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GOVERNMENT & POLICY
January 21, 2002
Volume 80, Number 3
CENEAR 80 3 pp. 30-33
ISSN 0009-2347
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NIGMS AT 40
National Institute of General Medical Sciences propels basic science with collaborative projects

WILLIAM G. SCHULZ, C&EN WASHINGTON

From the start, the National Institute of General Medical Sciences (NIGMS) has been something of a hybrid at the National Institutes of Health. Created by an act of Congress in 1962, its mandate was to support basic biomedical research and the training of biomedical researchers.

HQ NIH's Natcher Building in Bethesda, Md., houses NIGMS.
Today, as it celebrates its 40th anniversary year, NIGMS continues that same basic mission. It is a mandate that has resulted in enormous payoffs for the institute, for NIH, and for biomedical science in general. As just one measure, since 1962, 51 researchers supported by NIGMS funding have been awarded the Nobel Prize, including 22 scientists who have been awarded the Nobel Prize in Chemistry.

NIGMS "tends to react at boundaries," Director Marvin Cassman has said. "We have helped propel fields by stimulating programs at growing points." Some of those fields include molecular genetics in the 1970s; macromolecular X-ray crystallography and structural biology in the 1980s; and studies of the cell cycle, heat-shock proteins, chaperonins, and rational drug design in the 1990s. Both the Human Genome Project and GenBank, the publicly accessible repository for DNA and RNA sequence data, began as NIGMS-funded programs.

As Cassman himself predicted 10 years ago, the NIGMS focus today is again shifting, from a molecular, reductionist approach toward one of analyzing and reconstructing whole systems. For example, the institute is encouraging mathematical approaches to understanding systems' organization and behavior, while continuing to emphasize detailed molecular studies on genes, proteins, and cells.

ONE ASPECT of the institute's 40th anniversary celebration will be a full-day symposium as part of the Division of Organic Chemistry's program at the American Chemical Society national meeting in Boston in August. NIGMS's program director and the symposium organizer, John M. Schwab, says the symposium will highlight collaborative and integrative approaches to science, emphasizing the role of chemistry.

Four NIGMS divisions support scientific research and research training:

  • The Division of Cell Biology & Biophysics supports research on analytical and separation techniques; biomedical instrumentation; cell organization, motility, and division; lipid biochemistry; membrane structure and function; molecular biophysics; spectroscopic techniques; structural biology; and structural genomics.
  • The Division of Genetics & Developmental Biology supports work on cell growth and differentiation; chromosome organization and mechanics; complex biological systems; control of gene expression; control of the cell cycle; developmental genetics and cell biology; extrachromosomal inheritance; mechanisms of mutagenesis; neurogenetics and the genetics of behavior; population genetics, evolution, and the genetics of complex traits; and replication, recombination, and repair of genes.
  • The Division of Pharmacology, Physiology & Biological Chemistry supports research on anesthesiology, biochemistry, bioenergetics, bioorganic and bioinorganic chemistry, biotechnology, glycoconjugates and glycobiology, medicinal chemistry, molecular immunobiology, pharmacogenetics, pharmacology, physiology, and synthetic chemistry.
  • The Center for Bioinformatics & Computational Biology supports research and research training in areas that join biology with the computer sciences, engineering, mathematics, and physics. The center develops and manages programs in computational biology, such as the generation of mathematical models of biological networks, the development of modeling and simulation tools, the conduct of basic theoretical studies related to network organization and dynamic processes, and the development of methods for the analysis and dissemination of computational models.

"Of all the institutes at NIH, there's no doubt that we support the most chemistry," Cassman says. "NIH as a whole probably supports as much chemistry in chemistry departments as the National Science Foundation does.

Chemistry Nobel Laureates Funded By NIGMS Robe
"NSF does worry about chemistry as a discipline more than we do," Cassman continues. "We don't think about issues of disciplinary support very much. And there are significant areas of chemistry that we don't support because they're just too far out of the range of what could be considered biomedically related."

Most of the NIGMS budget--it was nearly $1.54 billion in fiscal 2001--supports investigator-initiated research grants. But after consultations with its own advisory board and the scientific community at large during the late 1990s, NIGMS has launched several major research initiatives that, to some extent, are defining its future direction. Chemistry research--including biochemistry and chemical engineering--plays an essential role in each initiative.

In general, Cassman says, the initiatives follow the trends of the postgenome era of biomedical research. That is, like NIH's Human Genome Project (HGP), they are big science initiatives that have become possible because of advances in computing and other technologies, and they are cross-disciplinary--merging the insights of research by many different scientists to tackle common problems or questions.

