Posts

Astrobiology IV: Photosynthesis and energy 2016-10-17T00:30:46.138Z
Astrobiology III: Why Earth? 2016-10-04T21:59:57.716Z
Astrobiology, Astronomy, and the Fermi Paradox II: Space & Time Revisited 2016-03-10T05:19:29.263Z
Astronomy, Astrobiology, & The Fermi Paradox I: Introductions, and Space & Time 2015-07-26T07:38:53.498Z
Irrationality Game III 2014-03-12T13:51:00.555Z

Comments

Comment by CellBioGuy on Am I anti-social if I get vaccinated now? · 2021-06-15T02:37:36.319Z · LW · GW

The other side is not using that reasoning.

Comment by CellBioGuy on Covid 6/3: No News is Good News · 2021-06-14T21:36:42.597Z · LW · GW

Because there is no evidence that they mean any of that.

Comment by CellBioGuy on Covid vaccine safety: how correct are these allegations? · 2021-06-14T19:14:14.301Z · LW · GW

The mechanisms stopping growth in vitro at obscene concentrations I agree are probably not operative in vivo, or at the very best not in the same way.  However there are other bits of data regarding the drug as an immunomodulator in other viral infections, and this virus is particular has much of its pathogenesis having to do with badly regulated immune reactions.

Basically I am at the awkward position where I think the risk to potential reward ratio is favorable and that good research is needed while thinking much of the existing research is shoddy.

Comment by CellBioGuy on Covid vaccine safety: how correct are these allegations? · 2021-06-13T21:48:04.123Z · LW · GW

While I agree that there is insufficient attention paid to ivermectin as a possible treatment in Western nations, I have seen far too much shoddy and conflicting data in the studies that are brought forward proposing it as prophylaxis and think the hype is a spiral that has amplified nonsense into prominence.  People LOVE the idea of a panacea.  While there is quite possibly something interesting going on there it has been hyped to the moon and back in a way it should not be.

The animal data I have seen that I trust the most (since it avoids many of the pitfalls of observational trials, and few people are doing randomized trials that are actually good and not shoddy as hell after chloroquine sucked all the oxygen out of the room) suggests there could be something there, but not in a way that would block epidemics.  Animals that are infected and then dosed have no difference in viral levels but recover their sense of smell significantly faster and when you take tissue samples the levels of inflammatory and tissue-destroying signaling molecules are lower while the ones that are more classically associated with antiviral responses are higher.  Leans me towards the idea that it could decrease severity and odds of falling into downwards spirals.  I have been following the in vitro work on this from  the beginning and my conclusion is that you're probably looking at immunomodulatory effects that can help you not fall into the pathological attractors, and deal with long infections better, rather than doing anything about viral binding or replication, if any of it pans out.  

See, as an example, https://www.biorxiv.org/content/10.1101/2020.11.21.392639v1.full

This being said, given the safety profile of the drug I say the risk to reward ratio is pretty good if you pay close attention to contraindications and I see no reason for it to not be used and studied more.

With regards to repurposing drug studies being almost impossible, I am much much more angry that there are no good studies, and no studies at all outside India, for indomethacin.  A much more promising and well defined antiviral mechanism there against cytoplasmic RNA viruses via host factors that works STUNNINGLY well on canine intestinal coronaviruses in vivo, and sars and sars-2 in culture, and when you dig carefully through the literature being already on it by prescription is associated with much lower hospitalization risk.

Comment by CellBioGuy on The Cult Deficit: Analysis and Speculation · 2021-06-13T21:31:25.769Z · LW · GW

I should try to dig up an essay I remember reading a few years ago, that argued that American social innovation and engagement regularly swings back and forth between the religious and the political on generational timescales...

Comment by CellBioGuy on Covid 6/10: Somebody Else’s Problem · 2021-06-10T18:07:02.303Z · LW · GW

I continue to state that most of what is being said by absolutely anyone about furin (and synonymous codon choice, in this case) to support lab ideas is simply nonsense.  There is nothing particularly interesting at all about the genetics.

Comment by CellBioGuy on Should we vaccinate against PGBD5 which codes for a transposase? · 2021-06-09T20:38:53.233Z · LW · GW

Dunno!

