When Eliud Kipchoge of Kenya crossed the finish line at the Berlin Marathon in September 2018, he smashed the world record with a time of 2 hours 1 minute 39 seconds. Just a few days before Kipchoge’s win, scientists identified a new factor that might have contributed to humankind’s capacity for endurance: the long-ago loss of a gene called CMAH.
Studies suggest that a mutation caused humans to lose function of the CMAH gene two to three million years ago—around the same time humans seem to have developed an increased capacity for endurance running. Since CMAH is involved in making a sugar called Neu5Gc, humans, unlike most other mammals, no longer have this sugar. Building on previous work led by study author Ajit Varki, a physician-scientist at the University of California San Diego, a new study suggests that losing the CMAH gene and Neu5Gc sugar might have given ancient humans an endurance running boost. These findings appeared in September 2018 in the journal Proceedings of the Royal Society B.
To learn more about CMAH function, the study’s first author, Jonathan Okerblom, a biomedical researcher at UCSD, and his colleagues engineered mice that did not express the gene and tested their exercise capacity and musculature. Mice in which CMAH expression was blocked ran at higher speeds and took on longer distances compared to mice who still expressed the gene, indicating improved endurance.
“They started running like 18 kilometers in a night,” Okerblom says of the mice in which CMAH was blocked. This was about 20 percent farther than the mice who still expressed CMAH.
Ellen Breen, a UCSD physiologist involved in this work, also examined the muscles of mice that didn’t express CMAH. She found that their hind limb muscles showed a greater resistance to fatigue and had more blood vessels. The team also observed changes in major metabolic pathways in these mice. Together, Okerblom says, their results suggest that loss of CMAH and the Neu5Gc sugar in mice may improve their muscles’ capacity for oxygen use—perhaps by changing how oxygen enters cells. If these results extend to humans, the loss of CMAH could help explain why humans became capable of running long distances.
“If you follow the evolutionary lineage of humans, the loss of CMAH is a clear genetic difference between humans and our closest genetic relatives: chimpanzees,” Okerblom says. To Okerblom and his colleagues, this difference suggested that CMAH loss could be linked to changes that set humans apart from their primate relatives.
Daniel Lieberman, chair of the Department of Human Evolutionary Biology at Harvard University, who was not involved in the study, calls it “terrific,” and says the work builds on the anatomical and physiological evidence he previously presented to suggest that humans evolved to run long distances.
“The one thing that was not available at the time [of his previous research] was any evidence of genes that were selected that gave us this capability,” Lieberman says. “This is exactly what we were looking for.”
In addition to endurance, Okerblom and his colleagues are exploring other ways in which CMAH loss might have affected our ancient ancestors. Some evidence suggests that loss of CMAH function might have altered immune and metabolic activity—particularly in terms of susceptibility to inflammation and diseases like diabetes and cancer.
If this connection to inflammation and disease is confirmed, then losing CMAH and becoming better endurance runners might have come “at an interesting cost,” Lieberman says. “We evolved to run in order to hunt for meat, but this genetic change also likely made us subject to inflammation when we ate meat. So there’s this interesting tradeoff because running is healthy but eating meat is not...but both probably helped our ancestors have big brains and survive.”
According to the evolutionary scenario Lieberman and others have described, endurance running played a crucial role as humans began consuming meat around 2 to 3 million years ago. They say that certain physiological changes linked to endurance—like large glute muscles and springy tendons—may have evolved around this time, allowing humans to become better long-distance hunters or scavengers. Before humans developed weapons, their ability to wear prey down over long distances might have made up for their lack of size, strength, and speed.
But not everyone agrees. “These scenarios are based on essentially one story about human evolution,” says Jeffrey Schwartz, a physical anthropologist at the University of Pittsburgh, who was not involved in the study. “It’s not as simple as people make it out to be.” Given the complexity of human evolutionary history, he says, it’s very difficult to draw conclusions about which genetic changes are connected to certain adaptations.
One thing most scientists can agree on is that humans are largely unimpressive physical performers within the animal kingdom. No matter how hard we hit the gym, we are not especially fast or powerful compared to many other animals. Aside, of course, from our one truly impressive physical feat, which is best observed on the sidelines of a marathon: an extraordinary ability to run long distances.
“Michael Phelps would get destroyed by a dolphin,” Okerblom says. “But only a handful of animals could outrun us in the marathon. When it comes to endurance, humans are exceptional.”