Tears welled up in Christopher Gardner’s eyes. Sitting in an airport terminal on a summer afternoon in 2011 awaiting a connecting flight, he had just read the email from the National Institutes of Health, and the news was good. Yes, good. Gardner, a mid-career professor at Stanford, had gotten a high score on his grant application, in the top 10th percentile, high enough to likely qualify to receive funding for a study he’d been trying to get off the ground for years — an investigation into why certain weight-loss diets work for some people but not others.

The thought “It’s still not a sure thing,” flickered through his mind. There was yet another review to clear. But it looked like the hundreds of hours spent writing and rewriting the proposal had paid off.

Gardner says he got into science because of a zeal to search for truth. He still has that zeal. But these days, of necessity, he’s on a search for funding. Gardner’s case is in no way unique. His ultimate goal is an R01 research project grant from the NIH, an independent research grant with up to five years of funding, the goal of nearly every medical researcher whose career depends on winning grants (the vast majority). Gardner had previously won NIH grants, but he had begun to wonder if he’d ever get another. Not only would it help fund his research, salary and the upkeep and growth of the medical school itself, but it’s a stamp of approval for his research program.

What’s involved? In an R01 grant proposal, a researcher has 12 pages to detail the project’s aims, background, preliminary data and research plan. But most of the effort isn’t the writing; it’s coming up with the idea for the project in the first place, then generating the preliminary evidence and rationale that it might really work.

Over the past decade, getting an NIH grant has grown increasingly difficult, and not just for Gardner. This is not surprising. It’s what happens when Congress halts the more than a half-century of prodigious growth in the NIH grants budget, and the number of proposals for those funds rockets upward. The result: Last year, the percentage of successful proposals was the lowest ever: 18 percent. NIH’s review groups of primarily peer scientists selected those from 49,592 submissions — also an all-time record, and up 8 percent from the year before.

What does a Stanford medical school professor do all day? Unless you work at a medical school yourself, you’ll probably be surprised by the answer. Professors engage in a variety of activities, of course. Nearly all do some teaching. Many provide health care. At research-intensive medical schools like Stanford, many devote most of their time to scientific investigation — designing experiments and analyzing data. But what nearly all faculty members whose specialty is research do for hours every day — not just at Stanford but at every U.S. medical school — is chase money.

The chase can be exhilarating, but it can also be exhausting. And after a decade of constriction in NIH funding, many people within medical research, even the institute’s leaders, think the U.S. system for fostering medical discovery is close to breaking.

That system is fueled largely by federal grants from the NIH, which made its first grants in 1947 and steadily increased its grant funding for decades. Then in 1998, Congress upped the pace, leading to a doubling of the budget in just five years. The budget reached $27.3 billion in 2003.

Not surprisingly, this ever-increasing grant supply has led medical schools to hire more faculty who in turn win more grants, which allows their schools to build yet more research facilities. Graduate students and postdoctoral fellows, also often supported by federal grants, conduct the research for relatively low pay in the spirit of apprenticeship, hoping one day to lead a lab of their own. This system has made the United States the world’s leading source of biomedical discovery.

It was great while it lasted. After the biggest, fastest increase in the NIH’s history — the spurt ending in 2003 that’s become known as “the doubling” — the grant budget hit a wall. Aside from the short boost of stimulus funding from the 2009 American Recovery and Reinvestment Act, grant funding has risen only minimally, and when inflation is accounted for, it has fallen.

‘Our buying power is back to about the year 2000.We still have excellent research going on. But you can imagine if we go on without increased investment we will be in the crisis stage.’

“It’s an undoubling,” says Sally Rockey, PhD, director of the NIH extramural grants program. “Our buying power is back to about the year 2000.

“We still have excellent research going on. But you can imagine if we go on without increased investment we will be in the crisis stage,” says Rockey.

“The long-term consequences of these declining investments in research are enormous and tragic, especially given the extraordinary opportunities that abound,” says Philip Pizzo, MD, dean of Stanford’s School of Medicine. “Even for the most seasoned and successfully NIH-funded faculty, concerns about the future are serious and highly worrisome. In addition to the amount of time spent in writing grants and exploring new funding sources, the ability to propose the most creative and innovative research becomes a question mark when study groups and research councils focus more on what’s achievable than what can be imagined.”

