Pauli Lectures 2016

Dr. Rothman has received numerous awards and honors in recognition of his work, including the King Faisal International Prize for Science (1996), the Gairdner Foundation International Award (1996), the Lounsbery Award of the National Academy of Sciences (1997), the Heineken Foundation Prize of the Netherlands Academy of Sciences (2000), the Louisa Gross Horwitz prize of Columbia University (2002), the Lasker Basic Science Award (2002), the Kavli Prize for Neuroscience (2010), and the Nobel Prize for Physiology or Medicine (2013). He is a member of the National Academy of Sciences (1993) and its Institute of Medicine (1995), and a Fellow of the American Academy of Arts and Sciences (1994).

Society mainly values and funds the scientific enterprise because of the technologies that result, improving the economy and the quality of life, and expects return on its investment in the short term, certainly within one life span. Scientists mainly do science because of the basic understanding it creates and its beauty, independent of how much time is required. How societies manage this dichotomy – balancing urgency with patience - is a major determinant of their ability to innovate and prosper. In particular, meaningful technological advances – the kinds that benefit billions of people - generally requires the integrative convergence of several lines of basic science, often from different disciplines and over many years. Innovative cultures that foster this take many decades to establish, require substantial and consistent public funding, and yet are easy to destroy. These ideas will be illustrated by tracing the lines of basic discoveries over the past century that resulted in vast improvements in public health in our time. This involved notable scientific lineages especially in Germany and the United States, embedded within innovative scientific cultures that dramatically evolved in relation to historic events that destabilized Germanic science and transplanted the culture to America, where short term focus now threatens its existence. I will also offer some advice to young scientists based on this history and on my own experience on the importance of balancing patience and urgency at the individual level for success in science.

A chain of discoveries over the past half century has revealed the mechanism by which cells organize themselves internally. This process began in the 1950s with the discovery of numerous specialized membrane-bounded compartments within the cell using the electron microscope, and culminated with the discovery of the ability to reproduce these events in test tube systems. Tiny transport vesicles carry highly selected cargoes from one compartment to another providing an internal distribution system not unlike a postal service. The specificity of the localization of proteins within the cell is generated and maintained by these vesicles enable the cell to self-organize in three dimensions as it grows and divides. Related processes enable communication between cells in the body by releasing and receiving signals from hormones, growth factors, and neurotransmitters.

Neurotransmitters stored in synaptic vesicles at nerve endings are synchronously released in less than one millisecond after the action potential arrives and calcium ions secondarily enter the pre-synaptic cytoplasm. This is by far the fastest membrane fusion mechanism in nature, as is required for all thought and action. Yet, neurotransmission relies on the same SNAREpin zippering mechanism that powers more leisurely and less coherent hormone release and vesicle trafficking within the cell. How can the same molecular machine provide for such action on time scales differing by up to a factor of 10,000? Answers are emerging from mechanistic studies of the two key elements of synaptic regulatory machinery that together allow many SNAREpins to synchronize spatially and temporally. The calcium sensor, Synaptotagmin, assembles into rings that can impede fusion until they disassemble upon binding calcium ions. The rod-like Complexin molecule can organize two layers of SNAREpins into zig-zag arrays while at the same time impeding completion of zippering.