The Mouse Trap

November 18, 2011 6:21 AM

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.

Slate has just finished a three part series on the pitfalls and promises of laboratory animals. (Part 1, Part 2, Part 3)

All three articles can also be read as a single, text-only article.

posted by tocts (21 comments total)

Meanwhile (pdf), in Europe the miniature pig is gaining popularity.
posted by Orange Pamplemousse at 7:07 AM on November 18, 2011

Mogil tested 11 different inbred mouse strains—albinos, white-bellied agoutis, dilute browns, Black-6—and ran them through a dozen standard tests of pain sensitivity. He found robust variation on every single measure. "That study made my career," he says. (He's now a named professor at McGill, and the recipient of copious research awards.) "At the time, the expectation was that all those strains were the same. Now everyone would say, 'Well, of course they're all different."

Also, the next time someone denigrates 'obvious' research, like proving the existence of bisexual men or multiple stab wounds being harmful to monkeys, I'm going to bring this quote up.

Plenty of obvious facts are completely wrong.
posted by Orange Pamplemousse at 8:30 AM on November 18, 2011

Even in a system as simple as growing E. coli in a big stainless steel tank or filtering the lysate of said culture after it's been through a homogenizer, there are huge differences between doing things at the bench top scale and running in a 1200 liter bio-reactor. The problem is the cost, both in terms of resources and time of trying to run a series of experiments at 1200 liters. A full factorial study that you could run in a week or two with bench top reactors would take months at scale and probably cost a lot more than 1200 times as much. So you do your initial development at bench scale and brace for scale up issues.

Did you flinch when I described a 1200 liter tank with all the issues of shear forces, O₂ diffusion and so on as simple? Or did you just think "A big bucket of sugar water with bacteria in it."? Now you see the problem.
posted by Kid Charlemagne at 8:54 AM on November 18, 2011

Thank you for waiting for the series to complete before posting :)

Will enjoy reading this.
posted by Afroblanco at 9:11 AM on November 18, 2011

I've only read the first two so far. It's interesting stuff, but mostly I'm reeling from seeing such good quality science writing, especially outside a specialist magazine or pop science book. I understand that it's a special feature rather than a time-pressured reaction to whatever scare story or press release has most recently reared its head, but it's still impressive.
posted by metaBugs at 9:26 AM on November 18, 2011 [1 favorite]

This reminds me of the recent article on replicability of published studies (showing that something like 65% of published results can't be replicated by industry). The researchers I work with attribute this to a number of issues, but I imagine the types of test subjects (whether animal or not) are high up there on the list of issues that prevent replication.
posted by jph at 9:46 AM on November 18, 2011

When I was vegan I was strongly against animal experimentation. Now that I'm not vegan, I think I still am. Mostly because I don't agree with experimentation on certain animals. Like most humans, I can admit that I put more value on certain creatures (such as ones we've bred alongside us to be strictly human companions, so much so that they have evolved to be more like us) in that I will strongly protest against their use as lab animals.

However.

I am not a scientist. I do not develop life saving drugs. I can provide no alternatives to animal experimentation and I never will be able to, that's not my field of study. Up to this point, although I hear that alternatives are being developed/discovered, none have reached the point to be used regularly.

Considering this, I generally have decided to stay out of telling scientists how to do their job.

But please stop using dogs and cats. It's horrific.
posted by Malice at 10:22 AM on November 18, 2011 [1 favorite]

Great post. Shades of Rat Park, which demonstrated that the environment rats are kept in can also have a major effect on experimental results.
posted by vorfeed at 10:26 AM on November 18, 2011 [2 favorites]

When interviewing for grad school, I thought this guy's research on innate immunity in lab mice verses wild-derived mice sounded fascinating*. Lab mice are the cows and chickens of this article - long divorced from their wild breathern. Wild-derived mice are a few generations descended from mice caught outside the lab. They've been a few generations inbred to get a more homogenous genome, exposed to the same feed, the same antibiotics, and the same environment their whole lives as the "control" lab mice. But only for 4 or 5 generations, instead of 100. In his presentation (to a group of potential grad students, so not too too much detail or anything) he described his finding that lab mice showed a lower immune response (less inflammation) to what I believe was sort of the mouse equivalent to the common cold than lab mice. That is to say, the lab mice had a disproportionally high immune response to a relatively harmless virus that the wild-derived mice did. That could affect a lot of immunology research being done in mice out there.

* Personal note: I would have considered joining his lab because that could be really fascinating to study, except for the part where he works on the two things I was avoiding: immunology and mice.
posted by maryr at 11:46 AM on November 18, 2011

Ahem, this guy.
posted by maryr at 11:54 AM on November 18, 2011

So this got me to thinking about a conversation I had with a researcher a couple weeks ago about a study he proposed. A biostatistician told him that he really had to have 90 mice per group for the experiment for statistical significance. The researcher said, "HA! These suckers are expensive! We're using 5 per group."

