Deep divide over the merits of animal research

BY BRYN NELSON, Staff Writer

Long before the trouble started, Columbia University neurosurgeon Dr. E. Sander Connolly asked a question: How, he wondered, could the brain damage he often saw in stroke patients be reduced, if not prevented?

The trouble began when veterinarian Catherine Dell'Orto asked a different question: How could Connolly's stroke experiments in baboons be justified?

For many of his supporters, the neurosurgeon's baboon-based stroke research continued the climb of biomedicine toward its noble goal of preventing suffering and death for millions of humans. But for many of his critics, the experiments were but the latest outrage in a field blamed for the suffering and death of millions of animals along the way.

For centuries, animals have served as human stand-ins for a broad range of experiments looking at how the body functions, or fails to function due to illness, injury and aging. Within the last century, such animal research has contributed to the development of insulin, kidney dialysis, vaccines for diseases like polio and diphtheria, and the coronary bypass surgery that New York surgeons performed last month on former President Bill Clinton.

But all of the advances have come at a cost. Although no government agency keeps track of the number of mice and rats used for research, a nearly two-decade-old estimate suggested an annual tally of 16 million to 22 million. For the year ending Sept. 30, 2002, the last for which statistics are available, researchers used another 1.1 million rabbits, guinea pigs, hamsters, dogs, cats, primates and other warm-blooded animals overseen by the federal Animal Welfare Act.

In a biomedical era of increasing demands and heightened tensions, is there a point at which the potential harm to animals outweighs the potential good to humans?

No single experiment can encapsulate a sprawling debate over questions -- some shouted through bullhorns, some chewed over in silence. And virtually every major research university has had to contend with objections over its animal-based studies, including recent controversies in Massachusetts, North Carolina and Washington.

But the story of a respected neurosurgeon, a disillusioned veterinarian, and the fight between a vocal animal rights group and a high-profile New York institution illustrate the deep divisions that persist over the limits of animal research.

The story begins with a clot.

Within a nasty cut, coagulated blood cells can act as the catalyst for a protective scab. But within a blood vessel delivering oxygen-rich blood to the brain, a clot can prove deadly.

Connolly, a well-published 39-year-old assistant professor of neurosurgery at Columbia and a graduate of Louisiana State University's School of Medicine, has focused much of his research on ischemic strokes, or those in which blood flow to the brain suddenly stalls. Every year, these strokes afflict well over half a million Americans, with blood clot-jammed vessels blamed for most of them. Inducing a baboon stroke

For these patients, death or long-term disability can result from a breakdown in the network of blood vessels beyond the blockage and an expanding zone of oxygen-starved brain cells -- akin to a perforated garden hose that develops a kink and leaves downstream plants with a mere trickle of water.

In his research proposal -- officially titled Experimental Protocol 2860.02 -- Connolly sought to answer whether drugs might limit this downstream microvascular failure by protecting the brain's blood vessels and neurons from damage. Experiments in mice had suggested he was on the right track. And so Connolly turned to young adult male baboons, whose brain anatomy closely resembles that of humans.

Experimentally inducing a stroke in a baboon is not for the faint of heart. According to Connolly's research protocol, it requires veterinary surgeons to clamp several major arteries that deliver blood-borne oxygen to the baboon's brain. To access those vessels, surgeons first anesthetize the baboon and remove its left eye, along with residual fat and muscles lining the eye socket. Then, using a high-speed drill, the surgeons remove bone segments forming the back of the socket. Finally, they remove two of the brain's outer coverings to reveal the inner arteries.

Connolly asked permission to induce strokes in 60 baboons by clamping their arteries for an hour. Thirty would receive one of three experimental drugs intravenously, including a derivative of Vitamin C called dehydroascorbic acid, and 30 would instead receive a placebo. Each baboon would be euthanized either three or 10 days later, and its brain examined to gauge the drug's effect.

In March of 2000, Columbia University's Institutional Animal Care and Use Committee signed off on the project -- just one of the dozens of animal experiments the review board would pore over that year. Some 41/2 years later, however, Experimental Protocol 2860.02 has become a flash point.

After holding an initial press conference last fall, People for the Ethical Treatment of Animals (PETA) launched a publicity blitz earlier this year against the perceived cruelty of Connolly and two other Columbia scientists conducting separate experiments on baboons and rhesus macaque monkeys. PETA supporter and political humorist Bill Maher sent Columbia's faculty and staff a mass e-mail in May, urging them to oppose the research. Protesters disrupted the university's graduation ceremony in June. An elaborate Web site appeared, labeling the researchers "Columbia's Death Squad" and including a video of caged primates at the university.

