166 Comments

Of course, there is another option: raise funds to perform a private double-blind study. The FDA is a “nice to have” not a necessity for doing the science.

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Yes, I took some issue with the claim, “Obviously the best course is to study it carefully and not do anything until you know more. The FDA has already closed off that route.”

Studying it carefully will involve human trials in some form, and the FDA isn’t preventing that from happening. They just didn’t find a set of feasible trials that both the FDA and the company approved of.

I do think allowing people to pay to be in this beta test / trial is fine, and people who are more adventurous than I am can elect to jump in while everyone else waits until larger samples reveal that it’s generally fine and effective or not. A double-blind trial would be much preferable, but isn’t the only way.

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I don't think they'd even need to raise funds. Probably they could just send out placebo to half the buyers – I think people who buy this kind of stuff would be OK with that.

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Speaking for myself, I definitely would NOT agree to that. If it were a genuine clinical trial, then I might participate in such a trial and run the risk of being in the placebo group (as I did with a Covid vaccine trial). But if I purchase a product, I am not willing to be sold a placebo.

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Why not? If you value the effect of the product at least $250, then wouldn't a 50-50 chance of receiving the product be worth $125?

For a product you definitely need then there's an opportunity cost to consider: a 50-50 chance of receiving a new phone from one source leaves you uncertain whether or not to go out and buy a phone from a guaranteed source and you might end up phoneless. But for something like this where there isn't an alternative on the market, your alternative to the 50-50 would be to simply not buy it at all.

Alternatively, they could have everyone pay $250 up front and then refund anyone who receives a placebo after the trial when it's okay to reveal, so placebo people don't lose any money aside from a small amount of interest.

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This is what prosecutors refer to as "fraud".

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Not if they're upfront about it, same as any other clinical trial. They straight up say "pay $125 for a 50% chance of Lumina and 50% chance of placebo." and people can make an informed decisions about whether they think that is worth it.

You don't need to be sneaky about it.

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>Why not? If you value the effect of the product at least $250, then wouldn't a 50-50 chance of receiving the product be worth $125?

No, I don't think that works. If you buy lots of products like that, there is a chance that you spend lots of money and get very few products. At least that's how I think about this. Money is a limiting factor for some things for me, I can't really bet it like that.

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I think the biggest risk here is that they'll say they give the product to 50% of customers, but actually give it to only, say, 25% (or 0%). It'd be hard to detect this type of fraud.

I think your refund idea solves this issue.

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As a small child in the 1960s, I had a lot of cavities -- I recall the dentist finding seven in one session. But I haven't had any in at least 50 years, which I attribute to flouride in toothpaste and water, as well as more recent improvements in toothbrush technology. Why would I want this Lumina Probiotic?

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My vague impression is that dentists took a financial hit in the second half of the 20th Century after they endorsed fluoride in toothpaste and water from the consequent decline in their cavity-drilling business. I was impressed by their professional ethics in doing this. My dentist around 1995, for example, appeared to be rather poor.

But then dentists switched to emphasizing more cosmetic procedures and appear to have done very well in this century.

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It reduces the risks of cavities.

You risk seems to be low, but it's probably not zero. And you want to stack the deck in your favour, so you can keep getting lucky in the future.

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There are con artist dentists out there who drill healthy teeth (I have met one and confirmed this!). I suspect your dentist was one of them if he found 7 in one session.

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It's hard to say. I got a new dentist within a year of a check where I had no cavities and they said I had eight, but I got my new and old dentist to send scans back and forth and she confirmed the diagnosis. This despite me having a solid dental hygiene routine per both dentists (and per the hygienists who actually clean my teeth). Some of this stuff is just a roll of the dice sometimes, which is why I'm cautiously excited about Lumina.

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Assuming this is a good-faith question and not a way of implying the product is undesirable for everyone: Maybe you don't want it, actually. Or at least don't want to be an early adopter.

In contrast, for someone like me who grew up with fluoride, usually manages to follow the standard dentist recommendations like 2x/yr checkup, brush 30 minutes after each meal, floss daily, etc... and *still* gets cavities every now and again... It's a more tempting prospect now that the asking price is less than I make in a month.

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Gallant is being an idiot, though, and will fall for speculative junk. There are an infinite number of interventions that do not help but have bad data that is compatible with there being a small positive effect. A susbtantial proportion of these will also do net harm, but this has not been proven either and will thus not be put forward by the proponents of this months flavour of lifestyle garbage. Such is the nature of confidence intervals, and to soften your standards for recommending medical intervention based on this faulty reasoning is a form of soft thinking. Pandemic reasoning made this error time and again and I guess it is only logical that it now infects other areas of science. Only question is how long it will take for the next EBM revolution to rid us of this nonsense.

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It sounds like you expect gallant to reason *poorly* under uncertainty? Or else why would he fall for the speculative junk?

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Even if your expected value estimates are perfectly calibrated, when you take an argmax across many options you are bound to be disappointed. See for instance https://www.lesswrong.com/posts/5gQLrJr2yhPzMCcni/the-optimizer-s-curse-and-how-to-beat-it and https://www.lesswrong.com/posts/RdpqsQ6xbHzyckW9m/why-we-can-t-take-expected-value-estimates-literally-even.

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I think those posts are saying that Gallant is doing the right thing - you should reason with uncertainty, rather than pretend that your probability estimates are precise best estimates. (And calibration is neither here nor there.)

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I was explaining why Gallant is likely to fall for speculative junk. It remains likely even if he reasons under uncertainty *well*, that is, even if his expected value estimates are completely unbiased. When he chooses the best option from a large number of options, he is selecting for options that are unusually good but also for options that seem better than they are. As a result, his naive estimate of the value of his chosen option will be wildly optimistic.

Explicit reasoning under uncertainty is hard. From the second article, "Why We Can't Take Expected Value Estimates Literally (Even When They're Unbiased)":

"We believe that any estimate along these lines needs to be adjusted using a "Bayesian prior"; that this adjustment can rarely be made (reasonably) using an explicit, formal calculation; and that most attempts to do the latter, even when they seem to be making very conservative downward adjustments to the expected value of an opportunity, are not making nearly large enough downward adjustments to be consistent with the proper Bayesian approach."

