Teaching molecular biophysics at the graduate level Norma Allewell and Victor Bloomfield Department of Biochemistry, University of Minnesota, St. Paul, Minnesota 55108 USA INTRODUCTION Molecular biophysicists use the concepts and tools of were students, in the 1950's and 60's, the idea that one physical chemistry and molecular physics to define and might obtain atomic-level structures ofproteins and nu- analyze the structures, energetics, dynamics, and inter- cleic acids was little more than a dream. A few heroic actions of biological molecules. The recent explosion of scientists struggled for decades to get crystal structures of new knowledge, methods, and needs for biophysical in- a few proteins, succeeding at best in tracing the chain sight has made the development ofgraduate training pro- backbone and observing some ofthe basic structural fea- grams much more challenging than was previously the tures (helices and sheets) predicted by Pauling. The pre- case. 25 years ago, the question was "What to teach?" diction that we would someday accumulate structures at Today, the question is "How can everything that must the rate of one per week, at a level of resolution that be taught be packed into a reasonable amount oftime?" would enable determination of arrangement of catalytic At the same time, the recent influx of relatively large groups in an enzyme, and subtle rearrangements upon cadres of gifted, excited students; increasing resources, binding ofligands, seemed beyond belief. That we would and the gradual shakedown and consolidation of the be getting similar quality of information on small pro- field combine to make the task more rewarding and in teins and oligonucleotides in solution from NMR would some ways more straightforward. Although graduate pro- have seemed even more unlikely. NMR had only re- grams in Molecular Biophysics have existed since at least cently been developed as a chemical tool for small or- the mid- 1960's, the recent establishment of a Molecular ganic molecules, and the enhancements that have made Biophysics Training Program by the Institute ofGeneral it feasible for macromolecules (particularly high field su- Medical Sciences ofNIH has generated new interest. Mo- perconducting magnets and Fourier transform methods) lecular biophysicists are now much less likely to define were not yet conceived. The advent of supercomputers, themselves primarily as chemists or biochemists, or to powerful desktop workstations, and personal computers, disguise courses in molecular biophysics as courses in enabling rapid analysis of huge data sets and simulation "physical chemistry for biologists." ofmacromolecular dynamics, was unanticipated. Lasers Teaching molecular biophysics at the graduate level is were not yet invented. The exquisite sensitivity ofmicro- difficult for the same reasons that research in the area is calorimeters was yet to be developed. The list of new difficult. The potential range ofthe subject is as broad as technology and theory on which modem molecular bio- physical chemistry itself, while the need to apply physi- physics depends could be extended almost indefinitely. cal chemical concepts and techniques to large, compli- Our graduate curricula were crowded enough before cated, strongly interacting molecules in solution and in these modern developments, with courses in thermody- partially ordered membrane phases pushes the state of namics, quantum mechanics, statistical mechanics, and the art in the physical sciences to its limits. Develop- mathematics, and with perhaps a course or two in ments such as the theory of the helix-coil transition in (mainly metabolic) biochemistry. How can we ask our double-stranded DNA, saturation-transfer EPR spectros- students to take the even more sophisticated physical copy to study dynamics of membrane and muscle, and chemistry courses they need today, along with the much molecular dynamics simulation ofprotein dynamics, are greater amount ofequally necessary biochemistry, genet- among the most ambitious and innovative in physical ics, and cell biology, and still have them graduate with a chemistry in the last several decades. To achieve such good thesis in five years? Frankly, we fear that we often advances requires deep, fundamental training in statisti- do not do an adequate job: students in biochemistry de- cal mechanics, spin quantum mechanics, and similar partments don't take enough advanced physical chemis- areas. We cannot help worrying whether our students try and physics, and students in chemistry and physics (who must spend considerable time learning about the departments don't take enough biology, to meet the biochemistry of proteins and nucleic acids, and about challenges of current and future research in molecular molecular genetics) are being trained to be innovators as biophysics. At best, they become experts in a specialized well as informed users of sophisticated physical science. area, and learn more by reading and self study through- The comparison with their fellow students in molecular out their careers (as most of us older scientists have biology, who after a few courses dive into laboratory done). But it is open to question whether today's stu- work that leads to ready publication, is not an easy one. dents trained as molecular biophysicists can realistically Molecular biophysics has undergone a revolution in achieve the breadth and depth of knowledge needed to the past several decades. When the authors ofthis article progress in the future as we have in the past. Perhaps it is 11446446 0006-3495/92/11/1446/040006 3495/92/11/1446/04 $2.00 Biophys. J. © Biophysical Society Volume 63 November 1992 1446-1449 more realistic to look for advances to come from collabo- community has not dealt with very effectively is the ques- rations between deeply trained physicists and physical tion of setting up undergraduate majors. The historical chemists who have some interest in molecular biology, diffuseness ofthe field, the paucity ofinterested students, with deeply trained biochemists and molecular biologists and resistance from university administrators and al- who have an appreciation of the potential contribution ready existing scientific communities have tended to dis- of the physical sciences. courage these efforts. However, times are changing, and the consolidation ofthe field combined with widespread interest and support argue for renewed efforts. UNDERGRADUATE PREPARATION All the course work in the world cannot substitute for Because molecular biophysics is both broad and deep, hands-on experience. Methods can be taught in formal laying the foundations at the undergraduate level is laboratory courses, but the thrill ofmaking a new discov- highly desirable. Ideally, a student entering graduate ery generally comes first from carrying out an indepen- school should have a good background in physics, chem- dent research project. Undergraduate research is one of istry, mathematics, and biology. The most useful courses the best ways to convince bright undergraduates to go on are the following: to graduate study in molecular biophysics. Physics: mechanics, electricity and magnetism, optics, and atomic and molecular physics; GRADUATE TRAINING Chemistry: general, organic, and physical chemistry; Mathematics: calculus through multivariate, differen- The typical Ph.D. program consists ofroughly two years tial equations, linear algebra and matrices, numerical of coursework, two or three laboratory rotations in the analysis, statistics, and computer programming; first year, auditing and presenting research seminars, Biology: introductory biology, cell biology, biochemis- oral and possibly written prelim examinations, and try, molecular biology, genetics; and, if time permits, roughly three years of research. In designing a graduate physiology and neurobiology. program, a balance must be struck between the student's The central discipline ofmolecular biophysics is physi- short term and long term needs. In the short term, the cal chemistry including thermodynamics, kinetics, the student needs to master the methodologies that are various forms of spectroscopy, diffraction and scatter- currently state of the art in his/her field of research; in ing, and statistical mechanics. This is the in the long term, she/he will need the survival skills to discipline move with the times. How many ofthe specific skills that which the quantitative understanding ofthe behavior of in matter is developed in molecular terms. A you acquired graduate school do you use today? At the typical under- same time, most graduate students are very goal oriented graduate course, preferably a year in length, will give and have little patience with broad philosophical discus- relatively little attention to the biological applications of sions, or learning that is seemingly irrelevant to the de- these topics. However, there are some texts, such as Phys- mands of the moment. ical Chemistry with Applications to the Life Sciences by The central questions in molecular biophysics deal Eisenberg and Crothers (1979, Benjamin-Cummings with macromolecular structure, energetics, and func- Publishing Co. Redwood City, CA), and Physical Chem- tion. The most widely used methods for addressing these istry: Principles and Applications in Biological Sciences questions are diffraction, magnetic resonance and ap- by Tinoco, Sauer, and Wang (2nd ed., 1985, Prentice- plied spectroscopy, hydrodynamic methods, and com- Hall, Englewood Cliffs, NJ), which do provide good bio- puter simulation. Students need