||Issue Date: 5 / 2007
In Memory of a Million Mice
Charles J. Alden
Lining two walls of my small office are over three hundred books bound in Venice blue, the product of my career for the past two decades. Each volume represents several years of effort by dozens of scientists and technicians, and altogether over a billion dollars were spent in their creation, one small part in the War on Cancer. I am the managing editor for this series of books, and my job is to keep the scientists from saying they are "elucidating" when in fact they are guessing. I work for the government.
This house mouse (Mus musculus), will never know the
life of a
laboratory research mouse.
Click image to enlarge.
With the rapid development of the synthetic chemical industry following World War II, there was concern about the possibility of an epidemic of chemically induced cancer. In the 1970s the National Cancer Institute began a series of bioassays to widely screen used chemicals for potential carcinogens. A few years later, this testing program was transferred to the National Toxicology Program, headquartered in North Carolina. The NTP determined that rats and mice could serve as suitable predictors of whether chemicals might have the potential to cause cancer in humans. And so the title characters of my books are vermin.
Whether you are a man or a mouse may say something about your character, but physiologically and biochemically you are pretty much alike. The major organ systems, enzyme sets, and metabolic pathways are similar, and genetically we are over 98 percent identical. Perhaps most relevant is the observation that all chemicals that have been established to cause cancer in humans do so in rodents too. So the basic structure of the bioassay is this: a few hundred rodents are exposed to a test chemical for the length of their normal lifespan, usually two years, to serve as surrogates for millions of people potentially exposed for decades.
The concept sounds simple, but the practice is enormously complicated. To establish that exposure to a chemical induces a disease, every other factor in the animals‚ lives, starting with their genetic makeup at conception, must be uniformly regulated. Thus for a given study every mouse is bred on the same day, from the same genetically identical lines. They are divided into groups so that their starting body weights are the same, and every facet of their lives is specified and monitored. Their formulated feed pellets contain precisely controlled percentages of each amino acid, vitamin and mineral. The clear plastic cages with wire mesh flooring have a particular brand of pine chip bedding changed at specified intervals; the fluorescent lights are on for exactly 12 hours; the temperature and relative humidity are monitored constantly. A standard study involving 800 animals may cost $4 million, or $5,000 a head for the care, treatment, and evaluation of each rodent.
Over 25 million mice are produced commercially each year, and many go to feed reptiles in pet stores. In the program to save the endangered California condor, fifty mice per day are fed to each bird. Of the several million mice produced for laboratory research most will have a brief biochemical experience and then face the guillotine or carbon dioxide bottle. But the lucky few selected to be in NTP studies have hit the rodent lottery. By all measures these are the royalty of mice. They are housed in laboratories in Alabama, Ohio or Washington, safe from talon and claw and fang, while a host of human servants and maids ensure their air-conditioned lodgings are cleaned regularly, their sterilized pine chip bedding is changed on schedule, and their feed containers and water bottles are always full. Their body weights, intake of feed, and consumption of water are measured and fed into a central computer database. Twice daily their wardens monitor their cells, and any hints of distress, from ruffled fur to watery eyes or hint of lethargy, are noted in voluminous logbooks.
There is just one job they must do, and even that is passive. Each animal is assigned at random to one of four groups: three groups are exposed to different concentrations of the test chemical, while the fourth group, the controls, are not. The chemical may be laced in the food or dissolved in the drinking water, painted on the backs of the animals, or contained in the air in special inhalation exposure chambers. This is the one variable in the lives of animals living in adjacent rows of cages for years, and it makes all the difference in their lifestyles. The exposed animals may experience a whole spectrum of effects, from slightly lower weight for the mildest chemicals to induction of aggressive, malignant tumors and early death for potent carcinogens.
The life of a laboratory mouse is safe but uneventful by design. Isolated from predators and each other by clear plastic walls, protected from airborne infection by positive air pressure in the holding room, unstressed by loud noises, they not so much animals as they are two-ounce metabolism machines. There is no advantage in being quick or strong, no reward for craftiness in avoiding predators or skill in detecting edibles. Courtship displays are irrelevant, as the participants in the experiment live enforced vows of celibacy.