Sounds like something to look for antibodies (or more functionally, T-cells) in the population at large and see if they are correlated with autoimmune diseases, and sounds like something to look for a mouse equivalent of and see what happens when you immunize them against a sometimes-expressed transposase.

 

They're also never exactly at high levels.

Comment by CellBioGuy on Why has no one compared Covid-19 and Vaccine Risks? · 2021-06-05T01:30:51.226Z · LW · GW

I actually care a lot less about 'never getting it' now, since I will never have to deal with that first burn though me when I have never seen anything like it at all since I am vaccinated.  Any memory is good, even in the face of drift or waning.

I couldn't tell you if there will be updated boosts over time.  If so, they'll certainly help...

Comment by CellBioGuy on Why has no one compared Covid-19 and Vaccine Risks? · 2021-06-04T15:24:43.934Z · LW · GW

I expect it to return as an endemic seasonal virus, especially in areas of low vaccination uptake, with continued antigenic drift allowing occasional mild infection of those with immune memory after enough time has passed.  It's the first infection of a naive set of lungs that matters though.

Comment by CellBioGuy on Why has no one compared Covid-19 and Vaccine Risks? · 2021-06-04T15:10:00.005Z · LW · GW

If you aren't vaccinated you WILL be infected eventually.  

Comment by CellBioGuy on Covid 6/3: No News is Good News · 2021-06-04T00:38:16.143Z · LW · GW

Indeed, it does not.

Comment by CellBioGuy on Are there reasons to think mixing vaccines is dangerous? · 2021-06-04T00:33:59.426Z · LW · GW

Opposite.  Them getting to your immune system from slightly different 'directions' likely increases effectiveness slightly, especially for the adenoviral vector vaccines where vector immunity might be an issue.

Comment by CellBioGuy on Covid 5/27: The Final Countdown · 2021-05-28T06:09:23.203Z · LW · GW

I am pretty sure the FDA thing is just simply completely factually wrong, actual fake news in the original sense of the phrase.

 

It is a small change that only applies to bulk drugs in compounding pharmacies and is being widely misinterpreted...  near as I can tell they are reviewing four supplements including melatonin for inclusion on the 503A Bulk List, which would make it legal for compounding pharmacies to use them, with that long list shown being things they are continually looking at for ADDING TO AUTHORIZATION FOR COMPOUNDING PHARMACIES. List two (not pictured, later in the document) is for things that are anti-recommended for compounding pharmacy approval, and  list 3 is things that were recommended but they don't think they have enough evidence for approving for compounding pharmacies.  No banning of supplements anywhere, nothing going away at all in any way shape or form in that document.  In fact, it means the OPPOSITE of what is being implied here!

N-acetyl cysteine does not appear anywhere in that document and appears to be an entirely separate and self-contained matter that refers to that substance and that subestance alone.  Seems to have been going on for a year now having to do with them enforcing something that was technically true but unenforced before, that it was marketed as a drug decades ago before people started selling it as a supplement.  Stupid and definitely an error but not a new regulation and companies are covering their butts.

Nobody is regulating parsley, sesame seeds, ribose sugar, and yeast as drugs.  This list should have been a dead giveaway and I am flabbergasted that anyone can take it seriously as some kind of ban list.  The referenced twitter accounts appear to be simply forwarding falsehoods and some seem to be kind of... interesting.

Comment by CellBioGuy on Covid 5/27: The Final Countdown · 2021-05-28T03:14:06.061Z · LW · GW

That... seems like almost precisely the opposite metaphor one would use to compare to reality?  Instead we are looking at something that happens naturally ALL THE TIME and you need special effort to sometimes maybe replicate if you really wanted to?

Comment by CellBioGuy on Covid 5/27: The Final Countdown · 2021-05-27T17:25:26.272Z · LW · GW

A hell of a lot of what they say about furin is simply wrong.  Insertions and deletions happen ALL THE TIME in nature and while rarer than SNPs are not uncommon, around the cleavage site loop there are other indels in related viruses, the furin site is DECIDEDLY suboptimal for cleavage such that all the fun lineages that are more contagious are optimizing it and creating actual canonical sites rather than something just good enough, it is generated out of frame in in a way that no sane biologist ever would, and the glycosylation pattern nearby weakly suggests it appeared in the context of an actual immune system rather than cell culture.  

