If you suffer from a chronic joint disease such as osteoarthritis, you may be overweight and put a strain on your knees. But you can also blame evolution and envy chimpanzees and gorillas, who are almost always exempt from this painful and debilitating condition. Associate Professor David Gokhman of the Weizmann Institute of Science in Rehovot has just conducted a study of the problem in collaboration with the laboratory of Dr. Fumitaka Inoue at Kyoto University in Japan. He and his team, led by PhD students Nadav Mishol of Gokhman’s lab and Yizhi Yan of Inoue’s lab, have just published their findings in the prestigious journal Nature, titled “Gene Regulatory Evolution of the Human Skeleton.” “That change made our joints less effective at absorbing impacts and exposed us to skeletal diseases, including osteoarthritis, spinal disc degeneration, and herniated discs, which are rare in other great apes, including those who live into old age. “Even chimpanzees who live to be 60 or 70 years old, for example. For example, they are almost as agile as the younger ones when climbing trees,” Gokhman, a molecular geneticist, told The Jerusalem Post in an interview. FROM LEFT: Dr. David Gokhman, Noam Priel and Nadav Mishol (credit: WEIZMANN INSTITUTE OF SCIENCE) At first glance, “it seems like we have reached a bad evolutionary deal. Natural selection is supposed to eliminate harmful traits, so why are we so much more likely to suffer from wear and tear disorders of the joints and spine than our cousins? “Osteoarthritis, for example, a leading cause of disability and reduced quality of life, affects hundreds of millions of people around the world.” The researchers proposed an answer based on hybrid chimpanzee-human cells and other advanced techniques. They reveal that painful joints may be a hidden price we pay for traits that make us human. “Unlike the joints of other great apes, whose composition has not changed for millions of years, human joints underwent a dramatic evolutionary change,” Gokhman added. He said he chose to look at the skeleton because it has been the main source of knowledge about how our species evolved. “It also reflects many of the characteristics that distinguish us from other great apes, including our upright gait, thin bones and long legs,” he explained. Cartilage cells release enormous amounts of molecules called glycosaminoglycans (GAGs) into the space around them. “GAGs, along with the water they retain, make up the majority of cartilage,” Mishol added. “Cartilage cells are like little islands floating in an ocean of GAGs that fill the joint.” The reduction in GAG content was found in all eight joints they studied, including hips, elbows, shoulders, wrists and finger joints, so “it was apparently the same throughout the body,” Gokhman said. “We saw differences between younger specimens, at 20 or 30 years old, so we think it was present even at birth. Human cartilage is thinner, more stable and stronger, so there is a benefit. “GAG molecules attract and hold water because they are both polar, with a negative charge on one end and a positive charge on the other, like with a magnet, and this makes the cartilage stronger, creating a dense gel-like network. They then constructed the first comprehensive atlas of genomic regulatory features that distinguished the human skeleton from those of our closest living relatives and explained the function of each mutation that made possible the upright posture of humans and other skeletal features. distinctively human, they said. To reach this result, the researchers in Inoue’s laboratory developed a “massively parallel reporter assay,” which attaches small genetic barcodes that determine changes in genetic activity to thousands of DNA segments at a time. They also used human-chimpanzee or human-gorilla hybrid stem cells. Japanese researchers and later refined at Weizmann, allows the human genome and that of another great ape to function within the same cell, under identical conditions. They forced these stem cells to mature into skeletal cells to identify skeletal-related genes whose activity differs between humans and chimpanzees or gorillas, a human being capable of walking upright, running long distances, developing an extraordinary brain and living much longer than most other mammals,” he said. Gokhman. “However, 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. Having smaller jaws can lead to orthodontic problems, including crooked teeth and chewing difficulties.” The reduction in GAG production took several million years, and the mutation probably occurred very quickly. It took the team five years to conduct their study. Japanese researchers identified 15,077 regulatory elements with human-specific activity. A few hundred of them were involved in the GAG pathway. The Israelis did the analysis. When asked why evolution would give humans weaker joints, Gokhman said: “If there are fewer GAGs, the brain develops more slowly over 20 years, but we pay for this in our skeletons. In a wolf, for example, it only takes two years.” The team suggested that early humans evolved for endurance running and long-distance hunting. Reducing cartilage cushioning actually improved running efficiency. On the path to better treatment. Compared to other great apes, humans have lighter and thinner bones, so fewer GAGs may have helped build this delicate skeleton. “That idea fits perfectly with one of the main hypotheses of human evolution: that our bodies were shaped to run long distances. We may be relatively weak and can’t run as fast as many mammals, but we can keep moving for hours,” Gokhman said. “This adaptation may have allowed early humans to chase prey over long distances until the animals overheated and collapsed,” he suggested. “I hate running myself, but when my father lived in Russia, he was an Olympic sprinter. Then he broke his wrist and had to stop; he suffers from this even today.” Gokhman believes his discovery could eventually lead to better treatment of patients. “Today, many hospital orthopedists give GAGS injections, so perhaps early treatment could help prevent disability. Simple genetic tests can identify some people with cartilage degeneration; better ones will have to be developed. But we are a long way from using it for gene therapy.” A much larger volume of GAG explains why other great apes tend not to develop osteoarthritis or other joint disorders, and show almost no signs of skeletal disease even as they age, unless their cartilage is severely damaged by trauma, he continued. Humans, by comparison, start life with much less cartilage, and what we have is less effective at cushioning joints. Since cartilage has almost no ability to regenerate, decades of use gradually erode. This already limited reserve makes joint diseases much more likely in the future. If thinner cartilage is so problematic, why would evolution preserve it? One possible explanation has to do with the brain. Although GAGs are best known for their role in cartilage, they are also abundant in the brain and the rest of the nervous system, where they help stabilize connections between neurons. High levels of GAG lock neural circuits in place, limiting the brain’s ability to continue rewiring itself. remain exceptionally malleable for much longer compared to other great apes, giving humans more time to learn, adapt and acquire increasingly complex skills, he explained. It is impossible to answer whether that trade-off was worth it. “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 very bad knees,” Gokhman said.
