LASKER BASIC MEDICAL ESSAY RESEARCH AWARD How lucky can one be? A perspective from a young scientist at the right place at the right time Ronald D Vale How amazing to receive a call that I, along I was also intrigued by the problem of how a ing trip to Woods Hole. Mike and I teamed up with my friends and colleagues James Spudich signal initiated by NGF binding to its receptor with Bruce Schnapp and Tom Reese from the and Michael Sheetz, won the Lasker Award for at the nerve terminal might travel back to the US National Institutes of Health (NIH), out- Basic Medical Research. An important part of nucleus, a question that brought me in touch standing microscopists who had a year-round the research cited for the Lasker Award stems with the literature of axonal transport. In 1982, laboratory at the MBL. It was a perfect team from a time when I was a graduate student. I I learned about the beautiful experiments that (Fig. 1), as we all brought different skills and was 21 years old when I first met Jim Spudich Jim and Mike Sheetz were doing on reconstitut- thinking and enjoyed the camaraderie of work- while applying to MD-PhD programs, 23 when ing the motion of myosin-coated beads along ing together on the problem. Mike Sheetz, Tom Reese, Bruce Schnapp and I actin cables1. I wondered, might a similar acto- The goal of the project was focused on began work on axonal transport, 25 when our myosin mechanism account for axonal trans- identifying the machinery powering axonal papers on microtubule-based transport and port of membrane vesicles? Mike and I decided transport. Bruce and Tom performed a tour kinesin were published and 27 when I started to test this idea using the squid giant axon. The de force experiment combining light and elec- my first job at UCSF. It was an extraordinary attraction of the squid was a consequence of a tron microscopy to show that single microtu- period of time. I was at the right place at the landmark paper by Robert Allen, Scott Brady, bules served as tracks for long-distance axonal right time, hanging on tight, and enjoying the Ray Lasek and their co-workers where they transport5,6. Our initial ideas of axonal trans- scientific ride of my life. This essay is aimed used Allen’s recently developed video-enhanced port being primarily driven by actomyosin at young scientists who are starting their own microscopy technique to image axonal trans- were not right. Next, we sought to reconstitute journeys. I will provide a perspective and ten port in the giant axon2,3. Never before had the transport from isolated components, a strategy lessons learned from my own experiences in fine details of the interior of a living cell been that worked well for many biological processes graduate school and travels to the discovery of visualized so clearly. Axonal transport could including DNA replication, transcription, ves- kinesin. now be studied in a ten-minute experiment icle transport, ubiquitination and others. In under a microscope rather than in a laborious the summer of 1984, reconstitution of vesicle An abbreviated history of my journey to week-long experiment with radioactivity, the transport worked, but unexpected results led Woods Hole and kinesin traditional measurement at the time. to even simpler and more powerful assays. In 1980, I interviewed with Jim Spudich for the A meteorological disturbance then changed Molecular motors, without membrane vesicles, MD-PhD program at Stanford University. We the course of the project and my life. We could be attached to glass cover slips and could had a great discussion, and his recommenda- arranged to get squid from the Hopkins Marine translocate microtubules across the surface; tion was crucial for my admission. Who would Station, a satellite of Stanford in Monterey, motors also could be attached to beads and have thought at that time that we would enjoy California. But no squid were caught that year. propel them along stationary microtubules7. sharing the Lasker Award together? With my It was 1983, the year that an El Niño warmed I asked Stanford whether I could postpone thesis advisor Eric Shooter, an eminent bio- the ocean waters and chased the squid away my medical clerkships, which were coming chemist and neuroscientist, I began studying from the Monterey coast4. What to do? If the up in a few weeks. That winter, the biochemi- the ligand binding and biochemical proper- squid would not come to us, we had to go to cal hunt for the molecular motor was on; with ties of the nerve growth factor (NGF) receptor. the squid. Mike and I decided at the last min- these powerful assays in hand, the dominant