September 9, 2012 - By Bruce Goldman
James Spudich's research helps to explain the molecular activity that enables heartbeats, makes muscles contract and powers immune cells.
Stanford biochemist James Spudich, PhD, has been flying small planes as a hobby since 1975. At his Pacific Ocean vacation home there's a private runway within walking distance from his cottage. But what's put him in the pilot seat with respect to his professional career is his consistent ability to develop ever-more-precise ways of measuring molecular movements.
Spudich, the Douglass M. and Nola Leishman Professor of Cardiovascular Disease at the Stanford University School of Medicine, will receive the 2012 Albert Lasker Basic Medical Research Award for his trailblazing investigations of the molecular motors that drive our skeletal muscle contractions and heartbeats, enable our cells to divide, and power patrolling immune cells through our tissues. The prize, sponsored by the New York City-based Albert and Mary Lasker Foundation, carries an honorarium of $250,000, which Spudich will share with two other researchers: biologist Michael Sheetz, PhD, of Columbia University, and cellular and molecular pharmacologist Ronald Vale, PhD, of the University of California-San Francisco.
Over the course of an ascent launched at age 6 when he got his first chemistry set, Spudich found ingenious ways to figure out how cells' molecular motors work. He eventually took his studies down to the single-molecule level to measure the minute displacements and forces produced by a single molecular motor.
Spudich's discoveries testify to the synergies of interdisciplinary science — his work has involved various combinations of cell physiology, physics, biochemistry, structural biology and genetics. In the late 1990s, he and then-Stanford physicist and current U.S. Secretary of Energy Steven Chu, PhD, pitched then-Stanford provost Condoleezza Rice, PhD, with an idea that spawned Bio-X, Stanford's pioneering interdisciplinary research program that fosters collaborations among scientists from the physical, biological and computer sciences. Spudich served as the program's first director.
Colleagues hailed Spudich as not only a superb scientist but a terrific person endowed with modesty, leadership, inspirational mentoring and vision. Asked how he felt about the award, he replied, "So many other people at Stanford alone could have received this recognition."
"Jim's not only an amazing scientist but an amazing colleague," said Mark Krasnow, PhD, professor and chair of biochemistry and a Howard Hughes Medical Institute investigator, who is also a member of Bio-X. "From his earliest discoveries, we've all known he was destined for greatness. He's bridged basic biological science with every other science, not stopping at the edge of his lab or even the edge of his department, but finding collaborators in other parts of the university, in other fields of science, and across the world when necessary."
Spudich's methods epitomize hard-core basic research — scrupulous scrutiny of one-celled creatures, painstaking protein purification, measurements of motion and energy conversion at the single-molecule level — but they have practical consequences. Clinical trials, now under way, of several drugs based on Spudich's hard-won understanding of exactly how muscles contract offer hope for people prone to heart failure, amyotrophic lateral sclerosis and perhaps even the frailties of old age.
Spudich is an avid pilot and regularly flies a Trinidad plane to his vacation home in Sea Ranch, Calif.
"Jim Spudich's work underscores the importance of investing in basic research as a means to understanding and improving the human condition," said Philip Pizzo, MD, dean of the School of Medicine. "He is a distinguished scientist, exemplary leader and wonderful member of the Stanford and global community, and we are deeply proud of his accomplishments."
Molecular motors reside inside every cell in our bodies. Thanks to the work of Spudich, Sheetz, Vale and others whose careers have often intersected, we now know how they work. These motors use the chemical energy of ATP — the small, ubiquitous molecule that serves as the body's energy currency — to produce forward motion. Much as a car's engine burns gasoline, these motors "burn" ATP by splitting it in two, liberating chemical energy that is then coupled to mechanical movement.
As Spudich showed, the molecular machinery that makes our muscles contract relies only on two key substances — an ATP-dependent "motor" protein called myosin and a structural protein called actin that assembles into long filaments, which act as roads along which the myosin motor moves. A myosin molecule, like a poorly drawn stick figure, has two hands and legs.
