BBE W1: HMCM and Notetaking Systems 2020-06-09T19:20:31.975Z
BBE W1: Personal Notetaking Desiderata Walkthrough 2020-06-09T19:19:05.860Z
Build a Better Exobrain: Week 0 Overview 2020-06-09T19:09:14.177Z
Coping and Cultures 2020-05-06T22:49:13.428Z
Does SARS-CoV-2 utilize antibody-dependent enhancement? 2020-03-14T22:46:38.293Z
Bioinfohazards 2019-09-17T02:41:30.175Z
Spiracular's Shortform Feed 2019-06-13T20:36:26.603Z


Comment by spiracular on Why isn't increasing ventilation of public spaces part of the best practice response to the Coronovirus? · 2020-11-27T03:39:03.083Z · LW · GW

Boy, it's been quite a while! Have a half-assed conclusion (/retrospective/answer).

Here's an article with a lot of illustrations whose models suggest that increased ventilation (in several common scenarios) results in a reduction in infection rate by a factor of about 5-7x, even when compared to mask wearing.

A room, a bar and a classroom 's model seems to be using a 5x reduction number for indoor vs "almost-outdoor," which seems to roughly line up with this.

For comparison, mCov's factor-reductions for surgical-mask wearing are 2x, and n95s are 10x. So "open-windows and heavy ventilation" lands basically right between the two in reducing risk.

My impression at this point is that adequate ventilation was a pretty strong target for reducing spread.

So... Kudos or BayesPoints to ChristianKl (whichever you prefer) for calling that 8 months ago.

Comment by spiracular on Is Success the Enemy of Freedom? (Full) · 2020-10-28T03:05:44.882Z · LW · GW

I suspect with Starcraft there might be the issue of... conflicting intuitions/muscle-memories? Muscle-memory mix-ups sometimes happen when you learn 2 things that have similar cues, and avoiding those mistakes can cost you in reaction-time.

If there's a batch of early-game keystrokes you need to drill into muscle-memory to begin a Zerg play, and a different batch of keystrokes for a Protoss play, having them mash-up on you under stress is a setback on both skillsets.

A more glaring example: learning to ride left-right reversed bikes is likely to disrupt your ability to do regular bike-riding for some time.

I'd have suspected that for things as different as baseball and basketball, this probably wouldn't apply as much. (And if you commit HARD to the switch, it's probably not as big of an issue; just a hill to climb initially, then smooth sailing for a while, but some transition-time needed when you switch back.)

...but the Michael Jordan article actually mentions that there was at least one case where MJ followed basketball intuitions to run more bases than anyone else thought was optimal. So the "misapplied cross-field intuitions" disadvantage might still have a role here.

(Something something generalizability vs hyperspecialization trade-off)

Comment by spiracular on March Coronavirus Open Thread · 2020-09-15T19:07:45.159Z · LW · GW

Chinese virology researcher released something claiming it SARS-2 might even be genetically-manipulated after all? ZC45 and/or ZXC21 backbone. Claims that the RaTG13 genome was a concocted cover-up. After assessing, I'm not really convinced of the GMO claims, but the RaTG13 story seems to have something weird going on.

See here for my further thoughts on this.

EDIT: After assessing, I'm not finding the GMO claims convincing. The RaTG13 story does seem to have something weird going on, and there's several people and papers that note weird inconsistencies (See the further thoughts, I don't have a simple explanation.).

Comment by spiracular on Jimrandomh's Shortform · 2020-09-15T18:55:20.546Z · LW · GW

Chinese virology researcher released something claiming that SARS-2 might even be genetically-manipulated after all? After assessing, I'm not really convinced of the GMO claims, but the RaTG13 story definitely seems to have something weird going on.

Claims that the RaTG13 genome release was a cover-up (it does look like something's fishy with RaTG13, although it might be different than Yan thinks). Claims ZC45 and/or ZXC21 was the actual backbone (I'm feeling super-skeptical of this bit, but it has been hard for me to confirm either way). (aka Yan Report)

RaTG13 Looks Fishy

Looks like something fishy happened with RaTG13, although I'm not convinced that genetic modification was involved. This is an argument built on pre-prints, but they appear to offer several different lines of evidence that something weird happened here.

Simplest story (via R&B): It looks like people first sequenced this virus in 2016, under the name "BtCOV/4991", using mine samples from 2013. And for some reason, WIV re-released the sequence as "RaTG13" at a later date?

(edit: I may have just had a misunderstanding. Maybe BtCOV/4991 is the name of the virus as sequenced from miner-lungs, RaTG13 is the name of the virus as sequenced from floor droppings? But in that case, why is the "fecal" sample reading so weirdly low-bacteria? And they probably are embarrassed that it took them that long to sequence the fecal samples, and should be.)

A paper by by Indian researchers Rahalkar and Bahulikar ( ) notes that BtCoV/4991 sequenced in 2016 by the same Wuhan Virology Institute researchers (and taken from 2013 samples of a mineshaft that gave miners deadly pneumonia) was very similar, and likely the same, as RaTG13.

A preprint by Rahalkar and Bahulikar (R&B) ( doi: 10.20944/preprints202008.0205.v1 ) notes that the fraction of bacterial genomes in in the RaTG13 "fecal" sample was ABSURDLY low ("only 0.7% in contrast to 70-90% abundance in other fecal swabs from bats"). Something's weird there.

A more recent weird datapoint: A pre-print Yan referenced ( ), whose finding (in graphs; it was left unclear in their wording) was indeed that a RaTG13 protein didn't competently bind their Bat ACE2 samples, but rather their Rat, Mouse, Human, and Pig ACE2. It's supposedly a horseshoe bat virus (sequenced by the Wuhan lab), so this seems hecka fishy to me.

(Sure, their bat samples weren't precisely the same species, but they tried 2 species from the same genus. SARS-2 DID bind for their R. macrotis bat sample, so it seems extra-fishy to me that RaTG13 didn't.).

((...oh. According to the R&B paper about the mineshaft, it was FILTY with rats, bats, poop, and fungus. And the CoV genome showed up in only one of ~280 samples taken. If it's like that, who the hell knew if it came from a rat or bat?))

At this point, RaTG13 is genuinely looking pretty fishy to me. It might actually take evidence of a conspiracy theory in the other direction for me to go back to neutral on that.

E-Protein Similarity? Meh.

I'm not finding the Protein-E sequence similarity super-convincing in itself, because while the logic is fine, it's very multiple-hypothesis-testing flavored.

I'm still looking into the ZC45 / ZXC21 claim, which I'm currently feeling skeptical of. Here's the paper that characterized those: doi: 10.1038/s41426-018-0155-5 . It's true that it was by people working at "Research Institute for Medicine of Nanjing Command." However, someone on twitter used BLAST on the E-protein sequence, and found a giant pile of different highly-related SARS-like coronaviruses. I'm trying to replicate that analysis using BLAST myself, and at a skim the 100% results are all more SARS-CoV-2, and the close (95%) results are damned diverse. ...I don't see ZC in them, it looks like it wasn't uploaded. Ugh. (The E-protein is only 75 amino acids long anyway. )

A different paper mentions extreme S2-protein similarity of early COVID-19 to ZC45 , but that protein is highly-conserved. That makes this a less surprising or meaningful result. (E was claimed to be fast-evolving, so its identicality would have been more surprising, but I couldn't confirm it.)


