Berg at Home at Helm of Nigms

The National Institutes of Health can be an intimidating organization. With its 27 institutes and centers, more than 18,000 employees, and $29 billion budget, the agency is the nation's steward of biomedical and behavioral research. Stepping in from outside the organization to take the reins of one of the agency's largest institutes is no easy task.

But that's just what Jeremy M. Berg was asked to do last November. He was tapped by NIH Director Elias A. Zerhouni to lead the National Institute of General Medical Sciences (NIGMS), which is NIH's largest source of funding for chemistry. Berg, 47, replaced Judith H. Greenberg, who had served as acting director since 2002, when Marvin Cassman left the institute after nearly 10 years at the helm. More than six months after taking his new position, Berg--a chemist by training--is still learning new things, but for the most part he is comfortably settling in.

"My life has changed a lot since becoming the director of NIGMS," Berg says. "There is an unbelievable amount to learn in terms of the people, the processes, and the issues. I've been learning a lot every day, which has been incredibly fun."

Berg, who lives in Baltimore and commutes daily more than an hour by train to the NIH campus in Bethesda, Md., says he came into the job without any preconceived notions of how things were going to unfold. "It was sort of like getting on a roller coaster and seeing what happens," he says. "The level of scientific excitement and direct involvement in new scientific advances has, if anything, been a pleasant surprise."

Nearly 20 years earlier, Berg was making himself at home in a different setting as an academic professor. He joined the chemistry faculty of Johns Hopkins University in 1986 and has since become well known for his research on the structural and functional role of metal ions, specifically zinc, in proteins. He has more than 100 research papers to his credit and has coauthored three textbooks: "Principles of Bioinorganic Chemistry," "Biochemistry" (fifth edition), and "A Clinical Companion To Accompany Biochemistry."

Prior to joining NIGMS, he was the director of the Institute for Basic Biomedical Sciences at Hopkins' School of Medicine as well as director and professor of biophysics and biophysical chemistry there--positions that he credits with helping to prepare him for his new role as director.

"I've been a department chair for 13 years, which has given me many opportunities to interact at all levels of the university. I was prepared for the transition into more administration," Berg says. The most difficult part for him was to adjust to how rapidly things happen at NIGMS. "Here, the pace is much faster, and the decisions need to get made pretty quickly."

Keeping on top of NIGMS activities--not to mention NIH as a whole--is definitely a challenge. Of NIH's $29 billion 2004 budget, NIGMS receives $2 billion, nearly all of which funds extramural activities. In fact, NIGMS will spend 87% of this year's budget to fund research grants and 10% to support research training. It funds approximately 4,500 research grants each year--about 10% of the total research grants made by NIH. The institute expects to fund 957 competing research project grants in 2004, which is a slight decrease from 2003.

THE MISSION of NIGMS is different from that of most other institutes at NIH in that it doesn't target a specific disease or disorder. The institute instead supports a broad range of basic biomedical research that serves as the basis for advances in disease diagnosis, treatment, and prevention.

Chemistry plays an important role in NIGMS's mission. "NIGMS has been very supportive of chemistry in a very broad sense, and that will certainly continue," Berg notes. "The support for chemistry and an appreciation for what chemistry can do are spreading across NIH."

This appreciation is helping to create tremendous opportunities for chemists to contribute to biomedical research. "I think chemists and biologists have come a long way in terms of realizing what each has to offer and how partnering can be a real win-win situation," he says.

"For example, a chemist can work on biological problems that are inherently fascinating and interesting. Chemists can use their creative abilities to help come up with broad strategies about how to attack and understand detailed technical aspects of a given problem," he says, adding that these abilities are key for molecular synthesis and analysis.

"Ideally, this relationship would be a synergistic effort instead of a biologist coming up with a problem and saying to a chemist: 'We need this molecule, can you make it for me?' Those collaborations certainly will work, but I think the ones where each participant learns something about both sciences are more beneficial," Berg explains. "A lot of times, once chemists understand the biology and know what the issues really are, they can make tremendously creative contributions in areas such as experimental design."

Berg is a good example of how effective a chemist can be in interdisciplinary research. From an early age, he has been fascinated by geometry and structure, which are fundamental to chemistry. His interest in chemistry came when his father, a mathematician, gave him a copy of Linus Pauling's book "The Architecture of Molecules" for his 12th birthday.

"The book was full of a wonderful series of one-page paintings, each of a different molecule. The depictions were accompanied by two or three paragraphs about the molecule's chemical significance," Berg recalls. "It's a fabulous book, and it really got me excited about structure in chemistry. I think from that point on I was pretty much sold."

But perhaps the most important piece of advice regarding his professional career came when Berg was applying for graduate school. "When I was doing an interview at Massachusetts Institute of Technology, I met with George Whitesides. During our meeting, he advised: 'Whatever you do in graduate school, learn how to make molecules, because it's what distinguishes chemists from other scientists. You can learn biology or materials science or a new spectroscopic technique, but unless you learn to think like a synthetic chemist, you won't be able to look at a problem, see the need for a molecule to address it, and be able to figure out how to make the necessary molecule.' This advice really dictated a lot of choices for me," he explains.

