Pioneering discoveries on molecular motors

The room was packed with a standing-room-only crowd. The year was 1963, and the setting was Woods Hole, Massachusetts, renowned for its summer classes in biology.

James Spudich (BS, ‘63, chemistry) had just finished his bachelor’s degree at the University of Illinois, and he stood at the front of the room, wiping the blackboard in preparation for the next speaker—U of I biochemist Woody Hastings. But as Hastings stepped up to the lectern, the professor suddenly threw a curve ball to the crowd. He introduced his young student, Spudich, who strolled up to the podium and began giving the lecture, in Hasting’s place, to the shocked audience.

“Nobody was expecting it,” Spudich recalled. Only he and Hastings knew the secret, and the crowd responded enthusiastically.

But for Spudich, even more important than impressing the audience was impressing a young woman at the back of the room whom he had his eyes on—and his lecture about his work did the trick. They soon began dating, and one year later they married. Spudich and his wife, Annamma, have now been married for 52 years.

Spudich has also gone on to become one of the most respected biochemists in the world. He credits his two years in Hastings’ lab at U of I and two summers in Woods Hole, where Hastings headed the physiology course, as the sparks that sent him from chemistry to biochemistry.

Spudich has made his mark with pioneering discoveries on molecular motors—the tiny powerhouses responsible for movement at the cellular level. For this research, he has won a 2016 Alumni Achievement Award—one in a long line of honors. He also won the prestigious Albert Lasker Basic Medical Research Award in 2012, an impressive honor as evidenced by the fact that almost half the Lasker awardees subsequently won a Nobel Prize.

Spudich grew up in the small coal-mining town of Benld, Illinois, about an hour south of Springfield. His parents always encouraged both Spudich and his brother, John, to pursue their greatest passion—chemistry.

“I had every chemistry set since I was six,” he says. His mother even cleared her only pantry for food storage in their 700-square-foot home so the brothers could have their own laboratory. 

By the time they were teenagers, the brothers were doing serious chemistry—and sometimes it was seriously dangerous. In one instance, the brothers placed a chunk of solid sodium in the bottom of an empty paint can. Knowing that mixing solid sodium and sulfuric acid would create an explosion, they taped a vial of acid inside the can.

Next, they placed the paint can in a deep drainage ditch, far from anyone who could be harmed, and then, standing at a distance, they shot at it with their BB guns. Eventually, one of the BB’s hit the mark, breaking the vial of sulfuric acid and causing the chemicals to mix.

“When we heard a hissing sound, we started running,” Spudich says. “There was a large explosion, and when we turned around, we saw a mushroom cloud that was probably two houses high.”

Fire engines rushed to the scene, but the brothers were long gone.

“We were lucky we didn’t get hurt,” he said.

His brother, who graduated from Illinois in mathematics in 1967, is now a professor and highly accomplished scientist at the University of Texas, while Spudich has spent most of his career at Stanford University.

His two years in Woody Hasting’s U of I laboratory was the first turning point in his career, followed by superb training in biochemistry and genetics at Stanford. Another turning point came during postdoctoral research in structural biology at Cambridge University in England. He worked with Hugh Huxley on muscle research from 1969 to 1971, setting him on the path of studying molecular motors.

Molecular motors are like microscopic automobiles, running along tracks in our cells and burning fuel called ATP. In a human muscle, the motor is called myosin, and the track is called actin. In his early research, Spudich and his colleagues purified out both myosin and actin and then coated microscope slides with the purified myosin molecules.

“Picture a lawn with blades of grass sticking up. These are the myosin heads,” he said. Next, they sprinkled actin filaments onto the myosin heads, making them visible with fluorescent dyes, “like putting little flashlights” on them, he said.  

In 1986, Spudich and his PhD student, Steve Kron, proved that out of the 5,000 or so proteins in a cell, you only needed these two proteins—actin and myosin—to create movement that was the equivalent of a muscle contraction.

“This was a huge breakthrough because it simplified what you needed to understand about how that movement was occurring,” he said. Today, scientists around the world who study molecular motors use the assay, or laboratory procedure, that he and his students developed from this research.

In another breakthrough, in 1994, Spudich’s team lowered a single actin filament onto a single myosin molecule, so they could watch what happens when one myosin molecule interacts with one actin. This helped open up a field of biology now called “single molecule biology.”

To do this work, Spudich’s team built a laser trap with the help of Steve Chu, a Stanford physicist who won a Nobel Prize in 1997 for trapping atoms. (Chu also served as the Secretary of Energy from 2009 to 2013.)

The collaboration between Spudich and Chu was unique. Spudich had his team work part of the time for a year or more in Chu’s physics lab, while Chu’s physics students spent some of their time for several years in Spudich’s lab learning biochemistry.

This student-swapping collaboration inspired Spudich and Chu to bring a new idea to Condoleezza Rice, the former Secretary of State who was then Stanford’s provost. They suggested to her the creation of a program that would bring together talent from physics, biology, chemistry, engineering, computational sciences, and the clinical sciences. They called it Bio-X.  Spudich served as its first director from 1998 to 2001, and today over 600 faculty members across campus are part of the Bio-X program.

Spudich also started his first company in 1998, developing a drug that makes the healthy part of a damaged heart work harder so that overall heart function remains the same. A second drug aims to improve muscle function for patients with ALS, or Lou Gehrig’s disease. Both are in late stage clinical trials.

Meanwhile, a second company, started in 2012, is developing a drug that slows down a racing heart in patients with a mutation that causes their heart muscle to overwork.

As for Spudich, he shows no signs of slowing down. But whenever he wants a break from this hectic pace, he goes to the air. He has been flying small planes for more than 40 years, and he even wrote a book on flying.

“You’re 1,000 feet above the ground and suddenly your whole perspective changes,” he said. “You realize there are all kinds of things going on down there, and it puts perspective on the things we spend all of our time worrying about. As Antoine de Saint-Exupéry expressed it, ‘I fly because it releases my mind from the tyranny of petty things.’”