JOHN DANKOSKY: OK. Since we’ve just talked quite a bit about cats, it’s only fair we devote some time to their mortal enemies, mice. Specifically, we’re going to be talking about the kind you find in the laboratory.

Mice and rats make up about 99% of animals used in research. But how did research come to be so dependent on these tiny rodents? And how exactly do scientists genetically engineer mice to be suitable to study pretty much any human ailment?

One of the largest suppliers of lab mice is the Jackson Laboratory for Mammalian Genetics. They’ve developed 11,000 genetically modified strains. And they ship out about 100,000 mice each month to scientists around the world.

Joining me now is Dr. Nadia Rosenthal, Scientific Director and Professor at the Jackson Laboratory, based in Bar Harbor, Maine.

Dr. Rosenthal, welcome to Science Friday.

NADIA ROSENTHAL: Great to be with you, John.

JOHN DANKOSKY: Let’s start with a bit of history first. Mice made their way into research labs with a little bit of help from an amateur geneticist at the turn of the 20th century, is that right?

NADIA ROSENTHAL: That’s correct. It’s a great story. It involves a woman with a big barn. In the US and Britain, people were keeping fancy domesticated mice as pets and breeding interesting specimens. And Abbie Lathrop was one of these mouse fanciers. And she was living in Granby, Massachusetts, and she was a really savvy businesswoman. And she established a mouse breeding business in her barn.

And she had more than 11,000 mice at one point. Now, I mean, barns are a good place to store mice, but that’s a lot of mice. And she kept very careful breeding records. And when she noticed that some of her fancy mouse strains were developing skin problems, she got in touch with some prominent scientists. And they diagnosed inherited cancer in some of her lines.

And they started working with Abbie. And she was actually performing breeding experiments in her barn. And she established that cancer is a heritable disease, even before we knew what DNA was. And it’s really interesting, because Clarence Cook Little, from Harvard, who founded the Jackson Laboratory, and his colleague George Snell, established the most frequently used mouse for the past 90 years. It’s a mouse called C57 black 6. It’s black. And it was this 57th mouse that Abbie had actually analyzed.

That mouse is still heavily used today. And George Snell went on to win a Nobel Prize for his work on genetics of immunology, using those mice.

JOHN DANKOSKY: Well, you mentioned the C57 black mouse. It’s still the most commonly used mouse in medical research. Why is that still? And why is that sometimes a problem?

NADIA ROSENTHAL: There’s a commonly held notion that drugs that are successfully trialed in mice don’t often pan out in humans. The very reason that we use one mouse all the time– in this case, the C57 black 6 mouse– in many experiments is because that takes out a variable. If all the mice are the same, it means that whatever else we’re measuring can be attributed to some other variable, not to the fact that they’re different genetically.

But the problem is, that’s not how people work. It’s an inconvenient truth that most medications that pass clinical trials in people work in only a relatively low fraction of patients, because we’re all unique. And the same is true in mice.

If you test a medication in a mouse, like C57 black 6, the chances of it working are about the same as if you tested it in one person. And to complicate matters, these lab mice are inbred, like purebred dogs, and they each have their own set of characteristics and disease susceptibilities.

So if you want mice to respond to medications like human, you need to make them more like human.

JOHN DANKOSKY: So that’s one of the things you’re trying to do, to try to diversify lab mice so they will be more similar to the genetic diversity of the human population?

NADIA ROSENTHAL: That’s correct. So we’re actually breeding mouse mutts, sort of like labradoodles or cockapoos. They’re designer mice. And they’re healthier and unique, and highly variable in their response to medications, just like people.

So if someone claims the drug doesn’t work in mice, I sort of channel my inner Abbie Lathrop, and ask them, which mouse? How many different mice did you test?

JOHN DANKOSKY: I’m John Dankosky. And this is Science Friday, from WNYC Studios.

Explain a little bit more about how you’re able to genetically modify mice to develop diseases that scientists want to research.

NADIA ROSENTHAL: Sure. Let’s say somebody’s child has a rare disease that’s caused by a defective gene that’s already been identified. We can often intentionally mimic that disease in a mouse by creating the human mutation in that mouse, with genetic engineering.

And the way we do that is with stem cells, embryonic stem cells– mouse ones, or fertilized eggs, sort of like IVF. And then we can modify with techniques, like CRISPR, which you may have heard of, that allow us to change the genetic makeup of that mouse to look more like the child we’re trying to cure, and to test therapies on that mouse, as a sort of an avatar.

