“Our Web site had 7,000 hits the night the project was announced in Nature online,” says project co-leader Nat Heintz, head of the Laboratory of Molecular Biology. And that number, which has since climbed to over 494,000, is just one indication of the worldwide interest in this first-of-its-kind project.

Why the excitement?

Heintz, Mary Beth Hatten, head of the Laboratory of Developmental Neurobiology, and their team of 20 have built a fully public, searchable database that links individual genes to the products they express in brain cells. “We are providing more information in our database than has ever been known about the central nervous system,” says Hatten, who is Rockefeller’s Frederick P. Rose Professor. “There isn’t a single gene among the 150 currently on our public atlas that has been studied in the range of detail that we have provided.”

It works like this: Say you’re a scientist who studies degenerative or developmental diseases of the brain, such as Parkinson’s disease, Huntington’s disease, autism or epilepsy. You log on to the Gensat Web site, www.gensat.org, where you can search the brain by structure, gene, cell type or any of several other criteria. What the database returns is a series of images showing gene expression in specific cell types in slices of brain tissue related to your query. The images are akin to classic anatomical images with gene expression patterns tagged and overlaid.

And they provide levels of detail never before available. With the information the database spits out, scientists can zero in on the exact places in the brain they need to investigate in order to further their research.

To build the database, Heintz, an investigator at Howard Hughes Medical Institute, developed a method of manipulating bacterial artificial chromosomes or BACs. In an early form, BACs provided the backbone of the Human Genome Project; Heintz discovered how to alter them by inserting, changing or deleting parts of the large gene sequences composing them. Once created, the modified BACs for individual genes are inserted into the genome of laboratory mice to assess gene expression. The BAC technology provides unparalleled insight because it identifies the actual cell types in the brain in which individual genes express themselves. Heintz also added a reporter gene to the BACs so that cells with the selected gene activity glow bright green.

Specimens from the mouse brains are then photographed using an automated microscope at three developmental stages. The images are captured at high resolution, checked for accuracy, and then annotated and placed in the database. So far, 150 genes have been uploaded to the Web site, and Hatten and Heintz are proceeding at a rate of about five genes per week.

In addition to the database and images, the researchers also make the BAC vectors and transgenic mice available to researchers who want to follow up on new disease-based insights revealed in the atlas. “The goal is to give scientists genetic access to the brain without all the effort required of doing their own molecular genetics from scratch, saving years of researchers’ time they would need to create their own tools. We’re making studying gene expression patterns in the brain available to all neurobiologists,” says Heintz.

Indeed, the transgenic mouse repository at the NIH has been inundated with requests for mouse lines and BAC vectors since the project was announced on October 30.

“With these tools researchers will be able to deconstruct the brain into not only cell types and subtypes, but also individual molecules and signaling pathways,” says Heintz.

Rockefeller Professor and Nobel laureate Paul Greengard has been using the Gensat tools for over a year to study Parkinson’s disease. Greengard and his lab colleagues now can study each cell type in the brain striatum where Parkinson’s strikes. They administer potential drugs developed to treat Parkinson’s and monitor cell subtypes to see how well the cells respond.

“Nat and Mary Beth have increased the momentum for significant breakthroughs in neurological disease,” Greengard, head of the Laboratory of Molecular and Cellular Neuroscience says. “The demand for their data is only going to multiply from here.”

December 12, 2003