"This Columbia case is especially poignant because of the incredible suffering -- it's the suffering of those primates in these laboratories that has really compelled us to push hard on Columbia to clean up its act," said Mary Beth Sweetland, PETA's director of research and investigations.

Strong allegations

One of the organization's allies, 22-year-old pop singer Nellie McKay, even released a song about the controversy, called "Columbia is Bleeding."

In its complaints to regulatory and law enforcement agencies, PETA alleged that Connolly's research was improperly conducted and the follow-up care inhumane. But a broader message emerged in statements from the organization and its supporters: The science itself was barbaric and shouldn't have been conducted at all.

In fact, other surgery-based experiments have proven vital to biomedical progress. The successful quadruple bypass surgery of former President Bill Clinton at the Columbia-Presbyterian Center of New York-Presbyterian Hospital, for instance, relied on a heart-lung machine and coronary bypass techniques -- both developed from research on dogs and other animals.

The victims of a rare human disorder known as moyamoya disease, in which the main blood vessels leading to the brain become narrowed or irreversibly blocked, have similarly benefited. For many of these patients, the chance of a stroke becomes all but certain without surgery. Dr. Connolly, one of the leading moyamoya neurosurgeons on the East Coast, specializes in bypass procedures that reroute the brain's blood supply past the blockage -- surgeries honed in past experiments with animals.

The mother of a former patient referred to Connolly on an Internet message board as a "skilled brilliant doctor" with a "great" bedside manner, while another concurred in an e-mail sent to Newsday, in which he described the neurosurgeon as "a very kind and caring person as well."

Columbia officials declined to make Connolly or his baboon research protocol available. Nor would the university confirm or deny the authenticity of a 15-page summary of Connolly's protocol that Newsday received from PETA, citing reasons of confidentiality. Dr. Catherine Dell'Orto, a former veterinary post-doctoral fellow at the university, said she could vouch for it, however.

Objections are raised

Dell'Orto, now 35, arrived at Columbia's Institute of Comparative Medicine in July of 2001 with her doctorate in veterinary medicine from Mississippi State University and a view that animal research was a necessary evil. By then, Connolly had finished the first phase of his research with 23 baboons and begun the second phase with a new contingent.

Within weeks, Dell'Orto said, she had raised multiple objections with a senior veterinarian -- that the baboons were receiving inadequate pain medication given the severity of the surgery, that they were receiving poor post-surgical care and being left to die in their cages. And, she contended, dogs and pigs in the facility were being mistreated as well.

But after a meeting with other veterinarians to address her concerns, she said, "I was told I was not allowed to go into the experimental surgery area, where they performed those surgeries. I was told that I should focus on rodents."

Licensed veterinary technician Idalia Padilla-Weiss also began working at Columbia in the summer of 2001. With Dell'Orto, she shared an office and a belief that some of the lab animals were suffering needlessly. Some baboons and monkeys bit themselves repeatedly, Padilla-Weiss said. Others ate their feces or wouldn't eat at all. She blamed their behavior on stressful housing conditions and a lack of environmental enrichment, a view she said was not shared by her colleagues.

"They just pooh-poohed me and told me I was new in the field and couldn't be too emotional about it," she said.

But she couldn't help it.

"Emotionally, you get involved. Some people can block it out. Other people can't," Padilla-Weiss said. "Just because someone gets emotional about what they've seen, doesn't mean they don't know what's going on."

To improve what she considered a poor environment for the primates, Padilla-Weiss said she requested a television (some rhesus macaques are known to chatter angrily if they can't watch "Sesame Street" on a daily basis). None was forthcoming. So she began bringing her charges treats like popcorn, nuts and cut-up fruit. She brought in a lava lamp, a radio, cardboard boxes, even a plastic gun that released soap bubbles.

Disputes over methods

Over the next year, Dell'Orto said, Padilla-Weiss or another technician would ask her to examine particular animals, such as a male baboon recovering from a stroke, or a female rhesus macaque in a separate project studying how stress alters the menstrual cycle.

PETA has contended that the latter experiment, led by Columbia researcher Dr. Michel Ferin, induced physical stress by surgically anchoring a metal cap to the monkey's skull.

Dr. Thomas Martin, director of the university's Institute of Comparative Medicine, disputed that allegation, instead describing the implant as a plastic tube "smaller than a toothpick," or a catheter, surrounded by a non-implanted flexible metal tether to prevent the catheter from being dislodged. The macaques, he said, received aspirin suppositories for pain relief after surgery. Dell'Orto, however, said that on at least three occasions, she found a macaque trying to remove the implant, bloodying itself and the cage in the process.

"There should have been tranquilizers," she said.

