BioWorld International Correspondent

LONDON - The U.S., Canada and Europe are pooling their mouse knockout programs to accelerate the discovery of the function of human genes. The objective is to create a mutation in 20,000 genes in the mouse genome, allowing researchers to determine the role of each in normal physiology and development, and create disease models.

The project will cost €56.6 million (US$71.6 million) over the next five years, of which the U.S. National Institutes of Health will contribute $52 million and the European Union $16.5 million.

That, the largest collaborative research effort after the Human Genome Project, will enable mouse mutants to be generated by any laboratory in a standardized, low-cost manner. Like the Human Genome Project, all data will be available publicly.

The combined program came together when the U.S. NIH launched the Knockout Mouse Project (KOMP) earlier this month, awarding grants of $47.2 million for the generation of knockout mice lines and a $2.5 million grant to pay for a data coordination center. The center, to be run from the Jackson Laboratory in Bar Harbor, Maine, will pull together all other existing mouse sequence databases and track the progress of knockout production.

The Canadian and European arms of the project, the North American Conditional Mouse Mutagenesis Program, NorComm and the European Conditional Mouse Mutagenesis Program, EuComm, respectively, have been in operation since October 2005.

To date, mouse knockouts of about 4,000 genes have been generated worldwide, while another collaborative project, the International Gene Trap Consortium, has mutated 8,000 mouse genes. Because of overlap between the two, about 15,000 genes remain to be knocked out.

In addition, not all published knockouts are freely available for research. In advance of setting up KOMP, the NIH purchased rights to existing knockouts from private companies and pulled together disparate resources in public institutes.

The NIH estimates that duplication of effort means that currently a single mouse gene is knocked out an average of 2.5 times. Collaborating across national programs and concentrating NIH grants in a few centers will avoid redundancy, create economies of scale and maximize the efficiency of techniques for generating knockouts.

Colin Fletcher, program director at the U.S. National Human Genome Research Institution, said, "The international projects will exchange information and coordinate their efforts in much the same way that teams from many nations collaborated on the Human Genome Project."

A steering committee of scientists from the three projects and representatives of the funding agencies will coordinate the work.

The program will use a combination of gene targeting and gene trapping to generate the knockouts. Researchers will harvest embryonic stem cells from 4-day-old mouse embryos, manipulate them to remove a gene and grow them for several days before injecting them into other mouse embryos and implanting them. The resulting mice have some tissues in which a gene has been knocked out, and it is then necessary to cross-breed them to produce lines of mice in which both copies of the gene are knocked out in all tissues.

Other researchers will be able to obtain the mutated embryonic stem cells to breed their own mice. Initially that will be from the individual organizations that carry out the work, but the NIH intends to set up a central KOMP repository.

Of the $42.2 million NIH awarded for the generation of knockout mouse lines, $18.4 million went to Regeneron Pharmaceuticals Inc, of Tarrytown, N.Y., to knock out 3,500 genes.

The company has granted a license to the consortium of research institutions that picked up the balance of the award, to use its VelociGene high-throughput knockout technology.

The consortium, consisting of the Children's Hospital Oakland Research Institute in California, the School of Veterinary Medicine at the University of California at Davis and the Sanger Institute in Cambridge, UK, will be responsible for creating 5,000 gene knockouts.

The Sanger Institute also has received grants from EuComm, and to date has produced mutations in more than 3,000 genes.

"Through this funding, we will be able to accelerate the contribution we can make to help researchers worldwide make advances against disease," said Allen Bradley, director of the Sanger Institute. "Our mission is the use of cutting-edge research methods to bring new understanding of normal biology and the role of genes in disease."