Biochemistry professor Suzanne Pfeffer, PhD, past president of the American Society for Biochemistry and Molecular Biology, says at Stanford, the high quality of research provides some cushion, “but across the country people are closing labs, retiring early. This is a crisis.”

Of course, medical leaders and researchers can be expected to decry a reduction in a flow of funds on which they’ve grown dependent. But the implications go beyond the ivory tower. While the United States is curtailing funding, other nations are boosting funding for scientific and medical research for the long-term good of their economic growth. This trend is most evident in Asia, where several nations have made medical research a priority. China’s government spending on medical research increased 67.3 percent between 2009 and 2010 to reach $567 million. India’s increased 15 percent to $135 million. South Korea’s government spent $1.05 billion in 2009, a 23.6 percent increase from the year before.

The widespread assumption is that U.S. federal spending for medical research will stay flat, or maybe continue to drop. “Nobody in their wildest dreams would expect to see anything like the growth we’ve had in the past,” says Ann Bonham, PhD, chief scientific officer at the Association of American Medical Colleges. “Institutions across the nation are coming to grips with the new normal.”

On the level of an individual medical researcher like Gardner, a failure to win federal research grants signals that he’s not making the grade, not only in his own eyes but also in those who decide whether he’ll be reappointed.

Stanford medical faculty members are hired into one of three categories: university-tenure line faculty are expected to achieve excellence in research, medical-center line faculty are expected to devote most of their time to patient care and clinically related research, and non-tenure line faculty focus either on teaching or, as in Gardner’s case, research. All three lines include some teaching. Faculty at most medical schools fall into similar categories.

“In the university-tenure line, it would be a very rare faculty member who gets promoted without any grant funding,” says Stanford medical school’s senior associate dean for research, Harry Greenberg, MD. “That’s because you generally need funding to do most kinds of medical research, and you get the funds because your peers think highly of what you propose to do.”

Non-tenure line faculty specializing in research like Gardner are uncommon at Stanford — there are only 56 in this role — but they are even more dependent on grants or contracts for funding. If for more than two years they fail to secure sponsorship that covers 80 percent or more of their salary, they are at risk of losing their job.

As biomedical leaders and faculty in research trenches don’t expect the federal grant budget to grow much if at all, they’re looking for other solutions.

Gardner’s experiences securing NIH grants are par for the course for a member of the Stanford medical faculty whose primary work is research and who began a career in the last few decades. In short, the experiences have gone from challenging to maddening.

“It used to be that you would think about funding all the time, but you wouldn’t talk about it, at least not about failing to get it or losing it. It was embarrassing,” says Gardner, an associate professor in the Department of Medicine’s Stanford Prevention Research Center. “Now people are open. You say you didn’t get funding and they’ll say, ‘I know, me too. It’s brutal.’”

When Gardner wrote his first NIH grant application, it was during the five-year doubling and he had a relatively easy time of it. In 1998, he proposed a study of the effects of chemicals in soybeans known as isoflavones on prostate, breast and bone as part of a massive joint proposal with other researchers. The joint proposal didn’t get funded but the next year he submitted just his part and obtained his first R01 grant, $1.25 million over five years.

Gardner was on a roll. In 2002, he got an R01 grant to compare the effects of garlic on cholesterol levels, with total five-year funding of about $1.5 million. (The only time he got an R01 proposal funded on the first-round submission.) Then in 2003, he won a grant to do his first weight-loss diet study. Landing that one, which led to the most important study of his career so far — a comparison of four popular diets, ranging from low- to high-carbohydrate intake — was not so easy.

Gardner first proposed the weight-loss study in 1999 before he joined the Stanford faculty. He takes a certain masochistic pleasure in tracing it from its beginnings. “This will be fun,” he says, launching into the history.

It started on a whim when he had a short-term faculty position at UC-Davis and competed for a $50,000 internal grant to compare several diets’ effectiveness. He didn’t get it. But a colleague suggested he make it much bigger and submit it to the U.S. Department of Agriculture. “So I spent a bunch of time and made it into a $3 million grant,” says Gardner. “They didn’t even read it.” That was because Gardner made a beginner’s mistake: He hadn’t realized the funding was capped at $1 million. So he resubmitted the grant the following year, rewriting it to fit within the funding limit. He didn’t get it. That was the third try.

