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Oxygen Atom Makes Difference
Sugar Chemistry, At Least, Separates Man from Primate Ancestors

By Rich McManus

On the Front Page...

There is a ubiquitous sugar molecule on the cells of humans that differs only by the lack of a single oxygen atom from a cousin sugar commonly found on cell surfaces of our nearest genomic ancestors, the great apes. Thus far, it is the sole genetic difference — species-wide — distinguishing man from chimp, orangutan, gorilla and bonobo. And from all other mammals studied so far.

Continued...

The sugar in question is sialic acid, which has long been known to take two major forms — Neu5Ac and Neu5Gc. While both have been found in all mammalian cells, including apes, the latter appears only in trace amounts in humans, probably due to meat consumed in the human diet. Thus, while humans are missing this common form of sialic acid, their closest evolutionary cousins — the great apes — express it in amounts similar to other animals.

This difference is the outcome of years of study of what separates great ape DNA from human DNA. The investigation was launched 25 years ago with publication of a paper showing that the DNA sequences of man and great ape differ very little, only by 1 to 1½ percent. More recent studies have reduced the figure further, to about 1 percent. Though many have investigated similarities in the genomes of the two species, relatively few have looked into what sets us apart, what makes humans human.

In a talk provocatively titled "Explaining Humans: A Window into the 1% Difference," Dr. Ajit Varki, a pioneer in the field of glycobiology at the University of California, San Diego, brought both biochemical rigor and catholicity of research tool use to this topic; he is as willing to seek clues from a fossil show in Arizona as from Yerkes Regional Primate Research Center, where he spent a month cataloguing many differences between humans and great apes.

Varki said he was happy to be "at the mecca of the genome," and immediately complicated the dominant paradigm of molecular biology (DNA to RNA to protein) with a marvelously intricate cartoon introducing the roles of lipids (fats) and saccharides, or sugars, in mediating all kinds of inter and intracellular activities.

"The structure and function of the saccharides has largely been left behind in the molecular biology revolution," he noted, then suggested folks could catch up on the field by reading a textbook he edited — Essentials of Glycobiology. "If you buy the book, I get two bucks," he quipped.

Varki said sugar chains are found everywhere on the cell surface, "like the leaves of the Amazonian forest" in their density and variety. One important family of sugars, sialic acids, have proven essential for cells' ability to recognize other cells as "self," or nonself, and to serve as receptors for pathogens. The most common form of the acid is known as Neu5Ac, which can be found throughout all mammalian cells, including those of humans. Its chemical cousin Neu5Gc, which differs by addition of a single oxygen atom, is found only in trace amounts in humans but is a major sialic acid in all great apes. Varki's group discovered that this is because of a genetic mutation that is shared by all humans on the planet. His lab has recovered only traces of Neu5Gc from human tissues including the spleen and liver, and from testes (prompting a woman in Varki's lab to joke that this is "the last vestige of the great ape"). But these trace amounts may originate from human consumption of animal foods, Varki speculated.

Varki has estimated that about 1 percent of the primate genome is involved in the biosynthesis and recognition of sugar chains, perhaps more. But by no means does he suggest a single sugar accounts for the myriad differences between man and ape. "Very little is known about glycan diversity in nature," he said. The field is considered "too descriptive and nonmechanistic" to attract funding nowadays. "Charles Darwin couldn't get funding in this kind of a climate," he jibed, taking aim at the popularity of mechanistic rather than naturalistic inquiry (though he is quick to acknowledge that NIH funds his work with a MERIT grant).

Showing various evolutionary charts, Varki explained that "human evolution is more of a bush than a ladder — we're a twig that emerged fairly recently." Man diverged from the orangutan about 12 million years ago, from the gorilla about 8 million years ago, and from the bonobo and chimpanzee about 6 million years ago. "Humans are actually closer to chimps than chimps are to gorillas," he noted.

While there is similarity on a gross level, things are quite different at structural and functional levels, Varki continued. "For instance, we give seminars, and (the great apes) don't," he said, jokingly. His lab compared proteins from the plasma of a diverse range of humans with those of the great apes, and discovered, as expected, great similarity, except with respect to sialic acid and a protein called transthyretin, which can influence thyroid hormone metabolism.

"An intriguing finding is that even in the chimpanzee and other mammals, Neu5Gc is found in very low levels in the brain," Varki observed. "There seems to be some reason why this sugar is 'not wanted' in the brains of mammals. Humans, of course, have completely eliminated it, by a systemic genetic mutation."

A "friendly competition" between Varki's lab and counterparts in Japan is therefore teasing out the consequences, for anatomy and behavior, of mice prompted to produce only the human form of sialic acid (the Japanese group — using mice modified to have the same gene deletion that results in humans producing only Neu5Ac) or transgenic mice raised to overexpress the enzyme that leads to Neu5Gc production in the brain (Varki's group).

The effort to dissect the 1 percent difference in the genomes of man and ape is not terribly far from the headlines — a few days before Varki's Mar. 16 talk, researchers in Blacksburg, Va., announced the cloning of five piglets, which is an effort to supply organs for human transplantation eventually. Varki concluded his talk by noting that "all attempts at xenotransplantation of organs from other primates to humans have failed for reasons yet unknown." He speculated that the difference he has found may account, at least in part, for these failures. Until the mysteries of the 1 percent are better understood, those pigs might be good only for pork sandwiches.


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