Nothing advances scientific knowledge more quickly than the interplay between deductive reasoning and good old-fashioned luck. While studying general features of the immune system, Frederick Alt, PhD, may have discovered the weapon to fight a very specific disease. His investigation of antibody construction fortuitously led him to develop a model for B-cell lymphomas, including Burkitt's lymphoma, a very aggressive cancer that normally strikes children, or adults without a functional immune system.
Organisms must fight infections from an enormous variety of continuously evolving chemicals in the body. An organism's genes could not have instructions for all possible antibodies needed to fight infection during a lifetime. Instead, organisms can reconfigure their own genes to create new antibodies. For genes to reconfigure, they must be cut, rearranged and reconnected. Dr. Alt and his team are investigating the mechanism underlying this process.
By eliminating the gene XRCC4 in mice, Alt found something very interesting. The first step of gene rearrangement was preserved; they were still able to cut their genes. However, the genes could not reconnect without the presence of XRCC4. The inability to reconnect left them unable to make antibodies and they ultimately succumbed to disease.
Mouse embryos that were lacking XRCC4 also died before birth because of extensive apoptosis, or cell suicide. In the developing nervous system, cells committed suicide when they detected major problems with the genome. The problem? The genes were getting cut, but were not rejoining in the necessary, or healthy, configuration required for survival. Alt's team reasoned that if they eliminated the signal used by the cells to jump off the proverbial ledge, the animals should survive. This signal is the tumor suppressor gene p53, which is mutated in almost half of all cancers.
The mice that have neither XRCC4 nor p53 survived through early development, as Alt had predicted. However, an additional finding showed that they quickly developed an aggressive B-cell cancer. Closer inspection revealed that the tumors were remarkably similar to Burkitt's lymphoma.
Alt's new model of lymphoma will shed light on this disease. He is currently looking to see if this model also will help in the study other types of tumors.