Is the straight road too narrow?

Congressional demands for cures and accountability—combined with a flat NIH budget—have increased pressure on scientists to produce findings with direct application to disease. Nonetheless, there’s great value in cultivating the art of finding what you’re not looking for.

Jeffrey Fisher

The stereotype of the basic researcher—driven by curiosity, absorbed in the arcane, immune to practical considerations—is only half right. The need to unravel a puzzle, to uncover the beauty and order in biological systems, or simply to follow one’s nose, asking and answering questions, is both the initial impulse and sustaining force for many a career in basic research. Yet these scientists are not indifferent to the practical applications of their work. They are just not starting out with that particular end in mind.

Take structural biologist Thomas A. Steitz, Ph.D., Sterling Professor of Molecular Biophysics and Biochemistry. Beginning with his doctoral work more than 40 years ago, Steitz has fixated on one question: How do proteins and nucleic acids carry out their diverse jobs in cells? For Steitz, that question is best answered by looking at the macromolecule’s shape; he is a leader in charting the topology of proteins and nucleic acids at the atomic level.

Steitz and his team were the first to see one particularly important biological machine eight years ago when they solved the molecular structure of the large subunit of the ribosome, the protein-making factory inside all cells. That discovery, coming after five years of effort, a few dead ends and a little luck, has turned out to have practical benefits. Many antibiotics work by interfering with the functions of bacterial ribosomes. Steitz’s lab was soon busy looking at the ways in which antibiotics recognize and bind to the bacterial large ribosomal subunit and shut it down. Hard data about molecular interactions are like gold to scientists looking to design new antibiotics—as they are now doing in a company that Steitz helped found.

“When I started solving protein structures as a graduate student, I had no idea, nor did anyone else, that this would ever be of any practical benefit whatsoever,” Steitz says. “We just wanted to know, how does this machine work? … Our work has led to translational research, but it wasn’t the goal. I never thought that I would end up building a pharmaceutical company around the study of the structure of the ribosome.”

It is a cliché of scientific exploration that even the most esoteric work can yield unexpected benefits. From synthetic insulin, the first biotech drug (a result of studies of bacteria) to the latest frontier of RNA-based therapies (started by work in worms), Steitz posits that every single medical discovery of major importance made over the last 30 years has its roots in basic research. “If you trace back through the history of molecular biology, which made biotechnology possible, you find that it all came from basic research,” he says.

So why are Steitz and his colleagues so worried about the future of creative, idea-driven biological research? He and researchers like him are proof that investments in ideas and individuals can and do pay off handsomely for human health. Nonetheless, these days a combination of painfully lean budgets at the government agencies that fund basic research, coupled with a current fashion for applied, disease-oriented studies (see related story, “Mapping the future of medicine”) have basic researchers asking where their next grant—not to mention the next generation of like-minded scientists—will come from.

Risk management

“What really gets me excited is a brand new project,” says fruit fly researcher Lynn Cooley, Ph.D., professor of genetics and cell biology.

Cooley is fascinated by egg production in female fruit flies, a process that reveals the ways in which the flies’ cells communicate and cooperate in order to form nurturing environments for developing eggs. Although her work has some application to the growth and spread of human cancers, Cooley’s research is guided by her team’s latest experiments. “When a set of experiments opens doors to unexplored areas of biology, that’s the fun part,” she says. “That’s what makes it exciting to go into the lab every day.”

The harder part is finding the funding to support her quest. The bedrock of basic biomedical research in the United States has long been the investigator-initiated research grant from the National Institutes of Health (NIH), known as an RO1. These grants cover salaries and laboratory expenses for an investigator and a few junior scientists to work on projects of their own design. RO1 grant applications are 25-page proposals that are reviewed by committees of researcher’s peers, who judge their merits and recommend the best for funding. The system has worked well for years to cull out the most promising new research for NIH support.

And that research has been well supported. With a total NIH budget of $29.5 billion in 2008, the United States leads the world in its funding of basic research in the biological sciences. Half of all federal funds devoted to scientific research are funneled to biomedical research through the NIH. That money pays for 80 percent of biomedical research done in the United States. Support for basic research boomed during the years between 1998 and 2003, when Congress oversaw the doubling of the NIH budget. The RO1 program was a major beneficiary of the increase.

“The fact is that the NIH has put us far ahead of the curve in biomedical research,” says Cooley. “And we have seen a huge payoff from research at the extremely basic level. Look at the examples of therapeutic RNAs or stem cells. In both cases, the researchers were driven by curiosity as to how organisms develop from single cells to complicated systems. Who would have known that their work would become the underpinnings of some of the biggest therapeutic advances we’ll see over the next decades?”

But what Congress gives, it can also take away. Since peaking in 2004, NIH funding has flatlined at $29.5 billion, and next year’s proposed budget looks to be more of the same. While Congress often kicks in a little more money to keep programs from further cuts, the effects of inflation mean that the NIH is operating with 13 percent less buying power than it had in 2004.

