Drugs That Work In Mice Often Fail When Tried In People

Apr 10, 2017
Originally published on April 10, 2017 7:50 am

Most potential new drugs fail when they're tested in people. These failures are not only a major disappointment, they sharply drive up the cost of developing new drugs.

A major reason for these failures is that most new drugs are first tested out in mice, rats or other animals. Often those animal studies show 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 make them more effective for human health.

When scientists first started using animals in research over a century ago, the animals were not regarded as human stand-ins. Scientists studying rats were initially trying to understand rats, says Todd Preuss, an anthropologist at the Yerkes National Primate Research Center at Emory University.

"As this process went on, people stopped seeing them as specialized animals and started seeing them more and more as prototypical mammals," Preuss says.

But is a rat really a generic mammal? Preuss says emphatically no. But that's how rodents were pitched when they became products sold to scientists.

"It wasn't strictly a financial interest," he says. The sellers "really believed that you could do almost anything" with these animals. "You could learn about almost any feature of human organization, you could cure almost any disease by studying these animals."

That was a dangerous assumption. Rats and humans have been on their own evolutionary paths for tens of millions of years. We've developed our own unique features, and so have the rodents.

So it should come as no surprise that a drug that works in a mouse often doesn't work in a person. Even so, Preuss says there's tremendous momentum to keep using animals as human substitutes. Entire scientific communities are built up around rats, mice and other lab animals.

"Once these communities exist, then you have an infrastructure of knowledge: how to raise the animals, how to keep them healthy," Preuss says. "You have companies that spring up to provide you with specialized equipment to study these animals."

Chances are, people studying the same disease study the same tailor-made strain of animal. Journals and funding agencies actually expect it.

"So there's a whole institution that develops," Preuss says.

And it's hard to interrupt that culture. (Preuss spoke about this subject in a 2016 talk at the National Institutes of Health.)

You can get a glimpse of the scale of this enterprise by passing through one of hundreds of facilities nationwide devoted to the care and feeding of mice. On the Stanford University campus, attendants roll supply carts through fluorescent-lit hallways and past row after row of doors at an expansive mouse facility.

I'm guided through the labyrinth by Joseph Garner, a behavioral scientist at the Stanford University Medical Center. We go into a windowless room stacked floor to ceiling with seemingly identical plastic cages full of mice.

The philosophy behind mouse research has been to make everything as uniform as possible, so results from one facility would be the same as the identical experiment elsewhere.

But despite extensive efforts to be consistent, this setup hides a huge amount of variation. Bedding may differ from one facility to the next. So might the diet. Mice respond strongly to individual human handlers. Mice also react differently depending on whether their cage is up near the fluorescent lights or hidden down in the shadows.

Garner and colleagues tried to run identical experiments in six different mouse facilities, scattered throughout research centers in Europe. Even using genetically identical mice of the same age, the results varied all over the map.

Garner says scientists shouldn't even be trying to do experiments this way.

"Imagine you were doing a human drug trial and you said to the FDA, 'OK, I'm going to do this trial in 43-year-old white males in one small town in California,'" Garner says — a town where everyone lives in identical ranch homes, with the same monotonous diets and the same thermostat set to the same temperature.

"Which is too cold, and they can't change it," he goes on. "And oh, they all have the same grandfather!"

The FDA would laugh that off as an insane setup, Garner says.

"But that's exactly what we do in animals. We try to control everything we can possibly think of, and as a result we learn absolutely nothing."

Garner argues that research based on mice would be more reliable if it were set up more like experiments in humans — recognizing that variation is inevitable, and designing to embrace it rather than ignore it. He and his colleagues have recently published a manifesto, urging colleagues in the field to look at animals in this new light.

"Maybe we need to stop thinking of animals as these little furry test tubes that can be or even should be controlled," he says. "And maybe instead we should think of them as patients."

That could solve some of the problems with animal research, but by no means all.

Scientists make far too many assumptions about the underlying biology of disease when creating animal models of those illnesses, says Gregory Petsko, who studies Alzheimer's disease and other neurological disorders at the Weill Cornell Medical School.

"It's probably only when you get to try your treatments in people that you're really going to have any idea how right those assumptions were," Petsko says.

In his field, the assumptions are often poor, or downright misleading. And Petsko says this mindset has been counterproductive. Scientists in his field have "been led astray for many years by relying so heavily on animal models," he says.

For many years that was simply the best that science could do, Petsko says. So he doesn't fault his colleagues for trying.

"What I am saying is at some point you have to cut your losses. You have to say, 'OK, this took us as far as it could take us, quite some time ago.'"

For neurological diseases, Petsko says, scientists might learn more from studying human cells than whole animals. Animals are still useful for studying the safety of potential new treatments, but beyond that, he says, don't count on them.

Preuss at Emory agrees that using animals as models of disease is a big reason that many results in biomedical research aren't readily reproducible. "I think that we have means to resolve that, though."

How? "You have to think outside of the model box," he says. Mice and rats aren't simplified humans. Scientists should stop thinking they are.

But Preuss says scientists can still learn a lot about biology and disease by studying animals — for example, by comparing how humans and other animals differ, or where they share common traits. Those can reveal a lot about biology without assuming that what's true in a rat is likely true in a human.

"Scientists need to break out of a culture that is hampering progress," Preuss says. That's tough to do right now, in a world where science funding is on the chopping block. Many scientists are reluctant to take a risk that could backfire. But the upside could benefit us all, in the form of a better understanding of disease, and effective new drugs.

Richard Harris did some of the reporting for this story while researching his book Rigor Mortis: How Sloppy Science Creates Worthless Cures, Crushes Hope, and Wastes Billions. You can contact him at rharris@npr.org.


