Pittsburgh - The program announcement for Mario Capecchi's lecture last Friday at the University of Pittsburgh mentions his "numerous awards, including the Albert Lasker Award for Basic Medical Research and the National Medal of Science."

But Capecchi's latest and greatest - the Nobel Prize in Medicine or Physiology, which he shared last week with Sir Martin Evans and Oliver Smithies "for their discoveries of principles for introducing specific gene modifications in mice by the use of embryonic stem cells" - had to be literally tacked onto the program, in the form of a golden sticker on the front.

Capecchi, distinguished professor of human genetics and biology at the University of Utah, gave a plenary talk on "Modeling Human Disease in the Mouse: From Cancer to Neuropsychiatric Disorders" at the Science2007 conference, an annual meeting organized by the University of Pittsburgh Medical School.

Extreme specialization is characteristic of modern science, and so the striking thing about the knockout mouse is that it is not specialized at all. It is the workmouse of biotechnology, and its influence is such that the Nobel Prize committee said that "gene targeting has now been used by so many research groups and in so many contexts that it is impossible to make a brief summary of the results."

And it seems like Capecchi is similarly catholic in his interests. He has, of course, long since moved on from the knockout mouse, which could be considered a new technology as much as a scientific discovery; and at Science2007, he reported on three different projects in his laboratory that range from cancer to neuropsychiatric disorders.

After his talk, Capecchi told BioWorld Today that the three projects, as wide-ranging as they may be, still represent only a small part of the scientific areas his group is involved in. But, he said, "I'm curious about many different things."

The first two projects he introduced were related. Both dealt with the molecular origins of rare cancers, alveolar rhabdomyosarcoma and synovial sarcoma. And in both cases, Capecchi used his knockout mouse technology to determine likely molecular causes of those cancers.

He found that in the case of synovial sarcoma, though the cancer itself forms near joints, the malignant tissue is not itself derived from joint tissue. Instead, what appears to happen in synovial sarcoma is that muscle cells with transformations appear to be able to turn into tumors due to prosurvival factors that may be secreted by bone or cartilage. Capecchi said his group now is working on identifying such factors.

More generally, his group's work showed that translocations could play a role in diseases other than cancer. Translocations occur when two chromosomes break and are joined together. The Philadelphia chromosome, a translocation that produces the bcr-abl kinase, is at the root of chronic myelogenous leukemia, and targeted by Gleevec.

But when Capecchi's group tried to mimic the translocation that is seen in human synovial sarcomas, his mice did not develop cancer. Instead, they developed gradual and severe myopathy, or muscle wasting.

Capecchi said that from a pure statistics standpoint, it makes sense that translocations could be involved in other diseases besides cancer. They occur in about one out of every thousand cells. "We have, in our lifetime, about 10 to the 17th cells, and therefore, we probably have about 10 to the 14th [or a hundred trillion] translocation events," he told the audience. So translocations could well be giving rise to other things than cancers.

His work on alveolar rhabdomyosarcoma, too, has implications for basic cancer mechanisms. The muscle cancer occurs when there is a chromosomal translocation that rearranges a transcription factor with a likely tumor suppressor gene. Trying to model that cancer, Capecchi's group found that for mice that develop cancer, the mutation had to occur in adult cells. Manipulating muscle precursors had other effects, but did not cause the animals to develop cancer.

"Right now, there is an enormous investment in stem cells and how they cause cancer," Capecchi told the audience. But his group's work on alveolar rhabdomyosarcoma suggested that investment will not result in equal payoffs for all cancers. "This particular cancer starts out with fully differentiated cells," he noted.

Capecchi demonstrated his wide-ranging interests by ending his talk with a complete switch of gears, describing a hox gene knockout mouse that turns out to be a model of obsessive-compulsive disorders. Such far-roaming projects in one laboratory are not easy to pull off, as Capecchi acknowledged to BioWorld Today, saying that "We're probably more spread out than is good for us."

Now that he has a Nobel Prize, perhaps it will take care of one difficulty of having wide-ranging interests: getting them funded. And Capecchi knows from experience what that is like. The NIH rejected his first grant application on knockout mice as "too speculative."