This discussion between Joe Rogan and Bret Weinstein happened after the major reveal (and full story) on The Portal podcast between Bret and his brother, Eric. I highly recommend listening to it: https://podcasts.apple.com/us/podcast/19-bret-weinstein-the-...
These brothers are smart and often interesting but they are also both audibly quite taken with their own brilliance and often not what I want to listen to.
Lab mice have extremely long telomeres compared to wild mice and humans. This would theoretically make them better able to heal but more prone to cancer. This also makes them a poor model for testing the toxicity of drugs because they would be better able to deal with the damage caused by drug toxicity.
Drugs that have been developed using these mice could have a higher toxicity than the lab mice data suggests. Weinstein uses the Vioxx scandal as a possible example of such a drug.
Agreed. I listened to one of their interviews on Rogan and couldn’t stand it after half an hour. It’s good to be smart but but it seems a bad character trait to be convinced of your own brilliance.
To my ears, Brett talks with the cadence of a man who believes that the thing he's going to say in the following sentence is profound. It might be unintentional on his part, but that's what I hear. Tone and cadence matter in audio formats.
elindbe2 nicely summarizes Bret Weinstein's paper and the Joe Rogan clip.
Eric Weinstein's 2hr+ Portal Podcast #19 on YouTube is frustrating but I'd summarize the "new" info from memory as:
- math oriented older brother Eric thinks biology oriented younger brother Bret is Nobel Prize worthy
- yet Bret and his mouse telomere paper live in obscurity
- reason 1: Bret chose Evergreen rather than a top tier University
- reason 2: the science establishment is biased against disruptive ideas and scientists
- Carol Greider’s 2009 Nobel Prize was based on work inspired by informal phone calls and emails from Bret
- Bret claims that Greider failed to recognize his contribution and then actively undermined his paper(s) through the peer review process
I wish we had TL;DR + Start/Stop Links into the original video. Long form audio/video podcasts are both a boon and a curse since the content cannot easily be searched or linked to.
> Carol Greider’s 2009 Nobel Prize was based on work inspired by informal phone calls and emails from Bret
Bret is quick to point out that Dr. Greider's Nobel prize is well deserved and for related, but earlier work. The contention is over later work.
Their conversation did inspire these findings about lab mice telomeres. But Dr. Greider's lab decided to keep the information "in house". This means that instead of publishing the source of the information, they can use their knowledge to start predicting other results, and publish a full stream of paper first. This is at 1:23:50.
Drug development has been maturing for decades. Both industry and the agency have had time to work out what animal models do and do not tell us. If you develop/discover a molecule/drug that treats some disease, it's typically found first in single-cells, then you move into higher and higher organisms. This is the flow of development. No one thinks any mouse, even humanized mice, are surrogates for actual clinical evidence. The whole shtick is risk mitigation, it's amazing how far society has come in such a short period of time where we forget non-clinical testing is not a perfect view into how a compound will interact in a human.
But in certain fields this current setup seems to be failing. The large majority of clinical trials related to neuroscience fail. To the point that pharma companies are starting to defund these departments, because the hit probability is just not good enough to outweigh the costs. This is despite the fact many of our treatments are woefully inadequate and often closely related to drug discoveries made 50+ years ago. And despite the fact that the field is well funded in academia, taking up entire departments distinct from biology.
Neuroscience is a hard problem no doubt, but I also think the current paradigm for how basic neuroscience research is done is way too limited, and that is impacting the viability of potential treatments that make it to clinical trial phase.
> I also think the current paradigm for how basic neuroscience research is done is way too limited, and that is impacting the viability of potential treatments that make it to clinical trial phase.
Our current paradigm is optimized to avoid injuring humans at all costs, including to the extent that it diminishes the chance of success.
By advocating for a different model, we're stating "Avoiding injuring humans in drug discovery is not our primary concern."
Maybe that's worth it in a broader calculation, but let's be honest about what we're talking about.
Pharma companies and regulatory bodies don't put in place billion+ dollar trial hoops on a whim: they do so to avoid permanently injuring or killing people with some pretty horrific side effects, to the extent we can.
>Our current paradigm is optimized to avoid injuring humans at all costs, including to the extent that it diminishes the chance of success.
I would characterize it as more avoiding the liability of injury to humans than avoiding injury overall (edit: and by liability i'm not just talking legal liability, there are also emotional consequences a person would experience if someone dies or is gravely injured as part of their medical research). A family member died of cancer this year. Nobody is liable for her 'injury' because there's no evidence it wasn't a natural occurrence and standard of care was followed in her treatment. However, a number of plausibly beneficial alternatives or adjuncts to that standard were in phase 3 trials that either her doctor flat out refused to consider or that she was ineligible for...not due to concerns of clinical efficacy of the treatment, but due to prior treatments that could have smeared the signal in the results (this is particularly true for immunotherapy trials).