I think Yan offers a reasonable argument that a method could have been used that avoids obvious genetic-modification "stitches," instead using methods that are hard to distinguish from natural recombination events (ex: recombination in yeast). Sounds totally possible to me.

The fact that the early SARS-CoV-2 samples were already quite adapted to human ACE2 and didn't have the rapid-evolution you'd expect from a fresh zoonotic infection is something a friend of mine had previously noted, probably after reading the following paper (recommended): (Zhan, Deverman, Chan). This fact does seem fishy, and had already pushed me a bit towards the "Wuhan lab adaptation & escape" theory.

Comment by spiracular on Spiracular's Shortform Feed · 2020-08-18T03:17:56.604Z · LW · GW

On Community Coordinator Roles

Some things I think help are:

  • Personal fit to the particular job demands (which can include some subset of: lots of people-time, navigating conflict, frequent task-switching, personal initiative, weighing values (or performing triage), etc.)
  • Personal investment in appropriate values, and a lasting commitment to doing the role well.
  • Having it be fairly clear what they're biting off, what resources they can use, and what additional resources they can petition for. Having these things be actually fairly realistic.

(Minimum expertise to thrive is probably set by needing to find someone who will advocate for these things well enough to make them clear, or who can at least learn how to. Nebulous roles can be navigated, but it is harder, and in practice means they need to be able to survive redefining the role for themselves several times.)

  • Having some connections they (and others) respect who will help support what (and how) they're doing, lend some consistent sense of meaning to the work, and people who will offer reliable outside judgement. Quite possibly, these things come from different people.

(Public opinion is often too noisy and fickle for most human brains to learn off of it alone.)

  • For roles that require the buy-in of others, it's helpful if they have enough general respect or backing that they will mostly be treated as "legitimate" in the role. But some roles really only require a small subset of high-buy-in people.
  • Also, some sort of step-down procedure.

Extracted from a FB thread, where I was thinking about burnout around nebulously-defined community leader roles, and what preparedness and a good role would look like. Parts of this answer feel like I'm being too vague and obvious, but I thought it was worth making the list slightly more findable.

Comment by spiracular on [META] Building a rationalist communication system to avoid censorship · 2020-06-25T23:52:32.477Z · LW · GW

I've seen some presentations about how to do style-matching off of GitHub repos to pretty-confidently ID anonymous coders. While set-up requires a sizable amount of compute and data, the results have gotten quite impressive. There are ways to work against this (stuff that deliberately obscures your coding style, usually by rewriting your code), but they're not that well known. And a similar thing can be done with writing style and writing samples.

Staying anonymous against high-effort attempts to discern your identity has gotten very hard, and is only likely to get harder.

At some point, all you can do is guard against the low-effort ones.

Comment by spiracular on [META] Building a rationalist communication system to avoid censorship · 2020-06-25T23:28:54.160Z · LW · GW

A quiz and a day's wait before adding a new user is another option. Make it something that a regular lurker who read the rules would be able to pass easily, but a rando couldn't. SCP wiki did something like this, it seemed to help with quality control.

Rotate through 3 different quizes, or scramble the quiz order sometimes, if you want to make automated sign-ups annoying for mobs and spammers. Have the web people track the number of sign-up-quiz fails (it's a nice metric for "is there a mob at the doorstep").

(Edit: Ah, someone already proposed a more-elaborate variant using GPT-X. Simple quizes with a few mild gotcha-questions should be enough of a screen for most cases, though.)

A proposal I think I haven't seen posed is giving new members a "trial period." If an average (or randomly-selected) post doesn't have a karma score of at least X by the end of the period (or if it dips below Y at any point), they're out and their stuff is deleted. Ban them from handing out karma until after the trial, or this quickly breaks. This probably still has weird incentive consequences that I'm not seeing, though... does mean having a bit of an evaporative-filter for quality-ratings, and it means links to crappy posts turn into deadlinks in just a matter of time.

Comment by spiracular on Does SARS-CoV-2 utilize antibody-dependent enhancement? · 2020-06-17T22:53:15.104Z · LW · GW

I did specify long-term, which for me meant time-frames of around a year to a decade out. Honestly, I suspect you're largely right about the short-term.

Well, except I might be more optimistic about vaccination efforts. Effective vaccination pushes in the past give me some hope.

Also, the mutation rate is a good bit lower than the seasonal flu. SARS-CoV-2's point-mutations per year is around 28 substitutions, which is about 1/2 as many as the flu. Or around 1/3 the rate, at ~1.1e-3 subs per site per year, compared to flu's 3.3 subs per site per year. (Different genome lengths, hence the different answers.)

Comment by spiracular on BBE W1: Personal Notetaking Desiderata Walkthrough · 2020-06-11T18:32:12.953Z · LW · GW

It's kinda weird to me how limited the options seem to be for flashcards and annotation/marginalia. While plenty of things perform the core functionality, I haven't seen anywhere near as many interesting experiments with these formats as I have with outliners.

And for flashcards particularly? You'd think it'd be the simplest damn thing to program!

I'm not much of an index card person, but there seem to be a lot of people who swear on elaborate index-card set-ups. That I haven't seen more of them implemented as software confuses me too.

(It does seem like it would be a good use of flashcards to set up a rudimentary priority queue, or stack. Possibly with added randomness. I'm honestly a little surprised it doesn't allow that.)

Comment by spiracular on BBE W1: HMCM and Notetaking Systems · 2020-06-11T18:10:14.395Z · LW · GW

I think this is a good question. Here are some probable components of programmability...

  • Did it surface most of its actual functionality to users?
    • A couple different settings: Closed proprietary cloud software, API (how friendly or permissive is it?), downloadable open-source...
  • How easy (and safe!) it is to call relevant utility functions?
    • Do you need to close the software to edit it? Did they merely surface the functionality, or did they also leave functions that were highly-exposed, labeled, well-documented, and easy to use? How well do they adhere to various standards, and therefore benefit from skill-transfer? Is it easy to screw up? To revert? What's the learning curve like?
Comment by spiracular on BBE W1: HMCM and Notetaking Systems · 2020-06-11T17:51:47.796Z · LW · GW


I really wish there was better flashcard and annotation/marginalia software out there! It's kinda weird to me how limited the options seem to be for both. While plenty of things perform the core functionality, I haven't seen as many interesting experiments with it as I have with, say, outliners.

While writing this post, I developed a vague suspicion that there's something in-between Annotator and Flashcard that could be pretty valuable if someone actually implemented it. This seems as good a place as any to describe it. (And if someone has already done it, or wants to do it, cool!)

Annotators and Flashcards are both often tracking an underlying dictionary-ish data-type, and a lot of flashcards seem to originate from textbooks. I have a suspicion that there should exist a good standardized-format notetaker that goes something like... this?

TextCards: 3 linked items

  • A bounded section of highlighted textbook (Any size, from a section to entire chapter. Sometimes discontinuous.)
  • An index-card laconic description (or answer)
  • A title (or question)

Sometimes, it could be used to pose standard quiz-questions (the highlighted section is just the part of the book the quiz came from, the title is the question, the description is an answer). But where it might really shine is in "Summarize Chapter X" questions; it encourages you to write along as you read the text, and if you miss something on a quiz, you can click right to the sections you were originally summarizing.

