Feature
Of Mice and Medicine
By Howard Bell
In the wee hours of April 5, 1999, masked members of the Animal Liberation Front (ALF) ransacked Walter Low’s laboratory at the University of Minnesota. Dressed in black, they smashed the neurosurgery researcher’s microscopes and splashed chemicals on equipment and papers. They destroyed an irreplaceable tissue culture that might have saved a man’s life. They smashed Low’s computers and obliterated two years of work on brain cancer vaccines. The ALF members destroyed everything except what they came to destroy—Low’s mouse room. They tried but failed to break into the room where Low keeps the mice he uses to test drugs that block neuron death in Alzheimer’s and Parkinson’s disease.
Other animals weren’t so lucky. The ALF activists stole 100 research animals from another lab, including pigeons, rats, and an irreplaceable population of patented mice used to study Alzheimer’s disease. The Animal Liberation Front claims its members find good homes for “liberated” animals, but several of the animals were found frozen or half-eaten in a suburban St. Paul field.
The vandals ransacked 12 labs on the Minneapolis campus that night. They inflicted $2 million in damage and disrupted dozens of research projects. It was considered the worst case to date of animal activist group terrorism against a U.S. research facility. “We were devastated,” Low says. “It was a real wake-up call.”
Since the break-in, the university has spent tens of millions of dollars beefing up security in its research labs on all campuses. They installed more video cameras, hired more guards and trained them specifically for animal activist attacks, and installed better lighting and key-card entry systems in all labs. “We’ve had to change the whole culture around here,” says Richard Bianco, the university’s director of experimental surgery and associate vice president for research and regulatory affairs, who oversees research compliance. “We’ve got a neighborhood watch attitude. We watch each other’s backs. We shake doorknobs to verify doors are locked. We take responsibility for the security of others’ labs, not just our own. We’re more safety- and security-conscious.”
The university also beefed up its public relations immediately after the break-in, when it notified local media and countered what Bianco calls ALF’s misinformation about “liberating the torture chambers.” “When we found our animals dead in suburban fields, the media realized ALF lied to them when they claimed they’d found foster homes for all the stolen animals.” Soon after the break-in, a protester dangled for a week from the outside of a university building until Bianco filed a grievance against the student group the protester represented. The group was suspended from engaging in its activities at the university.
Long before the break-in, Bianco regularly spoke to the media and at national medical conferences, schools, and other public forums about the importance of animal research. After the break-in, he got even more vocal.
Seventy percent of Americans support the humane use of animals in medical research, according to the U.S. Department of Agriculture (USDA). That number might be higher if the public was aware of the dense matrix of regulations all research centers must navigate before using a single mouse or any other animal. Polls show most people are unaware of these regulations. Lack of awareness makes the public more likely to believe erroneous charges—that animals are abused and animal research is not necessary and only done to “make scientists rich.” “The more the public understands what we’re doing,” Bianco says, “the more they’ll support it. Good science requires good animal care. Unhealthy animals don’t provide a normal biological or behavioral response necessary for reliable data.”
Answering to Many Masters
In the past few years, the university and other research centers have gotten more aggressive about letting the public know that animal research is done only when necessary and that it’s done within a complex regulatory environment. “We answer to a huge number of masters,” says Michael Joyner, M.D., Mayo Clinic’s associate director for research. The USDA regulates animal research. Every year, it conducts at least one unannounced inspection of every research facility. It can levy fines, terminate projects, or, in extreme cases, revoke a facility’s USDA registration. Most research centers depend on National Institutes of Health (NIH) funding, so they must also comply with NIH policies for the humane care of laboratory animals. The Food and Drug Administration (FDA) has its rules, too. In addition, all research centers have their own policies and procedures for animal care and handling.
Both the university and Mayo say their animal policies exceed federal standards. Both are accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International. Like JCAHO accreditation for hospitals, it’s voluntary, but it demonstrates that the facility goes above and beyond minimum federal standards for animal research. For example, rodents are not protected under the 1960 Animal Welfare Act, the basis for all federal regulations pertaining to animal research. But at Mayo and the university, all animals—rodents included—are treated according to the same standards, regardless of the funding source.
The USDA requires that every research center have an animal research review committee called an IACUC. That stands for Institutional Animal Care and Use Committee. Committee membership must include at least one veterinarian and one local citizen not affiliated with the institution.
Every IACUC has its own animal use and care plan. It is based on species-specific federally approved standards for handling, housing, cage size, feeding, watering, exercise, sanitation, ventilation, temperature, humidity, veterinary care, pain relief, enrichment and stimulation, and euthanasia.
The IACUC has peer reviewers evaluate all animal research proposals. Investigators must explain to the IACUC their reasons for using animals. Does this research really need to be done? Why can’t alternatives that don’t involve animals be used? Why this many animals? Why this particular species? Where will they come from? What will be done to them? How will discomfort and pain be limited to that which is unavoidable?
All studies must demonstrate “the three Rs” of animal research—refinement, reduction, and replacement: Refine methods to minimize animal stress. Reduce the number of animals to a minimum. Replace animals when possible with an alternative.
