7 ms·
Humans are unreliable models of mouse disease
- yieldcrv 2y agoThat’s a funny premise But I can only read the abstract on my phone, what is “itch” in this context and yeah any more of a summary available?
- tgv 2y agoPossibly HECT-type E3 (ubiquitin) ligase Itch: https://en.wikipedia.org/wiki/ITCH https://en.wikipedia.org/wiki/ITCH.
- asdff 2y agoItchy skin like what people get in dermatitis. The main crux (without digging into the weeds on the second crux regarding JAK signalling probably only interesting/comprehensible for immunologists) of the article is that they weren't getting asthma in their mice that were genetically engineered to get asthma like a human with a similar genetic background. This was because the lab environment is too clean and the mice weren't getting exposed to the allergen. When they introduced an allergen to these mice then they got asthma as expected. So in this case humans are unreliable models of this disease in mice because humans live in highly variable and dirty environments where they might get exposed to environmental conditions that drive certain phenotypes based on their genotype. so when you go and model these genotypes in the lab without an understanding of the environmental background, you might not get the phenotypes you expect to find based on those genotypes.
- deleted 2y ago[deleted]
- computerdork 2y agoHmm, interesting. If this is the case, isn't the article title misleading? It implies that the mice where the problem in the study, when it was the environmental conditions of the tests that the mice that caused the allergies not to show up. Seems like the title should be "Lab conditions are an unreliable model for human diseases."
- asdff 2y agoI think it was meant as a bit of a joke more than anything. This isn’t a real article anyway but more like a post mortem blog post.
- panabee 2y agoBalancing safety and innovation in human health is incredibly difficult. This isn't a criticism of the FDA, but rather an observation of facts underscoring both the challenges and opportunities. Some foods consumed safely by humans are toxic/harmful in mice, due to how mice react differently to key compounds. Common examples: 1. Chocolate - theobromine 2. Coffee - caffeine 3. Chili peppers - capsaicin
- amelius 2y agoIsn't coffee toxic to humans too?
- manmal 2y agoToo much coffee does make some humans toxic.
- osigurdson 2y agoEven humble hydrogen can be dangerous in high enough concentrations. This, and daylight savings time doesn't actually add any hours of sunlight.
- bumby 2y agoMy understanding is the toxic level of caffeine is so high that you’d die of hyponatremia first from the water in coffee before caffeine kills you.
- spondylosaurus 2y agoGenuine question: does that mean when people die after consuming way too much caffeine, it's not because of "caffeine toxicity" per se, but because the effects of the caffeine put too much strain on their body?
- necubi 2y agoNobody is dying from the caffeine in coffee (like 50-100mg per cup). According to the NIH, LD50 of caffeine is 150-200mg/kg (so say 10g for a small person). That's like 100 cups of coffee. Even with espresso that's hard to imagine. It would need to be in powder form or concentrated in something far beyond natural levels of coffee/tea/matcha/etc.
- Onavo 2y agoThey can use macaques which are much closer, but for some reason people are against it.
- syndicatedjelly 2y agoAny thoughts as to why?
- Teever 2y ago[flagged]
- luxuryballs 2y agoI can’t tell that they are pretending
- Nition 2y agoMight be a good example of Base Rate Fallacy. Assuming we can presume that the amount of people who truly wouldn't understand why anyone would be against testing on monkeys is extremely low, there can be a significantly higher chance of false sincerity than true sincerity, even if most people wouldn't lie.
- lukan 2y agoThey can use other humans, which are much closer, but for some reason people are against it.
- seydor 2y agoToo bad because mice have it all figured out
- devonsolomon 2y agoGuess all those breakthroughs curing mouse cancer in human models are null then… back to the drawing board, tiny scientists!
- wyldfire 2y agoNext we will find out that dolphins are right up there w the mice? "So long, and thanks for all the fish!"
- LinuxBender 2y agoAnd conversely mice may be unreliable models of human disease [1] [1] - https://www.youtube.com/watch?v=hKTV2R6TT0Y https://www.youtube.com/watch?v=hKTV2R6TT0Y [video][31 mins]
- the_optimist 2y agoInteresting that Weinstein and Ciszek are unmentioned anywhere else, given their widely known and recognized involvement in this matter. Weinstein's extended hypothesis is far more interesting and compelling that this particular paper.
- hprotagonist 2y agoThe first — and maybe only, or at least sufficient — use of tissue engineering at scale is not going to be growing organs for implantation, growing meat in a lab for human consumption, or anything quite that flashy. The first one is going to be the ability to grow liver slices at scale for tox screening in pharma. animal rights issues entirely aside: we spend entirely too much time and money killing a whole lot of mice all the while knowing perfectly well they’re barely semi-decent models for toxicology. if I can fill the lab with constant flow vats of slices of liver, they’ll read out fast, they’ll be a massive savings in time and money, and they’ll give us much more accurate results.
- bflesch 2y agoSounds like a worthwhile undertaking. Do you know someone who is actively working on this problem?
- shadowgovt 2y agoThe research has been complicated in the US because so many of the cell lines pass through fetal tissue. But IIUC it's ongoing (and not so encumbered in other countries). Not to say all are intertwined with fetal cell research, only that it's one of the cheapest sources of stem cells and law has made using it complicated.
- RangerScience 2y agoDo you (or a GP) know how I can donate already-extracted stem cells for this?
- lukan 2y agoMany are, it is just not a trivial problem to create or copy living organs.
- MattGaiser 2y agoIt it meaningfully easier than growing livers for transplantation?
