might not otherwise have been possible. That is certainly the case for co-recipients Hao Li and Long-Cheng Li, who will use a combination of genomic, bioinformatic and molecular biology approaches to study small RNA molecules and their role in gene regulation. Understanding these molecular mechanisms could transform the way gene function is studied and diseases are treated. Long-Cheng Li, an assistant professor of urology, first began studying small RNA molecules on his own, but soon realized that to investigate the underlying processes behind their behavior he would need an expert in computational biology and bioinformatics. “Long-Cheng came to talk to me and I fell in love with the problem, and we worked together to write the grant,” recalled Hao Li, a professor of biochemistry and biophysics. “We have some big ideas, and if they work out, they will have a tremendous impact.” UCSF’s other T-R01 recipient, Marshall, has been nurturing and refining his own research idea since the 8th grade, he said. That is when he first read about the single-celled organisms, Stentor, that form the basis of his study. Using modern genomic methods, Marshall and his team will work to understand the molecular pathways that underlie the organisms’ ability to regenerate themselves after being damaged. Through his work, Marshall hopes to introduce a “radical” new approach to regenerative medicine, and he acknowledges that without the T-R01, his project might never have gotten off the ground. Under normal circumstances, “if you haven’t published several papers, you have no chance of getting funding,” he said. “This puts anyone who wants to do something new into a catch-22 situation: Can’t do it without money, and can’t get money unless you’ve already done a lot,” he continued. “These high-risk research funding mechanisms are extremely important in allowing scientists to do real innovation rather than focusing exclusively on incremental advances.”

Related Links:

UCSF Scientists Awarded NIH Research Awards Encouraging Innovation UCSF News Release, Sept. 24, 2009 UCSF and the Future of Science: A Conversation with Keith Yamamoto Science Café, June 1, 2007 NIH High-Risk Research Awards