"NIGMS continues to support mainstream chemical research, as shown by the 170 or so NIGMS grants that pay for projects in synthetic organic chemistry," says Schwab, who is a chemist. "But a number of our new big science initiatives provide exciting opportunities for chemists who are willing to break out of the usual patterns and become involved in interdisciplinary, collaborative projects."

A new NIGMS initiative that Schwab says is particularly relevant is the Chemical Methodologies & Library Development Centers. These centers will support collaborative efforts by chemists and allied scientists to develop new ways to create, analyze, and maintain combinatorial chemistry libraries so they can be used to study biological processes.

One of the major collaborative research initiatives is the Protein Structure Initiative, which is designed to reveal the three-dimensional structure of all proteins in nature (C&EN, Oct. 15, 2001, page 23). Knowing the shapes of proteins helps scientists to better understand how proteins function normally and how faulty protein structures can cause disease. This initiative is also described at http://www.nigms.nih.gov/funding/psi.html.

ANOTHER INITIATIVE is the Glue Grant Awards. The idea here is to "glue" together large groups of scientists pursuing some of the biggest unsolved problems in biomedical research today--problems that are inaccessible to individual research laboratories because of their scale and complexity. It is the sort of cutting-edge effort in science that has long typified NIGMS and is certainly characteristic of the big science trends in biology.

"People wanted a way to work with others on similar problems," says Michael E. Rogers, director of the NIGMS Division of Pharmacology, Physiology & Biological Chemistry. He says the program is made up of large grants of up to $5 million per year for five years for large consortia of researchers. As many as 100 investigators might work on a single project.

One Glue Grant funds research on inflammation after burn or trauma injury. A consortium of clinical and basic scientists will attempt to tease apart the complex set of events culminating in the immune system's reaction to a traumatic injury. NIGMS officials say this Glue Grant consortium might provide opportunities for chemists, especially those who can think creatively about possibilities for collaboration. The principal investigator is Ronald G. Tompkins, a surgeon and biomedical engineer at Massachusetts General Hospital, Boston. More information about the project is available at http://www.nigms.nih.gov/news/releases/tompkins.html.

The Cell Migration Consortium (CMC) is another project funded by the Glue Grant program. Cell migration is an important phenomenon that is, for example, essential to physiological development, mounting of an effective immune response by the body, and wound repair.

Cell migration--that is, when cells fail to migrate or migrate to inappropriate locations--also contributes to pathologies, including vascular disease, tumor progression and metastasis, congenital brain defects, and chronic inflammatory diseases. It is pertinent to areas of biotechnology that focus on cellular transplantation and the manufacture of artificial tissues.

Understanding all of the mechanisms of cell migration is an enormously complex task beyond the grasp of individual investigators, says Alan F. (Rick) Horwitz, a professor of cell biology at the University of Virginia Medical School, Charlottesville, and the CMC principal investigator. With the research consortium approach, he says, the problem of understanding the process of cell migration has been divided up among some 30 investigators--representing such disciplines as biology, chemistry, biophysics, optical physics, mathematics, computer science, genetics, and engineering--from 12 institutions.

These investigators are organized into interdisciplinary groups, each aimed at attacking a major challenge in understanding the cell migration phenomenon. More information is available at http://www.cellmigration.org.

NIGMS "has really stuck its neck out in the Glue Grant initiatives," Horwitz says, "and people are watching. No one else is funding something like this on this scale. We not only want this to work, we think it is the future. It has also provided a way for people to get involved in the project from outside the field of cell biology."

One of those people is Barbara Imperiali, a professor of chemistry at Massachusetts Institute of Technology, who says she is "hoping to make new, noninvasive chemical probes to establish key events in cell migration. It's very exciting.

"I am in there as a chemist," Imperiali says of her participation in CMC. She says CMC allows her to consult rapidly with other consortium scientists at every phase of the work. She can tell the biologists, for example, what is possible in terms of designing and synthesizing chemical probes for specific macromolecules, and then work with the biologists to see how these probes can be used most effectively to integrate complex biological processes. The best part of the collaboration, she says, is the opportunity to implement new chemistry into biology with very little lead time.

Another consortium funded by an NIGMS Glue Grant studies carbohydrate function in cell communication. Carbohydrates and the proteins associated with them permit cells to transmit and receive chemical, electrical, and mechanical messages that underlie everything from growth to movement to thought.

But studying carbohydrates is difficult. In part, that's because carbohydrates are produced by a cascade of chemical reactions in the body, which are difficult to reproduce in the lab.

The Consortium for Functional Glycomics is bringing together some 50 scientists from 40 institutions around the world to boost cutting-edge carbohydrate research. Glycomics is defined as the systematic identification and characterization of all the carbohydrate chains used by organisms.

