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  • BioEthics

    Creation of Flawed Animals
    Raises New Ethics Issues

    Normal and immune deficient mice
    A genetically engineered "nude" mouse, which has no immune system, right, with a normal counterpart. (Courtesy Jackson Laboratory)
    By Rick Weiss
    Washington Post Staff Writer
    Sunday, June 7, 1998; Page A01

    In a windowless basement at the National Institutes of Health, scientists wearing white protective "moon suits," rubber gloves and disposable booties are creating a new generation of tools that could revolutionize medical research.

    The new tools are mice, genetically engineered to have human diseases.

    In the past, scientists relied on luck to find strains of mutant mice whose symptoms resembled those seen in human diseases, and even then it wasn't clear how relevant the animal versions were. Using new molecular technologies, however, scientists can genetically engineer mouse embryos from scratch to contain precisely the same biological defects that cause diabetes, cancer, multiple sclerosis, cystic fibrosis, arthritis and a host of other human ailments.

    The new breeds, which have never existed before in nature, can be dissected and analyzed by the hundreds or thousands until the biological mechanism underlying their problem is revealed. The animals can also serve as human stand-ins for tests of experimental drugs.

    obese mouse and normal mouse
    At left, a mouse genetically engineered to be obese, with a normal mouse. (Courtesy Jackson Laboratory)
    "These new animal models are going to be incredibly powerful," said Ronald Schwartz, an NIH immunologist who works with the mice. "They are at last giving us the opportunity to understand disease processes, and will eventually give us a way to look for treatments."

    Others, however, see this latest development as the dawn of a dark era in medical research. The use of animals in research is already fraught with ethical dilemmas, these critics say, but the mass production of animals intentionally designed to have debilitating diseases raises novel, more nuanced ethical questions.

    To purposefully bring into the world hobbled animals for experimentation is to treat living creatures as mere devices, some say, and fosters an attitude that could reverse a recent trend toward more judicious and compassionate use of lab animals. For some people, such research is tantamount to a sacrilege -- a malignant appropriation of the sacred power of creation.

    "Multiple pathologies are frequent in these animals," said Barbara Orlans, a former research physiologist now at the Kennedy Institute of Ethics at Georgetown University. "Genitals and other organs are sometimes deformed. Legless mice have been produced. It's sort of carte blanche where we're going: Knock out a gene and see what happens."

    The debate over genetically manipulated animals extends beyond the laboratory. Researchers are also altering genes in pigs, goats and sheep, with the goal of making these animals produce medicines in their milk or to make their organs more suitable for transplantation into people.

    But such scientists and farmers have a stake in keeping their engineered farm animals healthy. By contrast, said Rebecca Dresser, a bioethicist at Case Western Reserve University, engineered mice and rats are "genetically programmed to suffer."

    The issue is not simply a matter for philosophical debate. Today, Switzerland will address directly the ethics of high-tech animal research when its 7 million citizens vote on a referendum that would make it illegal for researchers to create or use genetically engineered animals.

    If the proposal is approved by a majority of Swiss voters -- and recent polls suggest that's a real possibility -- it could have an impact well beyond the Alps. Switzerland is home to three of the world's largest biotechnology and pharmaceutical companies -- Novartis, Roche and Ares-Serono -- all of which use genetically engineered animals in their drug-development efforts. Countless university labs also would have to drop current lines of inquiry.

    "Many people see this [referendum] as a real serious threat," said Thomas Cueni, secretary general of Interpharma, a Basel-based trade association representing the three Swiss companies.

    In the United States, engineered rodents are quickly becoming the mainstay of medical research. There is little to stop it. Mice and rats are specifically exempted from the Animal Welfare Act, the primary federal statute that protects other species of lab animals. And the NIH recently relaxed its restrictions on the creation and use of engineered rodents, to make it easier for scientists to pursue such research.

    About This Series
    Biomedical research is proceeding at breathtaking speed.

    Geneticists are gaining insights into how genes work. Biologists are unmasking the mysteries of how a tiny clump of cells develops into a fully formed human. Immunologists are deciphering the complexities of the body's defense systems.

    The research is yielding many potential benefits. Doctors can identify people at risk for genetic diseases and fashion strategies to save their lives. Reproductive biologists can help infertile couples have children. Researchers can engineer animals with organs that may be transplanted into humans.

