I spent a bit of time looking at Geert Vanden Bossche's ideas about six months ago. I came away extremely unimpressed; he takes reasonable sounding things ("viruses mutate under selective pressure") and tries to extrapolate from them things that we don't actually see in reality. He describes a plausible sounding reality, that is not our reality.
I'd point out that vaccine designers are extremely aware of ADE, and construct vaccines to be resistant to it. It's just something you wouldn't talk about, because it's second nature.
For a good discussion of what this looks like, there's a section on ADE in the RADVAC whitepaper; the section to look for is titled:
"possible mechanisms of vaccine-enhanced disease, vaccine-induced autoimmunity, and mitigation strategies"
Not only are designers aware of the risk, there are actually ways to mitigate/reduce it.
The counter argument is that we could never be completely sure; but that's as true about the covid vaccines as it is any other vaccine designed after ADE was understood.
The people at RaDVaC took measures to hit other targets then the spike protein as well for reasons to make the RaDVaC more effective with future variants. The officially approved one that just use the spike protein do not follow the ideas that RaDVaC advocates here.
I find his post incredibly uncompelling. I believe he's arguing against a straw man; economists in the real world doing real work involving real dollars are painfully aware of the issues he brings up.
My guess is that his experience in economics is heavily influenced by his PhD work and that he's arguing against "economics as he experienced it at universities" as opposed to "economics as practiced by professionals in a real economy".
https://blogs.sciencemag.org/pipeline/archives/2021/06/07/ivermectin-as-a-covid-19-therapy is one of the better, current overviews of Ivermectin. Basically, we don't have enough information.
One other thing to consider is that even small differences in replication rate might actually matter. Consider that it takes a week for the virus to really ramp up, and that's a large number of doubling periods. Even just getting a larger or smaller initial dose seems linked to how sick people get. Even a few percent difference may allow the immune system to stay ahead in the arms race, and result in a nonlinear change in death rate.
Note that I'm not saying this happens; I'm saying that because this is an exponential growth attacker (the virus) versus and exponential growth responder (the immune system), even small differences in growth rates might have a large impact.
Yeah, his second claim is bogus. That's not how it works, and that's not what we've been seeing with existing mutations.
As an example, look at E484K - this mutation changes the amino acid polarity, so that antibodies trained against the E variant will have a much harder time attaching to the K variant. If an antibody fails to attach, it doesn't 'crowd out' anything.
In the case where an antibody attaches but doesn't actually "inactivate" the virus due to a mutation, that's because the virus' attack surfaces are still present and exposed (otherwi... (read more)
#1 is where I would hinge a lot of objection. Specifically:
"The vaccines are targeting outdated variants, and some vaccines are already only partly efficient. This creates the perfect conditions for further viral evolution."
Yes, the vaccines are targeting outdated variants, and yes, the vaccines are only partially efficient. But the mRNA vaccines, even partially efficient, are still hugely overkill. From previous posts here on LW, even partially effective mRNA vaccines likely cut transmission by a factor of 100 between the reduced infecti... (read more)
The core issues I had with it are that the scenario he's envisioning just isn't playing out in the real world. He has a mostly coherent model he's working with, and he's making the valid claim that "for some set of parameters and constants, terrible things happen!" It's just that in real life, the parameters and constants are nowhere near what's needed for the badness he's claiming.
These extremely short responses discarding the bulk of my content feel less like you're attempting to understand, and more like you're attempting to get me to draw bright lines on a space I have repeatedly indicated is many different shades of grey. Disconnecting from the discussion for now.
Publisher, advertiser, the distinction does not matter. The point is that the target does not get to decide.
You might find it unpleasant, but it's it the job of Simurgh Followers to spread the Truth Of The Endbringers to everyone! Surely if people just watch enough of it, they will be converted.
The point is that the target gets to decide what's acceptable and what isn't, not the advertiser. The current system makes the advertiser the judge, and that's not ok, even if we have managed to construct a sorta functional system that mostly takes care of the worst abuses.
I'm not convinced I fully understand your distinction, let alone that we could codify it sufficiently to make it into law.
Regarding 'codify into law', that's not an excuse, and it disregards how the US legal system works. If we can codify slander, if we can codify "harm", if current advertising companies can codify "unacceptable ad", we can codify this.
If you visit a model railroading site, are ads for model locomotives push or pull?
Firm push, but only because of the physical realities of the current system.
The fact of the matter is that by default, ... (read more)
For bulk exchange of information and state, holistic is really good. I strongly prefer the holistic approach, but I've found that it only works for entirely friendly conversations. If it's adversarial, I find that branches get aggressively pruned to just the things that the opposing side can most easily attack.
And if you think about holistic being optimized for "exchange of information and state", this makes perfect sense: adversarial conversations are rarely if ever about information exchange; they're about "winning".
