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Why Drugs That Work in Mice Don't Work in Humans
- jimmy1 8y agoWe discard aborted fetuses because they are "clump of cells" and Planned Parenthood already sells off their body parts, why not take the next logical leap and test in utero of a woman that doesn't want their baby? (It's a serious question, regardless of the fact that society has reached the point where we do not apply intristic value to a baby inside the womb, only outside the womb and "wanted", biologically speaking, that is still a human life)
- JulianMorrison 8y agoAside from the obvious reasons why testing on a fetus is more ethically fraught than just ending it, it's also stupidly dangerous to test things in a live human, and a mother counts as a live human.
- ghostbrainalpha 8y agoYa, obviously that person only wants to talk about abortion. That joke/idea was only tangentially connected to the topic of this article.
- klmr 8y ago> society has reached the point where we do not apply intristic value to a baby inside the womb, only outside the womb This is completely false, and a typical mischaracterisation of abortion by anti-choice advocates. If what you said were true, abortion would generally be permitted up until the moment of birth. Yet virtually nobody wants that. Abortions are performed in extremely early stages of gestation. Where exactly to set the cutoff point is a touchy subject, but there’s a broad consensus that (with few exceptions) abortions are only permissible while the foetus hasn’t developed a connected central nervous system yet, has no functioning pain reception and no higher brain functions (in fact, in most countries the cutoff is considerably earlier than even that). In other words, “society” does not apply an intrinsic value to a clump of cells (if it did, chemotherapy and amputation would be similarly ethically problematic). Instead, value is derived through tangible qualities, such as thought, and pain reception. Disagree all you want but don’t invent irrational reasons because they’re easier to attack. That’s deeply dishonest.
- jimmy1 8y ago> and a typical mischaracterisation of abortion by anti-choice advocates. Be that as it may, whatever the "anti-choice" advocates are doing (I certainly don't know) this is my own opinion using my own reasoning and conclusions. You either value life or you don't. I don't subscribe to the unscientific viewpoint that at some magical point after gestation, a unique human biological life somehow went from being not valuable to valuable. > abortion would generally be permitted up until the moment of birth. Yet virtually nobody wants that. The recent events in the democratic party -- Governor Northam's statements, former Presidential candidate Clinton's desire to repeal the Hyde amendment, and the senate vote to block the Abortion Survivor Act -- strongly disagree with this. Sorry the cat is out of the bag, and you can't hide behind the euphemisms anymore. But it is OK -- just own it. > such as thought, and pain reception I am glad you said this! Dr. Jean A. Wright, a pediatric physician that graduated from Johns Hopkins states, "After 20 weeks of gestation [18 weeks post-fertilization], an unborn child has all the prerequisite anatomy, physiology, hormones, neurotransmitters, and electrical current to “close the loop” and create the conditions needed to perceive pain…The development of the perception of pain begins at the sixth week of life. By 20 weeks [18 weeks postfertilization], and perhaps even earlier, all the essential components of anatomy, physiology, and neurobiology exist to transmit painful sensations from the skin to the spinal cord and to the brain." Glad we agree there. > but don’t invent irrational reasons because they’re easier to attack. That’s deeply dishonest. You are the one building a strawmen here, maybe look in the mirror?
- sshumaker 8y agoLook up the statistics. Majority of abortions are before 21 weeks (only 1.3% after). The vast majority of late-term abortions are for medical reasons, such as non-viability of fetus or endangerment of mother. The point of the law is to prevent the government from interfering in a doctor’s ability to provide medical care. Northam made a gaffe when speaking, but he is an actual doctor who has witnessed the actual terrible tragedies that can happen during pregnancy, as opposed to armchair quarterbacks who are jumping up and down to get their religious worldviews validated by law.
- moosey 8y ago
- sctb 8y agoWe detached this subthread from https://news.ycombinator.com/item?id=19269700 https://news.ycombinator.com/item?id=19269700. > Eschew flamebait. Don't introduce flamewar topics unless you have something genuinely new to say. Avoid unrelated controversies and generic tangents. https://news.ycombinator.com/newsguidelines.html https://news.ycombinator.com/newsguidelines.html
- dtech 8y agoExcept for maybe the last paragraph, this is not new information to basically anyone performing studies. The problem is we don't have any ethically and scientifically better alternatives.
