Impending crisis in the NIH

The Journal of Clinical Investigation was misidentified as the Journal of Clinical Investigators.

The National Institutes of Health is the chief agency of the U.S. government responsible for biomedical research. It currently provides $28 billion annually to researchers, accounting for slightly less than a third of the total domestic funding for biomedical research. Its goal is to “acquire new knowledge to help prevent, detect, diagnose and treat disease and disability, from rarest genetic disorder, to the common cold,” according to its website.

But a vast increase in the number of grant applications coupled with a frozen level of congressional funding has thrown the institution into its worst funding crisis in more than 30 years. The budget for the NIH doubled between 1995 and 2003 from $12 billion to $24 billion. But from 2003 to 2005, the budget remained at about $28 billion, and in 2006 the budget decreased for the first time in over 30 years. President Bush has asked lawmakers to keep the funding at the same level for the fiscal year 2007.

During the five-year doubling period of the budget, the number of applications increased by 5,334. In the two years following the doubling period, there were 5,208 new applications. This “post-doubling effect” has caused the competition for NIH funding to increase dramatically.

The University ranked seventh in overall funding awards, receiving 975 awards valued at $386,027,410 for the fiscal year 2005, a boost of 30 awards and about $18 million dollars.

Still, according to Ron Koenig, professor of medicine and director of the medical scientist training school, if the current dilemma the NIH faces persists for the next five years, the consequences could be detrimental to thousands of scientists needing work and millions of Americans needing medical treatment.

“The NIH has been a national treasure for over 50 years, supporting the world’s best and most productive scientific enterprise,” Andrew Marks, the editor in chief of the Journal of Clinical Investigation wrote in an April editorial. Marks wrote that the current cutbacks in NIH support would be the equivalent of doubling the number of teams in Major League Baseball, then cutting their budgets so that one-third of the players are out of jobs. “The net effect on our nation’s scientific productivity is devastating and will be for years to come,” Marks wrote.

In 1992, according to data from the NIH, researchers aged 36 to 40 received 23.1 percent of R-series awards, grants that fund independent research. Historically, in a best-case scenario, R-series grants have been awarded to the top 20th percentile of grants, as reviewed by the NIH. While it’s difficult to apply absolute terms by the percentile, anything below 15 percent is considered bad. Today that number has fallen to about 12 percent.

“The R-series grants . are the most important part of funding,” Koenig said. “They are the foundation of biomedical research. They are the breeding ground for new scientists.”

Marks described the investigator-initiated RO1 grant as “the most tried and true mechanism for funding science.”

These are the numbers on every scientist’s mind, no matter what they are studying in the lab.

“If this situation doesn’t improve, the University could lose 40 percent of its research faculty,” said John Kao, assistant professor of medicine.

Koenig, however, pointed out that it is difficult to say exactly how many people would be shaken from academic science. Still, people are already being forced out of academic science and into other areas. Kao said he had a colleague who left research to go into private practice in Florida, after being unable to get funding.

“There are a number of forces conspiring against researchers,” said Charles Burant, an professor of internal medicine.

The post-doubling effect, coupled with a federal budget spread thickly on Iraq, homeland security and the defense department, money is scarce.

The result? There hasn’t been a worse time for a scientist to apply for funding from NIH.

The scientist’s struggle

It takes a long time to train the kinds of scientists who are directly affected by this crisis. Although there are hundreds of different types of scientists funded by the NIH, most can be lumped under two general training categories: M.D.Ph.D.s and Ph.D.s. Once a scientist has completed one of these two programs, he will enter nearly another decade of training before applying for an associate faculty position.

Kao’s road to his current position at the University is typical of the experience of an M.D.Ph.D. After completing a three-year Internal Medicine residency, Kao spent three years in a fellowship program at the University. After his fellowship, Kao spent three years as a lecturer. The experience of a scientist graduating a Ph.D. program would differ slightly.