It's also perhaps wo... (read more)
Given the current vaccination rates in the US, and the fact that supply is already beginning to exceed demand, I'd recommend full open in approximately a month. That gives most of the remaining unvaccinated people time to go get at least their first shot, and should allow us to get below exponential growth nationwide, even though we're likely to have it in sub-populations. IMO the target should be 'not overloading hospitals'.
After that, let it burn.
From the interviews and things I've seen so far, literally the only way to change a vaccine denie... (read more)
I'd just like to point out that while "facing these tradeoffs is stupid and avoidable" (which I agree with), it's much, much more accurate to say instead "facing these tradeoffs is effectively impossible to avoid even though it's stupid and avoidable". We might not like reality, but it's not going to go away no matter how much we call it stupid and avoidable.
Having an overarching model (or several competing models) of which different parts can be tested independently seems like a structure which is very amenable towards different scientists, so I am disappointed none of the biological/medical community has started doing something like this.
This is actually done, quite a lot in fact, it's just really hard and the search space is huge. Kudos to you for your analysis; it's unlikely to be a major step forward, but given that idea search space is effectively exponential, it's also entirely possible that it's ... (read more)
> its entire purpose is to alter people's mental state without their permissionI think that's the core of our disagreement?
> its entire purpose is to alter people's mental state without their permission
I think that's the core of our disagreement?
Yes, and I think that would be a better path to attack my position. There's two attack vectors in that quoted line - "alter peoples mental state without their permission", and "permission". I would recommend avoiding the first attack vector; that will be an exceedingly difficult sell to me.
Permission on the other hand is already a partially open attack vector, and you're much, much more likely to change my mind by that r... (read more)
Here's another version of your example: Some people aren't watching nearly enough snuff and torture videos. There are people who would like to watch them, but don't know it exists. If I place ads for torture and snuff videos and some people decide to click on them while other people don't, is that a problem?
As I mentioned earlier, advertising is like weaponry. Your example also reads to me like a classic justification for 'everyone having guns': "but what if I'm attacked by a rabid dog? If I have my gun I can protect myself! &... (read more)
As someone who also works on Ads at Google, I have to take the opposite stance; I view advertising as a blight upon the face of humanity, something to destroy if we can at all figure out how to do so. I comfort myself knowing that Google Ads is arguably the best of what's an awful ecosystem, and that I work in what's arguably the 'least bad part of advertising', which is fraud and abuse protection. At least the systems I work on make things less terrible.
However, the 'least bad part of advertising' is still not 'good'.
My favorite analogy for ad... (read more)
its entire purpose is to alter people's mental state without their permission
its entire purpose is to alter people's mental state without their permission
I think that's the core of our disagreement? Here's an example I think is about maximally sympathetic: in non-pandemic times I help organize a contra dance. There are people who would like our dance, but don't know contra dancing exists, don't know that they would like it, or don't know about our dance in particular.
If I place ads, and some people see them and decide to come to our dance, do you have a problem with that? Or is it that you think most advertising doesn't work that way?
I still have some remaining bitcoin, from the olden days when mortal man could mine it themselves. My advice to everyone I've ever talked to regarding bitcoin is to avoid it. I have been slowly divesting my holdings.
My rationale is that while both the dollar and bitcoin are fiat currencies, bitcoin is far, far less anchored to reality than most 'normal' currencies. The dollar and the euro at least have people trying to keep monetary levels somewhat tied to physical economic value. The value of bitcoin, meanwhile is largely driven by... (read more)
I've found lighting, melatonin, and caffiene regulation to be wonderful additions to my sleep regime. I take melatonin pretty consistently at around 8:30 pm, and it seems like it helps make me sleepy ~45 minutes later. As per SSC though, melatonin isn't particularly strong and the effect I'm noticing may very well be placebo. I always have caffiene, but rarely after 2 pm, and typically not more than two cups of coffee per day.
That said, I suspect my lighting and light policy is having a much, much bigger effect.
The primary light source in... (read more)
Quick comment: I noticed that in all of your examples above, I chunk substantially bigger and fewer pieces. For example, in the "15 different bold bits" clip, I chunk it into about 8 pieces instead.
This is likely experience/background dependent; I happen to have a relatively strong background in ML and have read a stack of research papers recently, so I probably have both stronger noise filters and more complicated primitives available.
One possibly interesting side note: I never once, in any of your examples, considered metadata about the... (read more)
Let's be blunt here: the NYT article is pure, unbridled outrage bait dressed up as journalism. It's not trying to solve a problem, and it doesn't have any agenda other than to pack as much outrage as possible into the publication form factor so as to maximize eyeballs. It simultaneously craps on EA, the tech industry, SSC, rationalists, MIRI, tech investors and a stack of others. (I'm surprised that they didn't also include jordan peterson, because hey, why not?) That's not the sign of someone being honest.
