The Problem with America’s Lab Mice and Why it Should Matter to You

I was a graduate student studying bats in, I was in Michigan, and I was interested in evolutionary trade-offs. That's my signature thing. And there was a very good piece of work from a guy I knew, George Williams, great evolutionary biologist, about the evolution of senescence, that is to say, the process by which we grow feeble and inefficient with age, what most people call aging. And basically, this classic paper explained why it is that creatures like us get old and die. And the answer was basically this, that you have a genome that's complex, it's full of genes, but there aren't enough genes to have a gene for every trait that you have. In fact, they're a tiny fraction of the number of genes you would need to cover all of the various characteristics you have. So genes always do multiple things. And in the case when a gene does something that's very good for you when you're young, at some cost when you're old, selection tends to favor it because you may not live long enough to suffer the cost. And so if you have the trait that makes you powerful when you're young, and you've got some cost that you're going to pay when you're old, but you're not going to live to get it, it may be a freebie, right? So selection sees early life much more clearly than it sees late life, and it prefers things that help you early even at a cost of harming you late. That's the basic answer. It's called the antagonistic pleiotropy theory of senescence. But at the point that I started working, we knew that this was right. We could tell that the hypothesis was true because it matched all sorts of observations about wild creatures. Certain creatures live longer than others even when you correct with things like body size. So creatures that fly live longer than creatures that are of the same type and size that don't fly. Why? Because they can fly away from danger. If you can fly away from danger, you're more likely to make it to an older age. The better selection can see the harms that afflict you when you get there. So selection doesn't prefer a bias in favor of youth if you can fly away from danger. Same thing applies if you're poisonous, if you have a shell. If you have a really good defense, then selection sees your late life better. So we knew that this hypothesis was right. But what we had never found at the point that I was working in the very late 90s on this was a gene that matched the description. We knew that selection was finding these genes and accumulating them, but we had never found one of the genes in question, and that was very conspicuous. I called that the missing pleiotropy. So anyway, I was sort of on alert about this. It was a curious fact. And I saw a talk given by somebody who was talking about telomeres, and he was talking about telomeres and their relationship to cancer. So telomeres are repetitive sequences of DNA at the ends of our chromosomes, and they grow shorter every time a cell divides. So it's like a fuse or a counter that ticks down each cell division, and it drops to zero. And in...or not zero, but it drops to a number that the cell refuses to divide after that. And some people were working in one set of labs on the possibility that this was causing us to grow feeble with age, because if your cells can't divide anymore, then they won't replace themselves, and your tissues won't be able to maintain. Another group was studying this question of telomeres with relation to cancer, and they were saying, Eureka, every time we look into cancer, it has this enzyme called telomerase turned on, which elongates telomeres. And these two groups were not talking to each other. They were each claiming that they were about to cure their respective disease. One group was saying, if we can activate telomerase, then we can lengthen your life. And the other group was saying, if we can turn off telomerase, we can cure cancer. Right? And I put two and two together, and I said, this is the missing pleiotropy. Here we have something that is protecting us. It's helping us in youth. We have a counter that is limiting the number of times a cell can divide and presumably preventing cancer. Right? And the cost is you can't maintain your tissues forever, so you grow feeble and inefficient. So that made a hell of a lot of sense to me. I couldn't convince anybody else that this was sensible. I couldn't even get them to understand what I was saying, because in evolutionary biology, there has traditionally been a bias against mechanism, the study of cellular biology. Not because there's anything wrong with studying cellular biology as an evolutionary phenomenon, but because early in the study of evolution, we just didn't have the tools to look into the cells. Evolutionary biologists got used to thinking about the form of creatures and the behavior of creatures, but not thinking about the internal mechanisms, because there just wasn't a lot that could be said. Anyway, I retained an interest in the cellular biology. I saw these two things that needed to be connected, and I started to work on the puzzle. It turned out that that hypothesis would answer a great many questions that were otherwise very difficult to answer with respect to how aging functions. But there was one huge obstacle. The obstacle was that a fact that was well known about mice did not fit with the idea that telomeres were fundamental to the aging process. And the