    But as science speeds ahead, it often pushes the edges of society's readiness to cope with its consequences. Increasingly, research creates possibilities before the accompanying ethical, social and legal ramifications have been resolved. The Washington Post is exploring these issues in a series of occasional articles.

    "More and more research is moving toward the use of these mice," said John Sharp, superintendent of induced mutant resources at the Jackson Laboratory, a mouse research facility in Bar Harbor, Maine. "It's where the future of research is headed."

    The approach is akin to unscrewing a building's fuses one by one to see which lights are controlled by each fuse. Scientists create mouse embryos in test tubes, then remove, or "knock out," single genes from those embryos to see what would go wrong.

    In some cases they knock out a mouse gene whose human counterpart, when defective, is known to cause a human disease, thus creating a precise mouse model of that disease. In other cases, they knock out mouse genes whose functions are unknown. By studying the problems these mice have as they grow up, scientists are learning what those genes -- and presumably what their human counterparts -- normally do.

    The technique does show promise. In one case, researchers knocked out part of the Huntington's disease gene in mice -- a gene that, when mutated in people, leads to dementia and a progressive loss of muscle control. Careful study of the brains of these Huntington's mice revealed small protein deposits that had never been noticed in the brains of Huntington's patients but which, upon reinspection of patients' brains, proved to be there. Although the relevance of those deposits remains unclear, Sharp said, "it looks like this is one of the causes of Huntington's disease symptoms."

    In another case, NIH scientists working with mouse embryos knocked out a newly discovered gene to see what its role might be. The result was a mouse with a single, Cyclops-like eye and massive head deformities, including an extra growth of skull protruding from the forehead and containing a portion of the animal's brain.

    Researchers recognized the pattern as similar to one seen in a rare human disorder called holoprosencephaly. Subsequent tests on people afflicted with that syndrome showed that they harbored a mutation in the human equivalent of the mouse gene, offering the first clue to the disease's molecular underpinnings, said Heiner Westfahl, the NIH developmental geneticist who oversees much of the work.

    Several floors below Westfahl's office, in the basement of NIH building 6A, is one of about a half-dozen NIH laboratories where scientists are making engineered mice.

    A poster on one wall describes the abiding sentiment: "Without animal research, we would all be guinea pigs." Another poster shows a young girl in a hospital bed, surrounded by her stuffed animals. The caption: "It's the animals you don't see that really helped her recover."

    Thousands of gene-altered mice scamper inside plastic shoe-box-size cages stacked 10 high and seven deep and arranged in long rows in climate-controlled rooms. Most of the animals look normal, but under their variably colored coats are carefully plotted genetic errors. Each of these glitches will gradually disable its mouse in subtle or gross ways, and perhaps help solve a medical mystery.

    Some engineered mice grow lumpy with tumors very early in life. Others are born with nerve damage or are blind or deaf or have inflamed joints or engage in self-mutilating behaviors. Some lack immune systems and can quickly die from exposure to everyday germs, which is why scientists and visitors must wear protective clothing in the lab.

    Many never get born at all, their imposed genetic defect having caused a fatal error in fetal development.

    The mice are not perfect models for human ailments, however, as evidenced by recent efforts to make a mouse with cystic fibrosis, a disease that in people mostly affects the lungs. Researchers knocked out the gene that, when mutated in people, causes the disease. But the resulting mice had perfectly healthy lungs and instead, surprisingly, had problems with their digestive systems.

    Since then, scientists have found that if they delete the same gene in a different strain of mice and feed them a special diet, they can get the mice to have lung problems that are in some respects reminiscent of cystic fibrosis. But no one knows how closely that model really mimics the human disease.


    Here is how scientists remove genes to breed mutant mice with certain characteristics.

    1. Scientists remove the designated gene -- say, the one that produces black pigment in fur -- from a single mouse cell.

    2. The cell is injected into a 3A-day-old mouse embryo, where it begins to divide with the other cells.

    3. The embryo, containing an expanding mix of normal and gene-deleted cells, is implanted into a female's womb.

    4. Some tissues in the resulting newborn mice lack the gene, but other tissues have it. In this case, they all would have patches of dark and white fur.

    5. The mice are mated, resulting in offspring with different colorings. Those whose parents' sperm and egg cells lacked the pigment gene have all-white fur.

    6. Scientists study these mutant mice to see what's wrong with them, an indication of what the gene would normally have done -- in this case, produce pigment.

