Putting Some Perspective on Research and Risk
For as long as there has been a National Cancer Institute, its leaders have attempted to strike a delicate balance between the potentially huge payoffs of risk-taking science and the benefits of more measured progress that comes from incremental research. It is, I believe, a healthy tension that should always be part of discovery—perhaps most importantly when it involves our work on a disease such as cancer. The work we do in our laboratories, we always hope, can eventually be used to help our patients. To me, that puts each experiment I plan in my lab in a different light.
This past Sunday, an article on the front page of The New York Times, “Grant System Leads Cancer Researchers to Play It Safe,” argued that our sense of balance has become skewed. Writer Gina Kolata posited that grants awarded by NCI—and the American Cancer Society and other organizations, as well—have become “a way to keep research laboratories going year after year with the understanding that the focus will be on small projects unlikely to take significant steps toward curing cancer.”
“The institute’s reviewers,” she continued, “choose such projects because, with too little money to finance most proposals, they are timid about taking chances on ones that might not succeed.”
Ms. Kolata’s arguments are not especially new. Around the world, many different systems have been designed to provide financial support to scientists. I dare say, despite its weaknesses and perceived faults, the NIH peer-review system remains the envy of the world—and one of the most duplicated.
Despite the high regard for our grant support structure, NIH, in an effort to continue to refine and better the system, last year released a report and an implementation plan for improving peer review. This year-long process sought input from every corner of the research community to examine the review system and address longstanding concerns that the process was too slow and biased against innovation and clinical research. Knowing the NIH system as a grantee, reviewer, and now institute director, I am particularly disappointed in the Times story. As I stressed to Ms. Kolata in a lengthy interview, an accurate account of how cancer funding priorities are set cannot be expressed in just a few simple phrases. It is a story of nuance and of leadership in moments of change, evolving technology, and scientific opportunity. Research, by its very nature, is always about new ideas, creativity, and hope.
From 2004 to 2008, as NCI’s budget increases hovered below the rate of biomedical inflation, most investigators wisely chose to put their best science forward in their R01 grant proposals, and they found other ways to generate resources for higher-risk, higher-reward projects. This is no more than simple logic. In turn, as riskier efforts mature, those that prove worthy tend to work their way into one’s principal grants. In other words, I suggested in the interview, scientists are not more risk-averse today; they are simply more careful about where they place risk.
Importantly, NCI counts on its division and center leaders to carefully study all grants that have received peer-review scores. NCI routinely searches through every grant that is above the year’s payline in order to fund exciting, innovative projects—and, yes, even risky applications—with potential value. For example, in fiscal year 2008, NCI used approximately $80 million to fund such innovative exceptions for grants that were above the payline. Likewise, each September, I personally review all new investigator grants that have not been funded to make sure we support as much worthy and innovative science as we have applications for, even if they fall outside the cutoff scores assigned by peer review.
What is the evidence that NCI places a high priority on high-risk, innovative science? Perhaps the answer can be found in the growing number of NCI grantees who receive national and international recognition for research excellence. Just last week, Dr. Chad Mirkin of Northwestern University was named the 2009 winner of the $500,000 Lemelson-MIT Prize, which is sometimes referred to as the “Oscar for inventors.” Dr. Mirkin is an NCI-funded investigator, as is Dr. Joseph DeSimone from the University of North Carolina, who won that same award last year. Also last week, two Stanford University graduate students won the inaugural IEEE Presidents’ Change the World Competition. Their work is also sponsored by NCI. Over the years, there have been 39 Nobel laureates who have been supported by NCI.
“Well, that is great,” you might say, “but what about making a difference for patients?” I think it’s important to remember that ingenuity, coupled with persistence, is almost always the hallmark of NCI-supported clinical research. Take for example Dr. Michael R. Grever from Ohio State University, an NCI grantee who is conducting early phase trials with a drug called flavopiridol. The drug was abandoned by industry because of potentially lethal toxicity, but Dr. Grever persisted in his belief that flavopiridol had potential benefits for cancer patients if the toxicities could be overcome. This clinical research is showing strongly positive results in chronic lymphocytic leukemia patients. There are many more such stories, including work on immunotoxins and re-engineered T cells to clear patients of advanced melanoma.
In my interview for the Times story, I suggested to Ms. Kolata that the very nature of cancer science is beginning to undergo fundamental change and that not all scientific risk takes place in the realm of the classic R01 or similar grants. Consider, if you will, our initiatives in cataloguing the cancer genome, which are in fact the next generation of a project once deemed highly risky by the scientific community. The Cancer Genome Atlas will increasingly require competitively awarded, task-driven science conducted by teams of researchers in order to understand the biologic function of genetic alterations associated with cancer that can be targeted by new therapeutic interventions. A sure thing? Certainly not. If we are to succeed, though, the road to new interventions, to new methods of individual prevention, and to the earliest detection, will require scientists to work as a team. Clearly, it is a different view of risk and reward.
In the months and years ahead, we will witness innovative, creative science in new centers of excellence like NCI’s forthcoming Physical Science-Oncology Centers, where physicists, chemists, mathematicians, and biologists will come together to develop entirely new perspectives on the physical forces involved in cancer. (Notably, 7 Nobel laureates either applied for or helped review this program, and 24 National Academy of Science members and 9 National Academy of Engineering members were included in the groups that applied to form centers.) My take is that this is certainly not business as usual.
We will also watch the progress of our existing programs in nanotechnology research, proteomics, and molecular analysis—all cutting-edge projects that will in turn, because of their boldness, benefit the entire research community. When NCI began each of these initiatives over 6 years ago, there were many critics.
To be sure, transformative science will still happen in individual laboratories. NCI will continue to foster aggressive programs to train and support young investigators, whose new ideas will fuel the field for years to come. Those of us running active laboratories commonly acknowledge that the creativity and surprise discoveries most often come from the young people in our labs—students and fellows—and that is how it should be.
We will look to our Specialized Programs of Research Excellence (SPOREs) for new knowledge and its translation to the clinic. We will closely watch the recipients of the Challenge Grants and Grand Opportunities grants made possible by economic stimulus funds. We will always monitor, always adjust, and always seek the right balance. Our progress depends on it.
Do we have enough resources? Of course not. We will never have enough money to do everything we want to do—or could do. Ours is not a bad system, but rather a responsible one. We strive to be good stewards of the people’s investment. From my desk, I am not seeing exciting, risky science going unsupported or witnessing stifled creativity in our programs. I see extremely dedicated scientists donating and sacrificing tremendous amounts of personal time to serve on review panels and to do their very best to make good judgments. They need to be given our loudest applause. That’s the story I wish I had read on Sunday.
In the end, it is about the power of research and the promise of hope.
Dr. John E. Niederhuber
Director, National Cancer Institute