(briefly) RaDVaC and SMTM, two things we should be doing

by Eliezer Yudkowsky4 min read12th Jan 202262 comments

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Effective AltruismCovid-19MedicineWorld Optimization
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Having not apparently the energy to write this longly, I write it shortly instead, that it be written at all.

People sometimes go about saying now, in this community, that there is collectively enough money that we could potentially go do more things with it, if there were things worth doing.

If that's true, I'd like to see us planting seed grains now for replacing the now-defunct state capacity of the USA and Earth, with respect to biodefense and ultra-high-leverage med R&D.

As a poster child of a previous intervention I backed here, Seasonal Affective Disorder affects 0.5%-3% of the population and higher in countries at extreme latitudes.  Call it a hundred million people at a guess.  Standard lightboxes don't work very well for treating it.  The Sun works great for treating it.  Reason suggests trying more light.  Earth, however, previously lacked the state capacity to investigate this obvious question of massive scope.  I put a private funder in touch with a group that did a preliminary investigation; they need to run a larger study but preliminary results suggest that they may, in fact, need to use more light and that doing so might be effective.  Again, that's for a problem that probably over a hundred million people have.  So it's not very surprising that investigation of it bottlenecks on there being a single interested medical researcher, who writes Eliezer Yudkowsky as the person who posed that question, and gets funding arranged by that route.  It was less than $100,000.

This sort of thing seems obviously competitive to me with QALYs/$ or DALYs/$ on global poverty interventions.

Really obviously competitive, actually.  I will not argue the point further because I expect that most readers who can be persuaded found a glance at the numbers sufficient.

EA's ability to do more things in this space, if it is not bottlenecked on money, is very likely bottlenecked on: good ideas to pursue; people who can pursue those ideas; and/or admin staff who can investigate grants, make them, and operate them.

I suspect that people who can do these things are, at the very least, valuable.  They should therefore be nurtured even in their earlier stages.  If you ever want an apple tree that bears fruit, you may need to at some point plant a seed that doesn't have any apples on it right then, and invest effort into watering it in proportion to how many apples you hope for later, rather than how much this tiny sapling has proven itself right now.

I think it was a huge, huge mistake that more money was not spent on AGI alignment when it was small and weird and unproven.  The resulting damage was not something that could be fixed by any or all of the money that became available later.  Someday I may write more about this.  Anyways, don't do that.

The Rapid Deployment Vaccine Collaborative, aka RaDVaC, is now past the small weird stage.  They've pretty much proved themselves.  They should be nurtured and scaled up to where they can start to replace US and Earth defunct state capacity to do the R&D that leads up to being able to rapidly design new vaccines that rapidly scale in production and deployment.  If we can't give RaDVaC $2M I'd like to know what it's being spent on that's more important.  Covid-19 was not very much of a pandemic and if Earth ran into a serious pandemic in its current state that would be a serious problem.

Some weird person [correction: 2 weird people] wants to investigate whether the real driver of our massive planetwide obesity epidemic is lithium contamination, probably in water.  If you are completely unfamiliar with the actual science on obesity you probably think that's dumb because obesity is caused by high-palatability foods.  Read the first page linked if you'd prefer to know why that's obviously wrong.  If you know about the actual epidemiology of obesity and how ridiculous it makes the gluttony theory look, you are still probably saying "Wait, lithium?"  This is still mostly my own reaction, honestly.  But obesity remains a massive growing planetary problem, and almost nobody is investigating it in a way that takes the epidemiological facts seriously and elevates those above moralistic gluttony theories.  If some weird person wants to go investigate, I think money should be thrown at them, both to check the low-probability massive-high-value gamble, and also to encourage them to maybe go investigate something else in the same space if the lithium thing doesn't pan out.  $200K maybe.  They advertise their effort under the name of Slime Mold Time Mold (SMTM) for no particular reason I can discern.  I think this is the kind of decision that some people make when they are small and weird, and I think that if we allow that to prevent us from throwing money at them then we are stupid and not learning from history.

That's all.  Writing this up now, briefly and hurriedly, because the lithium person wants lithium people want to apply for some EA grants.  Consider this my recommendation thereof.

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If you are completely unfamiliar with the actual science on obesity you probably think that's dumb because obesity is caused by high-palatability foods.  Read the first page linked if you'd prefer to know why that's obviously wrong.

I admit to being, at present, persuaded by the high-palatability hypothesis, which I roughly translate into the following thesis: "The general rise in obesity is primarily explained by the rise of highly processed, addicting foods, which raises our natural set point, tricking our bodies into eating more calories than we 'need' before feeling full."

I read the posts you linked (you referred to this one, right?), and I'm not convinced by them, but I'm open to people explaining why they think I'm still wrong.

First I'll summarize the article briefly, and then respond to each point.

My brief summary

The series begins by outlining 8 mysteries:

  1. Obesity has gotten a lot worse over time
  2. Obesity abruptly got worse some time in the 1970s
  3. There's good evidence that we're not winning the war against obesity
  4. Hunter-gatherers don't become obese
  5. Lab animals and wild animals have also become obese over time
  6. People and animals gain a lot of weight when exposed to palatable foods
  7. People at higher altitudes seem to get obese at a lower frequency
  8. Diets are not effective at reducing obesity, for nearly everyone

The series continues by arguing that CICO (as in calories in, calories out) cannot explain the current crisis, and cites an array of evidence that tries to argue against that model. Given the inadequacy of CICO as a model for weight gain, then, the reason for the current obesity crisis must be due to environmental contaminants, which neatly fit each of the 8 mysteries.

My interpretation of the mysteries

In my opinion, assuming the high-palatability hypothesis, very few of the mysteries are actually "mysteries" in the sense of being surprising.

For example, we can explain mystery 1 by saying that high-palatability foods have become more common over time (duh). We can explain 3 because very few people are effectively targeted by anti-obesity campaigns, and it's intractable to simply ban high-palatability food (which is probably the only solution that would actually work on a large scale, short of advanced technology). We can explain 4 by pointing out that hunter-gatherers don't eat high-palatability food. We can explain 6 for obvious reasons. We can explain 8 by pointing out that people don't have unlimited willpower, and thus, don't rigidly adhere to a dieting plan when given abundant choices to "cheat" and eat high-palatability food (which is highly addictive).

That leaves mysteries 2, 5 and 7, which I do think call out for more explanation. However,

  • Mystery 2 is practically equally mysterious under both the environmental contaminant hypothesis, and the high-palatability hypothesis, since by the author's admission, they have little idea about what chemicals were abruptly introduced into the environment starting in the 1970s. At the same time, I found their argument that foods were palatable before the 1970s to be weak. 

    Sure, you can name a few palatable foods from before the 1970s (Oreos, Doritos, Twinkies, Coca-Cola), but I don't find it particularly unlikely that the absolute number and variety of high-palatability foods has increased greatly since the 1970s, given the immense pressure for food corporations to hyper-optimize their food for consumption.
  • Mystery 5 is only a real mystery if indeed animals under controlled conditions are getting fatter over time. The author presents two sources for this claim. 

    Source one states in its abstract, "We examined samples collectively consisting of over 20 000 animals from 24 populations (12 divided separately into males and females) of animals representing eight species living with or around humans in industrialized societies." The palatability hypothesis can elegantly explain what's going on here. Animals who live near cities are exposed to human trash, and humans throw a lot of high-palatability food away. Animals eat the trash and get addicted to it, raising their set point, causing them to overconsume calories. Animals that live with humans get fed human-produced food.

    Source two is about horses, and I lack a coherent explanation for the details. But, this is mostly because I don't know how common it is for horses to eat hyper-palatable food, as I have very little experience with common horse-feeding practices. 

    Overall I wasn't able to find compelling evidence that animals in controlled conditions , that don't eat high-palatability foods, are experiencing increasing rates of obesity. (Though, of course, I might have missed this evidence in the sources). [Edit: it looks like I was mistaken and the first source includes laboratory rats and mice in the study.]

As far as I can tell, the most surprising mystery is 7. The author presents impressive evidence regarding altitude anorexia, and studies that looked into alternative factors (including carbon dioxide and oxygen). 