- bayesian_horse 8y agoWe are getting there. In-vitro methods, often involving cell cultures, are gaining traction. In-silico, also. Robotic automation and synthetic biology help with that a lot. Machine learning can help make sense of more limited data, for example predicting toxicity and other parameters for drugs so that you can better choose what to forward to Human trials.
- klmr 8y agoIn vitro studies have been done for ages, but are often a worse model than closely related organisms. For instance, there are various human cancer cell lines and while these are routinely used to study various aspects of biology (cancer being just one of them), they are generally a poor model for drug trials. The current research trend goes towards developing organoids — cell cultures with a distinct 3D organisation and biological makeup that mimics actual organs — that more closely resemble actual human tissues. It’s still early days though.
- bayesian_horse 8y agoOrganoids do count as in vitro. And as I said, synthetic biology, automation and machine learning help in improving these methods. Nothing can replace certain studies in Humans completely. We can only hope to make those more effective by better choice of candidate drugs.
- klmr 8y agoAbsolutely. My phrasing wasn’t clear, I was contrasting organoids with the cell cultures mentioned in your reply, not with in vitro studies in general.
- narrator 8y agoWhat about drugs that work in humans, but not in mice? Could you ever get them into trials without animal data?
- Aaargh20318 8y agoThis is more worrying, how many medications did we miss because they don't work in mice ? Do we humans only get medications that work in both humans and at least one other species ?
- ctz 8y agoThe same number we missed because, as it turns out, killing people with unknown medications is a bad thing.
- jonlucc 8y agoThere is some work in this direction that is based on work with human cells (preferably primary cells) and building an otherwise compelling case. You have to be incredibly careful to do the appropriate safety studies and find some way to show efficacy in animals before you put the treatment into humans still due to FDA (and ethics) requirements.
- VBprogrammer 8y agoIf I'm remembering correctly Aspirin is a drug which doesn't have the intended effect in mice studies. I could be wrong about the exact drug but it is something similarly common if it isn't. Hard to google because there are a million studies which pop up.
- ars 8y agoYou test on monkeys, or chimps.
- karosass1 8y agoShort answer: Humans are not mice
- danieltillett 8y agoWhile mice are not humans (who would have known), we could do a lot better by moving away from using inbred mice. More positively we could make a lot more use of domestic pets in research. If we started to treat more pets as research subjects we could really do a lot of great research.
- saagarjha 8y agoGood luck getting people to allow their pets being used for research!
- pmiller2 8y agoBeagles are already commonly used in medical research.
- jz_ 8y agoPeople are actually very motivated to contribute to science, here's an example of research involving pets and extending their healthspan across aging: http://dogagingproject.com http://dogagingproject.com Phase I clinical trial: https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/28374166/ https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/28374166/ Phase II is in progress. Interview with Matt Kaeberlein from the project: https://www.leafscience.org/dr-matt-kaeberlein-the-dog-aging-project/ https://www.leafscience.org/dr-matt-kaeberlein-the-dog-aging...
- opencl 8y agoThis is a study of a new application of a drug that has already had very extensive trials in both humans and several species of animals that have demonstrated it to be safe (it's FDA approved for human use). I think you will find people dramatically less willing to test brand new drugs on their pets.
- danieltillett 8y agoThis question has already been asked of pet owners and when it is explained to them why most are willing to let their pets participate in trials of even new drugs.
- ggm 8y agoI'm not arguing for pigs over mice but I ask since transgenic pigs are often said to be future potentially viable transplant sources would not trials in pigs be a better model? (Ethical nightmares)
- sametmax 8y agoCost. Growing pigs is expensive, it takes more space, more food, and more time.
- dmurray 8y agoPigs are used in research, but they are expensive. Maybe 1000 times the cost of mice? The techniques described in the article (bad choice of temperature and environment) are cutting corners, but testing on pigs instead would completely change the amount of testing you can do.
- interfixus 8y agoWe are closer related to rodents than to pigs. Whether this is an argument for one thing or for another or for nothing at all, I really have no idea.
- klmr 8y agoThis isn’t quite true. The issue is that rodents evolve a lot quicker due to effective population size and generation time. As a consequence, the genetic divergence between rodents and humans is in fact greater than that between humans and pigs (see e.g. https://europepmc.org/abstract/pmc/pmc1142312 https://europepmc.org/abstract/pmc/pmc1142312), even though pigs branched off earlier than rodents.
