The trouble with mice as behavioral models

The trouble with mice as behavioral models for Alzheimer’s – STATBy Adam Rosenberg – Apr 2019

It is becoming increasingly obvious that rodents cannot accurately model human diseases, let alone human behaviors.

I’ve always doubted the findings of pain studies that use rodents because these animals cannot possibly model what is claimed to be a bio-psycho-social syndrome.

There’s been a lot of talk about overinvestment in interventions aimed at amyloid in the weeks since Biogen discontinued a late-stage study of aducanumab, an experimental therapy for Alzheimer’s disease.

Although much of the focus has been on the amyloid hypothesis at the heart of that work — and other failed treatments — I believe we are overlooking another key driver for numerous translational failures:

the overreliance on behavioral readouts from contrived transgenic rodent models to guide drug development for Alzheimer’s, Parkinson’s, and other neurologic diseases.

We need to find ways to move beyond this flawed paradigm.

In many areas of drug development, the most important preclinical metric is whether the compound showed signs of efficacy in an animal model, most often mice.

This makes sense for some diseases, and for certain forms of data. In movement disorders, for example, motor dysfunction is arguably conserved between mouse and human.

Similarly, if an agent heals a wound in a mouse, it’s reasonable to assume it may do the same in people.

But this breaks down when it comes to neurologic disorders that manifest themselves in distinctly human cognitive and functional behaviors.

And pain is exactly such a neurologic disorder, with distinctly human cognitive and functional behaviors. There’s no way to model human behavior in any other creature.

It is hard to argue with a straight face that assessing how speedily mice find their way around a maze appropriately models the complex interplay of cognitive, behavioral, and functional symptoms in human diseases such as Alzheimer’s or autism spectrum disorder.

What seems obvious to me is that the animal model paradigm is broken when it comes to complex neurologic diseases.

Let’s start with the highly inbred mouse models largely used for this kind of work. They lack the genetic diversity that may contribute to the severity and complexity of Alzheimer’s and other complex diseases in people.

This is arguably one reason why many preclinical studies in rodent models have failed to translate to humans.

A recent paper in the journal Neuron illustrates this point

it is impossible to model in mice all of the complex environmental inputs — everything from nutrition to education to exercise levels — that affect cognition, function, and behavior in people with neurologic disorders.

This is especially true for studies on opioids.

On the one hand, the “experts” insist chronic pain is a biopsychosocial issue, on the other hand, they assume studies on mice that lack all these psychological and sociological features can be applied to humans.

We’ll never know how many compounds were moved into the clinic based on questionable behavioral data. We’ll also never know how many otherwise promising compounds were shelved for failure to show “efficacy” in improving cognition in a flawed mouse model.

I am confident that the next decade of neuroscience research and development will be better than the last — as long as we don’t continue overinvesting in mechanisms that have proved fruitless and as long as we don’t continue to use behavioral data from contrived mouse models as a critical gatekeeper before clinical trials.

It’s time for the industry to evolve. We should start by taking a hard look at old paradigms.

Author: Adam Rosenberg is the president and chief executive officer of Rodin Therapeutics, a company based in Cambridge, Mass., aimed at discovering and developing therapies to enhance synaptic integrity to treat neurodegenerative, neurodevelopmental, and neuropsychiatric diseases

4 thoughts on “The trouble with mice as behavioral models

  1. Kathy C

    The media loves misreporting the findings of these mouse model “studies.” Mouse models finding can be the basis for some really sensationalist findings. These finding are really good Click Bait, and often used for advertising, public relations and even fundraising for academic institutions. Mouse studies, like other misleading and misreported studies can be extrapolated to mean almost anything.

    Certain industry interests are seeking to do away with mouse studies, since they can be deceptive. Originally mouse studies were meant to study the toxicity of compounds, in the most general sense. Since then they have expanded to all kinds of research including chronic pain. A majority of the research on complex disorders like chronic pain, Alzheimer’s and human psychology were designed to deceive, and make headlines for advertising purposes.

    The mouse studies on chronic pain, follow a pattern. They damage a limb on the mouse, or put them on a hot plate to determine their reaction times. None of this even approaches the human experience of chronic pain, yet these studies are used to mislead the public on the nature of chronic pain, a long term condition that impairs all areas of ones life. Humans with chronic pain experience years of denial, Gas Lighting, inability to engage in work and social activities, and awareness of their situation. None of this compares to spreading capsicum on a limb, mangling or removing a limb, or exposing a foot on a hot pad. For the most part these studies merely torture mice not gain meaningful insight, yet the findings are expanded and hyped by an attention driven media and deceptive advertisers.

