Rewards of Risk

Charles Lieber, 2008 National Institutes of Health Director’s Pioneer Award WinnerPHOTO BY STU ROSNER PHOTOGRAPHY Charles Lieber was ready to do something new. A renowned nanoscientist at Harvard, he had developed a number of nanoscale materials for electronic and computing applications, but had long wanted to try his hand at biological problems. He imagined building nanoscale sensors to detect biomarkers and nanowires to probe individual cells, but he had no funding to pursue these ideas. Then in August 2008, Lieber learned that a short grant application he had filed was going to pay off in a big way: he was to be awarded a National Institutes of Health (NIH) Director’s Pioneer Award, a $2.5 million, five-year grant designed for high-risk research projects. According to NIH, these awards fund high-impact ideas that are dubbed too novel, that span too diverse a range of disciplines, or are at a stage too early to fare well in the traditional peer-review process. The award marked a shift in Lieber’s research career, he says. Two years later his team published a breakthrough invention—a virus-size probe that can enter a cell and monitor action potentials without affecting the cell’s structure (Science, 329:830-34, 2010). “I had a lot of these ideas for years,” says Lieber, “but this would have been really, really difficult without the Pioneer.” Today, more than half his team works on cell-nanoelectric interfaces. NIH will invest at least $108 million in visionary research this year through its four high-risk grant programs: the Pioneer Award, the New Innovator Award, the Transformative R01 Program, and the EUREKA Awards. Numerous other organizations also offer awards for innovative projects (See sidebar on opposite page: “Beyond Federal Funding”). Such awards “try to allow people the opportunity to pursue an out-of-the box idea,” says Ravi Basavappa, manager of the Transformative R01 program in the Office of the Director at NIH. But because of their popularity, “the competition is quite keen,” he adds. To give you a leg up on the competition, here are some tips for securing your own high-risk grant, including advice from researchers who took one home, and the inside scoop from NIH itself. Straight from NIH: Tips from the top Make them call you crazy At a 2008 retreat, engineer Andrea Armani of the University of Southern California (USC) overheard researchers complain about the difficulty of trying to measure DNA methylation using PCR. “I should come up with a better way of detecting [DNA methylation] so you don’t need PCR,” Armani told them. “That’s impossible,” they replied, staring at her as if she were crazy. But NIH didn’t think so: last fall, Armani was awarded a New Innovator Award—$1.5 million over five years to develop a nanolaser capable of detecting methylation of a single strand of DNA. Nothing in your application is more important than the big idea, says Judith Greenberg, principal leader of NIH Director’s Pioneer and New Innovator Awards. “There’s no substitute for presenting a truly, highly innovative idea,” she says. Without that, “nothing else that you do is going to matter.” Dig up your best science-fair projects A great idea is the first step, but the second is to convince a reviewer that you’ll be able to deliver. Reviewers for the Pioneer and New Innovator Awards want applicants to demonstrate evidence of past innovativeness. Since preliminary data is not required, the reviewers will want examples of your past creative, groundbreaking research to vouch for you. The NIH recognizes that many applicants, especially for the New Innovator Award, are young investigators without long track records, so don’t be afraid to strut your stuff from postdoc or even graduate school days, says Greenberg. “We just want some indication of how they think and whether they are really creative, innovative people,” she says. BEYOND FEDERAL FUNDING: A SAMPLING OF ALTERNATIVE HIGH-RISK FUNDERS The Bill & Melinda Gates Foundation: Grand Challenges in Global Health Up to $1 million for “innovative, early-stage research” on the world’s most pressing health problems. The application is two pages in length with no preliminary data required and anyone can apply. What are you waiting for? American Brain Tumor Association (ABTA) Discovery Grants These one-year grants fund up to $50,000 for high-risk, high-impact projects with “the potential to change current diagnostic or treatment paradigms for adult or pediatric brain tumors,” according to the ABTA. The focus is on basic research, so no translational projects. Department of Defense Breast Cancer Idea Award. This program is designed to promote new ideas and yield high-impact data in breast cancer research. It funds either a single researcher or collaborative groups at up to $750,000 for two years. Get a hotel room “It’s tricky,” says Valentin Dragoi, a neurobiologist at the University of Texas Medical School at Houston and winner of a 2010 Pioneer Award. “Sometimes with complexity, we hide how cool an idea is.” To keep himself on task while at a conference, Dragoi closeted himself in a hotel room for three days to write his grant application. “It was miserable but it paid off in the end,” he said—the isolation worked well for writing. In particular, Dragoi tried to constantly remind himself to think about the big picture. Skip the