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Medicine Science

Drug Testing In Mice May Be a Waste of Time, Researchers Warn 148

Posted by Soulskill
from the research-sponsored-by-mice dept.
An anonymous reader writes "A group of researchers including Dr. H. Shaw Warren of Mass. General Hospital and Stanford genomics researcher Ronald W. Davis have published a paper challenging the effectiveness of the 'mouse model' as a basis for medical research, based on a decade-long study involving 39 doctors and scientists across the country. In clinical studies of sepsis (a severe inflammatory disorder caused by the immune system's abnormal response to a pathogen), trauma, and burns, the researchers found that certain drugs triggered completely different genetic responses in mice compared with humans. The Warren-Davis paper was rejected by both Science and Nature before its acceptance by the Proceedings of the National Academy of Science, perhaps suggesting the degree to which the 'mouse model' has become entrenched within the medical research community. Ninety five percent of the laboratory animals used in research are mice or rats. Mice in particular are ideal subjects for research: they are cheap to obtain and house, easy to handle, and share at least 80 percent of their genes with humans (by some reckoning, closer to 99 percent). Over the past twenty five years, powerful methods of genetically engineering mice by 'knocking out' individual genes have become widely adopted, so that use of mice for drug testing prior to human clinical trials has become standard procedure."
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Drug Testing In Mice May Be a Waste of Time, Researchers Warn

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  • by h4rr4r (612664) on Tuesday February 12, 2013 @01:28PM (#42873661)

    A mouse can't even roll a joint, much less handle a lighter. Nor do they make syringes that small.

    Why was anyone suspecting their mice of using drugs in the first place?

    • A mouse can't even roll a joint, much less handle a lighter.

      This is why mice use vaporizers.

    • by BRGeek (2734365)

      No Mod points left or this would have one from me.

    • by rwyoder (759998)

      Why was anyone suspecting their mice of using drugs in the first place?

      It's because of that mouse that admitted it all in an interview with Oprah.

    • by FlopEJoe (784551)
      Plus the tests were culturally biased against inner city mice.
    • A mouse can't even roll a joint, much less handle a lighter. Nor do they make syringes that small.

      Why was anyone suspecting their mice of using drugs in the first place?

      I work for a background screening and drug testing company. Now ^^^ that's ^^^ funny, right there!

    • Because they were hanging out in the dead ends in the maze.
  • Rejection (Score:5, Insightful)

    by Anonymous Coward on Tuesday February 12, 2013 @01:29PM (#42873671)

    >> The Warren-Davis paper was rejected by both Science and Nature before its acceptance by the Proceedings of the National Academy of Science, perhaps suggesting the degree to which the 'mouse model' has become entrenched within the medical research community.

    Or maybe it was rejected because it isn't a good paper? Just a thought.

    • Aren't there some quotas for printed pages? If there are many good candidates, what do they do with the leftovers? Those don't necessarily have to be bad papers.
      • Re:Rejection (Score:5, Informative)

        by Silas is back (765580) on Tuesday February 12, 2013 @01:52PM (#42873995) Homepage Journal

        Science's and Nature's rejection rates are very high, there are just this many articles they can publish every week, 15 to 20 for Nature. Almost every paper gets rejected on the first draft, good ones are encouraged to resubmit after revisions. It can take a few years to get your paper into one of these journals, that's what makes the papers of highest quality -- not to be confused with "certainly true", even high quality research can turn out to be wrong.

        The leftovers get resubmitted to lower-ranked journals; that's what you usually do if you want to submit something, you aim for a high ranked journal and hope to get in, if not you revise and resubmit or submit to another journal.

        • by WillAffleckUW (858324) on Tuesday February 12, 2013 @02:35PM (#42874507) Homepage Journal

          Exactly. I've worked with some labs that got original biological and biochemical papers published in both Science and Nature, and it's very hard to get in those. Even with new biochemistry or new biology.

          Try publishing a paper on methodology of statistical inference. That's not easy at all.

          • by repapetilto (1219852) on Tuesday February 12, 2013 @03:37PM (#42875075)

            Its very hard to publish there, but the quality of publications is not that high, possibly even lower than elsewhere if you measure by false positive rate. There is a mass failure to understand the importance of the assumptions underlying statistical inference (as you mentioned), as well as the importance of completely reporting your methods and data so that it is possible for others to intelligently draw their own inferences and replicate your work. In short, those journals have a culture that encourages "sexy" and "conclusive" results at the expense of the fundamental basis for successful science that we learn in gradeschool.

