stanford medicine


McCain and Obama over a sick patient

In the crosshairs

Basic science under the microscope

In 1968, Stanford biochemist Paul Berg decided to abandon his studies of bacteria to concentrate on newly available human cell lines. He wondered what recently discovered tumor viruses could reveal about why cells become cancerous. And he wanted to apply findings about bacterial viruses to moving genes from one animal cell to another. His longtime mentor and the Nobel Prize-winning chair of his department, Arthur Kornberg, MD, was less than thrilled.

“He called me the Pied Piper,” says Berg, PhD, remembering that Kornberg accused him of selling out. “In his mind, I was misleading young, impressionable students by moving away from more basic research to something more applied. But I felt this was basic research, even though it had a connection to human health. In fact, those studies uncovered features of gene structure and expression that transformed molecular biology.” In 1980, Berg, now the Robert W. and Vivian K. Cahill Professor in Cancer Research, emeritus, was awarded the Nobel Prize for the work, which led directly to the development of recombinant DNA technology and the biotech industry.

Although the two scientists remained friends, they continued to disagree about the meaning of the terms “basic” and “applied” research until the end of Kornberg’s life in 2007. “To me, it’s a continuum,” says Berg. “I just don’t see the value of that distinction. But Arthur was very concerned that basic researchers were being excluded from funding in favor of applied, or translational, research.”

Berg and Kornberg’s debate has deep roots and tendrils that stretch across decades — perhaps because there is no “right” answer. Although Berg argues that the path from basic to applied research is bi-directional, and that curiosity-driven research supersedes labels, many biomedical researchers feel that the era of individual scientists following their noses is over. Research has become more driven by business than by curiosity, some say, more by outcomes than by process.

It’s not an unreasonable conclusion, as the price tag for laboratory work has grown substantially during the past decades and many senior scientists spend their days scrounging for money rather than planning experiments. Meanwhile, buzzwords like “collaboration” and “interdisciplinary” highlight a growing trend toward networks of researchers that make decisions by consensus rather than by intuition, and the twitching of the congressional purse strings is increasingly predicated on promises of results directly relevant to human health.

Some researchers who remember halcyon days of unfettered exploration have watched with dismay, worried about the repercussions of what they see as mere lip service to basic research. They foresee a decline in unexpected discoveries that lead to sea changes in scientific understanding — and, ultimately, advances in health care. Others, like Berg, counter that it’s simply time to reap the harvest of health benefits sown during the latter part of the 20th century, when the nation poured an unprecedented amount of resources into science and engineering. Proponents of applied, or “translational,” research argue that a lack of accountability by federally funded scientists has lead to a “valley of death” — a 10- to 15-year gap between potentially useful basic research discoveries and their appearance in the clinic — filled with unlucky patients for whom the advances simply came too late.

Muddying the waters is a lack of agreement over what really constitutes basic science: The distinction between basic and applied research can be difficult to draw. Most would concur that, in broad strokes, basic research is intended to increase knowledge in a particular area, without any direct or immediate goal of improving human health. The implication is that useful applications will follow naturally once the know-ledge is gained. In contrast, applied research is intended to fill a particular need or goal — speeding up the drug discovery process for a multiple sclerosis treatment, for example, or figuring out the role of inflammation in cancer metastasis.

The uneasy push and pull between the twin goals of free-form basic research and improvements in human health is an ongoing struggle at every level, from research institutions like Stanford to the huge federal research enterprise that is the National Institutes of Health.

“The National Institutes of Health has a long history of supporting basic science throughout the United States,” says John Gallin, MD, director of the institute’s Clinical Center, established in 1953 to promote clinical research within the institute. “But Congress gives money to the institute with the goal of finding new cures and treatments for disease. We have ‘health’ in our name for a reason. The people who supply the money never forget that. The people who receive the money shouldn’t forget it either.”

It’s the perceived potential of research to improve health that ultimately will keep federal dollars flowing, says U.S. Sen. Arlen Specter, who was the ranking Republican of the Senate Appropriations Committee when the stimulus package passed this year. “The NIH must prove its value to the American people to justify robust growth in its funding,” says Specter. “It must show that the resources are being used on the best science with the most opportunity to improve the health of Americans.”

Members of the increasing number of patient and disease advocacy groups certainly wouldn’t argue with that. From ACT UP, formed in 1987 to raise awareness of the need for more effective AIDS treatments, to the American Cancer Society’s Cancer Action Network, to FasterCures, a group focused on “accelerating medical solutions,” to any person struggling with inevitable aging and disease, improving human health is the goal.