The alignments they point to arguing for other differences in the cleavage sites in other viruses being due to SNPs rather than insertions are laughable, and from people who I have found to have a poor grasp of the underlying science.

On top of all that when conditioning on something that successfully changes species you will enrich for things that broaden their tropism, which that kind of cleavage site will do, so of course things that are rarer but helpful will pop up more than if you were looking at the space of all possible mutations without conditioning.

Comment by CellBioGuy on Covid 5/27: The Final Countdown · 2021-05-27T16:36:45.329Z · LW · GW

There is absolutely nothing about the biology of the virus that suggests laboratory anything.  Anyone who says it does does not know what they are talking about.  If anyone says something about furin being suspicious or indels being unlikely, or recombination patterns being odd, they can safely be ignored and their opinions discounted.  Yes, this includes David Baltimore.

One cannot exclude the possibility that someone had a stock in a lab being studied somewhere and it got into a lab worker by sheer bad luck.  That would look quite similar to the utterly normal zoonotic spillovers that happen all the time, especially for something like this that is a tenth as deadly as SARS classic such that the early thin transmission chains are effectively invisible to public health infrastructure.

SARS classic has infected lab workers before, but as something that caused a previous global issue it was being studied by many people in many places while in the scenario of a novel zoonotic transfer having occurred in a lab, you almost certainly just have one poorly characterized sample of something with no published sequence data someone happens to be growing for a quick one-off experiment spilling over such that the rate would presumably be much much lower.  

I see no reason to think that this is particularly likely over and above utterly normal outside-world zoonotic spillover that happen all the freaking time (several percent of Chinese villagers tested for antibodies against SARS-like viruses that live near bat caves have them in previous literature), especially since the invisibility of early thin overdispersed transmission chains mean the first big outbreak could occur somewhere quite different than the location of the initial zoonotic event.  Even SARS-classic had its first big internationally-noticeable explosion happen thousands of miles away from the initial site of zoonotic spillover, and if it were not as deadly as it was that initial spillover in southern China could potentially have gone unnoticed outside of local authorities and you could've been talking about SARS as originating in Hong Kong.

All this being said given the state of recombinant DNA technology and its power I do see the value in most virology work using reconstituted sequence in pseudovirus systems rather than infectious particles.

Comment by CellBioGuy on If individual performance is Pareto distributed, how should we reform education? · 2021-05-25T08:09:27.954Z · LW · GW

Returns on performance being pareto distributed is emphatically NOT the same thing as performance being pareto distributed.

Comment by CellBioGuy on Get your gun license · 2021-05-21T14:08:23.716Z · LW · GW

Optionality, to echo Nassim Taleb?

Comment by CellBioGuy on What will 2040 probably look like assuming no singularity? · 2021-05-21T06:26:28.137Z · LW · GW

Or you are seeing the working out of the logistic function that takes shape in so many systems.

Comment by CellBioGuy on What weird beliefs do you have? · 2021-05-14T04:51:38.341Z · LW · GW

I propose very few details and a low probability (and as I add more details from 'someone burned a lot of carbon' I give even less), and the scenario outlines above total carbon release could be split between an artificial release and later positive feedbacks (seafloor clatherate and the like).  As for no trace, finding bedding planes within the PETM itself is a celebrated event in many places and trying to hit a bedding plane within a short period is hard, and I would need to look into the work of a scientist I really like about erosion rates across continental crust to see what the odds of a carbon deposit near the surface now being near the surface millions of years ago would be...

Comment by CellBioGuy on What weird beliefs do you have? · 2021-05-14T04:50:36.441Z · LW · GW

I should start up that astrobiology and evolutionary biology blog again shouldn't I...

Comment by CellBioGuy on What weird beliefs do you have? · 2021-05-14T04:47:24.255Z · LW · GW

My brain goes interesting places from here.

Would there be wild descendants of the soybean all over the world if we disappeared, can the domesticates go wild without us?