fact that was known was that mice had extremely long telomeres, and yet they lived short lives. So if it were true that the length of your telomeres dictated how quickly you were going to age, then a tiny creature with very long telomeres ought to be able to replace its tissues really well, and it should age very, very slowly. So I thought, there's got to be something wrong with this. The hypothesis answers too many questions for that obstacle to be real. And I thought, maybe one person has run a test, and everybody else is just parroting it. And I went and I looked, and that wasn't the case. And I finally realized that all of the mice that had been looked at were coming from one source, that there was a laboratory in Bar Harbor, Maine called the Jax Lab that was the source for all of the mice being used in all of the laboratories in the country. And I started to wonder, is there something going on at that lab? Maybe mouse telomeres aren't long. The ultra long telomeres of mice aren't real. Maybe that's a feature of laboratory mice, and wild mice would have short telomeres, in which case the hypothesis would make sense. And I called up one of the leading people in the field, a woman named Carol Grider, who has now won a Nobel Prize. And I said, Carol, you don't know me. I'm an evolutionary biology graduate student. I have a question for you. Is it possible that all mice don't have long telomeres, that that's really just laboratory mice? Well, I think mice have long telomeres. But it's interesting, if you order mus spritus rather than mus musculus, and you order them from Europe, then how long their telomeres are depends on what supplier you get them from. So this is interesting. So anyway, we both agreed that it was really interesting. She decided she was gonna test the hypothesis. She put her graduate student Mike Heeman on the case. We exchanged some emails. And anyway, they tested it, and they got some mice that weren't really wild, but they were much more recently in captivity. And lo and behold, they had short telomeres. Okay, so that was an amazing moment. My prediction had turned out to be true, which meant, A, that my hypothesis about senescence and cancer and aging might well be true. That was important. But it also raised a bunch of really difficult problems. One was, if it is true that all the mice that are being used to study physiology are broken in this way, then how are we blinding ourselves? Is it possible that we are using all of these mice that would be terrible models for wound healing, for senescence, for cancer, for a whole number of things? How is it that we are allowing ourselves to take these mice who have been altered and using them as models for normal physiology? The other problem, maybe even more serious, was that we used these animals in drug safety testing. And the way we used them is, if you think about, if you'd come up with a drug that you thought was useful, and you wanted to test whether it was safe to administer it to people, you can't really afford to give people a drug and then wait 40, 50 years to figure out whether you've shortened their lives. Right, so at the point that you start testing these things on humans, you're really in the final stage. The way we test whether a drug is safe for long term use, or whether it is safe for your long term life based on short use, is we give large doses of it to small animals that live short lives. On the assumption that if it's gonna shorten your 80 or 90 year life by 10 or 20 years, that it'll shorten a mouse's life long enough to see it. But here's the problem. If you've altered a mouse in the laboratory environment by favoring the radical elongation of its telomeres, then it has the ability to replace its tissues indefinitely. A toxin that will harm you by killing tissue may not harm that mouse. In fact, it may actually help it because these mice are very cancer prone. So when we give a toxin that will damage you to a mouse that is highly resistant to tissue damage, you may slow down its tumors. And in fact, we've seen this a number of times, where a drug is given to mice and we get back the paradoxical result. Not only is it not toxic, it actually makes the mice live a little longer. All right, so my contention is that we had a problem where we were testing drugs to see if they were safe on animals that were predisposed to tell us that they were. And then when those drugs were released into the human population, it turned out they were not safe and people died. Now the problem is, I was absolutely unable to alert the world to this problem for reasons that still elude me. I published my paper, I went through, I don't think we need to bore your audience, especially if they've been through Eric's description, with the details of what happened in the attempt to bring this to public attention. But the world of scientists working on the question was unwilling to respond to the discovery that their model organism had this fatal flaw that was going to predispose us to see certain things and not other things in the laboratory environment. The governmental commission that was charged with studying the Vioxx scandal, which I believe was likely the result of something like this, in its 300 page report doesn't mention mice, it doesn't mention. The Vioxx scandal, which was a drug for arthritis, correct? It gave people strokes. Yeah, it did heart damage. And so anyway, heart damage is actually probably not heart