The possibility of failure has never kept Simon John from trying. One of the research lines that John, an investigator of the Howard Hughes Medical Institute  (HHMI) and a professor at The Jackson Laboratory in Bar Harbor, Maine, currently has going is the development of a wireless sensor so tiny it can be implanted into the eye of a mouse. John wants to use the sensor to monitor intraocular pressure around the clock to better understand the mechanisms of glaucoma, a blinding disease that affects about 70 million people worldwide.
Along with seven other projects, John’s research won HHMI support in 2008 as part of a 4-year, $40 million pilot program targeted at collaborative and potentially transformative research. “We were looking for projects that could really represent breakthroughs—those that could really change the way we think,” Jack Dixon, HHMI's vice president and chief scientific officer, wrote in the Collaborative Innovation Awards announcement . Funding agencies and institutes are dedicating more of their portfolios to transformative research, and that means new opportunities for scientists like John with the skills and attitudes needed to pursue high-risk, high-reward research.
The trend toward transformative research is fueled by nations’ efforts to use science and technology to leapfrog competition in terms of innovation and economic development in a globalized environment, says Robert Frodeman, a philosophy professor at the University of North Texas, Denton, and director of the Center for the Study of Interdisciplinarity. Today, he says, “We want even more change and we want faster change and we want … not just incremental change but quantum leaps.”
The European Research Council  was one of the first funding bodies to focus on this area, with the launch of its Starting Grants  in 2007 and Advanced Grants  in 2008 for “frontier research.” The same year, the U.S. National Science Foundation  (NSF) developed a new requirement: Researchers must now state how creative, original, or potentially transformative their proposals are. NSF also issued a series of new funding opportunities to support transformative research (see box). The latest of these new programs is Creative Research Awards for Transformative Interdisciplinary Ventures  (CREATIV), which offers up to $1 million to small teams of scientists. Starting next year, NSF is hoping to fund larger teams with grants of $2.5 million to $3 million each, says NSF Program Director Diane Witt. “We’re told that we need to have at least 5% of our portfolios in more of the risky areas"—that's 5% of the biological sciences research budget—"and … we’re being encouraged to grow that,” Witt adds. That percentage could be even larger across all of NSF, she notes.
Research institutions, too, are getting onboard—including the Friedrich Miescher Institute for Biomedical Research  in Basel, Switzerland, and HHMI’s Janelia Farm Research Campus  in Ashburn, Virginia, says Oscar Marín, a group leader at the Institute of Neurosciences of Alicante in Spain. Marín is also serving as a consultant to the Pasqual Maragall Foundation  in Barcelona, Spain, on a project to start up a small, transformative brain research institute; the institute aims to recruit four senior group leaders and between eight and 10 junior group leaders by 2018. “We have the feeling that perhaps if we bet on raising the stars that can approach problems in a different way, we can get some better benefits.”
NSF's Witt says that for a proposal to be transformative, it “needs to challenge the conventional wisdom, lead to unexpected insights that enable new techniques or methodologies, or redefines the boundary of science, engineering, or education.”
But what is truly transformative can be hard to pin down, she adds. “We always say potentially transformative because it usually takes about 10 years … for you to understand the impacts of it,” she says—and what looks transformative in one field can seem pretty basic in another.
When people talk of transformative research, Frodeman says, they also usually mean breakthroughs with cultural, social, or economic—rather than purely scientific—impact. A prime example, cited by Frodeman, is the discovery of DNA's structure by James Watson and Francis Crick (and Rosalind Franklin) in the 1950s, which is linked to the genomics revolution and the possibility of genomic enhancement, he says.
In its recruiting, the new Pasqual Maragall Foundation center will place a lot of importance on the backgrounds of the people they recruit, but what will be most important is that they have provocative ideas they want to explore, Marín says. “That requires a particular breed of scientists that are really willing to take risks and to move into and open fields.”
How is this achieved? Scientists need to read deeply and broadly and think critically about their (and other) fields, John says. Being able to collaborate, especially with scientists from other disciplines, is also key. Transformative research requires good personal and communication skills including flexibility, open-mindedness, and the ability to manage cultural differences across fields, John says.
