I worked in a Neuroscience lab as an undergrad research assistant for several years. My first year in particular involved a lot of cell counting and rat care.
There was a large room for housing rats for all of the labs in the building - mostly Sprague Dawley, which are very well studied at this point and chosen because they're easy to care for. The room was nowhere near 20 - 26C. It felt like walking into a fridge.
I think there are more problems than just the temperature that rats are kept at.
There are requirements for minimum standards of housing for animals - every university that does animal experimentation is required to have a LAR (lab animal resources) officer who verifies compliance. But researchers have to be frugal with money (even grad students are expected to live on a 20-30k research stipend), so they really do the bare minimum. Cages are as small as they can be, and rats are housed in pairs so that they can socialize, but their cages are almost barren. They're required to have some form of environmental enrichment, which means a little wooden rod in every cage that they can play with and chew.
It's frustrating to think that there are probably many studies that have been impacted by not studying "normal" rats. We're studying specific research breeds of stressed rats who're trapped in little boxes for their whole lives. It'd be like if you studied humans who've been trapped in their apartments for the last 4 months and assumed normal psychology and physiology.
> They're required to have some form of environmental enrichment, which means a little wooden rod in every cage that they can play with and chew.
The description you've provided--especially that line--is eerily reminiscent of the "Enrichment Center" from Portal.[0] As that game (humorously) demonstrates, it's unreasonable to expect that the physiology of an animal wouldn't change under those conditions. How much research would've resulted in different outcomes had the animals involved been kept under different conditions?
What a perfect analogy, though that's no doubt intentional in the game's design. Don't forget the "companion cube" that the game not-so-subtly implies the player ought to develop a relationship with haha
That was a really great piece of game design that grew out of a problem picked up in playtesting where some players didn't realize they were meant to keep the cube with them to solve multiple puzzles; they'd leave it behind and then get frustrated on the next puzzle.
So they added a heart to the texture and a few voice lines, and not only was that problem solved but they created one of the most memorable moments in the game by making people care about a cube and then having them get rid of it.
"While it has been a faithful companion, your Companion Cube cannot accompany you through the rest of the test. If it could talk - and the Enrichment Center takes this opportunity to remind you that it cannot - it would tell you to go on without it because it would rather die in a fire than become a burden to you."
Just to add on to this, a proper cage sized for 2 rats is probably going to take up at least a small kitchen table's worth of space. When have you ever seen a cage that size in a research lab? Besides, groups of 2 are the barest minimum you want for keeping rats.
As to the whole "studying stressed out rodents might not give representative results" point, I'm reminded of the Rat Park experiment [0].
The podcast he did with his brother Eric (The Portal #19) gives a very good history of the work he did as a grad student in finding that the telomeres of the lab mice supplied to US labs were elongated due the selective breeding process of producing as many mice as possible.
The implications are quite alarming for existing testing and they talk about how he was basically ignored and the mice quietly fixed.
Weinstein talks about how they are different and why it matters and how significant it is.
Articles like this just talk about how it changes results. Mice aren't people. Cold mice are not hot mice. Stressed mice are not chilled mice. We need to be aware of this and this is a good article and it talks on how to action it, but Weinstein is making a case (right or wrong) for something different and more significant.
I've read many research papers, and the emotionless way they describe doing things like breaking legs, breaking backs and inducing various medical conditions, always bothers me.
I can't see any good alternatives, and I know this is important to advance human medicine, but I can't help but feel it.
Oh, and we never killed mice - we "sacrificed" them (in the lab we said "sacked" for short).
Yeah, it never sat particularly well with me. We and other labs studied neurodegenerative diseases, so we studied a model form of those diseases by inducing it in rats. The Parkinson's lab adjacent to us gave their rats a drug that destroyed their dopaminergic neurons, we inhibited thiamine to cause severe memory impairment. Really horrible things, but I'm not sure that there's a good alternative if we want to study diseases so we can prevent or cure them in humans.
And, some of us are starting to reach our limits due to being boxed up for 4 months. When you study a population, you want to be able to study representative samples of said population. Global conditions for humans are not even close to representative right now. Given the known effects of confinement stress on humans, getting representative population samples for most sorts of studies seems difficult, at best.
