Tom Doetschman: Mice as mirrors of what ails us

For most bioscientists, a slice of Nobel Prize fame would be a very big deal. For Tom Doetschman of The University of Arizona (UA), it is minor compared to his new goal: helping prevent colon cancer.

Asked about his role in the 2007 Nobel Prize, Doetschman says drily, “I got mentioned.” Then he adds, “Those were heady days.”

But these days, he has high hopes for the UA’s “knockout mouse” program, which he founded and which has already achieved global prominence in the field that was honored with that Nobel Prize in medicine. It is a UA core facility, called Genetically Engineered Mouse Models, or GEMM Core.

GEMM Core allows biomedical researchers worldwide study any one human gene by observing mice with an engineered mutation in that gene.

In fact, the Nobel award cited a paper he coauthored with one of the three winners, Oliver Smithies, PhD. In the 1980s, he wrote about his own part: successfully correcting a defective allele of a mouse gene with a big name: hypoxanthine-guanine phosphoribosyl transferase, or HPRT, a gene that is defective in children with the Lesch-Nyhan syndrome.

Since then, about half of the 30,000 or so mouse genes have been targeted, making possible great leaps of biomedical research. Today labs can modify a gene in many ways—correction, mutation, deletion, humanization and more. Mouse models mirror human heart disease, cancer, sickle cell anemia, diabetes and cystic fibrosis, says Doetschman, a professor in the College of Medicine and a BIO5 member since 2006.

Looking back, he says he was lucky in several ways. He credits his doctorate adviser at the University of Connecticut, Professor Heinz Herrmann, with planting a seed of curiosity about complexity that has guided him in three decades as a bioscience pioneer.

Doetschman came to Arizona after 18 years at the University of Cincinnati, where he was a national leader in genetically engineering mouse models. His Cincinnati lab had made “knockout mice” for 300 genes by the time he joined the UA.

His introduction to the field came in its earliest years, with work on mouse embryonic stem cells, or ES cells, as a postdoctoral fellow at a Max Plank Institute in Tubingen, Germany.

“We demonstrated that you could put a gene into a mouse ES cell, and make a mouse from that cell,” he recalls. “The gene was stable through multiple generations.”

Doetschman worked with gene targeting in the Human Genetics Department at the University of Wisconsin, correcting a mutant gene, and then helping with the creation of a new mouse strain with that corrected gene. Both of those studies were cited in the 2007 Nobel Prize.

At Wisconsin, Doetschman was the first researcher to make ES cells from hamsters, a breakthrough that added a second species from which ES cells could be made. Years later, others have made ES cells from human tissue.

At Cincinnati and now the UA, he returned to a question from his graduate school days in Connecticut: complexity. There, Professor Herrmann challenged him to tackle the complexity within problems, in science and society. “That has really stuck with me over the years,” he says.

Now, he uses gene targeting technology to study some of the most complex genes around, ones called Transforming Growth Factor beta genes. They play a still-mysterious role in diseases like colon cancer, autoimmune disease and congenital heart defects, and he says that mice with mutations in those genes are helping him to sort out those mysteries.

At his BIO5 lab, he says he has the chance to ask, what does this gene do? “And not in a plastic dish, but within the complexity of the living animal,” he says. The seed planted decades earlier by his Connecticut professor flourishes.

“My dreams have come true,” he says.

Accomplishments

Tom Doetschman has helped shape the field of mouse genetic engineering, a technology honored with a 2007 Nobel Prize. At the UA, his current focus is colon cancer, autoimmune disease and heart disease.

Doetschman, a professor since 2006 in the College of Medicine and a BIO5 member, founded the UA’s “knockout mouse” program, a widely recognized core facility called the Genetically Engineered Mouse Models, or GEMM Core, which makes genetically engineered mouse strains for biomedical researchers.

Doetschman came to the UA from the University of Cincinnati, bringing his renowned Genetically Engineered Mouse Models program. Two years ago, the National Institutes of Health began funding the “knockout” of every gene in the mouse genome—30,000 in all. Doetschman’s lab in Cincinnati was responsible for generating knockout mouse strains for more than 300 of them before he came to Arizona where he continues that work as a service to researchers worldwide.

In the mid-1980s he worked with one of the three winners of the 2007 Nobel Prize for medicine, Oliver Smithies. They won for developing the “knockout” mouse model technique. While in Smithies' laboratory, Doetschman published two papers that played a significant role in the award. The Nobel award cited Doetschman’s successful targeted correction of a defective allele of a gene called hypoxanthine-guanine phosphoribosyl transferase, or HPRT, a gene which when defective in humans results in the neurological disorder Lesch-Nyhan syndrome.

Heinz Herrmann’s book on complexity:
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