Humans are unreliable models of mouse disease
cell.com
cell.com
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
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.
Not to mention that there is a much higher bar, ethically, regulatorily, and economically for testing a synthetic implantable liver vs a 'liver-on-a-chip'.
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
It would need to be in powder form or concentrated in something far beyond natural levels of coffee/tea/matcha/etc.
The lowest example of a lethal dose I can find in the literature is 57mg/kg. Caffeine overdoses are so rare that we don't know the true distribution, but it's clearly not the case that millions people will die from a few coffees.
Your other comment calculated the lethal dose as *a gallon of espresso*. That's like 125 shots. That is not a remotely normal amount of coffee. It would take multiple people over an hour to make that much espresso for you.
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Edit: I can't reply, but "LD1" isn't a group of people and you can't just claim it's 1% of the population. LD50 doesn't imply anything about the population distribution or how it varies by person. It refers to a particular experimental set up (or estimate from a natural experiment) in which 50% of the subjects died after a certain dosage.
For example, the LD50 of falling is ~50ft. Some people will be more susceptible to dying by falling a certain distance than others, but there are many other factors involved and it makes no sense to say someone is in 1% of falling-death-probability.
I agree that LD50 doesn't tell you everything you'd want to know, like the lowest possible dose that might kill someone. There might be people who are extremely sensitive to a substance, or situations in which it's particularly dangerous (in combination with other substances or another health condition, for example). For something safe and widely used like caffeine, I'd expect that the vast majority of people would experience roughly similar toxicity (say, within 2x of the median) with a tiny population of outliers; but you can't just assume that there's 1% of the population that's drastically more sensitive.
(cc @dang, seeing this growing trend of people misunderstanding the missing reply button and evading the timer via edits, perhaps UI affordances could be developed to better introduce folks to the feature?)
Also, FWIW the LD50 can be calculated with censored populations (ie not all subjects have died.) Think about it: if I administer a dose that kills half but leaves the other half living, the LD50 remains unchanged even if I continue increasing the dosage until all have died (or not). LD50 does not require a complete set.
Similarly with caffeine content "can be". All kinds of variables like roasting time affect the dose But the semi-standardized dose for a cup of coffee is about 100mg. Related to your link, they are a much larger cup of coffee for comparison. If you normalize it to the standard coffee size, it comes to 100mg caffeine, so right in line with what would be expected.
(based on 36ml espresso having 110mg caffeine, LD50 caffeine is 150-200mg/kg)
Healthy kidneys work through around a litre of blood a minute, so my guess is that, ahem, "breaking the seal" would keep caffeine levels in check.
Are there other caffeine delivery mechanisms that differ? Of course, but that’s not what the OP asked. The question was about the toxicity of coffee. That’s why it’s not worth arguing when something like caffeine powder provides the majority of ODs. Likewise there’s going to be variation in toxicity between individuals but those numbers are intended to be generalizable numbers to a population.
On average coffee is good, but you are not the average man.
This is quite a low amount, i.e., we're frequently consuming it at a dose that is close to or higher than the dose where you see negative effects.
Also, I don't think most people drink more than 2 cups of coffee per day -- if I know someone who drinks more than 2 or 3 I'd think they have a problem.
Yes and no. At certain concentrations, many safe compounds become dangerous in humans.
Even at tiny doses, foods like peanuts may be safe for the vast majority yet lethal for a minority.
Given how devilishly heterogeneous the human race is, the ideal solution provides safety testing at the individual level, not the population level [0]. But this is years away until computational and biological breakthroughs arrive.
[0] Population level is a misnomer. FDA trial sizes below.
Phase 1: 20 to 100 people
Phase 2: up to several hundred people
Phase 3: 300 to 3,000 people
https://www.fda.gov/patients/drug-development-process/step-3...
Panera used to sell a drink that contained close to the FDA maximum recommended daily quantity of caffeine, and also allowed free refills. Several people died, and sales were halted after some wrongful death lawsuits.
This isn't to say that caffeine is dangerous. Danger isn't an intrinsic property of a substance but rather an emergent property of the context in which it is used. (This is why the schedules of the Controlled Substance Act are inherently stupid.)
Why wouldn't it be? In many ways they've clearly lost the fight. They're much smaller and less supported than the entities they intend to regulate. There is a known revolving door problem between federal and commercial employment. The natural mission of regulating food _and_ drugs is no longer sensible in our current social and political environment.
Speaks volumes about the state of the USA given that y'all's regulations on food are so lax that the topic already tanked an agreement with the EU (TTIP) as well as a bilateral agreement with the UK (the one the Brexiteers proclaimed would be possible once Brexit came, but still isn't there).
The most obvious differences are washing eggs, washing chicken carcasses with chlorine and prophylactic (or worse, growth-stimulating) usage of antibiotics. All of that is banned here, but allowed in the US - mostly to mask the horrible sanitary and working conditions in farms and slaughterhouses. I'm not going to act like European slaughterhouses are paradises because they are everything but that, but nowhere near the levels of horror from the US.
When even regulation to prevent the worst of the worst isn't feasible any more, frankly I'd say your system has failed entirely.
But I can only read the abstract on my phone, what is “itch” in this context and yeah any more of a summary available?
>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.
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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.
[1] - https://www.youtube.com/watch?v=hKTV2R6TT0Y [video][31 mins]