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by Elise Wachspress

Ask just about any adult if they carry a scar, and most will admit they do. Some will point to the skinned knee that healed over badly or a rakish cleft like that in Harrison Ford’s chin; perhaps the line from a long-ago surgery or the vestige of childhood chicken pox left on an otherwise flawless décolletage. As Cormac McCarthy said, “Scars have the strange power to remind us that our past is real.”

Scars are actually webs of collagen. An injury leads to a healing response from multiple types of cells, including myofibroblasts, which manufacture the collagen that holds cells back together. Though scars may recall a painful moment in our past, they also restored our protective envelope of skin, leaving us healthy, though a little dinged.

But what if scarring becomes progressive, most often in our internal organs? In fibrotic disease, continued insults to the system lead to a runaway response, and the myofibroblasts don’t stop making collagen. The tissues involved get increasingly rigid, excess collagen starts encroaching on healthy cells, and eventually the organs involved begin to fail.

Progressive fibrosis is usually a slow process, making it hard to tell exactly what trigger or combination of triggers set the whole process in motion. This is often a particular mystery in the case of pulmonary (lung) fibrosis. With every breath, we take in everything from mold, bacteria, and viruses to environmental chemicals: which of these is the culprit? And as with allergies to substances like pet dander or peanuts, not every person responds aggressively to these factors, thus individual genetics are likely to be a factor in the disease as well.

Unfortunately, pulmonary fibrosis is fatal, and current therapies are not effective. Researchers are thus highly motivated to tackle this confoundingly complex problem from many angles. While many are particularly interested in the cell signaling that guides the process, Gokhan Mutlu, MD, and Robert Hamanaka, PhD, have been looking to starve the beast: they want to understand what nourishment myofibroblasts need to make the collagen.

Like a complex chemical plant, our bodies take in a variety of raw materials, refashion these into new chemicals, and finally manufacture the many specific compounds (proteins, lipids, nucleic acids) each of our cells need to survive and thrive. And like most chemical plants, our bodies depend on enzymes to lower the activation energy needed to get each of those chemical processes started. Mutlu and Hamanaka want to parse out the many steps in the process—from raw materials to pathological cellular outcomes—to find more than a few places to intervene in the production line and short-circuit the disease mechanism.

Knowing an amino acid called glycine makes up about a third of collagen’s structure, Mutlu, Hamanaka, and their team tried reducing this amino acid in the diets of their mouse models. But this didn’t work—it appears the fibroblasts prefer to make the glycine themselves.

They next turned to intervening in what is known as the “serine-glycine synthesis pathway,” to see if that might slow the whole fibrotic mechanism. The pathway is an important step in converting glucose—the most common carbohydrate circulating in our blood and energy source for our bodies—into the building blocks used for collagen production.

Mutlu and Hamanaka identified an enzyme crucial in the process: by using a drug to inhibit the enzyme, they could slow conversion of glucose into glycine in mice—a finding important not only in pulmonary fibrosis, but potentially in other types of organ fibrosis, like cirrhosis of the liver, as well as cancer.

Continuing to explore other parts of the collagen production process, they looked to see if they might intervene in the conversion of glutamine into proline, another amino acid essential to the collagen-making process. Proline, it turned out, also needed to be made fresh within the cells—ingesting glutamine and proline in food or as a drug did not seem to spark the collagen production. And just as with the first enzyme they identified, this second also may have relevance for many types of organ fibrosis and cancer.

This work again demonstrates how basic science—understanding how the body works and the many ways our metabolic processes can go wrong—can inform new treatments in multiple diseases.

And perhaps makes many of us grateful that our scars are evidence of the past, and not ongoing events.

Elise Wachspress is a senior communications strategist for the University of Chicago Medicine & Biological Sciences Development office