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Home , Molecular biophysics, Molecular physics

Teaching molecular at the graduate level

Norma Allewell and Victor Bloomfield Department of , 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 and molecular 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 . The recent explosion of struggled for decades to get crystal structures of new knowledge, methods, and needs for biophysical in- a few , 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 , 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 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 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 " 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 , , and the art in the physical sciences to its limits. Develop- , 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 simulation ofprotein dynamics, are greater amount ofequally necessary biochemistry, genet- among the most ambitious and innovative in physical ics, and cell , 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 , 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 ) 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 and physical tion of setting up undergraduate majors. The historical chemists who have some interest in , 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, , 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, , 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 , kinetics, the student needs to master the methodologies that are various forms of , 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 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 three types ofcourses in logical examples. molecular biophysics: courses in macromolecular struc- In the absence of a molecular biophysics major, stu- ture and dynamics, courses in biophysical methods, and dents can meet many oftheir needs by majoring in phys- courses in physical chemistry. In order to be prepared for ics, chemistry, molecular biology, and biochemistry, or the future, they also need exposure to cell and molecular even mathematics. Because the path from the physical biology. This is a tall order, and invariably creates a ten- sciences to biology tends to be less arduous than the re- sion between formal coursework and the need and desire verse, majoring in one of the physical sciences is proba- to "get into the lab." The general rule of thumb is that bly best. However, students graduating with a physical students should start working in a lab during the first science major will need to make special efforts in gradu- semester, and coursework should be largely over by the ate school to develop their molecular and biological intu- end of the third or fourth semester. ition, while students coming from a largely biological The graduate program in molecular biophysics at the background especially need a solid undergraduate University of Minnesota provides one possible model. course in physical chemistry. This course isjointly taught and cross-listed between the Clearly, a student must make some choices if there is Biochemistry and Chemistry departments; it does not to be anything in his/her life besides science, and many have a Molecular Biophysics designator. Typically, stu- deficiencies can usually be made up in graduate school. dents take several (but usually not all) ofthe following set A strong advising system is crucial to making intelligent, of courses, in one-quarter (10 week, 40 lecture hours) informed choices. One ofthe issues that the biophysical modules:

Allewell and Bloomfield Teaching Molecular BiophyalcaBiophysics 1447 Physical biochemistry: thermodynamics, binding, al- in molecular biology computing. However, instruction losterism, intermolecular forces, polyelectrolytes, hydro- in the sort ofcomputing most useful in biophysics tends dynamics, diffraction, and light ; to be informal; and students often teach themselves and Magnetic resonance: spin physics, NMR, EPR; each other about graphics and simulation packages. Applied spectroscopy: optical absorption, fluores- FORTRAN is still an extremely useful language forscien- cence, probes, , Raman and ; tific computation, particularly because a huge amount of Kinetics: steady-state, stopped flow, rapid kinetic already written, tested, and readily available FORTRAN methods, use in determining mechanism; code is available for all sorts of numerical analyses and and nucleic acid structure and dynamics: simulations. However, many argue that C is the language forces, mobility, crystallography, computer simulation of the future. and graphics. Although the breadth and depth offormal coursework It is not easy to find a suitable text for a graduate in molecular biophysics is probably greater than in most course in molecular biophysics. Currently, the leading other fields of modem biology, students also need train- text is undoubtedly by Cantor ing in how to keep up with and critically assess the and Schimmel (1980, Freeman Publications, San Fran- current literature. Because important developments are cisco). This comprehensive three-volume work has a reported not only in the standard biology journals, but range of coverage which enables many different courses also in the chemistry, physics, and computer literature, to be structured by selecting certain chapters. However, this may be an even more difficult task than in other it is somewhat outdated, requires a higher level ofmathe- fields ofbiology. Some ofthejournals which may need to matical sophistication than many graduate students with be consulted on a regular basis in molecular biophysics biological backgrounds find comfortable, and is expen- per se are: Biophysical Journal, Biophysical Chemistry, sive if all three volumes must be purchased. Texts that Biopolymers, European Journal ofBiophysics, and Jour- are less demanding, but may be suitable for a short nal of Biomolecular Structure and Dynamics. Broader course that emphasizes mainly solution methods rather journals that publish a good deal of biophysical work than NMR or crystallography, are Physical Biochemis- include: Biochemistry, Journal ofthe American Chemi- try by Van Holde (2nd ed., 1985, Prentice-Hall) and cal Society, Journal of , Journal of Physical Biochemistry:Applications to Biochemistry and Molecular Biology, Nucleic Acids Research, Proteins: Molecular Biology by Freifelder (2nd ed., 1982, Free- Structure, Function, and Genetics, and Protein Science. man Publications). Tanford's classic text Physical Chem- Some of the most exciting advances are rushed to print istry of Macromolecules (1961, John Wiley and Sons, in Science and Nature. The serious biophysical New York) is probably not suitable for a modem, gen- will want to scan Journal ofChemical Physics and Jour- eral course; but it has a detailed treatment of classical nal ofPhysical Chemistry, while the specialist in a partic- topics in polymer solution physical chemistry as applied ular area will need to read Acta Crystallographica, Jour- to biological macromolecules which has no parallel in nal of , Journal ofMagnetic other texts. The recent book by Nossal and Lecar, Molec- Resonance, or Macromolecules. Review articles are a ular and Cell Biophysics (1991, Addison-Wesley Pub- crucial way to gain an overview of the current status of lishing Co., Reading MA) covers an interesting selection particular fields of science. The leading review series in oftopics at a good level; whether it is suitable as a text for molecular biophysics are Quarterly Reviews ofBiophys- any particular course depends on the concordance be- ics, Annual Reviews ofBiophysics and Structural Biol- tween its table of contents and the course syllabus. Most ogy, and Current Opinion in Structural Biology. instructors will probably find themselves using one of Other issues are also important. Students need struc- these texts as a base, and supplementing it with addi- tured discussions of scientific ethics, how to choose a tional reading. research problem (described beautifully by Pollard in his Laboratory experience in purifying biological mole- accompanying article on cellular biophysics), how to de- cules and testing their biological activity is crucial ifbio- velop and write research proposals, and how to manage a physical experiments are to be done on biologically scientific laboratory. Any intelligent student will eventu- meaningful systems. Such experience may be obtained ally be able to solve technical problems; what students in thesis research or rotations; but if the research lab need most from their mentors is the benefit of wisdom expertise lies more in instrumentation or theory than in that can come only from experience. preparative biochemistry, a formal laboratory course may be desirable. A realistic discussion ofthe necessary knowledge, and where to find it, is given by Tom Pollard CONCLUSION in the accompanying article. During the past 25 years, molecular biophysics has The use ofcomputers in molecular biophysics is ubiq- evolved from being little more than a smorgasbord of uitous, ranging from data acquisition and analysis, topics from physics, chemistry, mathematics, and biol- through sequence database searches, to supercomputer ogy, to a cohesive, fast-moving discipline highly relevant simulations. Many departments have instituted courses to both and industry. Graduate programs must

1448 Biophysical JournalJoumal Volume 63 November 1992 reflect that change and create curricula that both develop field for women and minorities. Establishing a tone the student's scientific potential and prepare her/him for which encourages newcomers to enter the field will in the realities of the rapidly approaching 21st century. In the long run benefit everyone. developing these programs, it is important to keep in mind that the development of biophysics has been slowed in the past because it has not been an attractive Receivedfor publication and in finalform 4 September 1992.

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