The Primate Directive

Could the key to reversing human autism be found in the monkey trials at a little-known NIH facility? That’s what researchers there hope, as they work to unlock the mysteries behind that and other human diseases and disorders



Twenty-five miles northwest of Bethesda, the roads become narrow and winding as they traverse the rolling farmland outside Poolesville. Eventually a left turn leads to a 513-acre farm with a white barn. It looks like any other farm, but the sign at the entrance to a long driveway tells otherwise.

This is the National Institutes of Health Animal Center, where a guard booth blocks unauthorized entry onto the property.

The facility—NIH’s only dedicated animal research center—is little known outside tiny Poolesville, but it plays a key role in supporting research aimed at unlocking the mysteries behind human and animal diseases and disorders.

The agency and its researchers don’t publicize the facility’s existence—for good reason: Although the U.S. Food and Drug Administration requires animal testing to determine the safety of most new drugs, the practice remains a hot-button topic, and the NIH facility doesn’t want its employees targeted by animal rights activists.

Yet “we think we have a really good story to tell,” Dr. Ruth Woodward says as a visitor gets a four-hour, behind-the-scenes tour. Woodward is the Shared Animal Facility’s veterinarian, and she notes: “Our mission is to put out research that can really help the country.”

The NIH purchased the Poolesville land in 1960 and built laboratories, animal pens and a power plant to guarantee electricity after the agency outgrew a facility near Gaithersburg. The center opened in 1965, and today serves as a holding area to ensure animals are free of disease before being used in research projects elsewhere. It’s also a research animal breeding center. But perhaps its most compelling function is as a base for behavioral and genetic research projects involving primates.

Nearly 100 people, including government employees, contractors, fellows and volunteers work at the center. Several live on-site to tend to the animals.

As of mid-August, there were about 1,400 monkeys, 100 mice, six pigs and five sheep living here. The NIH won’t detail all the research projects the animals are used for, but generally speaking, researchers use pigs for cardiovascular research; sheep and monkeys for immunity and social psychology study; and mice for assorted biomedical projects.

Dogs live at the facility on occasion (none on this particular day), but an NIH spokesperson emphasizes that they’re rarely used in research. Those that are used have been bred specifically for the purpose, with the goal of arriving at treatments for cancer and other ailments.

It’s mealtime at a 5-acre outdoor enclosure situated in a corner of the animal center. An employee wearing boots, blue protective clothing and a mask stands inside the electrified fence with a bucket of grapes and peanuts, which he begins throwing as dozens of rhesus monkeys surround him. They grab the treats and walk away, some with their tails in the air, showing their pink behinds to the visitors nearby.

He’s “wearing protective clothing and boots because monkeys do transmit disease, and we to them,” Woodward says of the worker.

The NIH built the enclosure nearly three decades ago for Dr. Stephen Suomi, the scientist who has been guiding and collaborating on research into social behavior among primates here. The research is funded by various organizations, including the Eunice Kennedy Shriver National Institute of Child Health & Human Development’s Division of Intramural Research, the National Cancer Institute, and the National Institute of Allergy and Infectious Diseases.

In 2011, Suomi received two grants from the Shriver institute: $1.25 million for research into how the environment impacts genes, and more than $800,000 to study how infant monkeys mimic their mothers.

A 1967 Stanford University graduate, Suomi was lured to NIH from the University of Wisconsin-Madison, where he had been researching the development of personality. Suomi’s graduate adviser and mentor was Harry Harlow, a University of Wisconsin psychology professor famous for demonstrating that contact and affection between mother monkeys and their infants were more important to social and cognitive development than food.

At NIH, Suomi studies rhesus monkeys because they share about 95 percent of human DNA. They also resemble humans in their ability to thrive in most climates, their tendency to live in social groups, and their mother-infant interactions.

Suomi has used the monkeys to study nature vs. nurture—particularly in regard to how environment impacts the development of personality. He also has studied how genetics influences the development of anxiety and depression, and how proper nurturing can alter those emotional states. As in humans, about 20 percent of rhesus monkeys are anxiety-prone, Suomi says.

