Graduate training in cellular biophysics Thomas D. Pollard Department of Cell Biology and Anatomy, Johns Hopkins Medical School, Baltimore, Maryland 21205 USA INTRODUCTION In this article I will outline some of the knowledge and Good problems focus on important biological pro- skills that investigators in cellular biophysics find valu- cesses, offer growth potential, and are tractable experi- able in their work. Everyone has their own definition of mentally. Some newcomers imagine that previous gener- cellular biophysics. For me it is hard to separate cellular ations have already grabbed all ofthe good problems, but biophysics from molecular biophysics, so let us accept it is not true. The landscape is so vast in biological re- the inevitable overlap and differentiate the areas on the search that new knowledge creates new opportunities. As basis of emphasis. Both include quantitative studies of the frontiers broaden, so will the opportunities, at least the chemical and physical basis of cellular function. for the foreseeable future. Not only are there essentially Both involve characterization of proteins, nucleic acids, limitless details awaiting discovery; even more impor- and lipids and their interactions. But a molecular bio- tant, many ofthe general principles still need to be iden- physicist is more likely to be interested in electrons, tified. while a cellular biophysicist is more interested in macro- "Important biological processes" are those that cells molecular events that can be studied with a light micro- depend on for their basic function. Some of the best scope. Cellular biophysics emphasizes the molecular problems deal with universal processes used by all cells aspects that directly illuminate functions at the cellular such as the assembly oforganelles, motility, signal trans- level, while molecular biophysics emphasizes the proper- duction, and regulation of the cell cycle, but the parsi- ties ofthe molecules themselves. They really represent a mony ofmechanisms at the molecular level has the con- continuum with a common goal. sequence that investigation of specialized processes I write from the perspective of almost 25 years of re- usually reveals some basic principles with wide applica- search on the molecular basis ofcellular motility, an en- bility. For example, the wealth ofinformation on muscle deavor that started out as a purely biological fascination contraction has greatly enriched our understanding ofall and has taken on a strongly biophysical tone as our un- sorts of cellular motility. derstanding has broadened. I have a very practical view There are so many genuinely fundamental questions of training in cellular biophysics, since as an MD I had in biology that no one should waste their time repeating essentially no formal training in the subject. Instead, my established work in new organisms or with new methods students, postdocs, and I have learned on the job from unless they have an attractive hypothesis about why such the literature, books, and many generous colleagues. I repetitive work is likely to reveal new principles of gen- have also had the opportunity to learn what challenges eral interest. The scientific community responds more students while teaching a laboratory course during the enthusiastically to something novel. Discovery not only summer at Woods Hole. Consequently, I will propose provides the most gratification in research, but discovery what one needs to know to do creative research rather is the only way to gain the confidence ofthe community than what constitutes a formal course ofstudy. Although that is required to obtain the resources to continue our knowledge ofthis material will not replace a good idea, it research. One must not waste good training and re- does free one's thoughts from the constraints of igno- sources on boring problems. rance and can lower one's natural inhibitions to try new There is another side to this argument espoused by my things. Good ideas can come from many places, so I put friend Evan Eisenberg of the NIH. When we were post- a very high priority on developing broad interests in biol- docs together, he claimed that the best way to become ogy and a lifetime of reading widely about the natural famous is to identify the most important experiment in sciences. Ostrich-like individuals with their heads stuck one's field and to repeat it. Of course, he did not mean in the sand oftheir own subspecialty risk becoming fossil- that one should literally repeat earlier work; rather one ized. should try a creative variation of the important experi- ment in the hopes of expanding knowledge at the heart ofa field. This approach does not have the novelty that I WHAT IS A GOOD BIOLOGICAL PROBLEM? have advocated above, but it does focus one's attention Formal curricula almost always neglect the first and on the important issues in a field. Since experiments are most important prerequisite for successful research, a rarely replicated exactly, Evan is right that one has a good biological problem. Lest we not forget it here, I will good chance of finding something new that will com- start by considering some ofthe features ofa good biolog- mand attention simply because of the focus on an issue ical problem from my perspective as a cell biologist. of acknowledged importance. 14501 450 0006-3495/92/11/1450/05 $2.00 Biophys. J. © Biophysical Society Volume 63 November 1992 1450-1454 By "growth potential" I mean that one's hard work are not essential for most work in cellular biophysics. should be rewarded by expanding opportunities, not Some expertise with computers is essential, but I hesitate dead ends. Most research requires a substantial invest- to recommend a formal course, since most individuals ment of thought, time, effort and financial resources. learn their computing skills informally on the job. Ideally, each of our investments in research should open up new opportunities. Common examples include the Biology discovery of a new process or molecule, the determina- The aspiring cellular biophysicist needs to have a broad tion of a new structure, the identification and cloning of knowledge of biology to help identify a good research a new gene, the purification ofa new cellular constituent, problem and the most advantageous experimental sys- or the development of a new method. These contribu- tem to get the answers. Courses in general biology are tions can elevate a field to a higher level that allows work necessary for exposure to the diversity oforganisms and to expand in more sophisticated ways. In many cases for orientation, but are not adequate for appreciating the students or postdoctoral fellows have based their inde- merits of a research project. One needs to understand in pendent careers on the hard work they did to elevate some depth how cells work at the molecular level. The their field. Obviously, one should not leave loose ends best way is probably a semester or year long course in cell behind, but the scientific community places such a high biology. Either in this course or others, one must learn value on novelty, that we all should strive to find some- about classical genetics and molecular biology. Many thing new. biophysicists deal with topics like membrane channels By "tractable" I mean experimentally approachable. that are covered in physiology courses, another impor- Many important problems with growth potential are not tant option to consider. Each student will need to be easy or someone would have taken them on already. selective in choosing biology courses since the topics cov- What is usually missing is a good idea about what to do ered in cell biology, for example, differ widely from or how to get started, rather than the absence ofthe tech- school to school. nology to do the work. Many fields are idea limited What about an aspiring cellular biophysicist who rather than technology limited. How many times have comes from the physical sciences with little or no oppor- you said, "I wish that I had thought ofthat"? Since con- tunity for formal training in biology? I would strongly siderable physical labor is usually required to do novel recommend that they read and think about the material research with growth potential, be sure that you have in one ofthe big, comprehensive cell biology books such done some good thinking ahead oftime. Make sure that as the "Molecular Biology of the Cell" by Alberts et al., your strategy is sound and that the outcome will meet 2nd ed. (1989, Garland Press, New York) or "Molecular your goals of contributing something novel and giving Cell Biology" by Darnell, Lodish, and Baltimore, 2nd you the desired foothold for your future work. ed. (1990, Freeman Publications, San Francisco). Both Who should pick the experimental problem and the of these books cover cellular biology at the molecular research strategy? It must be the person with the best level in enough depth to provide an excellent basis for idea. Since no one has a monopoly on good ideas, these thinking about cellular biophysics. One shortcoming is decisions turn out to be team efforts. Ideally everyone in that neither book consistently highlights the limits ofour a lab is continuously hunting for good ideas. The group knowledge, so a naive reader is likely to get the impres- leader may have the best perspective, but everyone sion that there are more answers than we actually have in should contribute. In our laboratory the technical staff, hand. students, and postdocs have all contributed to the overall direction of the research in addition to providing solu- Biochemistry tions to the everyday experimental problems. The only Every cellular biophysicist needs a good working knowl- way for this synergism to develop is to have everyone edge ofbiochemistry, since virtually all experimental bi- informed about the details of their colleague's experi- ologists are biochemists, at least in part.