When rendered as marginalia, the small titles (until click) should make that experience more tolerable for frequent-margin-users. (Marginalia asyncing with the page seems like a really common problem, otherwise.)

For convenience, adding something that swipes all of the questions from a highlighted section of the text to form the front end of flashcards (that you then answer) seems pretty nice. For well-formatted answer-sections, you might even be able to get it to pair the two (but you'd probably need to highlight where to look). Additionally, it wouldn't be that hard for it to track which chapter's questions you're doing poorly on -and therefore what chapters you should re-read- if it knows where in the book you swiped them from. Bonus points if you can sort and cross-link notes by title, folder, tags, overlapping highlights, and/or order in text.

Presumably this is usually harder than I think it should be, because PDFs are just awful (I've dragged tables from PDFs before; I feel so sorry for Tabula!). But HTML books and ebooks don't have that problem, and often simulate a textbook-like structure.

Comment by spiracular on Spiracular's Shortform Feed · 2020-06-08T22:22:03.518Z · LW · GW

At minimum it's oversimplified. That's why I called it a parable.

I appreciate the nuance in your comment even as it is. But I'm curious about the facts/narratives you have that disagree with it?

(My personal strongest murphyjitsu was that "space program defunding" was more complicated than this. If you know more about that than I do, I'd be curious to hear about it.)

Comment by spiracular on Spiracular's Shortform Feed · 2020-06-04T18:43:42.702Z · LW · GW

A Parable on Visual Impact

A long time ago, you could get the biggest positive visual impact for your money by generating art, and if you wanted awe you could fund gardens and cathedrals. And lo, these areas were well-funded!

The printing press arrived. Now, you could get massive numbers of pamphlets and woodcuts for a fraction of the price of paintings. And lo, these areas were well-funded!

Then tv appeared. Now, if you wanted the greatest awe and the biggest positive visual impact for your money, you crafted something suitable for the new medium. And in that time, there were massive made-for-tv propaganda campaigns, and money poured into developing spacecraft, and we got our first awe-inspiring images of Earth from the moon.

Some even claim the Soviet Union was defeated by the view through a television screen of a better life in America.

And then we developed CGI and 3D MMORPGs. And lo, the space program defunded, as people built entire cities, entire planets in CGI for a tiny fraction of the cost!

Comment by spiracular on Stop saying wrong things · 2020-05-12T23:49:39.782Z · LW · GW

I didn't downvote it, but I did find the writing style mildly grating. (Relatedly: I cannot exceed your set-point of smug, it is over 9000 :) )

To be clear: I think the underlying point was pretty good, and I mostly had issues with the delivery. I still feel it was probably something worth writing, although I also think I'm not the target audience for this particular bit of advice.

Some of it was probably a tone thing, which I won't go into. But here are some things that seem tractable:

My experience of it was a bit better as soon as I switched out almost all the "You"s for "I"s. I have something of a distaste for the... puppety-feeling where someone seems to be trying to put words into my mouth, that don't fit with my actual experience. This set it off pretty badly. There are a lot of specifics, and it's clearly your personal account; own it.*

This got really stark for me at around...

First, you just end up being an asshole pretending to be honest

...which instantly broke my immersion. My experience of being painfully honest with myself, and then others, was radically different.**

It probably also could have used more short paragraphs, and some variety in presentation. Some of the goals you've acted on and then forgotten, such as Real Analysis or Mandarin, could have been better-presented as single bullet-points after going into only 1 of them in-depth. The Etsy section could have used a header, and been broken into more than 1 paragraph. That kind of thing.

*A lot of bad advice on persuasive essay writing encourages the formation of habits like this. One cannot list the number of times one has been told to make that unnatural substitution of "One," where "I" would have been better, and more honest. Teachers who do this are just... wrong. Technical writing is a real thing, but this way of teaching it is crap, and can ruin otherwise-decent writers.

** My experience was close to painful self-consciousness (for self-honesty), and weird social penalties (for honesty with others). Real honesty is often distinctly un-charming, but in my case... bluntness leaned closer to "overly-invested*** eccentric" than "asshole." If it had been framed as a self-account, this jarring wouldn't have been an issue.

*** Exhibit A: This overgrown write-up.

Comment by spiracular on Why don't we tape surgical masks to the face to seal them airtight? · 2020-05-12T21:48:30.494Z · LW · GW

I've personally found that just stapling shut the outer edge of the first fold on either side of a surgical mask results in a mask that mostly sucks to my face when I breathe in. It doesn't stick well when I breathe out, though.

This is much easier to implement than fancy adherents; all it takes is 2 staples and a stapler, or a needle and thread. It struck me as a plausible 80-20. (Well, less than 80%. Obviously, this is no N95.)

(It might only work for some face-shapes, though.)

This generates a new problem, which would also apply to taped/glued solutions:

The front is made of a softer fabric than N95s. After an hour of wear, it will suck to my lips if I breathe in with my mouth. And since it doesn't stick on out-breaths, air still gets out the sides and sometimes the top. I don't know how much additional risk this presents, but I would be curious to hear someone weigh in.

(It also has uncomfortably-high humidity, but that's even more true of N95s.)

Comment by spiracular on April Coronavirus Open Thread · 2020-05-09T19:32:46.520Z · LW · GW

Late Edit: Pangolins with this viral infection have been found from smuggled ones from both Guangxi and Guangdong provinces, but do not show up in wild pangolin populations in general.

Despite the virus being characterized in pangolins, after looking into this, I now think it is basically incorrect to think of this as primarily a "pangolin virus." The pangolins were a dying canary in a coal mine, and probably caught it from something else that serves as the real reservoir species for this nCOV precursor*.

These pangolins were being smuggled when they were captured by the authorities in Guangxi. They were dying of probably several diseases; they had lesions in their skin, intense congestion, and were in generally atrocious condition when they got sequenced for viruses. They turned up positive for all manner of things (herpes out the wazoo, but also a sendai virus which was most closely related to the sequence of a human-taken sample, a paramyxovirus, and yes, several coronaviruses).

Here's the original article on the pangolins whose virome they sequenced, and the article noting its relatedness to nCOV.

Given that so many of the pangolins died, the pangolins look more like a highly-susceptible secondary species, than a mostly-asymptomatic primary reserve species* to me.

* GD/PIL or GD/P2S is thought of as a possible nCOV progenitor, alongside bat-virus RaTG13. GD/PIL's receptor-binding motif (RBM) in particular is identical to SARS-2's, although nCOV otherwise appears more closely related to RaTG13.

** On educated priors, I think the true reservoir is probably rats, bats, or (less likely) humans in the Guanxi, Hunan, and/or Hubei province.

Personally, I assign >90% on either rats (strong priors + skin lesions) or bats (strong priors + simplest story). But these were exotic animal smugglers; there is a small chance that the original reservoir species could be any animal.

Comment by spiracular on Jimrandomh's Shortform · 2020-05-09T19:28:03.796Z · LW · GW

I think it's probably a virus that was merely identified in pangolins, but whose primary host is probably not pangolins.

The pangolins they sequenced weren't asymptomatic carriers at all; they were sad smuggled specimens that were dying of many different diseases simultaneously.

I looked into this semi-recently, and wrote up something here.

The pangolins were apprehended in Guangxi, which shares some of its border with Yunnan. Neither of these provinces are directly contiguous with Hubei (Wuhan's province), fwiw. (map)

Comment by spiracular on Coping and Cultures · 2020-05-07T15:45:10.972Z · LW · GW

True, and I've seen lab work cultivate something similar.