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“Unbiased” doesn’t mean “well”. It just means not biased upwards or downwards. “Unbiased” is compatible with lots of noise, and also compatible with foolishly calculating given noisy numbers and taking that as your best possible estimate.

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The comic could include a prudence who reasons like gallant but has a bayesian prior that most things are bunk and is indistinguishable by most people in most cases from goofus

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It isnt compatible. When you do that you might have an unbiased estimator of a value, but the argmax of that estimate is not an unbiased estimator of the true argmax.

The problem is that nonlinear operations generally dont preserve unbiased estimation, and so long chains of unbiased reasoning are rarely feasible to begin with.

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I am not interested in debating the meaning of the word "well". Once again, my point is that reasoning under uncertainty is hard. No human can make unbiased estimates, so if Gallant can that is very impressive. But even in that case it is easy for him to make subtle mistakes that invalidate the analysis. You can call him foolish, but he still did a better job than most people would have.

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Any good decision maker will "fall for" scams/ things that just don't work a non-zero amount of the time. If you optimise for never being taken in, you actually end up worse off, because missed genuine opportunities hurt you more than failed ventures do.

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Don't I know it. I could've bought some BTC for <$100 a number of years ago.

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Both of those not only point out problems with a Naive Bayesian analysis, but also suggest improvements. There are statistical tests that compensate for having multiple noisy estimates simultaneously. The Jelly Bean problem (https://xkcd.com/882/) is a known problem with known solutions.

Doing cost benefit analyses and reasoning under uncertainty are not by-definition forced to be naive and ignore this.

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You are correct. My point is that reasoning under uncertainty is difficult, with plenty of opportunities to make subtle mistakes. Most people will fail to avoid all of the mistakes. Therefore, just telling people "you should reason under uncertainty" is incomplete advice. You have to put in the effort to become good at it, or else it will likely blow up spectacularly.

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This would, I suppose, be bad news for someone who proposed that you should aim to do a super duper job estimating expected values and then argmax them

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Reminds me of a previous ACX post: https://www.astralcodexten.com/p/pascalian-medicine

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You are confused about what "reasons under uncertainty" means. Confidence about the quality of the data itself is also one of the uncertainties to take into account. Which part of the post did you interpret as recommending softening any standards?

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Apr 16·edited Apr 16

I don’t plan to get this soon. My reasoning is, my current microflora is probably fine given that i have had zero cavities in my life, despite brushing on average 0,6–0,8 times daily. I doubt it’s genetic given my sibling has had several cavities.

So either this helps a little bit for me (I would still need to brush AIUI, but i might half my already very low cavity risk) or it makes things worse by making my microflora worse. Of course, if it’s shown to be widely safe, or it reduces bad breath, then I’d be more likely to get it’

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Where are you in birth order with your sib(s)? Anecdotally I’ve noticed first born children have better dental health.

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I am indeed firstborn. I wonder why that's the case.

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I am the eldest child too and have better dental health. It’s just something I’ve noticed among the people in my orbit though.

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Anecdotally I am the eldest child and had tons and tons of cavities until I started brushing and flossing obsessively immediately after eating and I still get ~1 cavity per year

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Weird. I should test this on an ACX survey.

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I thought this was common knowledge, with a justification like the mother's calcium reserves being depleted by the firstborn and not fully recovered with each subsequent child. It is definitely hearsay, but I quickly found a study that defends the birth order effect on caries, although it has no comment on why it would happen (at least not in the abstract):

https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-020-8234-7

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Apr 17·edited Apr 17

I wonder if it could simply be due to more diligent parenting. It's a cliché that anxious first parents are more careful and more strict, and that they ease off with subsequent children.

Another theory: first children are more likely to be part of smaller families than third children are, and family size correlates inversely with socioeconomic status. Seems likely that rich kids have better teeth. (Though this was probably controlled for - I need to actually read the paper)

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Offhandedly, I'd blame an increasing amount of sugar in the diet, as parents get worn down by successive children, and then habits persist into adulthood. I know my younger siblings got away with a lot of stuff that I didn't.

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My brother is taller than me but I don't consider that a reason to doubt that height is heritable.

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I don't doubt the heritability, I doubt if the advantage I have is due to a genetic advantage, as opposed to an advantage of my microflora. My sibling and I also had different childhood diets, preferring more candy and otherwise sugary things than me, which may contribute to different microflora.

If your family were much richer during your brother's childhood (and therefore he had a healthier diet and healthcare), I think that would be fair reason to doubt that your height disadvantage is due to genetic factors, as opposed to wealth.

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> I don't doubt the heritability, I doubt if the advantage I have is due to a genetic advantage

Heritability is by definition the proportion of variance due to genetic factors, so I'm not sure what you mean here.

> If your family were much richer during your brother's childhood (and therefore he had a healthier diet and healthcare), I think that would be fair reason to doubt that your height disadvantage is due to genetic factors, as opposed to wealth.

Height is ~80% heritable so, given that prior probability, even in that case, we should expect that much or even most of the variance is genetic unless my nutritional deprivation was truly extreme.

I don't know how heritable the propensity for tooth decay is but in general I think a reasonable prior is that all traits are quite heritable so it would be surprising to me if it weren't true when it comes to tooth decay.

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> Heritability is by definition the proportion of variance due to genetic factors, so I'm not sure what you mean here.

What I mean is that I think that in the general population, some of the variance is explained by heritability. However, I think rather than my sibling and I having different genes leading to the advantage, my advantage might be due to a different microflora. This is because of the prior (mentioned below) that there is a significant non-genetic component.

I think implicitly I assumed that genetic variance between siblings is quite low, which is why I don't think such a large difference could be explained by genetic differences.