 

About a decade ago, scientists identified 5-HTT as the gene in humans that regulates serotonin, a neurotransmitter that affects mood. Serotonin irregularities are associated with anxiety and depression. In humans, the 5-HTT gene always has two variants called alleles. When one of those alleles is shorter than the other, the person appears to be vulnerable to anxiety or depression following stressful events.

Similar gene variants have been discovered in rhesus monkeys. But Suomi has learned that proper nurturing by the mother can prevent anxiety and depression.

“We have learned that genes aren’t destiny,” says Suomi, who lives in Bethesda and has been interested in animals and learning what makes people tick since growing up in Madison, Wis. “They don’t operate by themselves, but rather, they interact with experience.”

Researchers have found a similar dynamic between genes and the environment in people, says Helen Tager-Flusberg, a professor of anatomy, neurobiology and pediatrics at Boston University Medical School and president of the International Society for Autism Research.

“Suomi is undoubtedly the most preeminent researcher in the field of primate development,” Tager-Flusberg says. “We learn from what he is doing.”

Most recently, Suomi’s observations of monkeys’ interactions have suggested a potential early way to detect autism and possibly deter its effects. Most infant monkeys mimic their mothers’ facial expressions, much as human babies “mirror” their mothers’ expressions. But about a third of the monkeys that don’t imitate their mothers develop autistic type behaviors later, repetitively pulling their hair or banging their heads, for instance.

Suomi’s researchers further discovered that non-imitative monkeys seemed to focus on their mothers’ lips, not their eyes. In humans, eye-to-eye contact is key to mother-baby bonding.

To test whether the monkeys could be trained to focus on their mothers’ eyes and perhaps avert the development of autism, Suomi’s researchers created a computer avatar of a mother rhesus monkey with large, exaggerated eyes. Through eye-tracking technology, the researchers could see if the monkeys could be prodded into looking at their “mothers’ ” eyes and redirected onto a normal developmental track. A special helmet created for the infants enabled Suomi’s researchers to study the monkeys’ brain waves to determine if the non-imitators’ brains would develop more normally. At press time, Suomi’s team was still analyzing the data and hoped to publish the findings by year’s end.

“We are discovering that what is going on in the first few days and weeks of life is probably more important than we thought,” Suomi says.

With autism diagnoses rising in this country, the impact of Suomi’s work could be “a real discovery, because it would mean there is a possibility for remediation,” says Nathan Fox, a distinguished professor at the University of Maryland who specializes in neuroscience and developmental psychology and worked with Suomi on the project.

Tager-Flusberg notes that even if it doesn’t directly translate into human treatment, it could lead to other ideas.

Suomi also collaborates on studies looking at the use of antidepressants in juvenile monkeys and their impact on the later development of personality. And he’s looking at whether genetics plays a role in alcoholism; the impact of environment on the immune system; how the environment affects aging; and how genes determine metabolism and obesity.

Suomi is so involved in his various research projects and travel that he has little time for a personal life: He’s single, and “I don’t have kids or pets, just 400 monkeys and friends with dogs and cats,” he says.

It’s nearly feeding time for the pigs, and their squeals almost drown out Dr. Tanya Burkholder, the chief of the Veterinary Medicine Branch of NIH’s Division of Veterinary Resources, as she doles out jelly beans.

“They know when one of them is getting a treat, and the [others] want one, too,” she says as she reaches down to scratch a pig’s ear. The creature turns its face aside in delight.

Kris Eckard, facility manager of the Division of Veterinary Resources at Poolesville, says the staff often gives out treats when handling the animals or administering medication. “Pigs like jelly beans, Fig Newtons and Caramel Creams,” she says.

While Woodward oversees about 400 monkeys involved in research, Burkholder is involved with watching over the rest of the animals at the facility. Houston-raised, and married with two cats, she projects a friendly, no-nonsense style.