We have first hand experienced this - we couldnt induce disease in the same mice when our lab moved universities and we all knew the temperature was one of the biggest culprits.
But there are others too - gut microbiome and other microbiomes/viromes change from facility to facility and this is a huge deal for pretty much every topic except hardcore neuroscience. Probably. Who knew the bugs inside us are a big deal for everything that happens in us!
All of this notwithstanding the growing knowledge that no, you can't just give mice cancer/MS/autism and check if a drug works there, expecting the same result in humans. I'll chalk the majority of problems in our drug pipelines to this fallacy.
> All of this notwithstanding the growing knowledge that no, you can't just give mice cancer/MS/autism and check if a drug works there, expecting the same result in humans.
...to state the obvious, scientists aren't giving drugs to mice and then shipping them off to pharmacies. They're testing the drugs in mice first to see if it's worth testing in humans. Then, the human trials are used to determine efficacy.
It's not a perfect system to be sure, but what is the alternative? Bypass animal testing and go straight to human trials? I'd have a lot of obvious ethical issues with that.
I'd argue that minimally positive results in these experiments should not be taken as any indication that the same therapy will work in humans unless they can convince an _extremely_ skeptical and thorough committee of experts that this result is likely translatable. That would immediately disqualify all xenograft models, and probably most native tumor models as well. So what should we do then? If I have solved it I would be running a successful company selling that secret sauce. But if I were to bet money then I'd say the best approach would be to come up with well thought out in vitro (and some mouse model) experiments that will clearly test all the known ways this drug will interact with every system in the human body; especially the immune system if it's a monoclonal. The emphasis should be on complete declaration of bankruptcy on any hope of a model system showing therapeutic efficacy that's correlated with expected human efficacy.
Test on pets. Seriously our pets get all the same diseases we do (as always there are some exceptions). Millions of pets every year get cancer (just one example) and we make almost no use of this resource.
The other approach is to start testing in humans at a very, very low dose. While this would work it would require a change in the regulatory environment.
Everyone is aware that it's an imperfect model system. We just have nothing better to go off of. Granted, it got us to where are today so it obviously has had practical utility, but we may have exhausted the benefits of simplistic animal models as we try tackle more complex diseases (cancer, neurodegenerative disorders, etc.).
> “It is not easy for an investigator to go and say, ‘I want the room warmer,’” O’Hara said. “They can, but it will probably take multiple efforts, multiple times, and more often than not they will give up.”
In a lot of unis I've been in, the buildings are kinda centrally managed. Steam pipes serving multiple buildings that are often not even enabled during the summer. And in one case, the central management system for that stuff was running on a DOS PC from a vendor who went bankrupt and had no forseeable replacement. Fortunately I'm not around to experience what happens when that box finally can't be repaired.
According to Bret Weinstein who figured out the connection between telomere length and breeding, they seem to have quietly changed the breeding protocols to bring the telomere length back down to be in line with wild type mice. He talks about it in a long interview that gets really interesting about a hour in: https://youtu.be/JLb5hZLw44s?t=4083
For headline news, I think we would need studies that show that this effect changes results from high ranked studies that used mice. But publishing these would be hard in peer reviewed journals because the peers who will referee the papers will likely be researchers whose own previous publications would be questioned by these new results. In the same podcast, Bret talks about the failings of peer review.
Another problem is that even if the results are published, usually it takes a long time for information to diffuse into the wider community. I assume this is largely because finding a novel ideas is like searching for a needle in the haystack of common knowledge that has been spread far and wide.
I think that is Eric's facetious term for what Universities are (a play on the military/industrial complex) but the main problem he points to is the inventivisation through market forces to not release non-monitisable research and that the best researchers don't teach because they are more value to the University generating grant money and basically being salespeople.
The not publishing research was interesting in that holding research in-house, making predictions, getting grants to research those predictions and then using the original unpublished discovery as the basis for the whole lot makes a lot more money.
As I understand it the DISC was a bit more diffuse and while it had tendrils in Universities, it didn't stop there. But yes, that was the main thrust of the DISC in the discussions.
