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 topic relevant. This includes things like the author names, “tested”, “study proposed”, etc. I suspect I’ve learned that 1) author names are almost never important, 2) test procedures are only worth thinking about if they’re very explicitly detailed (which was not the case above), and 3) even if the test procedures are ok, they’re typically only relevant as a cleanup/sanitization pass once the main concept is understood.
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 response here is to recommend that friends and family unsubscribe or avoid the NYT. As far as as creating/finding a rebuttal and explaining things to others, don’t. Instead, say the article was a hit piece designed to make everyone look bad, and shrug. Give it the kind of attention you give to crazy preachers on street corners. Let it fade into obscurity.
Remember that with outrage bait, you being outraged and complaining about the article to others is entirely the point. The only winning move is not to play.
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”.
Roll out of bed, grab phones
While walking through hallway flip on heat
Wander to office, put phones on desk where they’ll sit all day long
Put on clothes and socks that were put on my chair the night before
Stumble to kitchen
Fill teapot, put on stove
Fill water purifier back up
Put coffee grounds in mug
Do a set of pushups
Go to office, power up monitors, start catching up
Go to kitchen after a few minutes, shut off stove, pour coffee
You know, from the outside, that looks pretty ridiculous. It is fast and efficient though. Thank you, Covid lockdown?
I think this might be (very slightly) unfair to mRNA vaccines, as the comparison between them and peptide vaccines is pretty situation dependent:
We have reason to believe that peptide vaccines will work particularly well here, because we’re targeting a respiratory infection, and the peptide vaccine delivery mechanism targets respiratory tissue instead of blood.
That said, mRNA vaccines are expected to elicit much stronger immune responses than peptide vaccines would.
I suspect that the low efficacy of mRNA vaccines (only 95% - low is relative) is likely because they’re only targeting the spike protein, which apparently has ‘high mutant escape potential’. We have a LOT more information about the virus now than we did when the mRNA designs were finalized. If companies had been allowed to make mRNA vaccine updates without resetting all the clinical trials, I believe we’d have a substantially better/stronger vaccine than just 95%, with a single shot instead of two.
mRNA vaccines are really just a technology demo at this point; sure, you can make vaccines with the tech, but that’s not the real superpower here. The superpower is that we have a platform we can use to generate arbitrary proteins in live cells, including proteins we know about but for which we have no reasonable delivery mechanism. Not all proteins/peptides are water soluble, and fewer are able to get through cell walls.
As a technology demo (and not a simple one at that), it’s surprising that companies have as much production capability as they do. I would expect that capacity to be ramped up substantially in the next few years as we start aggressively making use of mRNA treatments to address a host of issues.
To sum up, my view is that mRNA technology is pretty great and I’m really, really glad someone was able to make use of the disaster that was 2021 to ram through safety and clinical trials. My issue is less with the technology and it’s large promise, and more with how vaccine testing and rollout has been botched or unnecessarily slowed down at every level.
Peptide vaccines are easy and fast to both design and construct, while being safe unless you really screw up, and effective as long as designed correctly. However, they do have rather substantial limitations, and it’s just happenstance that they’re particularly well suited for the situation. I could see mRNA vaccines having a much wider berth.
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 for and reading research papers. When I found something I wasn’t sure about, I researched it and learned about it.
As examples, in early January, I spent about ten days reading up on VED (vaccine enhanced disease). Shortly after, I spent a few days digging into chitosan, and trying to understand how sensitive nanoparticle creation is to changes in the mixing process (hint: not very.) Everything I searched for I was able to find, and pretty much everything reinforced the same internally consistent view of the world.
When you find something that doesn’t make sense and you’re stuck, write it down, file it away and come back to it later. Eventually you’ll be able to make sense of it.
When you’re able to read through most or all of the whitepaper and understand both what’s being discussed and why specific things were selected, you’ll be in pretty good shape.
It’s not particularly difficult, it just takes time and effort.
I have two data points for dealing with this successfully, and both amount to “make it stop” instead of “improve things”:
One of my sisters “doesn’t have time for this crap” and one day just stopped taking the placebo pills from her normal birth control and stayed on the active hormones continuously. This apparently suppressed her period. After doing this for about ten years, she stopped and successfully conceived at almost 40 years old. This is not medical advice, do your own research, etc blah blah.
One of my female friends has had an IUD for ~15 years now, which over time reduced her period to occasional light spotting and dramatically reduced general symptoms and inconvenience. The startup period (first year) was rough though, as was the first six months after the first replacement five years in. The second replacement was basically not a problem.
