The scientists interviewed for this series agree: It's hard to find funding to support risky science. But most of them have managed to find it anyway.

Like many science trainees, structural biologist Rachelle Gaudet was sheltered from funding challenges during her graduate school and postdoctoral years. Her advisers, Paul Sigler of Yale University and Don Wiley of Harvard University, both deceased, were Howard Hughes Medical Institute (HHMI)–funded scientists, and she had no trouble attracting fellowships. But when she ventured out on her own and began to set up an independent lab, she quickly learned the harsh reality of trying to fund ambitious research in the current funding climate.


(Courtesy, Rachelle Gaudet )
Rachelle Gaudet

Now an associate professor at Harvard, Gaudet studies the structure of proteins that span cell membranes. She's especially intrigued by TRPV1, a membrane-spanning protein that helps modulate body temperature and pain related to inflammation.

Determining the structure of membrane-spanning proteins has been called one of the last frontiers in structural biology. There are many obstacles to “seeing” their structure, including the fact that they are well-integrated with the cell membrane and change shape as they perform their function. Nevertheless, Gaudet hoped to crystallize TRPV1 and determine its structure via x-ray crystallography. Then, she hopes, others will be able to use her results to improve treatments for inflammation-related maladies such as arthritis, heart disease, and autoimmune diseases.

Gaudet's first proposal to the National Institutes of Health (NIH), which outlined an ambitious plan to tackle the problem, was rejected. So were her second, third, and fourth proposals. The reviewers indicated that in order to get funded, she would have to scale back her plan and look at pieces of the protein, not the whole thing at once. She would, in other words, need to be less ambitious. That's “not quite what I had planned,” Gaudet says.

“Looking back at the critiques,” Gaudet tells Science Careers, “the reviewers expressed enthusiasm for the project but skepticism about the approaches. The main criticisms were that the approaches were overly ambitious and that the proposals should be more focused and take a more stepwise approach.”

The safety trap


(Carl Sidel)
Steven McKnight

Taking risks while a postdoc may help you land a faculty post, but once you've landed one the incentives change. “You get hired for the big and bold ideas, but you don't get funded for those,” Gaudet says. “The funding situation in the last 5 years or so has made it a big challenge for a lot of young investigators to balance being bold and being funded.”

Gaudet's experiences have tempered her boldness, if only temporarily, and she's worried about what that means for her lab's future. She is concerned that by researching the increments of protein signaling, she's getting further away from her original idea. What you publish is “the advertisement that you're providing to prospective students,” she says. If you aim to nudge your research into a bolder area but all you're publishing is the incremental, interim steps that are being funded, you will attract only students interested in incremental work, not bold ideas, she fears.

“I think the time to be bold and innovative and establish a culture in your research program for aiming high is at the beginning,” she says. “It's much harder to start safe and evolve towards aiming high.”


(Beatrice Ring)
Vilayanur Ramachandran

That's a very real trap, say several of the senior scientists interviewed for this series. Once “you get hired at a place, the biggest expectation is not necessarily to make great discoveries but to get grant funding and to publish a lot of papers,” says biochemist Steven McKnight of the University of Texas Southwestern Medical Center in Dallas.

“If you start doing the boring stuff and you get all these little, minor reinforcements, like you get a grant, and you get tenure, and you get people patting you on the back and some paper gets accepted in this journal or that journal, you start losing sight of what's really driving the enterprise,” adds Vilayanur Ramachandran, a behavioral neurologist at the University of California, San Diego. “I would never compromise on doing the exciting stuff, and the reason for that is it becomes habit. You get lulled into a false sense of security. You follow the crowd, and you become that.”

Can't buy me love


(University of Washington)
David Montgomery

If you want to get tenure, then you have to get grants–but is strong funding correlated with strong science? Not so much, say our sources, though it depends on the field. “It's a false impression that important discoveries necessarily need a lot of equipment and time and money. In fact, the opposite can be true,” Ramachandran argues. “If you've got a huge grant and 16 postdocs working under you, you become a lab manager. It stifles your creativity.”

Some of University of Washington, Seattle, geomorphologist David Montgomery's boldest investigations were done on the cheap. “Probably half the papers I've published in Nature and Science were not funded by anybody,” he says. That's partly due to the discipline he works in, he acknowledges. “I'm fortunate enough to be a field-based geologist and a GIS–based theoretician–so there's an awful lot of things that I've been able to do that ... weren't funded.”

Joan Roughgarden, a biologist at Stanford University in Palo Alto, California, adds: “I have found that my creativity varies inversely with the amount of money that I have.”