The activity of these two muscle-moving molecules (other proteins and chemicals make stage appearances, too) can be depicted as that of a series of sailors with legs fixed to the sand on a beach all asynchronously pulling a rope with a hand-over-hand motion to haul in their boat to the shore. The "sailors" are in reality molecules of myosin, and the rope is a long filament of actin. The energy released in the splitting of an ATP molecule causes a myosin molecule to shift its shape in a characteristic way, similar to the sailor's arm moving from a forward position to a rearward position as he pulls on the rope. This motion is always in a single direction along the actin filament.
In most cells actin filaments run every which way, forming complex three-dimensional lattices called cytoskeletons that vary from one cell type to the next, making it possible for myosin or similar proteins to ferry cargos of various materials from one part of a cell to another. In this case, each myosin molecule is free to move along actin filaments that are fixed in place, like a truck moving along a road. A cell, far from being just a bag of randomly floating chemicals, is in many respects as complicated as a major city. In order to function properly, said Spudich, each cell type — nerve, liver, skin and so forth — has its own "city plan" (its cytoskeleton) to help molecular motors move the right substances along its actin or similar thoroughfares so those substances get to the right place at the right time. In a muscle, actin filaments are mostly aligned, so mass movements of myosin molecules along them causes an entire tissue to contract.
Spudich was born at the tail end of the Great Depression in Benld, Ill., a coal-mining town. His early fascination with chemistry — at the age of 6 he acquired his first in a series of progressively more advanced chemistry sets — foreshadowed his scientific ambition. Recognizing this, his parents cleared the pantry of their modest home to create a laboratory space for his pursuits.
By his teen years, Spudich's prowess had progressed to the point where he succeeded in triggering a three-engine fire alarm. "My brother John and I set off an explosion in a drainage ditch that looked a little like a mushroom cloud from a small A-bomb," he recalled with some amusement.
In 1960, as a sophomore majoring in chemistry at the University of Illinois at Champagne-Urbana, Spudich met a young biochemistry faculty member, J. Woodland Hastings, PhD, in a chance encounter. Hastings was trying to determine how some phosphorescing plankton convert ATP's chemical energy to light. The two bonded immediately, and Spudich signed on to Hastings' bioluminescence-focused lab. Hastings also hired Spudich to be his lab assistant in the legendary summer physiology course Hastings headed at the Marine Biology Lab in Woods Hole, Mass.
"There were no undergraduates taking that course. It was a tough blend of biochemistry, physical chemistry and other hard sciences with maybe 10 MDs, 10 PhDs and 10 graduate students in it," recalled Hastings, now the Paul C. Mangelsdorf Research Professor of Natural Science in Harvard University's Department of Molecular and Cellular Biology. "But Jim was going around helping them all get their experiments going." More significant, it was there that Spudich met his wife of 48 years, Annamma, then a graduate student and now a scientist and scholar in her own right.
By the time he graduated in 1963, Spudich had already co-authored two peer-reviewed journal articles with Hastings, one as senior author. He then enrolled as a biochemistry graduate student at Stanford under the tutelage of Nobel laureate Arthur Kornberg, MD. In 1968 he earned his doctorate and took on two successive postdoctoral positions, first at Stanford in the molecular-genetics lab of Charles Yanofsky, PhD, and then in the Cambridge University lab of Hugh Huxley, PhD, in England, where he was introduced to the field of biological contractile processes.
Huxley was proposing a model for an actin/myosin/ATP-driven mechanism that in its broad outlines presaged Spudich's discoveries, but he lacked the experimental tools available to rigorously test it. Huxley is "the father of the field of molecular motors," said Spudich. "The rest of us are standing on his shoulders."
After six years at UCSF, Spudich returned in 1977 to Stanford as a professor of structural biology, chairing that department from 1979 to 1984. In 1992 he switched to the Department of Biochemistry, which he chaired from 1994 to 1998.
