How the Coronavirus Hacks the Immune System
newyorker.com
newyorker.com
> For the first half of the twentieth century, the going theory was that the invading element—the “antigen”—served as a template around which a corresponding antibody was molded. Only in 1955 did scientists discover the much stranger truth. It turned out that the cells that produce antibodies—called B cells, because they were first discovered in the bursa of Fabricius, an organ that does for birds what bone marrow does for humans—can produce only one kind each. Its structure is random, and nearly every B cell is discarded unused. If, however, an antibody created by a B cell happens to match some part of an antigen, that B cell will not just survive but clone itself. The clone incorporates many mutations, which offer the possibility of an even better match. After a few generations, an antibody with the best fit is “constructed” through a process of mini-evolution that occurs continuously in our lymph nodes and spleen. (Our ancestors the bony fish adapted the machinery of the B-cell system from an even more ancient parasite.)
So, natural selection discovered a way to run an embedded natural selection search process in an individual. Talk about meta.
[1]: https://en.wikipedia.org/wiki/V(D)J_recombination "V(D)J recombination"
So, in a way, different individuals have different immune strategies. For example, super-responders to HIV tend to be HLA-B57. This HLA "version" trades better response to virus that mutate quickly for more chances of autoimmunity as thymic selection is less stringent (because HLA-B57 presents less selfpeptides in the thymus).
That is exactly how lymphomas originate.
If you sum these two up they end on top respectively in that order. Albeit prostate cancer is really close.
It's an artifact of grouping used. For colorectal for example, adenomas and carcinomas are lumped for a change.
Prostate is the second most common worldwide, or skin cancer, depending on year. The big 5 are over 1.5 million. (WCRF data. They lump all lung cancers but split immune system and skin cancers. For reasons? Bladder and lung cancer incidence is highly dependent on factors such as smoking and specific chemicals used in manufacturing. Potentially the same with colorectal and diet. Rates for breast and prostate are high because they're easy to spot and well tested. So per country data varies a lot.)
phrased another way: could the same process that spawns these legions of B cells also inadvertently spawn cancer cells?
related: healthy cells exhibit properties that allow them to go ignored by the immune system, similar to a VIP pass for bypassing security at a basketball game. is this right? if yes, what are the minimal properties that constitute this cellular VIP pass?
thanks for your help.
Cancer cells typically have mutations, even just single base pair changes, which change the way that genes are expressed in the cell and thereby influence such behavior.
The original functions of the B cell aren't necessarily needed for other cell types to exhibit similar functions. The base plan is there, it just needs a nudge.
>As the virus spreads unchecked through the body, it drags a destructive immune reaction behind it. Individuals with COVID-19 face the same challenge as nations during the pandemic: if they can’t contain small sites of infection early—so that a targeted response can root them out—they end up mounting interventions so large that the shock inflicts its own damage.
Kind of similar to anaphylaxis to bee stings. The venom was never any threat to a human, but the immune response sure can be.
“Those cells die everyday!”
https://www.youtube.com/watch?v=LQmTKxI4Wn4
It's a 7 minute video, if you only have a little time, skip around, but make sure you listen to the part starting at 6:17.
DNA isn't just the blueprint for the machine or the blueprint for the factory that makes the machine, it's the blueprint for the entire supply chain required to build and operate an entire chemical industry of mind-bending complexity. Like doubling grains of rice on each square of a checkerboard, if you wanted to create a complete catalog of all possible combinations of a string of DNA that's 150 base pairs long, you would have to marshal all of the estimated matter in the observable universe and you'd still end up short. Most of the genes that create these proteins are tens of thousands of base pairs in length and the entire human genome is ~3 billion.
Never seen the chemical (proton concentration), converted into something mechanical (spinning), and back into chemical (adp + phosphate -> atp) in such a way before.
This channel has a ton of great videos:
https://www.youtube.com/user/WEHImovies/videos
Here's one on kinetichore and mitosis (which also shows kinesin and dynein which are comically odd) - https://www.youtube.com/watch?v=IvJrDsRuWxQ
There's a collection of their DNA ones here: https://www.youtube.com/watch?v=7Hk9jct2ozY
Here's another view of the ATP synthesis process that shows the chaos a bit more: https://www.youtube.com/watch?v=OT5AXGS1aL8
When I think of these systematically I just wonder what the intermediate steps were. The proton pump uses energy to create the potential gradient that ATP synthase runs on. You can't have a proton gradient without the proton pump, and without the proton gradient you don't have ATP. So these two exquisitely complex machines depend on each other and had to evolve together. It boggles my mind.
Edit: Ah! Was looking for this one, sodium potassium pump - https://www.youtube.com/watch?v=ZKE8qK9UCrU This is how our neurons propagate signals. They are driven by ATP.
The membrane is the later invention, dating to organelles which are suspected to be microcellular parasites that got integrated and then reduced. These membranes were much more efficient, however they were very hard to turn off for hibernation as the membrane is a static gradient and hard to disrupt temporarily.