> I don't know how heritable the propensity for tooth decay is but in general I think a reasonable prior is that all traits are quite heritable so it would be surprising to me if it weren't true when it comes to tooth decay.

According to Crémieux, it's not genetic https://www.cremieux.xyz/p/the-rise-and-impending-fall-of-the#footnote-1-143114296

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Caries scores and trajectories appear to be very heritable: https://journals.sagepub.com/doi/full/10.1177/0022034519897910

But I think the reason has more to do with vertical pleiotropy (people inherit tastes, tooth hardness, etc.) and active gene-environment correlation (people self-select into environments in a manner that's consistent with their genotypes, like choosing a similar food environment). This also seems like an area where the EEA might be violated because identical twins might push one another to eat more similar diets than fraternal twins might.

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What prevents bacteriophage from exploiting the new ecological conditions of the Lumina oral microbiome? I haven't seen anything about modifications to the bacteria that address this, nor have I seen any mention of this potential problem in any of the marketing done for this product. Can someone please enlighten me?

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Did you read Scott's first post on the subject? It supposedly emits small amounts of an antibiotic to deter competition.

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That addresses bacteria not bacteriophages.

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I misread that. Why do you think bacteriophages would be a problem? After all, this is just a slightly modified oral bacteria that was found in the wild.

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Apr 16·edited Apr 16

Because bacteriophage are viruses that infect bacteria, and for every bacteria there can be several strains of phage. My concern is that bacteriophage would infect S. mutans and all but extinguish it in the oral microbiome. At the very least it would probably lead to boom and bust cycles for the S. mutans in the mouth, giving other bacteria competitive advantages in that scenario, regardless of the small amount of antibiotic being released. This could also enhance genetic drift as the S. mutans population dwindles as the result of the phage.

The problem with having a dominant type of bacteria in your mouth is that it becomes an easy and plentiful target for phages.

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Why is this any different than what is happening in the wild?

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Three things. First when you stack the deck in favor of one bacteria over others, you create a disequilibrium that can have unstable consequences like boom and bust cycles, that would leave your mouth unprotected for periods of time.

Second, genetic drift is enhanced when small populations are created as the result of boom and bust cycles, with the busts creating more opportunities for S. mutans to evolve in ways we don't want.

Third, I haven't checked, but it's very likely that S. mutans isn't wild anymore. Most of the bacteria that are successfully genetically modified have been altered to make it easier to modify them, which often comes at a cost to their ability to survive in non-artificial environments. They've also been grown in an artificial environment for a while, and that increases the likelihood they can't survive in the same way as wild bacteria because they optimize for the environments they find themselves in.

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Getting rid of /S. mutans/ would be a massive win and a great reason for doing it as widely as possible.

Wild /S. mutans/ is basically an organism we don't really want in our mouths at all, and the only reason for having the proposed GM version is really to exclude the wild version.

Unfortunately, perhaps, I don't think there's any particular reason to expect the GM version to promote development of a species-wiping bacteriophage.

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I don't think all of my arguments are addressed by what you're saying. It may be unlikely that a species-wiping bacteriophage evolves, but it's more likely that there will be bacteriophage that evolve to significantly reduce the population of S. mutans periodically since bacteriophage would be more of a check on the population of S. mutans than other bacteria or nutrients scarcity.

Often in predator-prey relationships there are wild swings in the populations of each member of the organisms or entities involved. So there's reason to think that caries are still possible long term especially if genetic drift occurs during times when the GM S. mutans has a low population size which could lead to GM S. mutans with undesirable mutations.

I've also explained that the conditions of growth in a lab may render the GM S. mutans more susceptible to phage because they just don't have to deal with that in an environment of pure cultures and aseptic technique.

I think an analogy is crops that are grown as monocultures and which require more and more pesticides and herbicides as time advances because weeds and herbivores become more resistant to them. The mouth is a much less controlled environment than a farm, so I think ecological considerations are warranted.

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Are you worried about lytic or persistent lysogenic phage? Lytic, presumably?

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Well, I was initially just worried about that, but in the googling I've done today, there seems to be lysogenic and lytic phage that infect S. mutants. That said, most of my concern has to do with lytic phage. Immediately killing the bacteria and spreading in bursts becomes easier with a higher population density. I didn't think about lysogenic phage. My guess is that lysogenic phage would have other effects beyond simply killing the bacteria, but that's beyond my understanding without doing more research.

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Why would bacteriophages be more likely to infect this than wild-type s mutans?

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Because they are more numerous. So there's more chances.

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Normally though, wild s mutans is more common in people's mouths. There are a lot more people out there whose mouths are colonized by wild s mutans than there are with the experimental type, and despite billions of people living with them over, I don't know how long it's been with us, hundreds of thousands of years? We haven't seen any appreciable spread of bacteriophages targeting it.

Could some type of bacteriophage evolve which would target the experimental type? Sure, probably. But given the record the wild type has, it doesn't look like we have much reason to expect problems on that front in the foreseeable future.

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But the wild-type hasn't been designed to outcompete other bacteria. In that context, the population of GM S. mutans will be higher and probably denser than it would be normally, which would change the dynamics of the system. The bacteriophage would have more cells to spread to, and would spread more easily. It also is modified so that it doesn't transfer genes to other bacteria. Assuming the transfer edits work both ways, then it's more vulnerable to bacteriophage because it can easily get defenses that other bacteria have, it just has natural selection to work with in that case, which works slower in bacteria than it does in viruses. I guess in the end, we can disagree about what credence to assign to this problem, it's still a vulnerability in my view.

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In the event that it does get attacked by bacteriophages, then what? That wouldn't harm you, the host. At worst, if the bacteriophage only attacks the modified bacteria, your mouth would probably be re-colonized by wild s mutans.

The modified type doesn't replace the entire ecosystem of your mouth though, so I don't think it's significantly more likely to be attacked by bacteriophages than the wild type.

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That's what I'm saying. The treatment may not work in the long-run because of the worst case scenario you just described. The modified bacteria are supposed to work forever based on the marketing. It may not replace the ecosystem of your mouth entirely, it just needs to increase its population density, which is what it's designed to do, and that makes it more susceptible as a population.