The PETM was associated with a mixup of plant and animal ranges, but it is generally explained as being the result of the 5+ degree C temperature spike shifting all their ranges poleward and this then allowing them to wind up at different longitudes when they shifted back towards the equator, plus the general chaos of a minor extinction churning the ecosystems.

If we go with the least likely part of the scenario mentioned above (antarctic habitat), Antarctica and South America and Australia all were faunally related after the breakup of Gondwana...

Comment by CellBioGuy on Peekskill Lyme Incidence · 2021-05-13T06:19:22.925Z · LW · GW

Indeed the wasting disease first exploded in the west, and then nucleated new thick clusters near the great lakes and most recently in PA/MD/VA (which has been spreading fast).  The other places it is found outside the major clusters don't seem to be expanding the way they are in those places.

Comment by CellBioGuy on What weird beliefs do you have? · 2021-05-12T07:51:37.861Z · LW · GW

Add on the probability of "intentionally allowed to commit suicide" on top of that and the total odds seemingly become high indeed.

Comment by CellBioGuy on Biological Holism: A New Paradigm? · 2021-05-12T04:51:15.115Z · LW · GW

FWIW I find the book by Smith and Morowitz to be staggeringly illuminating.

Comment by CellBioGuy on Biological Holism: A New Paradigm? · 2021-05-10T04:15:30.994Z · LW · GW

I personally know two of the scientists spoken of in this post, and agree that greedy reductionism has a tendency to overshadow very interesting phenomena.

Comment by CellBioGuy on Peekskill Lyme Incidence · 2021-05-10T04:13:48.672Z · LW · GW

I find it fascinating that the modern range of lyme disease overlaps with the range of the chronic wasting prion disease of deer.  The two large clusters of lyme in North America overlap with the more recent two clusters of wasting disease (later spread than the first major cluster further west).  This suggests to me that there's a common factor driving the spread of both, probably something about messed up forest ecology.

Comment by CellBioGuy on Covid 5/6: Vaccine Patent Suspension · 2021-05-10T02:52:16.621Z · LW · GW

Do you have a good explanation to Moderna's market price drop?

 

1 - it was tiny compared to recent changes

2 - the efficient market hypothesis is quite quite false.

Comment by CellBioGuy on Covid 4/29: Vaccination Slowdown · 2021-04-29T17:08:03.912Z · LW · GW

destroyed normal life in substantial parts of the United States indefinitely

 

Huh?  How does this follow?  This mostly is in places with higher infection rates overall, and once most of the population is infected or vaccinated then all desire for mitigation by anyone goes away.  It's just about getting to the final state with more or less suffering.

Comment by CellBioGuy on Modern Monetary Theory for Dummies · 2021-04-27T21:39:54.673Z · LW · GW

This misses the role of private banks in creating currency.  Every time they issue debt the amount of circulating currency goes up by an identical quantity.

Comment by CellBioGuy on What weird beliefs do you have? · 2021-04-15T21:12:18.322Z · LW · GW

I think there could be a 5% chance that the paleocene-eocene thermal maximum 55 million years ago was the result of a prior global industrial civilization.  Conditional on that being the case, high probability they were birds and a decent possibility they lived on Antarctica.

We are an existence proof for smart industrial animals being a thing that can happen on Earth.  We are not an existence proof of smart industrial animals lasting for geologically long periods of time.  There is not necessarily reason to think that just because you are successful in an epoch that you burn the black rocks that you will continue to be so.

As you go back in time the fossil record degrades drastically and many species at this time are known from single digit numbers of specimens.  The PETM resembles what we are doing to the earth system entirely too closely, from a large release of biogenic carbon within a few thousand years to the spike in mercury levels to ocean anoxia.  At the time primates did not exist in significant diversity and any that did exist were tiny, but birds, whose brains differ from the default tetrapod brains in ways quite similar to the way that of primates do and allows very easy increase in neuron number, did exist in profound diversity. 

