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Randy Schekman: A passion for yeast

   
Randy W. Schekman
Randy W. Schekman, professor of molecular and cell biology at UC Berkeley and an investigator in the Howard Hughes Medical Institute

Randy Schekman's passion for science began in a southern California junior high school, where he first saw older students creating science fair projects. He was hooked.

"Starting in 8th grade and all the way through high school, that was my one outlet. The whole year was geared around doing some project for display," said Schekman, 53, professor of molecular and cell biology and a member of UC Berkeley's Health Sciences Initiative — a group of several hundred researchers from many disciplines working together to advance health care in the 21st century.

Born in St. Paul, Minn., in 1948, Schekman moved with his family in 1960 to a suburban development called Rossmoor in Orange Co., where he attended Western High School in Anaheim, the school from which golfer Tiger Woods would one day graduate.

Nurtured along by his biology teacher, he accumulated medals, trophies and even money at school and regional competitions and at the California State Science Fair, to which he advanced three times in high school. Upon graduation in 1966, he was one of a mere dozen or so students in his class of 650 to go on to college. His destination was UCLA, far enough away that his mother was afraid the family couldn't afford his commute. He enrolled anyway, as a premed student.

Exposure to research in his freshman year confirmed his passion for science. It also gave him the guidance he needed, as did James Watson, discoverer of the structure of DNA.

"Watson's book, called 'Molecular Biology of the Gene,' was my bible in my freshman year," he said. "One of the really amazing experiences I had in my sophomore year was (reading) Watson's autobiography, 'The Double Helix.' When it came out in 1967, it was serialized in the Atlantic Monthly, and I remember running to the library to pick up copies of the magazine to read it all night. Not that I ever expected to make discoveries like that or to act like that — but that one could actually plumb the depths of nature with intellect and intuition and work was a revelation."

He got a true taste of cutting-edge scientific research in a UCLA lab where he studied DNA replication, that is, how genetic material is copied in preparation for cell division. This interest led him to shoot for the top —graduate work in the molecular biology hotbed at Stanford University and the lab of renowned biochemist Arthur Kornberg.

"Kornberg was the master of DNA replication, and I decided that was what I really needed to do, go learn biochemistry from the master," Schekman said.

He was successful, moving north in 1970 to a whole new world.

"The ferment in that department was unbelievable – for DNA work, it was the center of the universe," he said.

While Schekman was purifying enzymes involved in chromosome replication, Stanford professor Paul Berg in 1972 created the first recombinant DNA by snipping and recombining segments from two different viruses. A year later, Stanford colleague Stanley Cohen teamed up with UC San Francisco professor Herbert Boyer to insert recombinant DNA into bacteria that could be cloned — a discovery that launched the genetic engineering revolution and the first company to exploit the technology to make pharmaceuticals, Genentech.

"I learned a great deal, not just about biochemistry or DNA, but how to look at a problem, how to take it apart and put it back together, how to focus on things," said Schekman. "It really set the stage for me. Focus, in particular, was critical to my work, and I learned that from Kornberg."

But the atmosphere in Kornberg's lab was highly competitive and the field of DNA replication contentious. So, Schekman found a less competitive niche at UC San Diego, where he spent two postdoctoral years with John Singer studying cell membranes. Singer was doing groundbreaking work with electron microscopy to study the membranes or outer shells of mammal cells, but Schekman was frustrated at the lack of tools to manipulate these cells. Used to the many tools available to study bacteria, he decided to focus on another easy-to-grow microbe, baker's yeast, in hopes that combining genetics and biochemistry would lead to an understanding of the machinery of secretion.

Thrilled to be offered a position as assistant professor of biochemistry at UC Berkeley in 1976, he left bacteria and mammalian cells behind to focus on yeast genetics. Unfortunately, while mammal cells bustle with transport vesicles which are easy to see with a microscope, yeast seemed to have less activity that was harder to see. It's well known that yeast exude alcohol through their membranes, but it wasn't clear how they secrete proteins.

Given Schekman's lack of experience with yeast and the question of whether secretion in yeast would apply to humans, his first grant application was turned down. But Schekman had faith, and has since proven the early doubters wrong.

budding yeast
Yeast cells grow a bud as protein-filled vesicles shuttle to the surface and merge with the cell membrane, at the same time releasing their cargo of protein.