Rather than spend time in a residency, after graduating a Ph.D. program, a scientist would enter a post-doctoral training period, working with established scientists to build up an application. In his last year as a lecturer, Kao was awarded a K-series grant – an NIH-supported award that assists clinicians and Ph.D.s seeking a career in biomedical research while they train with a mentor. Typically scientists will apply for a K-series grant during their post-doctoral studies. Kao’s grant, called a KO8 grant, guarantees 75 percent of his salary for research. Kao devotes the other 25 percent of his time to clinical work.

Kao’s generation of researchers faces the most trouble. While Kao has five years of salary guaranteed by his KO8 grant, many junior researchers – those who have received or are applying for K-series grants – are not as lucky. If researchers can’t get R-series grants to support their own research, many will leave academic science to pursue other paths.

Junior researchers are also at a strong disadvantage when it comes to the grant application process. With funding as tight as it is, grants need to be written impeccably in order to receive funding. Many younger scientists, who have not filed a grant before, can find the process daunting. Junior researchers can sometimes find themselves in a tough spot when writing their grant: If they support their hypothesis too much, the NIH might not feel it is necessary to fund the project any further. If they don’t demonstrate enough support, the NIH might not feel the project is ready to be funded.

“Writing a grant is a skill, just like anything else,” Koenig said.

Learning to file the grant can almost be as difficult as learning how to phrase and structure the grant itself.

“The current (grant application) process is not user-friendly,” Ezra Burstein, an assistant professor of internal medicine said.

Burstein explained that it is essential for a junior researcher to learn the grant-writing process as soon as possible, because they will basically only get to apply once a year. Fellowships usually only last three years.

“With only one in 10 grants being funded, junior researchers who don’t make it in three years will lose the opportunity to continue to pursue academic science,” Burstein said.

Burstein’s first grant received a score in the 48th percentile – a score far too low to get funding. If a scientist cannot get a grant in this period, he will often choose to pursue a new career path. Fortunately for Burstein, he received a score in the top seventh percentile on his second attempt, which should easily be high enough to merit funding.

Some scientists enroll in mini-courses on grant writing, but these can cost around $600 for a three-day course.

Burstein said that what he thought would be most helpful for junior researchers, would be to sit them down with an experienced scientist and go over 10 grants (four good, three mediocre and three bad).

The inexperience of junior researchers with grant applications often works to the advantage of senior scientists. Burant said that well-established investigators can often receive funding, even from poorly structured grants, based on their previous records and accomplishments.

This fierce competition for grant funding has sparked a debate in the scientific community concerning a new controversial proposal from its director, Dr. Elias Zerhouni.

Zerhouni’s proposal

Zerhouni took control of the NIH in the face of one of the tightest budget crunches for biomedical research of the past 30 years. He also came in with a vision that at the height of the budget debate has driven a wedge in the community between basic researchers and clinical researchers. Basic scientists investigate scientific questions to develop theories that enrich the general understanding of the scientific communities. Clinical researchers aim to study and understand specific problems that directly affect humans, by using human subjects. Zerhouni believed that a large problem with biomedical research was that it took too long for biomedical research at the basic level to translate directly into results for medical treatment. He also believed that the nation needed more clinical researchers. To address these issues, he developed a program called the “Roadmap Initiative,” which is largely based on a new award system called the Clinical and Translational Science Award. The CTSA is designed to get current clinical research centers, which operate under an older model, to develop a new, more effective model. He has proposed that about 1.5 percent of the NIH budget – $420 million – be set aside for this program, although currently only 0.8 percent is currently designated for it.

Under better times, the proposal might not have been as controversial. But a large number of basic scientists feel like this money will inevitably go to waste.

In the same editorial quoted earlier, Marks voiced his concern that the NIH is already wasting too much money on poorly structured clinical studies. In the editorial, he points to a $400 million study “proclaiming that high-fat diets do not increase the risk of disease.”