            • That, plus you need to have some sexy pictures. Not sure why, but it helps increase acceptance.

              OK, you might not think a picture of beta sheets is sexy, but they do.

      • Aren't there some quotas for printed pages? If there are many good candidates, what do they do with the leftovers? Those don't necessarily have to be bad papers.

        My understanding is that researchers shop them around, and that the large number of available journals, some more prestigious than others, and some more narrowly focused than others, is supposed to handle that(there has been some concern, especially regarding papers with negative results, that it may not do so optimally in some respects). If a paper is rejected from the very high prestige, relatively broad journals, it can work down the list toward journals more narrowly focused on its exact topic, and/or w

    • by Anonymous Coward

      Or more likely it was rejected because it was not a true Scotsman.

    • Being rejected by Science and Nature doesn't say much about the paper, other than the editors didn't want it in their magazine. Many possible reasons exist for this. These journals are very picky on the timeliness of the topic of research. Maybe they didn't think it was sexy enough.

      Also I must add that the summary takes liberty with the point of "challenging the effectiveness of the mouse model as basis for medical research." Clearly mice share some physiology and developmental characteristics with humans

      • But PNAS is dodgy... Was it really peer-reviewed or was it invited?

        It is true however that Science and Nature will publish on the grounds of sexyness above all consideration, sometimes at the expense of being actually correct. Also, there is a tendency to discount papers showing a mechanism in humans which is already known in mouse, despite the fact that there was no garantee of commonality and the fact that experiments using human cells are much harder.

        I guess there is some underlying truth to the fact tha

        • PNAS isn't 'dodgy', but it has a different twist. If you are a member of the NAS (not easy to do) you have a bit of influence - certainly not all that much - to get people to review the paper. It serves as a bit of an old boys club, but it also serves as an additional foil to the insular tendencies of Nature and Science. To be fair, there is so much published that it's hard to pick the winners all of the time. It's not even necessary. Good research tends to get out, maybe not as fast as some would like

          • Oh, no, if you are a member you can get paper passed pretty much without review. But I agree that godd research tends to get out, and I certainly have no particular sympathy for the hype-oriented selection process of Nature and Science.

        • by TheCarp (96830)

          > I guess there is some underlying truth to the fact that no-one wants too much questionning of the
          > usage of mouse models. The alternatives are much farther away from humans, or emotionally
          > difficult to work with (cat models are great I hear, but unsurprisingly no one wants to do to cats what
          > is commonly done to mice...)

          I personally know people who have done this sort of work with dogs. I have also worked in (not as a lab tech or scientist, but in the lab and around the people who were) labs

    • by JoeMac (102847)
      I agree. There are many alternative scenarios for rejection that the submitter did not mention, although we must admit the possibility that it was rejected for the suggested reason (community reticence and its significant funding implications). It's hardly a perfect process. PNAS isn't exactly slumming it, though.
    • by pesho (843750)

      >> The Warren-Davis paper was rejected by both Science and Nature before its acceptance by the Proceedings of the National Academy of Science, perhaps suggesting the degree to which the 'mouse model' has become entrenched within the medical research community.

      Or maybe it was rejected because it isn't a good paper? Just a thought.

      I would say it is a very good paper, but Science and Nature have somewhat higher benchmark for accepting papers: the paper has to be truly innovative and to open new directions for research. The PNAS paper that the post links to is very well research and convincingly shows how bad the mouse models for sepsis are in representing the human disease. Well, we know that animal models have quirks and some are really bad, and some are really good. So this is one more addition to the first list, which is very impo

      • The benchmark is not "higher". It could be said to be higher if the papers needed to meet proper scientific criteria as well as being truly innovative. The benchmark is different. The perceived "innovation" aspect is used at the expense of other qualities of good scientific reports (ie using statistics properly and reporting all your methods and data).

        • by pesho (843750)
          I agree with you. "Higher" wasn't the best choice of words, and I have had my encounters of irreproducible and not well supported but otherwise "innovative" discoveries in Science.
    • by sycodon (149926)

      The paper was torpedoed by Big Mice.