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What did the Company do with the test animals when done with them?

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A lot of the opinion on LK=99 was, try to replicate the experiment nd then we'll know. Then the replication attempts failed, and for most people that was that. Still, it was very cool to watch science being done by e.g. Andrew McAlip.

I guess this is similar .. $250 to be a guinea pig in a cool science experiment that might or might not work out,

I will totally admit to spending more than $250 of my own money on doing a cool experiment.

And i'll also admit to spending way, way more than that of DARPA's money on doing a cool experiment. (My magagement tells me my research group's published papers cost more than a million dollars each, so there's that.._)

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What can I say .. keeping your university departments 5* ranking in the Research Assessment Exercize can e an expensive business.

But given that expeiment sciene can be an expensive business, i think it's totally worth doing this trial to find out whether the bacteria work or not.

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oh, an without mentioning which paper it was, the one that caused me to inquire about per publication costs...

> We have lots of experimental data

> but we havent done X, because X looks too hard and would cost too much

> first draft of paper says we haven't done X, this is future work for someone

> referee says I was all ready to accept this paper, then I got to the bit where you admit you hadn't done X ... reject

> so we do X

> paper accepted the next time round

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https://twitter.com/natalia__coelho/status/1779610061658325461

Relevant tweet showing a table where the control group has about as much caries as the BCS3-L1-infected group. People should be free to try this, but Cremieux's post reminded me of podcasts hosts shilling supplements, which was fun and unusual to see in this sphere.

I wouldtrust the company more, if they publicly released the data of their ongoing testing. My trust already increased a little because they admit to failed colonisation in two cases.

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IIUC, Natalia's post compares BCS3-L1 mice to *naturally s mutans free* mice, showing that BCS3-L1 only fights cavities from s mutans, not other sources. My impression is both groups in that study would have about 1/3 cavities of natural mice. I think this meshes with what I said in section 2 of my post.

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Rats, but yes. It's just a response to Cremieux' claim of immunity to dental caries. I think you didn't make such a claim, but you did say it would be "king of oral bacteria" or something.

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the 1/3 result comes from gentobiotic rats, so germ-free. In rats without S mutans but with microflora BCS3-L1 caries score is actually higher: 1/2 of those infected with the JH1140 strain. I detail this here:

https://www.writingruxandrabio.com/p/on-lumina-and-the-need-for-human

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Coincidentally I just read about the biblical Hananiah, who was a false prophet. Doesn't seem to have said anything about teeth, though.

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Huge fan of judging people by their counterpart prophet in the Bible.

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look would you trust a president named Judas?

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Thank you for finally acknowledging that caries can come from bacteria besides for S. mutans

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What fraction of overall caries is caused by those bacteria? Seems a pretty crucial question that should be addressed.

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I think it is worth it. First of all, just as a non-FDA intervention it has a huge potential market. That's kind of how PRP

gained traction-- and even now, while it is not usually paid by insurance, it is incredibly common.

Once it's on the market with use in large enough numbers, there will be sufficientl data to establish its efficacy and then possibly go for FDA approval.

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I've pre-ordered, though I'm not sure how effective it will be for me.

I've had a lot, *a lot*, of cavities. I don't think I have single tooth that hasn't had something done to it. (My wife, who has had zero cavities, joke that it's a good thing we go to the dentist as a pair, so we average out to a normal patient.) With less real-tooth surface area, will that impact the ability of this new bacteria to strive and thrive and drive out the old bacteria?

I don't know. But I've got $250 to spare and I'm willing to give it a shot. I've spent $250 on a lot worse.

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Also, if Lumina wants me to spit in a tube to send to them in 6, 12, 18 months, or whatever, I would do that.

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I'm in a similar boat. The potential upside here is massive for me

The thing about having active cavities making it less likely for the colony to take hold has me deeply despondent. I assume that I have an active cavity right now, since to the best of my knowledge I have never *not* had at least one

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I'm in the same boat as you. It's funny to read the different reactions to this from people with poor oral health and those without such issues.

Based on what they said about needing a clean biome and lack of existing cavities at application for it to work, I'm gonna work with my dentist to apply it. I figure that gives it the best opportunity to succeed, and then we'll see how it does.

I'm not expecting lifelong no cavities. That would be great but also ridiculously optimistic, to me. If it can reduce my cavities to 1/3 my current incident rate and work for a time (perhaps having to be re-applied periodically; my dentist will stay in business yet!), I'd be thrilled.

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It seem still no shipping to Europe :/

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I know one European who has reached out to them directly and they have agreed to try and ship him some. You may want to reach out as well and offer to be a shipping guinea pig.

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Today I used their contact us page to ask when they'll start shipping to Europe. Maybe I would've had more chance if I phrased it like you said and offer to be a shipping guinea pig. Well, fingers crossed :)

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> I think two more likely explanations are: This is Trial 3, the one we know nothing about

That would make sense, because trial #3 is where he gave up, and also, the sample sizes usually go up the later the trial - it would be odd if trial #3 were planned to have fewer than 26 or 10 people, after all, and 100 is a nice round number.

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Goofus and Gallant - Wow, what a time machine! My parents got me a subscription to Highlights For Children when I was six. JFK would remain President for another few weeks.

IIRC, there was another feature called The Timbertoes, about people made of wood.

A reader's letter asked if the editor was a man or a woman, and the response was "yes", which young me found quite funny.

I saw a copy a few years ago, I think at the library, and it looked virtually unchanged from my childhood.

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For boys in my hardscrabble hometown the norm was to think Gallant was a sap.

¯\_(ツ)_/¯

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Love it!

I had sort of the opposite experience - I compared myself to the good characters (including Gallant) in my childhood reading, and always felt guilty for falling short.

Awareness of Solzhenitsyn's comment about the line between good and evil running right through the centre of every man's heart would have helped me process that there was some Goofus and some Gallant in everyone.

