In his 21 years at the University of Wisconsin-Madison’s veterinary school, Eric Sandgren has seen a lot of controversies. But the UW’s most prominent defender of animal research has never seen anything like this.
Sandgren says a typical research project protocol receives around four person-hours of scrutiny from an oversight committee; he estimates this one got more than 170.
“It is the protocol that’s received the most attention since I’ve been here,” says Sandgren, director of the university’s Research Animal Resources Center. “The most intense I’ve been a part of.”
Sandgren is referring to the first experiment at UW-Madison in more than 30 years that will intentionally deprive newborn monkeys of their mothers, a practice designed to impact a primate’s psychological well-being.
The research, submitted by UW-Madison Psychiatry Department chairman Dr. Ned Kalin, has drawn unusual scrutiny and dissent from within the university and intensified a debate about the extent to which benefits to humans justify the suffering of animals.
Kalin’s protocol, which outlines the methods and objectives of the research, was approved on April 24 by the graduate school's Institutional Animal Care and Use Committee (IACUC). It supersedes an almost identical protocol which was approved two years ago but never begun — for logistical reasons and because of internal opposition.
That earlier protocol was passed by the College of Letters and Science’s IACUC over the objections of two committee members, including UW-Madison bioethicist Rob Streiffer. At the time, he was the committee chair; he remains a member.
But Streiffer was not given a second chance to vote against the protocol. When it was resubmitted, the protocol was shown to only two members of the Letters and Science committee. They relegated jurisdiction to a subset of the graduate school committee, which gave its unanimous consent. No rules were broken.
The experiments build on the controversial studies of UW primate researcher Harry Harlow, which peaked between 1965 and 1972, as well as Kalin’s own past work.
For a year these 20 rhesus monkeys, as well as another 20 used as a control group, will be given tests intended to provoke and measure anxious behavior. After one year they will all be euthanized and their brain tissue collected for molecular analysis.
“We’re killing baby monkeys,” Streiffer says. “There are other things that have been done that are worse, but that's not a justification for saying that this isn't really really bad.”
The purpose of the experiment is to use state-of-the-art technology to examine the underlying neurobiology of anxiety and depression, which Kalin believes will lead to insights for treating struggling humans.
“My belief is that this work will provide an opportunity and a scientific rationale about early interventions and maybe even prevention of some of the problems that adults struggle with,” Kalin explains. “Our hope is that we’re going to come up with both new medication strategies as well as new psychotherapy strategies.”
The intensive discussions around this protocol’s approval ran counter to the usual culture of oversight committees, and have raised questions about the degree of suffering acceptable in an experimental design with uncertain outcomes.
Animal advocate Rick Bogle says the ethical ramifications of animal research are discussed very rarely, making the internal reaction to Kalin's proposal remarkable. The discussions surrounding the ethics of this study spanned seven meetings; normally approvals are secured after one or two meetings.
“This is an anomaly. This doesn’t happen,” Bogle says. “These discussions that they had about this study don’t occur with any frequency at all. In fact, I don't know of seeing them occur ever before.”
A mixed legacy
The ethics of animal research are often contentious, but non-human primate research at UW-Madison is especially polarizing.
There are around 2,000 primates housed and studied in several locations around campus. About two-thirds of these are at the Wisconsin National Primate Research Center; most of the remainder are at the Harlow Center for Biological Psychology. The buildings stand side by side.
The university’s first primate lab, founded by Harlow in 1930, produced what some consider to be groundbreaking research in the field of experimental psychology — and what others decry as needless cruelty.
Harlow’s work underlies much of both the science and unease surrounding Kalin’s current research.
“It's not like Dr. Kalin invented this approach,” says Craig Berridge, chairman of the Letters and Science IACUC. “He's piggybacking on decades of research, and that research has led to discoveries that have benefited people. The way we rear children these days stems from Harry Harlow's work.”
Harlow spent decades studying the need for maternal affection and social interaction by denying it to monkeys, often with gruesome results.
