The Chronicle Review

Reconsidering Research on Primates

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December 04, 2016

John Gluck still remembers the meeting, nearly a half-century ago, of his academic-journal club at the University of Wisconsin at Madison. Gluck was a graduate student in the laboratory of Harry Harlow, the psychologist whose research on maternal deprivation in rhesus macaque monkeys would be celebrated for insights into human development and vilified for the suffering those monkeys endured. That afternoon Gluck’s club discussed a hot new paper from the lab of the psychologists Allen and Beatrix Gardner, who had taught a chimpanzee named Washoe to use American Sign Language.

The students debated whether or not sign language was, in fact, a real language. They dug into the nature of response and reinforcement, whether the chimp truly communicated with intent or just went through the motions. And then a student posed a different sort of question. What would happen if Washoe signed, "Let me out of here?"

"There was dead silence in the room," recalls Gluck, now a professor emeritus of psychology at the University of New Mexico and senior adviser to the university’s president on animal-research ethics. It was a question that had never crossed the students’ minds, and it would stick in his own. "I began to think about this question. What is their moral standing? We know what they can do for us. So what kind of ethical treatment do we owe them?"

Gluck had no answer, but the seed planted that day would grow as he watched his own monkeys, the infants kept alone in soundproof, permanently illuminated rooms at a time when they’d normally be nestled into their mothers’ warmth. He’d previously been able to dispel his qualms by focusing on the potential benefits of that research to people, and on the researchers’ efforts to provide the best care possible within the parameters of their work. Though he continued his experiments, his conscience started to nag him.

To better understand the animals, he pursued extra training in clinical psychology, then completed a fellowship in bioethics. In the early 1990s he forswore experiments on primates and made ethics his focus. Two decades later, the research community would answer the question of ethical obligation to chimps: In 2013 the National Institutes of Health, following the recommendations of an Institute of Medicine panel, announced an end to invasive experiments except when absolutely necessary to advance public health. Any experiments that continued would require a much-heightened standard of care, and most of the NIH’s own 360 chimps would be retired to sanctuaries. (In 2015 the NIH announced that the rest would be retired, too.) The moral cost was too great to do any less.

“There's extensive evidence that stresses, even routine stress in labs, cause changes in physiology, biochemistry, and behavior.”
Still unresolved, though, and even magnified by that decision, was the question of monkeys and other nonhuman primates, of whom more than 70,000 are used in research in the United States alone. Scientists have come to appreciate what intelligent beings they are, possessing faculties that in many ways compare with those of chimpanzees — yet their relatively easy availability arguably made the chimp decision possible. "I don’t think we’d have got there were people not able to say, ‘We could do those studies with some other nonhuman primate model,’ " says Gluck, who in October published a memoir, Voracious Science and Vulnerable Animals: A Primate Scientist’s Ethical Journey (University of Chicago Press).

His book comes at an opportune time. A constellation of factors — insights into monkey intelligence, the refinement of computational and tissue-culture-based research methods, concerns about how lab-animal stress could potentially skew data — have put primates again in the public eye; questions raised about chimpanzees are being raised about other species, too. It promises to be a difficult discussion, and perhaps a necessary one. " ‘Responsible’ research is not enough," wrote Gluck in a New York Times op-ed essay published upon the release of Voracious Science. "What we really need to examine is the very moral ground of animal research itself."

In September the National Institutes of Health convened a much-anticipated meeting on the ethics of primate research. It was held at the request of Congress, whose attention was drawn by a campaign led by People for the Ethical Treatment of Animals against Stephen Suomi, a prominent neurobiologist at the Eunice Kennedy Shriver National Institute of Child Health and Human Development and a former labmate of Gluck’s. Suomi’s research involved keeping infant monkeys in near-isolation and investigating their responses to stress and alcohol consumption. In research argot, his team members produced primate models of neuropsychiatric disorder. In more conversational terms, they drove monkeys mad.

Back in 1972, Gluck and Suomi had written a paper with Harlow, "Generalization of behavioral data between nonhuman and human animals," in the journal American Psychologist. Late in 2014, Gluck was among the advocates and activists who testified to Congress that such research underscored the need for an ethical reckoning. They found a sympathetic ear in Rep. Lucille Roybal-Allard, Democrat of California, who added to a 2016 spending bill language instructing the NIH to "conduct a review of its ethical policies and processes with respect to nonhuman primate research subjects."

To be clear, biomedical research on primates doesn’t happen just at NIH or through the research it finances. Altogether that work accounts for only a portion of the roughly 95,000 monkeys, marmosets and baboons used or imported in U.S. biomedical research. The NIH represents, however, the gold standard of American research; it’s a bellwether, and the September meeting would be a stage for the community at large.

Held on the NIH campus, in Bethesda, Md., and publicly broadcast on the internet, the meeting began its first day with a panel moderated by David O’Connor, a University of Wisconsin at Madison pathologist who uses rhesus monkeys to study the Zika virus. A lineup of scientists surveyed the considerable human benefits of monkey research: treatments for HIV and tuberculosis and neurodegenerative disease. New drug-delivery systems. Insights into the spread of pathogens and the interplay of genetics and development. It was a thorough affirmation of how, as the NIH’s director, Francis Collins, stated in his opening remarks, nonhuman primates "have proven to be exceptionally valuable."

