People who suffer from chronic joint diseases such as osteoarthritis often blame excess weight or aging knees. A new Israeli-led study suggests they can also blame evolution, and perhaps envy chimpanzees and gorillas, which are almost always spared the painful and debilitating condition.
Associate Prof. David Gokhman of the Weizmann Institute of Science in Rehovot conducted the research with the laboratory of Dr. Fumitaka Inoue of Kyoto University in Japan. The team, led by doctoral students Nadav Mishol from Gokhman's lab and Yizhi Yan from Inoue's lab, published its findings in the journal Nature under the title "The gene-regulatory evolution of the human skeleton." The work took five years to complete.
"Unlike the joints of other great apes, whose composition hasn't changed for millions of years, human joints underwent a dramatic evolutionary shift," Gokhman, a molecular geneticist, told The Jerusalem Post. That shift, he said, made human joints less effective at absorbing shocks and exposed people to skeletal diseases including osteoarthritis, degeneration of the spinal discs and herniated discs, conditions uncommon in other great apes even into old age. "Even chimps that live into their 60s or 70s, for example, are almost as agile as younger ones while climbing trees," he said.
The researchers mapped about half a million single-letter mutations that distinguish human DNA from that of chimpanzees, then found that the vast majority had little or no effect on genome function. They focused on the roughly 3 percent of mutations that did change gene activity during human skeletal development, and built the first comprehensive atlas of genomic regulatory features separating the human skeleton from those of our closest living relatives. The Japanese team identified 15,077 regulatory elements with human-specific activity, a few hundred of them involved in the cartilage pathway, while the Israeli side carried out the analysis.
To reach these results, the scientists developed a "massively parallel reporter assay" in Inoue's lab, attaching tiny genetic barcodes to thousands of DNA segments at once to measure changes in gene activity. They also used hybrid human-chimpanzee and human-gorilla stem cells, an approach Gokhman developed during postdoctoral work at Stanford University and later refined at Weizmann. The method lets the human genome and that of another great ape operate inside the same cell under identical conditions. The team then coaxed the stem cells to mature into skeletal cells to identify genes whose activity differs between the species.
At the center of the findings are molecules called glycosaminoglycans, or GAGs, which cartilage cells release in enormous quantities. "GAGs, along with the water they hold, make up most of the cartilage," Mishol said. "Cartilage cells are like tiny islands floating in an ocean of GAGs filling the joint." Because both GAGs and water are polar, the molecules attract and retain water, creating a dense, gel-like network that works like a shock absorber. Humans produce far fewer GAGs, and the reduction appeared in all eight joints studied, including hips, elbows, shoulders, wrists and finger joints. Differences were visible even in specimens aged 20 or 30, leading the team to believe the trait is present from birth.
The payoff, the researchers argue, is a body built for endurance. Human cartilage is thinner, stable and strong, and reduced cushioning may have improved running efficiency. "That idea fits neatly with one of the leading hypotheses in human evolution, that our bodies were shaped for long-distance running," Gokhman said, noting that early humans may have pursued prey until the animals overheated and collapsed. Lower GAG levels may also have kept the human brain malleable for longer, since high levels of the molecules lock neural circuits into place. "If there is less GAG, the brain develops more slowly over 20 years, but we pay for this in our skeletons," he said, contrasting that with the wolf, whose brain matures in only two years.
"We seem to have struck a poor evolutionary bargain," Gokhman said of the result. "Evolution thus produced a human being capable of walking upright, running long distances, developing an extraordinary brain and living much longer than most other mammals. Yet we suffer from degenerative joint diseases that appear to be much less common in our closest evolutionary relatives. We have paid a biological price for becoming human." He cited other costs as well: narrower female hips that make childbirth more painful, longer lifespans that bring more chronic disease, and smaller jaws that can cause orthodontic problems.
Because cartilage has almost no capacity to regenerate, decades of use erode an already limited reserve, making joint disease far more likely later in life. Osteoarthritis alone affects hundreds of millions of people worldwide and is a major cause of disability. Gokhman believes the discovery could eventually improve treatment. Many orthopedists already inject GAGs, he noted, so earlier intervention might help prevent disability, and genetic testing could one day identify people prone to cartilage degeneration, though gene therapy remains far off.
Whether the trade-off was worth it is impossible to answer, Gokhman conceded. "Millions of years after those traits took hold, humans have become a species capable of studying their own evolution using sophisticated tools. We also have remarkably bad knees."