In October of 2002, Dell'Orto complained again -- this time to the administrator for the university's Institutional Animal Care and Use Committee, the panel that initially approved both experiments. The university set up a committee to investigate. But Dell'Orto said she became discouraged when a professor associated with Connolly's stroke research was named to that committee.

So she took her concerns to the enforcement arm of the USDA, the agency that ensures compliance with the federal Animal Welfare Act. And then she told her story both to PETA and The Humane Society of the United States. Dell'Orto would testify before the Columbia committee. So would Padilla-Weiss. Both said they were allowed too little time to press their case or make their questions heard.

"Everyone wants animal research," Dell'Orto said.

"But if you are actually seeing these animals suffering and dying, you can't but help to say to yourself, 'There's something wrong here.' "

Taunts and vulgarity

Dell'Orto said she voluntarily left Columbia in February of 2003, after enduring ostracism and retaliation from colleagues. After a stint as a veterinarian in Westchester County, she moved to an animal clinic in Tuscon, Ariz.

Padilla-Weiss, likewise, said co-workers began to treat her with derision after hearing of her role in the investigation.

"I was known as the 'monkey lady' and the 'baboon lady,' " she said. More vulgar names were whispered anonymously over the work telephone. Padilla-Weiss voluntarily left Columbia in January, and now works as a veterinary technician with the ASPCA in Manhattan.

"I could go back to that, I would make more money," she said. "But I won't."

After repeated requests by Newsday, Dr. Martin and Dr. Mark Underwood, chairman of Columbia's Institutional Animal Care and Use Committee, agreed to discuss some of the more contentious aspects of Connolly's research. In a joint interview, Martin said he had reviewed all of the university's investigation-related documents. "And what that supports is that Columbia moved very quickly," he said. "I don't think that the investigation could have been any more thorough or any more open."

According to a June 30, 2003, letter sent to Dell'Orto by Dr. Harvey Colten, vice president and senior associate dean for translational research at Columbia, the university's investigative committee discovered substandard record keeping. It confirmed "inadequate or questionable veterinary care to 11 of the 23 animals about which you expressed concerns, as well as to six puppies infected with scabies in an incident reported by another individual." And it found that many of the adverse events were not reported to the university's Institutional Animal Care and Use Committee.

No violations found

The investigation uncovered no evidence of significant violations in the conduct of the research, however. Nor did it find evidence of retaliation against Dell'Orto.

Every institution that conducts research on animals protected under the Animal Welfare Act must establish a review committee to ensure that each proposed experiment passes muster. Are animals the best way to tackle the research question? If so, what animals? How many? Will they feel pain or distress? If so, can they be treated? And, when necessary, killed in a humane way?

Even after permission is granted, researchers must report back on their findings and ask for permission before embarking on the next phase.

In answering these questions, biomedical researchers say they are paying unprecedented attention to issues like pain management and environmental enrichment.

At Columbia, Martin said, any scientist who proposes a procedure likely to cause pain must meet with a veterinary surgeon to devise an anesthetic and pain medication plan. Martin described the plan developed by Dr. Connolly, which also involved discussions with a hospital anesthesiologist, as "excellent." In addition to the mixture of drugs in the gas anesthesia administered during the surgery, he said, surgeons also used a local anesthetic at the surgical sites. For pain control, the surgeons used fentanyl, which Martin described as "a very powerful morphine."

Changes are made

He said the intravenous dose -- 10 times the amount normally given to animals in pain -- was continued at the same level for 20 hours after surgery.

With regard to environmental enrichment for the university's primates, Martin said a program existed before the investigation, but a review process with input from outside veterinary experts found it needed to be formalized. Columbia now has an enrichment coordinator, he said, who oversees the use of enrichment items like a television, a water fountain, and a variety of toys and puzzles.

In response to its own review, Martin said the university also extended the routine hours of animal care, established training sessions in record keeping and hired a coordinator to help veterinarians make sure animal research proposals comply with all guidelines and regulations.

And the university has established a new process for veterinarians to discuss whether unexpected events -- such as infections or post-surgery complications -- should be reported.

"Columbia didn't get to be a great institution by closing its mind and its door to ideas," Martin said. In an evolving field filled with hard questions, he said, "we're trying to do our best to lead the way."

Martin and other researchers concede that animal experiments, even those that exceed every guideline, can still present unpleasant choices.

"It's not easy to decide to use an animal," he said. If a research question could be answered another way, "there is not a researcher here who wouldn't jump at that. There isn't a researcher that is using animals because they want to."

A growing dilemma

With a lack of viable alternatives, other researchers say the dilemma extends beyond just scientists and activists.

