As science turns from chimp research, U.S. wants to restart
The debate surrounding the use of chimpanzees for medical research.
By Chris Adams | McClatchy Newspapers
ALAMOGORDO, N.M. — During Lennie's life under the microscope, science changed.
Starting in the 1960s, Lennie, a chimpanzee, was strapped in a spacesuit for U.S. government test flights, and subjected to spinal taps. He was fed a banana laced with triparanol, a drug already removed from the market for humans. In the 1970s, he was a breeder, used to increase the supply of lab chimps. In the 1980s and 1990s, he was infected with the HIV and hepatitis viruses and subjected time and again to blood draws and biopsies.
In 2002, Lennie died at a federal primate facility in the New Mexico desert, where many of his former cage-mates still live.
Today, those former cage-mates — about 180 of them — are at the center of an impassioned debate between the National Institutes of Health and the animal-rights community. The chimps at the Alamogordo Primate Facility have been withheld from research the past 10 years as part of an agreement between the NIH and the Air Force base where the facility is located. Now the NIH wants to move the chimps away from Alamogordo, where they'll be allowed to be put back into research. Animal-rights activists want them retired to a grassy sanctuary.
Even before Lennie's death from apparent heart disease, though, science was moving away from the kind of research that dominated much of his life. Two years ago, a major drug-maker said it no longer would conduct research on chimpanzees. Several countries have sworn off chimps as well.
Researchers say advances in laboratory techniques mean that knowledge once gained only by examining a live animal now can be learned in a petri dish. And an expanding body of evidence shows that chimps don't work as the human fill-in that researchers once hoped they would.
The ethics of animal research also have evolved. What once was commonplace is now controversial, and there's a growing feeling that chimps should be spared the pain and mental anguish of research.
"For primate research, you had better be able to show me that you've got something that's pretty promising: an HIV vaccine, a cancer drug," said Arthur Caplan, a University of Pennsylvania ethicist who chaired a government panel in the 1980s that set guidelines for animal research. "The burden of justifying the research is on the researcher, and it's very high."
Some see it differently. Calling chimps crucial to advancing hepatitis C research, the NIH wants to ship them from the facility in New Mexico to the Texas Biomedical Research Institute in San Antonio. The director of the Texas institute's primate facility called chimps "a wonderful model" for certain research.
The use of chimps in research has been a hot-button issue for years. When the NIH said last year that it planned to move the Alamogordo chimps back into research, there was an outcry from advocates and some lawmakers; the NIH announced in January that it will delay any move until an expert panel of outsiders has reassessed its scientific rationale.
To understand the evolving science of chimp research, McClatchy talked with researchers and animal-rights activists, reviewed the scientific literature and read through thousands of pages of medical records that recount the experimentation on and illnesses, behavior and deaths of Lennie and his peers. In Defense of Animals, an advocacy group, obtained the records after a five-year legal fight with the NIH. The group shared them exclusively with McClatchy with no strings attached; McClatchy conducted its own review of the records, which provide the most detailed look ever into the day-to-day life of chimp experimentation.
Lennie, the one-time space chimp, was born about 1962 in Africa and was brought to New Mexico, where he spent four decades in a range of experiments.
In 1970, he was given triparanol — it's not clear why — even after the drug had been removed from the market after it was found to damage human eyes. In the 1980s and 1990s, he participated in HIV/AIDS and hepatitis C research.
Lennie's 540-page medical file and "Chimpanzee Resume" detail the regular tests and blood draws, which required a "knockdown," an anesthetizing dart. It was something Lennie resisted.
"Animal excited at knockdown," a 1998 record said. "Excited knockdown," a record in 1997 said. "Pyrexia" — fever — "possible due to excitement of sedation," it read in 1998 again.
His medical records show four spinal taps and one bone-marrow biopsy. He was moved from cage to cage, often living alone, until 2001, when he moved in with two younger males. Within a day, he was injured in a fight; his weight dropped dramatically, partly because of his low standing among the other males.
On Feb. 23, 2002, soon after eating his morning fruit, Lennie grabbed the side of his cage with all four limbs and slowly collapsed to the floor. Efforts to revive him failed.
In the mid-1980s, scientists who were working to understand HIV and the disease it caused, AIDS, thought chimps would be a vital resource.
Eventually, at least 198 chimps were infected with HIV, according to a 1997 report by the National Research Council, a prestigious body affiliated with the National Academy of Sciences. But just one developed and died from an AIDS-like disease.
The council said chimps could still be of value. But in its report, it concluded that "chimpanzees have not been a universally satisfactory model for human diseases" and "HIV infection of chimpanzees has not been an ideal model."
Before that assessment, the U.S. government had bred about 400 chimps. The once-"critical model for understanding" HIV became "a surplus of chimpanzees and a substantial management problem," the council report said.
Why didn't chimps work out as hoped?
Despite their similarity to humans, chimps don't react to infection the same way. In HIV research, for example, a possible vaccine protected the chimps but not people, NIH scientists wrote in the New England Journal of Medicine in 2007. Also in 2007, an article in the British Medical Journal concluded: "When it comes to testing HIV vaccines, only humans will do."
Jarrod Bailey, the science director for the chimp-release campaign of the anti-animal testing New England Anti-Vivisection Society, pointed to one key difference: HIV infection doesn't generally result in a significant decline in T-cells — a type of disease-fighting white blood cell — in chimps; in humans, it does. Bailey said that about 100 vaccines had been tested in nonhuman primates, including chimpanzees, and success in animals didn't translate to success in humans.