The key insight by Schekman and graduate student Peter Novick, now a professor at Yale University, was that the best way to track down genes involved in the secretion pathway was to look for mutant yeast that die, since the pathway is critical to the life of the cell. To find strains to raise and study, they looked for those that survived at low temperatures but died at higher temperatures, around body temperature.

"When I first came here, I had no plans to be a geneticist. I was a biochemist," said Schekman. "But I found it was the most tractable way to begin. Define the process using genetics, then use the genetics to bootstrap into the molecular work. That was the game plan."

With this approach, he eventually found and identified nearly 50 genes involved in the secretion pathway of yeast. These govern every step from the formation of vesicles and selection of proteins in the endoplasmic reticulum — an internal "corral" for chemicals the cell doesn't want to mix with the rest of the cell's contents — to their transport along the rail system of the cell to the Golgi and then to the cell surface, expelling proteins and growing the membrane so the cell eventually can bud daughter cells. The work of Schekman and Rothman, who was looking for proteins involved in secretion by mammalian cells, soon began to complement one another, and it became clear that yeast and humans secrete proteins using much the same machinery.

scaffold protein complex
Proteins form a scaffold around a section of the cell's endoplasmic reticulum, recruiting cargo proteins (red triangles) destined for the cell surface. The scaffold protein complex, called COPII, warps the membrane surface until it pinches off into a vesicle.

One important finding was that a complex of three proteins must glom onto the surface of the endoplasmic reticulum before the membrane can bud to form transport vesicles. Thousands of these complexes, dubbed COPII, coat the budding surface, deforming it into a sac and also recruiting the correct protein cargo. Schekman and his UC Berkeley students proved this by creating artificial membranes, liposomes, in a test tube and coating them with COPII. Given an energy boost, the liposomes budded "with the same high efficiency and fidelity we have with yeast," he said.

Recent findings about Alzheimer's disease hint that some patients may have a problem with this secretion pathway. A protein called amyloid precursor protein is normally rounded up in the endoplasmic reticulum and packaged for transport to the cell surface. A hitch in the machinery makes the protein susceptible to an enzyme that clips it to produce amyloid, a nonbiodegradable protein that accumulates until the cell is so overloaded it dies. Schekman is investigating this lead in hopes of finding a way to prevent amyloid production.

Interestingly, a rare form of hemophilia — factor-5, factor-8 deficiency — may also result from a defect in the packaging machinery. Patients with this form of the disease have low levels of two different clotting factors, making a simple cut a life-threatening bleed. In 70 percent of these patients, the clotting factor membrane receptor that COPII binds to is defective and interferes with the secretion of these two clotting factors.

Even Type II diabetes, once known as adult-onset diabetes, can involve problems with secretion. Normally, insulin stimulates cells to take in glucose through specialized glucose channels that, like all cell surface proteins, are transported to the surface aboard membrane vesicles. Some patients don't respond to insulin because they have too few glucose channels, and the problem may be a bottleneck in the packaging of channels into vesicles for their trip to the surface. The challenge, Schekman said, is to find a therapeutic intervention that will bypass the normal process and stimulate the discharge of the internal reservoir of glucose channels so the cell can respond normally.

Since mobilization of glucose channels by insulin is hard to study in human cells, Schekman has begun to study regulated transport in yeast instead. The model he is looking at involves how stress triggers the release of enzymes that make the cell wall more rigid, using the same molecule, chitin, that insects have adapted for their hard exoskeletons.

Schekman admits that his once isolated research niche is now crowded, in part because his research opened up many new avenues for exploration. Although he can't pursue them all, he's grateful many of his students can.

His children won't be following that path, though. Both are musically inclined, reflecting Schekman and his wife, Nancy Walls', interest in classical music and opera. Joel is now a graduate student at the University of Southern California, a classical musician studying clarinet. Schekman's daughter, Lauren, is a junior majoring in economics at UC Berkeley.

"I've had a wonderful time here at Cal, but the high point of my 27 years was when she was admitted as a student. Even more so, when I had the opportunity as a proud father to tour the campus with her on Cal Day 2000. I was in 7th heaven."

He looks back with nostalgia at the trials he's weathered at UC Berkeley, among them the cramped lab space in deteriorating Barker Hall and his current relocation to Stanley Hall, itself slated for demolition.

"That's why I love this place. You come here and have to fight for what you get," he said. "That's the real world, and that's why I think this place is such a valuable experience. If you can make it here, you can make it anywhere."

— Robert Sanders

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