|NIH Launches Knockout Mouse Project
Genome-Wide Public Resource Will Provide New Mouse Models for Understanding
The National Institutes of Health (NIH) today awarded a set of cooperative
agreements, totaling up to $52 million over five years, to launch the Knockout
Mouse Project. The goal of this program is to build a comprehensive and publicly
available resource of knockout mutations in the mouse genome. The knockout mice
produced from this resource will be extremely useful for the study of human disease.
The NIH Knockout Mouse Project will work closely with other large-scale efforts
to produce knockouts that are underway in Canada, called the North American Conditional
Mouse Mutagenesis Project (NorCOMM), and in Europe, called the European Conditional
Mouse Mutagenesis Program (EUCOMM). The objective of all these programs is to
create a mutation in each of the approximately 20,000 protein-coding genes in
the mouse genome.
“Knockout mice are powerful tools for exploring the function of genes and creating
animal models of human disease. By enabling more researchers to study these knockouts,
this trans-NIH initiative will accelerate our efforts to translate basic research
findings into new strategies for improving human health,” said NIH Director Elias
A. Zerhouni, M.D. “It is exciting that so many components of NIH have joined
together to support this project, and that the NIH Knockout Mouse Project will
be working hand-in-hand with other international efforts. This is scientific
teamwork at its best.”
Knockout mice are lines of mice in which specific genes have been completely
disrupted, or “knocked out.” Systematic disruption of each of the 20,000 genes
in the mouse genome will allow researchers to determine the role of each gene
in normal physiology and development. Even more importantly, researchers will
use knockout mice to develop better models of inherited human diseases such as
cancer, heart disease, neurological disorders, diabetes and obesity. Recent advances
in recombinant DNA technologies, as well as completion of the mouse genome sequence,
now make this project feasible.
NIH today awarded five-year cooperative agreements totaling up to $47.2 million
to two groups for the creation of the knockout mice lines. Recipients of those
Regeneron Pharmaceuticals, Inc., in Tarrytown, N.Y., and a collaborative team
from Children’s Hospital Oakland Research Institute (CHORI) in Oakland, Calif.;
the School of Veterinary Medicine, University of California, Davis (UC Davis);
and the Wellcome Trust Sanger Institute in Hinxton, England.
In addition, NIH awarded another five-year cooperative agreement totaling $2.5
million to the Jackson Laboratory in Bar Harbor, Maine for the establishment
of a NIH Knockout Mouse Project data coordination center. Finally, NIH awarded
cooperative agreements to the University of Pennsylvania in Philadelphia and
to the Samuel Lunenfeld Research Institute of Mount Sinai Hospital in Toronto
to improve the efficiency of methods for creating knockout lines. Those agreements
total about $2.5 million and run for three and two years, respectively.
“Building a genome-wide library of knockouts will require the skills of researchers
from many different disciplines. We are confident that the multi-institution
team we have pulled together will meet that challenge and deliver this much-needed
resource into the hands of the worldwide research community,” said James Battey,
M.D., Ph.D., director of the National Institute on Deafness and Other Communication
Disorders (NIDCD) and co-chair of the Trans-NIH Genomic Resources Working Group.
To date, academic researchers around the world have created mouse knockouts
of about 4,000 genes. In addition, a random disruption strategy has been used
by the International Gene Trap Consortium to mutate 8,000 mouse genes. Due to
some overlap between these efforts, about 15,000 genes remain to be knocked out
in the mouse genome.
The NIH program, along with NorCOMM and EUCOMM, intend to closely coordinate
their efforts in order to avoid redundancy and maximize the efficiency of generating
knockouts for all genes in the mouse genome. Furthermore, the U.S., Canadian
and European groups are committed to making their data and resources rapidly
and openly available to researchers around the world.
“The international projects will exchange information and coordinate their
efforts in much the same way that teams from many nations collaborated on the
International Human Genome Project,” said Colin Fletcher, Ph.D., a program director
at the National Human Genome Research Institute (NHGRI), which will oversee administration
of three of the five cooperative agreements that form the core of the Knockout
Under its cooperative agreement, the team led by Pieter deJong, Ph.D., CHORI,
along with K. C. Kent Lloyd, D.V.M., Ph.D., UC Davis; and Allan Bradley, Ph.D.
