mystery of meat molecule

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Mystery of the meat-eaters' molecule

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. Highfield

explains more.

US bank of stem cells 'is dangerously contaminated'

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.

Not so rare: a molecule absorbed by eating red meat has been linked

to inflammation and auto-immune illnesses

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.

advertisementThis 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.