On top of that, the demand for RO1 funding is higher than ever. During the doubling period, the whole research enterprise grew as universities and academic medical centers expanded basic research facilities and faculties. That expansion takes time, so the NIH saw only modest growth in the number of grant applications received during the doubling years. As a result, a larger proportion of grant applications were funded. In the first two years of flat budgets, however, the number of grant applications doubled as new researchers came on line, and success rates in obtaining grants plummeted.

There is no relief in sight. According to a budgetary analysis by the American Association for the Advancement of Science, under the proposed 2009 NIH budget, the number of new grants, the average size of a grant, and the expected success rate for grant applications are all expected to fall.

“I have two new projects I’m really excited about but also kind of nervous,” admits Cooley. “The most exciting projects are the ones that are hardest to fund because they tend to be the risky ones—ones where our lab has no track record—and there’s not a big field of established work to point to and show where we fit in.”

Lean times force funding agencies like the NIH to be more conservative and favor surefire bets. That means that finding support for innovative science can go from difficult to impossible as budgets shrink, says Richard A. Flavell, Ph.D., chair and Sterling Professor of Immunobiology, professor of biology and an HHMI investigator. “Grant reviewers still recognize research that is new and exciting and worth taking a chance on. But in a super-competitive environment, those off-the-wall, risky, creative projects lose out,” he says.

Enter the Roadmap

Money, or lack of it, is not the only threat basic researchers perceive. Many report a growing unease with the wider world’s view of their work, and with what some think is a mistaken assessment of its value. Among researchers, there is a palpable feeling that a recent and highly visible growth in support for clinically oriented translational research programs means less funding for basic research. In this regard, some researchers blame a set of programs collectively called the NIH Roadmap for Medical Research for draining support from their labs.

The Roadmap had its start at the end of the period of rapid budget growth. Anticipating that the public and its representatives in Congress would be looking for payoff on their investment, the then-new NIH director, Elias Zerhouni, M.D., initiated a mass consultation in 2002 with hundreds of scientists to identify gaps in NIH programs. Over the course of a year, Zerhouni identified areas in which the NIH might do a better job of supporting multidisciplinary teams as well as translational and clinical research. The process was dubbed the Roadmap; its first projects began in 2004.

There was controversy about the Roadmap from the beginning. Just as RO1 funding was tightening, basic researchers watched money flow to translational research, multi-investigator grants and clinical research.

The School of Medicine has certainly benefited from that funding stream. The Yale Center for Clinical Investigation (YCCI), under the direction of Robert S. Sherwin, M.D., the C.N.H. Long Professor of Medicine, received a $57.3 million grant in 2006—the largest single NIH grant ever given to Yale. That grant included existing grants to Yale of $25.8 million, so the net increase to Yale was $31.5 million. Another recent NIH award supports the training of medical students to carry out clinical research.

No matter the merit of those programs, they create a perception problem, says Carolyn W. Slayman, Ph.D., Sterling Professor of Genetics and deputy dean for academic and scientific affairs. Compared to an average RO1 grant of about $1 million over four years, the new awards were eye-popping. “To starving scientists who are worrying about their own RO1, it’s hard to see Roadmap grants awarded in huge and very visible chunks of $20 or $40 or $50 million,” Slayman says. “Their immediate reaction is, how many laboratories like mine could be kept going very happily for years with that money?”

Even so, the idea that the Roadmap is a drag on basic science funding is exaggerated, says Jordan S. Pober, M.D., Ph.D., professor of immunobiology, pathology and dermatology and vice chair of the Section of Human and Translational Immunology.

The numbers support his view. Taken together, Road-map projects account for less than 2 percent of the total NIH budget; moreover, fully half of Roadmap funding goes to individual researchers in the form of RO1 or similar grants. The real culprit, Pober says, is the stagnation of the overall budget. His message: “There is pain, to be sure. But don’t blame the Roadmap, blame the budget.”

Moreover, the activities championed by the Roadmap are necessary for the NIH to fulfill its goal to improve people’s health, Pober says. “The NIH is not the Academic Scientist Employment Act. It’s a mandate from Congress to create a biological basis for improved therapies and for improving health care.”

The Roadmap initiative just happened to come at the same time as the NIH budget stagnated and the chances to obtain RO1 funding decreased dramatically, says Jeremy M. Berg, Ph.D., the director of the NIH’s National Institute of General Medical Sciences, which primarily supports basic, nondisease-targeted research and is heavily involved in Roadmap activities. “That does not mean those events are causally related.”

On the contrary, Berg says, the Roadmap has been a very good thing for basic research. The idea of setting aside a relatively small amount of money for new kinds of programs and approaches was a key provision of the Roadmap and has paid off by becoming quite popular in Congress. “In my opinion the Roadmap has been quite successful with Congress in terms of their seeing the value in what we’re doing. My sense is that the NIH would have been substantially worse off than we are right now if we had not had the Roadmap.”