- robwwilliams 2y agoFun article is you can get your eyes on it. Several interesting and wise comments about doing biomedical research. The comment you might NOT expect given the tile (a bit of clever click-bait) is this: >A common way to destroy a grant [application] in an NIH study section would be to suggest that ‘‘mice are unreliable models of X disease.’’ Just as I was uncomfortable with the negative tropes about translational work, a new pejorative rhetoric had emerged surrounding animal work." This is so true. Almost all scientists who state confidently that THE MOUSE is not a good model for X or Y do not really know enough mouse genetics or biology to weigh in on this complex topic. For good and bad reasons a great majority all mouse biomedical research (90% of more) is done using one fully inbred strain of mouse called C57BL/6 (or B6 for short). Almost all knockouts and transgenic mice are variants of B6. And this is the strain that was first sequenced. The good reason is genetic uniformity. The bad reason is also genetic uniformity. As Kim mentions when someone says "‘mice are unreliable models of X disease’ they almost always mean that some disease manifestation does not occur in B6 mice. Yes, but in may and often does, occur in other types of mice. The only way to know for sure is to study 5 to 100 diverse strains of mice, of which one or many may have just the disease you are looking for. This is really not different the disease variation in humans. Below is some of text from Kim's article, with the additional vital and true (but hardly surprising) conclusion that ENVIRONMENT matters too. -------------------------------- Notwithstanding these fears, my lab continued to thread the needle of doing mouse work and coupling this to translational exploration in humans. In 2017, when we identified JAK1 in sensory neurons as a critical mediator of itch, Stuart Turvey, a highly accomplished physician-scientist who focuses on inborn errors of immunity, reached out to me to highlight their discovery of the first germline JAK1 gain-of-function (GoF) variant in patients.8 JAK1 is a primary conduit for numerous cytokines to signal within immune cells. Thus, these patients had multi-organ inflammatory pathology, including diseases like severe AD, asthma, and food allergy. Stuart also pointed out to me that the children with this JAK1 GoF variant had itch that did not respond to even high-dose steroids. In fact, it was only when they received oral ruxolitinib (which inhibits both JAK1 and JAK2) that these children were relieved of their itching for the first time in their lives. He suggested to me that, consistent with our findings in mice, this was compelling evidence for JAK1 as a critical driver of itch in the nervous system in these patients. Unbeknownst to Stuart, our email conversation inspired me to generate mice that conditionally expressed the exact variant of JAK1 he had discovered in his patients. Truthfully, there was no clear hypothesis. My trainees found this proposition very uninteresting because we had already mapped how JAK1 functions in itch nerves in the skin, and Stuart had already identified a syndrome caused by the mutation. To make matters worse, we made the wrong mice. Instead of inserting the human JAK1 GoF variant exclusively in sensory nerves, a misunderstanding led to generating mice in which the JAK1 GoF variant was expressed in a germline fashion, just like in the patients. What was the point of reinventing a human disease in a mouse? This was the opposite of translational research. While serendipity is defined as unplanned fortune in science and understood to be a virtue, this was in many ways a misplanned misfortune. Nonetheless, I remained stubbornly persistent. The JAK1 GoF mice spontaneously developed AD-like skin inflammation akin to what the patients had displayed. However, in contrast the children, they did not develop asthma. There were so many reasons to abandon the project. I made the wrong mouse, I had no clear hypothesis, and the phenotypes did not match. My lab came to the biting conclusion that humans are unreliable models of mouse disease. However, this is where the story takes an unusual twist.Buried within the chaos was a biology that would not only explain why the children developed asthma while the mice did not but also reveal fundamental new neuroimmune mechanisms in the lung. In short, what we found was that for the mice to develop asthma-like disease, they had to be exposed to an allergen. However, in contrast to the conventional role of JAK1 as a mediator of inflammation in immune cells, we found that JAK1 within sensory neurons plays an anti-inflammatory function. Masato Tamari, a very talented pediatric allergist and postdoctoral fellow in my lab, was unde- terred by the challenges and decided to persist. He found that while the JAK1 GoF mice spon- taneously developed skin inflammation, unlike the patients, they did not spontaneously develop asthma-like disease. We then hypothesized that a major limitation in studying lab mice compared to humans is their lack of exposure to environmental allergens. Indeed, upon challenge withAlternaria alternata, an asthma-associated allergen, these mice exhibited enhanced susceptibility to allergic lung inflammation. Thus, the mystery was solved, and we could have simply stopped here. The conclusion was that of the classic scenario where genes interact with the environment to drive a clinical phenotype. However, we decided to persist and dig deeper.
- computerdork 2y agoDoes anyone have a link to the non-paywalled full-text?
- ag8 2y agoYeah, I'm a bit surprised that this has so many upvotes without any easily accessible text
- dang 2y agoUnfortunately it was probably just a shallow reaction to the admittedly witty title. I've downweighted the post now, in keeping with https://news.ycombinator.com/newsfaq.html https://news.ycombinator.com/newsfaq.html and https://news.ycombinator.com/item?id=10178989 https://news.ycombinator.com/item?id=10178989. If someone comes up with a workaround, we can restore the thread.
- RateMyPE 2y agoI've posted another comment on this parent comment saying how you could access the full-text, but I haven't directly posted the link to said text, as I'm not sure if it's allowed.
- RateMyPE 2y agoI'm not going to link the exact page because I'm not sure if it's allowed, but if you go to this Reddit post: https://www.reddit.com/r/scihub/comments/1g89i9z/best_alternatives_to_scihub_currently/ https://www.reddit.com/r/scihub/comments/1g89i9z/best_altern... And click on the link from the top comment, you can search for the article using the DOI code which is: 10.1016/j.cell.2024.08.006