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The Heart of the Matter

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Mario Deng knows just how valuable it is to be in a research setting with easy access to, and direct application for, a clinical environment. A cardiologist, Deng was a tenured medical director at the Muenster University hospital in Germany when he gave up the post and lifetime job security for a chance to combine research and medicine at Columbia University. He’s been director of cardiac transplantation research there since 2000, and already his research group has had a major impact on patients’ lives.

Deng and his team headed up a project known as CARGO, or the Cardiac Allograft Rejection Gene Expression Observational study. The clinical problem: there’s no simple way to tell when a heart transplant patient is at risk for rejection, so the current standard of care is to take biopsies of the heart at regular intervals to detect the signs of rejection as early as possible. It’s a painful, invasive solution.

In the CARGO study, Deng and his colleagues -- both within Columbia and at collaborating institutions such as Stanford -- hypothesized that there must be some way to determine, through gene expression, whether or not a patient was at risk for rejection. A gene discovery and analysis stage of research turned up 11 genes that together act as a barometer for a patient’s likelihood of rejecting the heart transplant.

The team took this panel of genes and began testing in independent cohorts, eventually confirming that these genes were reliable predictors. The test result gives a score, and “below [a certain] threshold then we know from the study that the chance of having rejection is less than one percent,” Deng says. “We can therefore avoid having to do biopsies” on those patients. While the ultimate extent of how many biopsies this will prevent is not known, he says the program could reduce the number of biopsies needed anywhere from 25 percent to 75 percent.

That was last year. Since then, the US government approved the 11-gene diagnostic test, and Medicare agreed to reimburse physicians who used it. Less than a year after the original CARGO paper was published, Deng and his peers were already implementing it in clinical environments.

Beyond that, Deng got funding from NIH last year to take this project to another dimension. Now working in collaboration with his peers at the Columbia Genome Center, Deng is using the data from the CARGO study to try to reconstruct the intracellular genetics behind the gene expression. With computational biology tools and this data, Deng believes, “you can characterize the molecular network” and use that as a backbone for chemical genomic and other studies that could eventually lead to related therapeutic targets.

Deng is the first to point out that while this information is highly relevant to heart transplant patients, there simply aren’t all that many heart transplants. There are about 3,000 such transplants per year, with some 40,000 or 50,000 people living with transplanted hearts. But the work done in the CARGO project is valuable as a standard for other studies, Deng says. “Beyond the clinical applications, we’re very excited about the methodological aspect that is a kind of blueprint for how to do this kind of transcriptomic study.”

Indeed, there’s already a project underway for lung transplant patients following similar protocols. That program, headed up by a group at the University of Toronto, “has basically the same approach,” says Deng, although it’s “learning from the childhood mistakes of the original study.” For one thing, the original study began before the era of whole-genome arrays and other genome-wide tools, so Deng and his team had to perform their discovery phase using genes known to be linked to the specific biology they were investigating. Now, Deng says, the Toronto team can scan the entire genome, ensuring that no connection is missed.

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