"This way of addressing a problem is not so much a different skill set as a different mind-set," Berg points out. "Now, I think that mind-set is catching on here at NIH."

According to Berg, the whole idea of disciplines coming together to conceive and synthesize molecules has really spread across NIH. Figuring out how to build the necessary collaborative relationships with chemistry is certainly an important part of addressing the most pressing scientific problems both at NIGMS and NIH, he notes.

CHEMISTRY WILL ALSO play an important role in the NIH Roadmap for Medical Research--a transagency research plan that Berg has been involved in (C&EN, Oct. 6, 2003, page 10). Although the plan was launched before he became director, there were still many details to be resolved.

"NIGMS had been very involved in the road-map planning. Fortunately, Judith Greenberg, who had been acting director, and the institute's staff had done a fabulous job," Berg says. Because the road map was relatively new to everyone at NIH, he was able to contribute right away, he notes.

"One of the clearest examples of chemistry's role in the road map is the Molecular Libraries & Imaging Initiative. The goal of this initiative is to take advantage of chemistry's ability to make molecules and combine that with screening techniques. The next step is to try to identify small molecules that biologists can use as probes for studying biological processes and for decoding the genome," Berg explains.

This initiative also includes a molecular imaging component. "There is a tremendous interest in molecular imaging, which includes everything from synthetic chemists being involved in designing and synthesizing new fluorescence probes or other sorts of probes, to physical chemists really understanding fluorescence," Berg points out. "The ultimate goal is to develop experiments to the point where you could look at single-molecule resolution inside cells. That is something where there is really synergy between synthesis, molecular design, protein engineering, spectroscopy, microscopy, image analysis, and so on. Chemists have a big role to play in a number of those cases."

Another place where chemists can get involved is the Bioinformatics & Computational Biology Initiative. "The centerpieces of this NIGMS-led initiative are the national centers for biomedical computing. These centers will be collaborative enterprises between computer scientists, computational chemists and biologists, biologists, and clinicians. The goal is to develop software tools that allow people to ask questions easily about big data sets," Berg says.

The Nanomedicine Initiative is yet another place where chemists can contribute to the road map (C&EN, May 10, page 28). The direction of this initiative is still being formulated, but "chemists have been involved in nanotechnology in areas like synthesis and characterization. I think the only different twist with nanomedicine is that it is now geared specifically for developing therapies. In order for this initiative to succeed, chemists are going to have to be involved," Berg says.

Although the road map provides many exciting research opportunities across NIH, NIGMS is also doing some fascinating work on its own. Perhaps the most exciting aspect to Berg is seeing how everything fits together.

"We've gone through this wonderful reductionist period of identifying and studying individual enzymes and cloning and sequencing individual genes. With the genome-sequencing efforts drawing to a close, we now know, in some sense at least, a little bit about a lot of the players," Berg explains.

"The question now really gets to putting it all back together and seeing how the pieces interact--systems biology is the current buzzword for a lot of things related to this," Berg notes. "For example, this includes seeing how individual molecules interact to form networks and understanding how things are integrated at the cellular, tissue, organ, and organism level. In a lot of ways, traditional fields like physiology and pharmacology are now coming back as very exciting disciplines.

"There are tremendous opportunities to try to capitalize on everything that has been accomplished in this area and really try to convert them to things that matter for the public at large," he says. "This isn't to say that we are now in a development phase as opposed to a research phase. There are tremendous challenges as to how to integrate the knowledge that we have. Some of the challenge is trying to work more on complex systems, while some of it may be geared toward doing fundamental work on an enzyme mechanism." In the latter case, he notes that using this systemic approach can help a scientist pick an enzyme that has real biomedical importance as opposed to picking out something that simply is readily available.

Berg does not plan to introduce any new large-scale initiatives within NIGMS, but he says the institute has some smaller programs coming online. For example, a request for applications has been released for the development of short courses on integrative and organ systems pharmacology.

"When molecular biology developed and gene hunting became an exciting thing to do, a lot of fields like physiology fell out of fashion. Now, there aren't that many people trained in how to design physiological experiments at the organ level or at the whole-animal level," Berg says, adding that funding for the program is anticipated to be $500,000 in 2005. "It's a good news/bad news story in that, given the budget constraints, we can't do it in a big way. On the other hand, the current level of activity is such that a relatively small program can have a large effect, nearly doubling the number of people who get this type of training."

Another new program that's being sponsored by NIGMS is the Models of Infectious Disease Agent Study. This program will develop powerful computer modeling techniques to analyze and respond to infectious disease outbreaks that either occur naturally or are initiated intentionally in a bioterrorist attack. "The idea is to develop computational tools that use real sets of data to successfully model how outbreaks spread and what factors influence the process."

