UCSF has arguably been the best basic biomedical research university over the past few decades — it has consistently garnered a healthy portion of National Institutes of Health funding, so when UCSF faculty single out one of their own colleagues for outstanding research accomplishment, they know what they are talking about.

The highest award for scientific research achievement bestowed by UCSF on its biological explorers is the Faculty Research Lectureship, now in its 46th year. This year's recipient, Ronald D. Vale, PhD, professor and vice chair of the department of cellular and molecular pharmacology, William K. Hamilton Distinguished Professor of Anesthesia and a Howard Hughes Medical Institute Investigator, was honored for the discovery and exploration of the world's smallest motors, enzymes that move all sorts of molecular cargo within cells by converting chemical energy to mechanical energy about six times more efficiently than your automobile. The motors are 100 million times smaller than a V-8 engine, but for their size they move their cargo faster than a passenger car on the freeway.

In 1983, while Vale was still a MD/PhD student at Stanford University, he and colleagues found evidence for the existence of a new microtubule motor, dubbed kinesin (from the Greek word kinein meaning movement). The quest to explain the force that drove this newly discovered and purposeful movement of cellular components so excited Vale that he discontinued medical school to pursue the research full time.

Twenty years later, the knowledge that has grown from the basic discoveries of Vale and his colleagues has changed biologists' view of the cell on a fundamental level and is leading to applications in the clinic.

Vale continues his academic studies aimed at advancing scientific understanding of molecular motors. He manages many postdoctoral fellows and graduate students and advises the training of researchers in the Department of Anesthesia, but he also joined three colleagues to start a biotech company, Cytokinetics, Inc. in 1998. Researchers at the company, which employs about 160 people, already have developed a drug that inhibits a key kinesin motor that is necessary for cell division. This drug inhibits the uncontrolled proliferation of tumor cells in animals and is currently being tested in cancer patients in Phase I clinical trials.

"On a personal note," Vale said, "having lost my mother to cancer and watching others go through the same process, if my research contributed a tiny part to a broad research effort that leads to successful drugs that help cancer patients and their families, then this would be a hugely gratifying achievement for me."

"Serendipity Rules" in Science

During his faculty research lecture on April 22, Vale displayed an impressive array of videos that revealed microscopic movements of cellular components, filmed using innovative microscopy techniques that Vale has adapted specifically to address questions about how molecular motors such as kinesin move along filamentous tracks within the cellular cytoplasm, the viscous milieu surrounding the cell's nucleus and bounded by the cell's outer membrane.

Directing a remark specifically to young researchers, Vale said not to worry if things don't go exactly as planned. "Serendipity rules," he said. In retrospect, Vale said, "It was always the unexpected result that was the most exciting, and it was always the unexpected result that most influenced my scientific career." And while Vale is noted in his field for building innovative devices, like the special microscopes that he uses to make new discoveries, he noted that meeting the right people at the right time and establishing relationships and exchanges of ideas with mentors and colleagues, many of whom were in the audience, have had more to do with his scientific success than has technology.

As a case in point, Vale related his early graduate studies in Eric Shooter's neuroscience laboratory at Stanford. He became interested in learning how certain protein receptors at the nerve terminals, the ends of the long processes called axons, traveled back to reach the cell body where the DNA-containing nucleus is located. If the cell body of a neuron that controlled muscle movement was a meter in diameter instead of being microscopic sized, the axon would be a length equivalent to the distance from Monterey to San Jose. Directed rather than random motion of molecules within the axon was required to explain the speed of certain material transport that had been observed in the neuron. But what was responsible for this directed movement of molecules?

Vale and his colleague Mike Sheetz decided to use the comparatively easy-to-manipulate giant axon of the squid as an experimental model. However, the oceanic temperature change engendered by the 1983 El Nino forced squid away from California's coast, leading Vale and Sheetz to the East coast to carry out their studies where squid were easily obtainable.

This was serendipity, Vale says, for at the Woods Hole Marine Biological Laboratory on Cape Cod, they were introduced to a revolution in microscopy taking place there and nowhere else. Video camera microscopy and computer-based enhancement techniques pioneered independently by Shinya Inoue and Robert Allen were enabling researchers for the first time to view fine details of the cell's interior in real time, including the orderly movements of sausage-shaped mitochondria, the cell's power plants, up and down the giant squid axon.

"These movies forever changed cell biology," Vale said, "because they showed that the inside of the cell was not static — in fact it was an incredibly dynamic environment filled with motion — and they also provided a huge impetus for us to go forward and study this phenomenon."

Before the discovery of kinesin and its relatives, studies of the microscopic mechanics of biological movement had been centered on filaments within muscle, composed of the proteins actin and the motor protein myosin. Studies of muscle date back to the 19th century. In the 1960s, Ian Gibbons (present in the audience) also discovered a different motor protein, dynein, which drives the beating of flagella and cilia, cell projections that power the locomotion of sperm and aid the clearance of particles from lungs.

"Movement in other systems was either considered to be too odd or too difficult to study," Vale said. And when kinesin was first discovered, Vale said, it was still considered to a more difficult system for understanding biological motion compared to myosin.

