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Prashant Nair Science Writer

As electrical signals course through brain Scheller: The major proteins in the com- cells, a stepwise process of information trans- plex have not really been implicated in any fer ensures that the signals are relayed across neurobiological disorders, but their functions junctions called synapses. Orchestrating the are so fundamental that their knockouts are process on either side of the synaptic gulf simply not viable. Tinkering with the proteins is a suite of proteins found on neuronal of the fusion machinery would not result in membranes and on tiny vesicles that ferry a viable brain. signaling molecules, called neurotransmitters, PNAS: After nearly two decades at Stan- across synapses. Beginning in the late 1980s, ford, where you carried out most of the neuroscientist Richard Scheller, now Execu- neurotransmission-related cloning and char- tive Vice-President of Research Administra- acterization, you moved to Genentech in tion at Genentech, identified several proteins 2001. What prompted the move? in the synaptic fusion complex, a byzantine Scheller: Most of the synaptic transmis- structure that mediates communication be- sion-related work was carried out at Stanford, tween neurons. Together with Stanford Uni- and it was a nice set of discoveries, but I versity neuroscientist Thomas Sudhof and thought that it was time to do something Richard Scheller. Image courtesy of cell biologist , else. The question then was what. I consid- Genentech Inc. who both shared the 2010 Kavli Prize with ered moving to other universities, but that him, Scheller helped unveil the mechanics of didn’t really make sense because my wife neurotransmission, a process central to sen- and I were both happy at Stanford. When PNAS: Among industry players, Genentech tience. For their contributions, Scheller and the opportunity at Genentech came up, I has often been lauded for its starkly aca- Sudhof were awarded the 2013 Albert Lasker thought it would be a way to apply the bi- demic approach to drug development, par- Basic Medical Research Award. To commem- ological intuition I had developed over 30 ticularly with regard to scientifically driven orate the honor, PNAS spoke with Scheller. years to medical problems. I was drawn to decision-making and willingness to back risky PNAS: In the late 1980s you identified the challenge of the learning experience. projects. In your view what is behind this VAMP (vesicle associated membrane pro- PNAS: At Genentech, you oversee re- characterization? tein), one of the first known protein compo- search and early development of drugs. Can Scheller: Ithinkit’sthecompany’shistory: nents of the synaptic machinery, in a marine you give our readers a couple of examples following the basic science, publishing high- ray. That discovery later revealed the me- of recent notable successes and failures? quality research more prolifically than many chanics of neurotransmission. Can you briefly Scheller: Early-stage drug development is other companies, and hosting a postdoctoral describe how you discovered the protein? a combination of success and failure, and it’s research program. Our postdocs are encour- Scheller: We had made a cDNA library often humbling to test molecules in people. aged to publish great research and to go out from the electromotor neurons of the Pacific We recently received approval for Erivedge, and get jobs in industry and academia. They electric ray (Torpedo californica)toisolate an inhibitor of the Hedgehog pathway, which don’t work only on translational projects but cDNAs encoding another protein called is mutated in 90% of basal cell carcinoma, on whatever is scientifically interesting to Agrin, which is involved in the development a skin cancer often treated by simply remov- them. Genentech has always tried to put sci- and maintenance of the neuromuscular junc- ing the lesions, unless the lesions grow and entific opportunities and unmet medical need tion. And others had developed antibodies become metastatic. The approval of this mol- ahead of commercial interests. That’showwe against proteins in synaptic vesicles. I thought ecule in the United States, and more recently make decisions on what projects to pursue I would use some of those antibodies to iso- in Europe, to treat the advanced forms of this and that’s part of the reason for our success. late DNA encoding proteins in the synaptic cancer, is a triumph for Genentech and the PNAS: From your vantage point at machinery using the cDNA expression li- result of years of work by a team led by Genentech, what are some of the most prom- brary, and then use molecular techniques to Frederic de Sauvage. On the flip side, we had ising therapeutic areas to watch for? unravel the functions of those proteins. We a program for an antibody against the oxi- Scheller: I’m particularly excited about on- did the screen, and the first clone we pulled dized form of LDL [low density lipoprotein, cology because of the huge amount of infor- out turned out to encode VAMP, which has which carries cholesterol in blood], which we mation gained from the cancer genome. sincebecomethefirst known vesicle-SNARE. thought might underlie some of the inflam- We now know most of the major mutated PNAS: Since the uncovering of the synap- mation in plaques related to heart disease. So oncogenes that drive tumor formation and tic fusion complex, our understanding of syn- we did a phase 2 trial of the antibody, but proliferation. Now we just have to develop aptic transmission has grown enormously. it failed to demonstrate any reduction in terrific therapeutics. Alzheimer’sdisease, But have any of the proteins in the fu- inflammation or plaque size. We halted the Crohn disease, asthma, and infectious dis- sion complex or their interacting partners trial. Clinical trials often serve as a reminder eases (such as drug-resistant Staphylococcus, been directly implicated in neurobiological that textbook versions of cellular pathways flu, and cytomegalovirus) are some of the disorders? might be oversimplifications of . other areas on our agenda.

www.pnas.org/cgi/doi/10.1073/pnas.1319727110 PNAS | December 10, 2013 | vol. 110 | no. 50 | 19973 Downloaded by guest on September 27, 2021