all-star recommendation Applicants sometimes submit letters of recommendation from big names in their field, yet these letters are often the weakest because the authors don’t always have a close relationship with and detailed knowledge about the applicant. “It’s generally better to have someone who knows you well [write the letter], even if it’s not somebody who is a household name,” says Greenberg. Details are valuable, agrees Dragoi: “the letters of reference should attest to your ability to solve problems, and point out when you’ve been successful.” How they did it: five grant writing tips 1. Keep it simple Explaining the physics of a nanolaser capable of detecting DNA methylation is not necessarily a simple task, but USC’s Armani made it her mission to write the five-page essay required for a New Innovator Award using language that was as jargon-free as possible. “Make it easy on the reviewers,” says Armani. “Literally make a heading in the proposal that says, ‘This proposal is innovative because it ____,’ and fill in the blank.” After completing her essay, Armani asked friends to read it to assure that it was simple and convincing before she submitted the grant. 2. Document…with pizza To prove an idea is truly innovative, it’s important to thoroughly document research in the area, emphasizes Dragoi. But reading your weight in papers isn’t something you have to do alone. For his Pioneer Award grant application Dragoi reached out to students and postdocs in his lab to help find and document all the papers he would need to demonstrate that the project proposal was novel (and grad students often work better when plied with pizza). “People shouldn’t be afraid to ask their postdocs and students, who understand the game, to help with good documentation,” he says. Although many grant applications restrict the length of citations, it’s important to know what’s out there, adds Dragoi, so you can confidently assert that your research will be novel. 3. Reduce the risk At Brigham and Women’s Hospital, Nathalie Agar wanted to develop a mass spec that could be fitted into a surgical probe to collect cellular data in real time. The information would help identify the margins of a brain tumor, allowing neurosurgeons to make more accurate cuts. In her application Agar acknowledged these risks, but then emphasized her training with a neurosurgeon who helped pioneer an MRI used during surgery, and cited Brigham and Women’s track record for creating innovative neuroimaging tools. She made it clear in her application that the risks were “well-calculated and buffered by all these different components.” 4. Show your planning A Bill & Melinda Gates Foundation Grand Challenges Explorations winner, Transderm Inc., is developing a painless, low-cost, no-refrigeration vaccine delivery system that could increase vaccine access to at-risk populations, and potentially improve vaccine efficacy. COURTESY OF THE BILL & MELINDA GATES FOUNDATION Any project, even one labeled “high risk,” has to be realistic, so make an effort to show the details of how it can be done, says Agar. “Writing the essay, I was almost putting together a business plan,” she notes, setting forth a concept and then profiling how she intended to fulfill it, including a feasibility assessment, and describing the potential market for the surgical probe. In addition to her training and collaborators, Agar described who would manufacture the parts of the probe, where in a hospital it could be used, and why it would be attractive to doctors. “You have to be very strategic about why you are in a position to make this work,” says Agar. 5. Never, never, never give up “Keep plugging away,” says Martin Blaser, a microbiologist at New York University School of Medicine. He wanted to design a vaccine against cholera and Campylobacter bacteria, both of which cause serious diarrheal diseases. His plan was to engineer a harmless version of the gut bacterium H. pylori to deliver the protective antigens, but the Gates Foundation wouldn’t bite. After being rejected twice for a Grand Challenge grant, Blaser resubmitted his application a third time without even revising the proposal and it was funded. But be warned, NIH has a policy of not accepting applications that have not been specifically changed, says Greenberg. So if you’re submitting to NIH, revise at length ahead of time. FIND YOUR FLAVOR Pioneer Award New Innovator Award T-R01 Eureka Awards Eligibility Open to all career stages; early- and mid-career scientists encouraged to apply Must be a “new investigator” who has never been awarded an R01 or equivalent NIH grant Open to all career stages Open to all career stages Only one PI allowed Only one PI allowed More than one PI allowed More than one PI allowed Foreign (non-US) institutions not eligible Foreign institutions not eligible Foreign institutions eligible Foreign institutions eligible Preliminary Data Not required; may be included Writing Requirements 3–5 page essay 10 page essay = 12 page research plan = 6 page research plan Funding Up to $500,000 in direct costs each year for 5 years Up to $300,000 in direct costs each year for 5 years No maximum limit Up to total project costs of $800,000 with $250,000 maximum for a single year Chart adapted from http://nihroadmap.nih.gov/pioneer/faq.aspx

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