King of the Roadmap

LOOKING FOR LESS-TRAVELED RESEARCH

The sheer size of the organization has prompted Zerhouni to start a research project of his own, a $2 billion, five-year plan he calls the NIH roadmap.¹ It aims to develop new ways to structure the institutes to yield better science that will travel faster from labs to patients.

Bioscience has advanced swiftly in the past few years; some questions have been answered, but many more have surfaced. The more we know the more complicated it gets, says Zerhouni. "Life self-assembled. We don't even know the degrees of complexity, the dimensions of the system. The problem is quite daunting." He adds, "I don't think the data quality we have is necessarily sufficient [or that] the way we pose the questions is necessarily sufficient."

An immigrant from Algeria, the 52-year-old Zerhouni had been executive vice dean of the Johns Hopkins University School of Medicine in Baltimore before his appointment to NIH in 2002. A specialist in bioengineering and medical imaging, Zerhouni holds a string of patents. He has been involved in several biotech companies and is not totally wedded to the classic grant-dependent model for research.

To many within NIH and outside the agency, Zerhouni's roadmap reflects a detailed and systematic approach to seeking information and building consensus. In designing the roadmap, NIH consulted more than 300 people in government, academia, and the private sector for more than a year. The roadmap is ambitious and brings a new emphasis on scope and risk-taking that agency critics have been advocating for some time. Just three days after allegations surfaced that senior NIH officials accepted lucrative consulting contracts and stock options from drug companies, Zerhouni had named a blue-ribbon panel to "identify systemic solutions for improvement."

Francis Collins, director of NIH's National Human Genome Research Institute, says an earlier attempt by former director Harold Varmus to fund cross-disciplinary initiatives at NIH by levying a one-percent charge on the institutes failed because it was too complicated and involved Congress. Many of the ideas laid out in the roadmap have been tried before, says Collins, but flopped because they were structured as one-off ventures. "No one previously attempted to put together this kind of ongoing program and make sure it gets funded," Collins says.

With powerful scientists at the head of the various institutes such as Collins and others, there are those who view the NIH director as a figurehead. "Integrator is more like it," Zerhouni asserts. "I don't see myself as a manager in the sense of getting the trains to run on time. I ask what [is] the right thing to do and then make sure there are management systems in place to support mission."

For Zerhouni with his engineering training, running the NIH, like science itself, is rooted in data and systems. He craves data. He appreciates that data have driven science forward for generations. Now, however, bioscience is awash in data points, and it lacks the models to make sense of it all.

Biomedical science traditionally has taken a reductionist approach, working from an understanding organs, down to DNA, to genes and to proteins, Zerhouni says. Now, he wants researchers to step back and look at how all the tiny bits of the system work together and play upon one another. "There's something in the middle we need to understand," he says. "How is this all translated, transcribed, and implemented?"

DATA PATHWAYS

Photos courtesy of the National Eye Institute, NIH

seeks to restructure the various institutes to yield better science that travels faster from the labs to the patients.

Zerhouni's roadmap deals directly with data and the arsenal of new technology that biomedical researchers have now to harness information. The roadmap calls for the creation of NIH-funded small-molecule libraries and screening centers, and protein production facilities. Another initiative would create a center to develop software that scientists could use to share data. NIH is planning to launch nanomedicine centers in 2005 that would help scientists develop devices such as tiny pumps for drug delivery or sensors to scan for infection. "Tools are one way to discovery," Zerhouni says. "However, you need to organize your mental teams in different ways to be able to grasp this reality."

That brings Zerhouni to another goal in the roadmap, which is to develop new ways for scientists to organize their work. "I need people who are just as good at mathematics and engineering as they are at zoology and biology," Zerhouni says. "All of them bring something different to the table."

The roadmap would create the NIH Director's Pioneer Awards, a sort of "genius" award for select researchers who have demonstrated exceptional creativity and the potential to generate breakthrough science if freed from the pressure of finding funding.

NIH may also use intramural funds to create interdisciplinary research centers, which would develop new models for uniting researchers with diverse expertise. The roadmap also seeks to remove barriers to interdisciplinary research in extramural funding. For example, the current system recognizes only the principal investigator and minimizes the role of coinvestigator, who may be from a different discipline. "Some people have worries that the roadmap may lead to diminution of support for the individual investigators," says David Korn, senior vice president for biomedical and health sciences research at the American Association of Medical Colleges.

BIG DISCIPLINE DOUBTS

The success of the Human Genome Project has led some individual researchers to worry that an increasing share of funding will go to "big science." "People in the field who have grown up and done well and made enormous contributions as single investigators are a little nervous about where NIH is going," says Korn, who adds that he supports the plan, which shifts only a fraction of NIH's overall resources to roadmap initiatives.

Clinical research is another theme in Zerhouni's roadmap. "We're the National Institutes of Health, not the National Institutes of Biology," he says. "We need to reengineer how we apply our research to humans."

James Huff, a scientist in the National Institute of Environmental Health Sciences, says he might have objected to Zer-houni's emphasis on applied research until recently. "It's hard for me to find the relevance of most of what we do here to public health," he says. "I am pro basic research, and at this stage for me to have to come to this conclusion is not pleasant."