We are tropical animals and spread across the entire world because we came from the hottest place on Earth and you can keep us warm just by wrapping us in clothes in a low-tech way.  If somebody evolved on the coldest parts of Earth, you need high technology (refrigeration) to survive anywhere else and they could be limited to polar latitudes, including the only continent we have almost no geological record of and has been poorly explored - Antarctica.  Antarctica and nearby continents also bore multiple great-ape-sized flightless bird lineages at this time, and was temperate while Canada was full of Amazon-style rainforest and the equator bore stifling hot supertropics.

Corollary:  Industrial civilization is an unstable self-limiting phenomenon and will be gone in centuries to millennia.

Comment by CellBioGuy on What weird beliefs do you have? · 2021-04-15T19:02:19.683Z · LW · GW

A significant set of possible models of such phenomena result in them being irreducibly personal and subjective, hampering detailed analysis.

Comment by CellBioGuy on Covid 4/9: Another Vaccine Passport Objection · 2021-04-15T09:15:45.646Z · LW · GW

The molecular details are not of a type that is caused by the pill.

Comment by CellBioGuy on Covid 4/9: Another Vaccine Passport Objection · 2021-04-13T09:15:34.633Z · LW · GW

These blood clots are unusual and triggered by immune-mediated platelet activation, and happening at higher rate than the base population in those subpopulations.  It's real and not the pill.

 

It's also lower than the risk of the pill.

Comment by CellBioGuy on Covid 4/9: Another Vaccine Passport Objection · 2021-04-10T23:10:50.373Z · LW · GW

No sane major corporation is going to have a batch of 15 million doses and not test it to see if it is the thing it was meant to be before shipping it out, and having something in there that wasn’t supposed to be there should get found many times over by the tests they’d run in all worlds. Ordinary corporate reputation and liability are more than enough to motivate catching this error. 

https://pubmed.ncbi.nlm.nih.gov/24785997/

A company bought by Bayer shipped out many doses of blood products that they knew were contaminated with HIV.

Comment by CellBioGuy on By which mechanism does immunity favor new Covid variants? · 2021-04-06T03:58:34.201Z · LW · GW

Taking this off in a different direction.

The selection pressure driving these things into existence is HIGHLY convergent all around the world, with about four mutations appearing again and again and again.  This is adaptation to the human host, not really evolution for immune evasion, especially considering that only like 30% of most populations at most has been infected.

You would expect immune evasion selection to be wildly divergent rather than convergent.  What is mostly happening is an interaction between the fact that regions of spike protein that are on the surface of the spike and are involved in host interactions are evolving to do do well in a new host, and the fact that these functional regions of host interaction are under many selective pressures and more likely to be 'sticky' and places where functionally important antibodies tend to bind.  Slight immune evasion is a side effect, not what drove them into existence in the first place, for the most part.

Comment by CellBioGuy on Dark Matters · 2021-04-06T03:27:36.443Z · LW · GW

Additionally, there's no reason to assume that all dark matter is just one thing.  There could be multiple things going on, as long as most of the things going on don't self-interact.

Heck, for that matter there could be a small (!) dark sector that DOES self-interact as long as its total mass was within the error bars for baryonic mass inferred from primordial nucleosynthesis.

Comment by CellBioGuy on Competent Elites · 2021-03-09T09:11:11.144Z · LW · GW

The reason the power elite don't talk to mortals is they don't want competition

Comment by CellBioGuy on Covid 3/4: Declare Victory and Leave Home · 2021-03-05T04:57:33.611Z · LW · GW

I remain extremely angry at the lack of clinical trials for indomethacin as an outpatient treatment.

Comment by CellBioGuy on What's your best alternate history utopia? · 2021-02-23T01:50:11.683Z · LW · GW

The Bretton Woods conference adopted Keynes' Bancor as the currency of international trade rather than the US dollar.  This encouraged industrial development much more evenly across the world and prevented large amounts of the imbalanced financial flows that have given certain countries exorbitant power over others, driven others into the resource trap, and driven still others into foreign-denominated debt spirals.

Comment by CellBioGuy on Prediction: The Defense Department Will Blame Trump for the Slow Response on Jan. 7, 2021 · 2021-01-11T04:23:59.805Z · LW · GW

There is also the fact that the top of the DOD was stuffed with loyalists in the immediate aftermath of the election and it would be in the president's perceived interest to allow a mob to scare the crap out of or harm the legislature at that time.

