Curtains Down for the NEPRC

The planned closure of the New England Primate Research Center shocks and dismays many in the close-knit community of HIV researchers who conduct primate studies.

As animal facilities go, the New England Primate Research Center (NEPRC) had attained a legendary status on the roster of U.S. biomedical research institutions. In the half century since it was established, a good number of important discoveries have been made within its walls. Researchers working at the NEPRC generated some of the earliest evidence that AIDS is a viral disease, and subsequently discovered the simian immunodeficiency virus (SIV), which causes the monkey version of AIDS. It was there, as well, that scientists demonstrated that a vaccine can prevent the transmission of SIV, suggesting that an HIV vaccine is possible. Nor were the NEPRC’s contributions to science confined to HIV and AIDS. The facility has hosted research of profound relevance to everything from cancer to neurological disease and addiction.

But lately it had become increasingly clear that this storied institution’s best days were behind it—so far behind it, in fact, that the Harvard Medical School (HMS), which oversees the center, decided it should be shut down. Its decline was slow, embarrassing, and fueled largely by management and money problems rather than the quality of its research. 

The NEPRC has, for example, been cited at least four times since 2010 by the US Department of Agriculture (USDA) for failure to comply with the requirements of the Animal Control Act. The most recent citation, issued last year, related to a cotton-top tamarin found dehydrated after an employee neglected to provide sufficient water to the animal. After examining its recent health history, the NEPRC veterinarian decided to euthanize the monkey, according to the USDA report.

John Harding, acting director of the Division of Comparative Medicine’s Office of Research Infrastructure Programs (ORIP)—the NIH arm that provides the core grants for all national primate research centers—notes that it is “ very uncommon to find violations of the sort where animals died.” Indeed, the animal care issues had become sufficiently vexing to prompt HMS to stop new research for a period of months in mid-2011, and then again in 2012. HMS says new research resumed over a period of time after the first suspension, with the more recent stoppage ending in August 2012.

A paucity of external research dollars, both private and public, didn’t help. Federal funding from the US National Institutes of Health (NIH) had been flat in recent years, even as many of the Boston scientists who had long relied on the facility began to take their business elsewhere. The sequester—the US$85 billion in across-the-board federal spending cuts that kicked in March 1—seemed likely to exacerbate the NEPRC’s funding troubles.

Still, HMS’s decision to wind down the facility by 2015, rather than seek renewal of its five-year operating grant with the NIH, has upset the close-knit community of primate researchers. “We were all shocked,” says Ron Veazey, a professor of pathology at the Tulane National Primate Research Center in Louisiana who, as a post-doc/instructor at Harvard from 1994-99, authored a study that identified the gut as a major site of viral replication and CD4+ T-cell depletion in SIV infection (Science 280, 427, 1998). “Very few people can say, ‘we saw this coming.’ In an ideal world, all those [NEPRC] investigators will be able to transfer projects to other primate centers and everything will go on. But we can’t be sure.”

The NEPRC decision to phase out its research also raises serious questions about the future of the approximately 130 research projects it hosts—many of which relate to AIDS. Ditto for the 2,000 or so primates housed at the facility in Southborough, MA. These include 1,286 rhesus macaques, 310 common marmosets, 169 cotton-top tamarins, 49 squirrel monkeys, and 46 cynomolgus macaques. Aside from guest researchers, HMS says, about 20 core scientists currently use those animals to conduct research on fields ranging from neuroscience to microbiology and immunology.

Seven other national primate centers—based in Louisiana, Washington, Oregon, California, Georgia, Wisconsin, and Texas—conduct a similarly wide array of research. But a primary focus of all the facilities has been infectious diseases, says ORIP’s Harding. He says about 50% of the research conducted at the facilities relates to infectious diseases, and roughly 80% of those projects are tackling AIDS.

As such, the closure of the NEPRC is likely to be widely felt throughout the field of HIV research, especially in the areas of vaccine and drug development. “Literally every class of HIV drug, with the exception of protease inhibitors, was first tested in monkeys,” noted Veazey.   

Louis Picker, a professor of pathology/molecular microbiology and immunology affiliated with the Oregon National Primate Research Center, says he was upset by the decision to shut down the NEPRC—where he did research during his laboratory and pathology medicine residency at Beth Israel Deaconess Medical Center in Boston. But he wasn’t surprised. “You could see the writing on the wall when this first started, two to three years ago, with the mishandling of the animal issues.”