Witt suggests that young scientists interested in transformative research should become “hybrid scientists” capable of putting together, for example, the molecular and behavioral aspects of neuroscience. As you educate yourself in a new discipline, “you don’t want to just borrow tools; you want to understand those tools. And you don’t want to just collect data; you want to understand how you’re going to analyze the data,” Witt says.
Interdisciplinary education should include ethical, social, cultural, and political aspects, Frodeman says. In addition to helping them choose ideas that are potentially transformative, this will give early career scientists “a better chance of anticipating what the effects are of their science, positive and negative” and to prepare for the challenges ahead, he says.
Once you are confident your project is worthwhile, go for it wholeheartedly, John advises. “Enjoy it and believe in it passionately so that you don’t get disillusioned or dejected,” he says. “When you get slapped in the face by failure, you have to think why” and find solutions.
High-risk, high-reward research often also means high-risk, high-reward careers. First the risks: They are becoming more common, but funding opportunities and environments supportive of transformative research remain scarce. John says he would not have been able to pursue research on his miniature pressure-sensing device had he not received the HHMI Collaborative Innovation Award. “We thought we could pull it off, but it was very high-risk and other funding sources would not have gone near it,” John says.
A major risk, especially for early-career scientists, is that transformative research may be slow to yield results. Transformative research may not be the perfect setting for a Ph.D. student to develop a thesis, Marín says. It is risky even for postdocs and junior faculty members aiming to secure a position or promotion, since ultimately you have to show productivity, John says. “Starting your own laboratory, if you take on a high-risk project it can kill your career.”
His solution: Weave a safety net. When John started his own lab, ocular pressure/glaucoma was already on his agenda. But the field was new and risky so he made sure that many of the tools he was using and developing could also be applied to his original field: research in high blood pressure. “Think of a strategy where you can use the same resources for something more conventional, which should be more likely to be funded and more likely to keep you alive if it fails.”
Another danger of transformative research is that recognition may be harder to win even when breakthroughs are made. Papers may be harder to publish. “People just are slow to [accept] things if there’s been a paradigm that’s been laid out for a long time and all of a sudden this is turning the paradigm on its head,” Witt says. Funding bodies (and grant reviewers), too, may be hard to convince—even those that have traditionally been amenable to transformative research. Bruce Beutler, 2011 Nobel laureate in physiology or medicine, “lost his HHMI funding and did the work shortly after that,” said Carl Rhodes, HHMI’s senior scientific officer, during a debate on transformative research in Barcelona last May. Witt and Marín also took part.
Still, transformative research can “make your career and is very fulfilling," John says. If you are able to overcome the challenges, “you have a chance to establish yourself with less competition,” he adds. “I think the plus side will outweigh the negative side.”
Frodeman calls transformative research "a mixed bag.” Scientists “can get marginalized. They can end up out of work because they’ve ended up in a dead end. Or they can be much more successful because they’ve struck something unique and distinctive. And so this will, in part, come down to the personality of the individual scientists. Are they risk-takers? Are they interested in gambling a little more with their career for a higher reward? Do they find interdisciplinary work and socially relevant work exciting? Or do they want to stay away from this?”
• The U.S. National Science Foundation (NSF) has several funding mechanisms in place to support potentially transformative research , such as the Early-Concept Grants for Exploratory Research  (EAGER) and Creative Research Awards for Transformative Interdisciplinary Ventures  (CREATIV).
• The U.S. National Institutes of Health (NIH) has four types of funding opportunities as a part of their High-Risk Research  program: the NIH Director’s Early Independence Award , the Director’s New Innovator Award , the Director’s Pioneer Award , and the Director’s Transformative Research Award .
• The Howard Hughes Medical Institute  (HHMI)
• The German VolkswagenStiftung offers funding for extraordinary projects .
• Thomas Kuhn’s 1962 book The Structure of Scientific Revolutions , which originated the concept of transformative research
• NSF’s Introduction to Transformative Research 
• The 2008 American Academy of Arts & Sciences report, Advancing Research In Science and Engineering: Investing in Early-Career Scientists and High-Risk, High-Reward Research  (ARISE)
• The Pasqual Maragall Foundation’s May 2012 debate on Good Practices for Fostering Transformative Research in Health and Life Sciences  in Barcelona
Elisabeth Pain is the contributing editor for Europe.