When vascular biologist John Cooke of Stanford University received a grant in 2007 from the California Institute for Regenerative Medicine (CIRM) to launch stem cell research in his lab, he never expected the agency to take back the money -- especially not when his research was just starting to take him in some exciting new directions.

Human embryonic stem cells Image: Wikimedia commons, Nissim Benvenisty

Within a year of starting the experiments on human embryonic stem cells (hESCs) he had outlined in his grant application, Cooke's group developed a protein-based strategy for generating induced pluripotent stem cells that they hope "will be a paradigm-shifting approach to vascular regeneration." The problem was that this was not what he had originally proposed to do.

Cooke's award was a SEED grant -- Scientific Excellence through Exploration and Development -- CIRM's attempt to jump start research in hESCs, and by nature, fund exploratory basic research. The SEED grant Request for Applications (RFA) called for "new ideas and new investigators...to carry out studies that may yield preliminary data or proof-of-principle results that could then be extended to full scale investigations." But after reading about this change of direction that Cooke clearly -- and proudly -- laid out in his first annual progress report, CIRM officials terminated the grant.

"I anticipated that they would be happy with that [new] proposal," Cooke recalled. "[But] they weren't happy." In January 2009, after a second, more detailed progress report, follow up phone discussions, and a petition for reconsideration from Cooke, CIRM revoked his second year of funding -- nearly half of what he had originally been awarded -- citing the new directions his research had taken.

"I can understand their reasoning," Cooke said. "I just wish I had understood that that applied to the SEED grants."

Cooke wasn't the only one. The annual progress reports, required of all CIRM grantees, spurred the agency to revoke two other SEED grants of the 74 awarded: Hari Reddi of the University of California, Davis, and Eric Verdin of the J. David Gladstone Institutes in San Francisco also suffered the same fate. All three grants were pulled due to "inadequate progress," CIRM's former chief scientific officer Marie Csete said at a CIRM board meeting last June. (Both the grantees declined to comment, and CIRM officials refused to provide further details regarding the specific circumstances surrounding any of the revoked grants.)

Clearly, funding agencies need to offer some oversight of grants to avoid misuse of funds. But can there be too much of a good thing?

Agencies that fund basic research generally expect the unanticipated shifts that come with exploratory science. "Our belief is that some of the biggest discoveries happen by twists and turns and serendipity," said Robert Finkelstein, associate director for extramural research at the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NIH). Under an R01 grant for basic research, "it's ok if an investigator goes off on all kinds of tangents based on his interests. The PI is pretty much in the driver's seat in terms of the way the project goes."

But the SEED grants walked a fine line -- on one hand, they undeniably targeted exploratory science, but on the other hand, their specific aim was to build up the field of human embryonic stem cell research. Arguably, that may have left Cooke's switch to pluripotent stem cells out of their purview. Interestingly, of the 14 Disease Team awards CIRM announced last month -- which support collaborations moving research to the clinic within four years -- only four focused on human embryonic stem cells. (Cooke ultimately got funding for his new work -- an initial $150,000 from the American Heart Association that kept his research going until he was awarded more than $11 million in two different NIH grants.)

There's also CIRM's short timeline, which may force the agency to monitor awardees more closely and be harder on those who veer off-target. While the NIH will exist for many years to come, CIRM has a 10-year lifespan, as approved by California voters in 2004. "CIRM has very defined goals," said the Burnham Institute for Medical Research's Huei-Sheng Vincent Chen, another SEED grant recipient. "[They] wanted something within 10 years so they have to be more aggressive."

In some ways, said Keith Yamamoto, a molecular biologist at the University of California, San Francisco, who cochaired the NIH's peer review working group last year, these grants sound more like a contract granting mechanism, in which there is a close working relationship between the funder and the investigator in pursuit of very specific goals. There's nothing wrong with such goal-driven research, he said, but it is "critical" for CIRM to make its intentions explicit from the get-go.

Basic research grants awarded by both NIH and CIRM require annual progress reports that summarize the previous year's achievements and any changes made to the research program, but the level of scrutiny that each CIRM report appeared to receive was, to some, a bit unexpected.

Ellen Robey of the University of California, Berkeley, also a 2007 SEED grant recipient, said she was surprised when she got a phone call from her project manager requesting more detail on her annual progress report. "I was used to the NIH system where the progress reports are really kind of a formality -- you get the sense that no one even looks at [them]," she said. The CIRM project manager was satisfied with the additional information Robey provided, and she was able to keep her grant. But, she admits, "I wasn't aware that they were revoking or taking away grants."

As for the NIH, program managers thoroughly review each annual report submitted, but only a minority of the projects require additional follow-up, and this only "rarely" results in the termination of the grant, said Finkelstein. A spokesperson at the NIH Office of Extramural Research said the agency makes decisions about terminating grants on a case by case basis and does not keep track of the numbers of revoked grants.

There are mixed reviews among the scientific community about whether CIRM's close watch of their grantees is a good thing. To some, it is an important practice for public funding agencies such as CIRM to show the tax payers that their money is going towards productive and fruitful research. "I think the oversight is outstanding," said John Simpson, the stem cell project director at the advocacy group Consumer Watchdog in California. "It shows that they're not asleep at the switch. CIRM is functioning as both a grant making agency [and] also something of a steward of the funds it hands out."

But others say this kind of intense supervision can burden investigators -- and the science itself. "In theory, it's a terrific thing," agreed David Kaplan of Case Western Reserve University in Ohio, who has written about the peer review system at NIH. "To have the granting agency being involved enough to be helpful to their grantees, I think that is a terrific idea. The problem with that kind of a system is that you can be too intrusive. That eliminates that kind of serendipity [in scientific discovery]."

In addition, such vigilance can imply a lack of trust that "is really important to the progress of science," said Yamamoto. "If the penalty [to not meeting specific goals] is to take [the money] away, the agency [is basically saying] 'We don't really trust you.'"

CIRM is not alone in its struggle to find the balance between "thoughtful oversight" and "micromanagement," said Larry Goldstein, director of the stem cell research program at the University of California, San Diego, and a recipient of a number of CIRM grants. "I think any agency confronts this problem," he said. "You want to have enough oversight [to ensure] that people make progress during the term of the grant, but you also want to leave room for changes of direction that make sense given what you discover."


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