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Yeah I identified with Gallant too. A lot of people did take me for a sap in that ‘life is a zero sum game’ small town.

One of my classmates at a reunion explained his simple philosophy to me: “What’s mine is mine. And what’s yours is mine too.’ Sheesh

I don’t go back to visit very often. I guess it’s a good place to be from.

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Rural Minnesota?

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Mesabi Iron Ramge

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That's probably (culturally) a world away from the north-central Minnesota bike trails (Paul Bunyan and Heartland) we so enjoy.

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I just looked it up, and, is that where your pseudonym is from? :-)

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The V in EV stands for value, think it should just be “+EV for society”

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Tyler Cowen is doubtful. https://marginalrevolution.com/marginalrevolution/2024/04/saturday-assorted-links-453.html

I am ready to try, but too far away

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I was thinking about this and asking how would TC model his skepticism.

Here is an idea.

Any long term bacteria hosted in humans is more likely to be a symbiotic relationship than a parasitic one. If you think you have cleverly outsmarted evolution, you are probably wrong. The fact that the original strain for this was found in the wild but on the whole is rare is strong evidence that it is not a better match for most humans, otherwise it would have taken over long ago. There may be clever transhumanists available, but the dollar bills on the side walk of evolution are much harder to find than they are in the market. Be severely skeptical by default.

Not necessarily my take, just playing along. Eager to see how it goes, then again I do kiss Asians...

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Well done. (Though biological evolution has its own constraints - see "sleep", see "photosynthesis" - which do not really apply here, admittedly) Married to Asian. We still kiss at times ;) xoxo

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Looking forward to the "Dentists HATE this one oral bacteria colonization treatment" ads.

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Apr 16·edited Apr 16

My feeling is that disastrous results - comparable to thalidomide - are well-nigh impossible. It's just a bacterium that colonises a rare niche in the mouth. It doesn't spread aggressively, so presumably won't infect other people by kissing etc. (it being hard to establish is not all a bad thing.) So really people should have at it, and if enough try then even anecdotal data will be good enough that a proper trial will be easy to arrange, and others will do studies anyway.

Personally I have no interest as whether it is due to mouth microflora, saliva, or sugar avoidance, I don't really get cavities any more. [EDIT: or fluoride, as mentioned by Steve Sailer. I too got lots of cavities when I was young. Now I have fillings that are over four decades old. My dentist at the time noted that I had a interesting amount of 'arrested decay', so something changed. But wouldn't dentists / public health scientists have noticed if fluoridation had a sudden massive effect on new cavity formation?]

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I like the categories and odds you laid out! Care to bet on them?

https://manifold.markets/Joshua/lantern-bioworks-lumina-probiotic-d?r=Sm9zaHVh

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I legitimately do not understand why so many people treat the LK-99 hype with such scorn. It's a good thing to be able to be excited and hopeful about potential breakthroughs. It's not a big deal if it doesn't pan out.

But for some very large subset of people, it is just infuriating and shameful to take these announcements with anything other than heaping skepticism, and I cannot wrap my mind around it.

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It also still seems true that LK-99 is an interesting and weird substance that is not hard to produce, and thus is worthy of excitement even if it’s not superconductor-level excitement.

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Because extraordinary claims require extraordinary evidence. "Hype" is what happens when sentiment becomes unmoored from reality, and I really don't see how this benefits anybody, other than various cranks and hucksters.

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Because people familiar with these things immediately pointed out that “dubious claims of room temperature superconductivity” is a very regular occurrence in physics and I think it was frustrating to witness how this fact gained no traction. That relevant expertise was unable to spread in the public discourse there does seem to indicate some dysfunction, imo.

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I don't really see what gain their would have been if the population as a whole had been significantly more skeptical. It didn't seem that anyone was treating it as a given that they had succeeded, nobody was making life-altering decisions on the assumption that it was real. We eagerly awaited replication attempts, and when they failed we moved on. What is the better hypothetical approach to researchers who, by all accounts, sincerely believed they had achieved a breakthrough?

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I don’t think there’s some direct gain or loss in this particular case. More like the credulousness here is inseparable from some wider culture, especially among tech enthusiasts, that could be bad in other cases.

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Uh, what does a "constant trickle of alcohol" do to developing baby brains? Since you mentioned in a previous post, your kids might get this bacteria from your wife...

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Probably nothing, due to the minute quantity. Wikipedia says, "The average human digestive system produces approximately 3 g of ethanol per day through fermentation of its contents." I wouldn't expect this to significantly increase that.

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Apr 16·edited Apr 16

A tiny amount that will have no effect. Even if it converted all the sugar in your mouth into alcohol every five minutes, how much is that?

Back in the day, my mother's gynaecologist prescribed her a bottle of Guinness mixed with a raw egg. To be taken daily.

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I think Yishan Wong's implication that "because Pfizer offered to buy the IP it must be safe" is very sloppy reasoning. Big pharma is VERY familiar with reasoning under uncertainty and VERY comfortable paying for drugs that they know further trials might show are unsafe or ineffective.

I agree that the Pfizer offer is indeed some evidence that some experts thought there was promise. But all that shows is that they thought it had a decent expected value. Given the gigantic potential market here that expected value could easily be justified with a very small probability of actually making it to market.

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Re. "and the other had his wisdom teeth removed (which involves rinsing the mouth with strong antiseptics).":

Would taking a 2 week course of amoxicillin or keflex kill the anti- cavity bacteria?

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On balance for me the cancer risk is the marginal factor. I had thought of this before Lao Mein's post, but without the genetic factor. My (lay person's) reasoning goes: alcoholics get oral/throat cancer at higher rates because they put large amounts of ethanol into their mouths and throats on a regular basis. Do we know if there is a similar increase in risk of these cancers if you have a low amount of ethanol in your mouth 100% of the time?

If I could get good evidence that this risk is negligible I would be good with trying this - but I'm not there now.

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Spirits burn, beer doesn't. I think it probably is negligible.