It's a medical version of the trolly problem and from what I can see and definitely in our experience doctors choose to ride the rails they were set on. I don't blame them either. With the current climate in medicine a wrong move could end their career and possibly prevent them from helping those in the future.
It's an extremely tricky situation and I empathize with those that are faced with these dilemmas every day at the office. I just don't buy the story that changing our current approach is somehow de-prioritizing injury avoidance.
Your comment reminds me of the recent Dilbert strips where everyone is acting like the main character doesn't care about safety because he didn't state the implicit assumption that safety matters and someone looking for cheap virtue points noticed and said "you didn't mention safety, why don't you care about safety" even though he obviously cares as much as anyone else.
Nobody in this entire comment section that I have seen so far is advocating for harming more people more frequently in the name of progress. Just because people are asking "are there any other ways of testing drugs" and the current testing system cares about safety does not mean that these people want to abandon safety in order to more cheaply test drugs. Maybe we can find some other way to test drugs that is cheaper per useful drug than the current system and equivalent or better in terms of safety to humans.
I didn't say that anyone wanted to abandon safety. I said that they wanted to deprioritize safety, presumably to increase successful drug development.
> Maybe we can find some other way to test drugs that is cheaper per useful drug than the current system and equivalent or better in terms of safety to humans.
Maybe. But we should start at a place of shared understanding.
HN is notorious for "if they just"isms with regards to other fields.
Consequently, I think it's fair to point out that the thing that most people are lamenting (strict adherence to standards, extremely conservative trial progression) are attached to a value (avoiding harm to humans).
If people are advocating to upend the apple cart, then they don't just get to say "We want to continue to prioritize safety and also not do some things that increase safety."
Personally? I'd be fine with an informed consent alternative that helped speed through population-targeted or riskier drugs. Better to have options. But implementing that system would have costs.
Who is saying this? Simply stating that a system is imperfect is not advocating abolishment (current social issues notwithstanding...), it's an invitation to explore other solutions.
someone: X is imperfect and has unsatisfactory outcomes
you: X implies Y, how dare you hate Y?
> By advocating for a different model, we're stating "Avoiding injuring humans in drug discovery is not our primary concern."
I don't know if you can see that your argument is a claim that safety can only exist iff we keep the current system unaltered. That there is no other system conceivable which could do better. Which is clearly absurd.
That's not true at all. The way the data is analyzed could be done differently for example- there are some cases where previous clinical trials were brought back up as possibly helping a subset of the individuals, but got thrown away because of p-values. When our disease labels are so bad this is the type of thing that needs to be especially carefully considered.
But also I was talking about basic neuroscience. The pharma companies don't just magically start a clinical trial, as you said. They base the clinical trials on previous results from academia and their own basic research labs. Which mostly doesn't involve humans at all. Perhaps those labs are not putting forward the best candidates, or not doing as good a job as they could be at eliminating candidates.
Disclaimer: haven't seen the video (I never click any video link, sorry), but I did read the text links provided in the thread. That said: one of the big reason to use mice as animal models is that we've obtained a bunch of pure-bred, homozygous lines for a bunch of different genes, and that process is expensive and above all lengthy. Mice have both (a) a relatively short generation time and (b) been experimented on for a very long time. This makes them particularly suited for experiments involving knocked-out genes and suchlike because you have near-perfect controls at your disposal.
Now just because we have a bunch of pure-bred homozygous mice doesn't mean mice behave the same way as humans with respect to e.g. metabolic pathways, immune system etc. It's just that we often don't have better models.
The problem is that the breeding protocols inadvertently created a selection bias towards long telomeres. Mice with extra long telomeres have exceptional tissue repair capacity while also being susceptible to tumor growth.
The supply of lab mice can be corrected to have a more natural telomere length. All past studies that used mouse models to study the impact of drugs are skewed to under report toxicity and over report carcinogenicity.
I imagine that “the fix” involves a new strain of more natural mice and a better breeding protocol moving forward. Part of Weinstein’s issue is that this fix has not been transparent. I hope someone can provide greater detail.
I don't think it is just about mice though- it is also about "pure bred" anything. Imagine there was a single human that we could do all kinds of knockout experiments with, but we would always be starting with that base human (and on top of that it would be inbred and always live in the same kind of environment). Some of the conclusions we would draw would certainly not extend to all humans, probably not to most even. If the entire field became centered around this human, we would be missing huge amounts of information in space we are not exploring at all.