Yes, the perverse incentives of the market play havoc with the spirit of the process of science. Which seems to be the source of the brain drain, in as much as talent leaves the university for the market instead of staying and teaching more talent.
It was interesting to listen to Bret in a podcast talking about whether it was a conspiracy of silence and in describing it as an emergent phenomena rather than being planned he was very much reading from Assange's manifesto on how they form and operate and the need for open government.
> a variety of factors, including researchers’ and technicians’ comfort at those temperatures, have prevented anyone from changing the thermostat.
As long as the temperature is kept consistently cooler for both the experimental and control groups (and whatever other groups), it shouldn't matter, right? Seems to me the problem is the variation and the fact that it's not controlled.
it is very common to see publications such as "regulation of [gene1] expression by interaction with product of [gene2]"
followed by "temperature dependency of [gene2product] regulation of [gene1]"
absolute temperature of culture can confound you into negative results so you will never see the genes activity until the experiment is replicated with culturally disparate subjects. thats just being simple as well, there is normally a continuum of influences and its up to experiment to tease out the largest contributor[s] to the effect of interest
I have read hundreds of research papers, and I don't think I've ever seen one that described the temperature that the rat housing is kept at. It's definitely not something that's controlled for right now.
Oh, totally understood, that clearly ought to change!
My only point was, the article was framing this as an issue of scientist comfort, ie human researchers don't want to work in hot labs. I don't see why they should have to, at least in most cases.
We study rats because they're an inexpensive and ethical replacement for humans, with the assumption that some of the research will carry over to other mammals. It's harder for that work to translate over if we keep them in abnormal environments that affect their behavior or physiology.
Is it even possible not to "keep them in abnormal environments that affect their behavior or physiology"? Putting a rate in a cage alone is an abnormal environment for a rat.
Not if the temperature has an effect on the intervention you are trying to study. Taken to an extreme, you obviously cannot house mice in a freezer and expect generalizable results.
the absolute is also a problem. rats have a hibernative state this is a physiological response to temperature.
The regulation of gene product expression has many factors, temperature being a common one at the biochemical level, and the whle organism physiological level. Hibernation or torpor is an exploitation of thermal dependency of regulation,providing on demand alternative physiological state.
I'm missing something here. What kind of mice have an environment of 30-32 degrees C in the wild? House mice live at the same temperature as people - they might be able to be warmer in their nest, but presumably so can lab mice, without making the room warmer. Are lab mice sourced from some species that is from a hot country?
Regardless of the temperature the mice prefer, obviously it would be a good idea to record the temperature the experiment was conducted at.
Walls may be better insulated, but to accumulate a high temperature you need a source of heat. Where is the source of heat in a wall? For attics you might be on to something as heat rises. Still, 30 degrees seems a lot to me.
Okay, I concede that Attics could be 30 degrees, at least some of the time :-)
Mine probably isn't because the insulation is on the 'floor' of the attic, so it should be approximately the same temperature as the outside air (well, if it were ventilated properly). This is one of the design choices of an attic. Still, I do wonder if this provides enough hot spaces for mice to have evolved to expect a 30 degrees environment. Maybe they do in some places.
The claim is that the walls can be hotter than the room around it. By the second law of thermodynamics, heat doesn't naturally move from a cooler object to a hotter object, or as Flanders and Swann would put it, "heat don't move from a cooler to a hotter" (https://youtu.be/VnbiVw_1FNs?t=127)
> The National Academy of Sciences recommends housing mice between 20 and 26 degrees Celsius — about 68 to 79 degrees Fahrenheit. But the natural comfortable temperature for mice is warmer — between 30 and 32 degrees Celsius (86 to 90 degrees Fahrenheit).
I didn't see an explanation of why this recommendation is below the "comfortable temperature" of mice. Is there a specific reason this temperature is recommended?
I dont have an answer, but could be for same reasons why hospitals keep it on the cooler side: Less fungal / bacteria growth. Less mites, insects, bugs, etc.
1) The recommended temperature in the lab is based on other factors than the mice's prefered temperature. E.g. comfort of the scientists and technicians, spread of bacteria etc.