Many of Harlow’s experimental monkeys were completely isolated at birth in a sensory deprivation device called the “vertical chamber,” or what Harlow called the “pit of despair,” according to the 2002 book, “Love at Goon Park: Harry Harlow and the Science of Affection,” by UW-Madison journalism professor Deborah Blum.
Elsewhere, Blum has written that some female isolates were put in a restraint device Harlow called the “rape rack” and forced to bear offspring. Blum wrote in “Goon Park” that one of these mothers bit off her baby’s fingers and feet. Another crushed her baby’s head in her own mouth.
When introduced to peers as adults, these isolated monkeys showed signs of permanent psychological damage. After Harlow left the UW in the 1970s, maternal deprivation work in primates fell quickly out of favor here, although similar research continued at other primate centers including the University of California-Davis and the NIH Animal Center in Maryland.
“It went to an extreme,” Streiffer says. “People look back on that and think, ‘Oh, that was really awful.’ And for decades, people didn’t do it for research purposes. The nursery at (the) Harlow (Center) was shut down. We didn’t want to do that anymore.”
Kalin, who has studied primates since 1979, agrees that the experiments Harlow did at that time would not be done today. “The level of oversight and the regulations around animal welfare have changed.”
But while Kalin maintains that he is “asking different questions” and employing different methods than Harlow, his work has also come under intense criticism.
“Kalin has a really long history of subjecting baby monkeys to fear,” says Bogle, the animal rights activist. “That’s the meat and potatoes of his work. It’s very crude.”
In a Kalin study published in 2004, the amygdalae of 14 rhesus macaques were damaged with acid after their skulls were cut open. The amygdala is a region of the brain that regulates fear and anxiety. The monkeys were then exposed to snakes and unknown humans.
Rhesus macaques are commonly used in psychiatric studies because of their brains’ similarities to humans. About 1,500 of the UW’s 2,000 primates are rhesus macaques.
Kalin’s study, which found that the brain-damaged monkeys were less prone to fear and anxiety, has not yet led to any new treatments for humans. But, he argues, the research has nonetheless proven valuable.
“We have a lot of evidence now to suggest that (the amygdala is) not only a region that we should be thinking about and focusing on, but also we have some ideas about the specific molecules in that region that might be important,” Kalin says. “Science is a process, and it’s one step building on the next. The only way that we’re going to make progress to help people is to do these types of studies.”
Sandgren offers a similar argument.
“Maybe we’ll never really be able to find something that targets those specific pathways,” he says. “But if we don’t try we’re guaranteed not to find something that can affect those pathways, and I think that’s the critical thing.”
According to Kalin, recent research in rodents and studies using brain imaging in rhesus macaques and humans has suggested new opportunities for studying the early development of emotional disorders as they involve the amygdala.
“Through our studies, we have identified specific altered function of genes in the brain region that is overactive in young individuals with extreme anxiety,” Kalin says. “And these are completely new leads -- nobody’s ever thought of these molecules before.”
Kalin speculates that these alterations occur within the first few months of life. Ultimately, he hopes to discover the neural pathways and genetic expressions that link malfunctioning stress signals to early adversity, possibly leading to new treatments for children at risk of depression, substance abuse and other problems.
According to the National Institute of Mental Health, about 6.7 percent of U.S. adults experience major depressive disorder each year, and as many as 18 percent experience anxiety disorders. Kalin is not satisfied with existing treatments.
"They are ineffective for many people and for some there are intolerable side effects," he says.
“In the best hands, you only get about probably a third of our patients with anxiety and depression fully well, and we get another third of our patients somewhat well, and we’ve got another third of our patients that unfortunately struggle chronically with these problems. So there’s a huge need to have new ways of treating people.”
Kalin’s protocol is the largest project within a research initiative led by Richard Davidson. He is a UW-Madison professor of psychiatry and psychology widely celebrated for working with the Dalai Lama in connection with the Center for Investigating Healthy Minds. The parent grant, titled “Early Neurodevelopment Origins of Anxiety,” is bringing over $2 million to the UW from the National Institutes of Health. Kalin’s research will bring in $525,540.