damage. And by that what I mean is, if you take a drug, a substance that damages tissues in the human body, it will show up as heart damage because of the special nature of the heart. So let's say that you took some drug that killed every 10,000th cell or every 1,000th cell. That would be destructive all over your body. The heart, though, is a special tissue. The heart has a very low capacity for self repair at a cellular level, very low for reasons we could go into if you wanted. But because it has a low capacity for self repair, it is also very vulnerable to something that does some kind of general tissue damage. And it's also an organ that when it fails, it's absolutely conspicuous. So you would expect that if we had substances that were body-wide toxins and we released them into the public, having tested them on mice and not discovering that they were dangerous, that you would see relatively young people die from heart conditions, which is where we would detect that there's a problem before we would detect it anywhere else. So anyway, the government studied this problem after Vioxx and it put together a report. And the report's 300 pages. It doesn't mention mice. It doesn't mention the genus musk. Do you think they did that to protect themselves? Well, what I know is that I attempted to call their attention. After the report came out, I looked at it and it had a physical form, but it also had it lives online. You can search it and I could see that telomeres weren't mentioned. Mice weren't mentioned. Rodents aren't mentioned. And so I tried to alert them to the fact that they had screwed up and they blew me off. They wouldn't talk to me. So that is it raises a question. And I to this day cannot answer the question. I can't even say whether or not. So when I've tried to raise this issue, I have run into various kinds of resistance. If I raise it with journalists, what I get back is typically I get interest back at first and they say, OK, I'm very interested in the story. I'm going to pursue it. I'm going to make a few phone calls. And then they come back to me and they either they go silent or they say, well, I talked to some people and they said it's been taken care of. Right. Well, I don't know what it's been taken care of means. I published a paper that said, here's a hypothesis about what's going on. Here's my I proposed a mechanism whereby telomere elongation would have happened in the breeding colonies in question. And it's been taken care of. It's a very strange way to describe something that could be an enormous problem. Well, not only let's say that it was taken care of. Right. Let's say that they have altered the the breeding protocol and they fixed the problem. You still have all those drug tests that they've done for. You've got all those drug tests. You've got all of the papers. You've got my paper, which proposes a hypothesis and I have a right to say, actually, it turns out to be correct or it wasn't. Right. But so anyway, we got back all of these weird answers. It's been taken care of or even more curious is the argument. Well, everybody knows that the mice are bad models, which is insane because this telomere problem. You actually got that response. Yeah. From several people. I went to several different journalists and it wasn't that I was told who they contacted. What I was told was that they contacted somebody and this is what they heard. And so they their enthusiasm evaporated at the point they make a phone call. So were they not aware of the consequences of this problem with these mice? So again, this is. We have a serious problem. It's not about mice. It's not about virology. Right. It's a general systemic failure of reason. So what I encountered as a young, somewhat naive graduate student was an instance which frankly woke me up to the fact that my colleagues, even when human life was on the line, were going to pretend they didn't know what was going on. It's quite possible they didn't know until I had put out my hypothesis and Carol Greider, who later pretended she didn't know what I was talking about, published the empirical work that revealed that indeed lab mice are unusual in having long telomeres. After that work was out, there's no excuse for not investigating what the consequences were. I cannot explain it except to say that the culture of science has become so rotten that this sort of thing is maybe standard operating procedure. Just protecting their ass and protecting the ass of those who give them jobs and and all the work that's been done that sort of establishes that they should be doing these tests in the first place. I'm sure they tell themselves some story in which they are the heroes and they are protecting us from something. But I look at my own medicine cabinet and even though I am aware of what likely happened, I am in no position to protect myself or my family. The only way to be protected from the downstream consequences of this error is to just not take pharmaceuticals. Jesus Christ. Yeah, it's a it's a it's a really huge problem. And the response of the system generally to shut down the lone individual trying to point out a serious problem is it's just breathtaking. When you've when you've seen it, when you've lived it, you never go back. You know, you've looked into the eye of something that is willing to ignore. I mean, it's willing to ignore not only human life. But it is willing to ignore the requirements of good science.