Zerhouni says the current model is linear: A government-sponsored researcher makes a valuable discovery that is then developed further by private industry. "As we go forward in academia and industry, clinical researchers are going to have to work in a circular mode in which clinical research is going to enlighten what it is in basic science that needs to be translated," Zerhouni says.

Roadmap initiatives include bringing basic and clinical scientists together in regional translational research centers to speed development of new drugs, biomarkers, and treatments. NIH also plans to improve the nation's clinical research network to improve the quality of clinical work and to develop trials that can address multiple research questions.

The roadmap includes initiatives to improve training and career development for scientists interested in clinical research. Zerhouni says it is essential to find ways to speed proof-of-concept before wasting resources on ideas that are unworkable. "The predictability of whether something will work or not work is very low," he says. "We need a more energetic academic effort not focused solely on basic research."

The line between NIH's role as a public entity supporting basic research and that of private-sector healthcare companies developing products has drawn closer scrutiny in recent years. Patients' rights organizations have been critical of the NIH for allowing the drug industry to build on NIH discoveries to market patent-protected, high-priced treatments.

NIH has been under increasing pressure to disclose its ties to industry. Congress last year established an ongoing ethics probe of the agency, which heated up in December following reports that top NIH scientists and administrators had earned more than $2.5 million in fees and stock options from private companies in the past decade.

"It's hard to imagine how NIH could be any closer to industry," says Jamie Love, director of the Consumer Project on Technology in Washington, DC, a leading organization in the global campaign to improve access to medicines for the poor. However, Love says elements of Zerhouni's roadmap could benefit taxpayers. "We are happy with some of the moves to be more systematic in how [those at NIH] think about drug development," Love says. "I was struck that there seemed to be some consciousness in asking, 'Gosh, we're spending a lot of money. What are we getting back for it?"'

Photos Courtesy of NIH

Zerhouni says there are signs that the new investment is paying off. He points to the early completion of the Human Genome Project and the ability to identify and decode the SARS virus within weeks.

But Zerhouni came to NIH just as the funding leveled off. Prior to his arrival, the agency's budget had doubled over a 5-year period. In a study ordered by Congress and released this summer, The Institute of Medicine (IOM) suggested that the huge organization should take on more risk to make that wealth pay off.

The roadmap echoes many of the recommendations of the IOM report, says Mary Woolley, president of Research!America, a nonprofit research advocacy group. "Innovation and risk-taking are not just nice, they're essential," says Woolley, who adds that the research community has concerns that the percentage of young investigators receiving NIH funding has been declining as established grant recipients reap in big money for their projects. "Reengineering the NIH grant-making process is the only way to keep a fresh competitive edge," she says.

BIGGEST BIG PHARMA

Zerhouni says that with the recent downturn in the capital markets for financing early-stage research, government programs have come under increasing pressure to move farther along in the development continuum. Drug companies are doing their part, he says, with big pharmaceutical companies spending $33 billion on research and private sector biotech firms spending $16 billion.

But Zerhouni says drug companies focus only on treatments with a large market. NIH, he says, needs to take more of a role in addressing so-called orphan diseases, or diseases that affect minority populations. Obesity, too, is a priority, he says. "Nobody goes out and says, 'I'm too fat. I want you to do something about it.' But as director of the NIH I have to serve the public health even if it does not have a constituency."

In creating the roadmap, Zerhouni says NIH also considered the "landscape of disease." The landscape's most prominent feature is a rapidly aging population increasingly susceptible to chronic long-term illnesses. "Diseases that used to be acute are now chronic," says Zerhouni. "If you had myocardial infarction it used to be that you lived or died. It was acute. Now you can survive. The same is true of cancer."

Zerhouni says NIH must also focus more attention on prevention, and when prevention is not possible, he says, NIH should be searching for ways to delay the onset of illness. "We know that if you intervene early, once the disease is there you can find strategies to reduce the severity of the disease."

The Sept. 11, 2001 attacks on New York and Washington, DC, have placed increasing importance on bioterror awareness within NIH, where Zerhouni presides as one of Washington's most visible Muslims. "Emotionally, there's a huge amount of misunderstanding," says Zerhouni of relations between the Muslim world and the United States. "But on the other hand I feel I need to be an example that the negative stereotypes and perceptions are not justified."

Zerhouni says his experience as an immigrant makes him more open to alternative views. He has faithfully administered the Bush Administration's policy on stem cell research despite criticism from much of the biomedical research community, and he refuses to disclose his personal views on the issue. He was the driving force behind the Institute of Cell Engineering, for the study of skin cells, at Johns Hopkins, however.

To Zerhouni, that is how the system is supposed to work. In his model, even though Zerhouni runs the NIH, he remains a presidential appointee answering to a higher authority. "Personal views should never drive policy," he says. "A leader is supposed to abrogate and have a sense of duty so that your personal views will not overpower those of the people you work for."

Susan Warner swarner@comcast.net is a freelance writer in Philadephia