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Probably too expensive to do irl, but I’m 39 and have never had a cavity and I’m wondering if I already have some natural version of this and if there’s a way to test for it.

Best correlational test I can think of:

Test a bunch of people like myself who have hit middle age without having a cavity. Are we much more likely to have this?

Test a bunch of people with a lot of cavities in the same age bracket. Are they less likely/completely missing this bacteria?

Best causal test I can think of (but is too expensive):

Give each of the above groups the intervention, keep a control group, and track how they progress over the next x period of time.

That seems totally good as an experiment and I don’t know why the FDA would want young people with dentures. Is it because of possible hazard of this causing some extreme negative effect? Just the fact that this is bacteria makes me think you could probably eat this and get rid of it if you really needed to. I mean, I eat day old food that’s been left on the counter all the time. Or cheese. Or milk. Or what have you.

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My problem with lumina is the constant lying. Combined with trying to charge 20k it just screams "scam" -- totally unethical.

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The 20k was for the rich to have a party and early adopter status. See Scott's earlier post. Sources for the lies? I am interested.

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Saying it's "for the rich" doesn't make it not a scam. It makes it more of a scam.

As for lies: Yishan's thread (linked by Scott) and his previous thread both contain a lot of lies.

One example here: https://twitter.com/genomerambler/status/1780237335050736021

Another example: https://twitter.com/yishan/status/1777927568110555397

"And, 20 years later, all the original volunteers have reported no cavities or ill effects since then." -- no source given, pretty sure (90% credence) this is false.

Another lie: https://twitter.com/yishan/status/1777928495471178142

Another: https://twitter.com/yishan/status/1777928960602689800

Or consider this: "The benefits for the poor, the old, infirm, and incapable of taking care of themselves, and the Third World are so large that there ought to be a public health initiative to spread this around. Such an effort would ultimately save many billions of dollars and hundreds of thousands, millions, or—in the long-enough run—potentially billions of human lives." (lol. Source here: https://www.cremieux.xyz/p/46ebd66b-8a68-41ff-801f-0935a12c6fc7)

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None of these claims are from Lumina.

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Apr 17·edited Apr 17

Yishan is an investor in Lumina.

Also, Lumina told both of these people to promote it, to tweet out a photo of them holding the product and tell their followers that they believe in it. As a reward, Lumina gave them a sample of their product, valued at $20k at the time. Then Lumina failed to correct any of the wrong claims they tweeted.

You can't just pay people to say wrong things about your product and then go "hey it's not my claim it's them".

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Apr 17·edited Apr 17

As far as I know, Cremieux never tweeted a photo of himself holding the product. I sure hope he did, otherwise you'd look very silly in a diatribe about lying. The photo he tweeted looks like a woman's hand, to me, and that seemed to be referenced in the comments: https://twitter.com/sentientist/status/1769532400218804667.

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My actual favorite part of the comment is him saying that an investor in the company got paid by the company to promote their product. It's Very Good.

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You accused me of lying about him tweeting a photo of himself holding the product, then you googled and found out I was right, so you edited your comment to... still accuse me of lying... because the photo wasn't necessarily of his own hand? Did I get that right?

They told him to tweet out a picture of himself holding the product, he didn't mention he is shilling for personal gain, and yet *I'm* the liar because the photo of him holding the product maybe wasn't actually of him?

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In the comments of the previous post on this subject, I mentioned that it probably won't work. I want to expand on a few reasons why.

Suppose a patient applies Lumina as directed, and it works exactly as well as anyone could hope. Within eighteen months, the Lumina strain has successfully outcompeted all other strains of S. Mutans, and for that matter all other bacteria within its ecological niche.

It still won't work forever. And probably not for very long. And the reason why is pretty obvious once you ask yourself why the grad student in whom the Lumina predecessor was found had other bacteria in his mouth as well.

There is a metabolic cost to producing M-1140. Once all the bacteria in the mouth have the make M-1140 gene and the immune to M-1140 gene, the evolutionary advantage goes to those bacteria that (through inevitable natural mutation) are immune, but don't produce the antibiotic.

Over time, ceteris paribus, Lumina's descendants will evolve away from the M-1140 producing gene. And if non-immune bacteria don't colonize the mouth before the producing gene goes extinct, the immunity gene will go extinct too (since there's no benefit to being immune to an antibiotic you're not exposed to).

The most likely outcome is a semi-stable yoyoing between immune + producing bacteria, and neither immune nor producing bacteria.

And this all assumes that there is no net evolutionary disadvantage to the other two genes that are essential in Lumina, which is doubtful.

For example, if a bacteria colonizes the mouth which produces a different antibiotic, to which Lumina is not immune, then lumina can only obtain immunity through natural mutation, not horizontal-gene-transfer, and will very swiftly be outcompeted by bacteria that can obtain beneficial mutations horizontally.

With all that said, I think your probabilities are pretty close to my own, although there is one outcome that I would add.

Lumina has a statistically significant benefit, but due to the evolutionary pressures outlined above, it must be reapplied on a regular basis: ~35%

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Thanks for highlighting these problems. I was wondering about the metabolic costs and competition as well.

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Evolution is not nearly as fast as you imagine. Also, this bacterium is intentionally stable against it.

I don't have any strong opinions on whether this will work or not. But I don't think that what you say is a reason why it won't.

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The generations of S. Mutans are measured in hours, not months or years. And the inability to perform horizontal gene transfer doesn't block evolution through internal mutation.

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"Once all the bacteria in the mouth have the make M-1140 gene and the immune to M-1140 gene"

Never going to happen

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I appreciate this. My question on whether I would recommend this to a grandchild seems to be answered.

As an aside, wish someone would have done this with the covid vaccine.

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Can we just rinse our mouths with an alkaline solution twice a day?

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That's essentially what people who use fluoride-free toothpastes twice a day are doing. It's not nearly as effective, because peak acidity occurs shortly after meals, and most people don't brush immediately following mealtimes.

