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January 4, 2011

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Scientists are building a searchable database that reveals the hidden connections between drugs and diseases with the click of a mouse. It should make the search for cures, even for rare diseases, a much faster process. This ScienCentral News video explains.

Connecting the Dots

There are thousands of diseases most of us have never heard of – usually because only a handful of people ever get them. Those who do are often out of luck – few treatments exist, and not much research is being done to discover new ones. Lisa Yue, now a grateful mother of three, lived through this nightmare. She lost her first two sons to an incurable, rare heart condition called pediatric cardiomyopathy.

"As a parent with a newly diagnosed child ... that was just overwhelming, you know, to hear the prognosis was going to be fatal," says Yue, who now runs a foundation dedicated to providing support for those affected by the disease.

Because biomedical research is such an expensive and time-consuming process, attention tends to get focused on the conditions that affect the largest number people. Now scientists at the Broad Institute of MIT and Harvard hope a new tool called the "Connectivity Map" will make it much faster and simpler to find cures, even for rare diseases, by revealing the hidden connections between drugs and diseases almost instantaneously.

A team led by Todd Golub and Justin Lamb created a searchable database of information from DNA chips, which monitor the activity of thousands of genes, revealing what genes are turned on or off by specific diseases and treatments, "thereby identifying a match between a signature of a disease and a signature of a drug," says Golub, director of the Broad Institute's cancer program and investigator at the Dana-Farber Cancer Institute. "In a similar way," he adds, "one might think about matching fingerprints in a database or doing, for example, a Google search."

DNA chips, or microarrays, are one of the main tools in the growing field of genomics, the branch of biology that studies how whole genomes behave rather than how individual genes do. The chips, small squares of glass or plastic, are covered with thousands of DNA segments of interest. Because of the complimentary binding properties of DNA, any genetic sequences floating around inside of a cell will bind to the matching probe sequence on the chip.

"Once the genes have attached themselves to the pieces of DNA on this glass chip, we add various reagents that allow those pieces of DNA to shine, essentially, to glow. And under a laser light we can measure the levels of those genes," explains Lamb.

As they reported in the journal Science, the team's pilot database included genetic profiles of 164 bioactive compounds, 50 of which were drugs already FDA-approved for human use. To generate the genetic signatures, human cells grown in the lab were individually exposed to the drug substances for a fixed period of time. The genetic material isolated from these exposed cells could then give a snapshot of the compound's effects on the cells' gene expression.

To test whether the database would work correctly at all, the researchers created genetic signatures of disease states using the same method, including a form of childhood leukemia and prostate cancer. The map was able to correctly match the diseases with their existing treatments, and also predicted new potential treatments.

"There were many reasons why this project might not have worked at all – it's too complicated, biology is too noisy. So it was very exciting to see that not only could we rediscover things that were already known based on what's been published, but we could also discover new things based entirely on the Connectivity Map approach," says Golub.

Golub and Lamb say this new method can be used right away to suggest new uses for drugs that are already FDA-approved, although they stress that this would be a resource for biomedical researchers rather than clinicians. Even if a new connection is made between a disease and an already-approved drug, more research would need to be done to test it in its new capacity. Still, this new approach is likely to make the process of drug discovery much faster, and consequently, cheaper.

"Literally with one click, you can be presented with a list of drugs which might suggest some hypotheses for experiments you might do," says Lamb.

Though still in pilot form, the Connectivity Map is already publicly available through an Internet portal. The Broad Institute team is focusing on expanding the project, and through collaborative work with other labs hopes to create profiles for all FDA-approved drugs within the next two years.

This research was published in the Sept. 29, 2006 issue of Science and was funded by the Howard Hughes Medical Institute and the Paul Allen Foundation.

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