Some scientists and animal advocates would later describe that as an overly simplistic picture, one that emphasized successes while playing down instances — stroke, Parkinson’s disease, hormone therapy to prevent heart disease in women — in which primate models haven’t helped much. Still, says Tom L. Beauchamp, a philosopher at Georgetown University’s Kennedy Institute of Ethics who attended the workshop and whom Gluck considers a mentor, "they were very good, high-level people from high-level places. You got a good picture of why these scientists believe it’s terribly important to use primates."

To Beauchamp and Gluck, though, some important voices were missing from the discussions that followed: primatologists and anthropologists who don’t use primates for medical experiments but simply want to understand them. They could have talked, says Gluck, "about who these animals are."

Even as medical research on primates has led to new treatments and understandings of human disease, research on primate cognition has flourished. Hardly a week seems to pass without some new report of capacities considered hallmarks of profound intelligence and self-awareness — monkeys remembering the past and imagining the future, communicating with something like language, treating one another with a sense of fairness. Quite poignantly, one recent study described how infant Japanese macaques smile spontaneously in their sleep, a characteristic also seen in human babies, and possibly a sign of dreaming.

"Macaques and baboons, so often the laboratory monkey of choice, are incredibly smart primates capable of great emotional depth," says Barbara J. King, an anthropologist at the College of William & Mary and author of How Animals Grieve (University of Chicago Press). She notes recent accounts of long-tailed macaque monkeys using stone tools to eat shellfish, and of snub-nosed monkeys evidently mourning the death of their matriarch. "We’re learning more all the time about their lives in the wild, so that the supposed cognitive and emotional gulf between them and chimpanzees is certainly less wide than once assumed."

Such a perspective, think Gluck and Beauchamp, would have been very relevant to the ethics-oriented discussions that followed the morning’s scientific talks. Although several ethicists, including Beauchamp, were present and participated in group dialogues, none gave presentations or had lead roles in framing conversation. Unexamined, says Beauchamp, was the most pressing issue of all. "What is the morally relevant difference between a chimpanzee and a research monkey?" he asks. "That’s a really tough question, and nobody attempted to answer it."

Asked about such criticisms, Carrie Wolinetz, NIH’s associate director for science policy and the workshop’s organizer, points to presentations by veterinary primatologists and experts on research regulations. "There was a robust discussion of a lot of relevant ethical issues," she says. Though Beauchamp’s fundamental moral question wasn’t examined, many other issues were.

Leading the afternoon talk on ethics was Ernest Prentice, a genetics professor and head of the animal-care-and-use program at the University of Nebraska Medical Center. "There’s an imperative to use the least-sentient species possible to achieve the aims of research," he said during his presentation. Though some animal advocates would later chafe at Prentice’s stated preference for using the word "cost" rather than "harm" to describe what research primates experience, he didn’t shy from describing those costs as rising in direct connection with sentience — and nonhuman primates, Prentice said, are "some of the most sentient species we have."

F. Claire Hankenson, a veterinarian and director of animal resources at Michigan State University, opened her presentation with a reflection that "when I started my career 20 years ago, the thought was that you weren’t supposed to anthropomorphize research subjects. That’s been completely thrown out." In keeping with that appreciation of similarities between human- and nonhuman-primate minds, Hankenson described improvements in research housing and management. Social housing rather than isolation is the norm; monkeys and other primates are given more things to do, more chances to be themselves, and there’s a growing attention to not just physical but also mental well-being.

Many researchers use so-called positive reinforcement, training primates to voluntarily present themselves for procedures rather than being physically restrained for procedures like blood draws. Any technique that decreases stress, said Hankenson, "is better for research outcomes" — an indirect nod to research on how animal well-being influences and sometimes confounds research. Just as a sick person may respond to treatment differently than a healthy person, so might a sick monkey.

“The harm of inaction gets left out of the discussion.”
Still, that discussion might have been pushed further. "There’s extensive evidence that stresses, even routine stress in labs, cause changes in physiology, biochemistry, and behavior" says the neurologist Aysha Akhtar, author of Animals and Public Health: Why Treating Animals Better is Critical to Human Welfare (Palgrave MacMillan). Akhtar pointed to research on marmosets describing the far-reaching neurological effects of even a month in captivity. "That’s going to affect research results, and I guarantee it has. But it’s not widely considered," she says. And roughly 40 percent of nonhuman research primates are still housed singly or in pairs, something that the primatologist Frans de Waal, of Emory University, considers unacceptable. "All primates in research facilities should be housed socially," says de Waal. "No exceptions."

Animal welfare is one of the factors that institutional animal-care and -use committees are supposed to consider. These committees must review research proposals at their universities and ask whether the research is necessary in the first place; they’re also supposed to look at whether ostensibly less-sentient species, such as mice or zebrafish, could be used, or even nonanimal approaches, such as computational modeling or tests using tissue cultures. NIH’s grant-application language was updated this year to require that researchers explain in much greater detail why they want to use a given animal model.