      They stand to lose billions I bet if they stop testing on mice.

  • Are they using synthetic urine to pass their tests now, too?
    • Are they using synthetic urine to pass their tests now, too?

      Have to. Their pH is insane!

    • by Sulphur (1548251)

      Are they using synthetic urine to pass their tests now, too?

      No, but they have a hard time maintaining a realistic temperature that doesn't trigger alarms. Borrowed is good as long as its not from a hamster.

  • How many (Score:5, Insightful)

    by canadiannomad (1745008) on Tuesday February 12, 2013 @01:39PM (#42873799) Homepage

    I often wonder how many drugs we reject long before human trials because some researcher used the wrong animal to test.

    Also an obligatory SMBC comic [smbc-comics.com]

    • Was about to post the same thing... damn you.
    • Folks have been working to produce inbred lines of pigmy marmoset for use as an improved model for drug testing. It has a 2-3 year life cycle, making it much more useful than typical primate (rhesus monkey, chimpanzee, etc) studies for early stage work like mice are used for. Unfortunately, there's still a lot of work before people will be using them instead of mice.
    • Undoubtedly an extremely small fraction of the number of cases in which the opposite happens: drug shows promise in cell culture or mouse trials, has no effect in humans or is toxic.
    • I often wonder how many drugs we reject long before human trials because some researcher used the wrong animal to test.

      Also an obligatory SMBC comic [smbc-comics.com]

      No kidding.

      Trial Drug 1035832B:

      Side effects in mice: Congenital defects, swelling of the urethra, kidney failure, liver failure, seizures, heightened blood pressure with occasional heart attacks, loss of vision and motor function, death.

      Side effects in Humans: Occasional diarrhea.

    • by blivit42 (980582)
      I can somewhat answer the inverse of this question, though: "How many drugs do we reject in clinical trials because some researcher used the wrong animal model to test?"

      My memory is a little fuzzy on the exact number from when I worked in the industry, but something like 70% of all drugs that pass Phase 1 trials fail in Phase 2 trials. Phase 1 trials are small and test for safety problems, and Phase 2 trials expand to a larger cohort to test for efficacy -- does the drug work. The pharmaceutical industr
  • by schneidafunk (795759) on Tuesday February 12, 2013 @01:40PM (#42873813)
    I found this in the article particularly interesting:

    Yet there was always one major clue that mice might not really mimic humans in this regard: it is very hard to kill a mouse with a bacterial infection. Mice need a million times more bacteria in their blood than what would kill a person.

    “Mice can eat garbage and food that is lying around and is rotten,” Dr. Davis said. “Humans can’t do that. We are too sensitive.”
  • Medical research or research to justify social policy is meaningless. The outcome is determined before the experiments begin.
    • Is so-called 'objective reality' also a social construct?

      • by gstoddart (321705)

        Is so-called 'objective reality' also a social construct?

        Only to those people who find objective reality gets in the way of the reality they prefer.

        If you can convince the rubes that objective reality is just an opinion, you can say anything.

        • Is so-called 'objective reality' also a social construct?

          Only to those people who find objective reality gets in the way of the reality they prefer.

          If you can convince the rubes that objective reality is just an opinion, you can have any job in education you wish.

          Tidied that up just a hair. :)

      • Is so-called 'objective reality' also a social construct?

        The parent comment is why teachers want you to "show your work", objective reality is where teachers lose consciousness with a bottle of booze in front of the television, or, you know, just give you a C- for the hell of it because they TOTALLY understood your non-linear thought. ;)

    • Medical research or research to justify social policy is meaningless. The outcome is determined before the experiments begin.

      You just mixed together medical research, which is why lots of things don't kill you anymore, with a fake category.

  • by fuzzyfuzzyfungus (1223518) on Tuesday February 12, 2013 @01:51PM (#42873989) Journal

    So, any word on how we managed to get from 'researchers identify class of conditions for which mice are an unexpectedly lousy model' to 'drug testing in mice may be a waste of time'?

    • I am somewhat confused by that leap of logic, too. I am afraid people will use this interesting work to support the idea that mice are not a good model to study anything human-related. TFS is pointed this direction anyway...
    • So, any word on how we managed to get from 'researchers identify class of conditions for which mice are an unexpectedly lousy model' to 'drug testing in mice may be a waste of time'?