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I tend to brush maybe half an hour after mealtimes. Maybe that's my secret.

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That's certainly a part of it.

The reason why it's so hard to tell if a particular intervention is effective against caries, and how much, is that there are so many factors that we already know have a clinically significant effect that it's all but impossible to control for all of them in a study.

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Apr 16·edited Apr 22

There were two attempted trials, not 3. Numbers 2 and 3 in your list are the same trial, and it didn’t succeed. It looks like it didn’t even get started.) Oragenics has described the process in detail in each year’s Form 10-KSB/Form 10-K, which they have been filing since 2003. All those forms are available on their website. I think it was in the 2012 form that they said they had given up.

None of the forms mention anywhere near 100 people required in a trial, or people under 30.

[Update: the second trial did require people under 30 (ten of them, with teeth), and it looks like it did get started (but didn't succeed).]

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Can you expand on this?

In https://ir.oragenics.com/all-sec-filings/content/0001193125-07-062141/d10ksb.htm , they say that they tried to do the denture trial, it didn't work, and they sought permission from the FDA to do something else. Then they say:

"Protocol changes from FDA were addressed in our third re-submission submitted in February 2007. We believe these changes, if approved in a timely manner by the FDA, will allow the Company to complete the enrollment of patients and thereby complete the study by the end of 2007. " I think this was the non-denture hospital-based trial. It looks like they got the approval they wanted in 2007: https://www.biospace.com/article/releases/oragenics-inc-receives-fda-go-ahead-for-smart-replacement-therapy-tm-trial-/

Then the next thing we hear is "While we commenced a Phase 1b clinical trial for SMaRT Replacement Therapy during the first quarter of 2011, the very restrictive study enrollment criteria required by the FDA made the enrollment of candidates meeting the restrictive criteria difficult"

If the 2011 trial is the non-denture hospital-based trial:

- Why did it take until 2011 if they said they were going to do it in 2007?

- Why are they doing a Phase 1b if they never completed a 1a? Why are they describing it as "the second" trial if they never completed a first?

- In what sense are the enrollment criteria difficult? If I understand right, the enrollment criteria for 2 were just people 18-30, don't need dentures, don't need anything else.

All of this made me think the 2011 trial wasn't the same as the 2007 trial. I could be getting this messed up, but if so I'm pretty confused.

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Apr 17·edited Apr 17

You’re right that hospital-based trial did require people under 30, my bad!

Regarding your questions:

> Why did it take until 2011 if they said they were going to do it in 2007?

They got approval for the second trial in late 2007. The 2008 and 2009 Forms 10-K basically have no updates, so I don’t know what happened during those years. The 2010 Form 10-K is more verbose but likewise doesn't have much information on what they did with BCS3-L1 in 2010 specifically.

> Why are they doing a Phase 1b if they never completed a 1a? Why are they describing it as "the second" trial if they never completed a first?

The dentures trial, which was run in 2005, is what they refer to as their first phase 1 clinical trial.

- In what sense are the enrollment criteria difficult? If I understand right, the enrollment criteria for 2 were just people 18-30, don't need dentures, don't need anything else.

I don’t know about this.

I’ll describe where I got each piece of information in the paragraphs below. This is from a set of notes I jotted down when reading Oragenics’s SEC forms last weekend, summarizing relevant information from each yearly report from 2003 to 2012. This is kinda long, but the most important part is the 2010 Form 10-K.

Based on the 2003 Form 10-KSB (https://ir.oragenics.com/all-sec-filings/content/0001144204-04-003117/0001144204-04-003117.pdf):

Oragenics said they submitted an investigational new drug (IND) application for their replacement therapy to the FDA in 1998. The FDA placed their application on a “clinical hold” — not allowing them to start a clinical trial. They then describe a lot of work they did to assuage the FDA’s concerns and lift the clinical hold (which mostly consisted of creating A2JM), but by the time they submitted this form (~April 2004) the hold had not been lifted. They mention that they expect 24-30 people in their first trial.

2004 Form 10-KSB (https://ir.oragenics.com/all-sec-filings/content/0001144204-05-007474/v14287_10ksb.txt):

They say the FDA approved their Phase 1 protocol in November 2004, and started enrollment in March 2005.

2005 Form 10-KSB (https://ir.oragenics.com/all-sec-filings/content/0001144204-06-009121/0001144204-06-009121.pdf):

They describe the FDA’s requirements for the first Phase 1 trial — it was expected to include 11 couples and 4 unattached males at Hill Top Research in West Palm Beach, Florida. All participants were required to be without teeth, with full sets of dentures, and under the age of 55.

In December 2005, due to the enrollment of only one subject in this trial, they submitted a new protocol to the FDA that was less restrictive. They mention that the critical changes to the protocol are that they’re going to recruit 10 subjects with teeth who would be quarantined in a hospital-like setting for 12 days. They expect/hope to start this new trial in 2006.

2006 Form 10-KSB (https://ir.oragenics.com/all-sec-filings/content/0001193125-07-062141/0001193125-07-062141.pdf):

They say they’re still discussing the new study’s protocol with the FDA.

2007 Form 10-KSB (https://ir.oragenics.com/all-sec-filings/content/0001193125-08-059549/0001193125-08-059549.pdf):

They say they finally reached an agreement with the FDA regarding the study protocol at the end of 2007, and that subject to available capital, they plan to run the study in 2008.

2008 Form 10-K (https://ir.oragenics.com/all-sec-filings/content/0001144204-09-018117/0001144204-09-018117.pdf):

They say “We have conducted a FDA Phase 1 clinical trial and we have been approved for a FDA Phase 1(b) clinical trial.”

2009 Form 10-K (https://ir.oragenics.com/all-sec-filings/content/0001144204-10-016984/0001144204-10-016984.pdf):

They say “We have conducted a FDA Phase 1 clinical trial and we have been approved for a FDA Phase 1(b) clinical trial. We anticipate initiating this second Phase 1 safety trial in the coming months.”