"NIH only wants to fund the best research using the best model for the questions that are being asked," says Patricia A. Brown, director of the institutes’ Office of Laboratory Animal Welfare. Tissue cultures and computer models — or, noted Brown, extremely careful, creative studies with humans — can’t yet replace all animal research, but they’re becoming steadily more sophisticated.

The NIH has worked to train committee members in making such judgments, which can be nuanced and scientifically complex. Yet critics have pointed to deeper issues: Though the Animal Welfare Act requires that the animal-care committees "represent society’s concerns regarding the welfare of animal subjects," the panels are often dominated by scientists with a professional stake in continuing animal research.

In a 2012 Journal of Medical Ethics paper, Lawrence Arthur Hansen, a neuropathologist at the University of California at San Diego, described the committees as an "ethical monoculture" prone to "unconscious bias and groupthink." Gluck seconds his concerns. "You’re stuck in a highly conflicted area of potentially getting in the way of a colleague’s career," he says. Aside from that, the sheer workload can be overwhelming. "When you’re sitting there in a meeting with 45 protocols in front of you, time is an issue," says Gluck. Worst of all, even people sympathetic to animals can burn out or feel unsuited to the duty.

Gluck recalls committee members who stepped down and explained, " ‘I can’t stand it. This is too harsh. I can’t stand knowing the research world is this painful.’ They’d see themselves as not proper for committee membership. And I’d think, ‘That’s exactly what makes you proper. You’re ambivalent. And ambivalence has got to be what we feel when we’re harming innocent, sentient beings.’ "

Response to the NIH workshop was mixed. The Humane Society of the United States complained that animal-advocacy groups were shut out; PETA issued a statement saying that the proceedings "did not acknowledge our evolving understanding of the astonishing abilities and complexity of nonhuman primates nor how this understanding should inform what we think is acceptable and unacceptable behavior by experimenters."

Supporters of animal research, meanwhile, were more positive. Allyson Bennett, a psychologist at Wisconsin, called it a "very thoughtful, very serious consideration of nonhuman primate research." Bennett, also a spokeswoman for Speaking of Research, an advocacy organization for animal researchers, said the workshop testified to how "we balance scientific objectives, public interest in new knowledge that benefits the public, and consideration of animal welfare."

Certainly, ethics were on the table and conscientiousness on display, but critics say that, to the extent Congress asked for a review "in consultation with outside experts," the NIH came up short. "There remains an us-versus-them mentality," says Stephen Ross, director of the Lincoln Park Zoo’s Lester E. Fisher Center for the Study and Conservation of Apes, in Chicago, and a member of the NIH working group carrying out the Institute of Medicine’s chimp recommendations. "They continue not to do a good job at having all the stakeholders in the room."

Some of the tension, perhaps, was inevitable given the format’s time constraints. There’s only so much that can be covered in a single day. Which raises the question: What next?

For now, said Wolinetz, the NIH science-policy associate director, the agency is focused on drafting its report on the workshop. "We don’t have immediate plans for subsequent actions," she says, "but we’re certainly thinking a lot about what we heard."

Toward the day’s end, Jeffrey Kahn, a Johns Hopkins bioethicist who chaired the Institute of Medicine’s chimpanzee review, floated the possibility of a similar review for other primate research. Responding to a comment about the necessity of that research, Kahn noted that similar claims had been made about chimp experiments. On closer examination, though, some chimp research was found not necessary — and there’s a distinction, he said, between what might be done only with primates and what, in light of the harm to them, is truly worth doing.

The legacy of the Institute of Medicine’s chimpanzee panel, after all, was a rigorous consideration of whether some questions might be answered in other, less morally fraught ways, and when doing so might also be a duty. The question, said Kahn, is whether that panel was a one-off or a precedent.

The latter possibility will unsettle some researchers. Primate research is already polarized; a review would stir more controversy and perhaps run the risk of slowing medical advances. "The harm of inaction," says Bennett, "gets left out of the discussion." The question of basic research on primates, focused not on some obvious human benefit but by definition exploratory in nature, with uncertain payoffs weighed against immediate suffering, would be especially thorny.

It’s worth noting, though, that Britain went through its own primate review not long ago. After reviewing all government-funded research, an expert panel concluded in 2011 that most of it was indeed justified, though some was not, because it produced no clear benefits. The panel recommended that invasive experiments with high welfare costs be funded only if highly likely to yield human benefits. The ramifications of that review are still being assessed, but it was at least possible for the research community to look in the mirror without breaking it.

Gluck emphasizes that it’s not only activists who care about research primates and think that more might be done to protect them. Many animal researchers do, too, he says, but the climate is so polarized that it’s often difficult for them to speak up. After his New York Times op-ed, says Gluck, "I got quite a few emails from people who have feet in both camps. They said they appreciated someone saying, that’s who they were. That they’d struggled with this as well. I know they’re out there."

Clarification (12/6/2016, 8:20 a.m.): The Humane Society of the United States, not its local counterparts, complained that animal-advocacy groups were shut out of the NIH workshop. This article has been updated to reflect that. 

Brandon Keim is a freelance journalist who writes about science, nature, and animals.