      I blame the cat and dog lobbies. They never liked mice.

    • by gstoddart (321705)

      So, any word on how we managed to get from 'researchers identify class of conditions for which mice are an unexpectedly lousy model' to 'drug testing in mice may be a waste of time'?

      Well, one of the linked articles says:

      The study's findings do not mean that mice are useless models for all human diseases. But, its authors said, they do raise troubling questions about diseases like the ones in the study that involve the immune system, including cancer and heart disease.

      It may well be a case of either the subm

      • The study certainly does suggest that mice(and some mouse findings) are much more troublesome than previously suspected. On the plus side, the methods that they used to establish that there was a real problem with mice(the examination of gene expression under the various conditions) seem like they might also be broadly applicable for examining the problem of what is and isn't a good model organism for a given problem...

        Obviously, in an ideal world further research would confirm that you are on the right tra

    • So, any word on how we managed to get from 'researchers identify class of conditions for which mice are an unexpectedly lousy model' to 'drug testing in mice may be a waste of time'?

      Honestly, that sounds like another way of saying "we don't know what to effing do now. We have no test Humans!"

      You know, capital punishment should include the obligatory 'island of murder/rape/pedophile criminals', but instead of serving time ad nauseam, you get to be randomly picked for drug trials.

  • Any volunteers to have doctors intentionally give you blood poisoning, then take experimental drugs to cure it? Keep in mind that a quarter of those TREATED for sepsis will die, and naturally you wouldn't be able to take other treatments or that would cloud the results. So you'll die of sepsis, unless the drugs they're testing kills you first.

    Anyone volunteering, you've clearly got some problems and would be unsuitable to study anyway. And forcing people to participate in the research and letting them
    • Anyone paying any attention to biomedical research knows that if some amazing cure is demonstrated in mice, it will likely never be heard of again since it didn't pan out.

      OTOH, if it's not demonstrated in mice, it's even more likely never to be heard of again. ;)

    • it's also important to realize that drug testing in mice IS necessary.

      See that is the part I don't understand... Why must it be mice? And how many drugs have a negligible effect in mice, but would work well in humans, or have a toxic effect in mice, but only minor side effects in humans? These days the drug would be overlooked or rejected. Humans are not mice... How often are we overlooking good drugs because of bad animal models?

      I get the point, we need to protect humans first, and not be doing stupid/dangerous tests on humans just for the sake of science. I think, for m

      • See that is the part I don't understand... Why must it be mice?.

        Because mice have short life spans, are cheap, are easy to squish between plates to test, and people don't go wonky on you researching on mice.

        That's "why".

      • Tissue culture is more expensive than mice in many cases. I'm not sure circulatory systems are well modeled in tissue culture yet anyway. So few agencies would be willing to fund it, they'd say "why don't you just do it in mice." At least, before this study.
    • Researchers already knew that mice models were far from perfect. Anyone paying any attention to biomedical research knows that if some amazing cure is demonstrated in mice, it will likely never be heard of again since it didn't pan out. It's important to realize if one hadn't already that mice weren't perfect models for humans, but it's also important to realize that drug testing in mice IS necessary.

      This isn't directed at you, but I don't understand the logic, and never will, where you can use an animal with a DNA model that is different from the animal that will be using the drug. Sure, it can show some serious negative effects or positive ones, but the DNA difference can also give you a laboratory set where one animal has 130 side effects (including death or worse), and the other has zero or one.

      Chemistry is a little more complicated with animals than it is with test tubes.

  • by Daniel Dvorkin (106857) on Tuesday February 12, 2013 @01:55PM (#42874045) Homepage Journal

    As a 13 year veteran of academic science, and a 3 year veteran of a pharmaceutical company, I can personally attest that scientists disagreeing on matters of great significance, difficulty publishing publishing what one believes to be important work, exasperation at peer review, and unending questions about the ability to translate findings in mice to humans are everyday concerns. I know of no scientist who has not faced criticism from their peers, despite how well respected they may be. I know of no scientist who has not had their papers rejected only to complain that the reviewers just didn't "get it." And contrary to what this article may assert, questions about how well mouse models recapitulate human disease are frequent topics of conversation. To read this article one would think that the scientific enterprise had never considered the notion that mice and humans are not equivalent. What a complete misdirection from reality.

