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A trick of nature

(Photo: Bill Marchel)

U scientists turn to the hibernating golden gopher for the key to surviving traumatic blood loss

Major blood loss is a medical conundrum. Lose enough blood and the brain, heart, and other organs starve for oxygen and die. Even if you survive the blood loss, restoring normal blood and oxygen levels—called reperfusion—can cause as much harm as the blood loss itself.

But three University of Minnesota scientists have developed a drug that prevents both from happening, a discovery that could save thousands of lives in trauma centers and on battlefields worldwide — thanks to a squirrel.

The drug, called Tamiasyn™, contains two compounds the 13-lined ground squirrel uses to survive Minnesota winters.

University of Minnesota, Duluth biologist Matthew Andrews, Ph.D., has studied the “golden gopher” since the mid-1990s. How, he wondered, can it survive extremely low oxygen levels and blood flow—a condition that resembles major blood loss—then wake up without any harm done when oxygen levels and blood flow are restored? In humans who experience blood loss, reperfusion releases a storm of cell-damaging, unstable molecules called free radicals.

Andrews discovered that when the ground squirrel hibernates, it switches from burning glucose for fuel to burning beta-hydroxybutyrate. A byproduct of fat breakdown, the compound is a more efficient fuel than glucose because it requires less oxygen to produce the same amount of energy for cells. “Beta-hydroxybutyrate gives you a lot more energy-bang for your buck,” Andrews says.

Medical School-Duluth Campus scientists Lester Drewes, Ph.D. (left), and Matthew Andrews, Ph.D., working with their Twin Cities colleague Gregory Beilman, M.D. (not pictured), discovered that a drug made with two compounds that help hibernating gophers

He also observed that as ground squirrels wake up, their melatonin levels skyrocket — ironically, the same melatonin people take to sleep. “Melatonin is a powerful antioxidant,” Andrews explains. “It scavenges free radicals by chemically binding to them and reduces the damage they do to cells when you restore normal blood and oxygen levels.”

Surges in beta-hydroxybutyrate and melatonin are two of the most striking changes that happen in hibernating animals, says Andrews. “That’s why they can live for six months with very little oxygen, a heart rate of only a few beats per minute, but wake up unharmed.

“Might these molecules have medical benefits for non-hibernating animals?” Andrews wondered. Two buildings over from his lab at the Medical School-Duluth Campus, Lester Drewes, Ph.D., was researching ways to protect the brain from the oxygen-depleting damage caused by strokes and heart attacks. And he was studying how to prevent reperfusion injury to the brain when oxygen and blood levels are restored. Beta-hydroxybutyrate was one of the protective molecules he was studying. “An instant collaboration developed between Matt and me,” Drewes says.

“We decided to apply what Matt discovered about the natural biology of hibernation,” says Drewes, who had tried unsuccessfully to reduce brain injury using antioxidant vitamins E and C. UMD graduate student Amanda Klein administered beta-hydroxybutyrate and melatonin to rats that had lost as much as 60 percent of their blood. Reperfused rats not receiving these molecules died within seven minutes. Those given beta-hydroxybutyrate lived for three hours.

To take their findings to the next level, Andrews and Drewes needed to replicate their results in large animals. About that time, UMD hosted an Integrated Biosciences (IBS) graduate program colloquium. Among the speakers was IBS faculty member Gregory Beilman, M.D., a trauma surgeon and professor at the University’s Minneapolis campus. Beilman presented his studies on prolonging survival in pigs after major blood loss.

Gregory Beilman, M.D.

“Our jaws dropped,” says Drewes. “This was exactly what Matt and I were looking for. We didn’t know Greg. It was serendipitous that he showed up at our symposium to talk about blood loss in larger animals.”

A colonel in the U.S. Army, Beilman had served four tours of duty trying to prolong survival in war zones. Back home in his lab, he’d experimented with a dozen ways to preserve organ function after blood loss. “Nothing worked,” he says.

Beilman conducted three pig trials of Tamiasyn™ to determine safety, effectiveness, and dose. After 24 hours, four times as many Tamiasyn™- treated pigs survived. “It also took less fluid to rehydrate the Tamiasyn™- treated pigs, and it was easier to restore their normal blood volume,” Beilman says. As for the drug’s safety, “We haven’t found a downside to it.”

The potential benefits of Tamiasyn™ are tremendous. Most people who initially survive motor vehicle accidents, gunshot wounds, or battle injuries but still end up dying do so because they bleed to death, explains Beilman.

A molecule called beta-hydroxybutyrate helps the hibernating ground squirrel survive the winter with extremely low oxygen levels and blood flow. (Photo: Dan Schlies)

Tamiasyn™ is not a blood or oxygen substitute. Instead, it buys time. The body survives on less blood and oxygen because—like the hibernating ground squirrel—it requires less oxygen to produce the energy needed to function. Tamiasyn™ delays death and organ damage while the victim is rushed to a hospital or MASH unit that can stop the bleeding and restore blood volume without reperfusion injury. “You can live with less oxygen,” says Drewes. “That’s pretty significant.”

Getting Tamiasyn™ into ambulances, trauma centers, and war zones will take several more years, says Doug Johnson with the University’s Office for Technology Commercialization (OTC). An early attempt to develop and market Tamiasyn™ fizzled out when the company could not secure adequate funding. The OTC is now exploring other options for commercializing Tamiasyn™, including licensing to a pharmaceutical company. In the meantime, all three researchers have secured funding from federal agencies to advance the technology. Once approved by the FDA, Tamiasyn™ could potentially save 33,000 lives in the United States each year, Johnson says.

For now, prolonging survival after blood loss is the focus, but eventually, says Drewes, “Tamiasyn™ may be used to reduce brain damage from stroke.” And it may prove useful during invasive surgery and as a way to prolong storage life of transplantable organs, adds Beilman.

“We simply had to observe what nature had already done for us,” says Andrews. “We observed a complex and elegant biochemical trick that 100 million years of mammalian evolution produced in a ground squirrel widely considered a pest in Minnesota.”

By Howard Bell

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