ute to go to the Marine Biology Laboratory motor was not hard to find. It was a previously Ronald D. Vale is in the Department of Cellular (MBL) in Woods Hole. Within three weeks, uncharacterized protein, which we called kine- and Molecular Pharmacology and the Howard airplane tickets were bought, an MBL lab was sin8. That same winter we also found evidence Hughes Medical Institute (HHMI), University of rented, an old, rusty Volkswagen Beetle was for another motor that moved in the opposite California–San Francisco (UCSF), San Francisco, purchased, the essential supplies from Mike’s direction to kinesin9, which was later found California, USA. University of Connecticut lab were packed in by Richard Vallee’s group to be a cytoplas- e-mail: [email protected] the car, and off we went on a scientific camp- mic dynein10. The work was published in five xvi VOLUME 18 | NUMBER 10 | OCTOBER 2012 NATURE MEDICINE ESSAY Figure 1 Mike Sheetz, Tom Reese, Bruce Schnapp and Ron Vale (left to right) at the Marine Biological Laboratories in Woods Hole circa 1984. papers in 1985, and I was lucky enough to get thought of gaining credit for something that adventure, beginning with a relatively last- a job offer at UCSF in 1986. I am still on leave might emerge? I did not completely appreci- minute decision to go to Woods Hole. Thinking of absence from completing my MD degree. ate at the time how different Eric’s unselfish of science as a grand adventure makes it fun attitude about his lab ‘family’ is from that of and allows unexpected things to happen, in Ten lessons many scientists. I also met lively older scien- terms of both scientific outcomes and your Here is my top-ten list of what I learned from tists at the MBL—Shinya Inoue and Andrew personal career. this experience, most which only became obvi- Szent-Gyorgyi who ‘adopted’ this kid from the 4. Read the literature but don’t be crippled ous in retrospect. I was immersed in the sci- West Coast during the Woods Hole winter. by it. It can be daunting to enter a new field ence, making and sometimes learning from They had small and focused labs (unlike the because of its considerable history and litera- mistakes and having very little idea of where generally larger labs at Stanford) and merged a ture. You have to be knowledgeable about prior it would all lead and how or where I would love of life and a love of science without com- work, but it is also good to avoid getting caught emerge at the end. promising either. in the trap of doing variations of prior experi- 1. Find good mentors, learn from them 2. Pick an important problem. Everyone ments and thinking along the lines of existing and then develop your own style. Soak up would rather solve a fascinating problem than models. Fresh eyes and some naïveté can be a your surroundings. Science is as much about a boring one. However, it is not easy to identify good thing. Fast axonal transport at the time philosophies of approaching problems, per- a project that is both important and ripe for had a long literature but relatively little clar- sonal styles of research and working with oth- solving. Furthermore, pragmatics dictate get- ity on the mechanism. The Allen, Brady and ers as the process of experimentation itself. As ting results in a defined time period in order to Lasek video microscopy studies, however, were a young scientist, you need to be exposed to obtain a degree, job or grant. As a result, most a turning point because they provided a new different ways of doing science, absorbing the of us are not always working on grand issues way to image small moving vesicles2,3. Going ideas and attitudes of more senior scientists. in biology all of the time. However, you should forward, it made sense to build upon that The net result is a maturation of a hybrid style be vigilant and thoughtful, looking for a wedge method by doing biochemistry and not stick- that best suits you and is a composite of the or an opening to tackle an important problem, ing to pharmacology, which had dominated characteristics that you admire in different even if it is not in your area of research or work in the past. individuals. Neither idolize nor ignore any- expertise. If the opportunity comes along (see 5. You don’t need a fancy lab to do good one. I was fortunate to have many great men- next point), seize it. In most cases, you cannot science. I came from a pristine, well-organized tors, which included the core group of Bruce make an important discovery if you are not laboratory in a relatively new building at Schnapp, Tom Reese, Mike Sheetz and Jim asking an important question from the start.