According to the latest estimates, Covid-19 may be responsible for more than 18 million deaths worldwide. While infectious diseases like this have devastated humanity, it may be wrong to assume they are always antithetical to our survival and flourishing as a species. Otherwise, why would ancient pathogens such as malaria (of the falciparum type), cholera, typhoid, measles and influenza A persist as human-only diseases – and why have we not evolved immunity to them?
That is a question professors Ajit and Nissi Varki (a husband and wife team) and colleagues at their lab at the University of California, San Diego, have 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 cap most of these chains. These terminal sugar chains are involved in everything from the regulation of 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 for longer without becoming fatigued – an advantage when pursuing prey.
Ajit Varki first became interested in sialic acids and glycobiology in the early 1980s, when he was treating a patient who had suffered an adverse immune response to a therapeutic horse serum used to treat a type of anaemia. Rather than the immune response being directed against the presence of foreign proteins – then the standard explanation in biology textbooks – Varki discovered it was because of the sialic acids on the horse proteins, which was surprising as every vertebrate, including humans, can make sialic acids.
His fascination with sialic acids deepened when, with colleague Prof Pascal Gagneux, he discovered that our ancient ancestors had lost one kind of sialic acid with an added oxygen atom, known as Neu5Gc, from their genomes around 3m years ago, before the emergence of the ancient human Homo erectus. This left descendants of Homo erectus, including our own species, Homo sapiens, with the inability to produce Neu5Gc and an excess of another type of sialic acid, known as Neu5Ac, from which most mammals can derive 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 significance as several studies have found that these sugar caps 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 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 seems 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 gonorrhoea.
“In the case of these diseases, it appears that the pathogen has learned to coat itself in the human kind of sialic acid, turning it into a wolf in sheep’s clothing,” says Varki.
What makes Varki and Gagneux’s research even more intriguing is that the Neu5Gc-eliminating mutation was the first reported biochemical difference between humans and chimps, whose DNA differs from ours by about 5%. The fact that it occurred long before the emergence of Homo erectus, the first species with a large brain that used 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 right up until the neolithic transition 10,000 years ago when, coincident with the shift from nomadic to agrarian lifestyles, Plasmodium falciparum, the parasite responsible for the deadliest form of human malaria, mutated to target Neu5Ac so abundantly present on human cells. It is thought that our more agricultural lifestyle made humans more vulnerable to the malaria-carrying mosquitoes that bred in stagnant pools near settlements.
“What makes the study of sialic acids so exciting is that they are a missing part of the puzzle of how parasites became adapted to humans,” says Dr Robert de Vries, a virologist at the University of Utrecht who is investigating the role of sialic acids in mediating our susceptibility to influenza A. “Ajit’s work is seminal. He’s one of the godfathers of sialic acid biology.”
In 2008, Varki’s insights led him to set up an informal thinktank, the Center for Academic Research and Training in Anthropogeny (Carta), to investigate other human traits that distinguish us from our nearest ape ancestors (anthropogeny is the study of the origin and development of human societies and cultures).
Every year, Carta hosts three meetings to bring together primatologists, anthropologists, palaeontologists, linguists and molecular and evolutionary biologists to share their research. Previous talks have addressed subjects such as the sequencing of the chimpanzee genome, the origins of bipedalism and the human penchant for storytelling.
“We are the paradoxical ape: bipedal, naked, large-brained, long the master of tools, fire and language but still trying to understand ourselves,” says Gagneux, an evolutionary biologist and anthropologist.
Infectious disease is just one strand 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 several biological processes that have undergone uniquely human evolution, including cancers linked to the consumption of red meat.
Beef, pork and lamb contain large amounts of Neu5Gc, and when humans consume this non-human sugar molecule it gets incorporated into our tissues. While our enzymatic machinery can readily use this foreign sugar and incorporate it, our immune system recognises the molecule as foreign and attacks tissues containing it, leading to inflammation and a higher lifetime risk of cancer. That is not to say that carcinogens produced by grilling red meat do not 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’s foreign but which gets totally incorporated into you despite the fact that your immune system recognises it,” says Varki.
Equally fascinating is the possibility that the buildup of Neu5Gc because of the overconsumption of meat and dairy products may 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 drawn from their study of human origins is that we are shaped as much by our cultural inheritance as by genes and biology. “Sialic acids give us a new appreciation of how we have been directly shaped by infectious diseases,” says Gagneux. “However, these tiny sugar molecules may also have repercussions for [cultural] processes that have nothing to do with disease.”
Gonorrhoea and the ‘grandmother effect’
Biologists have long been perplexed by the menopause. If natural selection favours genes that produce more descendants, then women ought to remain fertile throughout their lives. But women usually live for decades beyond their reproductive limit.
Curiously, this phenomenon is almost unique to humans: to date, only toothed whales such as orcas and chimpanzees indigenous to a remote region of Uganda have been found to exhibit similar post-menopausal lifespans.
To explain the menopause, biologists posit something called “the grandmother effect” – the notion that grandmothers contribute to the survival of the species by caring for related women’s children.
However, grandmothers would not be very effective carers if they were at risk of losing children because of conditions that affect memory, such as Alzheimer’s.
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 possess 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 clearing away damaged brain cells and the amyloid plaques associated with Alzheimer’s.
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 have picked up a mutated form of CD33 that is missing this sugar-binding site. The mutated receptor no longer reacts 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 in chimps, but 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 that we had over other ancient hominin species,” says Varki. “Grandmothers are so important, we even evolved genes to protect their minds.”
Intriguingly, the protective form of CD33 may have emerged in response to gonorrhoea. This is because gonorrhoea bacteria coat themselves in the same sugars that CD33 receptors bind to, thereby tricking human immune cells into not seeing them as foreign invaders.
Varki and Gagneux suggest the mutated version of CD33 emerged as a human adaptation against such “molecular mimicry” by gonorrhoea and that later, the gene variant was co-opted by the brain for its benefits against dementia.
“It is possible that CD33 is one of many genes selected for their survival advantages against infectious pathogens early in life, but that are then secondarily selected for their protective effects against dementia and other ageing-related diseases,” says Gagneux.