The first request for funding submitted to NIGMS was turned down, says the glycomics consortium's principal investigator, James C. Paulson, professor of molecular biology and molecular experimental medicine at Scripps Research Institute.

"On the first round, we had the right idea but the wrong approach--just 15 investigators," he says. "That didn't fly well."

8003paulson.photo
Paulson
On round two, Paulson explains, "we took to heart what the review panel said, and we put all of the money into research cores. We eliminated artificial constraints. We opened it up to the scientific community."

That proposal was successful, and the work of the glycomics consortium got under way in earnest last fall. The consortium includes scientists working in cell biology, chemistry, biophysics, genomics, bioinformatics, and genetics. The "glue" for the research is provided by several core areas: information acquisition and dissemination, analytical glycotechnology, carbohydrate synthesis, protein expression, gene microarray, mouse genetics, and protein carbohydrate interaction.

Immediate plans, Paulson says, call for identifying carbohydrate molecules--and proteins that associate with carbohydrates--that collectively play important roles in cell communication. Another goal will be to figure out how certain cells control the production of the many varieties of sugars involved in cell communication. Ultimately, he says, many of the findings will improve scientists' understanding of the immune system. Immune cells rely heavily on sugars to travel through the blood to lymph glands and to sites of inflammation, and to prompt normal immune responses to foreign invaders like viruses and bacteria.

There will be free and wide access to research results of the consortium, a condition that applies to all of the research programs funded by Glue Grants. The glycomics consortium will support four databases, including one to house 3-D structures of carbohydrates. Any scientist will be able to search the repository for structures related to his or her research interest. More information on the glycomics consortium is available at http://glycomics.scripps.edu.

YET ANOTHER Glue Grant consortium is the Alliance for Cellular Signaling (AFCS). With 50 scientists representing 20 institutions, including private labs such as Myriad Genetics, Salt Lake City, the aim is to study all aspects of cellular communication by two cell types: cardiomyocytes (heart muscle cells that can beat in a dish) and B cells (immune system cells of the bloodstream).

Researchers will seek to determine in both cell types signals that are communicated through molecules called G proteins, says Nobel Laureate Alfred G. Gilman, principal investigator for the effort and a pharmacologist at the University of Texas Southwestern Medical Center, Dallas.

Gilman says he began to develop the idea for the consortium as a participant in NIGMS planning meetings in the late 1990s. "The vast recurring theme at those meetings was for big collaborative projects to tackle big problems," he says.

"The human genome sequencing effort enables what we're trying to do," he continues. "We need a complete parts list to play with."

As is the case for HGP, all AFCS data will be posted on a consortium website. "There is no insider advantage," Gilman says. "The idea is to advance the field, not individual careers."

As for publishing, Gilman continues, "we plan to publish big-picture papers from concepts that emerge from the data. Any scientist can publish papers about the data after it is posted on the website."

AFCS leaders--like those for all the Glue Grant consortia--put a lot of time into simply coordinating the work and communicating with participants. But that task is also made easier by technological advances, Gilman says. "We have a videoconferencing system for regular meetings with participants. We can look at data together, pass it around, manipulate it--it's fabulous."

Another major initiative at NIGMS that builds on HGP is pharmacogenetics--the science of how a person's genes influence how he or she responds to medicines, including antidepressants, chemotherapy, and asthma drugs. It is a trans-NIH effort in which a network of investigators will store data in an electronic library--the Pharmacogenetics Knowledge Base at Stanford University Medical School--that is freely accessible to the scientific community. The long-term goal of the research is to help doctors tailor doses of medicine to a person's unique genetic makeup, making medicines safer and more effective for individuals.

8003gov1.cassman 8003gov1.rogers 8003gov1 8003gov1.cassatt
Cassman Rogers Long Cassatt

BOTH THE RESEARCH network and the library will receive informal input about the initiative from industry scientists. An Industry Liaison Group was formed, and it includes representatives from Pharmacia, Merck Research Laboratories, Hoffmann-La Roche, GlaxoSmithKline, Abbott Laboratories, and Variagenics. Membership in the group will change over time.

Because the research projects funded by this initiative deal with human subjects--people undergoing some drug therapy who are asked to provide a DNA sample--NIH has formed a Populations Advisory Group to help researchers work ethically and effectively with specific racial or ethnic groups identified for pharmacogenetics research projects.

One study funded by the initiative is a study of depression among Mexican Americans in Los Angeles. The Population Advisory Group has helped identify sensitive issues and will hopefully increase participation in the study, says Rochelle M. Long, an NIGMS pharmacologist and director of the pharmacogenetics initiative.

