Scientists Find Way to Improve Disease Detection

June 7, 2007 — -- They say what you don't know can't hurt you, but when it comes to heart disease, ignorance can be fatal.

This is especially true of hypertrophic cardiomyopathy (HCM), a genetic disease that thickens the heart muscle. About one in every 500 people have HCM, but the disease expresses itself differently, even among people in the same family.

Now researchers have discovered a new way to investigate HCM and other genetic diseases. In a study released today, scientists at Brigham and Women's Hospital and Harvard Medical School demonstrate a new procedure that measures changes in gene activities well before the disease itself appears.

For now, it's only been tried in mice, but it could eventually be used for human heart patients.

"It's not possible to predict what is going to happen with any individual patient -- a substantial portion do have symptoms or require a major treatment," said Barry Maron, the director of Hypertrophic Cardiomyopathy Center at the Minneapolis Heart Institute Foundation.

"It is the most common reason for sudden death among young people," he said. He estimates someone dies of this heart problem every three days in the United States. The number is probably higher, but, as Maron points out, "We don't have a mandatory reporting system."

The medical community doesn't fully understand why some people die in early life and others live much longer.

The new study should help change that.

New Way to Read Genes

Jon Seidman, professor of Genetics at Harvard Medical School and co-author of the study, said a new technique called PMAGE (Polony Multiplex Analysis of Gene Expression) is a way of defining RNA profiles in cells and tissues. "As a research tool it will be very valuable for dissecting complicated developmental processes," he said. Although their study focused on heart disease, the methodology translates to any disease involving a change in cell physiology, including diabetes, kidney disease or cancer.

The study is published in Friday's edition of the journal Science.

The first indicators of disease happen at the cellular level, and to understand it, a refresher in cell biology is in order. If a gene in your DNA has mutated -- or changed in an unhealthy way -- it gives out incorrect instructions to the cell, and that cell begins to malfunction.

Normal genes pass their instructions on through a process called transcription. In it, sections of DNA are copied into molecules called messenger RNA (mRNA), which carry the vital information.

But a gene mutation throws a wrench in the transcription process. And that means the cell begins to act much differently. Researchers figured out it's possible to look at this gene activity and identify disease before other signs of heart damage came about.

Cheaper and More Sensitive

Scientists have spent decades searching for good ways to study transcription. Existing methods are expensive, and only work if there's a lot of mRNA.

"We know there are 300,000 RNAs per cell, sometimes a little more or less. If we only count 50,000 we are missing a lot," Seidman said.

But with the new PMAGE technique, Seidman and his colleagues were able to examine much smaller quantities.

They were surprised to find hundreds of changes in the mRNA of mutant mice when compared to the normal mice. And this has great implications for future treatments. Seidman said if you can find those small changes you might be able to head off disease -- and that's where PMAGE comes in.

In a 2002 article published in the journal Circulation, Maron wrote, "While analysis of DNA is the most certain method for diagnosing HCM, it is time-consuming, expensive, confined to research-oriented laboratories and cannot yet play a role in routine day-to-day decisions for patients." It remains to be seen whether PMAGE will help change all of that. Until then, a yearly physical might be the simplest solution, especially for patients with a family history of heart trouble.