Aaccording to the latest estimates, Covid-19 may be responsible for more than 18 million deaths worldwide. While infectious diseases such as these have devastated humanity, it may be wrong to assume that they are always at odds with our survival and flourishing as a species. Otherwise, why would ancient pathogens such as malaria (from the falciparum type), cholera, typhoid, measles and influenza A persist as human diseases – and why haven’t we developed immunity to them?
This is a question that professors Ajit and Nissi Varki (a husband and wife team) and colleagues at their lab at the University of California, San Diego, has been asking for several decades. The answer, they believe, lies in the complex array of sugar chains called glycans that decorate the surfaces of cells, and the sugar molecules known as sialic acids that cover most of these chains. This terminal sugar chains are involved in everything from regulating immune responses to adaptations that may have played a key role in human evolution, such as the ability of our early hominin ancestors to run longer without tiring – an advantage when chasing prey .
Ajit Varki first became interested in sialic acids and glycobiology in the early 1980s when he treated a patient who had an adverse immune reaction to a therapeutic horse serum used to treat a type of anemia. Rather than the immune response being directed against the presence of foreign proteins – then the standard explanation in biology textbooks – Varki discovered it was due to the sialic acids on the horse proteins, which was surprising since every vertebrate, including humans, can make sialic acids .
His fascination with sialic acids deepened when, together with colleague Prof. Pascal Gagneux, he discovered that our ancient ancestors lost one type of sialic acid with an added oxygen atom, known as Neu5Gc, from their genomes about 3 million years ago, before the emergence of the ancient man Homo erectus. It has descendants of Homo erectusincluding our own species, Homo sapienswith the inability to produce Neu5Gc and an excess of another type of sialic acid, known as Neu5Ac, from which most mammals can obtain Neu5Gc.
First published in the Proceedings of the National Academy of Sciences in 2009, Gagneux and Varki’s report initially sparked interest among specialists working at the interface of animal and human medicine. However, in the wake of the Covid pandemic, it has taken on new meaning, as several studies have found that these sugar shells may be involved in Covid-19’s disease effects. They suggest that Neu5Ac may be associated with the more efficient binding of the Sars-CoV-2 spike protein to animal cells, suggesting that it may play an important role in the pathology and severity of the disease in susceptible animals, such as ferrets, minks and humans.
Our inability to produce Neu5Gc, combined with an increase in production of Neu5Ac, also appears to play a role in susceptibility to other diseases thought to be unique to humans, such as typhoid and cholera, as well as sexually transmitted diseases such as chlamydia, syphilis and gonorrhea.
“In the case of these diseases, it seems that the pathogen has learned to cover itself in the human kind of sialic acid and turn it into a wolf in sheep’s clothing,” says Varki.
What makes Varki and Gagneux’s research even more interesting is that the Neu5Gc-eliminating mutation was the first reported biochemical difference between humans and chimpanzees, whose DNA differs from ours by about 5%. The fact that it took place long before the origin of Homo erectusthe first species with a large brain to use tools suggests that it may have played a role in the evolutionary history of our own species, Homo sapiens.
Another implication of their study is that our ancestors enjoyed a malaria-free existence up to and including the Neolithic transition 10,000 years ago, coinciding with the shift from nomadic to agrarian lifestyles, Plasmodium falciparum, the parasite responsible for the deadliest form of human malaria, mutated to target Neu5Ac that is so abundantly present on human cells. It is thought that our more agricultural lifestyle has made people more vulnerable to the malaria-carrying mosquitoes that breed in stagnant pools near settlements.
“What makes the study of sialic acids so exciting is that they are a missing piece of the puzzle of how parasites became adapted to humans,” says Dr Robert de Vries, a virologist at Utrecht University who studies the role of sialic acids. investigation. in mediating our susceptibility to influenza A. “Ajit’s work is decisive. He is one of the godfathers of sialic acid biology.”
In 2008, Varki’s insights led him to found an informal think tank, the Center for Academic Research and Training in Anthropology (Carta), to examine other human characteristics that distinguish us from our closest ape ancestors (anthropogeny is the study of the origin and development of human societies and cultures).