Funding risky science


(Mark Rogers)
Joan Roughgarden

But let's be practical: Researchers need funding. “Even the field geologist with a hammer out in the woods needs the gas to get there,” Montgomery says. Even if you're willing to buy your own gas, you probably do need grants to keep your institution happy. So how do you find money without compromising your standards?

One approach is to seek funding designed to be flexible. The MacArthur Fellows Program is the prototypical example–but it's not one you can seek. “What's nice about the MacArthur grant is that I don't have to prove to anyone else that an idea I have will work. I can just say, ‘I think this is going to work,' and that's good enough,” says Adam Riess, an astrophysicist at Johns Hopkins University (JHU) in Baltimore, Maryland, who won the award in 2008. “I don't even have to run it by them. And that's a lot of freedom.”

What's not nice about the MacArthur fellowship is that you have to be nominated, and the nominators are all but sworn to secrecy. Praying for a genius grant just isn't a sound strategy.

Yet there are some awards you can apply for that come with fewer strings and are intended to free up scientists from pedestrian funding concerns. You can, for example, apply to become an HHMI investigator. (Until recently, its competitions required an institutional nomination–but not its last competition, which closed in 2008 and focused on early-career scientists.) HHMI investigators receive a 5-year, renewable contract during which the investigators are expected to follow their scientific muse. Sara Seager, a planetary scientist at the Massachusetts Institute of Technology in Cambridge, has funded risky ideas with grants through the NASA Astrobiology Institute. Many private foundations, such as the W. M. Keck, Michael J. Fox for Parkinson's Research, Ellison Medical Foundation, and G. Harold & Leila Y. Mathers Foundation, are willing to take on bolder ideas, as long as they fall within their, at times, narrow interests.


(Comstock)

Coming up in Part 4: How funding agencies are supporting, or not supporting, audacious science.

The government agencies, too, offer options intended to fund risky science. NIH offers the Director's Pioneer awards, the Director's New Innovator awards, the Transformative R-01 awards, and the EUREKA awards. The National Science Foundation (NSF) offers the EAGER awards–which recently replaced the SGER program–and empowers program officers to pull high-potential-payoff research out of the proposal pile for special consideration. We'll have more to say about federal funding for audacious research in part four of this series.

The problem with many of these awards–though not all of them–is that you have to establish yourself as a superior scientist, with a proven track record, before you're likely to prevail in the stiff competitions. Only 42 of the 700 applications for the inaugural cohort of T-R01 grants were funded, for example–a funding rate of just 6%. And though HHMI investigator awards are intended for scientists in the “ascending phase” of their careers, you still need to establish solid credentials before you're a strong candidate for one of those.

More often than not, building solid credentials means getting funded by the usual suspects.

Safe strategies for funding audacious science


(Johns Hopkins Medical Photo Dept)
Solomon Snyder

How do you extract funding for risky research from conventional sources, such as NIH's and NSF's standard funding programs? The veteran scientists interviewed for this series are pragmatic, almost cavalier, about funding bold science. It's not a big mystery, they say, or even all that hard.

“What many of us do is, we get the funds for the boring stuff and then do the exciting stuff on the side,” Ramachandran says. “The great thing about NIH is, they don't mind [if you] spend about 10 or 20% of [grant money] on other exciting stuff as long as you tell them it's vaguely related. That's an easy, easy way to deal with that problem.”

JHU neuroscientist Solomon Snyder doesn't write about new and exciting research directions in his grant applications. “I write about what we did that was exciting a couple of years ago and that was just published in the last year and say, 'Look, we discovered x, and we're going to do the boring follow-up of x.' ” When the money comes in, he works on what he wants to.

“My advice is, if you're selling your wares, which is what you're doing when you're applying for a grant, you try to find out what the customer wants,” Snyder says. “You sell the customer what he wants. And then in real life, you do what you feel like doing.”

Importantly, almost all of our sources put forward the concept of portfolio theory: Don't put all your eggs in a high-risk basket, they advise. Instead, pursue a range of projects with different levels of risk and potential reward and different timetables. Also pursue a range of funding sources; instead of relying on a single grant or source, spread the ideas and the applications around. Using strategies like these, you can establish a record of solid, if boring, productivity even as you pursue the big payoff.

Gaudet says she's in for the long haul and will keep pushing her research into bolder areas. “If you're interested in making breakthroughs in science, you have to keep trying to tilt towards the bold,” she says. “It's not going to be easy, but I think it's worth trying.”

Anne Sasso is a freelance writer and may be reached at amsasso at nasw dot org.

Anne Sasso is a freelance writer and may be reached at amsasso at nasw dot org.
10.1126/science.caredit.a0900143