Dr. David Gokhman of the Weizmann Institute of Science, who led the study in collaboration with the laboratory of Dr. Fumitaka Inoue at Kyoto University, explains that unlike the joints of other great apes, whose composition has remained essentially unchanged for millions of years, human joints underwent a dramatic evolutionary shift. That shift made our joints less effective at cushioning the forces of everyday movement and exposed us to a suite of skeletal disorders that are almost unheard of in our evolutionary cousins. Even chimpanzees that live into their sixties or seventies remain nearly as agile as younger individuals while climbing trees, a feat that would be unthinkable for a human of comparable age with worn-out joints.

Gokhman says he chose to focus on the skeleton for two reasons. First, it is central to the story of human evolution, and second, it has been the primary source of knowledge about how our species came to be. Our skeleton is mostly what survives of our ancestors in the fossil record, and it embodies many of the features that separate us from other great apes, including upright walking, slender bones and long legs. The central challenge was to identify which genetic changes produced these features. Simply comparing human and ape genomes was not enough, because most of the differences between them turn out to be functionally silent.

The research team, led by doctoral students Nadav Mishol from Gokhman’s lab and Yizhi Yan from Inoue’s lab, mapped roughly half a million single-letter mutations that distinguish human DNA from that of chimpanzees. They discovered that the vast majority of these mutations had little or no effect on the genome’s function. Zooming in on the small fraction that mattered, around three percent, they focused on mutations that actually changed gene activity during human skeletal development. The result was the first comprehensive atlas of genomic regulatory features that distinguish the human skeleton from those of our closest living relatives, spelling out the function of each mutation that enabled the evolution of upright posture and other distinctively human skeletal traits.

Two powerful techniques made this atlas possible. The first, developed in Inoue’s laboratory, is known as a massively parallel reporter assay. It attaches tiny genetic barcodes to thousands of DNA segments at once, allowing researchers to determine which segments contain mutations that alter gene activity. The second technique uses hybrid human-chimpanzee or human-gorilla stem cells, an approach Gokhman developed during his postdoctoral work at Stanford University and later refined at Weizmann. Although it sounds exotic, the method is elegantly practical: it allows the human genome and that of another great ape to operate inside the same cell, under identical conditions. The scientists coaxed these hybrid stem cells to mature into skeletal cells and used them to identify skeleton-related genes whose activity differs between humans and chimpanzees or gorillas.

One gene-regulation difference stood out above all the others. It involved the production of long, brush-shaped sugar molecules that make cartilage springy. Cartilage cells release enormous quantities of these molecules, known as glycosaminoglycans, or GAGs, into the space around them. Because GAGs carry a strong negative electrical charge, they attract water, creating a dense, gel-like network that behaves like a shock absorber. As Mishol puts it, GAGs, along with the water they hold, make up most of the cartilage; cartilage cells are like tiny islands floating in an ocean of GAGs filling the joint.

The researchers discovered that an entire group of genes responsible for producing GAGs is less active in humans than in other great apes. They then examined cartilage samples from eight joints across different species and confirmed the consequence: humans have only about one-third as much GAG material in their cartilage as chimpanzees, gorillas, orangutans and bonobos. Without abundant GAGs, cartilage is thinner, less elastic and less able to cushion the forces generated by walking, running and lifting. Bones begin to rub against one another, setting the stage for osteoarthritis. Importantly, the GAG molecules themselves did not change during human evolution; what changed was how many of them we produce. Gokhman describes the drop in GAG production as the most extreme genetic change our skeleton has undergone in the course of evolution, and the team believes it provides an evolutionary basis for why humans are so vulnerable to osteoarthritis.

The contrast with other apes is stark. Their much larger GAG volume explains why they tend not to develop osteoarthritis or other joint disorders, showing almost no signs of skeletal disease even as they age, unless their cartilage is severely damaged by trauma. Humans, by comparison, start life with far less cartilage to begin with, and what we do have is less effective at cushioning the joints. Because cartilage has almost no capacity to regenerate, decades of use gradually erode this already limited reserve, making joint disease increasingly likely later in life. Medicine has long known that people with degenerative skeletal disease have reduced GAG levels in their joints, but identifying this reduction as the major evolutionary change behind human susceptibility may open new avenues for studying osteoarthritis, pinpointing the genetic mechanisms behind cartilage thinning, identifying people at risk and potentially improving prevention and therapy.

This raises an obvious puzzle: if thinner cartilage is so problematic, why would evolution preserve it? The researchers propose two hypotheses, both plausible but unproven. The first involves the brain. Although GAGs are best known for their structural 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 GAGs lock neural circuits into place, limiting the brain’s ability to keep rewiring itself. Lower GAG levels may therefore have allowed the human brain to remain exceptionally malleable for much longer than in other great apes, giving humans more time to learn, adapt and acquire increasingly complex skills. The second possibility concerns the skeleton itself. Compared with other great apes, humans have lighter, more slender bones, and a reduction in GAGs may have contributed to building this delicate frame. That idea fits neatly with one of the leading hypotheses in human evolution, which holds that our bodies were shaped for long-distance running. Humans may be relatively weak and unable to sprint as fast as many mammals, but we can keep moving for hours, an adaptation that may have allowed early humans to pursue prey over long distances until the animals overheated and collapsed.

Whether this trade-off was worth it is a question that may be impossible to answer. From evolution’s perspective, painful knees at age seventy may be a surprisingly small price to pay for advantages that improve the chances of survival at age twenty, because natural selection often favors traits that boost reproductive success even when those traits carry heavy costs later in life. Millions of years after these traits took hold, humans have become a species capable of studying their own evolution with sophisticated tools such as hybrid stem cells and massively parallel reporter assays, while simultaneously possessing remarkably bad knees. The study’s findings suggest that our aching joints are not a design flaw so much as the residue of an ancient bargain, one that traded cartilage for cognition and endurance, and left modern humanity to manage the consequences with medicine rather than mutation.

Subject of Research: Evolutionary genetics of human susceptibility to osteoarthritis and joint disease compared with other great apes

Article Title: Blame evolution for your bad knees

Article References: Blame evolution for your bad knees. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: osteoarthritis, human evolution, cartilage, glycosaminoglycans, great apes, genomics, gene regulation, stem cells, skeleton, bipedalism, Weizmann Institute, Nature