Chimps May Have Something to Tell Us

Their brains are smaller, they can’t talk, they are covered with hair and they walk on their knuckles. They are also so very, very much like us that even 300 years ago, the anatomist who first dissected a chimpanzee concluded that they were neither monkey nor man, but something in between.

In fact, the chimpanzee and human genomes are nearly 99% identical. The chimp’s lesser-known sister species, the bonobo, is similarly close to us. Figuring out precisely which genes differ, and how, is a project of enormous complexity--but one that eventually could provide clues toward treating diseases ranging from AIDS to malaria and shed light on the reasons we age.

And it is the passion of a small but growing number of scientists.

Today, some of them will report a major advance: After analyzing nearly 18,000 genes in humans, chimpanzees, rhesus macaques and orangutans, they have been able to specify substantial differences in the way genes in the human brain are turned on and off compared with genes in the brains of the other three species.

The findings underscore how much more needs to be done to locate all the genetic dissimilarities between chimps and humans and learn which ones are biologically important.

“We are really just opening the door,” said Wolfgang Enard, one of the study’s lead authors and a scientist at the Max Planck Institute for Evolutionary Biology in Leipzig, Germany.

Some scientists study the genetics of chimpanzees or bonobos because comparing us with our nearest living relatives will deepen the understanding of who we are and where we came from.

Some, like Oliver Ryder, geneticist at the Center for Reproduction of Endangered Species at the San Diego Zoo, are especially interested in what science could do for the welfare of the chimp. Better genetic information, Ryder says, would help avoid inbreeding in zoos and provide a better understanding of how the animals migrate in the wild.

Evolutionary biologists hope that a chimp genome project will provide molecular data about how the human lineage evolved.

And scientists with a medical bent point to the biological differences between chimps and humans: Chimps don’t get AIDS. They don’t get malaria. They seem to have lower rates of cancers common in humans, such as those of the colon, stomach, breast and prostate.

Understanding the genetic reasons for such differences might potentially lead to therapies, says Dr. Ajit Varki, a UC San Diego professor and one of the coauthors of the study published today.

To advance understanding of the chimpanzee’s genetic code, Varki and many of his colleagues are urging the U.S. government to make deciphering the chimp genome the nation’s next big genetic project.

They face competition, however, from advocates of other genetic projects: the bee, platypus, pig, cow, dog, cat, macaque. The National Human Genome Research Institute is considering proposals and will announce its priority decisions in May.

Even chimp enthusiasts agree the animal is in many ways impractical to study.

It is endangered. And because the animal is so human-like--it’s been compared in demeanor and intelligence to a 2 1/2-year-old child--scientists balk at experimenting on it. Indeed, there is even a campaign afoot to grant legal welfare rights to chimps and other great apes.

In addition, the slow life cycle of chimps makes them unlikely candidates for breeding or mutant experiments, which are common strategies for learning about the function of genes.

Thus, for ethical reasons, as well as practical ones, chimps cannot be manipulated like a fruit fly or mouse.

“I would not do anything to a chimp that I would not do to a human,” Varki said.

Pressing the work ahead is a challenge, said Joseph Hacia, a USC scientist whose office is festooned with primate decor: monkey calendars, fuzzy toy orangutans, a chimp sitting on a pile of books pondering a human skull. “On the one hand, you are doing really cutting-edge research--but then you reach the roadblocks.”

Yet there is information to be gleaned--and high-tech machines like the ones in Hacia’s research lab are providing a lot of the push.

Such machines, for instance, can be used to scan little glass chips covered with tiny dots of DNA representing many thousands of human genes.

The chips are bathed in an extract of cells taken from chimp or human tissue. If a gene is switched on in that tissue--manufacturing strands of RNA that can later be made into protein--the dots corresponding to that gene will fluoresce. The glow will be bright if the gene is very active, dimmer if the gene is less active. There will be no glow if the gene is turned off.

The authors of today’s report, published in the journal Science, used this kind of approach to examine blood, liver and brain tissue samples from animals that died of natural causes.