Controls are great, and it makes perfect sense to have studies that produce these extremely well controlled results. But controlling does have its own tradeoffs in practice, as results may very well not be robust/not generalize to things we care about. My problem is that the entire system operates under essentially the same paradigm, so we have very little work trying to address these downsides.
Seeing how identical individuals from literally the same cell line in an exactly identical and controlled environment sometimes give different results I don't think you can ever achieve 'perfect controls' anyway. The solution is to delve deep into what things actually do (in the case of people I know, that involves a lot of live single-cell imaging and suchlike) but that's expensive.
I didn't propose any specific solution, all I said is that the field doesn't do enough to account for population variability. It is hardly acknowledged! You will find PhD students at top programs who say "huh hadn't thought about that being a problem before". Because the training and grants and whatnot largely revolve around this same experimental setup. And IMO it is not a good approach to have everyone working on these problems think in largely the same way.
Btw, in these cases where they find a result seems to only apply to a particular mouse strain, that feels like a pretty trash result to me too. What are we supposed to do with that knowledge? Currently what we often do is build on it, cite it completely out of context, and happily walk away with a publication.
It is a known issue, and has been talked about somewhat in 'mainstream': [1] wired.com [2] adam ruins everything. I think it isn't talked about more because most of us don't think about anything like this until it is brought up, not to mention that it is a big, complicated issue that really needs folks educated in the right areas to work out.
This is not some secret knowledge uncovered via youtube.
Every animal model is imperfect and the various tools to try to address them (e.g. greater genetic uniformity) have consequences as well.
If you pick the wrong model your research will fail. Even if it gets through the pure research phase, the FDA will want justification as for why your animal of choice is appropriate.
I had a program that required — ugh — guinea pigs. Those suckers ended up costing $1K when all was said and done (not the cost of acquiring them,but looking after them and running the program). Rats would have been cheaper and mice even more but theOr immune systems could reject the pathogen we were trying to treat; the GP was the least expensive animal it would attack. (There turned out to be other advantages too but that was that for research). And when it came time for the preclinical work for IND submission the agency wanted an EMEA more expensive animal because it was a better human model.
So it’s an engineering trade off, just like any other. One controlled for when possible. Sorry there’s no conspiracy.
I think the argument here is that scientists who work with mice are by-and-large aware of this. It's fine we're communicating this to the public, but the tone that's struck by the Rogan podcast feels a bit more like we're exposing something scientists are hiding or are unaware of.
I think his point is that those mice are misleadingly bad and it is a fixable problem that for some reason the scientific community is refusing to address.
The scientific community often comes to an incorrect consensus, and this consensus becomes dogma that must not be questioned because the consequences would be too damaging to reputation/credibility/whatever.
>The scientific community often comes to an incorrect consensus, and this consensus becomes dogma that must not be questioned because the consequences would be too damaging to reputation/credibility/whatever
While this does happen, science at least allows the possibility of enough evidence to force people into accepting the new model. Without science, many more things are considered untouchable dogma and there is no method to challenge that.
Scientists are still human and make dumb ego driven mistakes, science still provides the best theory out there.
The consensus on mice models is that they suck and we need something better, and until we do, everything needs to he tested in humans before widespread approval is given so we arent ever relying on mice data alone to make regulatory decisions. Seems like a reasonable consensus to reach
Fixable and refusing to address? At the end of this I've linked a grant request from the NIH for better models, and this isn't a u ique or one of grant request. Hundreds of researchers and companies are working tirelessly on things like organ on a chip. Every drug required human trials to prove they work and could never get approved on mouse trust alone. Preclinical work will use animals up to monkeys if needed to get the best data. Neuroscience is developing brain organoids we can use that are created from actual human cells so we can move away from mice. This is millions of dollars of research being poured into this space because it turns out the scientific community does not like spending billions of dollars on failed drugs that we might have known about if we had better models. Saying the problem is fixable and that the scientific community just doesnt care is incredibly naive - it's like saying higher energy density batteries are trivially achievable but battery researchers are just too lazy right now. Its difficult, and many mainstream researchers have literally dedicated their lives to it.
Can you elaborate more? I followed telomere research a bit for years and I had never heard about what Bret Weinstein said.
Isn’t his claim that the lab mice adopted to some change in telomeres that significantly distorted the results of tests? I guess famous intellectuals with PhD aren’t credible sources but Eric Weinstein said that for over a decade they tried to get publicity for the story but ran into resistance.
I am more familiar with the basic research phase but in my experience very few groups actually treat model choices as an engineering tradeoff. Labs usually write grants centered around whatever model organism(s) the lab is already used to, and it's rare to see a proposal that doesn't use one of a few "accepted" models. I've never seen anyone sit down and have a discussion at the proposal stage about this, to actually seriously consider alternative setups or even just acknowledge why they are choosing this same mouse again. The tradeoff defense comes after the fact, and really only if someone else brings it up.