- interfixus 8y agoHad a vague that something like that might be in play. I obviously have some reading up to do. My assumption was, that our branch would, until quite recently, have been rapid breeders too. And the pigs' one as well.
- chiefalchemist 8y agoI'm not sure how common the practice is, but I've been told (by a trusted source) that if a med study doesn't get the desired results they just get a new set of mice and try again. That is, results can vary based on the mice used for reasons not understood (but gut bacteria perhaps).
- jonlucc 8y agoI work in pre-clinical pharma research, and this isn't really true in my experience, but there are a couple caveats. At least in my experience, we wouldn't run the same study again, but we might change the model. There are a few models that all point to a similar indication, so we might try both. If a treatment works in one but not the other, it's definitely seen as less strong evidence of efficacy, unless there's some very compelling mechanistic reason. That's not quite as crazy as it sounds, though, because translation from mouse to human is already poorly understood, so it can be hard to know which model will suggest positive effects in clinical trials.
- VBprogrammer 8y agoI'm interested in how compounds are chosen for medical research. Do you just start with a wide range of compounds which you are able to make and fire them at a range of different potential medical issues? That seems staggeringly unlikely to find something useful. I know some drugs are extracted by isolating a compound from a traditional remedy. That obviously makes sense.
- natechols 8y agoIn my (admittedly indirect) experience, there's always a specific medical issue being targeted, and usually a specific biochemical system (i.e. protein binding partner). Very occasionally, they end up with a drug for a condition completely different from what they were trying to treat, but that's the exception. (Viagra was one of these; I would have loved to have been a fly on the wall when they realized the implications of the side effect profile from the original trial.)
- 8y ago
- AbyormPiranha 8y agoBecause mice aren't humans.
- Amygaz 8y agoAny mice trial should use 4 different breeds: one of the academic hallmark (black6 or balb/c) for publication purpose, one that represent your model (or so you think) because that’s the logical thing to do, and a truly wild type one (captured in the wild) to capture the noise. Even this bias longevity piece needs to do that. This 4 breeds will all have different immune system, cognitive behavior and lifestyles, which are all central to aging.
- woliveirajr 8y agoThat makes 3...
- magicalhippo 8y agoThe 4th is a group of dead mice, to make sure you don't accidentally start a zombie apocalypse.
- SubiculumCode 8y agoJokes are discouraged on HN, but you did make me snort out loud.
- klmr 8y agoThe issue with that approach is that you’d multiply the number of sacrificed animals by 3 (or 4, did you forget a breed?), for limited gains in insight. Your approach would be a lot more defensible if it didn’t involve killing vastly more animals, and a fairly large increase in research cost. These things are always a balance, and there’s no evidence that always using your approach would be worth it.
- ennisthemennis 8y agoI agree "any mice trial" is too strong a statement, and also 4 groups is kind of infeasible. But I do think there is not enough research on how these particular inbred mouse strains might bias research. Even the same strain sourced from different companies have produced different results, due to microbiome differences [1]. It's possible that we are way "overfitting" to these particular academic mice [1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870873/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870873/
- fallingfrog 8y agoThis all makes sense! I’ve heard there is a similar effect for single cell research, where a lot of the study of human cells says that they are full of support structures and making all kinds of chemical signals that actually are a stress response to being placed on a piece of glass rather than floating in liquid. Kudos to these researchers for making an honest attempt to get it right.
- leemailll 8y agoModel animals are used in researches mostly due to two reasons: cost, which is always a big hurdle for academic studies; and reproduction, especially for inbred mice. The use of inbred mice often is because the behavior and activity of the mice is well-characterized, high availability, and genetically more consistent. However, the second part nowadays is often challenged and they are not that consistently genetically as researches show. For drug development, the very first step is to create an animal model, however, this one also is difficult, since more often than not one cannot generate animal model replicates all symptoms, this could mean a model without the actual cause. I think this is also a reason why genetic studies of diseases nowadays is still a hot field, from there one can make an animal model and test whether that gene is the real cause in more confidence.