Comment by CellBioGuy on New SARS-CoV-2 variant · 2020-12-21T20:57:33.569Z · LW · GW

Yeah I was going with my quick and dirty numbers from earlier.  Way I see it what's probably happening is that doubling time for Britain as a whole has been ~2 weeks both about a month ago and recently (eyeballing graph from worldometer), and you are probably talking about a new doubling time of ~1 week for this variant under identical conditions.

Redoing math for a two week starting doubling time and the stated change in doubling time you get a R value going from ~1.25 to just under or circa 1.5, so basically similar order.

News sources do not use precise language, and precise language matters here.

Comment by CellBioGuy on New SARS-CoV-2 variant · 2020-12-21T20:41:54.977Z · LW · GW

Taking an effective R value from ~1.2  to ~1.8 would WAY more than double the growth rate.  I really don't think that this makes sense, and that number for an increased R value seems like it should be referring to the unmitigated R0 value that is then reduced by behavioral interventions.

EDIT: doubling time would go from 17 days to 4 days (!) with the above change of numbers. This doesn't fit given what is currently observed.

An R0 going up by ~0.4-0.9  also fits well with my imputation of a ~15% increase in infectiousness, as estimates of an unmitigated R0 range from circa 3 to 5.

I think this is what happens when people don't show their work.

Comment by CellBioGuy on New SARS-CoV-2 variant · 2020-12-21T19:18:26.501Z · LW · GW

The spectrum and rate of excess mutations (assuming they all came in one step) is similar to what has been recorded elsewhere in immunocompromised people chronically infected for a month or two straight, in which there's more time for multiple lineages to coexist in the same body and compete with selection against each other and a longer time with high viral numbers without transmission bottlenecks.

Comment by CellBioGuy on New SARS-CoV-2 variant · 2020-12-21T05:21:15.556Z · LW · GW

I've become enough of an arrogant SOB evolutionary biologist poking his nose where it doesn't belong over the last year that I believe I have answers to all of these, and a few other important things to say.  WHILE MAKING IT CLEAR I AM NOT A VIROLOGIST OR IMMUNOLOGIST OR EPIDEMIOLOGIST AND THAT I COULD EAT MY WORDS IN THE FUTURE, though I have been pretty good so far.

How likely is it that the spread of this new strain was caused by a few superspreaders, and that most of the above is blown out of proportion

That would make sense if the frequency was rising in early introductions or when spread was thin on the ground.  Increasing fraction of the total infections while spread is already thick makes me think that there is more likely to actually be an actual effect on contagiousness.  They report a decent detectable increase in genome copy number as measured by PCR and sequencing in upper respiratory samples which makes me think this is likely.  More on the virology later.

What, uh, does the "71% higher growth rate" mean

TLDR: I think that it's probably barely 15% more infectious and the math of spread near equilibrium amplifies things.

I admit that I have not read all available  documents in detail, but I presume that what they said means something like "if ancestor has a doubling time of X, then variant is estimated as having a doubling time of X/(1+0.71) = 0.58X"

This can only be related to a parameter like R0 in relation to how much R0 has already been reduced by behavior changes to its effective actual R since the math gets really nonlinear and I presume I am either missing their math or there will be more detailed documentation in the future.  In the mean time let's run through an example.

I have seen estimates of 'generation times' for SARS-2 clustering around 5 days in the presence of all the stacked up behavior changes.  Doubling time is related to the generation time and the effective replication number Re, by the equation:

doubling time = ln(2) * generation time / (Re-1)

If you have reduced the Re to 1.1 with a 5 day generation time then you get a doubling time of 35 days.  If you have reduced it to 1.2 then you get a doubling time of 17 days.  In the former case, if you take 35 days to 0.58*35 = 20.1 days, you get Re going from 1.1 to 1.172, only 7% higher infectiousness.  In the latter case, if you take 17 days to 10 days, you get Re going from 1.2 to 1.34, a 12% increase.  Presumably the base R0 increases by a similar factor.