(I'm pretty sure this particular skill is the inverse of programmer-style "laziness," funnily enough. In one field, seeing repetition is reassuring. In the other, it can be evidence that your code is not as elegant and modularized as it could be.)

I always thought you'd automatically learn the gait if you just did the work often enough, though. It's definitely a coping skill, but I read its origins as more cultivated than culturally-induced or taught.

It mostly follows the natural incentive gradients of the work. This can be in contrast to things like separation of self and client in psychology, which seems to feel actively un-natural for many people. Of course, there's something of a spectrum here, with heavy individual variation.

Comment by spiracular on Coping and Cultures · 2020-05-07T06:28:15.340Z · LW · GW

Thanks! Sounds like a promising lead.

Comment by spiracular on Coping and Cultures · 2020-05-07T06:26:13.183Z · LW · GW

It's more "Ugh, I hate pissing people off on the internet" than "Oh Noes the Governments." Whether I have good or bad things to say, it's a contentious and semi-political topic. That said, I'm still probably overreacting.

(I'm more worried that I'll be wrong about something, that people will badly misinterpret me or misconstrue my beliefs, or that I rub people's personal issues the wrong way than that I Awaken the Powers That Be by... armchair philosophizing about the influence of culture on PTSD?)

Comment by spiracular on Coping and Cultures · 2020-05-07T00:49:26.991Z · LW · GW

The set of cultures I most want to poke this lens at, and yet want to write up not at all, are the various military ones.

High-stress environment, with a strong culture and close-to-explicit transmission to young people. And the type of stress varies considerably depending on whether you're in the Army, Navy, Air Force... it seems like an ideal case-study. But it's also a Whole Can of Worms. I suspect it's a bad idea for me to try to publicly analyze subsets of American military culture with thoughts that are half-cocked.

At minimum: I kinda suspect the style of Boydian thought was an excellent fit to the challenges and culture of fighter pilots at the time. Agile judgements that take uncertainty into account, done within a competitive environment where "outmaneuvering your opponent without overextending yourself" is the name of the game.

Comment by spiracular on Coping and Cultures · 2020-05-07T00:45:00.184Z · LW · GW

I plan to flesh more examples out, but this had languished untouched in my Drafts folder for close to a month. So I settled onto "publish first, flesh out more later."

The idea mostly struck me when examining differences between good biology culture and rationalist culture, rather than from a particularly new cultural exposure on my part.

(The Catalyst conference may have highlighted the differences a bit.)

Comment by spiracular on March Coronavirus Open Thread · 2020-05-01T02:07:55.377Z · LW · GW

Despite the virus being characterized in pangolins, after looking into this, I now think it is basically incorrect to think of this as primarily a "pangolin virus." The pangolins were a dying canary in a coal mine, and probably caught it from something else that serves as the real reservoir species for this nCOV precursor*.

See: further explanation here

Comment by spiracular on Does the 14-month vaccine safety test make sense for COVID-19? · 2020-04-26T07:54:18.661Z · LW · GW

While we should at least ask and assess that question...

Yes, it would be good to rule out those things that we do know to expect. And I think animal results* could check this one somewhat. But corners are already being cut, and I still expect some degree of surprises.

I do feel like there's a lot we don't know with this virus. I don't know that the problems will be limited to the things we currently know to look for, and I'd be a little surprised if timing was not at least a bit of an influencing factor.

* Apparently they haven't found/developed an easy animal that catches the virus, but they are doing animal testing in parallel to check the type of immune response? And the vaccine test result with the 4 macaques at least seemed promising, now up by another 10 macaques tested with that same inactivated-virus vaccine.

While it definitely helps that we have some experience with SARS-1, we can't totally rely on what we know about SARS-1 and trust that it'll apply to SARS-2.

(I think SARS-1 and SARS-2's genetic similarity was said to be only ~80%? This is about as much as we share in common with cows. There can be meaningful differences between the two.)

Here's just one example. Did you see the "UPDATE" I added to my answer above? Says something like "Oh hey, I guess it probably does make immune cells apoptose?" SARS-1 doesn't do that thing. As in, the article specifically mentions that they tried with SARS-1 and SARS-2, and only SARS-2 gets into T-cells like this. And they weren't sure which receptor was responsible.

It's great to see a lot of science happening on this, but it's also something of a marker of our vast uncertainties paired with its high priority.

Comment by spiracular on Does the 14-month vaccine safety test make sense for COVID-19? · 2020-04-24T23:09:16.204Z · LW · GW

I'm normally on team "the FDA is making everything too slow," but in this case I actually think there's good reason to be really careful with those Phase-1 vaccine development trials. You don't need to be using a live vaccine to actively make things worse!

How long does testing for this problem actually take? I'm not sure.

If we were sure this was the only thing we needed to worry about (but I don't think that it is)... getting a line of evidence where some vaccine takers are exposed deliberately some time after vaccination could maybe speed up weeding out vaccines that trigger worse Th-2 reactions. But if it turned out that time-since-vaccination or current antibody-titer are major factors underlying outcome, we may genuinely need the full period of safety-testing.

And asking people to deliberately expose themselves doesn't strike me as a... safe cheap or easy thing to do.

This looks like a complicated immune effect, and it seems to be under-characterized. Overall, it looks hard to test in-vitro or in cell culture. I'm pretty sure you'd need animals or humans to do it. I'm not sure which is faster.

Comment by spiracular on Does the 14-month vaccine safety test make sense for COVID-19? · 2020-04-24T22:26:33.077Z · LW · GW

The article I summarize here goes over some of the specific bad vaccine reactions for SARS-1. I expect similar challenges for SARS-2.


In situations where someone took the vaccine, then gets infected by the contagion, they can have a bad reaction where the course of the disease is more severe than if they had not been vaccinated at all.*

Here's some of what we know about those bad reactions**

  • Th-2 type immune activation definitely happens
    • This is an allergy-like immune response
    • Th-2 reactions happen in severe cases of COVID-19 generally
  • There might also be a bad complement system related reaction
    • Complement system means protein complexes that kill cells by poking holes in membranes
  • Antibody Dependent Enhancement (ADE) might be possible, but is not likely
    • This is when imperfect antibodies are used as an anchor for the virus to infect white blood cells.
    • UPDATE: A related thing now strikes me as somewhat likely. It might be fusing with some white blood cells (at least T-cells) and ordering them to apoptose (activate cell-death). Article, h/t CellBioGuy.

* Going off of some other bits of research on this, these individuals probably have lower virus-titer, but higher severity and lethality. A damaging immune response, basically.

** Which vaccine types cause this bad reaction? For SARS-1, any whole-S-protein vaccines were more prone to this bad reaction. Some smaller S-protein fragments didn't have this issue, hopefully the same fix works for SARS-2. I heard of at least one case where an N-protein-only vaccine attempt also resulted in the Th-2 reaction, though. It's not totally clear how to avoid triggering it.

So maybe the speed-up you really want is to vaccinate, then deliberately expose to the live virus, and monitor what happens?

This is the type of test I'd rather we do on animal models than humans, to be frank. It seemed that you could test this phenomenon just fine with SARS-1 in animal models.

Comment by spiracular on Does SARS-CoV-2 utilize antibody-dependent enhancement? · 2020-04-23T22:02:39.228Z · LW · GW

Vaccines are still our best shot in the long-term.

