mapping the mouse brain

NATURE NEUROSCIENCE VOLUME 6 | NUMBER 11 | NOVEMBER 2003 1113

E D I TO R I A L

P aul Allen has big plans for neuroscience. In September theMicrosoft cofounder—ranked fourth on the Forbes list of theworld’s richest people—announced the donation of $100 mil-

lion over five years to create the Allen Institute for Brain Science, a pri-vate research foundation located in Seattle. The institute’s inauguralproject will be an atlas of gene expression in the mouse brain, to bemade freely available over the internet (http://www.brainatlas.org).This ambitious project pushes the limits of existing technology, but itseems that the right people, strategies and resources are in place to giveit a good chance of success.

The mouse genome contains about 30,000 genes, of which two-thirds are thought to be expressed in the brain. The researchers planto use automated in-situ hybridization to map gene expressionthroughout the brain at cellular resolution, in adult males of thestrain (C57/Bl) that was sequenced in the mouse genome project. Thedata, to be collected at the Allen Institute and at Baylor College ofMedicine in Houston, will be released periodically while the project isunderway, beginning in the first quarter of 2004. To meet their targetcompletion date of 2006, the researchers will need to map over 100new genes per week.

The scale of the data that will be produced is unprecedented inbiology. The biggest challenge for the new institute will be to makehuge quantities of information—the same order of magnitude as theentire contents of the internet today—accessible and useful to scien-tists. The institute’s director, Mark Boguski, a leading bioinformaticsexpert who worked on the human genome project, puts the problemin perspective: “This job makes my previous jobs look fairly simple.”

Months before the public announcement, a team of scientists andcomputer programmers was quietly assembled to work on the project.The software to collect and display the brain map data has been con-structed by scaling up existing relational database software and addingapplications to browse and mine the data. The researchers decided tocreate the software first, so that the collection of data could be tailoredto the software. Boguski says that the genome project taught him theimportance of not becoming distracted by discoveries made along theway: “We want the platform to be high-throughput enough that wedon’t have to make decisions about what’s interesting.”

The institute is committed to making the brain atlas publicly avail-able, and researchers will be able to download data from the atlas ifthey consent to the institute’s end user license agreement. However,this agreement has not yet been released. Thus it is not clear whetherthe institute will maintain intellectual property rights in discoveriesbased on the brain atlas data, although Boguski emphasizes that theinstitute is a philanthropic enterprise and that Paul Allen wants thenew atlas to have the broadest possible impact.

The Allen Institute has benefited from the planning processbegun in connection with the National Institute of Health’s BrainMolecular Anatomy Project (http://trans.nih.gov/bmap). Thisproject was initiated in 1998 and contracts have already beenawarded to several individual investigators; at the current rate of600 genes per year, however, a complete map would be decadesaway. The Allen Institute has tapped many of the same advisors asthe NIH project, and the scale of the newly announced investmentshould allow the project to be finished much faster. Thomas Insel,director of the National Institute of Mental Health, is enthusiasticabout the Allen Institute’s involvement, saying the atlas “will betremendously informative for neuroscience.”

The gene map will be only the first step in mapping the mousebrain. The decision to begin with mRNA localization was made fortechnical reasons, as high-throughput approaches are much easier todevelop for mRNA than for protein. Thus the gene expression map is“low-hanging fruit,” says Marc Tessier-Lavigne, chair of the institute’sscientific advisory board, who recently moved from StanfordUniversity to Genentech. However, it will also be important to mapprotein distribution, as soon as the necessary antibodies are available.In addition, given the diversity of cell types in the brain, molecularmaps will be difficult to interpret without information about themorphology and connections of the cells expressing a particular gene.Such connectivity maps can be made by knocking in a reporter thatwill fill entire cells, including axons and dendrites, under the controlof the promoter region of the gene of interest.

Although the Allen Institute will concentrate on industrial-scale‘big science’ for its initial project, in the long run its founders have abroader vision. They want the institute to become a world-class inter-disciplinary neuroscience center along more traditional lines, withscientists working on individual research projects in areas like cogni-tion, language, emotion, learning and memory. The institute cur-rently has about 25 full-time staff, and expects to expand to 100 overthe next few years. Allen has told journalists that he plans to continuefunding the institute after the initial brain map project is complete,and the institute is also seeking funds from other sources.

Steven Muller, then president of Johns Hopkins University, oncequipped that it was easier to raise money for clinical departmentsthan for the humanities because “Nobody ever died of English.” Noone has ever died for want of a brain map either, and we commendPaul Allen and his scientific advisors for their far-sighted recognitionthat support for basic neuroscience is a good investment. However,scientific progress is slower than software development, and more dif-ficult to measure. We hope this results-oriented businessman will staythe course long enough to see the full benefits of his support. �

Mapping the mouse brain

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