Human, Mouse, Rat . . . What’s Next?

What if some explorers of a remote region in the world stumbled across a lost colony whose members are immune to major human illnesses such as AIDS, Alzheimer’s disease, malaria, and even cancer? Imagine the rush by biomedical researchers to tease out the secrets behind the good fortune of such beings.

The colony’s advantage might stem from habits of nutrition, or lifestyle—maybe a vegetarian diet or regular physical exercise. Yet perhaps the immunity enjoyed by the colony’s residents rests, at least in part, upon their subtle genetic differences from people in the rest of the world. Investigators would no doubt eagerly start comparing the DNA sequences of these remarkable individuals with those of other populations.

This fanciful scenario isn’t far off from reality. For the lost colony, consider Pan troglodytes, the endangered species better known as the chimpanzee. Despite having an estimated 98 percent of its DNA in common with people, the chimp seems free of many illnesses that regularly afflict men and women, says Ajit Varki of the University of California, San Diego. In the September Genome Research, Varki details the primate’s apparent resistance to human diseases ranging from acne to AIDS. While doing so, he calls for a project to decipher all the genes of the chimp, an effort that would rival the human genome project in time and cost. Yet because such a scientific effort could provide unique insights into why people get sick, Varki contends that a chimpanzee genome project is a “biomedical imperative.”

The chimp may have to wait in line, however. Scientists have found funding to follow the human genome project with similar efforts for the mouse, the most commonly studied laboratory animal, and the rat, the favored animal for drug studies. Furthermore, investigators who study cattle, dogs, frogs, zebrafish, and other animals are all clamoring for genome projects of their own.

Still, the chimpanzee project may hold a trump card in the game to win that next round of genome funding. Among its promises are profound nonmedical payoffs. According to the limited DNA comparisons so far, the chimpanzee is Homo sapiens‘ closest relative. Many scientists predict that unraveling the genetic distinctions between the species will explain why people differ from chimps in crucial areas such as intelligence, language, and behavior.

“It’s almost a cultural obligation for the genome community to do this because it will have profound implications for our understanding of ourselves,” says Svante Pääbo of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany.

Primate family

Chimpanzees, along with bonobos, gorillas, and orangutans, make up a primate family commonly called the great apes. Unlike monkeys and other nonhuman primates, the great apes lack tails. They also have a more upright posture. Interest in the genetics of great apes took off with the discovery that on a DNA level chimpanzees show a closer relationship to people than to monkeys.

This unexpectedly strong genetic affiliation came to light in a 1975 paper by two biologists, Mary-Claire King and Allan Wilson, who were at the University of California, Berkeley. In one set of experiments, they examined comparable proteins in chimps and people and found that their amino acid sequences were on average more than 99 percent identical.

Another test employed so-called hybridization assays, in which the scientists determined how readily chimp and human DNA stick together. King and Wilson concluded that the genetic sequences of the two species were 98.5 percent identical. In contrast, mouse and human DNA are roughly 60 percent identical.

King and Wilson’s initial estimate has held up well as geneticists have used more recently developed methods to directly compare the DNA sequences of a few chimp and human genes. These limited studies have consistently shown that the two genomes differ by 1 to 1.5 percent.

What does that number mean? No one can say at the moment. Much of the variation between chimp and human genomes probably occurs in DNA sequences that don’t encode a protein. Some of those sequence changes may be meaningless, but some could affect when and where in the body genes give rise to proteins.

Indeed, the genetic changes most responsible for what some people call humanness may be those that alter a gene’s activity, speculates Pääbo. Finding the subtle variations in DNA that influence a gene’s activity is more difficult than spotting a mutation that modifies the protein that a gene produces, he adds.

Despite those obstacles, a letter published in the Aug. 25 Science argues that the chimpanzee genome, or that of another great ape, should receive the highest priority once the human, mouse, and rat genomes have been completed.