She previously had a career in business, but “I was working as a consultant, and one of the jobs I had was for the National Zoo, largely on fundraising, and I found I was much more interested in what the scientists and veterinarians were doing,” says Burkholder, who has worked at Poolesville for 10 years. “So I decided to become a vet.”

She and Woodward make sure the animals are treated according to guidelines set by the Animal Welfare Act, the NIH’s Office of Laboratory Animal Welfare and the Association for Assessment and Accreditation of Laboratory Animal Care International. That includes standards for handling, housing, sanitation, feeding, minimizing pain and other care practices for animals, as well as the protection of employees, such as the types of clothing they must wear to prevent injury or disease from spreading between humans and animals.

In addition, researchers must consider the animals’ psychological well-being, which means that social animals such as monkeys must be housed together unless there’s a compelling reason not to, and must be provided with environmental enrichment and exercise.

The Poolesville property is split into a “north” and “south” side. Suomi’s research and primate breeding occur on the south side; most of the holding, quarantining and other research occurs on the north side. Monkeys get time outside in large cages, some of which resemble giant corncribs. There are hidden treats and swings, food is varied, and families are housed together.

About 80 monkeys also live in the protected 5-acre outdoor enclosure built for Suomi. The monkeys are free to roam, climb on trees, play on jungle gyms or swim in a large natural pond.
On the north side, many of the animals live inside but have access to the outdoors. Rhesus and long-tailed macaques occupy large, square habitats, with one wall made entirely of glass so that visitors can see them playing and eating. The monkeys can climb between the different rooms or go outside to play.

 

Pigs—both farm and Yucatan—live in separate stalls, sheep sometimes graze the fields outside, and mice live in hermetically sealed boxes to protect them from potential diseases.

“We are always trying to think about ways to keep the animals enriched,” says Woodward, a petite, energetic woman who has worked at Poolesville for 11 years. “With monkeys, that means you can’t just give them a banana every day. It means you have to hide the food in their bedding so they forage, and we have to create situations so they behave as they would naturally.”

Woodward grew up in Rockville, and as a child she’d bring injured animals to her father, a physician at NIH. She briefly considered becoming an emergency medical technician, but kept ending up working with animals and eventually got her degree at the Virginia-Maryland Regional College of Veterinary Medicine. She married another veterinarian who works on the north side of the Poolesville animal center, and together they own a dog and raise cows and horses on their nearby farm.

“I love my job here,” Woodward says. “You have so many unique species. What we like to say as veterinarians is that medical doctors only need to know one species, but we have to know many.”

Woodward gets attached to the animals, but that’s not the only reason she tries to keep them healthy and minimize their stress. It’s critical to the integrity of the research. “If you try to do a study on an animal that is stressed or has an infection, you won’t get good results,” she says. “Good animal care and good research go hand in hand.”

That’s why, she says, a visitor isn’t allowed in the primate nursery on the south side. The infants are vulnerable, and visitors could disrupt research and spread disease.

Every year, about 60 female monkeys are used for breeding, and the infants are raised by their mothers or in the nursery. Some of these monkeys will be involved in Suomi’s genetics research.
Once the monkeys reach maturity, they’ll either stay at Poolesville for breeding and/or research or be sent to research institutions elsewhere.

Under NIH rules, researchers at each institution need approval to use animals. An oversight group called the Animal Care and Use Committee evaluates requests at each institute and monitors them to make sure animal welfare rules are followed.

Eckard has worked at Poolesville for 18 years and at NIH for 22, and sits on the animal care committee for the Office of Research Services (ORS). The Poolesville animal center gets funding from multiple NIH institutes, and the ORS manages the overall operations of the center.

Eckard grew up near dairy farms in Maryland, studied animal science at the University of Maryland, and then became a licensed laboratory veterinarian technician. She got a job at NIH and worked her way up to facility manager at Poolesville.

