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School of Medicine
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Molecular Biology and Genetics
on balancing a diverse immune system and a stable genome
How are we able to develop a specific immune response specific to a wide variety of assaults, including those never seen before by our bodies?
DESIDERIO: Our antibodies are made from banks of gene segments called V, D and J. Those gene segments are mixed in various combinations and stitched together. This recombination happens in white blood cells in the bone marrow. Each blood cell that emerges from the marrow has a different receptor. These recombinations happen tens of millions of times a day, allowing for many, many combinations of different antibodies to be made and displayed on cells for the purpose of finding a match against a foreign substance.
How does the way we mount an immune response meld with natural selection: that change occurs over time?
DESIDERIO: Darwin wrote in the Origin of the Species of variation being the source of evolution by natural selection, without variation there was nothing upon which to select. But he viewed variation as something happening gradually. Of course, if we waited for gradual processes like the slow generation of variability in the face of an infection, we would die before an infection was countered. The immune system is illustrative of natural selection just as Darwin conceived of it with the only difference is it’s happening in a fast-forward way.
What big picture question does your research address?
DESIDERIO: Either before an immune response is made in the course of the immune response, the modifications that are made to DNA involve DNA cleavage that renders the genome unstable, unless that instability is checked by an efficient repair system. That problem, the balance between the diversification of the immune response and the need to maintain a stable genome, is the question that has occupied my lab for the better part of the last 10-15 years.
What have you found?
DESIDERIO: The recombination of the DNA segments that make antibodies is started by a pair of proteins called Rag1 and Rag2. We have a mutant mouse that lacks functional Rag2 and its immune cells accumulate DNA breaks throughout the cell cycle. In these mice cells die too frequently in the thymus, where the T lymphocyte cells are made.
How does that translate to human health?
DESIDERIO: If you prevent thymus cells from dying in mice lacking Rag2, the animals develop tumors in the lymph nodes. And when we look closer at the immune cells, these animals have complex chromosomal rearrangements that resemble the ones that happen in children with T cell acute lymphocytic leukemia.
--Interviewed by Vanessa McMains
Stephen Desiderio on how making antibodies is like a slot machine :