I wouldn't phrase it as "vaccines do not look promising," but more as "SARS is relatively hard to vaccinate well." I do think we'll have a vaccine that works reliably, eventually. No other antiviral method has their price-to-effectiveness ratio.

We were able to find fixes to the problems with some SARS-1vaccines, and I think we'll be able to route around these problems for SARS-2 as well.

This just means that I don't expect vaccine development to be quite as fast as it would be for viruses without these known problems. Additionally, I suspect animal-testing could be crucial to the development of a safe vaccine, unless we're willing to risk a few human lives in their stead (which, maybe we are).

And speaking personally, until the clinical trial results are in, I'm inclined to be cautious about taking vaccines that use large swathes of the viral S-protein, although I suspect some with smaller fragments will turn out to be fine.

Comment by spiracular on Coronavirus: Justified Key Insights Thread · 2020-04-22T02:06:29.168Z · LW · GW

As for why blood clots are a problem in the first place... one of the hypotheses I've seen floating around is that it might be tied into complement system malfunction?

Warning that this is pretty speculative...

The complement system is an immune response that uses C-protein complexes to poke holes in membranes to kill cells and fight large infections.

This paper used results from 5 lung autopsies and tried to draw a link between the prolonged procoagulant state in the lungs with excessive activity of the complement system. I could barely follow it beyond that.

I had also heard before that complement system malfunctions were thought to be connected to bad vaccine response for SARS-1.

I don't feel certainty in this at all. But it comes up semi-consistently, and I don't have a better theory yet.

Comment by spiracular on Coronavirus: Justified Key Insights Thread · 2020-04-22T02:04:55.188Z · LW · GW

Here's a paper that situationally agrees with you on anticoagulants... Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy

449 people. Specifically, they observed no difference in survival between heparin users/non-users overall, but in the very-high-D-dimer subset (or in people with lots of sepsis‐induced coagulopathy), survival seemed to be better with heparin.

This link carries no new information yet, but seems to be a placeholder for a future review paper on this topic.

The "blood coagulation as a major contributor to death" bit generally matches pretty well with some early results where high D-dimer predicted worse rates of mortality fairly reliably, since D-dimer is basically a problematic-blood-clot indicator.

There's a potential complicating factor for the elderly, which is that many of them are already on anticoagulants (to mitigate stroke-risk). And going on some experiences of my grandparents, it seems to be hard to navigate the risks mitigated with anticoagulants with the risk of bleeding out unless you're pretty careful. All the same, it looks like a promising line of improvement to treatment of severe COVID-19.

Nitpick: __ice9 has 2 underscores, not 1.

Comment by spiracular on What are the costs, benefits, and logistics of opening up new vaccine facilities? · 2020-04-21T22:35:37.589Z · LW · GW

micpie's answer here is good! I don't have a lot to add to it.

Here are a few related reference-links* and a tiny bit of commentary.

*...some of which I heard about via other micpie comments. Go figure.

** 60 days from the nCOV DNA sequence to mRNA vaccines starting clinical trials! mRNA is a relatively flexible/easy-to-modify platform, but new and a bit untested.

Comment by spiracular on April Coronavirus Open Thread · 2020-04-20T01:58:31.486Z · LW · GW

I don't really know, I wouldn't do this. Here are a couple of possibilities that ran through my mind.

  • COVID's symptoms are basically "see: undefined flu-like symptoms." This might just be an equivalent of "I looked up my symptoms on WebMD and it's definitely cancer," only with COVID.
  • There was that revelation that Washington got it earlier than expected. Maybe they're pattern-matching blindly to this. It's really easy to do so, especially if there was another nasty flu or cold going around back then (which there probably was).
  • Motivated reasoning
    • People want an excuse to go about their life as normal (or to complain if they're not)
    • People especially hate taking the possibility of their own death seriously
    • Nobody wants to deal with the guilt of knowing that their "normal" actions may be endangering others (cough asymptomatic transmission), and they would rather believe something potentially-false than contend with that

It's probably a mix of all three, or even more.

With all due affection, I've heard that New Yorkers as a whole are fairly prone to contrarianism. So the frequency with which you're hearing this might also partially be local variance.

Comment by spiracular on April Coronavirus Open Thread · 2020-04-18T21:56:09.234Z · LW · GW

TL;DR: No. The earliest I'd buy for pandemic-track COVID is early-to-mid December, and in China or maybe Australia. Otherwise, it'd have to be a non-pandemic substrain that died out early, and left no children behind except the first Wuhan strain. The theory loses in an Occam's Razor fight with "your friends probably had something else back then."

ETA: This post mentions a second independent line of evidence on the matter (using antibodies), and also dates the first COVID-19 cases to no earlier than December.

I'm going to be basing most of this on nextstrain's COVID-19 phylogeny data and their accompanying chart.*

The earliest sequenced US case we have came from Washington. The Washington strain's earliest sequenced sample was 5 weeks of mutation out from the Wuhan strain at the time, leading to the inference that it arrived (or at least split off from the Wuhan gene-pool) in about mid-January. Australia seems to have a divergent strain that might have broken off even earlier, possibly as far back as mid-December.

Going on their graph, they dated the Wuhan last common-ancestor (LCA) strain to roughly mid-December, and the all-strain LCA is the same one.

(I'm not going to detail all of how this works, but LUCA is a similar concept.)

So, cases much earlier than mid-December (and in anyplace other than China or Australia) seem really unlikely to me**.

*Note that old phylogenies are often very inaccurate and rough, and rely heavily on your starting assumptions (I've played around with them, and it is wild how different the trees can be). But this is a fresh phylogeny, and should be a bit of a best-case-scenario. This a very recent series of mutations and splits, and on top of that, unlike with paleontology we can access, date, and sequence old blood samples just fine. I expect this phylogeny to get the occasional detail wrong, but to hit the broad-strokes and to be largely pretty accurate.

**If an earlier strain existed, it would have had to have left no lingering sequenced sub-strains in the present day. If even one of those theoretical highly-divergent sub-strains persisted, got sequenced, and were added to the phylogeny calculation... it would have introduced a new early-stage split into the phylogenetic tree that would have pushed the probable LCA way back into the past.***

*** I mention this in part because... HIV did have these. A non-pandemic ancestor that we found in some very old blood samples. It was nowhere near as contagious and persistent at the time, and even seemed to be a transient illness for those who caught it. But being a pretty unsuccessful virus at the time, only a very small pool of people had it back then.

Comment by spiracular on March Coronavirus Open Thread · 2020-04-18T20:47:40.977Z · LW · GW

More specifically:

  • It was not genetically modified for use as a bioweapon
    • The mutations don't resemble other well-known and well-characterized pathogenicity mutations too closely, in sequence or location
  • It probably wasn't cultured as cell-culture in a lab-setting for an extended period
  • The virus was not notable to science prior to this event

Or in other words, it doesn't look planned. Its most recent mutations look much more like a "natural variation let it jump species" sort of situation.

This doesn't address situations like, for example, "dead bats with a wild-type virus being left near a bunch of ferrets or pangolins," or something to that effect.

(ETA: Or... accidental release like this is still possible.)

Comment by spiracular on Does SARS-CoV-2 utilize antibody-dependent enhancement? · 2020-04-16T16:20:14.423Z · LW · GW

This article largely addresses the challenges of vaccine development for SARS-CoV-2.