IMO the correct resp... (read more)
I do a low-grade speedrun in the morning, every day. If you make it a habit, it becomes less of a stressful "speedrun", and more of "how you do things".
I think this might be (very slightly) unfair to mRNA vaccines, as the comparison between them and peptide vaccines is pretty situation dependent:
In my case, I'd estimate that I've spent around two hundred hours over the last several months coming sufficiently up to speed on the topics that I can reason about them. I started with about your level of biology (or possibly less), but probably a slightly stronger chemistry background.
For the basics, I started with cell biochemistry, DNA/RNA, mRNA and protein construction. From the vaccine side of things, I just started looking up things I found in the whitepaper which I didn't understand, and once I understood all the terms I started looking... (read more)
I have two data points for dealing with this successfully, and both amount to "make it stop" instead of "improve things":
Ugh. Thanks for the link.
I believe that initial post is what got me going down the rabbit hole of peptides and proteins and dna and rna and transcription factors oh my! It's been a long ride.
Sarah Constantin is confused, and likely has not spent significant time reviewing the vaccine design. From page 32 of the whitepaper:
"Empirical evidence should dominate selection criteria. Here are some best types of evidence:
Sorry about that; I believe I misread your comment as implying that if the moderator is ignorant, he won't have enough information to form a reasonable prior. My disagreement was along that line, as it seems that misinformation, especially about medical things, is so prevalent that everyone's default prior should be 'fraud unless lots of evidence points the other way'.
A couple of minor quibbles:
Yes. The differential tradeoff is how one should evaluate this. The only reason my evaluation came out in favor of trying the radvac vaccine is because I have a high-risk event coming up in the next few months, and I am extremely unlikely to be able to acquire a commercial vaccine before then.
In my case, yes. My bio expert indicated that it was likely to be effective (more than 50%, but less than 90%) and that the risks were effectively zero in terms of serious complications.
Regarding the food grade versus lab grade question, as well as inaccuracies or mistakes in construction of the vaccine, this was a question I spent a reasonable amount of time on. The TL/DR is that the engineering tolerances are incredibly wide; the molecular weight of the chitosan isn't that important, the mixing rate isn't that important other than it be fast ... (read more)
I wasn't sure what you meant by more dakka, but do you mean just increasing the dose? I don't see why that would necessarily work--e.g. if the peptide just isn't effective.
I'm confused because we seem to be getting pretty different numbers. I asked another bio friend (who is into DIY stuff) and they also seemed pretty skeptical, and Sarah Constantin seems to be as well: https://twitter.com/s_r_constantin/status/1357652836079837189.
Not disbelieving your account, just noting that we seem to be getting pretty different outputs from the expert-checking process... (read more)
Again, I have to disagree - misinformation is much more likely than information by default, and the moderator need only have a reasonable low-probability prior in order to reject unusual/uncommon claims without evidence.
Yeah, the pfizer vaccine looks like it just uses mRNA to construct the RBD (receptor binding domain) of the spike protein, which is about two hundred amino acids long. None of the default 9 peptides in gen 9 radvac are for that domain. See page 40 of the whitepaper for the full spike protein sequence; the highlighted blue is the RBD, and the short underlined sequences are peptides selected for the vaccine.
The moderna vaccine uses mRNA to construct pretty much the whole spike protein, including the RBD. This has overlap with 3 of the 9 rad... (read more)
Absolutely obviously yes. I have some level of concern that this post will go viral (ha ha), get a lot of attention outside of lesswrong, and the company I'm working with will cancel my order because it's "covid misinformation" related.
The FDA might be slow and take months to approve safe things while thousands of people die per day, but they're perfectly capable of announcing an immediate and indefinite peptide ban in under a day because a news article crossed the wrong person's desk.
About the "viral" part. This post is currently at the top of HN: https://news.ycombinator.com/item?id=26022750
My estimate for whether or not I would test positive on a blood test was only about 50%, since blood isn't the primary place that the response is generated. I'm already betting a substantial amount of money (peptide purchases and equipment) that this will be helpful, and I see no reason to throw an additional $50 on a break-even bet here.
I would, however, be happy to commit to sharing results, whether they be positive or negative.
... and now it occurs to me that if Lesswrong had a 'public precommitments' feature, I would totally use it.
A lot of people have been working really hard for the last year to discover, understand, and know these things. It's the foundation for how the mRNA vaccines work.
Perhaps take a look through this:
While I generally agree with the concept, I'm going to push back a little here. I read the 1-2% chance as less being about "why aren't companies doing it" and more about lack of information.
