On the sorting of proteins to compartmentalize the cell – The story of three Nobel Prizes from a modern perspective

1This lecture is intended for a broad scientific community as well as the general public. 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.

On the logic of the Golgi Apparatus – Continuous purification of proteins in the cell

2All eukaryotic cells have a Golgi apparatus, consisting of a series of stacked membrane-bounded compartments (termed cisternae). The Golgi apparatus plays a central role in the processing and distribution of newly synthesized proteins. The purpose of the stack-like morphology has long been a mystery. In this lecture I will develop the idea, first proposed in the 1980s, that the stack carries out a process of protein purification, separating proteins destined to remain in the endoplasmic reticulum (and the Golgi itself) from other locations. In this process of iterative protein sorting, the same purification process occurs sequentially at each level of the stack, resulting in high overall efficiencies. The cisternae function as if they were plates in a distillation tower in solvent separations. The details of the process are still debated. Retrograde flow is mediated by typical transport vesicles. Anterograde flow may be mediated by movement of intact cisternae or by vesicle-like carriers. Recent evidence emerging from synthetic biology – in which we have deliberately altered the adhesive properties of the cisternae to each other and to other organelles – will be presented.

On the structural biochemical mechanism of synaptic neurotransmission in the brain

3Neurotransmitters 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.

On the role of scientific research in society, and lessons learned from a life in science

4This lecture is intended for the general public and also the broad scientific community. 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.