Professor of medicine and director of the MDS Centre, Columbia University, New York
An obvious truth that is either being ignored or going unaddressed in cancer research is that mouse models do not mimic human disease well and are essentially worthless for drug development. We cured acute leukaemia in mice in 1977 with drugs that we are still using in exactly the same dose and duration today in humans with dreadful results. Imagine the artificiality of taking human tumour cells, growing them in lab dishes, then transferring them to mice whose immune systems have been compromised so they cannot reject the implanted tumours, and then exposing these “xenografts” to drugs whose killing efficiency and toxicity profiles will then be applied to treat human cancers. The pitfalls of such an entirely synthesized non-natural model system have also plagued other disciplines.
A recent scientific paper showed that all 150 drugs tested at the cost of billions of dollars in human trials of sepsis failed because the drugs had been developed using mice. Unfortunately, what looks like sepsis in mice turned out to be very different than what sepsis is in humans.
You must read the rest. I find the reasons for continuing the mouse model research particularly telling:
Robert Weinberg of the Whitehead Institute at MIT [Massachusetts Institute of Technology] has provided the best answer. He was quoted in the press, noting: “[There are] two reasons. First, there’s no other model with which to replace that poor mouse. Second, the FDA [the US Food and Drugs Administration] has created inertia because it continues to recognise these models as the gold standard for predicting the utility of drugs.”
There is a third reason related more to the frailties of human nature. Too many eminent laboratories and illustrious researchers have devoted entire lives to studying malignant diseases in mouse models and they are the ones reviewing one another’s grants and deciding where the NIH money [US government medical research funding] gets spent. They are not prepared to accept that mouse models are basically valueless for most of cancer therapeutics.
Raza focuses on cancer research because that is her field, and on mice because they are most often used in her field. One suspects much of what she says is applicable to other diseases and other lab animals as well.
One problem with lab mice is that they are bred and raised as couch potatoes:
“I began to realize that the ‘control’ animals used for research studies throughout the world are couch potatoes,” he tells me. It’s been shown that mice living under standard laboratory conditions eat more and grow bigger than their country cousins. At the National Institute on Aging, as at every major research center, the animals are grouped in plastic cages the size of large shoeboxes, topped with a wire lid and a food hopper that’s never empty of pellets. This form of husbandry, known as ad libitum feeding, is cheap and convenient since animal technicians need only check the hoppers from time to time to make sure they haven’t run dry. Without toys or exercise wheels to distract them, the mice are left with nothing to do but eat and sleep—and then eat some more.
That such a lifestyle would make rodents unhealthy, and thus of limited use for research, may seem obvious, but the problem appears to be so flagrant and widespread that few scientists bother to consider it. Ad libitum feeding and lack of exercise are industry-standard for the massive rodent-breeding factories that ship out millions of lab mice and rats every year and fuel a $1.1-billion global business in living reagents for medical research. When Mattson made that point in Atlanta, and suggested that the control animals used in labs were sedentary and overweight as a rule, several in the audience gasped. His implication was clear: The basic tool of biomedicine—and its workhorse in the production of new drugs and other treatments—had been transformed into a shoddy, industrial product. Researchers in the United States and abroad were drawing the bulk of their conclusions about the nature of human disease—and about Nature itself—from an organism that’s as divorced from its natural state as feedlot cattle or oven-stuffer chickens.
Think about the implications of this for every single piece of labrat tested science you thought was proven. (One report from 2008 found that lab rats and lab mice account for 4/5 of all animals used in animal testing in the EU that year):
Standard lab rats and lab mice are insulin-resistant, hypertensive, and short-lived, he and his co-authors explained. Having unlimited access to food makes the animals prone to cancer, type-2 diabetes, and renal failure; it alters their gene expression in substantial ways; and it leads to cognitive decline. And there’s reason to believe that ragged and rundown rodents will respond differently—abnormally, even—to experimental drugs.
That’s the drawback of the modern lab mouse. It’s cheap, efficient, and highly standardized—all of which qualities have made it the favorite tool of large-scale biomedical research. But as Mattson points out, there’s a danger to taking so much of our knowledge straight from the animal assembly line. The inbred, factory-farmed rodents in use today—raised by the millions in germ-free barrier rooms, overfed and understimulated and in some cases pumped through with antibiotics—may be placing unseen constraints on what we know and learn.
