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The Simon lab has two areas of focus. One is pediatric cancer, for which their work runs the gamut from identifying oncogenic drivers and studying malignant transformation to coordinating clinical trials. The lab’s second endeavor is to examine individual events to gain insight into biological systems. Using imaging and other tools, these studies include the movement of individual cellular components and the activity of single nuclear pores and proteasomes.

The Simon lab 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 animal. In addition, it often makes it possible to detect alterations of single molecules that produce pathological changes in the whole animal. 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.

A major new initiative of the lab is on cancers affecting children and young adults. This work includes population studies in patients with fibrolamellar hepatocellular carcinoma, a type of liver cancer, aimed to identify the alterations in the genome responsible for tumorigenesis. The biophysical and imaging tools developed in the lab are being used to characterize the molecular dynamics of the oncogenic drivers, as well as cell-biological alterations. At the same time, the lab is designing diagnostics, identifying potential therapeutics, and organizing clinical trials.

Another part of the lab focuses on the study of individual events in cellular function. The study of populations, whether of molecules or people, provides important insights into biological processes. However, valuable information is lost when one examines the population average. For example, if a cellular machine exists in two discrete states, the macroscopic measure is the average of the two states. Such a measure has shortcomings: it may reflect activity states that do not exist at the individual level, miss transient active states, or make it difficult to put different steps in a proper temporal order and to resolve between two microscopic mechanisms. A microscopic approach, however, does not face these problems.

Single phenomena that Simon and his lab members have followed include individual vesicles docking and fusing to the membrane, single proteins translocating across the endoplasmic reticulum, and single cells metastasizing in the lung. They have also succeeded in imaging the birth of individual HIV particles, and a variety of events involved in 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 previous models has allowed lab members to formulate new ones: 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.

Another key area of research in the lab is to develop new technologies that can improve the spatial or temporal resolution of images obtained through microscopes or other modalities. Simon and his colleagues are working to improve the sensitivity of the imaging systems they use so that molecules can be followed for longer time periods, and they are developing new reporters that can follow biological processes and act as actuators for these processes.