Heads of Laboratories
Sanford M. Simon, Ph.D.
Laboratory of Cellular Biophysics
The Simon lab studies individual events as a way of gaining insight into biological systems. Using primarily biophysical tools with a heavy emphasis on imaging, lab members examine the movement of single proteins in the cell, single proteins and toxins as they cross membranes, assembly of single viruses, transport of single vesicles, single mitochondria and single cells during apoptosis, and metastasis of single tumor cells through the body.
Why imaging? Dr. Simon uses imaging techniques to observe and clarify dynamics and interactions in living systems. Imaging enables his group to study molecules in isolation, in the living cell or in the living animal and, often, to detect alternations of single molecules that produce pathological changes in the whole animal by allowing studies in both spatial scales. Imaging single molecules or cells provides the means to report not only the average behavior of populations, but also the diversity of their individual behaviors.
Why study individuals? Dr. Simon also focuses on individual entities and events. The study of populations (whether populations of molecules, cells or people) has provided important insights into many biological processes. However, sometimes valuable information is lost when one examines the average of a population — information that is retained when one studies individuals. For example, if a cellular machine exists in two discrete states, the macroscopic measure will give the average of the two states. But such a measure has several shortcomings, according to Dr. Simon. First, the averaged (macroscopic) measure may reflect an activity state that does not exist at the level of the individual. Second, often in biology the active state is transient. Macroscopic measurements report the average and therefore miss out on these transients; short-lived but functionally significant states can be detected and studied by examining individuals. Third, macroscopic measurements can make it difficult to put the different steps in a proper temporal order. On a macroscopic level this can be addressed by synchronizing a system. However, as it progresses through subsequent steps, the relative temporal ordering is lost. At the single-molecule level the temporal order is unambiguous. Fourth, at a macroscopic level it is often impossible to resolve between two microscopic mechanisms that can be resolved by studying single molecules.
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. They have also succeeded in imaging the birth of individual HIV particles and a variety of events involved with apoptosis. The sensitivity afforded by these imaging studies has 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: They were the first to propose localized calcium transients in cells and the first 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.
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 LlinaÅLs. He came to Rockefeller as a postdoc in GŁnter 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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