While a four-year international project is attempting to speed the development of knockout mice using the techniques his lab pioneered (see sidebar), Capecchi is moving on. Once again he is taking the long view. “This next project we're working on is probably 20 years,” he says.

He elaborates, noting that most mammals share the vast majority of their genomes; mammalian bodies are all based on the same set of constituent parts. Mice have tiny paws and bats have huge wingspans, but they're both created from the same set of components. Capecchi explains that many evolutionary changes appear to be additive; they happen because members of a given species acquired new, usually added, characteristics as a consequence of random genome modifications or mutations that provided them with a selective advantage.

If, for example, he were to take a set of genes from a bat, add them to the DNA of a mouse embryonic stem cell, and then generate mice from these cells, he may be able to observe changes in the mouse that reflect what the added genes were doing. If the mouse fingers grew abnormally long, he'd know the added genes were important for controlling digit length.

The logic is elegant, but there are many reasons to judge that the experiment might not work. Normally, only tiny fragments of exogenous DNA are introduced into a cell nucleus, yet Capecchi is talking about adding very large, defined pieces of DNA encompassing a significant portion of a chosen chromosome. Even if he does get the DNA in there, he'll still have to successfully generate a mouse. Multiple copies of a given gene can be fatal to embryos. Indeed, not long before he won the Nobel, the NIH rejected a grant proposal that outlined this work.

This HHMI investigator is going ahead anyway. The high risk, in Capecchi's eyes, is worth the potential payoff.

		Although a couple of thousand mouse knockouts have been described in scientific papers, fewer than 1,000 are available at repositories such as the Jackson Laboratory in Maine, primarily because of the expense of archiving and distributing them. Because knockouts have become so essential to medical research, an approach to improve accessibility is needed, says Francis S. Collins, director of the National Human Genome Research Institute at the National Institutes of Health (NIH). As a result, the NIH, European Union, and Genome Canada are funding efforts to create a public library of mouse embryonic stem cells with knockouts of each of the more than 20,000 protein-coding genes—and to do it within the next four years. Scientists who engineer a new knockout mouse from embryonic stem cells obtained from the library will be required to send back a frozen sperm sample of their creation. By eliminating much of the up front work, the hope is that the project will encourage researchers to create mouse models of rare diseases. Collins says that this effort is perhaps the best reflection of the importance of the work of Mario Capecchi, Martin Evans, and Oliver Smithies. —R.M.

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