Teaching molecular biophysics at the graduate level

Molecular biophysicists use the concepts and tools of physical chemistry and molecular physics to define and analyze the structures, energetics, dynamics, and interactions of biological molecules. The recent explosion of new knowledge, methods, and needs for biophysical insight has made the development ofgraduate training programs much more challenging than was previously the case. 25 years ago, the question was "What to teach?" Today, the question is "How can everything that must be taught be packed into a reasonable amount oftime?" At the same time, the recent influx of relatively large cadres of gifted, excited students; increasing resources, and the gradual shakedown and consolidation of the field combine to make the task more rewarding and in some ways more straightforward. Although graduate programs in Molecular Biophysics have existed since at least the mid1960's, the recent establishment of a Molecular Biophysics Training Program by the Institute ofGeneral Medical Sciences ofNIH has generated new interest. Molecular biophysicists are now much less likely to define themselves primarily as chemists or biochemists, or to disguise courses in molecular biophysics as courses in "physical chemistry for biologists." Teaching molecular biophysics at the graduate level is difficult for the same reasons that research in the area is difficult. The potential range ofthe subject is as broad as physical chemistry itself, while the need to apply physical chemical concepts and techniques to large, complicated, strongly interacting molecules in solution and in partially ordered membrane phases pushes the state of the art in the physical sciences to its limits. Developments such as the theory of the helix-coil transition in double-strandedDNA, saturation-transfer EPR spectroscopy to study dynamics of membrane and muscle, and molecular dynamics simulation ofprotein dynamics, are among the most ambitious and innovative in physical chemistry in the last several decades. To achieve such advances requires deep, fundamental training in statistical mechanics, spin quantum mechanics, and similar areas. We cannot help worrying whether our students (who must spend considerable time learning about the biochemistry of proteins and nucleic acids, and about molecular genetics) are being trained to be innovators as well as informed users of sophisticated physical science. The comparison with their fellow students in molecular biology, who after a few courses dive into laboratory work that leads to ready publication, is not an easy one. Molecular biophysics has undergone a revolution in the past several decades. When the authors ofthis article were students, in the 1950's and 60's, the idea that one might obtain atomic-level structures of proteins and nucleic acids was little more than a dream. A few heroic scientists struggled for decades to get crystal structures of a few proteins, succeeding at best in tracing the chain backbone and observing some ofthe basic structural features (helices and sheets) predicted by Pauling. The prediction that we would someday accumulate structures at the rate of one per week, at a level of resolution that would enable determination of arrangement of catalytic groups in an enzyme, and subtle rearrangements upon binding of ligands, seemed beyond belief. That we would be getting similar quality of information on small proteins and oligonucleotides in solution from NMR would have seemed even more unlikely. NMR had only recently been developed as a chemical tool for small organic molecules, and the enhancements that have made it feasible for macromolecules (particularly high field superconducting magnets and Fourier transform methods) were not yet conceived. The advent of supercomputers, powerful desktop workstations, and personal computers, enabling rapid analysis of huge data sets and simulation ofmacromolecular dynamics, was unanticipated. Lasers were not yet invented. The exquisite sensitivity ofmicrocalorimeters was yet to be developed. The list of new technology and theory on which modem molecular biophysics depends could be extended almost indefinitely. Our graduate curricula were crowded enough before these modern developments, with courses in thermodynamics, quantum mechanics, statistical mechanics, and mathematics, and with perhaps a course or two in (mainly metabolic) biochemistry. How can we ask our students to take the even more sophisticated physical chemistry courses they need today, along with the much greater amount ofequally necessary biochemistry, genetics, and cell biology, and still have them graduate with a good thesis in five years? Frankly, we fear that we often do not do an adequate job: students in biochemistry departments don't take enough advanced physical chemistry and physics, and students in chemistry and physics departments don't take enough biology, to meet the challenges of current and future research in molecular biophysics. At best, they become experts in a specialized area, and learn more by reading and self study throughout their careers (as most of us older scientists have done). But it is open to question whether today's students trained as molecular biophysicists can realistically achieve the breadth and depth of knowledge needed to progress in the future as we have in the past. Perhaps it is