- Balgair 8y agoFor those that are interested, the Animal Welfare Act of 1966 (an the many amendments to it) specifically spell out the animals that can be used for research and testing. There aren't that many of them, hence why rats and mice are so popular, as they are some of the few animals that can be used for testing. The AWA is structured such that all animals are covered by default, and only a few species are specifically excepted. It's an expansive law that also covers herding, meat processing, cosmetics, hunting, etc. In general, the AWA is very restrictive in terms of animal testing for scientific research. Getting exceptions to use an animal for research is very intensive and highly regulated, taking years to get the approval. Getting approval for studies that may involve studying intentional pain, harm, etc to an animal can take up to a decade for approval, and with much study and research on other possible methods. Internal Review Boards (IRBs) are required to include local lay people, clergy, other non-scientists, etc in order to approve a study. Vivariums are also highly regulated and frequently inspected. The US, at least nowadays, takes the welfare of animals extremely seriously with stiff fines and real consequences for breaches and lapses in protocol. https://www.aphis.usda.gov/animal_welfare/downloads/AC_BlueBook_AWA_FINAL_2017_508comp.pdf https://www.aphis.usda.gov/animal_welfare/downloads/AC_BlueB... https://en.wikipedia.org/wiki/Animal_Welfare_Act_of_1966 https://en.wikipedia.org/wiki/Animal_Welfare_Act_of_1966
- 8y ago
- openloop 8y agoTest the drugs on poor children without asking. No one will notice.
- nonbel 8y agoHow many of these drugs actually do work in mice? Every study that comes out on the topic shows at least 50% and often closer to 90% of preclinical research does not replicate or even is not replicable in principle.
- hjk05 8y agoResearch and drug development are pretty different leagues. A research paper might be 3 researchers with 20 mice. When your looking at preclinical trials it’s more like 300 people and 5000 mice per trial and god knows how many trials before something goes through. The reproducibility crisis is happening in academia. There isn’t that much room for uncertainty when it comes to industrial drug development. You won’t find drugs making it all the way to market only for “another group” to be incapable of reproducing the effect.
- nonbel 8y ago> "When your looking at preclinical trials it’s more like 300 people and 5000 mice per trial and god knows how many trials before something goes through." This is sampling to a foregone conclusion. It is guaranteed to yield unreproducible effects. > "You won’t find drugs making it all the way to market only for “another group” to be incapable of reproducing the effect." I doubt this from the description above.
- dalbasal 8y ago"Only 14% of drugs that are tested on humans succeed in demonstrating effectiveness[1], and all of these are drugs that have been found efficacious in animals, so successful animal studies are very far from a guarantee by themselves." Regardless of the reason, this seems fine/workable. Animal studies are a step in the funnel. I assume the step from petri dish to mouse is similar. I wonder how many false negatives get produced. Drugs which would have worked on humans, but don't on mice, for similar reasons.
- ramraj07 8y ago14% is bad when you consider that the NEXT step after preclinical experiments is basically clinical trials (and Phase I is not to test efficacy ) which effectively costs several hundred millions of dollars or more. And the pharmas would just add the cost of 86% failed trials to the other meds that do pass, so they effectively pass the cost of their bad decisions to us. I worked in a lab that studies antibody therapeutics for almost a decade and can go on a tirade of all the shitty decisions companies seem to make in candidate identification, but fundamentally I really believe that this number won't be this low if the people making the decisions in pharma companies know what they're doing but then the CEO of gsk used to sell lipsticks so who am I to talk right?
- fredophile 8y agoI've always assumed that the reason for the low rate of success at that stage was just a result of things that work on rats not working on humans. Your post is suggesting that there is some evidence available before testing on people that would help increase this rate but gets ignored. I haven't seen anyone express this view before and would like to learn more about it. Would you please elaborate on what kind of information isn't being used for decision making but should be?