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RACHEL MARTIN, HOST:

We're going to talk now about how scientists test new drugs. A lot of the drugs made for humans are tested first on mice or other lab animals, although one of the big problems is that most drugs that work in mice don't work in people, leading to major disappointments and increasing the cost of developing new drugs. Scientists know that animals are unreliable stand-ins for humans, but they use them anyway. Today in Your Health, NPR's Richard Harris looks at efforts to avoid this particular pitfall.

RICHARD HARRIS, BYLINE: When scientists first started using animals in research over a century ago, the animals were not seen simply as little, furry people. Todd Preuss at Emory University says people studying rats were trying to learn about rats, at least at the start.

TODD PREUSS: As this process went on, people stopped seeing them as specialized animals and started seeing them more and more as prototypical mammals.

HARRIS: The generic mammal - scientist started inferring things more broadly about mammals just from studying rats.

PREUSS: The people who were selling these things - it wasn't strictly a financial interest. They really believed that you could do almost anything that you could learn about almost any feature of human organization - that you could cure almost any human disease by studying these animals.

HARRIS: That was a dangerous assumption. Rodents have been on their own evolutionary trajectory distinct from ours for perhaps a hundred million years, so it should come as no surprise that a drug that works in a mouse won't necessarily work in a person. Even so, Preuss says, there's tremendous momentum to keep using animals as human substitutes. Entire scientific communities are built up around rats, mice and other animals.

PREUSS: Once these communities exist, then you have an infrastructure of knowledge - how to raise the animals, how to keep them healthy. You have companies that spring up to provide you with specialized equipment to study these animals.

HARRIS: Chances are, people studying the same disease you are used the same animal models. Journals and funding agencies actually expect it.

PREUSS: So there's a whole institution that develops.

HARRIS: And it's hard to break that culture.

You can get a glimpse of this by passing through a facility that's devoted to the care and feeding of mice. Attendants roll supply carts through fluorescent-lit hallways past row after row of doors at an expansive mouse facility on the Stanford University campus.

(SOUNDBITE OF DOOR CLOSING)

JOE GARNER: I just got lost. Perhaps this way.

HARRIS: Joe Garner, a behavioral scientist at Stanford, guides me through the labyrinth. We go into a windowless room stacked floor to ceiling with seemingly identical plastic cages full of mice. He says mouse researchers in one facility often have trouble repeating the exact same experiment done somewhere else. And that's because, despite outward appearances, there is a huge amount of variation.

GARNER: When people talk about this being a standardized environment, it just isn't. Right? There's the effect of the bedding. There's the effect of the diet, which may well be changing.

HARRIS: Mice on the top shelf have a different experience from those tucked away in the shadows at the bottom. And that difference can skew an experiment.

GARNER: This rack and that rack are different.

HARRIS: For decades, scientists have been operating under the assumption that they can control all these variables in order to get consistent results. Garner says it hasn't worked, and he argues it doesn't even make sense.

GARNER: So imagine that you were doing a human drug trial. And you said to the FDA - OK, I'm going to do this trial in 43-year-old white males in one small town in California, where everybody lives in identical ranch homes. They all have identical, monotonous diets that never change. Their thermostats are all set to the same temperature, which is too cold and they can't change it. Oh - and you all have the same grandfather.

HARRIS: The FDA would laugh that off as an insane setup.

GARNER: But that's exactly what we do in animals, right. We try and control everything we can possibly think of, and as a result, we learn absolutely nothing.

HARRIS: Garner and some like-minded colleagues argue that research based on mice would be more reliable if it was set up more like experiments in humans, recognizing that variation is inevitable and designing to embrace it rather than ignore it.

GARNER: Maybe we need to stop thinking of animals as these little, fairy test tubes that can be controlled or even should be controlled. And that instead, maybe we should think about them as patients.

HARRIS: That could solve some of the problems with animals but by no means all. Dr. Gregory Petsko at the Weill Cornell medical school studies Alzheimer's and other neurological disorders. And he says scientists make far too many assumptions about the underlying biology of disease when creating animal models of those illnesses.

GREGORY PETSKO: And it's probably only when you get to try your treatments in people that you're really going to have any idea how right those assumptions were.

HARRIS: So do you think the field is being led astray by relying so heavily on animal models?

PETSKO: Yes, I do. I believe it's been led astray for many years by relying so heavily on animal models. Now, that's not as much of a criticism of the people who develop those models and use them as it sounds.

HARRIS: It was the best they could do at the time, he says.

PETSKO: What I am saying is, at some point, you have to know when to cut your losses. You have to say, OK, this took us as far as it could take us quite some time ago.

HARRIS: For neurological diseases, Petsko says, scientists might learn more from studying human cells than whole animals. Animals are still useful for studying the safety of potential new treatments. But beyond that, he says, don't count on them.

I asked Todd Preuss from Emory if he also thought that the problems of drug development and understanding disease are due to overreliance on animals.

PREUSS: I think it's a big problem. I think that we have means to resolve that, though.

HARRIS: That requires breaking from the scientific mindset that has built up over the decades.

PREUSS: You have to think outside of the model box.

HARRIS: Mice and rats aren't simplified humans. Scientists should stop thinking that they are.

PREUSS: There's just a lot more that we can learn about humans from studying animals, by the way they're different from us as well as the ways in which they're similar.

HARRIS: And that gets back to his earlier observation. Scientists need to break out of a culture that is hampering progress. That's tough to do right now in a world where science funding is on the chopping block. Many scientists are reluctant to take a risk that could jeopardize their careers. Richard Harris, NPR News.

(SOUNDBITE OF KOLOTO'S "PRIMER")

MARTIN: Richard did some of the reporting for this story while researching his book, titled "Rigor Mortis." Transcript provided by NPR, Copyright NPR.