Let's get Physical ... Biophysical

Even before Francis Crick used his physics training to help calculate the structure of DNA, physics has informed biology. And while many biophysicists focus on basic research, they increasingly use their discipline to predict the effects of drugs before they are used in animal or human trials. Scientists also use quantitative and computational biophysics tools to answer questions about the cell: to predict protein folding or observe interactions between biological macromolecules in vivo. But computational tools cannot answer one of the most fiercely debated questions among biophysicists: What is biophysics? "It's obviously applying physics to biological systems," says Juan Alvarez, associate director of computational chemistry at Wyeth in Cambridge, Mass. "But for me, biophysics is really the thermodynamics and the quantum mechanics and calculating electrostatic interactions." Definitions aside, biophysics is clearly a field of rising interest as reflected by the Biophysical Society's recent expansion: membership has grown to 7,000 in 2002 from 4,200 in 1998. The US government is investing in the twinned discipline, and pharmaceutical companies seek biophysics-trained candidates. But no two biophysicists necessarily perform the same tasks. "Many biophysicists are the only ones in their department, so everyone has a different definition of it," says Ro Kampman, executive director of the society. Because biophysics changes over time and with technology, definitions do not remain permanent anyway, she says. Scientists pursue both theoretical and practical biophysics. "There are many groups in this community who work on protein folding and pathways," says Adrian Bax, section chief of laboratory physics at the National Institute of Diabetes and Digestive and Kidney Diseases, whose own research focuses on protein-protein interactions and their energetic and entropic contributions in complex formations. Such work can translate to drug discovery leads. The other side to biophysics is more theoretical. Klaus Schulten, director of the theoretical biophysics group at the University of Illinois, Urbana-Champaign, and self-proclaimed "world champion of biological simulations," says that biophysicists work to describe the matter in cells and how they carry out their functions. "When many cells are working together on common tasks, you want to understand how systems network themselves and respond to signals from the outside and organize a hierarchy of chemical processes in the body," Schulten says. Structure-based approaches to drug design have helped fuel theoretical biophysics, according to Brian Shoichet, associate professor of molecular pharmacology and biochemistry at Northwestern University. "It's become an increasing trend, where theory labs are doing more of the experiments themselves," Shoichet says. Some will argue, however, that such biological simulations become studies in other fields: "I wouldn't consider clinical simulations biophysics, because you start to step away from the physics and more toward physiology," Alvarez says. Other biophysics tools aid in drug discovery. Molecular simulations are often performed in silico (computer-based) to predict toxicity, side effects, and ligand metabolism. "The design of drugs is very expensive, so anything to help make this search process for potential drugs more efficient can help companies," Schulten says. "You try to make as much sense as possible from observations so that you don't have to sacrifice animals as much." THE CAREER ZIG ZAG For those who seek a biophysics career, the path is rarely direct. "Every time we ask someone how they got into biophysics, no one thought they would initially," Kampman says. "Somewhere along the line they realized that biology could be fun, using their skills to solve problems." While people debate the definitions of the discipline, they do agree that job candidates need a solid rooting in quantitative skills such as math, computing, and spectroscopy. "Biology is probably easier to pick up, but the most important thing is to be committed to measuring biological phenomena," says Stephen Burley, chief scientific officer of Structural Genomix, a drug discovery company in San Diego. The company recently received an $18.1 million, three-year grant from the National Institute of General Medical Sciences (NIGMS) to use a genomics-driven, high-throughput, structure-based platform to increase the efficiency and effectiveness of the drug discovery process. This grant transfers leadership of the New York Structural Genomics Research Consortium to Structural Genomix, which in turn will provide access to its state-of-the-art X-ray beamline facility for high-throughput X-ray crystallography capability. The grant to Structural Genomix is one of the largest in protein-structure research, and Shoichet says the money available in biophysics compares favorably to resources for traditional fields like chemistry. The National Institutes of Health tends to fund at a higher rate than pharmaceutical companies do. "I believe that the more disease-oriented a research project can be, the more funding will be available," he adds. Shoichet also receives funding from NIGMS and from pharmaceutical companies, including Indianapolis-based Eli Lilly, Pharmacia of Peapack, NJ, and Proctor & Gamble in Cincinnati. "When a pharma gets into the game, it allows us to test way more compounds," Shoichet says. "They were doing high-throughput screening, which really got us some statistics." The Santa Fe Institute works with both theoretical and nontheoretical biophysics and offers a one-year, full-time appointment with a possibility of renewal for a second year. The Biophysical Society also provides fellowships for research. Some funding opportunities in biophysics include: National Science Foundation Subject: Molecular biophysics Deadline: January 10, 2003 Contact: Kamal Shukla (kshukla@nsf.gov) (703) 292-8444 National Institute of General Medical Sciences Subject: Evolutionary mechanisms in infectious disease Deadline: February 1, 2003 Contact: Irene Anne Eckstrand (Irene_Eckstrand@nih.gov) (301) 594-0943 University of Cambridge Subject: Broodbank fellowship for biochemistry or biophysics Deadline: April 26, 2003 Contact: Christine Botha (mv213@cus.cam.ac.uk) +44 (0) 1223 330-228 Hal Cohen can be reached at hcohen@the-scientist.com.

Let's get Physical ... Biophysical

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