    Mouse studies used be a baseline, now they are a vehicle for distorting and misreporting science for commercial purposes. Of course there are political and industry interests in undermining the use of mouse studies, https://sciencebasedmedicine.org/donald-trump-versus-the-fda-part-2/

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    1. Zyp Czyk Post author

      I agree: the various sadistic methods they use to “induce chronic pain” are not and cannot be representative of human chronic pain, with all its associated burdens and disabilities.

      I wonder how they can believe that a mouse’s experience of long term pain are in any way correlated with a previously “successful” human whose intractable chronic pain costs them their employment, their social life, their financial status, their hobbies and pleasures…

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  2. Kathy C

    Yes, it is amazing how many of these mouse studies get amplified by media and the medical sites that are just fronts for deceptive advertising. Of course there are plenty of stupid human studies that get media attention too. They have healthy young college students put their hands in ice-water, or they put capsicum cream on them, then they announce they have findings related to chronic pain. Mice only live about three years, so there is no way they could be indicators for anything to do with human loss, and the awareness every day, that you cannot work, engage with friends and otherwise lead a fulfilling life. The intent of a lot of this “research” is get attention, often for commercial purposes, they are not about science or expanding knowledge.

    It is truly astounding how many of these junk studies get published in respected journals, and referred to, by policy makers, science illiterate journalists, and deceptive content marketers.

    https://www.upi.com/Health_News/2018/04/24/Light-effectively-relieves-chronic-pain-in-study-with-mice/3141524580092/

    I do not have the time to track down how they caused the “neuropathic” pain in the mice, they probably damaged the skin or something even worse to approximate neuropathic pain. Mice do not talk so we will never know if it was “effective.” Of course if the “light” is not destructive it would have been easy to find human subjects with neuropathic pain. Often these types of “studies” are front for the marketing of some miracle device.

    Here is another one in STAT, they have been using botulinum toxin for certain spastic disorders for years, in humans, and apparently they did not notice that the pain relief was due to the release of the spastic muscles.

    https://www.statnews.com/2018/07/18/botox-chronic-pain-mice/

    “Touch and pain were assessed by measuring reflexes in mice affected by neuropathic pain in their limbs. Affected mice will normally quickly withdraw their paw when it is gently touched. After the light therapy, however, they exhibited normal reflexes upon gentle touch. The effect of the therapy lasts for a few weeks, after which the nerve endings grow back and gentle touch causes pain again.” The “findings” are dependent on the observations and feelings of a biased observer. It is not quantitative like actual science.

    Here is the worst of the worst, but this one is on college students, it got lots of media attention, and shows how much misogyny there is in “pain research.” This “study” was amplified by media, local TV stations ran this, and even the college newspaper.

    ” A University of New Mexico study published in the journal Human Nature in June has found that curvy women are more sensitive to pain than other women. Another finding from the study was that men with broader shoulders could tolerate more pain.”

    ““The types of behaviors that we were measuring were, for example, the retraction of the arm from the water as well as the self-reporting of how much pain intensity the participants were experiencing at any given time,” said Vigil.”
    “The results of the study could help doctors better meet people’s individual needs in the ever-changing field of health care.”

    We will never know how this impacted women with pain, since they do not track that kind of thing. It is really clear that lots of women are gas lighted when they seek medial care, especially for pain. Unfortunately this “researcher is in charge of our medical marijuana research fund, and his sensationalistic and deceptive “research” has impacted local marijuana policies.

    https://www.womenfitnessmag.com/curvy-women-more-prone-to-pain/
    The term “scientists believe” is extremely deceptive, one porney professor and a bunch of gullible students, who have probably rethought the whole thing and should be ashamed.

    “In a study entitled the Curse of Curves, researchers took the measurements of 96 students. These were used to calculate the women’s waist to hip ratios and the men’s shoulder to hip ratios.”
    “Lead researcher Jacob Vigil said: “We have shown for the first time that sexually attractive features of body shape which signal attractive body shapes to the opposite sex are associated with pain.”

    I wonder how much money, time and resources they have put into these “studies” which are not only meaningless, but they perpetuate dangerous and destructive stereotypes.

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