The Simon lab has two areas of focus: The first, pediatric cancer, includes work to identify drivers for the disease, as well as therapeutic blockers. The second examines individual events as a means of gaining insight into biological systems. Using imaging and other tools, these investigations include studies of the movement of individual cellular components, the activity of single nuclear pore and proteasomes, and the assembly of single viruses.
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 animal and, often, to detect alternations 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 to understand the effects of individual genomic changes on the behavior of cells during tumorigenesis. The goal is to understand how a single change in a cell results in cancer. The work includes population studies on patients with a pediatric liver cancer, fibrolamellar hepatocellular carcinoma, identifying the alterations in the genome responsible for tumorigenesis, characterizing the molecular pathology, identifying potential therapeutics, and designing 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 — information that is retained when one studies individuals. 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 does not face these problems.
Single phenomenon Dr. Simon and his lab members have followed include individual vesicles as they dock and fuse to the membrane, 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 allowed 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.