A paper published online ahead of print by Nature on Dec. 7, 2006, presented the Paul Bunyan of atlases: a comprehensive 3-dimensional atlas of gene expression in the mouse brain.

"As far as I know, the scale is unprecedented," Allen Institute research alliance manager Kelly Overly told BioWorld Today. "It's the only internally consistent dataset that covers the entire brain, as well as all of the genes" - all of the roughly 20,000 genes of the C57BL/6J mouse, that is. The atlas contains 85 million images and 600 terabytes worth of data - or as Overly put it, "20,000 iPods."

The atlas, which has been publicly available since September, is the work of the Seattle-based Allen Institute for Brain Research, founded and largely funded by Microsoft co-founder Paul Allen.

Like Microsoft's other co-founder, Bill Gates, whose Bill and Melinda Gates Foundation has managed to change the general funding landscape for developing-world diseases like malaria, Allen thought big in his foray into biomedical research funding: With seed funding of $100 million, he specifically wanted the Allen Institute to tackle "something large-scale that might not be done otherwise," Overly said.

To develop the atlas, the scientists chose a highly inbred mouse brain, which means less inter-animal variation, and treated its brain essentially as "a complex but highly reproducible 3-dimensional tissue array," as they wrote in the paper. They used automated in situ hybridization and image acquisition techniques to determine gene expression patterns at a cellular level of resolution.

Kelly said that the findings presented in Nature represented no more than "the tip of the iceberg" of what can be done with the atlas. But even that tip should prove to be interesting to drug developers - and not just to those going after neurological diseases. The team found that more than 80 percent of all mouse genes are expressed in the brain. From a drug development standpoint, that makes side effects in the brain more likely for drugs targeting other organs.

"If someone is developing a liver drug, the target may well be expressed in the brain as well," Overly said.

The same holds true within the brain. "Very few genes are restricted to particular structures within the brain," she added. So even when a disease affects a very specific brain structure, as for example with Parkinson's disease and the substantia nigra, "genes that encode [drug] targets are more widely distributed than the disease area."

Allen Institute scientists themselves plan to continue to mine the atlas to gain a deeper understanding of the neocortex, both in terms of cellular diversity and its circuitry. Overly said that the institute also hopes that other researchers will use the data to expand their own work, or as she puts it, "polish those gems of information that can help them to focus their research projects."

Resources constrain many projects to looking at one or two genes in a given structure. The atlas could allow researchers to see things that an individual laboratory does not have the resources to look for. If a scientist is interested in a given structure, he or she can look at the expression of all the genes in that structure - which might allow the identification of genes that are the most specific to a structure, and thus might be specific drug targets. On the other hand, if a scientist is studying a specific gene, the atlas has data on the expression of that gene in the entire brain.

The atlas has its limitations. For example, the firing characteristics of different types of neurons are determined by their ion channels, and such ion channels exist in various splice variants, but Overly said that "our probes do not pick up every single variation of every gene."

Nevertheless, interest appears to be considerable. Overly said that there is no registration process, so the institute does not know the characteristics of individuals who look at the atlas. But it's clear from where the atlas is being accessed.

"There are people around the globe who are accessing the site," she said, "as well as researchers from all of the leading institutions in the U.S. and all of big pharma."

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