EDIT: I now think that oxygen is the leading culprit for altitude anorexia, even though the author says it isn't. Their evidence against the oxygen hypothesis is the following: one study found a small effect, and another study was methodologically flawed. Putting aside the second study, the effect found in the first study was not small at all in my opinion; in fact, it found that people who exercised in a low oxygen environment lost about 60% more weight than those who didn't! Scott Alexander has written about this and finds the oxygen hypothesis plausible. 

Yet, all things considered, I still don't think that enough alternative hypotheses have been explored to say that mystery 7 is anywhere near conclusive. It's well-known that obesity rates vary by demographic groups, and that there are genetic confounders involved, and demographic groups are also not evenly distributed between high and low altitudes.

In poorer nations, such as China, it seems highly plausible to me that altitude correlates strongly with access to supermarkets and fast-food restaurants that carry lots of high-palatability foods. Urban centers are generally clustered in low-altitude areas, along coasts and alongside rivers. If people in urban areas are exposed to more high-palatability foods, as opposed to more traditional dishes, then it seems obvious that you'll find a correlation between altitude and obesity. The contamination hypothesis is not needed to explain this fact.

My take on CICO

Given that I don't find any of the mysteries very surprising (with the possible exception of 7), I don't see why the contamination hypothesis falls out as a parsimonious explanation of the data. Admittedly, however, my main disagreement probably boils down to the section on the plausibility of CICO.

Being honest, I found many of the parts of the CICO post to be riddled with misleading statements, sometimes simply confusing CICO with the idea that diets and attempts-to-increase-willpower work (which I emphatically do not believe), or strawmanning CICO into a generic position that absolutely nothing other than calories and exercise matter, or that an excess 3500 calories precisely and linearly adds 1 pound of fat to your body. 

Obviously other factors, including genetics, matter. Obviously diets do not work on a large scale. And obviously the formula is not as easy as "eating an extra 3500 calories always means you gain an extra pound, even extrapolated to people eating 10,000 calories a day." None of these facts are strongly inconsistent with the high-palatability hypothesis as the dominant explanation of the data. In my opinion, these are quibbles, not knock-down arguments.

And, in any case, the author admits,

Sure, consumption in the US went from 2,025 calories per day in 1970 to 2,481 calories per day in 2010, a difference of 456 calories.

That's a lot! As someone who has very carefully controlled my eating before, I saw first-hand how eating a 500 calorie deficit made me lose weight, and conversely, how eating a 500 surplus made me gain weight. The author seems quick to handwave this fact away, as if a few hundred calories can't add up over time. Their interlude responding to objections on this point also seems handwavey to me, and doesn't give any evidence inconsistent with the high-palatability hypothesis.

Conclusion

Given a biologically plausible mechanism, its consistency with practically all the "mysteries", common sense, and general scientific wisdom (from what I gather), it seems highly likely to me that the high-palatability hypothesis is correct. This, in my opinion, diminishes the case that money should be spent investigating alternative hypotheses (though the value of being proven wrong might be so high that it's worth it anyway).

Impression: One of the articles also made a point about how certain tribes started becoming obese when exposed to Western culture. The high-palatability food hypothesis explains this reasonably well, whereas I'd need to see more details to imagine how lithium poisoning could have happened through their water supply. 

Long ago, when SSC had an article about the altitude/obesity thing, a friend and I looked more closely at the data. I concluded that it seems like the bulk of the effect is explainable by selection effect, since there are very few people who live above a few thousand feet elevation, and they're probably disproportionately upper class and active. See https://slatestarcodex.com/2016/12/11/open-thread-64-5/#comment-443619 (and the original post at https://slatestarcodex.com/2016/12/05/thin-air/). I'm serious about these selection effects--the data linked in my comment includes BMI values up to 3km or 9,800 feet above sea level. I don't think there are 10,000 Americans living at that elevation total, and they almost all live in towns that primarily exist to serve wilderness recreation. 

When Scott more recently posted about this hypothesis in one of the ACX open threads, one of the SMTM authors answered some questions in the comments. The mechanism tying elevation to pollution is allegedly that elevation is a proxy for how upstream you are in the water cycle, since water will accumulate toxins from the ground or being pumped into the water as it goes. To me, this seems like an extremely loose association. The relationship will depend strongly on how many pollutants are in the local area and how quickly the water loses elevation. Also, where people get their water from may not reflect exactly where they live: Consider Dillon reservoir (https://en.wikipedia.org/wiki/Dillon_Reservoir) at 9,100 feet. This water serves people in Denver, 4,000 feet below, after a fairly direct route through a tunnel and then into the Southe Platte River. The people who live near the reservoir get their water from the Green Mountain Reservoir (https://en.wikipedia.org/wiki/Green_Mountain_Reservoir) over 1,000 feet lower. And both reservoirs are filled largely from snowmelt, with the former being surrounded by generally higher mountains. And there's clearly a lot of other factors that are visible in the obesity map at the top of Scott's original post other than elevation--for example, there's clearly a large drop in obesity from Kansas to Colorado, even though the state border is in a flat area 100 miles from the Rockies. You can also see large differences between New England, the upper Midwest, and the South, despite all those places being the exact same elevation. 

Given the exceedingly noisy part that pollution must play in this story, and the extreme selection effects that are required to see a clear relationship between elevation and obesity, I think the latter is a much more likely explanation of the link than pollution. 
 

The mechanism tying elevation to pollution is allegedly that elevation is a proxy for how upstream you are in the water cycle, since water will accumulate toxins from the ground or being pumped into the water as it goes. To me, this seems like an extremely loose association.

I agree, but moreover it looks like it should be an easy theory to test. My guess is that there are basically three routes for contaminants to enter our body and make us fat. The chemicals could be in the air, the water, or our food. If the SMTM authors believe that it's in our water, then drinking distilled or purified water should make us thinner. Do we have any evidence of this?

I have no idea, although I expect any such effect to be a very long-term thing and thus tricky to design and measure. 

When I looked into it, you could see an effect on birthweight for babies born to mothers in high altitudes vs their lower-altitude siblings, and vice versa, which suggests to me something non-genetic is going on.  And the effect of altitude on birth weight held up in countries where altitude was associated with both lower and higher income (although that wasn't the sibling study), which pushes against and doesn't eliminate income effects.

(I'm not actually sure if e.g. median income is positively associated with elevation in the US, since a bunch of those people are "ski bums" working a series of seasonal jobs at ski resorts, white water rafting companies, etc. I used the word class because I think those people are still disproportionately drawing from upper-class cultures and probably have high education on average, and there are definitely a lot of rich people hanging around as well, and the latter are more likely to live closer to the resorts. Mean income is definitely higher in those areas, though.) 
 

That's a really neat set of data in that blog post which I will have to go over in more detail later. The effect size doesn't seem to be that large to me, but maybe I don't have a good intuition for birth weight; 100 g = 0.2 pounds corresponds to 4% of the low range of what is considered healthy in European babies. And that's over a fairly wide elevation range of 3,300 feet. So I would be surprised if that could explain the very large difference in adult average BMI, but I could also be totally wrong about how fetal weight translates to adult weight. Given the limitations of "controlling for observables" I'm also still leaning towards selection effects, but the close linear relationship does cast doubt on that idea. I think it casts doubt on the pollution hypothesis too, FWIW, since there's no way that's cleanly linear, and it probably fits better with hypoxia but still not perfectly, since air pressure decreases sublinearly with elevation. 

The mechanism tying elevation to pollution is allegedly that elevation is a proxy for how upstream you are in the water cycle, since water will accumulate toxins from the ground or being pumped into the water as it goes. [...] And there's clearly a lot of other factors that are visible in the obesity map at the top of Scott's original post other than elevation--for example, there's clearly a large drop in obesity from Kansas to Colorado, even though the state border is in a flat area 100 miles from the Rockies.

Isn't this specific point evidence in favor of SMTM's hypothesis? Eastern Colorado and Kansas are at similar elevations, but Colorado gets most of its water from rivers that start in Colorado and Kansas gets most of its water from an aquifer (https://geokansas.ku.edu/water-kansas). SMTM suspects aquifers are more contaminated (with lithium?) (https://slimemoldtimemold.com/2021/10/19/a-chemical-hunger-interlude-h-well-well-well/).