    This article takes the tone of a courageous and noble researcher struggling valiantly against an entrenched evil empire intent on stifling dissent. While this may be a good approach for a movie, it should have no place in serious discourse from a reputable organization like the NYT. A pragmatic discussion of the research and implications are in order, not the quasi-sensationalist man vs empire approach taken here.

    It's really important to remember this, because people just eat the "courageous and noble researcher struggling valiantly against an entrenched evil empire intent on stifling dissent" narrative up, and it's hardly ever the way things actually work. Most important discoveries in science, positive or negative, have been building for years in the field--with many, many people on both (or all, as the case may be) sides of the debate--before they ever reach the public eye.

    • by jfengel (409917)

      Sadly, the New York Times isn't all that much better at science reporting than other general newspapers. It's better than tabloid journals, of course, but they're still scanning science with an eye to making Big Exciting News rather than the incremental work that makes up the vast majority of science. Which makes them prone to blowing things out of proportion on the slow science news days (i.e. most days).

      Honestly, when it comes to science stories, I wait until I see it in a dedicated science source such as

    • by luckymutt (996573)

      it should have no place in serious discourse from a reputable organization like the NYT.

      BWAHAHAHAHAHAHAHAHA!!!!!!!!!!!!!!!!!

  • by WillAffleckUW (858324) on Tuesday February 12, 2013 @02:00PM (#42874107) Homepage Journal

    1. Mice have no lobby.

    2. Mice have shorter lifespans.

    3. You freak out every time we use chimps or human analogues in the simian world.

    4. Mice are easier to squish between plates to measure changes, especially when we use flourescent tags on the meds or target we're looking at, so we don't have to cut them up to find out what's going on.

    (yes, my point 4 is really what happens - we used to cut them up before we figured out how to make them glow with jellyfish gene tags - and once you cut open the brain, it's game over)

    • Mice are cheap, ubiquitous, readily available, and have very low genetic variation between samples (unless variation is purposefully induced.)

      • A lot of the cheap part is they are small. If there was a variant of human that didn't have intelligence and was small and had a short life span we'd probably use that, if we're looking at medical drug experiments.

        • by rahvin112 (446269)

          Your branching off into a discussion that's teeming with ethical concerns. In fact we have the ability right now to make "human" mice, or in other words mice with human organs and genes. These mice don't exist (in wide use) right now because of the ethical concerns.

          You might find it silly, but there are people that don't even want mice with human organs because of the ethical and moral (read religious) concerns of creating such an organism.

    • 1. Mice have no lobby.

      Oh, God. Don't let animal activists read this or even mice won't be valid test subjects anymore.

      Wait.... Keep talking. ;)

  • by sirwired (27582) on Tuesday February 12, 2013 @02:09PM (#42874231)

    The Researchers did not warn that "Drug Testing in Mice May Be a Waste of Time"; they suggested that Drug testing for drugs for sepsis, trauma, and burns may be a waste of time. The discovery was that the process that induces death in humans for those problems (capillary leakage leading to uncontrollable blood pressure loss) works differently in mice vs. humans, and therefore, for those specific conditions, the mouse model is of limited usefulness. The discovery was NOT: "Drug tests in mice are pointless."

    It has been known for some time that the mouse model is not universally applicable; it's finding those times when it's not that is tricky. We still use mice because they are much cheaper than the alternatives... using the alternatives when not necessary would drive up research costs.

  • by mutube (981006) on Tuesday February 12, 2013 @02:20PM (#42874351) Homepage

    TFA doesn't say what the headline says it does.

    Even if did say that, as someone working in medical research, I can vouch for the fact that the first question to follow any claims of something working in an animal model is "so what about in humans". It's a running joke that we can cure every disease known to man - in mice. But that's what a model is: a controlled, repeatable, system in which to roughly test hypothesis before moving onto the real subject.

    • That joke is there because the "cures" are most often based on faulty statistical inference. A closer look at much of the data will reveal the cure did not exist for mice in the first place, the results were just much more likely to occur by chance than conveyed by the literature. The issue of mice not being completely analogous to humans is an issue faced by researchers but it is being used to hide failure to correctly report and interpret the results of studies (systemic incompetence). All the evidence po

  • Everyone knows you need to expose the mice to radioactive waste before their genes come anywhere close to resembling human genetics. After that, then you can think about doing trauma and burn research on them. However, last I heard, that research department was raided by some ninjas. No one knows quite what happened.
  • The one thing we learned is that medical research causes cancer in mice.