“We cannot fully comprehend human genome function until we have identified genetic features that underlie uniquely human anatomical, physiological, behavioral, and cognitive characteristics. To identify uniquely human aspects of gene structure and expression requires comparative data on related species. The mouse genome will help, but analysis of rodent genomes will never tell us why we are not great apes,” says the appeal.

Edwin H. McConkey, an evolutionary biologist at the University of Colorado in Boulder, originated the letter, which was signed by Varki and more than a dozen leading primatologists and molecular biologists.

“We’re trying to reconstruct human evolution by looking at our closest relatives, which are chimpanzees, bonobos, and gorillas,” says primatologist Frans de Waal of Emory University in Atlanta, one of the letter’s signers. “Most of us find it hard to believe we differ by only 1.5 percent from an ape. It’s absolutely critical that we know what that 1.5 percent is doing.”

Even as they lobby for funding for a comprehensive chimpanzee-genome project, investigators have begun some relatively modest gene-deciphering efforts. Pääbo’s group examines how chimp genes vary in activity in different tissues and studies the genetic diversity among chimps and among people. His group is also looking for cellular and genetic distinctions that explain why people can live for more than a century, but the life span of a chimp rarely passes 60 years. Something such as differing DNA-repair abilities could account for that, Pääbo suggests.

Other chimpanzee-genetics projects are also on the horizon. This summer, Japan’s Institute of Physical and Chemical Research announced plans to study how people and chimps differ in genetic activity within the brain areas known to have roles in speech and language.

Practical reasons

While sequencing the DNA of a chimpanzee may one day answer such mysteries as why the human brain is twice the size of the chimp’s, Varki’s support for the genome project arose from more practical reasons. As a physician, Varki had little interest in great ape genetics until his research on sugar molecules called sialic acids led him in that direction.

Dotting the surfaces of most cells in all animals, sialic acids influence cell-cell interactions but can also serve as docking stations for microorganisms that infect cells. Several years ago, Varki and his colleagues surprisingly observed that one form of sialic acid, clearly present in the tissues of the great apes, was almost completely absent from the human body. Human cancer cells, however, sometimes sport this particular sugar, known as N-glycolylneuraminic acid.

Varki’s group and one in Japan subsequently found that, the human genome harbors only an inactive version of the gene that in chimps encodes an enzyme for the sialic acid. Many researchers hailed this finding as one of the first clear genetic distinctions between the great apes and people, but biologists can’t say how the loss of this gene affected human evolution.

After all, cancer cells somehow find another way to create the sialic acid. Intrigued by his discovery, Varki took a short sabbatical to learn more about the great apes. He spent time at the Yerkes Regional Primate Research Center in Atlanta, home of the oldest chimpanzee colony in the country. There, Varki learned that chimps and people are so similar that the veterinarians rely on a textbook of human medicine when they treat the animals in their care.

Nevertheless, Varki soon grew aware that chimps seem to be free of certain human ailments. The vets had never seen any of their chimps develop asthma, even though the apes were breathing Atlanta’s relatively polluted air and living in crowded conditions, presumed risk factors in people for the respiratory condition. Nor had the vets ever seen in their animals other human diseases, such as rheumatoid arthritis or the form of acne that strikes kids around puberty.

Chimp health

Fascinated, Varki began to search the scientific literature on chimpanzee health and talk to other primatologists. He found many more human illnesses that seemed to spare chimps.

Consider AIDS. In 1984, scientists identified the retrovirus now called HIV as the causative agent of a mysterious syndrome resulting from a weakened immune system. Not long after its discovery, some investigators began injecting chimps with the virus. The biologists expected that the animals would develop AIDS, enabling experimental studies of the disease and tests of drug therapies.

Although scientists worldwide have infected more than 150 chimpanzees with HIV, only one has died from AIDS. Just three more have experienced the gradual loss of immune cells seen in most HIV-infected people.

“If we could delineate the differences in the genes that HIV interacts with, maybe that would help us understand why humans are so affected and chimps are much less so,” adds David Nelson of Baylor College of Medicine in Houston, who studies the chromosomal structure of chimpanzees.