This might just be nitpicking. I disagree with or perhaps don't understand the "set point" usage that is common here. I see it more as a balance of inputs to the brain from the mouth and stomach/other satiety sensors. 

Plain boiled potatoes have a taste pleasure score of 3, and thus a satiation score of 3 from the stomach is required to stop you eating more of them. 

Chocolate cake has a taste pleasure score of 8, and so a satiation score of 8 from the stomach is required to stop you eating more. 

As you require a stronger satiation score to overcome the pleasure of the chocolate cake, you naturally eat more of it before the satiation score overpowers the pleasure score. 

This explains the common experience of feeling full on a healthy dinner, then immediately being able to eat 500kcal of dessert. 

Relative to the "set point" idea (or at least my understanding of it), this means if you switch to the only plain boring foods diet (or natural and healthy if you want a positive frame) then you can successfully lose at least some of the added weight. I do find the idea of some permanent regulatory damage plausible. 

This dynamic will essentially create different set points on different diets. The whole range of set points for different diets being moved up over time by a hyperpalatable diet, due to it being an unnatural stimuli, does seem plausible. 

(Actual reality advisement, do not read if you'd rather not live in actual reality:  Things really worth doing, thus in AGI alignment, are hard to come by; MIRI is bottlenecked more on ideas worth pursuing and people who can pursue them, than on funding, at this point.  I think that under these conditions it does make sense for EA to ever spend money on anything else.  Furthermore, EA does in fact seem bound and determined to spend money on anything else.  I therefore think it's fine for this post to pretend like anything else matters; much of EA with lots of available funding does assume that premise, so why not derive valid conclusions from that hypothetical and go ask where to pick up lots of QALYs cheap.)

MIRI is bottlenecked more on ideas worth pursuing and people who can pursue them, than on funding

Ideas come from (new) people, and you mentioned seed planting which should contribute to having such people in 4-6 years, seems like still a worthy thing to do for AGI if anything is worth doing for any cause at all (given your short timelines). If you agree what's the bottleneck for that effort?

If ideas are the bottleneck, perhaps there should be monthly pitching sessions where people get to pitch their AI safety ideas to MIRI? Obviously, I imagine that you'd need to find someone who'd be a good filter - to ensure that there are only a reasonable number of pitches - whilst not cutting out any "crazy" ideas which are actually worth considering.

Well, this has inspired me to finally make an account for LessWrong commenting! 

As someone very familiar with the "science on obesity", I do not find SMTM remotely persuasive. https://basedprof.substack.com/p/smtm-mysteries canvasses the reasons why in detail, for those who are going to look at the link in the above article and be inclined to trust it. SMTM repeatedly misrepresent not just scientific consensus, but also literally the articles which they cite. There are multiple examples of it in the "Mysteries" post, but this isn't even the worst offender. 

If you do not believe that EA should be in the business of giving money to proven liars, shown to be rather specifically lying about the thesis which they would be given money to study, you should not give a cent to them, and you should point out that others should (not) do the same.

For those who don't want to read my (admittedly ranty) post about them (the reasons for said rantiness are, well, the consistent lying), here are three such lies/misrepresentations (two from the above, another from the second post in the series).  As an aside, I'm not merely asserting that they are often wrong (though that would also, by extension, and in addition, be true). 
 

(1) "their [our grandparents/great grandparents and older] diets were worse, not better. They ate more bread and almost four times more butter than we do today. They also consumed more cream, milk, and lard." - and the linked article once more: https://academic.oup.com/ajcn/article/91/5/1530S/4597478
I suppose this is not "strictly" a lie in the same way that "When did you stop beating your wife?" is not strictly an unreasonable question to ask. But it's deeply misleading, and SMTM must know it is misleading if they actually read the article they use as evidence. That very article cites a massive increase in consumption of other fats, and carbohydrates- so even if our ancestors ate more butter and bread, they were still consuming far fewer calories. This, in fact, is what the article concludes: "The increase in childhood obesity mainly reflects increased energy intake". 

(2) "A Tanzanian hunter-gatherer society called the Hadza get about 15 percent of their calories from honey. Combined with all the sugar they get from eating fruit, they end up eating about the same amount of sugar as Americans do. Despite this, the Hadza do not exhibit obesity."
They provide literally no evidence for the proposition that the Hadza eat as much sugar as Americans do, their citations certainly do not demonstrate this.  And as I cite in my response ( https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0040503 :

“Western diets are certainly more sugar-rich and energy-dense than more “traditional” diets and wild foods [4], [8], [9], many hunter-gatherers seasonally consume a large portion of their daily calories as honey” which, ok sure, “a lot of daily calories as honey”, but look at the “western diets are more sugar rich and energy dense” bit.

They move from a claim about percentage of energy intake for individuals to an entirely unwarranted claim about overall energy intake between two different cultures. This section is actually way worse, but feel free to read my post for more. 

(3) "“This model seems to exist mostly to make lean people feel smug,” writes Stephen Guyenet, “since it attributes their leanness entirely to wise voluntary decisions and a strong character. I think at this point, few people in the research world believe the CICO model.”" 

This is a "lie by equivocation". Guyenet is a respectable scientist, who works on hunger signalling.  When he talks about "CICO", he means "the model by which people just eat more as a purely voluntary thing and gain weight". And he is totally right that no-one thinks weight-gain is purely voluntary. Even the "hyper palatable food" people don't think that. But that isn't what SMTM mean by CICO. Here is what SMTM say: 

"A popular theory of obesity is that it’s simply a question of calories in versus calories out (CICO). You eat a certain number of calories every day, and you expend some number of calories based on your metabolic needs and physical activity. If you eat more calories than you expend, you store the excess as fat and gain weight, and if you expend more than you eat, you burn fat and lose weight. This perspective assumes that the body stores every extra calorie you eat as body fat, and that it doesn’t have any tools for using more or less energy as the need arises. But this isn’t the case. Your body has the ability to regulate things like its temperature, and it has similar tools to regulate body fatness. When we look closely, it turns out that “calories in, calories out” doesn’t match the actual facts of consumption and weight gain." 

So SMTM are misrepresenting what a hunger scientist means to gain a little bit more epistemic credibility for their take. He is talking about what drives hunger, which leads to increased energy intake. They're talking about mechanisms for bodily fat regulation. 

R.e. #2

They provide literally no evidence for the proposition that the Hadza eat as much sugar as Americans do, their citations certainly do not demonstrate this.

The cited paper has a chart showing that Hadza get 14% of their calories from honey. A quick google search claims honey has 17g sugar per 64 calorie serving. So assuming 2000 calories/day, that's 280 calories of honey, which contains 74g sugar.

According to some google results, Americans consume around 70 (highest I saw was 77) grams of total sugar per day.

So it does seem to be similar. SMTM writes that this is "Combined with all the sugar they get from eating fruit". The same paper says 19% of their calories are from berries and another 18% from baobab fruit.

So it seems entirely plausible that SMTM is correct here.

I think I could grant they are actually correct there- it's just not actually in their evidence. Thanks for doing the math though. 

I just read your post, and it seems like you're arguing against something SMTM don't support. They admit that they describe it badly in their initial post, but right after the CICO section there's a link to this additional post about CICO.

My understanding is that they're arguing two things: against the "linear relationship between calorie intake and weight change" meaning of CICO, and that it's mysterious that people are eating more over time:

The overfeeding studies provide extremely strong evidence against this version of CICO [the linear relationship], since people gain very different amounts when overfed by the same amount, the difference appears to be mostly genetic, and some people actually lose weight, even when overfed by moderate (1000 kcal/day) amounts. Many people still believe something like “for every extra 3500 calories you eat you always gain one pound”, but all available evidence comes down very strongly against that.

At low levels of overfeeding, people at normal weight often don’t gain any weight at all.

[...]

[...] A common interpretation tied up in CICO is that differences in willpower explain the difference between obese and lean people. The idea is that weight gain is easy and weight loss is hard for everyone. This interpretation says something like, everyone would be 300lbs if they didn’t use their willpower to eat healthy foods rather than cake — you have to control yourself. From this perspective, people who are obese lack willpower and people who are thin/fit are virtuous resisters of temptation.