Carta hosts three meetings each year to bring together primatologists, anthropologists, paleontologists, linguists, and molecular and evolutionary biologists to share their research. Previous conversations addressed topics such as sequencing the chimpanzee genome, the origins of bipedalism, and the human penchant for storytelling.
“We are the paradoxical ape: bipedal, naked, big-brained, long the master of tools, fire and language, but still trying to understand ourselves,” says Gagneux, an evolutionary biologist and anthropologist.
Infectious diseases are just one part of Varki and Gagneux’s research. They believe that the binding of these sugars on the surface of our cells by receptors on immune and other cells may also be involved in various biological processes that have undergone unique human evolution, including cancers related to the consumption of red meat.
Beef, pork and lamb contain large amounts of Neu5Gc, and when people ingest this non-human sugar molecule, it is absorbed into our tissues. While our enzymatic machinery can easily use and incorporate this foreign sugar, our immune system recognizes the molecule as foreign and attacks tissues that contain it, leading to inflammation and a higher lifetime risk of cancer. That’s not to say that carcinogens produced by grilling red meat don’t also play a role in bowel cancer. But what makes the Neu5Gc process unique is that the sialic acid becomes part of our own cells.
“This is the first example we know of something that is foreign, but is completely absorbed into you despite the fact that your immune system recognizes it,” says Varki.
Equally fascinating is the possibility that the build-up of Neu5Gc due to the overconsumption of meat and dairy products could be linked to cases of human infertility.
However, Varki and Gagneux do not believe that everything can be reduced to biology. One of the key insights gained from their study of human origins is that we are shaped as much by our cultural heritage as by genes and biology. “Sialic acids give us a new appreciation of how we are directly shaped by infectious diseases,” says Gagneux. “However, these tiny sugar molecules can also have repercussions for [cultural] processes that have nothing to do with disease.”
Gonorrhea and the ‘Grandma Effect’
Biologists have long been confused about the menopause. If natural selection favors genes that produce more offspring, women should remain fertile throughout their lives. But women typically live beyond their reproductive limit for decades.
Strangely enough, this phenomenon is almost unique to humans: to date, only toothed whales such as orcas and chimpanzees native to a remote region of Uganda were found to show similar post-menopausal lifespan.
To explain the menopause, biologists propose something called “the grandmother effect” – the idea that grandmothers contribute to the survival of the species by caring for related women’s children.
However, grandmothers would not be very effective caregivers if they were at risk of losing children to conditions that affect memory, such as Alzheimer’s disease.
This is where sialic acids come in. In a 2022 paper, Ajit Varki and Pascal Gagneux found that humans possess a modified version of a sugar-binding gene receptor known as CD33, which is found on immune cells – and the version we have is protective against Alzheimer’s.
Standard CD33 receptors interact with many cells in the body, including brain immune cells called microglia. Microglia help control neuroinflammation and play an important role in removing damaged brain cells and the amyloid plaques associated with Alzheimer’s disease.
However, by binding to the sialic acids on these cells and plaques, regular CD33 receptors suppress this important microglial function and increase the risk of dementia.
Fortunately, somewhere along the evolutionary line, humans picked up a mutated form of CD33 that lacks this sugar binding site. The mutated receptor no longer responds to sialic acids on damaged cells and plaques, allowing the microglia to break them down. Indeed, higher levels of this CD33 variant are protective against late-onset Alzheimer’s.
This mutated form of CD33 is not only missing from chimpanzees, but is also absent from the genomes of Neanderthals or Denisovans, our closest evolutionary relatives.
“This suggests that the wisdom and care of healthy grandparents may have been an important evolutionary advantage we had over other ancient hominin species,” says Varki. “Grandmas are so important, we even evolved genes to protect their minds.”
Interestingly, the protective form of CD33 may have emerged in response to gonorrhea. This is because gonorrhea bacteria coat themselves with the same sugars that CD33 receptors bind to, thus tricking human immune cells into not seeing them as foreign invaders.
Varki and Gagneux suggest that the mutated version of CD33 emerged as a human adaptation against such “molecular mimicry” by gonorrhea and that the gene variant was later co-opted by the brain for its benefits against dementia.
“It is possible that CD33 is one of many genes that are selected for their survival benefits against infectious pathogens early in life, but then secondarily selected for their protective effects against dementia and other aging-related diseases,” says Gagneux.
