The History of the Lab Rat Is Full of Scientific Triumphs and Ethical Quandaries

Science
چهارشنبه 8 اسفند 1397 ساعت 18:9
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Smith sonian mag
More than 20 years ago, two Harvard University medical researchers, Joseph and Charles Vacanti, led a team that successfully grew a human-ear-shaped piece of cartilage on the back of a lab mouse. The experiment used an ear-shaped mold filled with cartilage cells from a cow. The “ear” was first placed into an incubator, and once it began to grow, it was transplanted into the body of a nude mouse (a species of laboratory mouse with a genetic mutation that causes a degraded or absent thymus organ, inhibiting the animals’ immune system and ability to reject foreign tissues).
“Earmouse” or the Vacanti mouse, as the animal has become known, continued to grow the piece of tissue out of its back until it resembled the size and shape of a human ear. The team published their research in Plastic and Reconstructive Surgery in 1997. The experiment was designed to test the viability of growing tissues for later transplant to human patients. And just last year, human children in China suffering from a genetic defect called microtia, which prevents the external ear from growing properly, received new ears grown with their own cells —a similar process to growing the “ear” on earmouse.
The Vacanti mouse with a human-ear-shaped piece of cartilage growing out of its back. ( Wikicommons under Fair Use )
The mouse with a human ear on its back may have been one of the more bizarre and visually unsettling experiments carried out on a rodent, but mice have been used for scientific experiments since around 1902, when a quirky and enterprising breeder named Abbie E. C. Lathrop recognized the animals' potential for genetic research. The first use of rats in experiments started even earlier, with records dating back to the 1850s. Scientists purchased their subjects from professional breeders known as “rat fanciers” who prized the creatures as pets for their unique coats and personalities. For decades, lab rats and mice have been used to make great scientific and medical advances , from cancer drugs and HIV antiretrovirals to the yearly flu vaccine.
Lab mice—most often of the species Mus musculus, or house mouse—are biomedical swiss army knives, with genomes that are easily manipulated for genetic studies. The physiology of the human body, however, is more closely mimicked in Rattus norvegicus , or the Norway rat , and its various strains. Rats are also easily trainable and perfectly suited for psychological experiments, especially considering their neural networks so closely resemble our own . (In the 1950s and '60s, for example, researchers studying the biological underpinnings of curiosity noted that lab rats, devoid of any other stimulus or task, prefer to explore the unknown parts of a maze .)
Rats are also much larger than mice and have thicker tails and blunter snouts. But it's the characteristics shared by mice and rats that make them both scourges of the city and the perfect scientific guinea pigs, so to speak.
“They reproduce quickly, they are social, they are adaptable, and they are omnivores, so they’ll eat pretty much anything,” says Manuel Berdoy, a zoologist from Oxford University. Additionally, the rodents’ diminutive size allows relatively easy storage in labs, and their shared evolutionary roots with humans mean the species’ genomes overlap overwhelmingly.
As a result, rodents have all but taken over our labs, making up nearly 95 percent of all laboratory animals . Over the past four decades, the number of studies using mice and rats more than quadrupled, while the number of published papers about dogs, cats and rabbits has remained fairly constant. By 2009, mice alone were responsible for three times as many research papers as zebra fish, fruit flies and roundworms combined.
Studies with rodents address everything from neurology and psychology to drugs and disease. Researchers have implanted electronics into mice brains to control their movements , repeatedly tested the addictive properties of cocaine on mice , administered electric shocks to rodents as a negative stimulus , implanted human brains in mice skulls , and sent mice and rats scurrying through endless labyrinths of tests . NASA even keeps lab mice aboard the International Space Station for experiments in microgravity.
For all that lab mice and rats have helped humans accomplish, the day-to-day experience of the animals takes place largely out of the public eye. But the life of lab rodents may be key to understanding and improving their role in the course of scientific discovery.
Scientists must complete animal handling and ethical training before they are permitted to work with laboratory animals, though the rules vary depending on where the experiment takes place. While Canadian and European scientists are overseen by a national governing body, the rules in the United States vary by institution with some overall guidance from the National Institute of Health . (The U.S. Animal Welfare Act , which protects most animals used for research, excludes mice and rats.)
Most universities offer a training course on how to handle the animals in a way to best reduce stress and suffering. The best practices have been updated over the years to reflect a changing understanding of the rodents and their needs. After a 2010 study published in Nature showed that handling lab rats by the tail causes more anxiety than guiding the animals through a tunnel or lifting them with cupped hands, labs around the world abandoned the previously common technique.
Scientists who want to experiment with rodents are required to fill out a detailed application explaining why the work requires animal subjects. The applications are judged based on a framework known as the three R’s : reducing the numbers of animals used, replacing the use of animals when possible, and refining the experiments in order to improve animal welfare.
“A rat or a mouse is not a test tube on legs,” Berdoy says. Housing conditions for the rodents, for example, has become a raison d’etre for lab animal welfare proponents. Most lab mice are kept in shoebox-sized cages (for rats, the space is about doubled) with a few squeaky companions. And although having fellow rodents satisfies the social needs of the animals, most laboratory housing lacks any sort of environmental enrichment objects to occupy the subjects. The size of their confinements also means they are restricted from natural behaviors like burrowing, climbing or even standing up straight.