The overfeeding studies also provide strong evidence against this hypothesis, since they find that it is hard for most people to gain weight and easy for them to go back exactly to the weight they were before the overfeeding. We think this leaves “willpower” explanations dead in the water. Most skinny people have no trouble staying that way.

[...]

Another interpretation is something like “calories matter for weight gain”. Other things being equal, you generally gain weight when you eat more calories and you generally lose weight when you eat fewer calories.

We are not trying to argue against this at all! If you eat 400 kcal/day, you will lose weight (there are studies on this). If you eat 10,000 kcal/day, you will gain weight (there are studies on this one too). But the amount of calories you eat matters much less than most people think, and there isn’t a strong linear relationship between calories consumed and weight gained (see above).

You can lose weight by consistently eating at a calorie deficit, but people who do this either struggle to maintain their lower weight or gain it back. For two people who are the same height, one might weigh 150 lbs and the other weigh 200 lbs. If the 200 lb person loses 50 lbs, it will be hard for them to maintain a weight of 150 lbs, but easy for the person who weighed 150 lbs to begin with. Why is that? And why has the number of people struggling with their weight grown so dramatically since 1980?

The final line is really the mystery here. It's obvious that people eating significantly more will gain weight, but why are people suddenly eating significantly more? It's possible that food limitations explain some of this, but it would be surprising if so many Americans were starving in 1980 for the obesity rate to go up by 20% since then (but I'd love to see an argument that this is the case!).

Since SMTM's mystery is (among other things) "why are people eating more", your argument that SMTM are stupid lying liars because obviously people are eating more and historical people ate high fat/high sugar diets but ate less overall misses the point.

Well, I never called them stupid. In fact, quite the opposite. I promised a series on SMTM on my new blog, but life has got in the way somewhat the last few weeks. I should perhaps get around to that now. Just a few notes on this: 

Their interpretation of overfeeding studies is extremely odd. That's an aside, but it's one that I'll make good on in a few days. I've already discussed it at length on the ACX discord server, but not in a format conducive to just reposting here. So, a little note on my distaste for their appeals to "common interpretations", since those literally do not matter- something that is a mystery to Bob on the street and not a mystery to diet scientists, is not a mystery that requires extra research. It requires education and publicity, maybe.

The "linear relationship" is one such appeal- it's not something I think anyone actually believes. Or rather, there is a sensible and a less sensible interpretation. The sensible interpretation is that your metabolism changes as you get fatter, because fat is metabolically active tissue. A person with 300lbs of "extra" fat on them will "be" a metabolism which is burning through more calories daily/weekly regardless. Add 3500 calories onto what they eat weekly for maintenance of that weight and you'd expect about a lb of gain, holding things like activity level equal (and probably for someone very fat you can). But you can't stop at time t1, determine the caloric surplus for such a person would be, say 4500 calories a day for a surplus of 1lb a week, and just run that forever. That's not how any of this works. 

Also I know of literally not a soul writing in the literature today (maybe random "diet coaches" at weightwatchers and the like) that thinks weight loss is equally hard for everyone. You have different cultures, access to different foods, tolerance of different foods, different leptin signalling, different hormonal responses, different fat distribution, so on- oh and just differing lifestyle factors between individuals. Much of this explains how some get fat in the first place and how some fail to do so. It also explains how those differences could become more stark in environments where suddenly lots of hyper-palatable and not-very-satiating food becomes the norm. 

But anyway, these are just a few notes, and I'll cover more when I write up the post responding there. I'll just add that I think there is clear intent to mislead in various places (to the "why would I call them lying liars and aren't I really missing the point" issue). I refer you to (1) especially here- if you don't think, having read the underlying article, and their commentary, that they are being even remotely misleading, well, that's an interesting data point at least. Because I'm not seeing a retraction or an edit there, which would be reasonable if one thought there was danger of misunderstanding. And it seems to me the reason why is because it's a nice hook- "people ate all the bad food years ago and they don't eat the bad food as much now even, but they're getting fatter", "never mind about the fact that we just swapped what fats we consume and have quadrupled our intake or whatever". 

Since SMTM's mystery is (among other things) "why are people eating more"

If I thought their only point was "environmental contaminants might be making people hungrier" then, well, I'd still have lots of issues- not least that we already have plenty of research on diets which talk about this very issue. But, y'know, fine. There are plenty of interesting things which do affect hunger-signalling, But the "among other things" troubles me, and the main one- which SMTM very evidently devote quite some time too, is the "ability of the body to just dump fat stores". It's noted in various places, sometimes explicitly, sometimes through the writing equivalent of raised eyebrows and nodding in a certain direction. But it's there. And (1) to reference back, goes precisely to that issue. The claim isn't that people just feel like they must eat more now, it's that they ate "badly" in the past and yet didn't seem to gain weight in spite of it. No mention of calories specifically there, but of course that does come up later with overfeeding studies and this utterly ludicrous "we don't deny that if you eat only 400 calories a day you'll lose weight, and10,000 a day you'll gain weight", as if this is a concession to common sense. They seem to believe, or at least write as if it is the case that, a person at weight [x] today, could eat the same amount as someone 100 years ago, also at weight [x], calorically, and yet gain more weight, for reasons having nothing to do with exercise (obviously not diet since that's the control here). That is where I have serious issues. If you think that is not something in the SMTM canon, then let me know why I'm misreading them, please. 

The "linear relationship" is one such appeal- it's not something I think anyone actually believes.

People definitely believe this.

Also I know of literally not a soul writing in the literature today (maybe random "diet coaches" at weightwatchers and the like) that thinks weight loss is equally hard for everyone.

People definitely believe this.

"people ate all the bad food years ago and they don't eat the bad food as much now even, but they're getting fatter", "never mind about the fact that we just swapped what fats we consume and have quadrupled our intake or whatever".

There are definitely people who think that if they just eat less butter/sugar/etc. but replace it with the same amount of calories in something else that they'll lose weight.

They seem to believe, or at least write as if it is the case that, a person at weight [x] today, could eat the same amount as someone 100 years ago, also at weight [x], calorically, and yet gain more weight, for reasons having nothing to do with exercise (obviously not diet since that's the control here).

What makes you think SMTM believe this?

It seems like you don't believe that layman beliefs can be as wrong as they are, and then assume from that that SMTM is bringing these things up to mislead people, but the article makes way more sense if read it literally, as-if people actually believe these things and SMTM is arguing that they don't (fully) explain the rise in obesity.

The weird thing is that none of this matters, since this is just the "Why are we writing this series?" article. SMTM's actual hypothesis (so far) is that there's some sort of contaminant that makes people gain weight in an unspecified way. It doesn't actually matter if comtaminant x makes you eat more or makes you gain more weight while eating the same amount. If this hypothesis is right and we could eat less of the contaminant, then we'd stop gaining weight (and hopefully lose some).

To be clear I think you've misunderstood me here, and that may be my fault. But, to clarify, I'm not saying anything, really, about the laymans' beliefs. Whenever I talk about "people believing x", I'm meaning "people who research diets and such". I don't care what laymen believe. As I said, laymen believe all sorts of silly stuff in all sorts of fields. But laypeople disproportionately believing astrology would not, for sake of argument, mandate that we do more research showing why astrology is bunk (no, I am not comparing the arguments of SMTM to astrology, I am only using the comparison for the specific point here about laymen and their irrelevance to research). It might be the case that we should do more to educate laypeople on matters of calories and and weight-gain and all the adjacent funky stuff too. But none of this requires more research. 

Actually my second quote does make it clear "not a soul writing in the literature today"- so I think that one is on you, but the first is on me, fair enough. 

"What makes you think SMTM believe this?"
All of the talk about mechanisms for dumping fat, in relation to changes in weight at the population level. Also their later commentary about diets basically not being possibly workable, which would only be true if there was some mechanism meaning people retained fat way more than others, instead of "some people have disproportionately strong hunger signalling relative to others". But mostly the prior stuff. 

"If you eat more calories than you expend, you store the excess as fat and gain weight, and if you expend more than you eat, you burn fat and lose weight.