So just as I was writing in to mention that amusing/terrifying exchange, I heard the researcher in the hallway and ducked out to tell him that I had just been thinking about him and his mice because of this Slate series on lab animals and how they're all inbred and factory-farmed and how it reminded me of his recent exchange with the biostatistician.

He said, "Yeah, they say all that stuff about biostatisticians as well!"
posted by jph at 1:22 PM on November 18, 2011 [1 favorite]

Will no one speak up for the humble mouse?

Aside from the mouse's obvious but cheap failures as a model for disease (particularly cancer) when the wrong questions are asked, the author seems to be attacking something much deeper with roots and benefits he plainly doesn't understand.

From the 1920s to the 1930s there was a mass movement of out of work physicists, having suddenly run out of things to do when we figured out to much of physics, to biology. They brought with them a mechanistic view of how the universe works that they used to cause massive transformations in how we understand and interact with biology. One of the most influential of these scientific interlopers was Max Delbrück who quickly reasoned that, if we were ever going to understand how life works, we would need to start with the simplest organism possible and work our way up. He isolated seven bacteriophages against E. coli B, originally just his lab strain, and named them in a series T1(previously) through T7. The central idea was that he and his growing number of colleagues* would focus on truly understanding how these phages worked and use that knowledge to generalize to Escherichia coli, then the mouse, and then the elephant and us. An essential component of this was the "Phage Treaty" among researchers in the field, which Delbrück organized in order to limit the number of model phage and hosts so that folks could meaningfully compare results. What came out of their original focus, in many respects encapsulated in Erwin Schrödinger's What is life?, has shed light on so much as to truly redefine our self-understanding, much less medicine

The Luria–Delbrück experiment elegantly demonstrated that in bacteria, genetic mutations arise in the absence of selection, rather than being a response to selection, that is in all of life.

The Hershey–Chase experiment showed once and for all that nucleic acids were in fact the heritable molecule in not just T2 phage and E. coli, but indeed all of life.

Easily the snarkiest, most badass, and likely most important published scientific paper ever, written as an accessible single page, about the double helix structure of DNA. Jim Watson changed majors from ornithology to genetics after reading What is Life and became Luria's graduate student, while Crick was an older former physicist who also claimed inspiration from Schrödinger. The structure of DNA, and its relationship to function that they discovered, is true for all of life.

Soon afterwards the adapter hypothesis and central dogma, both of which are (at least simplistically) true for all of life.

Mouse models are part of those next steps up from understanding phages to understanding ourselves. Yes, that includes the fat, alcoholic, teenage ones we can go through like tissue paper. The International Mouse Phenotyping Consortium's 900 billion dollar project to identify the function of every gene in the mouse genome is amazing and inspiring in so many ways that have fuck all to do with mice. It is pathetic that it takes the author until the second to last paragraph in the last article to acknowledge that:

"For all their promise, neither the Burmese python nor the naked mole rat can exist on its own, as a stand-in for every other animal in the lab. When Buffenstein tries to give her mole rats cancer, she uses Black-6 mice as an experimental control. When the team in Boulder finally isolated its snake oils, it tested them in Black-6 mice. Even the pythons themselves were treated to the standard strains: Every other week, they got a single Sprague Dawley rat for dinner."

The appropriateness of mice for modeling human disease is intensely dependent on the questions that are being asked of those models. Of course you can dig through the literature from mice, which has millions of papers, to find examples of dramatic misuse of the model. However, to blame a focus on mice for the dearth of new antibiotics, and not the fact that micro-organisms only makes so many different kinds, is ridiculous. Researchers were driven to more mechanistically oriented drug discovery processes when serendipity stopped working.

I haven't met a researcher who uses mice to model infectious disease who likes the model. The article is right that there really isn't much that it models well. However the primary reason the folks I know use mice, isn't immediately obvious and isn't mentioned in any of the articles, there isn't another model. Mice make, if nothing else, a fantastic common shitty denominator for all of the reasons stated in the article. They're cheap, accessible, easy to care for, can be worked with in almost any lab not requiring special facilities, fuck tons are known about them, and they are unequally reproducible.

"Jackson employs about 1,200 people here, mostly from Bar Harbor, and while we're in mind of sorting one strain from another, the workers do seem of a type: Ruddy, goateed, and prone to non-rhotic vocalizations. It's a fact that Clarence Little himself prized this spot on the Northeast Seaboard for its purebred locals: The population of Maine is "composed largely of the best New England stock," he once boasted to a reporter, and "nearly as homogeneous as is possible to obtain at the present time.""

After a frequently exaggerated piece that pretends to be about the effects of the larger role of their mice in science, and focuses myopically on their failures as models of disease, this is just low and fucked up.

