It began with genetic mutants: The research of new Nobel laureate Randy Schekman

October 28, 2013

These “How and Why” columns are usually descriptions of how things in nature work, such as what gives a flower its scent. Sometimes they explain technology, such as why you can’t run high-speed trains on ordinary track.

This will be a sort of meta-How and Why about how and why the researchers who appear in the column do the work they do. How do they decide which questions to study? How do they know which research methods to apply? Do they have the whole process planned out, or do their findings usually send them in entirely new directions?

There’s no better person to explore these questions than Randy Schekman, a professor at the University of California at Berkeley, who was among the three scientists awarded this year’s Nobel Prize in physiology or medicine for their insights into the machinery that regulates the transport and secretion of proteins in our cells.

How did Schekman, 64, choose this field of study?

He credits the availability of affordable public education with launching his career. His family could not have afforded private school tuition, he says, and Schekman hopes to use his Nobel publicity to revive interest in public education.

Randy Schekman credits the availability of affordable public education with the launch of his scientific career. (UC BERKELEY/EPA)

In the late 1960s, Schekman was assigned to a research laboratory in the University of California system, where one of his mentors handed him the “Molecular Biology of the Gene.” Written by James Watson, the co-discoverer of DNA, the book inspired Schekman to pursue the genetic basis of cellular functions.

“Our cells engage in protein production, and many of those proteins are enzymes responsible for the chemistry of life,” says Schekman. “About 10 percent, on average, are specialized for export from the cell. They are packaged and encapsulated in vesicles, and they travel to the cell perimeter where they fuse to the cell membrane, which allows the proteins to be secreted to the cell exterior.” These proteins make possible the processes that sustain human life.

By the time Schekman came along, biologists had long since worked out the basic processes of cellular transport, with materials carried to the cell membrane, fusing, then passing to the outside. But no one had nailed down how genes coordinated the process.

Schekman was a convert to Watson’s idea about how cells work. He looked deeper, at the smaller molecules that governed the cell’s behavior. Watson’s work took biology by storm, and Schekman was swept up in it.

Schekman decided that the best strategy would be to first identify those that don’t work: to create “mistake” cells in which proteins can’t make it to the surrounding environment. His first idea was to use chemical inhibitors. According to Schekman, the attempt was a total failure. Then he had the idea that would one day earn him a Nobel Prize.

“When I was a postdoc, I jotted every fresh thought on a three-by-five card and kept them in a card catalogue,” Schekman recalls. “There was one card that said ‘yeast secretion mutants.’”

Creating these mutants is pretty simple. Schekman and his graduate student Peter Novick — who Schekman feels should have shared the Nobel with him — used chemicals to create random genetic mutations in baker’s yeast cells. They suspected that the genetic mutants that suffered from cellular transport problems might be able to survive at room temperature, just like non-mutant cells, so they applied heat to identify the mutant cells, which were too compromised to handle the stress. Within the first 100 trials, using little more than petri dishes and toothpicks, they had identified two genetic mutations that caused proteins that were supposed to be secreted to instead build up within the cell — a clear indication that the cellular transport system had been undermined.

“We knew we had found a golden vein of information,” Schekman says, “so we reorganized the lab to focus on the process. It ended up being straightforward, and the research went swimmingly well.”

“Swimmingly well” is a relative term: The process took more than a decade. Schekman identified his first secretion mutants in 1977 and 1978. By 1980, the team had found 23 genes involved in the process. An important gene they had previously missed was identified in 1987. Even today, there may still be unidentified genes involved in the process.

I asked Schekman whether, at the time he made his first mutants, he had any potential applications in mind.

“I was driven completely by a desire to understand how cells worked. The implications of the research never entered my mind,” he insisted.

I repeated the question three or four different ways, because this seemed to hard to believe, but Schekman insists he never considered using the information for medicine or financial gain. In fact, he missed an opportunity to make a tidy profit by patenting some portion of his discovery.

Shortly after Schekman’s discoveries, the biopharmaceutical company Chiron took genes from the virus hepatitis B and inserted them into a yeast cell. The resulting cell produced the same proteins that appeared on the surface of the virus, but they lacked the properties that made the virus dangerous. The process became the basis for the largest hepatitis B vaccine in the world.

There’s also an application of Schekman’s work that’s far more familiar to the average American. By implanting a human gene into a yeast cell, biotech engineers have commandeered yeast to manufacture a large portion of the world’s insulin.

That’s the story of how and why Schekman began studying cellular transport and eventually went on to win the world’s most prestigious science prize.

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