In short, the closer you are to equilibrium when measuring the effect the larger the effect a small change in contagiousness will have.  Given that compared to unmitigated situations we are pretty close to Re=1 and I never see cases doubling recently in Britain in less than two weeks, I doubt that the total factor of increase of infectiousness is actually all that large.  You get a huge nonlinear effect as you move the numbers around near one, even when the total factor of increase is not huge, but mitigation increasing by only a small factor can counteract it.

Prepared to eat this, hard, if I am misinterpreting what has been said.

Is there any reason to suspect this new strain might have an impact on vaccination plans? Are the currently approved vaccines (pick a country of choice to decide what this means) possibly better/worse/other against this strain?

It is almost certain that the vaccines (all of which present exactly the same piece of the virus to the immune system) work a bit less well on this variant, but at the same time I think it changes absolutely nothing important of substance for the near future.

For now, ignore EVERYTHING except the spike protein.  This lineage bears several mutations in this gene, responsible for fusing the virus to target cells and the main target of antibody responses (and a good fraction but not all of the T cell response).  They are, separated thematically:

deletion 69–70
deletion 144


 N501Y
A570D


D614G
P681H
T716I
S982A
D1118H

Deletion 69-70 and deletion 144 are in what's called the N-terminal domain.  This is not quite the business end of the spike but is near to it and is involved in invasion to some degree via mechanisms that are not well understood.  The double deletion has appeared independently several times, and seems to be helpful in becoming more invasive to human cells to some degree and also may help escape a subset of antibodies possibly as a side effect. Bit of a loooong story there I won't quite get into here.  Anyway, these are in a domain that constitutes about 20% of human neutralizing antibodies and are quite possibly somewhat immunologically relevant.

N501Y& and A570D are particularly interesting because they are in the receptor binding domain that actually sticks to ACE2.  In particular, N501Y has already been identified as a mutation that increases the strength of binding to the ACE2 receptor.  It also functions as a known escape mutation, and the other one could as well.

An escape mutation is a mutation that causes a subset of antibodies functional against the ancestor to become inert.  However, vertebrate immune systems generate a small quantity of a large number of antibodies against their targets, so generally speaking when an escape mutant comes along there are other antibodies around to take up the slack.

I  have seen papers exposing large numbers of recovered human serum samples against various escape mutations.  When one at a time was presented, only the weakest ~7% of responses (presumably consisting of the fewest antibody types) were affected at all and only a subset of those dropped below likely having an effect.  When two escape mutations were added, it went up to about 20%, still biased strongly towards the weaker responses.  But again, not all those responses dropped to zero, some just got weaker.  Of note, natural responses to the virus vary in strength by a factor of TWO HUNDRED, and a weak response is very different from a strong response.

I would expect that each escape mutation you add makes the fraction of responses that have a problem go up, and the size of the problem to go up.  We are talking 2-4 escape mutations here, so there is likely some immunological impact.

D614G is one of the first mutations  in the history of this virus from January and is likely associated with a mild increase in contagiousness to humans, via a slight change in the geometry of the trimer that is completely immunologically irrelevant.  

The rest of the mutations are in parts of the spike that are a lot less likely to be immunologically relevant, even if maybe one or two of them changes something about the arrangement of the three spike monomers  in the trimer that could theoreticaly affect binding or synergize with others to affect binding efficacy or shedding of the S1 domain from the protein or any number of other things, but dont necessarily and a bunch of them are probably just silent.

Given the sheer strength of responses created by immunization so far, as strong or even stronger than the very strongest natural responses, I find myself doubting that even multiple escape mutations will be able to break through the response to the vaccines.  I would presume they would make the speed with which immunization immunity decays increase, and mean that fewer additional mutations on top of this base would be needed to properly evade it.

But we will have do deal with this anyway!  It is now known that the human coronaviruses do evolve on a timescale of circa a decade to be able to escape previous antibody responses, we just constantly get exposed to these  new changes as they barely break through into us.  Over a timescale of somewhere in the single digit years, I would presume that this virus would evolve to escape immunity be it natural or vaccinated.  And there is a hell of a difference between getting infected when you are completely naive and have never seen anything like it, and when you just barely can be broken through into and you are still generating antibodies and T cells that both are still reactive, even if it can slip past well enough.  A vaccination rolled out to prevent this first burn through a naive population is vital, and we will see if we can keep ahead of eventual evolution with later boosters or if we just live in equilibrium with another respiratory virus which will not be like the current situation.