It was extremely clarifying for me. It seems to have consulted several experts for opinions, but is written for close-to-layman reading.

Here are a few bullet-points, but I recommend the whole thing.

  • Th-2 type immunopathology, "in which a faulty T cell response triggers allergic inflammation," plays a big role in bad vaccine response to SARS-CoV-2
    • Ralph Baric: "There is the potential for ADE, but the bigger problem is probably Th2 immunopathology"
    • Me: Th-2 responses are extensively documented in both severe COVID19 disease, and SARS-1's bad vaccine responses. This makes a lot of sense. I would like to understand what is upstream of that, sometime.
  • Another likely problem: Complement system malfunction
    • "poorly functional antibodies that form immune complexes, activating the complement system and potentially damaging the airways"
    • Me: There is most likely a scientific term for this phenomenon. I'll add it when I find it.
  • ADE is possible, but less than likely to play a major role
    • FIPV is a coronavirus where ADE is a major concern. But FIPV productively infects macrophages. I've seen no evidence so far that SARS-CoV-2 productively infects WBCs.
    • UPDATE: It looks like it isn't productively replicating in WBCs, but it probably is fusing with them and telling them to apoptose. Receptor uncertain, but they were checking T-cells specifically, which are exactly the WBCs that get severely depleted in severe COVID-19. Consider me pretty convinced. Article, h/t CellBioGuy. (P.S. SARS-2 is much better at this than SARS-1.)

For RSV* (Respiratory Syncytial Virus) and SARS-1, bad vaccine response gets blamed on both Th-2 immunopathology and antibody complexes activating the complement system. This can lead to severe disease, including the infiltration of lung tissue by neutrophils (for both) and eosinophils (for RSV?).

For SARS-1, whole-S-protein vaccines seemed more likely to produce this detrimental enhanced immune response. S-fragments containing only the receptor binding domain offered protection, but did not produce this unwanted effect.

They are hoping that the same logic and fix goes for SARS-2, but are still waiting on the test results.

*Me: Side-tangent, but both SARS and RSV seem to be nasty lung infections with some propensity to form syncytia in severe disease. Heck, one of SARS-2's novel mutations seems likely to be involved in increased syncytia formation. However, the viruses are not close relatives, and they seem to show different preferences for which particular lung cells they reshape into syncytia. I find it interesting that they ran into a similar bad reaction here.

Comment by spiracular on April Coronavirus Open Thread · 2020-04-14T19:28:56.282Z · LW · GW

Here's a snippet from it...

novel platforms based on DNA or mRNA offer great flexibility in terms of antigen manipulation and potential for speed. Indeed, Moderna started clinical testing of its mRNA-based vaccine mRNA-1273 just 2 months after sequence identification. Vaccines based on viral vectors offer a high level of protein expression and long-term stability, and induce strong immune responses. Finally, there are already licensed vaccines based on recombinant proteins for other diseases, and so such candidates could take advantage of existing large-scale production capacity.

It also links to WHO's spreadsheet of COVID-19 candidate vaccines, which looks like a good resource in its own right (although this particular copy is probably a bit old).

Comment by spiracular on Does SARS-CoV-2 utilize antibody-dependent enhancement? · 2020-04-02T19:03:57.989Z · LW · GW

Something weird is going on with white blood cell (WBC) counts, but I'm currently leaning towards believing something else is causing it.

Specifically, they're seeing T-cell lymphopenia & neutrophilia during acute infection (too few lymphocytes, too many neutrophils), along with blood-clot markers (high D-dimer, a thrombosis indicator, presages death).

T-cells seem to be the worst-hit WBC (hyper-activated, decreased numbers), and I'd have expected them to be close to immune to Fc-based ADE once mature; they only express the receptor while young.

This points to some other factor being at play, and leans me against ADE being a major determinant of individual disease severity. I still expect vaccine development to be challenging, and to come with risks of bad reactions if there is not extensive animal testing (since SARS-1 and MERS vaccines repeatedly ran into issues, including for a vaccine against N-protein that shouldn't trigger ADE in-vitro).

A few theories I've seen floating around for the blood results (I'm sure there's more out there):

  • This old (2008) SARS-1 paper posits that glucocorticoid reaction (too much cortisol) could be an upstream cause of the lymphopenia + neutrophilia reaction seen in SARS, RSV, Ebola.
  • Something is causing/reacting to the cytokine storm
    • Both severe COVID19 disease and bad vaccine reactions steer towards Th-2 type immune responses (vaguely allergy-like responses)
    • I haven't deep-dived this.
    • If I want to follow up on this, from a paper-skim it seems to be a Th2-type cytokine reaction. Confused about IL-10 results.
  • Some sort of immune-cell suppression effects, either infecting or indirectly impacting cells at an earlier stage of blood cell development/differentiation.
    • We've found some additional receptor-binding affinities for SARS-CoV-2, so it's not just ACE2-binding. But by far the most productively-infected tissues seem to be the lungs and bowels.
    • I have the impression that it's not productively replicating in white blood cells, but also feel that doesn't totally rule out interference with them.
Comment by spiracular on March Coronavirus Open Thread · 2020-04-02T09:52:53.910Z · LW · GW

Additional little bit that reminded me of that cell-cell fusion trait... another paper described the SARS-CoV-2 autopsy results, and included this:

Multinucleated syncytial cells with atypical enlarged pneumocytes showed viral cytopathic-like changes, without obvious intranuclear or intracytoplasmic viral inclusions.

Translation: The paper-thin, high-surface-area (for gas exchange) cells wrapping your lung balloons (the pneumocytes in your alveoli) fuse together with each other into an ineffectual, clumpy mess with a way lower surface-area-to-volume ratio. These are fragile cells to begin with; they don't even replicate themselves (other cells have to replace them when they break). They don't seem to be producing virus themselves, but they do seem to be getting badly screwed up by things the virus is doing.

Comment by spiracular on mRNA vaccine development for COVID-19 · 2020-03-24T01:19:15.704Z · LW · GW

Protein origin shouldn't matter, but mRNAs are not yet proteins. So for mRNA vaccines, they still need a lipid coating for delivery that evades the immune system but will still fuse with cell membranes.

(Normal cell-to-bubble-to-cell delivery involves mostly protein-based tagging and anchoring, and viruses often imitate parts of this process (this is much of what coronavirus spike-proteins are doing, for instance). But if you are using variants of tags that appear unfamiliar to the immune system, you can easily get an immune reaction against them. I'm not precisely sure how these companies have solved this problem, whether it's by using protein-tagging some entirely-lipid-based solution, or what.)

They might not need to be targeting particular cell-types very heavily, it's true. But they still need to be targeting for delivery to cells-in-general.