[Now, based on the 2008 and 2009 forms, someone might conclude that they ran the 10-subject hospital trial quickly in 2008 and that’s what they mean by “have conducted a FDA Phase 1 clinical trial.” But the 2010 form gives more detail, and makes it clear that what they have completed is the 1-subject dentures trial, as I describe below. Moreover, the Forms 10-Q (quarterly reports) filed in 2008 don’t mention any ongoing clinical trial.]

2010 Form 10-K (https://ir.oragenics.com/all-sec-filings/content/0001193125-11-082222/0001193125-11-082222.pdf):

In this form, on page 3 (page 7 of the PDF) they reiterate what happened in 2005-2007 — they had issues recruiting subjects for the first trial and received FDA permission for a new, less restrictive trial in late 2007. They refer to their 2005 one-person trial as their first phase 1 trial — “We initiated our first Phase 1 clinical trial in April 2005.”

Then, in the next paragraph, they immediately jump to saying that they commenced a second Phase 1 clinical trial. They don’t mention having run a trial in 2008. The requirements are the same as those of the trial protocol approved in late 2007 — ten healthy subjects with teeth in an institutionalized setting.

On the following page, they mention some qualitative results from their “first phase 1 clinical trial,” but nothing from a second trial. If they had run such a second trial, they presumably would have mentioned some qualitative results on that page too.

You can control-F “second phase 1” in this PDF. The document is pretty clear that at that moment in time, that was an ongoing trial, rather than something that happened in the past.

2011 Form 10-K (https://ir.oragenics.com/all-sec-filings/content/0001193125-12-163736/0001193125-12-163736.pdf):

They say they’re trying to complete their ongoing clinical trial. Again, they describe it as a 10-subject trial in an institutionalized setting.

Q2 2012 Form 10-Q (https://ir.oragenics.com/all-sec-filings/content/0001193125-12-348771/d361986d10q.htm):

Some of the language they use makes it seem that they’re having some difficulty actually starting this second trial. Specifically, they say “We are currently in the process of commencing a second Phase 1 clinical trial to examine the safety and genetic stability of an attenuated version of the SMaRT strain in humans.” In other parts of the document they say they have already commenced it. I interpreted this as the trial being stuck in the recruitment phase -- that sounds consistent with both descriptions, but I could be wrong.

Q3 2012 Form 10-Q (https://ir.oragenics.com/quarterly-reports/content/0001193125-12-467844/d398655d10q.htm):

They say that the enrollment criteria for the second trial were too restrictive to allow the trial to proceed, and say they’re considering getting the FDA to revise the enrollment criteria again.

2012 Form 10-K (https://ir.oragenics.com/all-sec-filings/content/0001193125-13-126950/0001193125-13-126950.pdf):

This is when they gave up, citing recruitment difficulties. Again, they repeat the story of their FDA difficulties from 2005 onwards, without mentioning any trial that took place in 2008.

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Thank you so much for this!

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I preordered it, partly because I think they'll get shut down at some point and I wanted to maximize my chances of getting this cool thing. But I'll probably keep it in my freezer for a few months to a year to see more analysis before committing.

And I don't really get cavities, my main dental concern is gingivitis and bad breath. It seems there's a good chance this will not help with those, so there's that.

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It's not a good deal if you actually need ior want the benefit of the product. The opportunity cost of ending up on placebo for months might mean forestalling other steps you could take to mitigate against decay. And if it were structured as it should be for a true DB trial, you would never know which group you were in, and so potentially take no other positive action while using a placebo.

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Is every other western drug approval process as horrible as the FDA, or would it make sense to seek regulartory approval in a less broken (if less lucrative) market?

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I think you're underestimating just how much less lucrative everywhere else is, and this is a product of greatest value to those with the least money to spend on it.

If you have $250 dollars to spend on cavity prevention, the best value for money isn't an experimental biotech treatment, it's a couple regular tooth cleanings, followed up with regular home care.

The only real market for Lumina right now is people who have more money than time, and who aren't as diligent as they might want to be about scheduling dental visits or brushing their teeth.

The bulk of those people are American.

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Some people are just genetically predisposed to having lots of cavities. I’ve probably had almost a dozen in my life and I have very normal twice a day brushing habits and regularly go to the dentist

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I have chronic heartburn and can't tolerate alcohol... Sounds too risky to be worth trying in my particular case, otherwise I'd be interested.

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Shot in the dark here, but does anybody know anything about how this product might interact with liver function? This sounds great, but I don’t want to mess with my liver enzymes.

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This is helpful, thanks. I was one of the first fifty people in the West Coast to get the SMiLE surgery (in the LASIK family but newer; no flap, and fixes astigmatism) in 2017. Seven years later, I still haven't grown any horns, and I see 20/20. No more excuses not to train. Now, I am looking into Lumina.

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So does it actually exist? Your post and the comments make it seem like it's available in the wild, but the linked website says pre-orders won't ship until June 2024. I'm happy to spend $250 to apply a potentially dangerous bacterial treatment to my mouth, but I'm not prepaying to a biotech startup long before a ship date.

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People who are connected have gotten free samples, and the general sale starts June 2024.

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I haven't been this enthusiastic about new tech in a long time.

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What countries qualify as Asian fit the purposes of the aldh concern. Is it just east Asian or south Asian as well

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Anyone who gets the alcohol flush reaction. I think it's mostly Chinese, Japanese, and Korean.

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Among the Swartzentruber Amish, it is common to get dentures by age 21 because most in the community do not practice oral hygiene. Of course, the Swartzentruber Amish community is uncommonly insular, so getting them to participate in this study might be a challenge.

https://ideaexchange.uakron.edu/cgi/viewcontent.cgi?article=1281&context=amishstudies

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Would these bacteria help with tooth decay in dogs? My dog won't let me brush his teeth and he's already had to hava a lot of teeth pulled.

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(I've just spent about US $1000 on dental work...)

If this product works, it would be an incredible win. I mean, look at how much people are paying for dental work at the moment.

I wish them the best of luck, and hope it works.

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