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METABOLITES, MORE THAN JUST WASTE, ARE:
Providing early indicators of disease // Allowing for less invasive diagnostic exams // Helping us better understand human biology.

Metabolomics: Telltale Patterns

By Linda Keslar // Photographs by Peter Hapak // Winter 2011
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Peter Hapak

Though the experiment involved strenuous exercise, the implications went far beyond the defining health benefits of working up a sweat. Robert Gerszten, a cardiologist at Massachusetts General Hospital, led a team of researchers that recruited two groups of several dozen middle-aged men. Those in the first group were fit and healthy; those in the second had been referred for testing because of shortness of breath or suspected heart disease. The men in both groups were asked to work out for 10 minutes on a treadmill or stationary bicycle at an accelerated pace, and their blood was drawn three times—right before and after the workout and then an hour later.

Gerszten’s team had undertaken the study because scientists have little knowledge about many of the chemical mechanisms involved in physical exertion. When they analyzed the blood samples, they chose to focus on metabolites, molecular by-products of the hundreds of thousands of chemical reactions always going on in every human cell. Identifying metabolites can be exceedingly difficult because they come in diverse and often unstable chemical forms, sometimes undergoing transformations even as they’re being isolated. Earlier exercise studies had measured only a handful of metabolites, mostly related to amino acids. But recent improvements in techniques to analyze such metabolites as lactate, pyruvate and glutamine—known to be involved in how the body burns fats, sugars and amino acids during exercise—helped facilitate Gerszten’s monitoring of more than 200 substances. Twenty or so proved particularly interesting, with levels that changed significantly during and after the 10-minute workouts.

The concentration of glycerol, a metabolite released into the bloodstream when fat is burned, rose sharply, whereas levels of allantoin, an indicator related to a cell’s ability to regenerate, went down. What’s more, while there was a boost in glycerol for all test subjects, the spike was much larger for those in the fitter group at their exercise peak, suggesting that there was something about their physiological makeup that helped them break down fats more quickly than did their less fit counterparts. In leaner subjects, levels of niacinamide, a metabolite involved in regulating insulin or blood sugar levels, increased more than twice as much as it did in heavier individuals.

Those results, and a wealth of other information Gerszten’s group is continuing to explore, are helping expand the frontiers of exercise physiology. But more than that, the study represents a major advance in metabolomics, the study of metabolites’ role in health and disease. Like genomics, which focuses on genes, and proteomics, which considers the proteins that genes encode (produce), metabolomics attempts to increase what we know about human physiology. And by focusing on the by-products of metabolic processes—which produce such substances as sugars, amino acids, lipids and fatty acids—metabolomics may relate most directly to how the body functions.

Involved in everything from digestion to waste elimination and temperature regulation, metabolites provide here-and-now evidence about conditions ranging from Alzheimer’s to breast cancer and Huntington’s disease. “Genes give the blueprint of a house, while metabolites give you a minute-to-minute snapshot of what’s actually going on in the house,” Gerszten says. “We can’t take pictures of every brick, but we can look at hundreds and hundreds of them through metabolomics.”

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1. “Metabonomics,” by Jeremy Nicholson and John Lindon, Nature, October 2008. In a concise overview of a field alternately called metabonomics, the authors offer insights into the discovery of metabolites, plus the applications of metabolic profiling to disease risks for populations and patients’ responses to drug therapy.

2. “Metabolomic Profiles Delineate Potential Role for Sarcosine in Prostate Cancer Progression,” by Arun Sreekumar et al., Nature, February 2009. Groundbreaking research that sifts through more than 1,000 metabolites to find that sarcosine is a strong indicator of advanced prostate cancer.

3. “State of Metabolomics Technologies in Translational Research,” presented by the Metabolomics Special Interest Group at the National Institutes of Health, Sept. 17, 2010. More than seven hours of presentations by metabolomics researchers address emerging technologies and research.

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