“We all want cures for everything quicker, faster, better,” says Margaret Anderson, the incoming president of FasterCures. “Everyone is a patient or will be a patient, so we all have a vested interest in medical research working well.” And yet, some researchers question whether setting milestones and goals for basic biomedical research is the most effective way to stimulate progress, and whether lawmakers should be the ones to do it.

“Biological laws are not the same as the laws of physics,” says Stanley Falkow, PhD, the Robert W. and Vivian K. Cahill Professor in Cancer Research at the Stanford School of Medicine. “Finding a biological law that doesn’t have an exception or a variation is very difficult, and advances can be unpredictable. But Congress and the taxpayers want to see some kind of tangible return for their investment. Spending on molecular biology and genetics in the 1960s paid off in the early 2000s in the Human Genome Project. That’s a very long period. In contrast, politicians are lucky if they know what they are going to do next week, let alone next year.”

So it’s no wonder some researchers interviewed for this article said they feel that their grant proposals must invoke human health in order to compete well. Food safety is a good example, says Falkow.

“A grant proposal focusing on the natural history of E. coli in a manure pile is less likely to be funded than one in which a scientist proposes making a vaccine against the dangerous forms of the bacteria,” he says. Although he points to the NIH’s extensive human microbiome project, created to catalog the bacterial diversity naturally occurring in and on humans, as a “pleasant exception” to the focus on human health, he cautions “even in that, the expectations are that we’re going to develop some kind of new probiotic, which is going to be extremely difficult to do.” [See "Caution: Do not debug."]

Still, nearly 80 percent of the public believes the federal government should continue to support basic research — defined as research that advances the frontiers of knowledge — even if it seems to have no direct applicability to human health. Furthermore, the National Science Board, which establishes the policies of the National Science Foundation and advises the president and Congress on science-related issues, warned in 2008 of a need for “serious national attention” to our country’s basic research enterprise, citing concern about stagnation and decline. Is it possible to have our research cake and eat it too?

The sponsors

As Gallin points out, the mission of the NIH is to improve human health. It grew out of the Marine Hospital Service, founded in 1798 to care for sick and disabled merchant seamen; about 100 years later, in response to rising concerns about global disease threats like cholera, Congress appropriated $35,000 to create the Hygienic Laboratory to investigate “contagious and infectious diseases and matters pertaining to public health.” The Public Health Service was formed from the Marine Hospital Service in 1912, and in 1944 the PHS was divided into, among other things, the Office of the Surgeon General and the NIH.

“There’s clearly a tension between researchers as to where the money is going.”

Today the NIH is the world’s largest funder of biomedical research, with an annual budget of about $30 billion. Most of the remaining research is funded by the $6.5 billion allotted annually to the National Science Foundation, which supports fundamental research and education in all science and engineering disciplines. Additional federal funding for biomedical research trickles in from a few other agencies, primarily NASA, the Department of Energy and the Department of Defense. Other funding in the form of grants from industry and nonprofit foundations, state support of public universities, and mission-specific, publicly funded groups like the California Institute of Regenerative Medicine, rounds out the pool of research dollars up for grabs.

According to Sally Rockey, PhD, the acting deputy director of the NIH’s extramural research program, which funds research conducted by non-NIH staff, the institute’s relative proportion of funding for basic versus applied research has not changed significantly during the past few years — 56 percent basic and 41 percent applied (the remainder is classified as “other” research) — reflecting the NIH’s commitment to the earliest phases of research. About 84 percent of the NIH’s $30 billion budget goes to support extramural research.

Regardless of these assertions, “There is no question that we have emphasized translational research much more than we have in the past,” says E. Albert Reece, MD, PhD, who heads the Association of American Medical College’s Council of Deans and is himself dean of the University of Maryland’s medical school. He took part in a roundtable convened by the Institute of Medicine in 2000 to explore concerns about the future of clinical research in the United States, particularly in academic medical centers. The group recommended, and Reece agreed, that better systems were needed to promote academic clinical research and training in order to increase the movement of research from the laboratory into the clinic.

