Heads of Laboratories
Professor
Laboratory of Cellular Biophysics
simon@rockefeller.edu
Cells and their organelles are each enveloped by a permeable membrane, and how molecules cross this membrane and are shuttled to the correct place within the cell is of immense interest in multiple fields of biology. Dr. Simon studies the organization of living cells, with emphasis on the mechanisms that control the compartmentalization of cellular components.
Membranes that form the exterior of cellular organelles must serve as an effective seawall, separating the organelle from the surrounding cytosol. But since no organelle is entirely self-sufficient, the membrane must also allow the entry and exit of various ions, sugars, nucleotides and proteins. Dr. Simon is interested in the principles that govern how these macromolecules cross cellular membranes, and in the physiological and pathological consequences of proper and improper compartmentalization. The cellular compartmentalization processes studied in his lab include protein translocation across the endoplasmic reticulum, exocytosis and endocytosis at the eukaryotic cell surface, transport of molecules through the nuclear membrane, entry of viruses into cells and assembly of viruses at the cell surface. The lab is studying the dynamics involved within each of these systems, looking to understand how they allow transport without compromising the membrane’s integrity as a permeability barrier.
The lab also studies the physiological consequences of these transport phenomena to understand how the regulation of a particular endocytic or exocytic pathway affects cell growth, polarity and migration. Then, by examining the physiology of these processes in living organisms, they hope to determine how localized secretion, or localized proteins or lipids, affects the migration of a stem cell or a tumor cell or the development of polarity in a living mammal. Protein transport is a fundamental cellular process that is essential for secretion, intercellular communication and organelle biogenesis, and observations from the Simon lab have numerous clinical implications. Dr. Simon’s studies on the biogenesis of opsin have characterized the etiology of some forms of progressive blindness, and one of the transporters they are studying moves peptides for antigen presentation.
Dr. Simon puts a strong emphasis on imaging as a means of studying biological processes. Imaging can bridge many scales of analysis, from visualizing the steps of single molecular motors on the scale of a few nanometers to mapping the activity in the cerebral cortex on a millimeter-by-millimeter basis. The lab uses imaging to study physiological as well as pathological processes that involve dysfunctions at the molecular level and that are observed as disease on the systemic level. Optical imaging allows the individual pathological processes to be examined at the level of single molecules, at the level of individual organelles, at the level of single cells, at the level of cellular systems and at the level of whole organs. Members of Dr. Simon’s lab also use imaging to study biological processes in living cells that are lost when a cell is fixed or homogenized. Further, they are imaging the dynamics of molecules in real time and using the results to discern variations in a biological system.
The ability to follow single events has allowed Dr. Simon and his lab members to follow individual vesicles as they dock and fuse to the membrane, individual endosomes as they form, single proteins as they translocate across the endoplasmic reticulum and single cells as they metastasize in the lung. The sensitivity afforded by these imaging studies has also allowed them to critically test, and in some cases eliminate, models that had been proposed for biological mechanisms. The ability to test — and at times negate — models has driven lab members to formulate new models, including the first ones to propose localized calcium transients in cells and the first models to suggest that protein movement in the cell may be driven by a Brownian ratchet.
A key area of research in the Simon lab is in developing new technologies that can improve the spatial or temporal resolution of images obtained through microscopes and other modalities. Dr. Simon and his colleagues are working to improve the sensitivity of the imaging systems they use so that molecules can be followed for longer periods of time, and to develop new reporters that can follow biological processes and act as actuators for these processes.
CAREER
Dr. Simon graduated with a bachelor’s degree in neurobiology from Princeton University in 1977. He received his Ph.D. in physiology
and biophysics in 1984 from New York University Medical Center, where he studied with Rodolfo Llinás. He came to
Rockefeller as a postdoc in Günter Blobel’s lab and was promoted to research associate in 1986. He was named assistant professor
in 1989, head of the Laboratory of Cellular Biophysics in 1992, associate professor in 1994 and professor in 2000. Dr. Simon was a
2004 recipient of the John and Samuel Bard Award in Medicine and Science.
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