Marks snidely wrote that while the study was probably designed “by a committee of well-intentioned experts . the NIH should not fund large clinical studies that divert hundreds of millions of dollars away from hypothesis driven scientific research; pharmaceutical companies should.”

Some would argue that this experiment isn’t unusual. In August, John Ioannidis published an essay titled “Why Most Published Research Findings Are False,” in the Public Library of Science Medicine journal. The essay is currently the third most popular article on the PLoS medicine website.

Marks is not nearly as critical as Ioannidis of the current state of research, but his Marks’s editorial is still heavily critical of Zerhouni’s initiative. In his editorial, he issued four solutions to the current problems the NIH faces:

1) Increase congressional support.

2) Shelve the roadmap initiative.

3) Have pharmaceutical companies fund large clinical studies.

4) Revamp the process for funding established researchers.

Marks’s points have inspired a lot of debate among biomedical researchers. Many basic scientists have taken his side, giving their support to the current system based on investigator-initiated research. The RO1 grant, the primary award for independent investigation, is based off hundreds of years of the scientific tradition, in the pattern of Pasteur, Newton, Da Vinci and other historic scientists. The vast wealth of resources biomedical research draws upon is based in the tradition of science for science’s sake. Marks, and many other basic scientists, justifiably feel that this established model for funding with the NIH, a cornerstone of which is the RO1 grant, is highly effective and needs as much support as possible.

Not all basic scientists are completely opposed to the new initiative. Kao said that he is in favor of more funding for clinical research.

Burant pointed out that clinical researchers often face different challenges in their research than basic scientists. For example, basic scientists can breed knockout mice, which can have certain genes activated or deactivated for absolute control in an experiment.

“You can make a knockout mouse. You can’t make a knockout human,” Burant said.

Most clinicians who favor Zerhouni’s plans do not think the established model is ineffective: They are excited by the possibility of developing a system for the future.

“It all depends on which side of the equation you sit on,” said John Wiley, an associate professor of medicine and director of the general clinical research center. Michigan’s GCRC is one of about 70 in the country.

Part of the driving force behind the development of Zerhouni’s model is the new nature of biomedical research.

The field draws heavily from a wide array of other sciences, incorporating things like nanotechnology, which requires different types of specialists.

Zerhouni’s ultimate goal for the CSTA is to bring different types of scientists together to perform research more effectively.

Zerhouni hopes to fund between eight to 10 clinical research centers a year for the next four years, which could leave up to half of the current centers without funding.

Despite this, Wiley said he supports the new directive.

“I believe it’s time to try something different,” he said. “Somebody’s going to have to take a chance on this.”

Time will reveal whether or not Zerhouni’s plan will be effective. In the meantime, there are several things people can do to save the NIH.

How to save the NIH and the consequences of avoiding the issue

Institutions can do a lot for their younger researchers. Seminars on grant writing or other training programs for grant writing can make an enormous difference to scientists.

In the end, these issues primarily concern funding. Many groups, including the American Gastroenterology Association and the American Diabetes Association, have come out with their own awards for junior researchers.

The most powerful opportunity to make an individual difference will come in November. Electing government officials who know and care about the issue will be a vital component to remedying the situation.

The contributions that researchers who are driven out of science would have contributed are impossible to determine concretely.

But in the early 1990s, under George H. W. Bush Sr.’s administration, the nation faced a similar funding crisis. The result? The scientific community suffered tremendous losses.

In June, Marks published a second editorial, one that contained responses to his first editorial from many active scientists. One scientist wrote the following response:

” ‘a wonderful editorial. It perfectly echoes the feelings and frustrations [of] many of us (young investigators) who look for the support of NIH . Many of my bright colleagues are considering leaving science forever.’ “

The duration of the crisis will determine its ultimate impact. If the University wishes to remain among the leaders and best in biomedical research, it must act on behalf of its research faculty before it’s too late.