Comment by spiracular on mRNA vaccine development for COVID-19 · 2020-03-22T07:30:59.266Z · LW · GW

How can this possibly happen non-pathologically in humans? What really confuses me is... getting DNA outside the nucleus in the first place as a non-freak occurrence requires at least one of:

  • Generation of loose DNA partial-transcripts while trying not to generate extra confusion during cell replication
    • If it's handled as ssDNA, that actually would leave it in a form pretty distinct from the usual dsDNA storage. And even as dsDNA, there are epigentic tags you could use to see that it's handled correctly.
    • This does have the benefit of being an "out" channel from the nucleus, not a security-vulnerability "in" channel.
    • I think I've reasoned myself to thinking this is the most likely explanation? I'll have to do more research to confirm/negate this guess.
  • DNA cut-outs that permanently leave the nucleus, never to return (resulting in its absence in the next replication cycle)
    • You could come up with a clever working version made from frequently-duplicated genes with extra copies (ex: transposons), but... I've never heard of this. And it's a little evolutionarily-fragile.
    • This does have the benefit of being an "out" channel from the nucleus, not a security-vulnerability "in" channel.
  • Reverse-Transcriptase (the most insidious of all viral proteins, that thing that crafts DNA from RNA)
    • Humans do have a special RT for extending telomeres, but it's rarely expressed, and if a random cell is expressing it that's a cancer waiting to happen.
    • There are retrotransposons that copy-paste themselves around the genome. But like... that's basically a nasty virus that got lazy and whose deck is short a few cards.
  • Cytoplasmic replication
    • I am under the impression that this is not happening

In eukaryotes, I get the impression that DNA is usually not getting replicated out there in the cytoplasm, at least? DNA viruses usually have to do at least one of two things:

  • Get themselves into the nucleus somehow (via small size and/or transport proteins)
  • Carry their own replication proteins around with them in the virion, to produce those initial RNA transcripts that produce enough replication proteins for them to get by.

If the treatment involves entering the nucleus of fully-intact undamaged cells, or replicating itself (so really, either of these methods), the alarm bells in my head would be blaring.

But if it's just circles of extracellular DNA... I'm now kind of conflicted and confused? How virus-like do you have to be to make that a viable thing to do?

Some other lingering points of confusion/research:

Plants use ambient restriction-enzymes to make being a random cytoplasmic DNA a hazardous game (on the assumption that ambient cytoplasmic DNA is usually viruses, and the non-viruses will have co-evolved with the particular restriction enzymes to make this system work). I don't actually know that animals do, though. And you could always species-tailor it...

I also have no idea how efficient or inefficient extracellular transcriptase would be for producing mRNA transcripts. If it's inefficient, you might have to use a pretty strong primer, and I find myself a tiny bit concerned about that in a long-lived human therapeutic.

Comment by spiracular on mRNA vaccine development for COVID-19 · 2020-03-22T07:30:04.019Z · LW · GW

In our previous related thread of related conversation, you mentioned:

Inovio Pharm that also develops a COVID-19 vaccine. It's technology is based on delievering DNA based.

I noticed that I feel more worried about DNA-based vaccines than mRNA based vaccines. I probably should try to articulate some of why.

After doing some preliminary skimming and examining my pre-existing knowledge around this... I'm now kind of conflicted and confused?

(Exploring this turned into a giant sprawl. It would be multiple research projects for me to fully dissolve my confusion here. I'll leave the majority of my thoughts as a comment on this, but it may be so biology-dense that it mostly serves for my own reference.)

mRNA practically degrades itself. If an mRNA enters the cytoplasm, it might get diced by DICER but it otherwise is probably only good for a limited number of protein-producing ribosome-reads before it gets degraded or digested into unreadability.

DNA is a more robust molecule, befitting the archive-storage of the cell. In eukaryotes, almost all of it is permanently locked up in the nucleus, both for access and regulation reasons and as a protection against UV and other mutagens. DNA outside of the nucleus in a eukaryotic cell usually only comes up only in the context of viruses, cancer, GMOs, or ongoing problems or oddities with that cell.

(But apparently bits of it exist naturally, but have probably been understudied? That's something that I didn't fully realize until today. Pathology and pathogen-imitating GMOs are literally the only context where I have ever heard this come up before.)

Comment by spiracular on mRNA vaccine development for COVID-19 · 2020-03-22T05:58:01.920Z · LW · GW

mRNA production has fewer dependencies than protein production. To me, it feels reasonably intuitive that this might be a bit faster to assemble, especially at scale and in the face of QC. However, I have a lot of uncertainty around this.

About this next thing, I am more sure. What is more challenging about mRNA, and a good part of why it hadn't been a major method before, is delivery* into cells, and maybe targeting that delivery (if needed). If they've got a great lipid coating already configured for this, at that point it's easier to treat this like a modifiable platform and not just a single product. And that could help turnaround time a lot.

Being able to treat this as more of a modifiable-platform than a tailored product is where I suspect the big gains of this method lie.

*Delivery method being a major challenge is generally true of all large-molecule drugs and therapeutics (ex: protein-based), and probably even some of the small-molecule ones. Although I've seen more and more biotech companies specializing into this kind of thing, so humanity is probably getting better at it.

There's something almost comical or ironic about immune response probably foiling most attempts to develop something whose eventual goal is to trigger an immune response, but later. But that's probably a good part of the story of why this was so hard.

P.S. I was about to recommend you make a high-level post about this. I'm glad to see that you already did! I'm probably going to continue a bit of that conversation here, as this seems like a better place for it.

Comment by spiracular on Sarah Constantin: Oxygen Supplementation 101 · 2020-03-22T05:13:30.101Z · LW · GW

Ah. Then that is an error on my part because I had no prior knowledge on this topic, and assumed that rebreather oxygen masks were the default form of oxygen masks.

Thanks for the correction!

I've tried to update the relevant bullet-points towards what you described.

Comment by spiracular on Sarah Constantin: Oxygen Supplementation 101 · 2020-03-21T11:14:19.664Z · LW · GW

Some notes/highlights (but it's not that long and you should read the whole thing)*:

  • Generally thought to be more helpful if you can get both oxygen and pressure (pressure helps keep alveoli open)
  • At least several oxygen supplementation methods will aerosolize the virus and increase contagiousness nearby, and are not allowed in a healthcare setting as a result. Perhaps particularly methods involving pressure.
    • This is not, or is less of a problem, for low-pressure oxygen (ex: (non-rebreather) oxygen masks). These oxygen masks are probably what is meant by standard oxygen therapy.
    • This is a problem for CPAP machines
    • (Deleted a somewhat-incorrect/confused bullet-point)
    • (Personal thought: Is this part of why hospital outbreaks were so nasty with SARS-1?)

suppose you’re a person with respiratory failure, but you have an oxygen mask, CPAP, BIPAP, or high-flow nasal cannula at home. 40% of the time or so, your noninvasive home equipment is going to fail and you’ll need to be intubated. Usually this happens quite urgently; if you need to take an ambulance to get to the hospital it might be too late.

  • Invasive intubation tends to be be urgent, and is a very seek-a-medical-professional do-not-do-this-at-home procedure
  • From ~300 pneumonia cases: From the set [oxygen mask (rebreather), high-flow nasal cannula, non-invasive ventillator], high-flow nasal cannulas have the best outcomes associated with them (much better 90-day mortality rates). But for all of them, 30-40% ended up needing invasive intubation within 4 days.
  • Given the frequency with which people go on to need invasive intubation, hospitals are probably better than at-home with NIV unless you really can't access the hospital (ex: overun). The rates for needing intubation are still high (~30%-40%).
    • But see also: NIV seems better than standard oxygen therapy (oxygen mask), in the follow-up post

Many of these [open-source ventillators] are automated bag masks, or CPAPs, which aren’t recommended for use in hospitals because they spread COVID-19; and they won’t work on the more severe cases of respiratory distress anyway. Only two projects that I found, the Pandemic Ventilator and the Flometrics project, are explicitly trying to match the specifications of the type of mechanical ventilators found in ICUs.

