Randy W. Schekman, PhD

Professor of Cell and Developmental Biology
Howard Hughes Medical Institute Investigator
University of California, Berkeley

Randy Schekman has been called one of the founding fathers of modern cell biology, and many of the basic “rules” that govern this discipline and that are now taken for granted were established through the work of the Schekman lab. It’s difficult to imagine a time when it appeared impossible to dissect the molecular machines that control the shape and growth of cells and the transport of proteins within cells, but Schekman spearheaded the development of novel biochemical assays and genetic screens, primarily using a model eukaryote, the yeast Saccharomyces cerevisiae. This marriage of biochemistry and genetics allowed Schekman and his colleagues to characterize the multi-protein complexes that engineer protein and lipid trafficking.

Before Schekman’s pioneering work, the state-of-the-art technique in cell biology was electron microscopy. Not surprisingly, the cell was defined then as a complex yet ordered array of intracellular membranes, compartments, vesicles, cytoskeletal elements, and ribosomes. The continuous movement of each cellular component was shrouded by this “static” view. The research challenge was to define how cellular architecture was established and how materials like proteins and lipids were exchanged between each compartment.

To tackle this problem, Schekman developed several ingenious assays. Among the seminal advances made by his lab were the following:

• The development of a novel yeast screen that led to the identification of most of the components required to select and then move proteins from one cellular compartment to another. All of these components are conserved between yeast and humans, and several are altered in human diseases.
• The development of a novel yeast screen to identify components that engineer the transport of proteins across membranes after their synthesis on ribosomes. These components are also conserved, and their identification has helped to elucidate how disease-causing proteins are recognized and handled in the cell.
• The development of biochemical assays in which protein and lipid transport could be recapitulated. By employing either wild type (normal) or mutant (defective) components from yeast, the function of each corresponding component could be defined.
• The development of genetic and morphological tools that elucidated how groups of isolated factors work together and where they function in the cell. Specifically, electron microscopy techniques were improved and then co-opted to uncover how the ablation of specific genes—and combinations of genes—affects the structure of cellular compartments.
• The development of biochemical systems in which the functions of specific compartments from human cells could be analyzed for their impact on protein transport.

These pursuits have resulted in the publication of more than 220 papers, many in leading scientific journals. More importantly, Schekman’s assays and systems have allowed researchers to “see” in the test tube how material could be exchanged between cellular compartments and then to isolate and characterize the factors that catalyze those steps. Because nearly all of the factors are encoded by genes that are highly conserved, the pioneering work by Schekman and colleagues has led to efforts to develop the same tools in mammalian cells. As a result, it is nearly impossible to attend a large meeting in cell biology, biochemistry, genetics, or molecular biology and not hear someone mention a homolog of one of the genes discovered by the Schekman lab.