    Critics of the mouse technology suspect that differences between mice and people will ultimately render many other engineered mouse models less useful than scientists hope. In particular there are doubts about the relevance of new highly touted mouse models for Alzheimer's disease and other cognitive and behavioral syndromes, given the enormous differences between mouse brains and human brains.

    But of more fundamental concern are the ethical implications of the work, including the intense attitude of objectification that is fostered by the calculated engineering of ailing animals.

    "I can rationalize some harm to an individual [animal] in exchange for a valuable research result," said Paul B. Thompson, a philosophy professor at Purdue University who has focused on issues of animal research. "But when we are in such a dramatic position of control that we are designing these animals from scratch, this is a different issue."

    Some say it is a matter of common sense, and that the need for restrictions simply rings true to most people who think about it. "There really is something primordially horrible about replicating animals that will suffer endlessly," said Bernard Rollin, a Colorado State University physiologist with dual appointments in the department of philosophy and the veterinary school.

    Others invoke sophisticated philosophical concepts, such as the Greek concept of telos, which posits that every species has a "life goal" of sorts -- be it to live peacefully in a burrow or to attack prey on the savanna -- and that it is unethical to interfere with an animal's ability to attain that goal.

    Still others suggest that it might be ethical to interfere with an animal's telos only if the animal were unaware of that interference. With that standard in mind, Rollin has studied the possibility of growing research mice with no brains, to make them "incapable of perceiving their hideousness."

    Ultimately some feel that the engineering of life -- and in particular the intentional inducement of malformations -- is an affront to religious and spiritual beliefs that see creation as the sole province of a beneficent deity.

    "This notion that we can own, buy, sell and exchange fundamental life processes can lead to a fundamental transformation of how we understand life as sacred," Thompson said.

    Moved by these and perhaps other sentiments, 112,000 Swiss citizens signed a petition asking for a constitutional referendum on the banning of research on engineered animals. The initiative, sponsored by a coalition of 60 environmental, humane and religious groups and being voted on today, would also ban the release of genetically engineered microbes and plants, limit the patenting of life forms and prohibit many avenues of genetic research.

    The Swiss constitution can be changed by a simple majority of voters as long as 12 of the nation's 23 cantons tally a majority in favor. Public opinion polls in the past two months have found that 28 percent to 50 percent of those with an opinion intend to vote for the change -- close enough to the needed 51 percent to worry scientists and their supporters.

    The amendment would affect about 500 of the 870 biotechnology research projects underway in Switzerland -- a country with a reputation for excellent science -- and about 2,000 university researchers, said Cueni of Interpharma. That is a frightening prospect, he said, but it is also a prospect that has prompted a remarkable and apparently positive social shift.

    First, Cueni said, the Swiss government recently passed several bills limiting the use of genetic technology in an effort to preempt the passage of the more extreme amendment. Other European countries, facing similar pressures, have also been working toward compromise.

    In Holland, for example, laboratory animals -- including mice and rats -- were recently deemed to have "inherent value," a status that makes them deserving of higher standards of physical and psychological care than was previously the case.

    Moreover, Cueni said, the ballot initiative has inspired Swiss scientists to look up from their benches and involve themselves in an array of social and political activities, including laboratory "open houses" for the public and other educational programs about their work.

    That suggests to Cueni and others that the historically polarized debate over the use of animals in research may find its resolution in a fresh dialogue prompted by the new genetic technologies.

    "The Swiss referendum speaks to the larger issue of engaging society in more of the discussion," said Andrew Rowan, a senior vice president of the Humane Society of the United States. "There's a tendency to regard the general public as ignorant and, therefore, you can't talk to them about these very complicated issues. I think that's a mistake."

    It may be difficult or even unwise to completely prohibit the generation of mutant mice and other animals, Rowan said, but it is definitely possible and worthwhile to develop ways of minimizing the physical and emotional distress endured by these animals.

    One way, he and others said, is to push for the U.S. Department of Agriculture to include mice and rats under the provisions of the Animal Welfare Act, as a coalition of groups last month petitioned the department to do. Another goal is to develop standardized measures of pain and suffering, so researchers can have objective means of measuring their impact on their research animals.

    At the same time, researchers are learning from their Swiss colleagues that it is possible to win at least some people's hearts and minds by being upfront about what they are doing and remaining amenable to compromise.

    "It's a constant struggle, and there's never going to be an easy answer," said Westfahl. "But my personal conviction is that the more public discussion of the issue, the better for both sides."

    © Copyright 1998 The Washington Post Company

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