2) The temperature prefered by mice was determined by studying them in the wild or in the lab. E.g., if given the choice between two places of different temperature, which do they pick?
Lab lighting can also skew the outcomes. Rats exposed to constant white light, for example, have elevated baseline corticosterone concentrations in plasma (Scheving & Pauly, 1966).
There are a few of such variables which it's not clear are taken into account or not, and probably more are unknown.
The idea is intriguing but lab mice have also plenty of food and in warm blooded animals this, and the proximity of other mice, should provide the extra heat.
I can confirm that lab mice in our mouse house are alway huddled up together.
Our lab studies E. coli, and mice require pre-treatment to permit intestinal colonization by E. coli. However, about 2 in 5 mice are colonized without antibiotic pre-treatment. I wonder if these are the the colder and more stressed out mice (outside the cuddle puddle).
That's a good point that this is not a new phenomenon. I am aware of some labs that do keep mice at warm temperatures already so maybe the scientific community already managed to make changes in some places.
There was a large room for housing rats for all of the labs in the building - mostly Sprague Dawley, which are very well studied at this point and chosen because they're easy to care for. The room was nowhere near 20 - 26C. It felt like walking into a fridge.
I think there are more problems than just the temperature that rats are kept at.
There are requirements for minimum standards of housing for animals - every university that does animal experimentation is required to have a LAR (lab animal resources) officer who verifies compliance. But researchers have to be frugal with money (even grad students are expected to live on a 20-30k research stipend), so they really do the bare minimum. Cages are as small as they can be, and rats are housed in pairs so that they can socialize, but their cages are almost barren. They're required to have some form of environmental enrichment, which means a little wooden rod in every cage that they can play with and chew.
It's frustrating to think that there are probably many studies that have been impacted by not studying "normal" rats. We're studying specific research breeds of stressed rats who're trapped in little boxes for their whole lives. It'd be like if you studied humans who've been trapped in their apartments for the last 4 months and assumed normal psychology and physiology.
The description you've provided--especially that line--is eerily reminiscent of the "Enrichment Center" from Portal.[0] As that game (humorously) demonstrates, it's unreasonable to expect that the physiology of an animal wouldn't change under those conditions. How much research would've resulted in different outcomes had the animals involved been kept under different conditions?
[0]: https://en.wikipedia.org/wiki/Portal_(video_game)
So they added a heart to the texture and a few voice lines, and not only was that problem solved but they created one of the most memorable moments in the game by making people care about a cube and then having them get rid of it.
"While it has been a faithful companion, your Companion Cube cannot accompany you through the rest of the test. If it could talk - and the Enrichment Center takes this opportunity to remind you that it cannot - it would tell you to go on without it because it would rather die in a fire than become a burden to you."
As to the whole "studying stressed out rodents might not give representative results" point, I'm reminded of the Rat Park experiment [0].
---
[0]: https://en.wikipedia.org/wiki/Rat_Park
The implications are quite alarming for existing testing and they talk about how he was basically ignored and the mice quietly fixed.
Weinstein talks about how they are different and why it matters and how significant it is.
Articles like this just talk about how it changes results. Mice aren't people. Cold mice are not hot mice. Stressed mice are not chilled mice. We need to be aware of this and this is a good article and it talks on how to action it, but Weinstein is making a case (right or wrong) for something different and more significant.
I can't see any good alternatives, and I know this is important to advance human medicine, but I can't help but feel it.
Yeah, it never sat particularly well with me. We and other labs studied neurodegenerative diseases, so we studied a model form of those diseases by inducing it in rats. The Parkinson's lab adjacent to us gave their rats a drug that destroyed their dopaminergic neurons, we inhibited thiamine to cause severe memory impairment. Really horrible things, but I'm not sure that there's a good alternative if we want to study diseases so we can prevent or cure them in humans.
But there are others too - gut microbiome and other microbiomes/viromes change from facility to facility and this is a huge deal for pretty much every topic except hardcore neuroscience. Probably. Who knew the bugs inside us are a big deal for everything that happens in us!