For example, Long says, the advisory group raised questions about how to "de-identify" a person's medical records so that important data can be preserved without compromising a person's privacy. The group also explored ways to talk to people who are potential research subjects in order to encourage participation in the study.

"As researchers, we're not always thinking like the group we're studying," Long says. Community consultants, she says, recommended that potential subjects for the depression study be given time to talk with their neighbors about the study and come back with more questions for the researchers before deciding to enroll. She says it was a technique that has helped boost participation.

One of the most tangible results of the Population Advisory Group was the production of a brochure, "Medicines For You," that helps explain pharmacogenetics to a lay audience, Long says. It is made available to researchers funded by the initiative for them to pass along to participants in their studies. An online version is available at http://www.nigms.nih.gov/funding/medforyou.html. More information about this initiative is available at http://www.nigms.nih.gov/pharmacogenetics.

One of the more recent initiatives at NIGMS involves complex biomedical systems research. A key part of the Complex Biomedical Systems initiatives, says Program Director James J. Anderson, will be awards for Centers of Excellence, the first of which should be announced in June. Areas of NIGMS interest include computationally based modeling of processes such as the cell cycle, pattern formation during embryogenesis, the flux of substrates and intermediates in metabolism, and the application of network analysis to understand the integrated systemic host response to trauma, burn, or other injury.

The idea, Anderson says, is to support development of multi-investigator teams capable of engaging biomedical complexity with a scope of activities not possible with other funding mechanisms. The centers will support research activities that may include the development of new instrumentation and methods, bioinformatics infrastructure, and theoretical frameworks to advance knowledge of life processes at the system level.

The quantitative aspects and systems approaches to biological research today demand that research institutions begin integrating the work of different scientific disciplines, he says, typically, math, biology, chemistry, computer science, and others. This is of particular concern, Anderson adds, in developing curricula for the training of the next generation of scientists, an activity expected of these centers.

"But what we've heard is that institutions are grappling with this demand," Anderson continues. He says language and cultural barriers often make it difficult for administrators to lower the boundaries between disciplines. Centers of Excellence funding, he says, "should give institutions a prop."

ANOTHER PART of the Complex Biomedical Systems initiatives was creation of the Center for Bioinformatics & Computational Biology (CBCB). "This is clearly an area where we would like to see more research," says Acting Director James C. Cassatt, who is also director of NIGMS's Division of Cell Biology & Biophysics.

Key research goals of CBCB, Cassatt says, will be to encourage biomedical scientists and so-called quantitative researchers to work together to generate mathematical models of biological networks, develop modeling and simulations tools, conduct basic theoretical studies related to the organization of biological networks, and design bioinformatics tools for analyzing and storing data.

As an example of the type of research needed, Cassatt mentions cell biology. For the past 50 years, he says, researchers have focused on understanding the cell and all of its component parts. "Now we need to put it all back together. That effort is dependent on huge amounts of data, and that is the bioinformatics challenge."

Cassatt continues: "Biology has changed from a data-poor to a data-rich science. We are in a discovery phase in which the emphasis is on collecting the data and seeing the emerging principles from the data sets."

Still other NIGMS initiatives are helping to shape the institute's future directions. They include the following:

  • Synchrotron support--NIGMS is supporting major instrumentation enhancements and the hiring of additional staff at the Stanford Linear Accelerator Center, Menlo Park, Calif.; the Advanced Light Source at Lawrence Berkeley National Laboratory; the National Synchrotron Light Source at Brookhaven National Laboratory; and the Cornell High Energy Synchrotron Source. It is also, with NSF, supporting development of a beamline at Louisiana State University's Center for Advanced Microstructures & Devices in Baton Rouge. And together with the National Cancer Institute, NIGMS is constructing a new sector at the Advanced Photon Source at Argonne National Laboratory.
  • More powerful NMR machines--A breakthrough in technology allows the construction of a new generation of more powerful nuclear magnetic resonance spectrometers. This initiative will provide a few of these machines to groups of scientists who will use them to develop new methods and biological applications.
  • Metals in medicine--A huge number of biochemical reactions require metals such as iron, copper, calcium, and zinc. But very little is known about how metals are handled in the body. This initiative aims to change that, and insights derived could lead to new drugs, diagnostics, and other clinical benefits.

"What was true 40 years ago is still true today: NIGMS supports basic biomedical research that increases understanding of life processes and lays the foundation for advances in disease diagnosis, treatment, and prevention," says NIH Acting Director Ruth L. Kirschstein, who was NIGMS director from 1974 to 1993. "As science turns another corner, NIGMS continues to enthusiastically support research and training in cutting-edge areas such as proteomics, bioinformatics, computational biology, and integrative and collaborative approaches to research."

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