*****

This is where I nerd out randomly on something else.  Almost nobody is commenting on the fact that this lineage also contains a nonsense mutation in ORF8!  

ORF8, the 8th identifiable reading frame in the genome, is one of the several tricksy accessory proteins that the virus uses to subvert and confuse the adaptive and innate immune system both - in particular, it gums up the MHC complex that body cells use to present viral protein fragments to the adaptive immune system, both to train it upon first exposure and to tag a cell for destruction by eventual trained T cells.  This and other accessory proteins are almost certainly a large fraction of why this disease is so immunologically weird and causing such messed up immune responses in severe cases.

A nonsense mutation is a mutation that turns one of the codons that codes for an amino acid into a STOP sign, preventing the production of everything downstream of that position in the protein.  This nonsense mutation is practically right at the beginning of the protein, so functionally speaking it is obliterated.

This protein has, in the various lineages around the world, accumulated less impactful mutations at a faster rate than almost any other position in the genome, indicating that it is not under a lot of selective pressure to be maintained.  The accessory proteins are probably needed to replicate in bats, whose immune systems are tuned  differently than ours - their antiviral interferon responses are on a freaking hair trigger and their inflammatory responses are damped incredibly low.  They are probably a lot less necessary in other mammals.  A similar protein literally fell to pieces over the course of the first SARS outbreak twenty years ago, and multiple lineages have been seen with big deletions in this gene over the course of the SARS-2 outbreak but none of them became particularly common, and indeed several are basically confirmed to have died out entirely.

If NOTHING else, this lineage proves that the loss of the tricky accessory proteins is not a death sentence for the virus and the possibility of them being lost over time in the future remains.  This may be a mechanism of eventual self-attenuation, if previous research in Singapore indicating that the ORF8-deleted lineages were significantly less likely to send people to hospitals pans out (there was not enough research for me to be confident of this buty there were some reports that really need to be followed up on).  It is possible that this utterly broken ORF8 basically 'hitchhiked' alongside the spike protein changes that are likely responsible for increased transmissibilty, even if it is mildly harmful to the virus.  This virus does not seem to be doing recombination in the human population, so such evolutionary hitchhiking can become an important force.

Comment by CellBioGuy on How long till Inverse AlphaFold? · 2020-12-18T03:24:22.336Z · LW · GW

From what I understand the pipeline depends strongly on homology to existing proteins that have determined structures to use substitution correlations to create an interaction graph which it then allows to evolve via learned rules.

I strongly suspect that as such it will not be very good at orphans without significant homology, be it sequence to structure or the reverse.

Comment by CellBioGuy on Some things I’m looking forward to in 2021: probable post-pandemic edition · 2020-12-18T03:18:01.254Z · LW · GW

Seeing my long distance boyfriend who is an ICU nurse

Not being in the lab nocturnally

The gym

More literature search time into evolutionary biology and SETI rather than immunology

Comment by CellBioGuy on On the stagnation of energy technology and the Cabal of Scientists · 2020-12-17T18:37:33.386Z · LW · GW

Watts per unit of infrastructure machinery necessary, including ancillary things not in the actual engine.  Not joules per unit fuel.

Comment by CellBioGuy on On the stagnation of energy technology and the Cabal of Scientists · 2020-12-14T04:35:39.390Z · LW · GW

Or, fossil fuels provide the greatest energy flux per unit infrastructure of any option in the whole past and future of humanity and are as good as it gets and until they run low there is no reason to use anything else.

Comment by CellBioGuy on Pre-Hindsight Prompt: Why did 2021 NOT bring a return to normalcy? · 2020-12-07T18:35:47.844Z · LW · GW

Low grade smouldering domestic insurgency instigated by the de facto Shadow President In Exile.

Rural hospitals continuing to be overwhelmed after urban hospitals as vaccination is not taken up sufficiently in rural areas (see the rates of flu vaccination in urban versus rural areas)