All of this notwithstanding the growing knowledge that no, you can't just give mice cancer/MS/autism and check if a drug works there, expecting the same result in humans. I'll chalk the majority of problems in our drug pipelines to this fallacy.
...to state the obvious, scientists aren't giving drugs to mice and then shipping them off to pharmacies. They're testing the drugs in mice first to see if it's worth testing in humans. Then, the human trials are used to determine efficacy.
It's not a perfect system to be sure, but what is the alternative? Bypass animal testing and go straight to human trials? I'd have a lot of obvious ethical issues with that.
The other approach is to start testing in humans at a very, very low dose. While this would work it would require a change in the regulatory environment.
Are you going to be happy with a researcher coming to your home and breaking your dog's back? Or injecting it with toxins to induce neuropathy?
There is even a class of them called psychobiotics.
In a lot of unis I've been in, the buildings are kinda centrally managed. Steam pipes serving multiple buildings that are often not even enabled during the summer. And in one case, the central management system for that stuff was running on a DOS PC from a vendor who went bankrupt and had no forseeable replacement. Fortunately I'm not around to experience what happens when that box finally can't be repaired.
Another problem is that even if the results are published, usually it takes a long time for information to diffuse into the wider community. I assume this is largely because finding a novel ideas is like searching for a needle in the haystack of common knowledge that has been spread far and wide.
The not publishing research was interesting in that holding research in-house, making predictions, getting grants to research those predictions and then using the original unpublished discovery as the basis for the whole lot makes a lot more money.
Yes, the perverse incentives of the market play havoc with the spirit of the process of science. Which seems to be the source of the brain drain, in as much as talent leaves the university for the market instead of staying and teaching more talent.
As long as the temperature is kept consistently cooler for both the experimental and control groups (and whatever other groups), it shouldn't matter, right? Seems to me the problem is the variation and the fact that it's not controlled.
https://en.wikipedia.org/wiki/Rat_Park
followed by "temperature dependency of [gene2product] regulation of [gene1]"
absolute temperature of culture can confound you into negative results so you will never see the genes activity until the experiment is replicated with culturally disparate subjects. thats just being simple as well, there is normally a continuum of influences and its up to experiment to tease out the largest contributor[s] to the effect of interest
My only point was, the article was framing this as an issue of scientist comfort, ie human researchers don't want to work in hot labs. I don't see why they should have to, at least in most cases.
Regardless of the temperature the mice prefer, obviously it would be a good idea to record the temperature the experiment was conducted at.
I would guess that the interiors of walls and attic spaces are a good bit warmer than the open portion of a room where we live.
It was perhaps 22C at my home yesterday, and by chance I had to get something from the loft - I'd be surprised if it wasn't 30C.
Mine probably isn't because the insulation is on the 'floor' of the attic, so it should be approximately the same temperature as the outside air (well, if it were ventilated properly). This is one of the design choices of an attic. Still, I do wonder if this provides enough hot spaces for mice to have evolved to expect a 30 degrees environment. Maybe they do in some places.
Hmm, mine too.
> Still, I do wonder if this provides enough hot spaces for mice to have evolved to expect a 30 degrees environment
Yeah, this does seem quite questionable to me too, at least for temperate countries.
The rooms around it.
[1]
I didn't see an explanation of why this recommendation is below the "comfortable temperature" of mice. Is there a specific reason this temperature is recommended?
Anyway, here is my guess for the two questions:
1) The recommended temperature in the lab is based on other factors than the mice's prefered temperature. E.g. comfort of the scientists and technicians, spread of bacteria etc.
2) The temperature prefered by mice was determined by studying them in the wild or in the lab. E.g., if given the choice between two places of different temperature, which do they pick?
There are a few of such variables which it's not clear are taken into account or not, and probably more are unknown.
The article is from 2016 in any case
Our lab studies E. coli, and mice require pre-treatment to permit intestinal colonization by E. coli. However, about 2 in 5 mice are colonized without antibiotic pre-treatment. I wonder if these are the the colder and more stressed out mice (outside the cuddle puddle).
I'm not an expert on mice but that doesn't sound like a good thing.