Shortest distance between two points

Money talk aside, researchers still worry that the hoopla surrounding new clinical and applied programs that began under the Roadmap may divert attention from the fact that successful medical research relies on a foundation of basic knowledge about the functioning of healthy cells and organisms. The only way to get that information is to turn over the rocks in the field of biology and see what is underneath. And that means an investigator in a lab working steadily over years and decades. That means Steitz tinkering with the ribosome. It means Cooley finding out how flies make eggs.

That theme—the long and winding road from disease to cure—was echoed in a recent editorial in the journal Science. Editor in chief Bruce Alberts, Ph.D., argued eloquently for the importance of basic research in spurring medical progress.

“We have all been taught that the shortest distance between two points is a straight line,” Alberts writes. “But the same idea has repeatedly proven not to be true for progress in medical research.” The reason, he says, is that we understand so little of what there is to know about the basic functions of cells that researchers tracing a path from disease to cure must navigate largely uncharted terrain. Scientists continue to rely on lessons learned from simple organisms—yeast, bacteria, plants, fruit flies, worms—to guide progress through the terra incognita of human disease.

John Carlson, Ph.D., the Eugene Higgins Professor of Molecular, Cellular and Developmental Biology, has been looking for answers in the fruit fly’s sense of smell for 20 years. Carlson has spent that time figuring out the workings of odor receptors and the olfactory system of flies, which use their sense of smell primarily to navigate the world. He and his colleagues mapped out the chemical receptors and brain pathways involved in the uncanny ability of these pests to appear out of nowhere in response to the aroma of a banana left outside to ripen on a warm day. On the way, he has found both beauty and some unanticipated applications.

“The same way that fruit flies find bananas, mosquitoes find humans,” Carlson explains. “They both depend on their sense of smell.” That insight propelled him into the field of malaria, a disease that infects hundreds of millions of people around the world each year. Carlson is working with European and African colleagues to find chemical compounds that confuse the sensory receptors on a mosquito’s nose and prevent them from finding humans. In the future, he foresees using a similar approach to keep crops free of agricultural pests. Carlson says the work may also be adapted to use odor receptors as detection devices for explosives.

For two decades, Carlson has been able to keep his research program on track with an uninterrupted stream of funding from NIH. His applied research draws support from private foundations, including the Bill and Melinda Gates Foundation for the malaria work. Nonetheless, he says, “I do worry about the NIH dropping support for individual labs exploring questions that excite their curiosity about basic science.”

The long view

The Nobel Prize-winning biologist Arthur Kornberg, M.D., liked to tell a story that starts with a surgeon out for his morning jog. While passing a lake, the doctor sees a man in the water about to drown. So he dives in, pulls the man out, resuscitates him and continues running.

A bit farther down the path, another man is flailing in the water in another part of the lake. The surgeon saves him, and no sooner sets off jogging again than he sees two more people in trouble in the water. He notices his friend, a neuroscience professor, loitering nearby and calls out for him to save one person while the surgeon rescues the other. When the neuroscientist does not move, the exasperated surgeon shouts at him, “Why aren’t you doing something?”

The neuroscientist answers calmly, “I am doing something. I’m desperately trying to figure out who’s throwing all these people in the lake.”

The point is, of course, that the fight against human disease occurs on several fronts. Someone has to rush in and save today’s victims. Solving fundamental problems, however, requires other people with different skills and interests. Neither group is more important than the other. That is one message that researchers fear is being lost on lawmakers and the public, and even on budding young scientists as the funding freeze continues.

Pietro De Camilli, M.D., Eugene Higgins Professor of Cell Biology and co-director of the program for Cellular Neuroscience, Neurodegeneration and Repair, sees this loss of perspective in his experience with up-and-coming researchers. “There is a perception I see in young people that if they want to be a scientist and successfully compete for funding, they have to work on applied problems. A career in basic research seems less and less attractive.”

The boom-and-bust cycle of congressional appropriations to NIH over the last decade has left some senior researchers struggling to maintain long-term projects. When young investigators see their mentors not being funded, they get the message, says stem cell researcher Diane Krause, M.D., Ph.D., professor of laboratory medicine and cell biology and associate director of the Yale Stem Cell Center. “This is dissuading people from trying to succeed as academic researchers. We certainly make it look difficult to our students and postdoctoral fellows.”

At current levels, the NIH budget overall is a prescription for slowing medical progress in the future, not speeding it up, according to immunologist Flavell. He supports the Roadmap but cautions that any success depends on maintaining a healthy basic research environment and pushing forward with applied and clinical programs. One without the other makes no sense, yet increasingly he sees outstanding researchers unable to win grants. Unless something changes soon, he says, we may find ourselves 20 years down the road with an impressive clinical and translational infrastructure but few new basic findings to translate. YM

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