"It's terrible to use dogs in heart disease studies, but as soon as your older family member needs heart care, you want the best," said Dr. Alan Beck, Director of the Center for the Human-Animal Bond at Purdue University's School of Veterinary Medicine. And despite the objections of activists, he said, few people would forgo new cures in exchange for a total ban on animal research.

In the absence of a complete ban, should some research be off limits -- a position adopted by some foreign countries?

"In Europe to a degree, and especially in Great Britain, there's a point where animal concerns trump human needs," said University of New Mexico bioethicist John Gluck. "In theory, there is no experiment in the United States, no matter how invasive, no matter how excruciating it is to the animal, that could not be approved on some level, if the argument is that the benefits seem to be sufficiently valuable."

Great Britain, whose review committees operate under some of the most stringent animal welfare regulations in the world, differs from the United States in another major respect: Unlike Americans, a majority of Britons believe medical testing on animals is morally wrong.

In this country, animal research is governed by a complicated system of guidelines and regulations that some have likened to the federal tax code.

University passes muster

Martin said Columbia reported its findings to two federal agencies, each of which expressed satisfaction with the university's handling of its investigation. One of them, the USDA's Animal and Plant Health Inspection Service (APHIS), completed its own review in May and issued what's known as a stipulation, fining the university $2,000 in the process. Some of the agency's findings echoed those of Columbia's investigation, while others cited specific faults with animal housing and with the university's internal oversight.

Of similar cases resolved in 2001, the last year for which detailed records were available, APHIS issued 130 stipulations in all and imposed fines totaling roughly $143,000. Separately, judges working on behalf of the agency delivered 83 legal decisions as a result of animal welfare violations, imposing fines totaling more than $365,000.

APHIS spokesman Jim Rogers said the Columbia findings did not reach the level of violations that would spur legal action. "We're just essentially saying, 'Cut it out, pay this fine.'"

Columbia did, and APHIS took no further action.

But other questions remain.

In a Feb. 28, 2001, letter to the university's Institutional Animal Care and Use Committee, Connolly wrote: "We completed a trial of a novel anti-oxidant compound (DHA) and were able to show that its efficacy in lower rodent models is not mirrored in primates."

The effectiveness of the Vitamin C derivative in protecting mice from stroke-related brain damage had not extended to the 23 baboons he studied. And so he requested permission to use 30 baboons to test a separate drug. PETA provided the letter to Newsday. Columbia, citing reasons of confidentiality, would not confirm or deny its authenticity, but Dell'Orto again vouched for it.

Yet Connolly, quoted in a press release 10 weeks later, touted the drug's effectiveness in a mouse study and its potential "to protect patients against the debilitating consequences of stroke," but never mentioned its less promising results in his own baboon study.

Tarrytown, N.Y.-based Progenics Pharmaceuticals, which developed the drug, issued the release. A Progenics spokesman did not return multiple calls and e-mail inquiries seeking comment.

Critics have decried the omission of negative research results from human clinical trial press releases, and two ethicists contacted by Newsday similarly criticized the integrity of the Progenics release.

Barbara Orlans and John Gluck, both affiliated with Georgetown University's Kennedy Institute of Ethics, stressed the importance of animal-based stroke studies to the medical field. But they also raised concerns about Connolly's experimental design -- citing as a "major failure" its lack of a proper post-surgery pain and distress assessment for the baboons. And they questioned the reliability of what they termed "crude" behavioral and physiological measurements to assess the drug's impact.

As for the USDA's settlement agreement, Orlans and Gluck characterized it as "a serious indictment of a committee and some researcher(s) who failed to follow basic welfare commitments."

Did Dell'Orto's complaint make a difference? Whether Columbia's own review would have occurred without it is debatable. But as Underwood, chairman of the university's Institutional Animal Care and Use Committee, said, "We are doing things differently now."

So is PETA. Citing animal cruelty, the group asked the New York County District Attorney's office to investigate and prosecute Connolly and 19 other Columbia-affiliated individuals, including most of the university's internal review board. A spokeswoman for the district attorney confirmed the request but declined to comment further except to say, "We are looking into it."

PETA is pushing the envelope in other ways. Sweetland portrayed the Columbia researchers as torturers and lowbrow "Joe Six-Pack" scientists who do "cutting up," not "cutting-edge," experiments.

Martin said Connolly stopped his own baboon experiments -- not because of any complaint or threat, but because of an agreement to suspend the research during the university's investigation. "I and others believe that biomedical research is one of the most powerful forces for good that there is," Martin said. He confirmed that some Columbia scientists have received threats from those who believe otherwise, but he declined to elaborate. He vowed, though, that the university wouldn't halt its animal-based research in response to "terrorist tactics."

For now, at least, one biomedical project has yet to resume.