Hired back to Stanford in 2001 (he was a postdoc and a research associate from 1993 to 1999), Gardner called the NIH program officer for advice. “Could I submit this massive thing? Or should I drop it?” The program officer suggested that since Gardner had no track record in weight-loss studies he submit it as a smaller, less expensive project — a pilot study. After many hours of discussion, research and rewriting, Gardner sent in the scaled-down proposal, but it was rejected too.

‘Donors do not give us money to turn the lights on, repair the roof, prepare financial statements, improve the wireless infrastructure or pay for an ugly seismic retrofit... . No one’s going to give us money for that.’

It was only after additional revisions, and a resubmission in 2003 (the fifth overall try since 1999) that he got the grant. Not only that, but a few months after he started the pilot study he learned to his delight that he had been awarded an additional $1.5 million for the study — he was the recipient of a portion of the $5 million court judgment against dietary supplement-maker Metabolife. He used the additional funds to expand the study, a clinical trial of diets. He published the results of what he called the “A TO Z weight-loss study,” in 2007 in the Journal of the American Medical Association, one of medicine’s top journals. The trial, which made him famous in nutrition circles, compared the results of a year of the Atkins diet (extremely low carbohydrate), Zone (low-carbohydrate, high protein), Ornish (very low fat) or USDA/Food Pyramid LEARN (high carbohydrate/moderate-low fat) for 311 overweight women. What he found was that none of the diets worked well for all followers, but on average, those on the Atkins diet ended up with a modest advantage in both weight loss and metabolic health.

It was a finding that flew in the face of accepted nutrition tenets, and raised a lot of new questions. For Gardner, the biggest was why each of the diets worked great for some people but not for others. “It’s an obvious question — there was huge variability within each of the diet groups, much more so than between any of the diets.” He submitted proposals to NIH to investigate this question, refining the approach after each rejection. Initially he proposed testing whether someone’s insulin status — insulin resistance vs. insulin sensitivity — explained an important amount of the within-diet variability. These weren’t funded. Now on the seventh try, a proposal to test whether a genetic signature can predict which diet will work best for different individuals finally made it into the top 10th percentile. Each NIH granting body sets a payline — a percentile rank up to which nearly all R01 applications can be funded, and Gardner’s proposal had passed that test.

The proposal had just one more gauntlet to run. It had to pass muster with the body’s advisory council — a group of scientists, patient advocates and community representatives that makes recommendations based not only on scientific merit but funding priorities. But with obesity a major public health problem, he thought it had a good shot.

As Gardner and other faculty apply for grants, Marcia Cohen, monitors the health of the school’s finances. Clinical activities and research grants and contracts are the largest sources of revenues at Stanford, as at most medical schools. Then come various other smaller sources, including tuition, the parent institution (the state if the school is public, or the university if it’s private) and philanthropy. Stanford medical school’s revenues have been on an even keel — for the most part. The big question mark is the grant funding, which accounts for 38 percent of the medical school’s budget. “This year our research revenues are 5 percent lower than last year because the majority of our grants from the federal stimulus program ended. With the possibility of more NIH budget cuts in January, I am worried,” says Cohen.

While Stanford University’s fundraising success and its approximately $17 billion endowment provide a degree of security few universities enjoy, those dollars won’t solve the potential problems at the medical school.

“We can be rich and still feel very constrained, because in medical school finances we have a lot of restricted funds,” says Cohen. “Donors are passionate and interested in giving you money for specific research. They don’t just say, ‘It’s for the general support of the medical school.’ Donors do not give us money to turn the lights on, repair the roof, prepare financial statements, improve the wireless infrastructure or pay for an ugly seismic retrofit to make sure the building doesn’t collapse. No one’s going to give us money for that. It’s still tricky for us to balance our operating expenses.”

Hence, the reliance on federal funds to help cover overhead costs. With every federal grant, a research institution receives not only the funds budgeted specifically for the proposed project but an additional percentage that goes to the institution for overhead. Every few years, research institutions negotiate this percentage, called the indirect cost rate, with the federal government. The government establishes the rate after examining the costs for facilities and administration incurred since the last assessment. Stanford’s current rate, 57 percent, is a bit lower than those at many comparable institutions: Harvard Medical School’s is 69 percent, Yale’s is 66 percent, Johns Hopkins’ is 62 percent. Neighboring UC-San Francisco’s is nearly identical to Stanford’s at 56.5 percent.

What this means for Stanford is that for every $1 million the researcher gets for the direct costs of the project, the university can receive up to $570,000 for the indirect costs. Non-NIH funding sources rarely pay full indirect costs.