This perspective assumes that the body stores every extra calorie you eat as body fat, and that it doesn’t have any tools for using more or less energy as the need arises. But this isn’t the case. Your body has the ability to regulate things like its temperature, and it has similar tools to regulate body fatness."

So we have this. In the same article, we also have them talking about how fat and carbohydrate consumption have gone down, yet obesity has gone up. Frankly, if they sincerely believe people are eating less (I do not believe this to be true, I think we have good reasons to think this is not true), then its' not just hunger-signalling that they're talking about as being a difference maker. 

I think the most straightforward way to prevent people from giving SMTM money is to stop questioning their motives and just answer the question (if it really is so easy): Why does the obesity rate curve look the way that it does?

And note that "because people are inexplicably eating more" doesn't really answer the question, and an explanation like "Americans had substantially easier access to delicious food in 2018 (obesity rate 42%) than they did in 2008 (obesity rate 34%)" would be surprising and need evidence backing it up.

To be completely clear, I honestly want the answer to this question (and I like SMTM since they seem to understand why it's an interesting question)..

There is nothing at all inexplicable about that. Access to very palatable and not-very-satiating (cal for cal) food will change behaviours over time, these behaviours are also inherited in familial environments, and compound since once someone is obese, it becomes increasingly hard to get not-obese. With micro-cultural behaviour change which favours obesity, we're also seeing actual cultural changes toward acceptance and promotion of obesity-promoting behaviours, excessive eating among family and friends, increasingly sedentary lifestyles (lord knows the last two years will have accelerated that), forgetting how to cook, or deciding to not bother cooking the sorts of foods which are satiating and lower cal. 

(1) "their [our grandparents/great grandparents and older] diets were worse, not better. They ate more bread and almost four times more butter than we do today. They also consumed more cream, milk, and lard." - and the linked article once more: https://academic.oup.com/ajcn/article/91/5/1530S/4597478 I suppose this is not "strictly" a lie in the same way that "When did you stop beating your wife?" is not strictly an unreasonable question to ask. But it's deeply misleading, and SMTM must know it is misleading if they actually read the article they use as evidence. That very article cites a massive increase in consumption of other fats, and carbohydrates- so even if our ancestors ate more butter and bread, they were still consuming far fewer calories. This, in fact, is what the article concludes: "The increase in childhood obesity mainly reflects increased energy intake".

For those who would like to check this quickly, the data is on page 2 of this pdf.

I concur that the quoted statement is disingenuous albeit literally true.

In defense of bread, butter and milk: 

A traditional bread like sourdough has a glycemic index of 54 and 12g protein per 100g. While I love the taste, I wouldn't classify it as hyperpalatable. It only has 4 ingredients: flour, salt, water and bacteria. I would classify it in the middle between hyperpalatable and bland. 

I don't think plain butter or milk are hyperpalatble either. Only when used in certain ways in recipes do they result in hyperpalatable foods. Personally, I don't like plain milk and couldn't eat butter on its own. 

Nutritionally, I would also dispute that these are unhealthy if this is being implied. To my knowlege, saturated fats are no longer thought to be bad for health.

Good news: my mental model of SMTM could also have them just skimming/cherry-picking the butter quote cited by BasedProf

Bad news: that's not much better than the scenario where SMTM is, in fact, lying on purpose. And I haven't looked deeply enough to tell if there's reasonable alternatives.

More bad news: Yudkowsky and AppliedDivinity both seem to be on the giving-money-to-SMTM-without-checking-on-their-trustworthiness/responding-to-basedprof's-criticisms-publicly grindset. And has SMTM responded to BP publicly either?

It's pretty disheartening, yeah. Putting aside the lying for a moment, I'm also pretty deeply concerned at the damage SMTM could do to public health, if funding and attention allowed them to reach a wider audience. From https://slimemoldtimemold.com/tag/a-chemical-hunger/ 

"Our suggestions are very prosaic: Be nice to yourself. Eat mostly what you want. Trust your instincts. 

Diet and exercise won’t cure obesity, but this is actually good news for diet and exercise. You don’t need to put the dream of losing weight on their shoulders, and you can focus on their actual benefits instead. You should focus on your diet — not to get thin, but to make sure that you have enough energy to do everything you want to do in life. This means eating enough and making sure you get what you need. You should exercise — not to slim down, but to gain strength and energy, and you shouldn’t get discouraged when you don’t drop 50 lbs fast."

Obese? Don't worry about it! It's chemical, maybe with an added bit of genetics to explain why you're fat and your friend who drinks the same water isn't. "Don't diet to get thin but to have enough energy" is basically "don't diet to lose weight, in fact, if you feel low-energy, then don't worry about gaining weight". And this is terrible advice to give the obese and morbidly obese. Yes, you shouldn't be terrible to such people, because that is no way to encourage change, and because you should not add to someone's woes. But being fat, even "healthy eating and fat, and walking periodically and fat", is still tied to worse actuarial outcomes, and direct and obvious health consequences. And it's avoidable! I didn't say much about this in my earlier comments, or on my own blog, because it's not relevant so much to the population-level stuff, but it really is entirely possible to lose weight at the individual level. There are studies on this too. 

It may be, especially for some people, not-easy. But lots of things that will add years and QALYs are not easy. What I'm quite sure doesn't make it easier is imbibing this talk from SMTM, concluding that nothing can be done, and only wising up 2 or 5 or 10 years down the line, when you're fatter, and afflicted potentially with conditions that ride along with additional weight gain, and decide to try losing weight then

Like seriously, Eliezer, if you're reading this, I'm happy to walk you through any research on this topic to your hearts content- I won't ask for a "bounty" like Applied Divinity is offering, and I promise to patiently respond in any forum to any question on this, within my power to answer- where it is not I will appeal to others I know who are more knowledgeable. But please do not give money to these people, or encourage others to do the same. This is a time when providing money is at best a waste, and at worst, likely to actually make the world worse in a small but obvious way. At least, if you think I'm full of it, require a little more of them before taking said plunge. 

Please don't throw around accusations of "lying" because you had a different interpretation of some studies than they did. Even if they are objectively wrong about some, this could easily be errors, not malicious lies. (Not arguing about the object level here).

I do not merely have "a different interpretation of some studies" to SMTM- or at least, this is not centrally why I make the rather specific accusation I do (which I stand entirely by) (A few points of closer-to-object-level disagreement to follow, concluding with my "real" response here, if you want to skip ahead). 

The first of three instances I cite here is closest to the pattern you describe, and even there, I wouldn't suggest they were being purposefully misrepresentational if they had cited and disagreed with the paper in question. What we have instead is a paper clearly stating/providing, in its abstract and conclusion (and quite frankly, there is no other reasonable interpretation of the data they provide- one could dispute the data, but SMTM does not go this route) a causal story for secular weight gain (specifically during childhood), and SMTM using that citation narrowly to, in effect, make the contrary point (that this is a big old mystery, that our forebears ate more "bad" food than we did and mysteriously didn't get fat). It gets worse, mind you, though I was trying to keep my initial comment (relatively) brief- since this is immediately followed up wth "we don’t seem to have any idea what that thing was". I'm of the view that if SMTM had good reason to disagree with this and other papers they cite (to say nothing of the mass which address this question besides, but I'm not merely accusing them of being uninformed, as I said), then they should either explain why in individual cases, or give some reason for a blanket-dismissal of the literature (which they remain happy to cite for their own purposes, mind you, so the reason can't be "utter incompetence of people in the field). 

The second point simply leaps from a claim about percentages of intake to a claim about absolute intake with precisely no citation, explanation, or argument, in a way that clearly equivocates (I've had several conversations with people who have, in fact, "fallen for" this). SMTM are not fools, and they're often praised for the quality of their writing, so I struggle to believe this was an innocent mistake. I won't go over point 3, but I'll make a more general point, a little further from the object level here too. 