It should be noted that I’m aware of multiple attempts to use IUDs within friends and family, but only have one data point that was long term successful. Apparently the first year of an IUD can be brutal and it’s not uncommon to give up after a few months.
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:
Mapping of epitopes in blood and other samples collected from convalescent patients (ideally stratified by severity of illness). This can be accomplished by a few primary means:
3D structural studies and modeling of neutralizing antibody binding to a viral antigen (e.g. Spike protein)
Mapping of linear B-cell epitopes by binding antibodies in convalescent sera to a library of peptides representing viral antigens. A strong signal in a linear epitope mapping study does not guarantee that the epitope peptide in the context of a vaccine will trigger the production of an antibody that binds to this epitope within the context of the virus. However, it is a good indicator that this is at least possible. Peptides can be constrained to approximate native conformation, making it more likely to bind the native epitope.
Mapping of T-cell epitopes by stimulating convalescent T-cells with epitope peptides, and measuring their response (e.g. cytokine secretion; ELISpot)
Epitope peptides from a peptide vaccine that has shown protection againstinfection
Successful use of epitope peptides in vaccines that elicit antibodies (or serum)effective in virus neutralization assays. B-cell epitopes that allow antibody bindingto the virus but don’t block viral function might increase risk ofantibody-dependent enhancement.
Mapped epitopes that are effective in virus neutralization assays (e.g. peptidescompete with viral sequences in cellular infection assays).
Successful use of epitope peptides in vaccines that elicit T-cell responses, orpeptides shown to stimulate T-cells or cytokine production in ELISpot or otherT-cell assay in cells from convalescents.”
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:
The peptides did not “come from in silico studies”; they came from the antibody profiles of real patients, who really had covid, and really recovered from covid (ideally without having a Bad Time during recovery.) So there’s more than just computational reasons to believe they will be useful.
It’s questionable to complain that radvac did not have a single “research study using any of the peptides in the RADVAC white paper that found they inhibited SARS-CoV-2 infection in cells, let alone animals or humans”, when the pfizer vaccine (which we know works) was designed via the same process a year ago, when we had even less information about effectiveness.
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 enough, the quantities aren’t that important, exact peptide quantities aren’t that important etc. A lot of these can be off by not just percentage points, but integer factors, and the result will still be acceptable.
It’s also worth pointing out that unless you make serious, significant mistakes that dramatically impair effectiveness, you can always just use “more dakka” to overpower the variations. My plan is to mix each batch independently, such that at least some of the construction variations are expected to cancel. (Also, freezing the final vaccine is likely to impair effectiveness, from what little I’ve found on the topic.)
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 radvac peptides.
This paper has one of the better lists I’ve found of commercial vaccine types:
From the list in that paper, it seems like pretty much all commercial products are using spike as the primary target; radvac is unique in that it also targets ORF and Nuc.
Amusingly enough, when talking about the commonly targeted spike protein RBD sequences, the radvac whitepaper lists on page 29: “Spike 450-500; ACE2 binding residues of the RBD (Zhang et al); low degree of conservation; probably moderate to high mutant escape potential”. So they pretty much called it in regards to the new virus strains with mutations like E484K.
Another radvac whitepaper quote, which seems to line up with my independent research: “It is important to note that most published neutralizing antibodies target Spike RBD, as do many vaccines in commercial development. However, given the high degree of mutability of the RBD portion of Spike, it is highly recommended to identify and select targets outside the RBD because of mutant escape potential.”
And lastly, more specific to why no RBD peptides were selected, page 34:
“Therefore, rather than focusing on ACE2-binding epitopes in the highly mutation prone RBD to inhibit virus binding to the ACE2 receptor, we targeted these B-cell epitopes in the highly conserved portions of the Spike protein to strategically neutralize proteolytic cleavage and membrane fusion. Furthermore, all three are bound by antibodies present in the sera of large fractions of convalescents, and they produce among the highest signals in linear epitope mapping studies, which are far higher than signals measured for binding to any linear epitope in the RBD.”
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.
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:
“there’s a lot of fraud out there, and by default my prior for things like this being valid is very low”
“factoring in that a couple of lesswrongers seem to think it’s ok that only pushes my estimate up into the handful of percent range”
“but there’s also evidence against, in that we don’t see any commercial products based on this, which pushes my estimate down to 1-2%”
I think this is a pretty reasonable place to start from.
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.