“I consider myself lucky to be working out here,” says Eckard, who lives nearby with three pet dogs and is active in American Kennel Club competitions. It’s a lot better, she says, than being in “the busy, busy city of Bethesda.”

Since 1987, the National Institute on Aging has funded a calorie-restriction study involving monkeys on the north side of the NIH facility. One group of monkeys was getting 30 percent fewer calories than a control group to determine the impact of diet on aging. In August, the NIH announced the results: Calorie restriction didn’t appear to extend life, though it did help delay age-related diseases such as diabetes, diverticulitis and arthritis.

Aside from that one study, though, the NIH is mum on the focus of other research. “I wish I could tell you more,” Burkholder says. “I don’t think we have anything to hide, but there have been animal [rights activists] who have done nasty things to investigators and their families, and [the researchers] just don’t want to get attention unnecessarily.”

Several years ago, members of Primate Freedom Project, an animal activist group based in Fayetteville, Ga., camped out with signs in front of the facility and protested in downtown Poolesville. They describe Suomi as a “sadist” on the organization’s blog. (The group didn’t respond to requests for comment.)

“I don’t enjoy” being targeted, Suomi says, but “people are entitled to their own opinions.” He says he’s happy to address concerns. “Our goal is to make this place second to none with respect to concern for animal welfare,” he says.

Burkholder, too, emphasizes the facility’s efforts to treat the animals humanely. “Sometimes people ask: ‘You’re a veterinarian, you must love animals. How can you work for a research [facility]?’ And I say, ‘That is exactly why I work for [animal] research. I am passionate about making sure the animals are treated humanely and receive the best care that they can.’ I am very proud of how much care goes into taking care of the animals.”

There’s no denying, though, that using animals in research remains controversial. In a 2011 USA Today/Gallup poll, about 55 percent of those surveyed said the use of animals in medical testing was “moral,” down from 65 percent a decade earlier.

Groups like the Animal Liberation Front have used extreme measures against scientists known to be involved in animal research, even vandalizing their homes.

The Humane Society of the United States has taken a more moderate approach, trying to work with scientists even as it raises questions about the use of animals. Kathleen Conlee, the Humane Society’s vice president of animal research issues, asks, for instance, if Suomi’s research couldn’t just as easily be conducted on humans.

“Are we using our tax dollars to fund the best research?” she asks.

Suomi says: Yes. Studying monkeys in a lab enables researchers to control genetics and the environment, he says. They also can measure behavioral and physical changes daily, which they cannot with humans. And because monkeys age four times faster than people, a researcher can study how many characteristics of a parent are passed on to a child more quickly.

Still, scientists themselves are questioning what kinds of animals should be used. In December 2011, the Institute of Medicine (IOM), an independent medical advisory organization for the government, determined that most research involving chimpanzees wasn’t necessary.

“We have used animals because they are readily available and because they have long been used...as a way of doing early research that can’t be done in humans,” says Jeffrey Kahn, the Levi professor of bioethics and public policy at the Johns Hopkins University Berman Institute of Bioethics who oversaw the IOM report on chimpanzees. But, he adds, it’s perhaps time to question those assumptions.

Public and private institutions in the United States use about 17 million animals a year for research. That number is down from two decades ago, according to Johns Hopkins University’s Center for Alternatives to Animal Testing.

In September 2011, NIH, the Defense Advanced Research Projects Agency and the FDA announced that they would jointly invest more than $100 million in developing three-dimensional human organs on computer chips for medical testing. The work is being conducted at multiple academic, research and NIH institutions through the agency’s newly created National Center for Advancing Translational Sciences in Bethesda. The goal is to successfully reproduce human tissue on chips in five years and develop a more reliable method for testing new drugs and devices within a decade. If the technology succeeds, there could be a significant reduction in animal use.

“I think we are a long way from that,” Burkholder says. But “I would love to have to retire because I wasn’t needed anymore.”

Bara Vaida is a longtime health policy and business writer who lives in Washington, D.C.

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