I think what can be an epistemic virtue in discussion can risk becoming a failure mode in action. Extending the sort of charity required to assume SMTM are merely misguided, or that a mere factual disagreement exists among us, despite evidence to the contrary, is a Good Thing, even if not strictly accurate, while we're debating diet models, or considering the effects of lithium on body fat, or whatever else. We want to engage with the strongest possible version of our counterparts position, or at least engage on assumptions of good faith. That's all great, and a positive thing in general about the LW/ACX/Rationalist community. On the other hand, if you're trying to buy a car, or are contemplating a business deal, or (as here) are considering where to give money to charity, between "nets for african children", "AI alignment", "   When thinking in the domain of "giving people money", I think one should be more, not less, than averagely sensitive to the possibility that you are being deliberately misled. If someone shows all the signs that they are:

(1) omitting important information; "This car lacks brakes!" "Well, I would have told you but the email just didn't have room for that information"

(2) interpreting data differently to how the modal reasonable person would without any explanation (and without providing the data upfront); [no patients in the hospital and only admin staff on payroll] "The hospital is operating at peak efficiency and achieving its strategic goals!" 

(3) Equivocating or jumping from one claim to a different one without good reason; I honestly can't think of a better example than the Hadza case for SMTM so I won't try, and will just invite people to look at that again

then you should, in fact, model them as liars, and don't give them your money. I think this is a reasonable heuristic, at least, but one is free to do whatever of course. I'd just put around a credence of 0.0000001 in you getting any sort of return on this investment. You might ask why one should not say "This person is radically wrong in this case, don't give them money to study this" instead of accusing them of deliberate misrepresentation. Well, understanding when someone is lying is helpful to modelling future action. I think we would all mostly agree that it would be deeply unwise to "invest" in Bernie Madoff, or someone else who made their money convincing people to invest on the promise of good returns a la pyramid schemes. At least, the burden should be on them to demonstrate, with quite a high bar, that this time they are being entirely on the level with you. 

Jacob Lagerros got excited about RaDVaC early and came to the Lightcone team a few months ago saying we should arrange funding for them. I believe talks have occurred between relevant parties though I'm not certain of exactly where things ended up.

Summary: I suspect funding has been provided, mostly want to give credit to those who noticed early and worked to make it happen.

I found a low six figure donor who filled 25% of their funding gap. The rest has not been filled. EDIT: They also got an ACX grant, but not enough to fill the whole funding gap I believe. I can intro donors who want to fill it to the radvac team. Email me at jacob at lesswrong.com

Original thread and credit to ChristianKl who picked up on and alerted me to rumours of the funding gap: https://www.lesswrong.com/posts/fBGzge5i4hfbaQZWy/usd1000-bounty-how-effective-are-marginal-vaccine-doses?commentId=XwA8mtvK8YCob2pLK#comments

I'm happy to hear that my cries resulted in at least some founding being moved to them even if it's still sad that there's still a funding gap.

In addition to what Eliezer already said about RaDVaC being good because it uses technology that can easily scaled up, RaDVaC has the potential to reduce infection by COVID-19 when given in addition to traditional vaccines because it potentially creates a mucosal immune system response in the upper respiratory system which the vaccines we currently have don't. 

While there's some potential that Omicron will end COVID-19 that is optimistic. We might need something like RaDVaC to finally end this pandemic. 

Regarding the remaining funding gap you mention, did you take the recent $100,000 ACX grant into account?

Alex Hoekstra, $100,000, for the Rapid Deployment Vaccine Collaborative (RaDVaC) to make open-source modular affordable vaccines.
... RaDVaC still needs more funding ...

Hi all, this is Alex and Preston from RaDVaC. Thank you Eliezer for your thoughtful words of support. And thank you again Jacob L, your ongoing support is very much appreciated. We're also thrilled about receiving an ACX grant; not only is the money enabling, but the added recognition has already been extremely positive, and we have received additional donations following the award announcement. As Eliezer noted, we still don’t have all the funding we need to accelerate badly needed change in vaccine access and independence, but we do have funds to make great progress this year in ongoing projects.

One key goal is to establish an iterative cycle of vaccine improvement and testing, which will depend on improving our ability to measure immune responses. Another major goal for this year is to move toward full vaccine production independence, especially of vaccine antigens that are likely to be resilient against ongoing mutations. Vaccines based on recombinant antigen proteins produced in yeast are increasingly common, and we are in the early stages of designing yeast antigen factories that can be stored, shipped, and used as a foundational component for rapidly deploying vaccine factories just about anywhere in the world. And unlike peptides, RaDVaC should be able to share them freely, since the strains are not drugs or vaccines. This approach using the industrial yeast Pichia pastoris (a.k.a. K. phaffii) is highly scalable and relatively inexpensive, especially after the upfront design and optimization work which we're taking on. We continue to watch the mRNA vaccine space, and will ramp up investment when the time is right, but at the moment, the most affordable and scalable vaccines are based on these more tractable technologies.

One major goal that we are working on, but do not have sufficient funding to complete, is the establishment of working models for accelerated vaccine trials. Such trials create protracted delays in otherwise rapid vaccine deployments. We are working with others outside the US on improving both challenge trials and more conventional randomized clinical trials. If you would like to contribute to this effort, please get in touch us.

We've just started a RaDVaC project Discord where you can connect with us, and where we plan to post regular updates to the project, as well as communicating + collaborating with others interested in the work. If you're interested in keeping up with our work there, please let me know and I'll pass along an invite. Thanks from the RaDVaC core team!

Is there any empirical evidence yet that RaDVaC's alleged vaccines are in any way effective in making those who use them less likely to get COVID-19, or less likely to get it badly?

[EDITED to add:] I did take a look on the RaDVaC website, and if I'm understanding the FAQ there correctly the answer is (1) you have "positive indications" from your "preliminary assays" (I am guessing this means: very weak evidence?) that RaDVaC elicits some sort of immune response in the nose, and (2) you have no direct evidence at all that it has any effect on either whether one gets COVID-19 or how severe its effects are if you do. But maybe you can say more here than you have on your website?

Starting with early generations of RaDVaC vaccine designs, some of our core group engaged in self-experimentation to assess safety, as well as testing of some immuno-efficacy biomarkers. Four of us took a series of blood, saliva, & nasal wash samples over several months to determine antibody response in each. A few others also donated samples, which we also tested. We performed early antibody ELISA testing in our lab with custom tests. In parallel with our own testing efforts, we also established collaborations with academic researchers to perform antibody testing and neutralization assays on our samples, and we connected with colleagues in industry to perform T cell testing of various kinds. 

In our lab, some of the data were encouraging but some results were conflicting, and overall, they were irreproducible. At the time we were self funded and couldn't afford more mistakes. Collaborators in both academia and industry were instructed by management and legal counsel not to test our samples. Even though our samples were obtained with full disclosure and individual consent, lawyers for otherwise collaborating institutions declared our project untouchable due to the absence of institutional review board approval (which was impossible to obtain on the accelerated timelines required during the pandemic).

Unfortunately, the available commercial antibody assays at the time were very insensitive and barely registered a signal from our positive control convalescent samples. Those tests use full-length Spike, RBD, or nucleocapsid and are optimized for detecting the presence of multiple antibody species against these larger targets. Plus, our intranasal mode of delivery results in lower levels of systemic IgG. These limitations rendered commercial antibody tests insufficient for our needs.

We didn’t get these testing problems sorted until early 2021, at which point all of us had received commercial vaccination, which prevented us in the core group from obtaining meaningful antibody test data using epitopes that weren’t differentiated from commercial vaccines. 

Nevertheless, a collaborating group publicly presented data from antibody assays of their parenteral adaptation of Gen 8/9 (https://www.youtube.com/watch?v=eH7i0aPTFEU), which helped validate the antigen selection in those generations of vaccine design. As we have reported in white papers since Gen 10, because of these and other data, we substantially redesigned Gen 10 because vaccination of these naive recipients with pre-Gen 10 designs elicited immune responses in only a minority of them. Since the launch of Gen 10, we have not attempted to retest ourselves because each of us has been vaccinated with multiple commercial and RaDVaC vaccines; instead, we've been focused on vaccine design, production, and longer-term and more rigorous testing in animals, and eventually in human clinical trials. 

