Mouse megascience

    A Correction to this article was published on 16 June 2010

    This article has been updated

    Mouse research for human diseases has grown, and researchers must defend and promote it accordingly.

    From cancer to cognitive disorders, the mouse has become an important biomedical model, in both academia and industry. During the past decade, the creation of mouse resources has consumed untold millions of research dollars. Large-scale efforts have contributed to the sequencing of the animal's genome; developed smart tools to make genetically modified mice in which specific genes can be switched on and off in different tissues at will; and established repositories to house and supply mouse mutant strains or genetically engineered mouse embryonic stem cells that can be developed into mice 'to order'. Within a few years, embryonic stem cells with modifications in every mouse gene will be available.

    But if the mouse is to fulfil its biomedical potential, that, unfortunately, is still not enough. The function of each gene must be identified through phenotyping: comprehensive screening to see what happens to the animals' organs and skeletons, and to their general physiology and behaviour, when individual genes are knocked out.

    This has been understood by the cognoscenti for years. The European Commission has already spent several hundred million euros pioneering large-scale systematic phenotyping, and 'mouse clinics' are starting to spring up around the world. The International Mouse Phenotyping Consortium (IMPC) has just been launched (see Nature 465, 410; 2010) to focus these efforts into a single global programme, which the US National Institutes of Health, under the leadership of Francis Collins, has endorsed with an injection of US$110 million.

    The IMPC estimates that with 'just' $900 million it can phenotype 4,000 mutants in a five-year pilot project. To put this into perspective, the mouse has about 20,000 genes. Mouse genetics is launching itself into the league of stratospherically expensive science projects, a domain currently occupied by international physics mega-projects such as the Large Hadron Collider (LHC) and the fusion-energy project ITER.

    Certainly, phenotyping will become cheaper and more efficient as technologies develop, but the scope of the IMPC pilot project will also have to expand in important ways that scientists are discussing. Secondary phenotyping may be needed to investigate particularly interesting hits from primary screens in more detail. Full phenotyping under different environmental challenges — yet to be decided, but possibly including high-fat diets — will also be incorporated. The inclusion of ageing mice to model our ageing society is also likely — an expensive prospect, given the time periods over which such mice must be kept. Phenotyping is, in fact, an infinite task, as long as a piece of string.

    Mouse geneticists will have to prepare themselves for this new league in which they will no longer be competing for funding only within the life-sciences community, but with all scientific disciplines.

    First, they will need to advocate the benefits to broader audiences. A full catalogue of mouse genes and functions will be invaluable in helping to crack currently intractable diseases. Individual scientists can certainly make slow progress laboriously creating and phenotyping knockout mice from scratch to model the plethora of candidate genes weakly associated with such diseases — but would save themselves years of possibly dead-end research by simply looking in a database.

    Second, and most importantly, political paymasters must be reassured that the IMPC's aims are clearly ring-fenced and limited to the minimum effort that will serve all of biomedicine effectively; they will rightly fear the infinite piece of string. They face shrinking budgets, and the LHC and ITER have shown how easily — and by how much — billion-dollar budgets can overrun. They also have responsibility for competing social priorities such as climate change.

    The international mouse-genetics community is now as united and cohesive as the international particle-physics community was when the LHC was conceived. It just needs to be as politically coherent.

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    • 17 June 2010

      This article was corrected on 17 June 2010.

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    Mouse megascience. Nature 465, 526 (2010).

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