JOHN DANKOSKY: There are a number of studies that show that mouse studies don’t always translate that well to humans. We’ve already talked about that a little bit. So maybe we can talk for a moment about why that is, and how we get away from a model that doesn’t really replicate what humans have going on inside of them.

NADIA ROSENTHAL: I can give you an example from our current COVID-19 pandemic. Scientists were stuck, because mice don’t get COVID-19, so they couldn’t be used to test vaccines or antivirals. It’s because there’s a protein on the surface of human cells that lets the SARS-CoV-2 virus to get into the cell. And it’s slightly different in mouse than it is in humans, so the virus can’t get into the mouse cell.

So the solution was kind of obvious. Let’s get that human version of the gene into the mouse. And that was done. And suddenly the mouse comes down with COVID-19 when exposed to the virus. And by the way, it was a C67 black 6 Mouse, the same mouse that was in the Abbie barn.

Only problem was, the effect was really severe. As we know now, there’s a broad spectrum of responses to COVID-19. So we needed to model that spectrum of response in the mice. So how do we do that? You try it on the mutts.

So we crossed the mouse bearing the human gene to 10 different strains of mice in our collection, and tried the virus on the next generation of mouse mutts. And the results were spectacular. One mouse got very sick. Another got respiratory infection and then recovered. Another got infected and still shows no sign of illness.

And so because we know where the grandparents and the parents of these mice come from, we can trace the inherited basis of the disease, and use that knowledge to understand how to better treat the consequences of like long COVID in humans.

JOHN DANKOSKY: There’s also been research showing that mice that are stressed aren’t necessarily very good test subjects. What are you doing to improve the living conditions of mice so that they’re actually living better lives, and thus not under the types of stress that might influence in some way how they behave and how they behave in these experiments?

NADIA ROSENTHAL: Now, mice are really perceptive, and they can pick up on human behavior, just like dogs can. So our caretakers have to be highly trained to minimize stress when they handle the mice. They’re on the lookout for any illness or injury.

So our first goal is to keep them very healthy and stress free. As you say, a sick and depressed mouse is not a good topic for study. This includes their housing. Fortunately, mice actually love small spaces, to make them feel safe, like under your kitchen floor.

So my pet project at the moment is to redesign the boxes we use to give mice a more natural setting, with little spaces they can cram themselves into to sleep, with a separate latrine, which they really like, and a design that minimizes the number of times we need to clean the cages. Because we learn a lot more from a happy, healthy mouse than a frazzled, depressed one.

And we strictly follow the framework of what we call the three R’s, which was established 50 years ago to ensure humane treatment of animals in research. It’s replacement, reduction, and refinement. So we try to replace an animal test with another test, like using cells whenever we can. We reduce the number of mice used whenever possible. And we refine the approaches in our research, to try to minimize any stress or pain.

JOHN DANKOSKY: There is of course a larger ethical consideration here, and you’ve addressed this somewhat already. But we breed and destroy millions of mice a year for experimental purposes. It’s an enormous toll, in terms of living, breathing life forms. So what’s being done to just get away from this model entirely?

NADIA ROSENTHAL: A lot is being done. It’s something that really disturbs all of us who work with mice. So as you know, every cell in your body contains the same genetic material, and it’s unique to you. And for every mouse, it’s the same. So especially those mutts have unique genetic material.

So if we extract a cell from a mouse, we can actually then generate an embryonic stem cell that is what we call totipotent. That means that we can make any tissue we want out of that cell, and the tissue will literally be identical to the tissue in the mouse.

Now, it’s not perfect. Because, of course, you don’t have a full circulatory system. You don’t have hormones raging around in the tissue culture dish. And you don’t have immune cells. But it’s a big step away from animals. If you have cells in a dish, you can add different drugs to the cells, and you can do that to thousands and thousands of cells, in thousands of dishes, at a much, much cheaper and more ethically appropriate way.

You’re always going to need to go back to the animal, because of the complication of the organism. But if we can get most of the answers out of cells, and then do the final tests in the animals, we could drastically reduce the use of animals in research.

JOHN DANKOSKY: It’s really fascinating. That’s all the time we have.

I’d like to thank my guest. Dr. Nadia Rosenthal is Scientific Director and Professor at the Jackson Laboratory for Mammalian Genetics, based in Bar Harbor, Maine.

Thanks so much for your time.

NADIA ROSENTHAL: Oh, it was my pleasure, John.

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