*Frank Stahl famously wrote: "The Phage Church, as we were sometimes called, was led by the Trinity of Delbrück, Luria, and Hershey. Delbrück's status as founder and his ex cathedra manner made him the pope, of course, and Luria was the hard-working, socially sensitive priest-confessor. And Al (Hershey) was the saint."

posted by Blasdelb at 1:39 PM on November 18, 2011 [7 favorites]

I don't think Luria as a priest. More of a medium.
posted by maryr at 5:29 PM on November 18, 2011

Wait what? Luria was an Italian Sephardic Jew who fled Paris for Marseilles on bicycle to escape the Nazis so he could somehow catch a ship to the US. Luria was the priest-confessor in the Delbrück trinity because... oh wait... I get it...

Funny story, LB medium wasn't originally called Luria Broth, Lennox Broth or Luria-Bertani medium though all of these have sadly been used in the literature. Lysogeny Broth is a terrible medium for any purpose other than the very specific one it was designed for, and even then its not that great. Its inadequacies have caused at least as much frustration, heartache, failed careers, and wrong shit in the literature as mice ever have. To understand why you must first understand what was is for.

Back in the day, tired of counting phage plaques by eye and losing count constantly. So someone in the original Phage Group figured that they would just make a machine that would backlight a plate, so you could see, with two pokey sticks that would activate a counter every time a circuit was completed between them. The idea was that you would stick one of them into the plate and "count" with the other. The problem however was that the agar medium they used was only barely conductive enough for it to work so they just dumped A SHIT TON of salt into the medium so they wouldn't get frustrated. Sure it would stress the E. coli, but no one cared because it was just the host they were using to make plaques.

People have been discovering that LB doesn't work well for any other purpose and doesn't work at all for biochemical ones since non-phage people started using it for whatever reason. Even without the stupid amounts of salt its not such a great medium, there are still cells in lag phase while others are in stationary phase so you can never actually keep things consistent between flasks, much less know whats going on.

Incidentally, If you ever want to know if a microbiologist is worth paying attention to, ask them why they use the media that they do. The quality of the response is strongly predictive.
posted by Blasdelb at 7:28 PM on November 18, 2011

Also, even when I was doing the kind of experiment were it would actually make sense to break out the prongs on the ancient plaque counters, I never used Lysogeny Broth. I'd just run the experiment in normal Tryptic Soy Broth and add a few pinches ~(5-10 g/L NaCl) of salt to the Tryptic Soy Agar I was enumerating phage on. Worked just fine.
posted by Blasdelb at 7:40 PM on November 18, 2011

Huh. Interesting to here about an early colony/plaque counter like that. Now it's all just imaging. (At least, that's how our automated colony picker works - I presume that you could use it to pick plaques given a strong backlight and a different set of selection criteria).

And dammit, now you have me looking up media recipes from home at 11 PM on Friday night. No! I refuse! This is why I'm avoiding grad school, dammit! I am stopping...right after I look up the recipe for Terrific Broth. Huh, no salt at all? How weird!
posted by maryr at 8:29 PM on November 18, 2011

Scientists: why white mice and rats?
posted by ryanrs at 9:30 PM on November 18, 2011

To match the labcoats.
posted by sneebler at 8:55 AM on November 19, 2011

*nod* It's not like we ever clean those things.
posted by maryr at 8:55 AM on November 19, 2011 [1 favorite]

Another reason is that people like things that are standarized, all the "same", and don't look like the wild version. PLUS they go with the labcoats.

Actually, the reason I remember being told was that white would show up better against the dark(er) institiutional baseboards in many labs, making escaping experiments easier to catch. I don't know if I believe that.
posted by sneebler at 9:00 AM on November 19, 2011

They're still useful, I've got one and my old lab has a stockpile of three intended to last the ages. At the San Diego ASM I went around the plate counter booths where one of them mentioned that they had tested their machine with plaques, apparently it can be made to work, but why pay for it?

Terrific Broth doesn't have NaCl, but be careful, it does have a whole bunch of potassium phosphate added to also work as buffer right? SCIENCE is exactly what Friday nights are for, but don't worry, I won't tattle to your P.I..

"Scientists: why white mice and rats?"

They arn't all white, the pigmentation of Black-6 (discussed in part 2) is actually pretty useful for making mutants.

I don't deal with Eukaryotes, much less rodents, but my understanding is that the simple answer to why many lab rodents are albinos its that it is simply another useful genetic marker. The second article goes into this somewhat but back in the day, before the discovery of DNA and how Mendelian Inheritance works mechanically, people were already mapping the mouse genome by figuring out which genes assort with others. They knew that albinism assorted with the "pink-eyed dilution" trait in what was then known as mouse linkage group I and what we now know to be chromosome 7. They were both visible and strongly recessive traits and so useful in making sure that you could always breed linkage group I true.

I think there is also a lot to be said for how it matched the lab coats and how they suddenly looked totally different from freaky and contaminating wild mice.
posted by Blasdelb at 9:12 AM on November 19, 2011 [1 favorite]