My initial reaction to seeing it was that it was a combination factors along the lines of:
Yes, I still plan to get the commercial vaccine once it's available to me (likely some time in august.) As I understand it, the commercial vaccines hit different areas of the virus from the ones that radvac selected, improving protection even further.
There is actually an optional peptide for radvac which does cover one of the same regions as the commercial vaccines. I elected not to include it under the assumption I'd be getting it from the commercial vaccine.
Yes; sorry I was unclear. Those peptides generate the antibodies we care about, that are known to be effective against the full virus.
Regarding the 33.4% approval rate: based on what I've learned about traditional vaccine development and production in the last few months, I am not at all surprised. Both peptide and RNA vaccines are effectively "state of the art" technologies compared to traditional vaccine techniques. It's like comparing modern non-invasive out-patient surgery to the 1970's equivalent.
You need look no further than the russian and chinese vaccines - those use the rather crude technology of "throw big chunks of inactivated virus particles at the immune sy... (read more)
My understanding is that it helps a lot.
The biggest benefit seems to be that the immune system is primed in at least some fashion; it knows what to look for, and it has readily available tools that should be effective. It doesn't have to take a day or a week to try random things before it finally discovers a particularly effective antibody and gets the production chain ramped up to start a proper immune response.
Instead, your immune system will very quickly get a signal it understands as bad and can immediately start ramping up when it does detect th... (read more)
I agree as well. It takes a non-trivial amount of knowledge and research to evaluate the the whitepaper and its claims, and I wouldn't expect the moderator of a "neoliberal" group to have that expertise. We have options with a known risk profile (the commercial vaccines), and there's a spot of fraudulent "cures" out there. The safe thing for a moderator to do is blackhole potentially dangerous claims they don't have the time and/or experience to evaluate.
Regarding the final paragraph, "you need some level of expertise yourself before you can distinguish real experts from fake": that has been the number one reason I didn't beat johnswentworth to the punch and post first with my experience.
I have learned more about biochemistry in the last three months than in my entire prior life combined. It has taken me three months of research, asking questions, and conferring with experts to get sufficient confidence in my understanding to commit to the project.
I'm incredibly thankful to you (johnswentworth)... (read more)
I'd be very interested in a post on what you learned! I relied mostly on general bio background from undergrad, it sounds like you probably went into more depth in areas specifically relevant to this.
My personal estimate is that the the percentage of nurses who have done this is effectively zero (less than one in a thousand with high probability, less than one in ten thousand with moderate probability.)
Further, those who did do it are likely to have read through the whitepaper, and therefore are also likely to get the commercial vaccine, as it covers different epitopes than the radvac vaccine.
The whitepaper is a good source, but like johnswentworth, I also contacted a medical professional to evaluate it. The response came back quickly and confidently, and was along these lines:
"Oh, yeah, this is safe. Nasal vaccines are safe. The biggest worry is that it might not work, so make sure you get the commercial vaccine too. I'd be interested in doing this with you as a joint project and giving it to my family, and I also have a colleague who might be interested in doing it."
The biggest point of disbelief on their part was that it's possible to order all the equipment and peptides online and have them shipped to your door.
My rough guess is that there's a 75% probability of effectively full immunity, and a 90% probability of severity reduction. This is a pretty well tested and understood vaccine mechanism, and the goal isn't "perfect immunity" as "prime the immune system so it doesn't spend a week guessing about what antibodies it needs to combat the virus effectively".
As to why established companies don't do it, I believe it's partially logistics, and largely red tape. Logisitics first (though it should be noted that at least some of these could likely be tackled with... (read more)
This is a very in-depth explanation of some of the constraints affecting pharmaceutical companies that (mostly) don't apply to individuals, and is useful as an object-level explanation for those interested. I'm glad this comment was written, and I upvoted accordingly.
Having said that, I would also like to point out that a detailed explanation of the constraints shouldn't be needed to address the argument in the grandparent comment, which simply reads:
Why are established pharmaceutical companies spending billions on research and using complex mRNA vaccine
Why are established pharmaceutical companies spending billions on research and using complex mRNA vaccine
Oh, it's far, far worse (better?) than $2 per dose. As a thought experiment, I price estimated buying enough peptide for a hundred thousand doses, and it only costs about ten thousand dollars. Ten cents a dose is closer to realistic if you buy in bulk.
Which also brings to mind a question of civilizational inadequacy: if we really cared and it really mattered, why not have every university with a lab in the country crank out a hundred thousand doses per week to their local populace?
I don't think this has ever been possible in previous epidemics, at least for at-home manufacture.
That being said, I would strongly support compiling a list of low-risk interventions like this, so next time we can publicize them at the outset and try mitigating the problem while waiting for the low-risk&high-success solution to be developed.