FRS, and William Skarnes, Ph.D., at the Wellcome Trust Sanger Institute, plans
to systematically create mouse embryonic stem (ES) cell lines in which 5,000
genes have been knocked out by gene targeting. The VelociGene division of Regeneron,
led by David Valenzuela, Ph.D. and George D. Yancopoulos, M.D., Ph.D., will take
aim at a different set of 3,500 genes. Both groups will utilize information from
the finished mouse genome sequence to design targeting vectors, which will be
built by large-scale, automated technologies. The combined collection of mouse
ES cells with knockouts in 8,500 genes will be useful for producing knockout
Other researchers will be able to obtain the ES cells and the vectors, which
can be used to swiftly and efficiently to make live lines of knockout mice for
use in biomedical studies. During the initial phase of the project, the ES cell
lines and vectors used to mutate the genes will be available from the grantees
who produced them. In addition, NIH is preparing to issue a solicitation for
a program to implement a Knockout Mouse Project repository, which will be funded
in the next year and through which all these materials will be available to the
entire scientific community.
Another crucial component of the effort will be the collection and coordination
of data. Under the leadership of Martin Ringwald, Ph.D., the Jackson Laboratory
will set up a Data Coordination Center for the Knockout Mouse Project. The center
will collect information that will allow the research community to track the
scheduling and progress of knockout production. The center will also serve as
a central information resource for all publicly available knockout mutants and
will integrate with other databases that contain mouse DNA sequence, additional
information on mouse genetics and information on the physical and biochemical
characteristics of the knockout mice.
Under two cooperative agreements administered by the National Institute on
Drug Abuse (NIDA), Klaus Kaestner, Ph.D., and his colleagues at the University
of Pennsylvania will focus on developing methods to create ES cell lines suitable
for high-throughput gene targeting or trapping in C57BL/6, the strain of mouse
used most widely by the scientific community. They will be joined in this effort
by Andras Nagy, Ph.D., and his colleagues at the Samuel Lunenfeld Research Institute.
In addition, Regeneron will receive funds to optimize its existing ES cell line
for the C57BL/6 strain and its proprietary growth medium, both of which will
be supplied to the CHORI-led team for use in the Knockout Mouse Project.
“Development of ES cell lines that can be used to make mutants in the C57BL/6
strain will be an important step forward in capitalizing on the vast amount of
information obtained from years of research already done in this mouse strain,” said
NIDA Director Nora D. Volkow, M.D.
While today’s awards mark the official launch of the Knockout Mouse Project,
NIH has been laying the foundation for several years. In the fall of 2003, NIH
co-sponsored an international meeting that concluded that the time was right
for a coordinated effort to produce knockouts in every mouse gene, and a commentary
calling for such a project was published in the September 2004 issue of Nature
In October 2005, NIH and the U.K.'s Wellcome Trust took the first concrete step
by awarding contracts that gave academic researchers access to a set of well-characterized
knockout mouse lines created by Deltagen, Inc. of San Carlos, Calif., and Lexicon
Genetics, Inc. of The Woodlands, Texas. NIH has expended about $11 million to
acquire about 250 lines of these mice in the first year of the three-year contracts.
Researchers can obtain information on what knockout mouse lines are available
from this procurement and how to order them at: http://www.nih.gov/science/models/mouse/deltagenlexicon/list.html.
In June, NIH moved another step closer to its goal of a genome-wide library
of knockout mice with the award of $800,000 to two public mouse repositories
for the acquisition of existing knockout mouse lines that are not yet widely
accessible to researchers. The award recipients were the Mutant Mouse Regional
Resource Centers at UC Davis and the University of Missouri/Harlan in Columbia,
both supported by the National Center for Research Resources (NCRR). NIH anticipates
that more than 350 existing mouse lines will be deposited and made available
to the research community over the next two years as a result of this effort.
Researchers can obtain information on what knockout mouse lines are available
from this effort and how to order them at: http://www.mmrrc.org/.
The 19 NIH institutes, centers and offices contributing to the Knockout Mouse
Project are: NCRR, National Eye Institute, NHGRI, National Heart, Lung and Blood
Institute, National Institute on Aging, National Institute of Alcohol Abuse and
Alcoholism, National Institute of Allergy and Infectious Diseases, National Institute
of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Child
Health and Human Development, NIDCD, National Institute of Dental and Craniofacial
Research, NIDA, National Institute of Environmental Health Sciences, National
Institute of General Medical Sciences, National Institute of Mental Health, National
Institute of Neurological Disorders and Stroke, National Institute of Diabetes
and Digestive and Kidney Disease, National Cancer Institute, and the Office of
For more information on the Knockout Mouse Project, go to www.nih.gov/science/models/mouse/knockout/.
For a fact sheet describing what knockout mice are, how they are made and what
they are used for, go to www.genome.gov/12514551. To download a high-resolution
photo of knockout mice, go to http://www.genome.gov/pressDisplay.cfm?photoID=5006.
The National Institutes of Health (NIH) — The Nation's Medical Research
Agency — includes 27 Institutes and Centers and is a component of
the U.S. Department of Health and Human Services. It is the primary federal
agency for conducting and supporting basic, clinical and translational medical
research, and it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs, visit www.nih.gov.