- busyant 8y agoI am not the parent, but I worked at a few biotech startups. My impression is that you are _mostly_ correct (a lot of animal models for disease don't accurately reflect the analogous state in humans). However, I was privy to a situation similar to that described by the person to whom you replied. * A start-up that I worked at developed a "candidate drug" to treat a condition (I don't want to get too detailed). * The drug was good at ameliorating the disease in our simple models, but we also had a strong suspicion that the drug would be toxic in humans, higher animals. * A decision was made that we would determine if the drug was toxic in three different species of large animal (I think we chose some type of monkey, dogs and I don't remember). * Our "go/no-go" decision was: If the drug was NON-toxic in at least 2 of the 3 animal species, we would move to clinical (human) trials. * 6 months later, we got the results: drug was NON-toxic in 1 of the 3 species. * This looks like "no-go", right? * Wrong. Board of directors put pressure on the CEO and senior management ("We put 8 figures of our hard-earned $ into round B and you promised us clinical trials over a year ago."). * CEO folded like an accordion and got everyone to agree that we should proceed w/ Phase I trials (small n of humans tested, primarily to determine toxicity and maximum tolerated dose) despite the results of the animal studies. * Phase 1 trial starts. Everyone gets sick (maybe 10 patients) after about 5 days of taking the drug. Trial is halted. * We go back to square 1. CEO should have never folded under the pressure because it was a waste of money, time, and it put people at risk. I've only seen this once (going to trial with a risky drug), so I think it is a rare event. edit2: Ironically, this is an example of a situation where the animal-studies CORRECTLY predicted what would happen in humans.
- syntaxing 8y agoI wonder if it's possible to use machine learning to speed up this process. Rather than doing computational biology, can we use a hybrid system? For instance, can we test this on mice and then feed some sort of parameter into a model to see the probability it working on humans rather than testing it directly on humans. I'm sure this won't be a perfect model but I wonder if it can raise the 14% to 20% while using less resources.
- aaavl2821 8y agoML (or anything really) that could predict which molecules would work in humans without testing them in humans would probably be on of the most important advances in medicine ever, and would massively lower drug costs and open up new areas for drug research Phase 2 failure -- ie stuff failing in humans after working in mice -- is the biggest cost driver in drug dev. You spend $50-100M+ to get there and 35% of things fail. If you could eliminate you'd cut a massive chunk of the cost and risk of drug dev However I don't think ML is the thing to study if you want to create ML to predict whether drugs will work in people. There is not enough data about how the human body works to develop a good model. Better to work in biology to develop good models of disease, or in developing tools to better measure the molecular biology of the living human body. It's unclear if predicting drug effectiveness with ML will be possible in our generation For more near term applications of ML in drug discovery and development see here: https://www.getrevue.co/profile/nathanbenaich/issues/6-impactful-applications-of-ai-to-the-life-sciences-new-essay-150757 https://www.getrevue.co/profile/nathanbenaich/issues/6-impac...
- zinclozenge 8y agoThe short answer is "probably". The use of AI in drug design is only just now starting, we'll see the results in about 10 years. I optimistically expect AI to be able to shave off ~2-3 years of the drug lifecycle. edit: but it won't do much to optimize P2 trial success specifically, it'll simply help iterate substantially faster in the pre-P2 trial phases.
- Mitchhhs 8y agoI wonder if a similar proportion of drugs that work in Humans wouldn't work in mice. Are we missing out on a ton of potential?
- foobaw 8y agoBecause we are not mice.
- dkural 8y agoActually; we're 75% mice, genetically speaking.
- Amorymeltzer 8y agoMy go-to example is Vitamin C: it's an essential nutrient for humans, but mice, like most other animals, are capable of simply producing it. That's usually a good starting point for the "they're really different" conversation.
- anitil 8y agoFor the curious: https://en.wikipedia.org/wiki/L-gulonolactone_oxidase#Consequences_of_loss https://en.wikipedia.org/wiki/L-gulonolactone_oxidase#Conseq... I couldn't really make sense of the two proposed theories, other than one suggested perhaps it was an advantageous adaption in the presence of malaria.
- dumbfoundded 8y agoIs the converse true? Are there drugs that would only work in humans but not any animal models?
- najarvg 8y agoFascinating and very timely for me. I was privileged to sit through a talk by the head of cancer immunotherapy at our institution where he was explaining the past, present and future journey of cancer immunotherapy research and this exact topic of mouse model applicability to human subjects came up. His TLDR on this was that differences are likely due to - 1. Controlled lines of mice bred specifically to minimize confounding during pre-clinical studies 2. Immune response activation pathways differing from "in the wild" situations for actual subjects 3. The immense diversity of gut microbiota, their temporal and inherited gene signatures and impacts on drug metabolism which are incredibly hard to control for in experiments Very nice to see an approachable post out there outlining a lot of these issues.
- AngeloAnolin 8y agoHuman !== Mice We can even argue that Human !== Human due to a million variables that differentiates them at microcellular level.