Picker says that what he regards as Harvard’s overzealous and seemingly punitive response to the animal care issues—replacing NEPRC director Ron Desrosiers and two on-site veterinarians—served to drive investigators away rather than fix the problem.

“The [NEPRC] has a 50-year history and has arguably been the crown jewel of NIH-supported primate centers,” he notes. HMS, however, did not single out the animal care issues in explaining its decision. It says the decision, supported by both the NIH and Harvard University—though reached with a “heavy heart”—was driven by the shortage of external funds. In evaluating its long-term needs, HMS says, it concluded that closing NEPRC would be more beneficial, and efficient, than pouring more resources into maintaining and renewing its supporting grant.

In a release posted on its website, the HMS says it is working with the NIH and members of the scientific community on an “orderly transition of the NEPRC research programs.” The school said the primates will either be transferred to other sites, including the other national primate research centers, or be managed at the NEPRC in accordance with approved protocols.

“I am personally committed to instituting a transition that embodies our tremendous respect and gratitude for the center’s faculty and staff, and one that guarantees the welfare of all animals in our trust,” said Jeffrey S. Flier, dean of the faculty of medicine at Harvard University, in the April 23 release. “I am also confident that we can achieve our research goals through collaboration with a vibrant national scientific community.”

Harding, whose agency is working with HMS to ensure a smooth transition, echoed Flier’s sentiments. He says it is not unusual for scientists to conduct their animal research at primate facilities hundreds and even thousands of miles from their academic institution, though he admits that model may be better suited to infectious disease research than it is to behavioral research.

Because the NEPRC will be winding down operations over a period of 24 months, some ongoing projects may continue there, though HMS said it is too early in the process to specify which ones. Scientists have been told that some recently awarded contracts might even get started at the New England facility—as long as the work can be completed within 24 months.  However, studies that extend beyond this time frame will obviously need to be shifted to other sites. And that could raise new problems. While the other national primate research centers have told the NIH’s ORIP that they have the capacity to host those animals, reworking the contracts will take time and is likely to get quite complicated. 

Another unresolved question concerns the future location of the rhesus macaque breeding colony that supplies the NEPRC. “These animals are precious to all of us,” says Nancy Haigwood, director of the ONPRC. “They are already in productive breeding groups, and you need to find appropriate homes so that you can keep the groups together.”

This is easier said than done, thanks to Mother Nature and the climate-controlled habitats that shelter the NEPRC animals. Due to New England’s chilly weather, the NEPRC uses indoor enclosures for breeding. The centers in California, Oregon, Texas, Louisiana, Washington, and Georgia, meanwhile, maintain breeding colonies outdoors and in some cases in indoor/outdoor facilities. The NIH program that provides funding for the breeding colonies will be working with all of the other seven centers to determine the best place to move the entire population or individual breeding groups. Haigwood acknowledges that many of the researchers will also have to find new homes for their research and their teams, though she seems confident that many of them will be sought after by other primate centers.

Researchers are wondering whether the closing of the NEPRC will translate into a shrinking of overall funding for the national primate research centers. “To me, a key question will be: How will the NIH respond?” said Picker. “Will they take $10 million from [NEPRC’s core grant] and re-invest it, or will they give it to other primate centers to keep the level of infrastructure?”

Obviously, Picker advises the latter. He and four other AIDS scientists advocated, in a Nature Medicine commentary earlier this year, more investment in NHP research, in part to support larger studies in more relevant primate models (Nat. Med. 19, 30, 2013). “Recent studies using repeated limited-dose mucosal challenge, which more closely reflects human sexual transmission, and larger group sizes have revealed immune vulnerabilities of highly pathogenic SIV that could not have been appreciated with previous standard approaches, including a vaccine-mediated protection against acquisition of highly pathogenic SIV infection that has clear similarities with the protection observed in the RV144 human vaccine trial,” they argued.

Harding says the decision to close the NEPRC was Harvard’s, not the NIH’s. “We were surprised,” he says. Harvard’s decision should not be viewed, he says, as a signal that interest in funding NHP research is waning. “In fact, we see a continued need for this.” If anything, says Harding, the recent termination of the large HVTN 505 trial (see blog, Large AIDS Vaccine Trial Shudders to A Halt, April 26, 2013), suggests more NHP research is needed.

Still, even researchers unaffected by the closure of the NEPRC find its disappearance from the HIV research map hard to take in. “Personally, I see it as a loss for Harvard and for the New England research committee,” said Ana Aldovini, a scientist at Boston Children’s Hospital who once used the NEPRC but now collaborates with Tulane. “I can’t imagine it not being a loss.” —Regina McEnery