Animal research is expensive, time-consuming, and administratively cumbersome, according to Bianco, who oversees the U’s IACUC. “First,” he says, “you ask if there’s a way to do this without animals. If the answer’s no, you design a study that uses the least number of animals in the shortest amount of time as humanely as possible.”
The IACUC can approve, reject, or ask for changes to an investigator’s plans. “Usually they approve with stipulations,” Bianco says. “Denial is rare because investigators know not to submit proposals likely to be rejected. The committee is not a rubberstamp. We cannot and do not condone compliance violations. We take federal guidelines for animal care very
seriously.”
The university’s IACUC enforces federal standards and the U’s own policies. It makes sure rodents are purchased from national dealers. Larger animals come from farmers and veterinarians. Federal law requires that all suppliers be USDA-approved. Lost or stolen pets are never used. That’s illegal. Eighty percent of research animals are “purpose-bred,” meaning they are bred specifically for laboratory use.
Laboratory animal technicians provide day-to-day care and feeding of the animals. Many are certified by the American Veterinary Medicine Association and have both traditional veterinary nursing skills and an understanding of research methods. Many lab animal technicians are trained to draw blood, take X-rays, give medication, administer IV therapy, induce anesthesia, assist with surgery, give postoperative care, and painlessly euthanize an animal.
Research animals that undergo surgery receive postoperative care that is similar to the care humans receive, according to Mayo’s Joyner. “We use the same anesthesia machines and the same drugs. It’s not only humane, it’s good science. We’re applying the information we get from animals to our patients, so it’s good science to treat them as similarly as we can.”
Through the Freedom of Information Act, animal activist groups can and do request information about the animal care and handling policies at Mayo and the university, according to Bianco. “Usually they edit it and distort it to fulfill their agenda,” he says. “It’s a tremendous waste of our resources, but by law we must provide the information.”
Man’s Best Friends
Animal research has been crucial to every major medical advance in the past 100 years—in cancer, birth defects, vaccines, antibiotics, asthma, hypertension, diabetes, cardiac surgery, the list goes on. “Animals are essential for developing new drugs, surgeries, medical devices, and therapies,” Bianco says. “The U was the birthplace of open-heart surgery,” he says. “We couldn’t have achieved that without animals. The next generation of nonthrombosing heart valves is going to come from animal research.”
The FDA requires that all medical innovations be tested in animals for safety and effectiveness before human clinical trials can begin. Animals are also essential to training doctors, Bianco adds. For example, many physicians must learn new minimally invasive and robotic procedures to stay current. “Animals play an obvious key role in this,” he says.
Here’s the paradox: Alternatives to animals—tissue cultures, computer simulations, and population studies—play a bigger role in medical research than they used to. Yet animals are more important than ever. That’s because recent, huge advances in gene alteration and stem-cell implantation let us learn more from animals about the genetic basis for human diseases.
Animals are genetically and physiologically similar to humans. They are vulnerable to more than 200 of the same diseases. That makes them good models for the prevention and treatment of human diseases, according to Joyner. “Animals with a spinal cord are more similar than dissimilar to humans,” he says. “What’s learned in animals almost always applies similarly to humans. Exceptions are just that—exceptions—not the rule.”
Researchers use an array of animals. Sheep are used to test cardiac devices and artificial heart valves. “Sheep hearts are similar in size to human hearts,” Bianco says. “Their valves calcify at an accelerated rate, so in six months we can model what takes decades to happen in humans.”
Because pigs and humans have similar cardiovascular systems, they’re used for testing new cardiovascular medications. Pig heart valves have been used for years to replace diseased or damaged human valves. The university is studying the use of pig stem cells for rejuvenating damaged human heart muscle. Transplanting genetically modified pig stem cells into humans may one day treat stroke and Parkinson’s disease.
Mayo uses zebra fish to study how proteins in the heart contribute to heart failure. “We like zebra fish,” Joyner says. “They’re transparent. You can see their hearts working. Their eggs and their genes are easy to work with. You can make a lot of them fast.”
But 95 percent of animals used in biomedical research are rodents—mostly mice. Mice are nice. The animals are excellent models for studying any human disease because 98 percent of mouse DNA is identical to human DNA. And their short life spans make it possible to study disease development over a much shorter period of time than is possible with humans.
Mice have long been used to study Parkinson’s, Alzheimer’s, cardiovascular diseases, psychiatric disorders, spinal cord injury, stroke, diabetes, surgical techniques, transplantation, autoimmune disorders, cancer, and bone healing. They’re also used to test new drugs and devices. Medical device makers design miniature versions for testing in mice before human trials begin. With rodents, Bianco says, “it’s easy to repeat studies to ensure the results you’re seeing are real.”
Transgenic mice are particularly useful. Called transgenic because human DNA is inserted into a “founder” mouse, they are bred to have a genetic defect that increases their risk for a particular disease—Alzheimer’s or hypertension, for example. The mice over-express these genes because extra copies have been introduced into their genome. Transgenic mice help researchers learn how genes trigger the molecular and physiological chains of events that cause disease—or prevent it. And because they are virtually identical genetically to one another, it is easy and quick for researchers to distinguish between the influences of genetics and lifestyle.
