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A Virtual Map to the Root of Diabetes and Other Metabolic Disease

Researchers have developed a "global human metabolic network" that could pave the way for new treatments aimed at disorders like diabetes and high cholesterol
Diabetes Insulin Metabolism



© KAREN KASMAUSKI/CORBIS
Sure, it is just on a computer but a new reconstruction of human metabolic activity, created by researchers at the University of California, San Diego, could revolutionize the study of how the body breaks down food into energy and assembles hormones and proteins to power biological processes crucial to daily life. The work could lead to new treatments that target common metabolic maladies such as high cholesterol and diabetes as well as hemolytic anemia, which occurs when red blood cells break down prematurely.

The research, the results of which are reported in this week's Proceedings of the National Academy of Sciences, was led by Bernhard Ø Palsson, who notes that the effort "took six people a year and a half" to complete. The reconstructed network covers 3,300 metabolic transformations that occur in tissue and cells as well as more than 2,000 metabolites. It was assembled using the penultimate model of the human genome released in late 2004, which accounts for 99.99 percent of human genes, according to Palsson. "This was nine man-years' worth of work. This is genome-enabled science, basically," Palsson says, adding that sourcing and collecting the previously published research probably accounted for at least two thirds of the time it took to build the network. "The result," he says, "is the first comprehensive reconstruction of the human metabolic map that is biochemically, genetically and genomically accurate or structured."

Among other things, the new map gives researchers the ability to pinpoint missing information about human metabolism. "We can actually computationally interrogate it to see what it can do and what it cannot do," Palsson says. And interrogate the team did, peppering their virtual model with nearly 300 known tasks, like synthesizing the hormones estrogen and melatonin from the raw materials of sugars and amino acids.

The model was able to perform almost all of the tasks. One job it failed at, however, was to build a pathway from sugars to the q10, a natural enzyme and functional food thought to provide benefits for cardiovascular disease. The researchers made up for the shortfall by filling the gap with information on q10 synthesis gleaned from rats or mice or some other model organism closely related to humans. Despite the hitch, Palsson insists these sorts of findings can actually be helpful. "A model like this just leads to a whole bunch of hypotheses about what's missing that then becomes a focused experimental effort," he explains.

Another use of the new system is the ability to study gene expression profiles to predict how patients may function after certain surgeries. In the paper, the team modeled the state of gene expression in skeletal muscle both before and six months after gastric bypass surgery (commonly known as stomach stapling). For the post-op patient the model came back with alarming news. "You can see that patients are basically in a starved state six months out," Palsson says. "Even if they are being fed, the restrictions of the stomach are such that it puts the body into a permanent starvation state."

He notes that if a physician were to run this simulation and find this was happening, he could devise a way to prevent it: "One [result] of this kind of study would be to help design a nutritional regimen for the patients."

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