Telltale Chemistry
“The exciting part is not the metabolome, not the transcriptome and not the proteome,” says Mike Sussman, a biochemist and director of UW-Madison Biotechnology Center. “It’s the integration of them all.”
Figuring out how these four systems work together is one of the most pressing problems in systems biology, and billions of dollars are being invested to learn how their interconnection affects our health. One notable example comes from Sussman’s own lab, which is studying a special breed of rat to try to find the biochemical signals associated with colon cancer. Developed by UW-Madison oncologist William Dove, the rats have a genetic mutation that causes them to develop a rat form of the cancer. Scientists already know this mutation has a human analog, and patients who are missing the gene are more likely to develop colon cancer. But they can’t predict when in someone’s life that might happen. Sussman’s project is part of a larger effort to follow the chain from gene to RNA to protein to metabolite, which scientists hope will lead them to key signals that can sound the alarm when the cancer starts growing.
“Using metabolomics, we are trying to find a small molecule whose concentration precedes and predicts colon cancer,” he says. And success in this case would have a result that everyone over the age of 50 could appreciate. “People won’t have to get colonoscopies,” he says.
Unfortunately, the story for PCOS isn’t so simple. Despite exhaustive searches, scientists have yet to find a cause for the syndrome, which seems to arise from multiple layers of dysfunction. Current thinking is that the path to PCOS starts in the womb, when a fetus is exposed to a blast of testosterone—or possibly some other chemical signal—that permanently reprograms the genes her body will start expressing at puberty.
But what causes this blast in the first place? Because PCOS cases tend to cluster in families, signs point to some kind of heritable genetic factor, possibly a large group of problem genes that add up to initiate the syndrome. But very little is known about how this might work.
“PCOS behaves like it’s caused by a dominant gene that doesn’t always express itself, and that’s just baffled people for a long time,” says endocrinologist Dave Abbott, a professor of obstetrics and gynecology at the UW-Madison who has spent 18 years trying to understand the in utero conditions that trigger PCOS.
When Abbott heard about Assadi-Porter’s PCOS project, he jumped at the chance to join the team, eager to approach the disease from a new angle. “The metabolome approach allows us to go from just having a diagnostic test to being a mechanistic cause investigation,” he says. “It may allow us to figure out what’s causing the metabolic [part of the] syndrome and lead to new therapeutic approaches that haven’t been applied because the knowledge isn’t there.”
But the clearest and most devastating calls for answers have come from patients themselves. From the moment the project was announced, Assadi-Porter says she has received numerous emails from women with PCOS, asking how they could participate in the search for a diagnostic test. And while the test wouldn’t help these women directly, they were eager to participate in something that could help future generations catch the disease early enough to intervene and keep the syndrome’s symptoms under control.
“These women were in the later stages and had so many symptoms,” says Assadi-Porter. “They were sending me their blood chemistry and asking, ‘Can we help you in any way? It’s so terrible to have this disease.’ They didn’t want their daughters to have to go through what they went through, should they have it.”
Each volunteer spent 12 hours inside a metabolic chamber at the UW Hospital, where they ate a prescribed dinner, ran on a treadmill and slept, all while machines recorded their breathing. Along the way, they gave samples of blood, urine and saliva that were later packaged and sent to Assadi-Porter at the NMRFAM for analysis.
From the vast pool of metabolites in these samples, Assadi-Porter has found a handful that rise to the surface as indicators of PCOS. If all goes well, this suite of metabolites will enable the creation of the medical community’s first-ever diagnostic test for the syndrome, which Assadi-Porter plans to undertake next.
The test would not merely save time, although that’s an important outcome for women who endure the guesswork currently involved in diagnosing PCOS. An immediate answer would eliminate mis-diagnosis, a common problem, and get women on therapies faster, before symptoms become severe. But mostly, an immediate answer would be just that: an answer. A way for a woman to know what her body is up against, deal with it and move on with her life.