If these rodents are obscure in life, after their deaths they become famous. Their remains are preserved and processed like the bodies of saints, holy relics to be examined for meaning. Each tiny organ is carefully excised, fixed in a 10 percent solution of formaldehyde, and embedded in a block of paraffin. Slices two ten-thousands of an inch thick are taken from each organ, stained, and mounted on microscope slides. The paraffin blocks and bags of tissue remnants are stored in large refrigerated chambers at the NTP Archives in Research Triangle Park, the Arlington Cemetery of the tiny soldiers in the War on Cancer. Over 40 different tissues are examined for each animal, and over 30,000 microscope slides are prepared for each bioassay of a chemical. For the next two or three years these slides become the object of intense scrutiny by teams of pathologists, who examine magnified cross-sections of tissue that resemble aerial views of Mars for subtle differences in cell structure. They debate their diagnoses in an arcane vocabulary and code them into another database.
By this time the mice themselves are a distant memory--their bodies dissected, minced, and photographed; their diseases tabulated and pooled, sorted and sifted by a set of computer programs. For the toxicologists and risk assessment specialists it is all about numbers and statistical analyses. Just as one smoker living to a ripe old age does not prove the safety of tobacco, neither does the occurrence of one or two cancers in exposed animals establish that a chemical is a carcinogen. What counts is the overall trend, if increasing dosage corresponds to an increase in tumors.
One in four Americans will develop some form of cancer in their lifetimes, and this disease has touched the lives of virtually everyone. Yet there are some who object to using animals, even rodents, to develop cures or identify hazards. Animal rights organizations largely known for protesting fur coats and the display of live lobsters in seafood restaurants ("embarrassing and humiliating for the crustaceans") are vocal critics of animal research. While their efforts have helped promote more humane treatment of laboratory animals, they have also led to increased security requirements in research facilities. In some cases, particularly in England, more zealous activists have attempted to liberate research animals to the wild, where they promptly became supper for the local predators. Most in the scientific community find the protection of human health of more importance than the sensitivities of what are considered disease-bearing pests in the wild. Still, sometimes I have wondered what life is like on the front line of the bioassay.
Despite our cartoon images, the worldview of laboratory mice is limited to within a few feet of their immediate vicinity. Even for elite mice, life is lonely at the top. Female mice are housed five per cage, which gives sufficient opportunity for murine gossip, but male mice are sentenced to life in solitary. Conjugal visitations are strictly prohibited, not because of moral restrictions on behavior at federal facilities but because pregnancies would compromise interpretation of the studies. And male mice housed together have the constant tendency to fight, despite all attempts at counseling and anger management programs. Again the concern is not the spiritual development of the subjects but the negative effects on the experiment when they try to wound and kill each other. In early experiments with five males housed per cage, a curious pattern appeared. Rather than all the animals growing at the same pace, there would be one large dominant male standing guard in front of the feeder while the other four huddled in the corner. While perhaps a more accurate model of the human condition, this skewed analysis of the experiments.
Some questions are left unasked by scientists. One is whether these rodents understand their good fortune (not to mention heroism) in being permitted to participate in the scientific endeavor. Continued participation is not voluntary, as the inmates are always inventive in trying to find ways to escape (or better yet, get to the female cages) if their wardens ever turn their eyes.
There is no mouse theology, no worship of the creators of their universe, no displays of gratitude. Rather, rodents are only too willing to bite the hand that feeds them. Nor is there any faithful acceptance that their illnesses are part of some Master Plan. But in fact they are. These little lives do amount to more than an endless routine of eating, excreting, sniffing, and scratching. The fates of a few hundred mice can affect an entire industry and save countless lives. The main components of dry cleaning solvents, laxatives, and hair dyes have been changed because the original formulations were carcinogenic in rodents. Other studies have served to relieve fears: magnetic fields around power lines and fluoridated water, long the objects of alarm, have been shown not to pose major hazards after all.
In the end, we might not expect these mice to thank us for their comfortable lives, but we can be grateful to them for helping save ours.
Charles J. Alden is a science writer living in Durham, North
Carolina. A native of Minnesota, he received a doctorate in
biophysics from Purdue University. Besides technical articles
he has written a variety of other essays. Once national junior
chess champion, he also runs with the Carolina Godiva Track