While still at Stanford, Sheetz and Jim Spudich had shown that, even in the absence of cells, myosin-coated tiny plastic beads, easy to see under an optical microscope, could move along actin filaments. Perhaps individual actin filaments in axons served as a track on which molecules could be carried, Vale and Sheetz reasoned. On Cape Cod, the researchers teamed up with video microscopists Tom Reese and Bruce Schnapp. They extracted the contents of the squid axon, "like squeezing tooth paste out of a tube," Vale said, and they still were able to observe the movement of mitochondria and other membrane organelles along tracks in the cell-free preparations. They then used video microscopy to see if the coated beads, propelled by myosin, could be observed moving in orderly fashion within the extracted "axoplasm." But the myosin beads did not move. The control beads, however, which were not coated with myosin, did move.

"In fact, we had no idea what that result meant," Vale said, "So of course we ignored it. We should have paid more attention to it, because it foreshadowed an important result that was to come a year later." In the meantime, the researchers succeeded in using a high-magnification electron microscope to view a "transport filament" upon which the organelles had moved, and determined that it was not actin, but an entirely different biological polymer, called a microtubule.

Like taking apart a car engine and putting it back together to understand how it works, Vale separated components of the axon and began combining only certain ones to see if he could reconstitute movement. Vale combined purified microtubules, organelles and the cellular fuel ATP, and very few organelles moved. But he found that if he also added a slew of soluble proteins from the axon, then mitochondria and other cellular organelles would move. But serendipity was ruling again — the control experiment, in which the organelles were left out, yielded a more curious result, one that, Vale said, "blew my mind, when I saw it at 2 o'clock in the morning."

The microtubules had dropped down to the glass surface of the slide and began crawling along it like little worms. There must have been huge numbers of motors that were unattached and free in the axoplasm, Vale soon realized. In the absence of organelles to which they normally attach, these molecular motors opportunistically stuck to the glass, where they actively passed the microtubules overhead, like rowdy Big Ten football crowds passing helpless fans through the stands. Like the glass slides, the control beads in the earlier, unexplained experiment must have been picking up the motor molecules, enabling the beads to move along the microtubules in the axoplasm, whereas the beads that were already coated with myosin were prevented from picking up the motors and therefore did not move.

In the dead of winter, still working at the nearly deserted Cape Cod lab, Vale called up Stanford to postpone medical school, determined to stay on to purify the motor. He accomplished this goal by separating groups of proteins from the axoplasm to see which fraction retained the ability to move microtubules on glass slides. He parsed the fractions ever more finely until he found the protein, kinesin, which was responsible for the movement.

From Squid Axons to Tumor Cells

In the ensuing years Vale and many other laboratories have identified additional molecular motors in the kinesin family and learned in great structural, mechanical and biochemical detail how kinesin uses ATP to grasp microtubules and move in well-defined steps along the microtubule. (Some kinesins move in one direction along the microtubule track, while others move only in the opposite direction.) In pursuing answers to his research questions, Vale has traveled the globe to learn new microscopic techniques and returned home to build his own microscopes, including one with which he used a technique called total internal reflection microscopy to image light emitted from a single fluorescent dye attached to a single molecule of kinesin so that he could precisely track its movements.

Scientists now have identified 45 different human kinesin-related proteins. These kinesins now are known to play a variety of roles in virtually all cells, such as moving proteins, membranes and RNAs and helping to physically move and separate DNA that is replicated during mitosis prior to cell division.

The kinesins that play a role in mitosis have been a key focus of Cytokinetics, Inc. During mitosis, the cell first replicates its DNA and packages it into chromosomes. A special microtubule-containing structure called the mitotic spindle aligns the chromosomes and separates the "sister" chromatids away from one another before the cell pinched in two. This leaves the two "daughter" cells with equal copies of the genetic material. Specific kinesins are involved in arranging the microtubules to make the mitotic spindle and in moving the chromosomes and sister chromatids. There already are cancer drugs that target microtubules to kill dividing tumor cells, but these drugs also target microtubules in normal and non-dividing cells, resulting in toxic side effects, including neurotoxicities. Cytokinetics researchers have developed and screened inhibitors of kinesins involved in mitosis, which targets only dividing cells. They and their partner GlaxoSmithKline have taken a potential drug, an inhibitor and of a mitotic kinesin called KSP, all the way to clinical trials, which is rapid progress for a 5-year-old company. Results of a Phase 1 trial of the drug will be announced in May at the annual American Society for Clinical Oncology meeting in Chicago.

Growing Up in Hollywood

Traditionally, recipients of the faculty research award usually share early life experiences that may or may not have shaped their career choices. Vale grew up in Hollywood, and he made his already clear and entertaining presentation of research even more engaging by comparing his career trajectory with that of the entertainer Michael Jackson, who was in Vale's six-grade class, singing precociously (and famously) about love, Vale noted, well before he himself had any interest in the subject.

Vale got as much fuel efficiency as his own molecular motors out of the comparison. At one point during his talk he used an exquisitely rendered animated segment to illustrate how kinesin uses the cellular fuel ATP to take steps along the microtubule, a distillation of what had been learned over two decades of research. Then, taking great liberties with his own research findings, he cued "Beat It." As the song blasted through the auditorium's sound system, he led the spirited audience in a clap-along as the cartoon kinesin appeared performing a choreographic dance routine.

Clearly Vale feels fulfilled with the choice he made to pursue a career in biological science, and would not trade his success for that of his former classmate. In the world at large, where Michael Jackson is familiar to nearly all and Vale is all but unknown, most might not have understand, but to the UCSF audience, Vale was the real star, and it all made perfect sense.

Source: Jeffrey Norris

Last updated January 28, 2005

Ron Vale, professor of cellular and molecular pharmacology and an investigator for the Howard Hughes Medical Institute, first identified kinesin, tiny motor proteins inside cells.