“Knockout” mice are another star player in biomedical research. These genetically identical mice carry genes that have been switched off or “knocked out” of commission. Like transgenic mice, knockout mice are used to study how a particular gene or gene sequence causes or prevents disease. “We know a particular gene affects blood pressure,” Joyner says. “So we turn it off to see what happens.”
Both Mayo and the U use these mice to study how Alzheimer’s plaques and tangles develop and cause cognitive impairment. And they use them to study cancers, heart disease, and multiple sclerosis, among other things.
Use of genetically altered mice as human pathology models has dramatically increased in 20 years. They’re the biggest reason use of other animals has decreased 33 percent since 1973. “We used to use a lot more large animals like dogs and cats,” Joyner says. “Now nearly all our research is done with transgenic and knockout rodents.” Both the U and Mayo say they are using fewer large animals than they used to, but they are using more rodents. In fact, there has to be a critical reason for using higher animals. “At Mayo, it’s rarely done,” Joyner says. Bianco says University of Minnesota researchers are using monkeys to study heroin and cocaine addiction because it’s essential in the last phase of research to mimic the human model as closely as possible.
Animal Alternatives
Computer modeling, the culturing of tissue and cells, population studies, and animal studies are spokes on the research wheel—all complementary and all necessary for the wheel to advance. Nonanimal alternatives are growing in importance and have helped reduce the number of animals other than rodents used in research.
Computer modeling, for example, can reduce study time and the number of animals needed by simulating biochemical cascades and their outcomes, according to Joyner. “It makes the drug-screening process more efficient,” he says. “We use fewer animals because computer simulation eliminates the need to screen in vivo 1,000 different molecules.” Computers can’t, however, simulate how the circulatory system will respond to an experimental drug. Nor can they come close to simulating the complex physiology of a single cell, let alone the 50 to 100 trillion cells in the human body. Tissue cultures can be genetically manipulated, but the altered genes don’t interact with proteins, hormones, or neurotransmitters as they do in an intact animal. “You can’t test a heart valve or any other medical device on a tissue culture,” Bianco says. The same goes for cell lines. They don’t show how cancer spreads through the body or how medication affects physiology. Tissues and cells don’t show how the brain works or how organ systems interact.”
Population studies shed light on how lifestyle and genetics interact in a disease. They don’t necessarily replace animal studies. But as Joyner points out, “Any research that directly obtains human data is very valuable as an adjunct to animal research.” Despite these alternatives to animals, Bianco says, “we’re still a long way from replacing animals.”
Opening the Public’s Eyes
Each year, hundreds of high school science students tour the University of Minnesota’s animal labs. The purpose, according to Bianco, is to show students that animals are important to medical research and well cared for. “The animal rights movement is anti-science. We must not lose the next generation of scientists because of them. Students see with their own eyes that what the animal activist groups tell them is untrue. If we hide behind our laboratory doors, it looks as if we’re hiding something. At the same time, we can’t just let the public wander through. It’s a tough balancing act.”
Animal activist groups stage media stunts and demonstrations, often featuring celebrity spokespersons such as Bay Watch’s Pamela Anderson. They produce chilling public service announcements and brief videos viewable on their Web sites that would make many, especially young people, oppose the use of animals in research.
They also mass distribute to schools leaflets claiming there’s nothing left to cure that animals can help with, that computer modeling is better, and that scientists are using animals only to attract more grant money and raise their incomes. Bianco says science teachers generally support animal research, but others sympathetic to activist causes distribute their materials.
Although the university has had no major break-ins since 1999, destructive acts have occurred at many other research centers nationwide. Activist groups threaten, harass, and intimidate biomedical researchers and their families. Bianco has been harassed many times, mostly by what he calls “vicious e-mails—some bordering on physical threats.” He’s been screamed at on the street. And at one seminar, he had to be surrounded by police. “Since I’m in charge of the animal care program,” he says, “I’d rather they focus on me than on other faculty.”
Last November, President Bush signed into law the Animal Enterprise Terrorism Act, which essentially treats assaults on research facilities as acts of domestic terrorism. It stiffens penalties for threats or acts of violence, mandating fines and imprisonment that vary depending on the extent of the damage to persons or property. Wiretapping of radical animal rights groups is legal under the Patriot Act.
Bianco says people don’t understand that there’s a difference between animal welfare and animal rights. Animal welfare means treating animals humanely—keeping them in conditions that allow them to be as healthy and comfortable as possible. Animal rights means bestowing on animals the same rights humans have, including legal standing in courts, which some activist groups are trying to get. “I believe my children are more important than my pets,” Bianco says. “That doesn’t mean I abuse my pets.”
Bianco would like more people to appreciate the fact that, thanks to animals, medicine’s understanding of human disease is growing at an unprecedented pace and breadth. “The media talks about the human benefits of research but never about the animals that made it possible,” Bianco says. “We have to frame the question this way: Do I want the new heart valve that will save my father’s life—or don’t I? I would take the valve. So would most people.” MM
Howard Bell is a medical writer in Onalaska, Wisconsin, and a long-time contributor to Minnesota Medicine.