According to Berg, NIGMS plans to continue its course with a mix of investigator-initiated projects and larger scale initiatives. "The majority of what NIGMS funds is investigator initiated. But, certainly during the budget-doubling period, NIGMS has done more larger scale initiatives in areas such as structural genomics (the Protein Structure Initiative), pharmacogenetics, and collaborative research (including the large-scale, interdisciplinary group grants known as glue grants). Those will all continue," Berg says. "Even in the present budget climate, we are certainly not backing away from the idea of doing larger scale things. But they are going to be viewed with tremendous care to make sure that we are really getting something more than we would have gotten with smaller, investigator-initiated projects."

In terms of the success rate--the percentage of reviewed applications that receive funding in a fiscal year--NIGMS predicts the 2004 rate to be approximately 30%, down significantly from the past few years, when the rate was 37 to 38%. Two key factors in this drop are a surge in applications and slower budget increases to fund them. The former is a sign of lots of interest in the community but requires careful management, Berg explains. The latter is not unique to NIGMS.

NIH IS EXPECTING a second straight year of smaller growth in fiscal 2005. This situation comes on the heels of a five-year budget-doubling period. Many people at NIH are bracing for hard times ahead, but Berg points out that NIGMS acted wisely during the doubling period and is in relatively good shape to weather the slowing budget growth.

"NIGMS did a very good job trying to plan for what happens when the doubling is over. There have been a number of steps taken to ensure that there wouldn't be any surprises," Berg says, "for example, investing in things like a synchrotron or a 900-MHz NMR, where there was clearly a big need to have those facilities available. The money was sufficiently available during the doubling time that we could afford to fund them, and they had the advantage that we don't have large out-year costs--that is, grant costs for the years following the award year. You spend the money, buy the machine, and get it up and running. If you fund an investigator-initiated research grant in year one, then you've got years two, three, and four coming in periods where the budgets are getting tight."

As the federal budget continues to tighten, the competition for funding will only increase. One way scientists can help their chances of winning a grant is to choose their topics wisely, Berg points out.

"I think the biggest key to a successful grant is picking the right problem," Berg says. "There are tremendous opportunities for chemists and all scientists to work on problems that are very significant. If you pick a problem where solving some aspect of it is really going to matter to people, then that's something from my experience on NIH study sections [peer-review groups] that will count a lot in your favor. Conversely, if you pick the wrong problem to start out with--such as one that's not directed toward understanding fundamental mechanisms of how things work or one without potential for real impact--it's going to be an uphill battle. And no matter how good your grant is technically, at that point you're starting off with a disadvantage."

One area that has not done well in terms of reviews by study sections is research to develop technology. That's something that Berg and his staff are trying to change.

"Technology development is something we are trying to find ways to support. The study sections tend to be geared toward very hypothesis-driven research questions. Proposals that are more technology development related have tended not to fare very well. For example, 2002 Chemistry Nobel Laureate John Fenn's grant, which led to the development of the electrospray mass spectrometry technique, was actually something that didn't do very well in the study sections. But NIGMS program staff saw it as something that might have a big impact, so they decided to give it a chance."

Berg notes that keeping an eye out for the next great idea is a challenge. "We don't have a monopoly on good ideas. But we can pick an area, talk to the community, and figure out what really needs to be done. Then, through the grant proposal process, we can pick the best ideas among a set. It works very well."

FOR THIS PROCESS to be effective, communication and interaction with the community are essential. To that end, Berg says, not only has he been attending a lot more scientific meetings, but "I go to meetings with a whole different set of ears about what's going on scientifically and what areas people are concerned about. I try to gauge whether the level of concern is normal anxiety versus something that everyone feels needs some attention." He emphasizes: "Community involvement is a formal part of the development of new initiatives. Nothing is done in a top-down manner."

An example of one area that Berg has been hearing a lot about is the visa issue. He notes that the concerns range from the amount of extra time needed to get foreign students or postdocs into the U.S. to the inability of foreign students and postdocs in the U.S. to return to their homeland to visit without fear of not being allowed back into the U.S. As a result, some young foreign scientists are becoming frustrated with the situation and choosing to get their training in the U.K., Canada, or Australia, for example.

Berg admits he has joined the "spamming generation" in that he sends out mass notices to NIGMS grantees about what NIGMS is doing. The messages also seek feedback. "People aren't shy about giving us feedback. And when you hear the same thing from more than 10 people, you start to think that clarification is in order."

Even as Berg continues to grow into his new position, he remains involved in research--a practice that is common among NIH institute directors. His research group will be moving from Hopkins to NIH in the near future. But maintaining a research group in addition to leading an organization the size of NIGMS will not be easy.

"Certainly, time management is going to be a big challenge. I don't think I could just go cold turkey and completely give my research up," Berg says. "Plus, I think it's important to keep in touch with what it's like to be a researcher and participate in the scientific excitement of research."