Mystery of the meat-eaters' molecule

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Last Updated: 12:01am BST 08/07/2008

 

 

 

Our inability to produce a chemical present in every other primate

may be linked to a series of chronic diseases. Roger Highfield explains more

 

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 Ajit Varki, a doctor-cum-scientist who works in

California.

 

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, when Prof Varki was working at the

University of California, San Diego. When treating a woman with bone-marrow

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, Prof Varki found that Neu5Gc 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 cancers and auto-immune illnesses. Prof Varki

stresses, however, that " we have not proven any link to disease, just suggested

that it is something to explore " .

 

This sialic acid plays a number of roles: it helps us recognise

cells and helps cells stick together (this stickiness is also exploited by

microbes, which latch on to the sugary molecule to invade our cells). It also

helps regulate our immune response, which may influence the progression of

diseases and even play a part in human evolution.

 

The first evidence that this particular molecule is of unique

importance to humans came a decade ago. Prof Varki's team, along with Prof

Elaine Muchmore, also of the University of California, studied blood from

chimps, bonobos, gorillas, orangutans and humans.

 

They found that we are the only primates whose bodies do not produce

Neu5Gc - although further research established that our Neanderthal cousins were

missing this version of the sugar acid, too.

 

Instead, human (and Neanderthal) cells bristle with a sugar called

Neu5Ac. The two molecules are identical, apart from one little 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.

 

Profs Muchmore and Varki then found out why this oxygen atom is

missing: 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 Neu5Ac (or, to give it its full name, N-acetylneuraminic 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 acid to latch

on to our blood cells.

 

In recent studies, Prof 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 micrograms 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 twenties.

 

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, Profs

Varki, Muchmore and Pascal Gagneux ate pure Neu5Gc to see what would happen.

 

Not only did the foreign sugar show up in the body soon after

eating, but tests also revealed that many people carry antibodies that react to

Neu5Gc - a protective immune response, but one which could trigger damaging

inflammation.

 

Prof Varki's colleague - and wife - Prof Nissi Varki then found that

small amounts of Neu5Gc 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.

 

Because the animal version of the sugar is so similar to the human

one, the latter could be caught in the friendly fire directed by the immune

system. Chronic inflammation is also linked with cancer; intriguingly, the team

found that Neu5Gc was concentrated in tumours, 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 tumours 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. But these

focused mostly on the role of saturated fats, and on products that arise from

cooking.

 

Prof Varki, however, believes that his little molecular difference

could also be to blame: Neu5Gc 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 Neu5Gc from the body.

 

But the question remains: why are humans unique among primates in

not producing Neu5Gc?

 

By studying the mutations in the enzyme that makes this molecular

difference between apes and humans, Prof 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 Neu5Ac 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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