I think it is in part a symptom of the cost of research causing labs to be centered moreso around a methodology than a question. Having some labs like this isn't a problem, but when an entire field starts to trend this way, and almost everything that gets funding chooses a particular side of a tradeoff (that isn't super well quantified to begin with), then I think we could end up missing a lot.
If you look at it another way, groups that have a handle and understanding of a particular tool may have insight into how that tool can be used to answer a biological question. I don't think there is anything really wrong with that, but grants should be denied if they aren't proposing ways to move the field forward.
There are tons of mouse labs, however some have specialized mice or mouse systems. There are also other labs that specialize in other animal systems. These systems are nontrivial to switch between for many reasons, which I think you acknowledge. It is useful for the field in general to have access to the results of a variety of research tools that every individual wouldn't necessarily have access to.
Guess you have missed his point. The mice is bad as they are bias. They are too good to survive in a lab. It is not a trade off. The result is invalid.
In my humble opinion it's not that bright to think of animals as an utilitarian resource for the human race to plunder, or to consider their monetary value as any sort of a yardstick.
Certainly if we hold these kind of ethics we've got no excuses if an advanced alien race wants to use us in their medical experiments.
In the end, all non-human testing of potential treatments are meant to be fail-fast/fail-cheap. In terms of fail-fast, the timeline for seeing "lifetime" effects of a drug is far shorter in a rodent than in a human. In terms of fail-cheap, the ethical and monetary cost of a rodent suffering or dying due to unwanted effects of a drug candidate is judged to be lower than similar suffering in a human.
I do agree that lab animals aren't a resource in themselves – they're just the currently "next best" model to test in before trying a drug out in humans. In fact, mice are actually quite expensive in terms of time and money – custom-genotype mice can cost hundreds of dollars each, and that's just the up-front purchase price. The overhead of maintaining a mouse line is also quite high, with a huge loss incurred for accidental death or euthanization before they've been used as a model. When many research facilities were first shut down due to COVID lockdown this year, I heard that many labs at my university had to euthanize all their mice as they wouldn't be able to care for them. This represents a loss of months of research time and possibly thousands to tens of thousands of research dollars.
Another thing to consider is that many drug candidates that make it to the animal testing stage don't succeed with safety and/or efficacy testing. According to the FDA, 92% of pre-clinical animal tests actually fail to predict drug effectiveness in humans. This highlights a pressing need for other fail-fast/fail-cheap methods that should precede animal testing, like cell culture methods that could be used as a pre-animal screen.
>the ethical and monetary cost of a rodent suffering or dying due to unwanted effects of a drug candidate is judged to be lower than similar suffering in a human.
Thank you for the insightful comment, I'll cite the part that is relevant, since my (very serious) point was indeed that by this logic a more "advanced" being than us would have (by our own morals) the right to conduct medical experiments on us humans, because we are capable of feeling less pain.
>Certainly if we hold these kind of ethics we've got no excuses if an advanced alien race wants to use us in their medical experiments.
If an advanced alien wants to use us in experiments, I doubt they'd care much about what we say on the matter. And for all we know, the aliens might come from a predator background and only consider vicious species as true equals.
Just to drop you down a peg, I can invent a sci-fi scenario in which my point is made too: An advanced race views how we treat animals beneath us and decide to reciprocate as we are as far beneath them as mice are to us.
Many cell line stores are basically HeLa cells, and not whatever cell line they are labeled as, because probably at some point some grad student accidentally contaminated one petri dish with another and the HeLa s took over. heLa cells themselves have an interesting history.
The publications section on Bret Weinstein’s Wikipedia page [1] lists the paper [2][3]:
> Weinstein, Bret S; Ciszek, Deborah (2002). "The reserve-capacity hypothesis: Evolutionary origins and modern implications of the trade-off between tumor-suppression and tissue-repair". Experimental Gerontology. 37 (5): 615–27.
There doesn’t seem to be a succinct write up on how this hypothesis led to Carol Greider’s 2009 Nobel Prize [4]. Greider did not recognize Weinstein’s contribution [5].
I had never heard of Mr Rogan before but I guess I should not be surprised that people These days seek medical advice from a comedian/martial arts commentator. Or from a video of two people having a conversation.
I mean historically people would take medical folk wisdom from all sorts of sources that are probably even worse than Joe Rogan.
This reminds me of people complaining about others taking financial advice from reddit, ignoring that on average the financial advice you get from finance subs there is probably much better than the advice you get asking random friends and family -- which is a common practice.