However, opportunities have arisen recently that allow us to return to testing aspects of immunity due to RaDVaC vaccines. First, Omicron is very different from previous variants and vaccines, allowing clear differentiation of antibody responses. Therefore, we have designed a Gen 12 vaccine containing a new Omicron-specific receptor binding motif epitope that should allow us to differentiate between antibody responses generated by commercial vaccines and by Gen 12 (or omicron infection).  Second, we have begun working with a company in California to do T cell testing specifically for epitopes in RaDVaC vaccines that are not present in the commercial vaccines most of us have received. They are a small company and our individual consents are sufficient for them to test our samples.

We have funding to do these limited tests on animals and in human subjects on a small scale, but eventually we will need to test vaccines in more complex and costly human clinical trials–challenge trials may be ideal–after we have solid animal data.

[Edited to clarify the legal complications of testing human samples]
 

Thanks for the detail. I think that means that the answers to my questions are "no, not at all, for the more recent versions of RaDVaC, and in fact for earlier versions what we have is evidence that it usually doesn't produce any immune response", and "no, not at all, for any version of RaDVaC".

For the avoidance of doubt, I'm not saying that this means you're bad people, or that it means your thing doesn't work, or that it means no one should give you money. I'm just trying to assess how likely we should think it is that what you're doing will turn out to be useful.

I think, in particular, that when Eliezer (in the OP) says

They've pretty much proved themselves.  They should be nurtured and scaled up to where they can start to replace US and Earth defunct state capacity to do the R&D that leads up to being able to rapidly design new vaccines that rapidly scale in production and deployment.

that first sentence is 100% false unless "proved themselves" means something like "proved that they are smart people" or "proved that they are acting in good faith" rather than "proved that they have something that works", which means that the second is waaaay premature.

Which, again, doesn't mean that the RaDVaC project shouldn't be nurtured. Maybe it should. All science and technology starts out unproven, after all.

Eliezer, if you happen to be reading this: Do you, in the light of the discussion above, still consider that "they've pretty much proved themselves", and are you still confident that the project needs only nurturing and scaling-up before it is ready to start replacing the planet's existing vaccine R&D efforts? If so, what is it that you think I'm missing?

Following up to affirm two things:

Actoverco's data were informative about (positive) safety and immunogenic response in RaDVaC's Gen 8+9 designs. These data aren't immediately straightforward (antibody response was greater in immunologically "primed" individuals than in immunologically naive individuals), but really informative along the line of antigen selection, presentation, and dosing. 

We (writ large) need vaccines that can be deployed rapidly and are focused on that rapid accessibility. There's no question that safe & effective vaccines can be made. The question for us is how to make safe & effective vaccines rapidly & simply enough to be widely accessible. Our approach has been to create and share designs openly, that can be (re)produced, adapted, tested, and studied without restriction. We couldn't do every stage of development in our own lab, so we invited others to use their expertise to contribute. Several have and still are, but I agree that it's time for us at RaDVaC to invest more (and more directly) in producing data that we can guarantee be shared openly.

that first sentence is 100% false unless "proved themselves" means something like "proved that they are smart people" or "proved that they are acting in good faith" rather than "proved that they have something that works", which means that the second is waaaay premature.

RaDVaC is not only about the particular technology but also about the way the organization runs differently. The approach of being public about the technology and regularly iterating it is very different than the way vaccines are traditionally produced.

RaDVaC is for example right now both looking into the small peptide version they started out with as well as looking at subunit vaccines. 

This is correct. RaDVaC is not committed exclusively to a single technology platform; we evaluated (and continuously re-evaluate) the advantages and disadvantages of vaccine platforms like VLP, subunit, peptide, DNA, and mRNA.

All our designs so far have been based on self-assembling nanoparticles transporting peptide antigens, because all materials for both nanoparticle and peptide antigens are highly accessible: readily available, relatively inexpensive, individually safe (not requiring any advanced biosafety conditions for shipping, storage, or use), and quick to source. This design is also very easily produced.

That basic nanoparticle platform (which we've open-sourced, along with our peptide designs) is adaptable to other antigens, such as larger recombinant subunits, which we are working on now, for consideration to add to a future version of our white paper. Advantages to recombinant antigens include likely better immunogenicity than peptides, and greater production independence/decentralizability–plus, cells producing such an antigen would likely be a shareable resource.

Adaptability is, I think, quite a cool feature of a platform, and it's a feature that's shared in principle by nucleic acid vaccines. The drawback there is largely one of accessibility: modifying code is no big deal, but executing that code is, in practice, far more difficult than producing peptides or even larger proteins. (For now. Many of us at RaDVaC anticipate that the costs associated with both pseudouridine-mRNA and LNP production will come down drastically over the next few years. We're excited about that.)

One major goal that we are working on, but do not have sufficient funding to complete, is the establishment of working models for accelerated vaccine trials.

Do you have an idea of what order of magnitude of funding this would need?

We're working with outside people and groups to create appropriate trialing models and protocols, including a focus on challenge trials. We're looking to hire at least 2 consultants for the process (medical writing, trial design experts) and at least 2 onsite medical staff with fluency in the regulatory & logistics context of wherever a trial is to be run. (Depending upon location, we may also need an IRB's services to review and approve any trial design; definitely necessary for anything done within the US). One of the groups we are working with, 1DaySooner, has already created and published trial designs, and our trial design will be different but informed by the excellent foundation they've provided. We estimate that this preparatory phase will cost $500k-$1M.

An order-of-magnitude estimate for the full cost of a completed trial would depend on scale and location, but the cost for a relatively small but sufficiently powered trial in our current focus location of the Bahamas is in the $10M range.

That's awesome, I didn't know this. 

There's an easier study I'd like to do before the lithium experiment: compare water contamination to obesity rates. I have two decent but not amazing datasets to do this (the water one tracks 18 contaminants but not lithium by zip code, the weight one tracks % obese not BMI by county) and a statistician who will analyze the results if I get the data in a single spreadsheet. I expect there are APIs to do that fairly easily but haven't had time to dig into it myself. If someone gets the 18 contaminants plus % obese in a single spreadsheet, and fixes the issues with county vs. zipcode aggregation, I can get this analysis done fairly quickly. Bonus points if you find better DBs than I do (I wish it was BMI by zipcode, not % obese by county) or incorporate additional data, like income, age, well water usage, and density. 

I've discussed this with SMTM previously, they agree it's worth doing although are less excited than me because the water quality database doesn't include lithium. So additional bonus points if someone finds a database of lithium concentration in drinking water by county.

I'd happily pay $100 + credit on the eventual blog post for the spreadsheet combining the two DBs listed, and am open to negotiation on larger amounts if it's more difficult than I think it is or additional features are included.

One of the mysteries mentioned in the SMTM article was that the obesity epidemic began abruptly some time around 1980. The authors state,

This wasn’t a steady, gentle trend as food got better, or diets got worse. People had access to plenty of delicious, high-calorie foods back in 1965. Doritos were invented in 1966, Twinkies in 1930, Oreos in 1912, and Coca-Cola all the way back in 1886. So what changed in 1980?

This article argues (convincingly, in my opinion) that the obesity epidemic began much earlier, probably around the turn of the 20th century. If you track the evolution of BMI over time in different birth cohorts, you get a very continuous, smooth rise in obesity.

Figure 2. Trend of BMI decile curves of US-born white men by birth cohorts 

Guyenet, who's palatability theory you seem to prefer, shares the same interpretation as SMTM. His chart from The Hungry Brain:
 

 

And his commentary:


In 1960, one out of seven US adults had obesity. By 2010, that number had increased to one out of three (see figure 2). The prevalence of extreme obesity increased even more remarkably over that time period, from one out of 111 to one out of 17. Ominously, the prevalence of obesity in children also increased nearly fivefold. Most of these changes occurred after 1978 and happened with dizzying speed. [emaphasis mine]

Wait what? This isn't even a chart of the same thing.

  1. It's a chart of data from 1880 to ~1980, whereas SMTM as looking specifically as the change in 1980
  2. It's a charge of BMI, whereas the SMTM chart is looking at growth in extreme outcomes. Say you have a normal distribution with mean 24 and SD 2. Only 0.13% of the population will have BMI over 30. But as the mean BMI slowly increases, you see rapid growth in extreme outcomes. At mean BMI of 26, you're up to 2% over 30, at mean BMI 28 you're up to 16%. So the fact that BMI growth is smooth doesn't imply that obesity growth is smooth too.