  • ...These little guys can get up to some crazy stuff, http://www.youtube.com/watch?v=WP60WCrQl4U [youtube.com] No wonder they are poor models for drug use. Think of the children. Wait, what? Awesome dude.
  • I remember when doing addiction research I treated my rats so well and allowed them time for social interaction, just because that's the way I am and I couldn't stand the way other researchers treated their animals.

    The problem with this? I could NOT get the rats to self administer any drugs.

    That really doesn't matter when you're slicing brains to map out pathways, however it is telling us something more important. Social animals that socialize don't take drugs.

    • That really doesn't matter when you're slicing brains to map out pathways, however it is telling us something more important. Social animals that socialize don't take drugs.

      That's called extrapolating beyond the data. If you go to a bar, you'll find that some social animals take drugs while socializing with great consistency.

      • by Jmc23 (2353706)
        Depends if you're using laymen's terms. A properly socialized individual doesn't require drugs to 'be social'.

        There are studies both with rats and humans that point this out. I'm just mentionning my experience because even having read the studies I didn't quite believe it.

    • by Hatta (162192)

      Social animals that socialize don't take drugs.

      Explain hippies.

      • by Jmc23 (2353706)
        Drugs were needed to open the individual enough to be social. Are they really socializing though, i.e., making meaningful connections. Most hippies almost don't recognize any/differences between the people they interact with. Is that really socializing?

        Ever meet an ex-hippie? They'll either close way back up again or they'll finally be in/a place where the fear of opening up isn't there anymore. Just/think of how sad it is that saying "i love you" is almost taboo in most societies and cultures.

  • Mouse testing is cheap and easy. Even if it doesn't work half the time and differs significantly from human reactions, it's still worth doing because you learn quite a bit from it. The only thing that would be unfortunate is if you reject a safe and effective drug prematurely based on a mouse model, but I'd guess that's pretty rare.

  • Mice aren't humans, human experimentation is still morally objectionable and illegal, and medical testing on primates / apes is much more expensive and considerably less ethical in most people's minds. It's important to note where mouse research fails to properly recapitulate human biology, but sensationalist journalism acting as though the animal rights crowd is finally vindicated in proving, through a few heroes in the scientific community, that animal testing is cruelty without merit is harmful to the fi
    • by dhomstad (1424117)

      Like you said - no reason to test the mouse-toxic drugs on human beings before chimpanzees. I'm guessing you wouldn't have to match the sample size, or kill the same amount of chimpanzees, compared with testing on mice.

      I'm confused with the resistance on drug testing in animals. Like Bastiat said, you always have to consider the "unseen." If you aren't drug testing on animals, you are forgoing the knowledge received from said testing. Would you stop killing thousands of mice per day via drug testing if it

  • Last time I checked, drug testing on(in?) mice wasn't the only step in passing a drug through the FDA. Actually, I haven't done much checking, but I do believe big pharma has to perform clinical trials on humans before giving the "OK GO" to manufacture & mass distribute drugs for general public

    From a pharmacology perspective, it would be a good thing to know that mice react differently from humans. More importantly - how do they differ, and for what reasons? For instance - maybe some drugs have severe s

  • This has the potential to be a genuinely big deal if the results hold up. Despite the article’s somewhat misleading title, the paper’s authors are not suggesting that we should just throw away the mouse model. They are saying that in one limited area, the treatment of sepsis (burns and trauma are also mentioned, but the emphasis is on sepsis) the mouse may not be the best organism to use as a model. According to their research, mice respond to sepsis in an entirely different manner than humans,
  • How can we ever trust the legitimacy of the Mouse Olympics results if we don't tests the medalists for doping?
  • We have cured Alzheimers in transgenic model mice at least thrice to my last count. Not one of these drugs have shown significant benefits in Phase III trials.

  • they shouldn't be used for testing. The 10th mouse is actually the inventor of the Pan Galactic Gargle Blaster, and also has 42 good reasons to recommend mice as the perfect lab experiment creatures.

This is clearly another case of too many mad scientists, and not enough hunchbacks.

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