Most of the $2 million grant, Davidson says, will go for research involving humans, including a subproject to non-invasively scan the brains of 180 human infants between the ages of one and 24 months. Their families will be monitored to provide behavioral data on adversity.
Davidson supports the Kalin protocol in particular and animal research in general, saying it has “undeniably made major contributions to the reduction of suffering” in humans. But he thinks the use of animals in research could be reduced and made more humane.
“You have to do a mental calculus to determine if it's appropriate or not, and each scientist needs to make his or her own moral decision about that,” Davidson says. “And it's the same thing with eating meat or wearing leather. You know, the Dalai Lama eats meat.”
Here’s how Kalin’s experiment will work, according to the protocol: On the day they are born, 20 rhesus macaques will be taken away from their sedated or manually restrained mothers.
For the first three to five weeks of their lives, the monkeys will be singly housed in a large shoebox-sized incubator with a stuffed animal to cling to for contact comfort. This is standard laboratory practice for baby monkeys who have been abused, neglected or rejected by their mothers.
The infants will be fed formula at regular times by humans clad head to toe in plastic in order to prevent the transmission of disease. Eventually, their caretakers will move them to an adjacent cage with a peer. Instead of the stuffed animal, this cage is equipped with “an upright mobile surrogate covered with a soft material.”
Besides regular brain scans and blood draws, the monkeys will be given several kinds of behavioral tests. These include being occasionally exposed to a series of environmental stressors, such as seeing a live snake, to gauge their levels of fear and anxiety.
“We're most interested in finding out the earliest time points at which there may be alterations in brain function,” Kalin says, adding that “the earlier we can identify altered brain function, the more likely it is that early interventions will have a bigger impact.”
The study’s hypothesis, he says, is that “early adversity of this type will result in alterations in the circuit that underlies anxiety, and possibly depression.” Kalin says this would “allow us to understand how early adversity impacts brain function that results in early psychiatric symptoms.”
Previous studies have shown that some adult laboratory monkeys separated from their mothers as infants exhibit such behaviors as clinging, self-biting and habitual rocking. But the Primate Center maintains that its nursery-reared monkeys usually do not display these overt signs of distress.
Streiffer, the bioethicist, remains unsure that the study’s gains are worth the monkeys’ pain.
“Will we learn something useful?” he asks. “Well, probably. But (Kalin) was kind of hard-pressed to say much more than that, and I thought that given the cost to the animals and that we’re dealing with non-human primates, the bar should be really, really high. And I wasn’t convinced.”
Sweet Corn and Stuart
Newborn rhesus macaques are about half as long as a human forearm, their heads about as large as a fist. They are wide-eyed and curious, blinking as they slowly grasp at their cages with their tiny, hairy hands.
During a recent visit to the Primate Center, a reporter was taken to the nursery that will be used in Kalin’s study. The two incubators were both occupied by a rhesus monkey born the day before. The infants were being housed in the nursery for monitoring.
Sweet Corn (r14030) was sleeping and Stuart (r14031) was awake. The monkeys’ names are bestowed by animal caretakers, but only their numbers are used in their records.
Earlier that week, only blocks from the primate lab, half a dozen members of the Alliance for Animals and the Environment stood outside of the Wisconsin Institutes for Discovery holding signs featuring a young rhesus macaque behind bars. The group, which is devoted to “ending all forms of animal abuse,” was protesting a conference of animal researchers.
“I feel their time would be far better spent finding humane alternatives,” says protester Alexa McCormack, the group’s executive director. “I think globally people would get behind any researcher who delved into humane alternatives rather than these horrific tests.”
Sweet Corn and Stuart are in the nursery for clinical reasons, not experimental ones. In time, the caretakers will try to return them to their mothers. But when Kalin's new imaging equipment arrives in the coming weeks, 20 other newborn monkeys will be on their own.
This is a joint project by the Wisconsin Center for Investigative Journalism and Isthmus, a weekly Madison newspaper, written by freelance journalist Noah Phillips. The nonprofit Center (www.WisconsinWatch.org) collaborates with Wisconsin Public Radio, Wisconsin Public Television, other news media and the UW-Madison School of Journalism and Mass Communication.