The follow-up post on non-invasive ventillation (NIV)

  • Lot more data surveyed, but across several ventillators and conditions (ex: COPD (definitely helps), pulmonary edema (somewhat less consistently)).
  • NIV does seem to improve outcomes by quite a lot, including in pneumonia.
    • Strong results on intubation there (60% changed to 15-20%), but only 136 total pneumonia samples across 2 studies. And one of them noted no difference in mortality.
  • NIV makes a pretty big difference on the overall intubation rate, changing 30% to 15%

This means that, in a world where ICUs are overrun, there’s a good chance that a home non-invasive ventilation device could save lives for people with COVID-19.

* Also, I'm not likely to sync this as it updates, I may be out-of-date, errors in bullet-points are mine, etc. etc.

Comment by spiracular on LessWrong Coronavirus Agenda · 2020-03-20T22:47:36.460Z · LW · GW

Whoah, lipid-coated mRNA vaccines, not as an intermediate step but as the actual delivery method? That's actually new to me! Sounds like it's mRNAs coding for some subset of the viral proteins, which probably get assembled into proteins in your cells and then get used as something for antibodies to respond against. mRNAs should then just degrade themselves with time.

I have no idea what the most efficient method for producing those is; I am very used to vaccines being protein-based. This probably is in the realm where it's simple enough that modifying PCR-protocols to produce RNA instead might actually work reasonably well, although RNA is generally more fragile and error-prone and that could be a problem.

You'd be using nucleotides, not amino acids, but mRNA from DNA is a short-enough assembly line that you might not need cells to do it.

(Protein production has a lot of dependencies. mRNA transcription should basically just require your DNA of interest, nucleotides (x4), and a transcriptase protein. Maybe add a transcription factor or two.)

HeLa definitely is a human cell line (although that was for Ebola, they may end up using a different cell line). That's good, that probably scales up easily.

Comment by spiracular on LessWrong Coronavirus Agenda · 2020-03-20T09:18:46.646Z · LW · GW

...I'm confused about what method you're even trying to gesture at.

They're viruses*, they need a full set of environmentally-provided cell machinery to replicate or produce proteins: ribosomes, transcription machinery (ex: t-RNAs), ATP, the works. They need cells, so you'd need need at least a cell culture. All of biology has heavily optimized protein assembly lines, you're not going to beat it acellularly.

The cells near the outside of an egg are probably used because they're an elegant and self-contained little solution to sterilization (against everything but your virus) and the quality-control problems you'd have to contend with otherwise. It's not really about the protein content, mostly.

(Cell culture is probably more expensive than eggs because 1) bioreactors are kinda expensive, 2) bioreactors are a bit of a pain to maintain, and sterilization is hard, two problems that using an egg pretty neatly solves, and 3) which cell culture will work best is surprisingly hard to predict, you basically have to test it experimentally.)

* Well, technically it's weakened viruses, or single-gene plasmids, or something similar. The need for cells still holds either way.

Comment by spiracular on LessWrong Coronavirus Agenda · 2020-03-19T20:19:38.613Z · LW · GW

I've heard that the eggs used are special, more sterile than usual (you don't want the chicken to have other diseases now, do you?), and usually require ordering at least a year in advance.

(Came up when I was researching flu-vaccine development.)

Some other vaccine production methods involve cell cultures, but the output of different cell cultures is pretty wildly variable and the preferred cell culture is different depending on the specific virus. This is probably a more expensive means of production. You may be able to scale it up faster and with less early prep-work, however.

Fair warning: While there have been coronavirus vaccines that have just worked, there have also been a lot of them that seemed to make the course of infection worse, probably due to antibody-dependent enhancement or a similar phenomenon. The set that were somewhat challenging to develop vaccines for seemed to include SARS-1. The lengthy process of animal testing would probably spot this, but it may make getting a reliable vaccine slower and harder than it would be with viruses that don't have this problem.

Comment by spiracular on March Coronavirus Open Thread · 2020-03-18T01:09:30.702Z · LW · GW

Paper on some of nCOV's mutations

Incidentally, also strong evidence against it being a lab-strain. It's a wild strain.

Closest related viruses: bats and Malayan pangolins

Mutation Descriptions

Polybasic Cleavage Sites (PCS): They seem to have something to do with increased rates of cell-cell fusion (increased rate of virus-induced XL multi-nucleated cells). Mutations generating PCS have been seen in Influenza strains to increase their pathogenicity, and they had similar effects in a few other viruses. So it's not exactly increasing virus-cell fusion, it's actually... increasing the rate at which infected cells glom into nearby cells. Fused cells are called syncytia.

O-linked glycans : Are theorized (with uncertainty) to help the virions masquerade as mucin, so hiding from the immune system. (Mutation unlikely to evolve in a lab on a petri dish)

Arguments strongly in favor of it being a wild strain

  • It's not that similar to one of the known lab-strains, so it probably was wild
  • The "polybasic cleavage site" and "O-linked glycans" mutations would have required a very human-like ACE-protein binding site, so basically only human or ferret cells
  • O-linked glycans are usually evolved as an immune defense, which isn't something cell cultures do.

(Just following the recommendation to move this out of shortform so it can be tagged later.)

Comment by spiracular on Why isn't increasing ventilation of public spaces part of the best practice response to the Coronovirus? · 2020-03-18T00:53:43.081Z · LW · GW

I have not read through all of it yet, but even the abstract seems to suggest that someone agrees with you, thinks it contributed to that outbreak, and has at least started looking into it.

I'm not sure how extensive the suggested edits were, but I do have to comment that in all likelihood, sporadic crisis-based funding is not conductive to altering the ventilation architecture of a large fraction of hospitals.

(It has been my weak impression that pandemic-related funding has historically relied heavily on a tiny handful of interested politicians and on taking full advantage of policy-windows whenever there's an outbreak or a scare.)

If there is a good argument that a ventilation redesign would help prevent pneumonia or other common hospital-acquired-infections, I suspect that would be a good thing to look into and add to the proposal. If true, it would make the argument a lot stronger, and also likelier to get implemented and upkept.

Comment by spiracular on Credibility of the CDC on SARS-CoV-2 · 2020-03-18T00:44:44.386Z · LW · GW

Appreciate the added information.

For what it's worth, even if aerosol transmission were proven (which it has not been), I'd still assume that breathing in close contact is higher-risk.

SARS-1 and SARS-2 both seem to spread mostly via close contact and large-droplets.

Comment by spiracular on Why isn't increasing ventilation of public spaces part of the best practice response to the Coronovirus? · 2020-03-18T00:38:24.582Z · LW · GW

Here's a paper on SARS-1 that seems highly-relevant:

Role of air distribution in SARS transmission during the largest nosocomial outbreak in Hong Kong.

Our study revealed the need for the development of improved ventilation and air-conditioning systems in an isolation ward or a general hospital ward for infectious respiratory diseases. The outbreak in Ward 8A, which was in a general hospital and could house nearly 40 patients, demonstrated the cross-infection risks of respiratory infectious diseases in hospitals if a potential highly infectious patient was not identified and isolated. Our example simulation, which extended the SARS Busters' design for an isolation room to Ward 8A, demonstrated that there was room for improvement to minimize cross-infection in large general hospital wards.