Totally agree! I stumbled upon the SMTM link 6 months ago or so and it was a big view-changer for me. I'd previously thought calories-in-calories-out was the main thing to be focusing on but, uh, yeah, I was super wrong.

I do think you're too critical of the high-palatability theory. The SMTM page finds the theory reasonable:
 

“Palatable human food is the most effective way to cause a normal rat to spontaneously overeat and become obese,” says neuroscientist Stephan Guyenet in The Hungry Brain, “and its fattening effect cannot be attributed solely to its fat or sugar content.”

Rodents eating diets that are only high in fat or only high in carbohydrates don’t gain nearly as much weight as rodents eating the cafeteria diet. And this isn’t limited to lab rats. Raccoons and monkeys quickly grow fat on human food as well.

We see a similar pattern of results in humans. With access to lots of calorie-dense, tasty foods, people reliably overeat and rapidly gain weight. But again, it’s not just the contents. For some reason, eating more fat or sugar by itself isn’t as fattening as the cafeteria diet. Why is “palatable human food” so much worse for your waistline than its fat and sugar alone would suggest?


So I wouldn't call the SMTM link evidence that obesity being partially caused by high-palatability foods is obviously wrong. The gluttony theory of, like, self-control being the main important thing, or calories-in-calories-out being the main thing, I do think is obviously wrong; but I personally see the high-palatability theory as very different than the gluttony theory.

Isn't lithium in water linked to lower depression rates and not really something you'd want to straightforwardly remove even if it turned out to be making people fat?  I guess you might win on net if it turned out you could cure about that much depression with lotsalightboxes and be rid of obesity in the bargain, but it's at least a little complicated.

For those who'd rather read that, the author of the obesity articles series summarized them in a twitter thread (Thread Reader). There's also discussion of it on LW (though it took place before most of the articles were published) 

Other types of causes I would like to see more groups working on and more people supporting are those that would help make human communities more robust against civilizational collapse (minus scenarios where we're all turned into paperclips, of course). Right now, billions of humans are utterly dependent on global economic infrastructure to supply food, water, energy, shelter, etc. If some event breaks down this infrastructure, billions could die, since not only do most people lack survival skills, but the local resources in most areas of high population density are not sufficient to provide enough for (even a small fraction of) everyone. Ideally, every local community, from small villages to sprawling metropolises, could become locally self-sustaining to the point where getting cut off from the global economy would lead to the loss of luxury items and foods rather than to mass starvation.

Things that come to mind include the Global Village Construction Set, an open-source set of 50 blueprints for technologies explicitly designed to require minimal material and manufacturing resources to construct but that could be used to rebuild civilization in the event of collapse.

Food production is also a big issue, of course, and efforts to provide year-round local produce using geothermally-regulated greenhouses or vertical farming could help immensely to minimize costs of both production and distribution for communities that use them at sufficient scale. (One limitation to hydroponics/aeroponics that currently outweighs their resource-efficiency is the fact that they tend to focus on just salad greens, which are the easiest to grow. Are there any groups working on genetically engineering fruit trees to produce fruit without the trees?)

Mycelium is another group working on providing automation for community gardens, as well as more effective waste-handling and housing technologies.

I don't know how effective these projects, specifically, would prove to be if given enough funding, but I feel like they are reaching in the right direction. Local, resource-efficient sustainability technology seems like one of the most impactful areas to focus on for ensuring humanity's long-term survival, after things like AI alignment. An additional benefit of putting more effort into these sorts of projects is that they could also be applied to helping people who are struggling in "third world" countries today. And if you could get self-sufficiency technology good enough to work in deserts or on ice sheets, we could also apply it to supporting space colonies. Maybe Elon Musk could be convinced to invest more in this area.

The Alliance to Feed the Earth in Disasters (ALLFED) is one of the recipients of donations for the Survival and Flourishing Fund.

In the same vein—Isn’t about time for the rationalist community to found a little city? A place maybe somewhere in Canada, nice and isolated from climate impacts, altitudinally disposed against obesity, enough LED wattage to offset the extra microSADs…

But in all honesty, we’d get to test better voting systems, bring smart minds together, pioneer new education plans, and obviously explore how to achieve autarky.

You could start it off small— as a mini hub for organizing retreats. Offer EA grants to come work there. Slowly expand outwards.

If we carry on the rest of the planning phase on paper and pencil, who knows, maybe we can even keep it secret from the AI overlord.

Is there any reason we can't quickly test the lithium hypothesis by buying a bunch of random food and paying a lab to grind it up and figure out how much lithium is in it (use a mass spec?)? I assume this would cost thousands of dollars, but that's pretty cheap.

As far as I can tell, SMTM's lithium obesity hypothesis is mostly about groundwater contamination. So testing random food for lithium wouldn't help; testing random people for lithium might (?), but that sounds much more expensive.

I thought it was a mix:

Fort Collins, CO gets water almost exclusively from rivers starting nearby and still has an 18% obesity rate (and Boulder is similar but has 12%). Both of those are "low" compared to other places, but still way above the historical level.

(I admit that I'm less interested in the water hypothesis since I live in Fort Collins so that part is already solved for me)

This would be bad news for the tourism industry in Banff. Below was taken on my honeymoon. 

Guests of the Banff Springs enjoy royal hospitality as they are served bottled lithium water as they soak in the outdoor pool at Banff Springs. circa 1930s. 

To boot:

Not only did tourists soak in the spring water, they drank it, too. Bob Elliott, acting operations manager at Banff Upper Hot Springs, said, “Local bars sold bottled hot springs water as a tonic and cure for hangovers. Banff's mineral water was bottled and sold as ‚Lithia water' for a short time until the medical experts realized that one of the active ingredients found naturally in the hot springs, Lithium, was addictive. This ended the bottling and consumption, by drinking, of Banff's mineral springs.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2228356/

Having not apparently the energy to write this longly, I write it shortly instead, that it be written at all.

 

Just a comment on writing for understandability — compare Benjamin Franklin, writing in 1750:

I have already made this paper too long, for which I must crave pardon, not having now time to make it shorter.

Shorter is (almost always) better, please don't write things longly just for the sake of it!

Eliezer's post has one paragraph on RaDVaC. It's a good paragraph but I wouldn't expect anyone that didn't hear about RaDVaC before and doesn't take Eliezer as an important authority to be convinced by that paragraph that RaDVaC is worth funding. A longer post would likely have included a more clear case of why RaDVaC is worth funding. Writing that case down wouldn't have been just for the sake of length. 

Most people have not put tens of thousands of deliberate hours of practice into their writing skills so do not have the clarity to be able to say what they think shortly, and this lack of skill is typically why their writing is long. Eliezer has worked hard to be able to write clearly, and also to build a rare skill of being able to expose more of the cognition behind a thought as he writes longer, which is in many important domains more valuable to do than just stating the output of the cognition.

I'm saying: Eliezer's has built the skill to say his thoughts precisely and clearly; but he has also built the next-level skill of being able to expose the cognition behind a thought, and this is the sort of valuable length that he hopes to have in his writing.

I like the shortlyness of this post and think it perfectly suits the subject. For many purposes longlyness can be counterproductive.

I’m looking at getting into grant writing; would that be something worth applying for grants (heh) for?

If you ever want an apple tree that bears fruit, you may need to at some point plant a seed

You're going to need to plant more than one.


Having not apparently the energy to write this longly, I write it shortly instead, that it be written at all.

It's nice to see a decent post that's short.

From what I have heard (I have not researched any of this very thoroughly), the palatability is not the problem directly but something very related is. It is not the case that someone would eat a lot, just because it is just so tasty. It is rather about that the composition of processed food is often very different from unprocessed food. And this affects how our body responds, like when we feel full. Eating some Froot Loops is very different from eating a mango.

This might not be the only, or even the main effect, but I would guess that it is a significant factor. Intuitively it seems much less likely to me that if you put somebody on a diet of vegetables, fresh fruit, legumes, and whole grains, that they would then become obese (probably also make it low sodium to decrease to normal levels palatability).