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Opportunities for Chemical Biologists: A View from the National Institutes of Health Jeremy M. Berg* National Institute of General Medical Sciences, 45 Center Drive, 2As-12, Bethesda, Maryland 20892
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greatly from technical advances such as new synthetic methods and novel instrumentation as well as from completely new concepts that are developed as components of chemical biology research. The National Institutes of Health (NIH), including its National Institute of General Medical Sciences (NIGMS), has been supporting research in chemical biology for many years. The primary mechanism for support of this research is the investigatorinitiated grant, typically an R01 grant. More than 60% of the $1.94 billion NIGMS budget this year is devoted to R01 grants or their equivalents. Approximately one-third of these grants have a significant chemical component. A more complete description of the NIGMS budget is available at http:// publications.nigms.nih.gov/loop/20060616. html#1. Through investigator-initiated grant applications, researchers are free to submit ideas of their choosing relevant to the broad NIH mission and to compete for available funds through peer-review processes. NIH highlights areas of particular interest by issuing program announcements. One announcement of relevance to chemical biology is called Metals in Medicine (http:// grants.nih.gov/grants/guide/pa-files/ PA-05-001.html). This announcement, from NIGMS and several other NIH components, solicits research in specific areas at the inorganic chemistry–medicine interface, including metal metabolism and regulation and the interactions of inorganic complexes with living systems. No funds are set aside forprogram announcements, and applications
Image courtesy of the National Institutes of Health
T
he most exciting and vibrant areas of research often lie at the interfaces between disciplines that have traditionally been separate. In the case of the chemical and biological sciences, such interfaces have been fruitfully explored for more than a century. The fields of pharmacology, biochemistry, and biophysical chemistry are relatively mature, yet they are still quite active and full of challenging problems and opportunities for new discoveries. These fields are integral to biomedical research and have had a tremendous impact on human health. Chemical biology is a new variant at this interface. The definition of this interdisciplinary field is evolving as more researchers become actively engaged and more progress is made. Chemical biology is an outgrowth of the revolutionary advances in molecular biology that have taken place over the past two decades. The ability to manipulate DNA molecules and their expression at will, made possible by a combination of advances in our understanding of central biological pathways and enzymes as well as powerful and inexpensive methods of chemical synthesis, has linked biological sciences and chemistry in unprecedented ways. This marriage of chemical synthesis and molecular and cell biology is a major theme in chemical biology. Other chemical biology research involves the application of concepts from biology, such as the use of Darwinian selection and evolving systems, to chemistry. Biomedical science and public health can benefit
*Corresponding author,
[email protected].
Published online October 20, 2006 10.1021/cb6003993 This article not subject to U.S. Copyright. Published 2006 by American Chemical Society
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The greatest contributions to emerging fields such as chemical biology come from individual scientists.
compete directly with unsolicited applications for support. Another NIGMS initiative relevant to chemical biology is a network of centers for Chemical Methodologies and Library Development (CMLD) (www.nigms.nih.gov/ Initiatives/CMLD). Four active CMLD centers are developing new methods for chemical library synthesis and collaborating with other chemists and biologists on applications of these libraries. NIGMS also supports two large-scale collaborative project awards (“glue grants”) that have substantial chemical components. Glue grants promote integrative and team approaches to important, complex biological problems. The Consortium for Functional Glycomics (www.functionalglycomics.org/ static/consortium) is directed toward understanding the role of carbohydrate–protein interactions at the cell surface in cell–cell communication, and the Lipid Metabolites and Pathways Strategy consortium (www.lipidmaps.org) addresses global changes in lipid metabolites that occur during biological processes such as signaling. These consortia are actively developing and disseminating important new tools and resources for broad scientific communities, including chemical biologists. Research training programs also play a significant role in promoting the development of new fields like chemical biology. NIGMS has supported a chemistry–biology interface Ph.D. training program since 1993, with grants to 20 institutions at present (www. nigms.nih.gov/Training/Mechanisms/NRSA/ InstPredoc/#chemistry). These training programs involve faculty and students from both chemistry-related and biological science departments and promote student exposure to scientific concepts and cultures from both sides of the chemistry–biology interface. Interactions among students from different backgrounds play important roles in these training programs. Individual fellowships are available to support postdoctoral training in chemical biology. 548
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Chemical biology is well represented in a more recent set of initiatives collectively called the NIH Roadmap for Medical Research (http://nihroadmap.nih.gov). The Roadmap was developed with broad input from the scientific community to focus on areas of considerable relevance to the NIH mission that were not being adequately addressed by existing programs supported by single institutes or groups of institutes. The Roadmap is thus not a strategic plan, but rather an attempt to respond to perceived gaps in the NIH portfolio. The Roadmap’s Molecular Libraries and Imaging Initiative (MLII) (http://nihroadmap. nih.gov/molecularlibraries) has the largest chemical biology component. The backbone of this initiative is the Molecular Libraries Screening Center Network (MLSCN) and an associated NIH Molecular Libraries Small Molecule Repository. The goal of the MLSCN is to offer the public sector access to the large-scale screening capacity necessary to identify small molecules that can be optimized as chemical probes to study the functions of genes, cells, and biochemical pathways. Ten pilot-scale centers are currently in operation and are soliciting potential assays from the scientific community. The activities of the MLSCN and related initiatives are integrated through a publicly accessible database called PubChem (http://pubchem. ncbi.nlm.nih.gov). This database allows researchers to navigate parts of the universe of small molecules with links to relevant entries in other biomedical databases developed and maintained by NIH’s National Center for Biotechnology Information. Other components of the MLII include programs in New Methodologies for Natural Products Chemistry, Pilot-Scale Libraries for High-Throughput Screening, and Novel Preclinical Tools for Predictive ADME–Toxicology and the development of new tools and methods for high-resolution cellular imaging. See http://nihroadmap.nih.gov/ molecularlibraries for more details about BERG
funded research and potential funding opportunities. Additional Roadmap activities that have significant relevance to chemical biology include Nanomedicine; High-Risk Research (through the NIH Director’s Pioneer Award program); and Building Blocks, Biological Pathways, and Networks. Because the Roadmap programs cut across all of NIH, they are substantial in scope and depth, yet they have only a modest impact on the budgets of individual institutes. In fiscal year 2006, 1.2% of the overall NIH budget goes to support Roadmap activities, including 0.9% of the NIGMS budget. Regardless of funding mechanisms, the greatest contributions to emerging fields such as chemical biology come from individual scientists. This past May marked the passing of R. Bruce Merrifield, a scientist whose seminal discoveries greatly influenced chemical biology and many other fields. Solid-phase synthesis, first applied to peptides, then to oligonucleotides, and now to a wide range of chemicals, transformed both chemical and biomedical research. Without this fundamental chemical insight, much of the now-routine operations in molecular biology, such as amplification of DNA by the polymerase chain reaction and DNA sequencing, would be vastly more difficult. In fact, many of the activities now associated with chemical biology would not only be much more difficult, they probably would never have even been conceived. As a science administrator and a scientist whose own research lies at the chemistry–biology interface, I look forward to many new discoveries and advances that can be expected as chemical biology continues to evolve.
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