Earlier this year, Ajit Varki of the University of California-San Diego and his colleagues reviewed chimp research, disease by disease, and found that chimps and humans experienced disease differently. As they concluded in The Annual Review of Pathology: "Humans appear to have several surprising differences in the severity and/or incidence of diseases and pathologies that cannot be explained by environmental factors."
It called into question chimps' usefulness as human stand-ins.
"Chimps and humans are extremely close genetically, so there is this feeling that they should be a good model to study human diseases," Varki said. "But most attention has been on what is similar. We should also pay more attention to the differences."
Varki researches molecules known as "sialic acids." Fewer than 70 genes are known to be directly involved in sialic acid biology, and many of those changed after humans and chimps shared a common ancestor. Because sialic acids play a role in disease formation, that could partly explain why chimps and humans react differently to disease, he said.
Even so, Varki doesn't think that chimps should be completely exempt from research of the kind done on humans. His own research starts at places such as the Yerkes National Primate Research Center in Atlanta, where veterinarians doing annual physicals on animals are asked to take a little extra blood. It's packed up and shipped on ice to Varki's lab in Southern California to be tested and cultured.
"The technologies we use are getting more and more sophisticated," he said. "We can use smaller samples. So we can do a lot more than we could 10 or 20 years ago."
Chimps now in federal labs could be used the same way, Varki said. Chimps already infected with HIV or hepatitis, he said, could be monitored during their annual exams. But Varki supports research only if it's no more invasive to the chimps than it would be for a human test subject.
Animal rights groups say the failure of chimps in AIDS and other diseases shows that it's time to abandon them as lab subjects.
"Why keep poking away at something that doesn't work?" asked John Pippin, a doctor who works with the advocacy group Physicians Committee for Responsible Medicine. "The NIH is struggling with a research model that is a failure because they simply don't know what to do."
For its part, the NIH doesn't emphasize chimp use in HIV research. Instead, it focuses on hepatitis. Chimps "proved invaluable in developing the hepatitis A and B vaccines that are in use today," and they're the only reliable animal to study the liver disease hepatitis C, the NIH said. The chimps also could be used in drug testing, it said.
One example of the chimps' importance, the NIH said, can be found in an article in the journal Science.
The research was conducted at the primate unit of the Texas Biomedical Research Institute, which is scheduled to receive the Alamogordo chimps. The study used an experimental drug to suppress hepatitis C virus in the liver; the four chimps in the study underwent weekly blood draws or liver biopsies for about six months. Researchers saw a decrease in the virus, and the institute's chief scientific officer, John VandeBerg, said the study showed "great promise."
But will it translate to humans?
In the journal Genome Biology, a reviewer said the results were "very exciting" but cautioned that "results obtained in chimpanzees will not necessarily extrapolate to humans. ... The chimpanzee is a very useful model for HCV infection, but there are significant differences" in the way the species experience hepatitis.
In fact, the drug already was being studied in humans before these chimp results were in.
The chimp study began on April 29, 2008. A month later, drug maker Santaris Pharma said it had begun a human safety trial with the drug. In starting that trial, Santaris cited previous research in monkeys — not chimps, a higher level of primate — and said, "We are excited now to be able to evaluate the drug's efficacy and safety in human subjects."
If the drug already was being studied in humans, was the chimp experiment even necessary? Bailey of the New England Anti-Vivisection Society said it clearly wasn't: If the human trial showed the drug to be safe, the company probably would have moved to the next stage of the process, no matter what the chimp study showed. If it were unsafe in humans, it wouldn't progress.
"I would be extremely surprised to hear of any drug already in human clinical trials that is looking effective, safe and showing real promise to be terminated based on some experiments in chimpanzees," Bailey said.
The company disagrees, saying the chimp studies were necessary and that they provided information vital to later steps in the drug development process. If the chimp studies hadn't succeeded, Santaris spokesman Navjot Rai said, the company "would not have moved forward" with more human studies. He said regulators didn't require the company to use chimps, but that the company itself considered them critical.
Nonetheless, the U.S. is increasingly out of step with the world.
Several countries have said they'd stop using chimpanzees in research. That's one reason the NIH said "the United States maintains the only chimpanzee resource worldwide" for hepatitis C research. Most countries don't have such a resource because they stopped — or never started — chimp testing.
GlaxoSmithKline, a drug maker that's involved in hepatitis C research, said in 2008 that it would stop chimp research. While chimps had played an important role for three decades, Glaxo said, "the case for using great apes in the future is less clear than it may have been previously." New scientific techniques had helped science move beyond the chimp, it added.
Beyond that, the ethics of chimpanzee research have evolved. In its 1997 review, the National Research Council said using chimps was acceptable, but it noted that chimps were different and couldn't be used like rats, canines or even lesser primates.
"The similarity of chimpanzees to humans distinguishes them in substantial ways from other laboratory animals and implies a moral responsibility for the long-term care of chimpanzees that are used for our benefit in scientific research," it said. Given its connection from decades of watching chimps on television or in zoos, the public "expects a high level of respect for the animals," it added.
VandeBerg said his Texas institution did treat chimps differently.
"They are much closer to humans in every respect than monkeys are, in physiology, immunology, cognitive ability," he said. "We accord chimpanzees a special place among all the animals." They are used in experiments only if no other animal will do, he said.
To animal-rights activists, the very act of the research — let alone infecting chimps with viruses — is wrong. The simplest blood draw requires them to be anesthetized by darts. Some animals — such as Lennie — react to that with fear.
Asked about that, VandeBerg said: "I haven't actually witnessed this."
"I'm not a veterinarian, and I'm not involved in handling the animals," he added. "I certainly wouldn't even use the term knockdown. ... The chimp is sedated or anesthetized. Certainly there's some stress." But, he added, human patients experience stress as well. The complaints about regular biopsies, he said, are overstated.
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