“This is important for scientists,” says Mattson, “but they don’t think about it at all.”
They don’t think about it at all. But, science! That’s almost a direct quote from somebody who was trying to convince me about something or other- the what is neither here nor there. The point is that yes, science is great, it’s lovely, I love it (really, I do), but it’s also done by scientists, who are human and not demigods.
Raza (quoted at the top of the post) works with cancer. Clifton E. Barry, III, is the government’s top researcher on Tuberculosis, and he’s noted problems with the mouse model as well.
The process of drug discovery has been carried out in the same way for decades. You start by testing a new compound in a Petri dish, to find out whether it can slow the growth of a particular bacterium in culture. That gives you the smallest dose that has an effect, known as the minimum inhibitory concentration, or “MIC”—the first M. Then you move to a living animal: Does the compound have any effect on the course of disease in a lab mouse? If so, you’ve cleared the second M, and you’re ready to test the compound in the third M, man. Each step leads to the next: No drug can be tested in man until it’s been shown to work in mice, and no drug is tested in mice until it’s been shown to have a reasonable effect in the dish. “The bad part of that,” says Barry, “is that no part of it is predictive:” A new compound that succeeds in the dish might flunk out in the mouse, and something that can cure tuberculosis in a mouse could wash out in people.
The fact that nothing gets to humans today without first passing the mouse test, says Barry, “has cost us a new generation of medicines.”
He doesn’t say so, but Raza alluded to it- this obviously means the converse is true- drugs that did pass the mouse text have made it to humans- and then failed.
Back to tuberculosis:
Indeed, there’s been no real breakthrough in treating tuberculosis—no major pharmaceutical discoveries—since the early 1970s. The first antibiotic to have any success against the tuberculosis mycobacterium, the first that could penetrate its waxy coating, was discovered (and tested in guinea pigs) in the early 1940s. The best vaccine we have was first used in humans in 1921. (It works pretty well against severe childhood forms of the disease, but less so otherwise[emph. mine- dhm].) And the closest thing we have to a miracle cure—the multidrug cocktail that doesn’t work against every strain and requires a six-month course of treatment with severe side effects—was finalized during the Nixon administration. Since then, almost every new idea for how to treat TB has come from experiments on lab mice. These have given us enough new data to drown the infected in a tsunami of graphs and tables, to bury them in animal carcasses. Yet we’ve made little progress—OK, no progress at all—in treating the human disease. Tuberculosis causes more than 2 million deaths every year, and we’re using the same medicines we had in 1972.
One major problem with the mouse model—and the source of its spotty track record in the clinic—is well-known among those in the field: The form of TB that mice happen to get isn’t all that much like our own.
Emphasis mine, again.
Why? Basically, we keep doing this because we started doing it in the first place. Because we started doing it in the first place, government grants, government contracts, and industries worked together to create a situation that feeds back into itself, requiring that we continue to do things this way:
The feedback loop began more than 60 years ago, when federal investment in biomedicine was growing at an exponential rate. To eradicate the last vestiges of infectious disease, win the war on cancer, and otherwise mobilize the nation’s resources for an industrial revolution in science, the government needed a more streamlined research model—a lab animal, or a set of lab animals, that could be standardized and mass-produced in centralized facilities, and distributed across the country for use in all kinds of experiments. An efficient use of federal research funds demanded an efficient organism for research.
In part because of their size and breeding capacity, and in part because they’d been used in laboratories since the turn of the century, the rat and mouse were selected for this role. As major research grants began to flow from Washington in the 1950s and 1960s, private rodent breeders picked up huge contracts with government-funded labs.
A few researchers are moving to other animals for research, but it’s hard, it’s expensive (the article says it’s almost like changing your religion), and it’s difficult to convince other scientists that it’s necessary.
It’s not clear how one might prove, in a satisfying and scientific way, that any given lab animal is better than another. We can’t go back and spend the last 50 years studying monkeys instead of mice, and then count how many new drugs came as a result. The history of biomedicine runs in one direction only: There are no statistics to compare; it’s an experiment that can’t be repeated.
One last quote, but you really should read both articles (the first is short, the second quite long):
Assembly-line rats and mice have become the standard vehicles of basic research and preclinical testing across the spectrum of disease. It’s a one-size-fits-all approach to science. What if that one size were way too big?
Think about how this information applies to other topics as well.