Sachs 9532055 The investigator models chromosome aberrations in live mammalian cells, emphasizing implications for large-scale chromosome geometry and for the biology of ionizing radiation damage. He analyzes formation of chromosome aberrations after induction of DNA double strand breaks by radiation during the interphase part of the cell cycle, using probabilistic models for DNA geometry, motion, and reactions at the macromolecular level. For example, one area concerns the combinatorics and kinetics of illegitimate recombinations, involving the exchange of fragments between several different chromosomes. Polymer models are used for large-scale chromosome structure and motion. Statistical questions arise when very detailed experimental information about specific individual chromosomes is made available by modern fluorescent in situ hybridization techniques; these he addresses by extending already developed Monte-Carlo simulations. The study involves developing computer algorithms, explicitly solving stochastic process models, and collaborating with experimental groups. Ionizing radiation damage to chromosomes is being studied mathematically. When ionizing radiation hits cells, as occurs for example in tumor radiotherapy or radiation accidents, one gets breakage and large-scale reshuffling of DNA molecules. The resulting chromosome aberrations have been implicated as symptoms or causes of most major radiobiological effects. They are especially important in biodosimetry, the estimation of past exposure to radiation dose by looking at residual cellular damage. They are also a window on fundamental biology because they are influenced by, and symptomatic of, chromosome geometry and motion. Recent developments, whereby specific human chromosomes can be "painted" different colors, have dramatically increased the amount of information obtained from aberration studies. A very rich and colorful variety of aberrations can now be observed. Trying to und erstand the number and kind of reshufflings one sees leads to mathematically nontrivial problems, amenable to computer simulations or "pen and paper" calculations. The simulations and calculations are being carried out under the grant. The results allow systematic comparisons of cellular radiation damage effects observed by different laboratories using different chromosome painting schemes. In addition, mechanistic modeling of how chromosome aberrations evolve in time is helping to attack the main mystery of radiobiology: how to extrapolate from the larger doses needed for statistically significant experimental results to the much smaller doses relevant to risk estimates for large human populations subjected to radiation from environmental or man-made sources.
