Later, as a postdoc with Jon Singer at the University of California, San Diego, Schekman studied membrane biology but felt squeezed by the experimental limitations of mammalian cells. When he set up his own lab, he decided he would exploit the power of yeast genetics to unearth the molecular players in membrane assembly.

By 1976, when Schekman joined Berkeley, scientists knew that membrane-bound containers called vesicles ferry proteins among cellular compartments. They had seen vesicles bubble from the surface of one compartment, detach, and float off to fuse with another—and they had established that different types of vesicles shuttle distinct protein cargo to specific sites. For example, secreted proteins—those the cell exports to its surroundings—travel from a compartment called the endoplasmic reticulum (ER) to the cell surface by way of a structure called the Golgi apparatus. Schekman wanted to know how transport vesicles form, choose their protein cargo, and home in on their destinations.

Reviewers trashed Schekman's first proposal. “He was not a geneticist, he had never worked with yeast in his life, and he had no preliminary data,” says David Sabatini of New York University School of Medicine, who served on the National Institutes of Health study section that evaluated Schekman's request.

Yet he persevered, with funding from the National Science Foundation. He had “incredible optimism and a can-do spirit,” says Peter Novick, one of Schekman's first graduate students, now at Yale University School of Medicine. Novick and Schekman triumphed, identifying 23 so-called SEC genes involved in protein secretion.

Even then, intellectual sparks flew in the lab, recalls Susan Ferro-Novick, another former Schekman student, now an HHMI investigator at Yale University School of Medicine (and married to Peter Novick). “Randy would build these models and we thought 'Oh no, it can't be that way.' And then we'd have debates. Or he'd encourage us to do experiments that seemed crazy. But they got us started.”

With Schekman's projects, “you weren't just filling in facts,” says Ferro-Novick. “You had to make leaps. He made it clear that science was not easy and you had to rise to the challenge. I learned how to be a scientist in his lab.” Ferro-Novick is one of three former graduate students from the Schekman lab who are now HHMI investigators.

Schekman's discoveries about yeast secretion dovetailed with findings that James Rothman of Columbia University was making in mammalian cells. The two researchers leapfrogged over each other to establish key features of many protein-trafficking steps.

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