In 1982, he and co-prize winner Sheetz performed an experiment that combined disciplines ranging from microbiology to biophysics. It was known that the inward-facing surface of the membrane surrounding cells of a plant called Nitella was studded with actin filaments that are all oriented in the same direction. The researchers cut open these cells and splayed them on a surface to expose those filaments. They then added myosin-coated 1-micron plastic beads. This allowed Spudich and Sheetz to observe unidirectional movement of the beads along the filaments. While scientists had theorized about this coordinated activity, it had never before been documented.
To show for the first time that pure actin is, by itself, enough to support myosin movement at physiologically relevant speeds, Spudich and one of his graduate students subsequently performed analogous experiments using a scaffold of identically oriented filaments of purified actin, ruling out any necessary participation by other components of Nitella's membrane.
But observing mass motions of myosin along actin filaments wasn't enough to satisfy Spudich, who wanted to measure the exact amount of energy consumed in each forward ratcheting step of myosin versus the actin filament, as well as the size of that step. This would mean getting down to the single-molecule level, made possible in the early 1990s by an auspicious interaction.
Chu, then at Stanford, had designed a device he calls an "optical tweezers" that used lasers to trap atoms and that would earn him the Nobel Prize in physics in 1997. One of Spudich's graduate students and a visiting professor on sabbatical in Spudich's lab spent several months in Chu's lab building a modified form of Chu's optical tweezers. This enabled Spudich's team to lower individual actin filaments onto slides coated with sparsely spaced myosin molecules, so that a single filament would interact with a sole myosin molecule. Using this approach, they calculated the distance and force of each ATP-driven step. Spudich reciprocated by providing Chu's students with space in the Department of Biochemistry so they could learn to manipulate DNA and become acquainted with biology in general.
In 1997, Chu and Spudich approached Rice to suggest that these interdisciplinary exchanges should be encouraged by the creation of an environment dedicated to them. "Condi very quickly said, 'Yeah, this sounds like a very good thing.' That really got the ball rolling," said Chu. At this point, several other individuals helped to provide more impetus.
"When you're provost, you get all kinds of ideas from people needing funding for them," said Rice, now a professor of political economy in Stanford's Graduate School of Business and of political science in the School of Humanities and Science, as well as the Thomas and Barbara Stephenson Senior Fellow on Public Policy at the Hoover Institution. "I'm not a scientist. So a big factor in my decisions about what to throw my weight behind was my confidence in the people proposing the ideas. Jim's a great basic scientist, a real innovator. And he's a wonderful teacher and mentor. His PhD students and his medical students think the world of him. He's the complete package."
Rice's high regard for both Spudich and Chu led her to recommend the project to Stanford President Gerhard Casper. He gave the nod to what was to become Bio-X, a campus-wide program that has the Clark Center as its hub, and is at the intersection of Stanford's schools of Medicine, Engineering, and Humanities and Sciences.
Having validated the model for molecular motors, Spudich is now focusing on applications of that model. Cytokinetics, a biotechnology company he co-founded in 1998, is conducting clinical tests of heart-failure drugs that work by increasing myosin's contractile force in that organ. Another Cytokinetics drug in clinical trials is designed to strengthen skeletal muscle. This could help patients with ALS (Lou Gehrig's disease) and, Spudich suggests, perhaps address the frailty of old age. "It would be great if a small-molecule drug that bound to skeletal-muscle myosin could strengthen muscles with minimal side effects and let you get out of a chair, or walk down the street," he said.
As for Spudich, he'd rather fly. "I find flying a wonderful way to clear my head," he said. An enthusiastic aviator since 1975, he wrote a book in 2004 about flying, called Piloting with Confidence.
But he has soared even higher on the wings of science. Spudich has authored hundreds of peer-reviewed papers and served as president of the American Society for Cell Biology. He is a recipient of the Guggenheim award, fellow of the American Association for the Advancement of Science, fellow of the American Academy of Arts and Sciences and member of the National Academy of Sciences.
Spudich's wife, two daughters, two sons-in-law and five grandchildren ages 4-12 will join him for the Sept. 21 ceremony in New York where he and his two co-honorees will receive the award, which was first given in 1945.
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