Even though lab mice and rats are, at this point, genetically distinct from their wild counterparts, they retain many of the same instincts. Repressing these needs could cause undue stress on the animals and compromise scientific findings. Berdoy’s film, The Laboratory Rat: A Natural History , details how lab rats released in the wild behaved and interacted in a similar way to their wild ancestors. Scientists, he believes, should consider the nature of rats when designing experiments to get the best results. “If you are going to do experiments,” Berdoy says, “you need to go with the grain of biology rather than against it.”
A laboratory rat with a brain implant used to record in vivo neuronal activity during a particular task (discrimination of different vibrations). The scientist feeds the rat apple juice through a pipette. ( Anna Marchenkova via Wikicommons under CC BY 4.0 )
In some cases, the impacts of going against the biological grain have already been observed. While the genetic homogeneity of lab rodents helps to remove distracting variables from focused experiments, it may also, more subtly, be skewing scientific results. In a 2010 study on the impacts of intermittent fasting diets, Mark Mattson, chief of the laboratory of neuroscience at the National Institute of Aging, observed that the positive neurological impacts that “metabolically morbid” lab rats derived from the diet regime did not translate to healthy, active humans. The results were only applicable to “couch potato” critters in a “bubble boy type scenario where … their immune systems are not being challenged with different viruses or bacteria.” As Mattson succinctly notes, “What you discover may not be reflective of a healthy animal.”
In other words, the use of static, homogenous, sheltered animals may not always be the best way to accomplish the ultimate goal of using lab rodents: to better understand, and in some cases cure, the human body and mind.
In general, the process of transitioning an experiment from rodents to humans is not haphazard. Besides the reams of paperwork, new drugs are required to be tested on two different animals—a small one, like a mouse or rat, and then a large one, usually a pig, dog or primate—before they move to human trials. According to the Pharmaceutical Research and Manufacturers of America, only one out of every 250 compounds tested on animals moves to human trials. For those that make it to approval, the entire process usually takes 10 to 15 years.
Even after the long road to human trials, many drugs and procedures that work on mice and rats do not work on people. The rodents' "couch potato" lifestyles could influence the results, or perhaps the slight differences between rat, mouse and human genomes produce different responses to drugs. In Alzheimer’s studies, for example, mice and rats are artificially given a condition that resembles the disease because they do not develop it naturally.
When a drug doesn’t work, the results are often disappointing and costly, but sometimes mistakes can be tragic. Thalidomide, a drug used to treat morning sickness in the 1950s and 60s, caused deformities in human babies despite being successfully and harmlessly tested in rats. The drug breaks down much faster in rats, and their embryos have more antioxidant defenses against its nastier side effects. In many cases, however, the reasons for a failed drug remain mysterious.
“This is one of the questions at the heart of medical research. No one has a good answer to it, and there may not be a good answer to it,” says Richard Miller, a professor of pathology at the University of Michigan. “There are enough success stories that people are optimistic, but not everything that will work in the animals will work in people.”
Whether an experiment will end successfully may be uncertain, but one thing is always guaranteed: death of the lab rodents. The body count is unavoidable; an estimated 100 million lab mice and rats or more are killed every year in U.S. labs for the sake of science. While some of the bodies are creatively repurposed as snacks for birds in sanctuaries , most are frozen and incinerated with the rest of the biological waste.
Rats and mice used in aging studies often live out their natural lives, but most lab rodents are terminated at the end of a study. Some are killed via lethal injection or decapitated with strict guidelines to reduce pain and suffering, but most often, they are suffocated in cages with carbon dioxide.
For some time CO ₂ has been considered the most ethical end of life practice for these lab animals, but Joanna Makowska, adjunct professor at the University of British Columbia and Lab Animal Advisor for the Animal Welfare Institute, believes there is a better way. The carbon dioxide poisoning, she says, mimics the feeling of running out of air when you are holding your breath underwater, which causes undue fear and anxiety. “It’s not a good death. Anesthesia is more humane, but people are not really doing that because carbon dioxide is more practical and cheaper.”
In general, Makowska believes researchers should be making more of an effort to meet the “reduction” principle of the three R’s . “That really should be the first R ,” she says. At Harvard, scientists made an organ on a chip to help study drugs and model disease without using animal subjects. Researchers have even developed computer algorithms based on thousands of animal trials that can accurately predict the way tissues will react to certain compounds.
But these lab rodent reduction-based advances have yet to take off, and the number of studies using the animals continues to grow. And while animal rights groups will raise hell over the treatment of our other furry friends, the lab rat rights fight has yet to make a splash.
“I think it comes down to how much we like them,” Makowska says. “People invest themselves much more in non-human primates. When it comes to dogs and cats, we have relationships with these animals. We are much more likely to acknowledge that they suffer.”
After all, if a mouse or rat escapes the lab to the streets of the city, it is considered a pest; anyone can kill it with impunity.
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