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Gary Patti: Metabolomics of Health and Disease

Gary Patti: Metabolomics of Health and Disease
Assistant professor, Washington University in St. Louis
Recommended by: Oliver Fiehn, University of California, Davis

Patti.jpgGary Patti was studying bacterial resistance when he realized that to understand what was going on, he was going to have to analyze a lot of metabolites. That led him to using NMR, but since that approach could only tackle a hundred or so metabolites at once, he started using mass spectrometry. That, in turn, led him to finding a fellowship in a metabolomics lab.

"It fit with the way that I thought about science really well so it's just accelerated even though I am no longer doing any work with bacterial resistance," Patti said.

Instead, his lab at WashU is focusing on cancer and chronic pain.

Patti has been influenced by the story of Otto Warburg, a German biochemist who won the Nobel Prize in 1931 and trained Hans Kreb, among others. Warburg noticed that cancer cells behaved oddly: they broke down glucose through glycolysis rather by more efficient oxidative phosphorylation. Warburg, though, was ignored as he offered this theory.

But Patti noted that Warburg's hypothesis has held up — metabolomic and other tools have shown that cancer cells do funny things that indicate that their metabolism has been rewired.

As mass spec and other tools become more and more sensitive, they are also capturing more and more unknown metabolites.

Another focus of the Patti lab is on chronic pain. Acute pain, Patti noted, makes sense as something like fire can damage tissue, and so a signal to remove your hand from a hot stovetop before it blisters is understandable. But chronic pain, which tends to develop after an accident, makes less sense.

"We don't really understand the chemical basis of what's actually happening with the condition, and so we asked whether or not some of these unknown molecules that we're detecting might actually be contributing to this phenomenon," Patti said.

A challenge of dealing with metabolomic data, as compared to genomic or proteomic data, is that metabolites are less well defined. Genes are made up of nucleotides and proteins of amino acids, but metabolites are much more diverse, Patti said.

"You have molecules that are just long, hydrophobic chains, very sticky molecules, very organic, fatlike molecules. And then you have molecules that have tons of charges that are very polar, water soluble-type molecules," he added.

He noted that researchers once thought there would be one approach that metabolomics researchers would use, but he said it's becoming increasingly clear that a number of tools will be necessary.

Paper of note

For chronic pain, Patti and his colleagues compared the metabolomes of rats suffering from such pain after a surgery and rats that underwent a sham operation. As they reported in Nature Chemical Biology in 2012, they found that the metabolite N,N-dimethylsphingosine (DMS) was associated with the condition and seemed to be able to induce chronic pain in rats that hadn't been injured. More recent studies, he added, indicate that people suffering from chronic pain have elevated DMS levels.

This also, Patti said, opens up a potential avenue for treating chronic pain by blocking DMS, and he noted that his lab is collaborating with a few pharmaceutical companies.

Looking ahead

Going forward, Patti said that it will become easier to identify new peaks, rather than just note that a peak corresponds to a compound, and that the field will become increasingly quantitative.

"I think that where we are headed is not only being able to assign and to detect with structural confidence a lot of these compounds, but getting a huge amount of quantitative information that is also going to contribute to our modern-day vision of biochemistry," he said.

And the Nobel goes to…

If Patti were to fly to Stockholm to receive the Nobel Prize, he'd like it to be for challenging the fundamental ideas of biochemistry. Recent metabolomic work, he said, has shown that the current understanding of metabolism and the regulation of metabolism is incomplete. Filling that knowledge in, he added, will help in understanding health and disease.