“If we don’t have a growing research base, or if it doesn’t at least stay flat, then the school doesn’t have as much money to pay for the infrastructure costs that we need to house and manage all the research we do,” says Cohen.

As for solutions? NIH is typically the source of 70 to 75 percent of Stanford medical school’s grants, but Cohen is seeing a trend among faculty to apply for funding from other federal sources, in particular the Department of Defense, Department of Energy and USAID, as well as State of California grants and contracts, including awards from the California Institute for Regenerative Medicine.

The medical school’s Research Management Group also provides an exhaustive collection of funding opportunities on its website, ranging from a $100,000 innovation grant from Alex’s Lemonade Stand Foundation (“fighting childhood cancer one cup at a time”) to a $2.5 million clinical trial award from the Department of Defense to test treatments for combat injuries. Beyond this, the school’s institutes and some of the departments have staff that match faculty to prospective grants and then help prepare and submit the proposals. One of Cohen’s quandaries is how much to increase the staff in these positions beyond the current handful, if at all.

Ultimately, however, unless the federal grants boom again — and no one interviewed for this article was counting on that, or even expecting it — medical research must find other sources of support or risk atrophy.

Gardner has a new passion. “I want to build an interdepartmental program around food systems, partly because I think this will be the wave of the future for improving diets in the country, but also partly because of my frustration with getting funds through traditional routes,” he says. He’s not giving up on federal grants but he’s also seeking philanthropy. He believes such a program could become a magnet for individuals willing and able to fund research the NIH won’t. In part to build a case for a program, in 2010 he began hosting the Stanford Food Summit, an annual interdisciplinary conference on food. He’s also raising his profile by speaking at conferences and workshops beyond the walls of academia. He’s already had some success, securing two grants totaling $75,000. He’s using these funds to support studies designed to improve the quality of hospital food, to assess the feasibility of increasing the amount of produce distributed through food banks, and to see whether a farm-themed summer camp can improve preferences for vegetables among low-income children.

With food a national obsession, and Gardner an enthusiastic fundraiser, his hopes for philanthropic support seem justified. But researchers like Pfeffer, who study more arcane topics, like the basic molecular workings of cells, probably don’t have that alternative.

That’s troubling because basic research enlarges our understanding of health and disease and opens new routes for developing treatments and cures. It’s the kind of work the United States excels at. But it’s expensive to run a lab, and it requires a great deal of university infrastructure to support it — in terms of technical support staff and research space. For these indirect costs, the nation’s medical schools have relied on federal grants.

“Universities have set up a business model dependent on grants with indirect costs,” says Pfeffer. “If you say, ‘Well, we have to cut indirect costs,’ we’ll have to think of different ways of how to operate.” And she holds out hope for philanthropy as well. “What will really help Stanford is endowments. I think that’s how Stanford is going to survive,” she says.

In the here and now, though, the NIH still offers a tremendous amount of research funding and investigators expend tremendous energy trying to obtain some of it.

Gardner estimates he has spent hundreds of hours each year writing and rewriting proposals. In addition to applications for grants to fund his own research, he led the writing of a massive $6 million proposal for more than 50 Stanford investigators to create an interdisciplinary nutrition/obesity research center. The proposal was 500 pages long. He submitted it in 2009, and when it failed to get funded he and his colleagues revised and resubmitted it in 2011. Still no dice. “I easily spent pretty much full time two months on each one. Obviously pretty frustrating to put in all that time and get no funding out of it.”

As for the seventh iteration of the weight-loss study follow-up, he really wants to do it. “This is the logical follow-up for the last decade of weight-loss diet studies,” says Gardner. “For decades people said low fat was best, but the obesity epidemic didn’t end. So people said, ‘No no, you got it wrong, it should be low carb,’ but they didn’t have any evidence. Until recently the conclusion was forget both and just focus on calories. What I’m saying is it’s still a reasonable question, but just stop randomizing the average person. Look for predictors of different responses to the same diet. Use insulin-resistance status or genetic information to guide which diet to recommend. I think this is where the field is going.”

On Sept. 13, 2012, Gardner got his happy ending: notice of award for the project, “Do Genotype Patterns Predict Weight Loss Success for Low Carb vs. Low Fat Diets?” The award, for $3.3 million over five years, comes with full indirect costs.

E-mail Rosanne Spector