The chimpanzee may have had more time to evolve the means to keep the virus in check. Scientists suspect that the great ape is the natural host of HIV, and the virus only recently began infecting people (SN: 2/6/99, p. 84).

“This retrovirus seems to live in a symbiotic state within the chimpanzee immune system, whereas it almost routinely destroys the helper T [immune] cells of humans,” Varki notes in his Genome Research article.

Chimpanzees may also be the natural hosts of viruses that cause hepatitis in people. A large percentage of the people infected with the hepatitis B virus go on to develop severe cirrhosis or potentially fatal liver cancer, but the effects are rarely that dramatic in deliberately infected chimps.

Another infectious disease that takes a different turn in chimps is malaria, which is caused in people by the parasite Plasmodium falciparum. The mosquito-borne microbe seems to have less luck infecting chimps, says Varki, citing a 1997 report on a primate center in Gabon where malaria runs rampant. Most of the chimp’s keepers at the African facility became infected with P. falciparum, but few of the great apes did, even though they were exposed to the same mosquito-infested environment.

The chimp’s protection from malaria could stem from something as simple as mosquitoes preferring to feed on people. Yet researchers speculate that genes underlie some of the immunity.

The great apes do get malaria when infected with a relative of P. falciparum, but even then, the disease is rarely as severe as the one that afflicts people. “Although one cannot predict which factors are most important,” contends Varki, “the bulk of the evidence predicts that genetic differences determine at least a portion of the observed differences in susceptibility.”

The chimpanzee veterinary literature also offers the tantalizing hint that the primates don’t develop Alzheimer’s disease. When scientists have studied the brains of elderly chimps, they’ve never found the cellular lesions, known as tangles, that characterize the brain disorder.

While menopause isn’t a disease, Varki notes that chimps may sidestep this natural phenomenon that women experience in their 40s or 50s. Captive female chimps who live that long continue to undergo regular menstrual cycles.

The biology of the female breast also differs between women and female chimps. The breasts of male and female chimps are usually difficult to distinguish. Only at the end of a pregnancy do a female chimp’s breasts enlarge. “Breast cancer has never been reported in a chimp, as far as I know,” notes Varki.

Indeed, resistance by chimps to certain cancers is perhaps the most provocative medical story of all, albeit one built on sparse evidence. The great apes regularly develop leukemias and lymphomas, which are cancers of the blood. In contrast, there’s evidence from hundreds of autopsies that the apes have only low rates of cancers of the breast, prostate, ovary, lung, stomach, colon, and pancreas.

These cancers cause more than 20 percent of deaths in people today, but the incidence of such cancers in nonhuman primates is apparently 2 to 4 percent, and perhaps even lower in chimps and other great apes, Varki says.

Healthier diets or other environmental factors could account for the lower incidence of cancer in great apes than in people, but Varki’s not convinced that they provide the whole story. “There’s something tantalizing there,” he says.

Baylor’s Nelson agrees. Noting that cancer researchers have identified many human genes that contribute to tumor formation, Nelson suggests that a chimp genome project could determine if those genes differ in any significant way in the great apes.

Not cheap

Deciphering the chimpanzee genome won’t be cheap. It could cost several hundred million dollars. Neither Celera Genomics, the Maryland biotech firm that tackled the human genome privately, nor any governmental agencies have committed to doing the chimp genome.

The National Human Genome Research Institute in Bethesda, Md., which helped coordinate the international human genome effort that competed with Celera’s private foray, is funding work on the mouse and rat genome but has yet to decide what to tackle after those projects.

“We’re obviously interested and intrigued by [a chimpanzee genome project], but there are a lot of other organisms that we’re interested in, too,” says Jane Peterson, program director for the institute’s large-scale genetic sequencing efforts.

Even if the chimp genome isn’t next, advocates the project believe it will be done someday. “It’s too interesting of a question for too many people,” says Nelson. “It’s tantalizing to think we can define what it means to be human by comparing the genomes.”