Medications That Work In Mice Often Fail When Tried In Individuals
Chances are, people studying the same disease study the same tailor-made strain of animal. Journals and funding agencies actually expect it.
Most potential new drugs fail when they are tested in people. These failures are not only a significant letdown – they aggressively drive up the cost of developing new drugs.
An important reason for all these failures is that new drugs are tested out in mice, rats or other creatures. Frequently those animal studies demonstrate great promise.
But mice aren't simply furry little people, so these studies often lead science astray. Some scientists are now rethinking animal studies to cause them to become more powerful for human health.
When scientists first began using animals in research above a century past, the animals were not regarded as human stand-ins.
"As this process went on, people stopped seeing them as specialized creatures and started seeing them more and more as prototypical mammals," Preuss says.
But is a rat really a mammal that is generic? Preuss says decidedly no.
"It wasn't purely a financial interest," he says. The sellers "actually believed that you simply could do virtually anything" with these animals. "You could learn about almost any feature of human organization, you can cure almost any disease by studying these animals."
That was a dangerous premise. Humans and rats have already been on their own evolutionary paths for tens of millions of years. We've developed our own unique attributes, and so have the rodents.
Therefore it should come as no surprise a drug that works in a mouse frequently does not work in a man. However, Preuss says there's tremendous momentum to keep using animals as human replacements.
"You've companies that spring up to provide you with specialized gear to analyze these creatures."
Odds are people examining the same ailment analyze the same tailor-made form of creature. Journals and financing agencies anticipate it.
"So there is a whole institution that develops," Preuss says.
And it is hard to interrupt that tradition.
By passing through one of the hundreds of facilities nationwide devoted to the care and feeding of mice, you may get a glance of the scale of this enterprise. About the Stanford University campus, attendants roll supply handcarts through fluorescent-lit hallways and past row after row of doors at an expansive mouse facility.
Joseph Garner, a behavioral scientist at the Stanford University Medical Center, guided through the labyrinth me. We go right into a windowless room stacked floor to ceiling with seemingly indistinguishable plastic cages full of mice.
The philosophy behind mouse studies have been to make everything as uniform as you can, so results from one facility could be the same as the identical experiment elsewhere.
But despite substantial attempts to be consistent, this setup conceals a huge level of variation. Bedding may differ from one facility to the following. So might the diet.
Garner and coworkers attempted to run identical experiments in six distinct mouse facilities. Even using genetically identical mice of the same age, all over the map varied.
Garner says scientists should not even be attempting to do experiments this way.
"Imagine you were doing a human drug trial and you said to the FDA, 'OK, I am going to do that trial in 43-year old white men in one small town in California,'" Garner says — a town where everyone lives in identical ranch homes, together with precisely the same monotonous diets and also the same thermostat set to precisely the same temperature.
"That will be too chilly, plus they can't change it," he goes on. "And oh, they all possess precisely the same grandpa!"
The FDA would laugh off that as a crazy set up, Garner says.
"But that is just what we do in animals. We make an effort to control everything we can think of, and as a result, we learn absolutely nothing."
Garner contends that research predicated on mice would be more reliable if it were set up more like experiments in humans — designing to adopt it rather than dismiss it, and understanding that variation is unavoidable. He and his colleagues have recently released a manifesto, advocating colleagues in the field to take a look at animals in this new light.
"Maybe we need to prevent thinking of animals as these little furry test tubes that can be or even ought to be controlled," he says. "And perhaps instead we should think of these as patients."
That may solve some the problems with animal research, but by no means all.
When creating animal models of those illnesses, scientists make too many assumptions about the underlying biology of disease, says Gregory Petsko, who studies Alzheimer's disease and also other neurological disorders in the Weill Cornell Medical School.
"It's likely only when you can test your treatments in individuals which you're going to possess any idea how right those premises were," Petsko says.
In his subject, the assumptions are totally misleading, or commonly poor. And Petsko says this mindset has been counterproductive.
For attempting so, he does not fault his colleagues.
"What I'm saying is at some point you've got to cut your losses.
Creatures are still helpful for analyzing the security of new treatments that are potential, but beyond that, he says, do not count on them.
Preuss at Emory agrees that using animals as models of the disorder is a large reason that lots of results in biomedical research aren't readily reproducible. "I think that individuals have means to solve that, however."
How? "You need to think outside of the model box," he says. Mice and rats aren't simplified, people. Scientists should stop believing they're.
But Preuss says scientists can still learn a lot about biology and disease by examining creatures — for example, by comparing where they share common traits, or people, as well as other creatures, differ. Those can reveal a whole lot about biology without assuming that what is true in a rat is true in a human.
"Scientists have to break out of a culture that's hampering improvement," Preuss says. That's tough to do right in a world where science financing is really on the chopping block. Many scientists are unwilling to take a hazard which could backfire. However, the upside could all benefit us, in the sort of a better understanding of the disease, and new drugs that are successful.