Tuesday, August 5, 2008

Produce a chemical present - to a series of chronic diseases

Missing element

our inability to produce a chemical present in every other primate may be linked to a series of chronic diseases.

What does it mean to be human? For most people, it all comes down to that extraordinary object between our ears, and how it blesses us with language, laughter and logic.

But not for Prof Ajit Varki, a doctor-cure-scientist who works in Califnmia. For him, being human is also about a single chemical that separates us from our closest relatives, and which could be linked to many of our most debilitating illnesses.

The story began in 1984, whenVarki was working at the University of California, San Diego. When treating a woman with bonemarrow failure, he injected her with horse serum, The treatment carried the risk of a side effect called "serum sickness", in which the patient's immune system launches an attack on a molecule present in the serum called Neu5Gc.

Sure enough, her skin erupted with an itchy red rash. Investigating further, Varki found that NeuSGc was foreign to humans, even though we carry a very similar version of the same molecule - which may be one reason why animal-to-human organ and tissue transplants do not work well.

But in recent years, he has come to believe that the implications of this molecular difference are much wider, He has built up a range of evidence that potentially links
Neu5Gc, a so-called sialic acid, to chronic disease. This is because the animal version is absorbed by humans as a result of eating red meat and milk products, and there is evidence that the body views it as an invader. Eating these foods could trigger inflammation and, over the long term, heart disease, certain :ancers and auto-immune illnesses. Jarki stresses, however, that "we lave not proven any link to disease, ust suggested that it is something o explore".

This sialic acid plays a number of roles: it helps us recognise cells and helps ceils stick together. It also helps regulate our immune response, which may influence the progression of diseases and even play a part in human evolution. Varki's team, along with Prof Elaine Muchmore of the University of California studied blood from chimps, bonobos, gorillas, orang utans and humans, and found that we ate the only primates whose bodies do not produce NeuSGc - although further research established that our Neanderthal cousins were missing this version of the sugar acid, too.

Instead, human (and Neanderthai) cells bristle with a sugar called Neo5Ac. The two molecules are identical, apart from onedittle detail: the ape molecule has a single extra oxygen atom. Because of the many different jobs this sugar does throughout the body, this one atom was the first example found of a fundamental genetic and biochemical difference between humans and our closest relatives,

Muchmore and Varki then found out why this oxygen atom is rfiissing: our molecule is the precursor of the animal version. Unlike chimpanzees and other great apes, humans lack a particular version of an enzyme that converts NeuSAc (or, to give it its full name, N-acetyl-neuraminie acid) into Neu5Gc. This tiny change could potentially explain some of the more unusual differences between humans and apes, Chimpanzees do not seem to suffer from heart disease, cancers, rheumatoid arthritis or bronchial asthma - common conditions in humans. Nor do they get sick from the human malaria parasite, which uses sialic add to latch on to our blood cells.

In recent studies, Varki's team has found tantalising evidence that this mysterious molecule could be exerting a wider effect on our health, through the substances we eat.
After testing a range of foods, they found the highest levels of Neu5Gc in red meat: up to 11,600 microgrammes could be absorbed from the recommended daily serving of beef, 5,100 from pork and 4,900 from lamb, The level in goat's cheese was 5,500, but fell to around 700 in milk and salmon. Cod, tuna, turkey and duck were in the 20s.

Given that food is broken down in the stomach, did eating animal tissue present the same dangers of provoking an immune attack as transplanting it? Following that great scientific tradition of self-experimentation, Varki, Muchmore and Pascal Gagneux ate pure NeuSGc to see what would happen. Not only did the foreign sugar show up in the body soon after earing, but tests also revealed that many people carry antibodies that react to Neu5Gc - a protective immune response, but one which could trigger damaging inflammation.

Varki's colleague - and wife -Pmf Nissi Varki then found that small amounts of NeuSGc were present in normal human tissue, probably as a result of long-term consumption. And as well as food, many biotherapeutic products made in animal cells and/or using animal materials were also contaminated with Neu5Gc.

This raised the fascinating possibility that anti-Neu5Gc antibodies are involved in auto-immunity. Auto-immune diseases, such as type-1 or juvenile diabetes and some types of arthritis, occur when the body mistakenly attacks healthy tissue. Chronic inflammation is also linked with cancer; intriguingly, the team found that NeuSGc was concentrated in turnouts, particularly those that spread throughout the body. This could aid detection of
such diseases, by getting scientists to look for the animal acid rather than the turnouts themselves. .

Some of this might sound familiar: several previous studies have linked ingestion of red meat to cancer and heart disease, and possibly to some other disorders involving inflammation, such as arthritis and lupus, gut these focused mostl) on the role of saturated fats, and on products that arise from cooking.

Varki, however, believes that his little molecular difference could also be to blame: NeuSGc elicits an immune reaction that might contribute to a whole spectrum of human-specific diseases. Although they have not proven this yet, the evidence is sufficiently compelling for his team to start work on ways to eliminate NeuSGc from the body.

But the question remains: why are humans unique among primates in not producing Neu5Gc? By study- ing the mutations in the enzyme that makes this molecular difference between apes and humans, Varki, along with Prof Naoyuki Takahata of the Graduate University for Advanced Studies in Kanagawa, Japan, estimates that the genetic change first appeared up to three million years ago, which coincides with the emergence of Homo erectus, the first of our ancestors to venture out of Africa.

At the time, life was nasty, brutish and short: any subtle but chronic effects of this foreign sugar would not be felt until old age, and Homo erectus did not survive that long. If the mutation that kept us producing NeuSAc rather than Neu5Gc helped shrug off a particular disease, it would have spread rapidly through the population. It is ironic that what may have protected our ancestors then could be responsible for much of the pain of their long-lived descendants.



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