“One thing impacting our funding is a movement toward multidisciplinary and multiple principal investigators,” says Rockey. “The nature of the science has become so complex that the problems are beginning to require a multidisciplinary approach.” According to a recent analysis in Science magazine, the proportion of NIH funds dedicated to R01 grants — those given to an individual investigator to pursue a particular research question — has declined steadily since 2000 relative to other types of NIH grants: If R01 grants had increased at the same rate as the NIH grant budget, their funding in 2007 would have been about $1.2 billion greater than their $10 billion total that year.

According to biochemist Daniel Herschlag, PhD, the NIH is overemphasizing large collaborations and consortiums. “I’m all for collaborating,” says Herschlag, a professor of biochemistry at Stanford’s School of Medicine, “but these partnerships have to happen naturally. If you have to collaborate to get the money, you’ll get shotgun weddings or marriages of convenience that aren’t going to work. And if big science gets all the big money, the people doing basic research in individual projects feel less valued and their unique contributions are lost.”

This is precisely the situation that medical school dean Philip Pizzo, MD, is trying to avoid. “Basic research has been and remains our foundation at Stanford,” says Pizzo, a professor of pediatrics and the Carl and Elizabeth Naumann Dean. “Without outstanding basic research, there would be nothing to translate in the future. My focus on translating discoveries has been opportunistic — namely, to create an environment in which ideas that could move from the laboratory to the patient, or vice versa, have an opportunity to move forward. But this should not occur at the expense of fostering and sustaining excellence in basic research.”

And yet, Herschlag argues, even at Stanford, known for its excellence in basic research, more funding opportunities and incentives exist for applied or translational research programs than for basic research in areas like biochemistry and structural biology — a pattern that may be nationwide.

“There’s clearly a tension between researchers as to where the money is going,” notes Gallin.

Even introducing the idea of “translated” or applied research may create an expectation that is difficult to fulfill. And in some ways the scientists themselves are to blame. “We’ve created our own Frankenstein monster in our rush to get federal funding,” says Herschlag, who uses the Human Genome Project as an example. “We said, ‘Give us the money and we’ll get you the genome’ and then we made all sorts of promises about cures that would naturally follow. Certainly we’ve got some very powerful information now, but the expectations of that project overran what has been delivered — not because of an unexpected finding, but because it was oversold. So now we’re saying, ‘Give us more money, because now we need large-scale technology to make sense of all this data.’”

A real shift

Some of the push to connect individual research projects to advances in human health may be related to a movement toward greater accountability on the part of the two main federal funding organizations. In 1993, Congress passed the Government Performance Results Act intended to “systematically hold Federal agencies accountable for achieving program results.” The act requires goal setting and annual, public reporting of how each agency is meeting its goals.

For example, the NIH’s fiscal year 2008 report ranks scientific research goals in terms of difficulty and expected time commitment to achieve specific objectives. Similarly, the National Science Foundation now asks researchers to justify the “broader impact” of their proposed work, including any possible benefits to society.

Arthur Kornberg felt that researchers are inherently bad at justifying their need for funding, however, and to do so would jeopardize the research endeavor. In his 1991 autobiography, For the Love of Enzymes, he writes, “People do not realize that when it comes to arguing their case for more funding, scientists who do basic research are the least articulate, least organized, and least temperamentally equipped to justify what they are doing. In a society where selling is so important, where the medium is the message, these handicaps can spell extinction.”

Requiring scientists to delineate the course and expected outcome of their proposed research is a much different approach than that fostered by the influx of funding for research seen in the Sputnik era, says Falkow. “In the ’50s and ’60s, the philosophy was to fund the best and the brightest, no matter what,” he said in a recent Stanford Report interview. “The idea was that creativity was very important and should be encouraged, and that paid off in the explosion of genomic research findings in the ’90s.” In those days, basic research was considered the most prestigious type of research.

“A half a century ago, biochemistry was pure basic science,” says Berg. “You didn’t hear about anybody patenting anything or trying to cure a disease. But now we can apply these very fundamental principles and tools to attack real clinical problems. There’s nothing demeaning about that.”

But the current structure of government funding allows little leeway for trial and error, says Falkow. “Students today talk about proving a hypothesis, rather than testing it,” he said in the interview. “It’s a subtle, but very real difference. But very creative people often don’t really follow the same drum.” Failing to fund these innovators could have serious consequences, he feels.

“The vast majority of legislators cannot accept the seeming irrelevance of basic research,” wrote Kornberg in 1991. “Were there a record of research grants in the Stone Age, it would likely show that major grants were awarded for proposals to build better stone axes and that critics of the time ridiculed a tiny grant to someone fooling around with bronze and iron.”