Humans’ Brains Stand Distinct From Chimps’

In the case of blood and liver, the patterns of chimp and human gene activity were more similar to each other than to the patterns found in rhesus macaques and orangutans.

When it came to the brain, however, chimps were more similar to the macaques and orangutans than to people--even though humans are actually chimps’ closer kin. Humans stood out as distinct--as if the human brain had been the site of especially busy change during the course of our evolution.

Such gene regulation differences are hugely important in biology: A brain cell and a skin cell both contain a full set of genes. They differ because only some of those genes are active in each type of cell.

Similarly, scientists suspect that many chimp-human differences will be caused by slightly different control of genes that both species share. Certain genes may be cranked up higher in one species than in the other or turned on earlier, later or in a different part of the body.

But there are other genetic alterations that might be important. A gene may be totally inactivated in one species. Or a gene may mutate so that the protein it encodes has brand-new functions.

Each of these kinds of changes might have profound consequences for development: perhaps causing embryonic brain cells to divide more times as an individual grows, thus creating a larger brain; or maybe creating subtle alterations in bone growth that help make walking upright easier.

On the other hand, scientists also recognize that much of the 1% to 2% difference between chimp and human genomes will have little or no consequence.

As they seek to find the changes that are important, some scientists have decided to examine genes one by one rather than scan thousands at a time.

Varki and his UC San Diego colleague Pascal Gagneux, for instance, have been studying a gene that is involved in creating a certain type of sugar. The sugar decorates the surfaces of cells in many species--dogs, cats, mice and chimps--but not the cells of humans.

Varki and Gagneux discovered the apparent reason: Several million years ago, after the lineages of chimps and humans diverged, a key human gene was inactivated.

It’s possible (though still highly speculative) that the inaction of the gene and the absence of the sugar are linked to our susceptibility to certain diseases, including cancers, Varki said.

Seeking Clues for Differences in Aging

Other scientists are exploring chimp-human differences in aging and diet.

We live longer than chimps: In the wild they live 40 to 45 years, and even in zoos they only live to about 55 to 60 years. Humans, under the best of conditions, can live decades longer than that. Evolutionary biologists speculate that we evolved a longer life span because our culture is so complex and our young require long periods of rearing and learning in order to reach full productivity.

If human aging is slower than chimp aging, one might be able to discover the genetic reasons why, said Caleb Finch, director of USC’s Alzheimer’s Disease Research Center.

“It seems plausible that we may be able to discover genes that modify human aging and that could be new targets of intervention in disease,” he says.

Finch believes that a gene called ApoE may be involved in this aging difference. Chimps and humans have the gene. But the gene exists in more than one form. All chimps examined so far have a version of the gene that--when it is present in humans--is known to increase the risk of Alzheimer’s, a disease associated with aging. Most human beings have a form of the gene that confers a lower risk.

Finch suspects that as humans evolved, the low-risk version of the gene became more prevalent in human populations because those carrying the lower-risk gene would be more likely to live longer.

The ApoE gene may also be involved in another difference between the two species--one involving diet. Humans eat a lot more meat than chimps, and not surprisingly, chimps are less adept at dealing with all the fat that such greasy fare provides.

“The same amount of fat that will do nothing to us will triple the chimp’s blood cholesterol,” says chimp expert Craig Stanford, head of USC’s anthropology department, who is collaborating with Finch. “Something happened in our ancestry--a genetic change happened, a mutation--that allowed us to deal with eating meat.”

Seeking Answers to Ourselves

The version of the ApoE gene that all chimps carry is associated with a higher risk for heart disease and a lowered ability to manage a high-fat diet. The ApoE gene that most humans have, by contrast, is better at handling high fat.

A better understanding of such health-related differences may well have the potential to help people. Still, many researchers say that is only one reason--and not necessarily the strongest one--for studying the chimpanzee.

For many, the main reason is the inherent fascination with understanding a creature that is so like us, but so different.

“I think,” says Ryder, “it’s as natural for us to want to understand that as to ask why the stars are up there.”