Although the NIH has attempted to rectify the problem with new programs that support exceptionally creative researchers, those grants — the Pioneer and the New Innovator Awards — make up only a small proportion of its budget. In contrast, the proportion of money the NIH provides through Research Project Grants to address NIH-posed questions increased slightly from 1995 to 2006, from 14 percent to 15.5 percent of the total.

And, regardless of how you slice it, getting funding has become more difficult: The odds of an NIH R01 or equivalent grant application being approved on the first try plummeted from 21.2 percent in 1999 to 8.4 percent in 2008.

Alarm bells

The National Science Board took note of the squeeze affecting basic science in a companion piece to its congressionally mandated, biennial Science and Engineering Indicators 2008. Although the report did not specifically parse out the life sciences, the board warned that a decrease since 2005 in overall levels of federal funding for academic research and development — the first multi-year decline since 1982 — coupled with shrinking support for basic research on the part of industry could have “severe implications” for U.S. competitiveness.

“We urge all Americans to support sustaining our nation’s long-term commitment to basic research and to a strong U.S. R&D enterprise,” concluded board chair Steven Beering. The board recommended increased federal funding for basic research and more academia-industry collaboration.

“We’ve underfunded research in so many different ways and at so many different times in this country over the years,” agrees Mary Woolley, president of Research!America, a nonprofit organization dedicated to making medical and health research a higher national priority. She and others are looking forward to the influx of so-called stimulus money from the American Recovery and Reinvestment Act. “We’ll be catching up ground we lost over the last six or so years,” she says, “which put us in a negative place both financially and in terms of morale.”

But many researchers have concerns about the requirement that the stimulus money (about $10 billion to the NIH and $3 billion to the NSF) be spent within two years. Although the intent is to provide a rapid economic boost, research science tends to move at a slower pace — on the order of years rather than months. They’d like to avoid a repeat of the boom-and-bust cycle of federal funding of the late 1990s and early 2000s in favor of more sustainable funding that supports all types of research.

“The idea that increasing our support of translational research means that we must cut basic science funding assumes a truly steady state,” says Maryland medical school dean Reece. “I hope that is not the case anymore. I believe that we will see a continued increase in NIH funding over the next eight years. To do otherwise would put us back in the same position we were in during the previous administration.”

So where are we now?

Although President Obama campaigned on a promise to significantly increase the budget of the NIH, his 2010 budget request contains only a 1.5 percent increase for the institute. Kathleen Sebelius, secretary of the Department of Health and Human Services, has said the discrepancy is due to the large amount of stimulus money the agency has yet to spend.

And yet the fact remains that the funds available to support these and other research efforts are decidedly finite. Although President Obama has pledged to increase federal spending on research and development to 3 percent of the national GDP (an increase of about $60 billion, and more than the 2.88 percent all-time high achieved in 1964), that all won’t be devoted to biomedical research. He’s pledged to double the budgets for several organizations that traditionally focus more on the physical sciences: the National Science Foundation, the Department of Energy and the National Institute of Standards and Technology. He’s also staring down a health-care system in urgent need of reform, a growing global warming crisis, a severe economic recession and a Congress that may not share his priorities.

Some, like Sen. Specter, argue that basic research boosts the economy. “Investments in biomedical research have spurred the development of the biotechnology, nanotechnology and pharmaceutical industries,” he says, adding that acting NIH director Raynard Kington, MD, PhD, estimates that each dollar invested in the NIH stimulates $2.50 in associated economic activity. “Since 1980, almost 5,000 new companies have been formed around technologies from U.S. research institutions. These companies have brought to market thousands of new technologies and employ hundreds of thousands of Americans in good, high-paying jobs,” says Specter.

As the discussion continues, it becomes clear that there may be an argument for discarding the “basic” and “applied” labels entirely. “I like to talk about good science, solid science, without defining it as applied or basic,” says Berg. “When I was younger, I wanted to argue, ‘Just give me the money and let me do what I want to do.’ Up to a point that’s acceptable and it’s still being done. But what piques people’s curiosity has changed and the breadth of our current understanding leads us to go up to the next level. There should be no boundaries.”

And yet in 2009 that money will almost undoubtedly come with strings attached. FasterCures’ Anderson says: “It shouldn’t just be, ‘Here’s your money, we’ll talk to you in 10 years.’”






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