I wonder if maybe an intermediate step could be just channels and turbine. But no pump. If the amount of protons surrounding membrane varies over time, the cell can open the channels when there are many protons outside, and close the channels when there are few (forcing equalization through turbines).
Or maybe it can use acid protolysis to create protons?
This one has a little more, even if a lot of questions still remain https://www.youtube.com/watch?v=LEefVREZ1Ao
https://www.amazon.co.uk/Genome-Autobiography-Species-23-Cha...
Even that is only theoretical - we generally know some level of detail to know what many of these routines are approximately up to, but rarely in the detail needed to figure out what a cell is up to in general.
In some ways studying what a cell is upto using our current methods is comparable in certainty to how we poll the US before elections.
The fun part is that it's not like DNA is just expressed, it needs to be "unwound" from it's natural state as a highly dense structure. Elements within the cell actually regulate the unwinding itself, that's one way genes are turn on/off.
And in addition, once DNA is unwound, split into a single strand and transcribed into RNA, the RNA itself becomes a regulating mechanism through siRNA. So the very act of transcribing DNA has regulating effect up the transcribing itself.
(If for some reason we had to work with that kind of computer we'd probably enforce a conventional, graspable approach on it by finding a way to simulate a conventional computer once and then conveniently forget about the underlying madness, clearly that wouldn't be the path taken by evolution)
I can do this myself! "On a bald September day, a man walks into a barber shop, languishes at the occupied seats, and voilà, while sensing upcoming bowel movements, he discovers the next great theory of economics."
The New Yorker is known for that style, it may even be the prime example of it.
People who don't like that style are not the audience. And there are many people who like it.
It's like asking why Linux Weekly News never runs poetry. Because it's not that kind of publication.
(Or worse - being unable to appreciate a good novel because you're too impatient for it to get to the exciting bits!)
Not always what you're looking for but it can be a good way of cracking into a subject you're unfamiliar with, or a good way of merging the human element with something that would otherwise be quite dry.
By no means a substitute for regular news, but a good complement to it.
Clearly a matter of opinion whether it's good.
You mean it can be a good way of stretching an article to fit more ads and increase monetization.
Long form is good if you have something long to say. Trying to construct a story where there isn't one frustrates the reader.
I enjoy in depth exposes, but I don't need the alice, bob and malory viewpoint anchoring.
This is my general attitude towards this style of writing, not this specific piece.
> Just one piece of general advice from a writer has been very useful to me. It was from Colette. I was writing short stories for Le Matin, and Colette was literary editor at that time. I remember I gave her two short stories and she returned them and I tried again and tried again. Finally she said, “Look, it is too literary, always too literary.” So I followed her advice. It’s what I do when I write, the main job when I rewrite
> I: What do you cut out, certain kinds of words?
> Adjectives, adverbs, and every word which is there just to make an effect. Every sentence which is there just for the sentence. You know, you have a beautiful sentence—cut it. Every time I find such a thing in one of my novels it is to be cut.
[1] https://www.theparisreview.org/interviews/5020/the-art-of-fi...
Alternately, it's a way of expanding readership. If you don't know anything about molecular biology, they have to write an article at a layperson's level to explain what they mean. But if you, the reader, don't want to go through the effort of trying to understand even that, then there's this human-interest stuff that may still cause you to decide to buy their magazine.
It's journalists writing for other journalists.
In French, “logorrhée”, means literally “verbal diarrhoea”.
It’s symptomatic of people who have not much to say.
George Orwell is turning in his grave...
When I see a five page article, I know that I'll get background information and I might discover something I didn't expect from the title. While you might only be looking for the study results, I like spending my Sunday afternoon reading long articles teaching me all kinds of interesting information I wouldn't have looked up on my own.
The purpose of longform writing is to provide flavour and context, which are important parts of an information diet. Not everything has to be about the freshest facts delivered to your brain as urgently as possible. Just because you've happened across this in a frenzied binge of clicking HN headlines, doesn't mean it was designed to be consumed that way. If you don't feel you have time to sit through a New Yorker article, save it for later.
The thing is, this isn't news reporting at all. It's a popsci writeup of the history of the immune system, the history of the discovery of the immune system and a glimpse into its complexity that uses Covid news as the textual equivalent of a cover image. If you have a print of 20000 Leagues under the Sea and the cover shows the kraken attack, would you complain about the number of chapters that don't contain a kraken at all?
> Usually, the viruses that humans care about are successful because they shut down both of these signalling programs. The coronavirus is different. “It seems to block only one of those two arms,” tenOever told me. It inhibits the interferon response but does nothing about the cytokines; it evades the local defenses but allows the cells it infects to call for reinforcements. White blood cells are powerful weapons: they arrive on an inflammatory tide, destroying cells on every side, clogging up passages with the wreckage. They are meant to be used selectively, on invaders that have been contained in a small area. With the coronavirus, they are deployed too widely—a carpet bombing, rather than a surgical strike. As they do their work, inflammation distends the lungs, and debris fills them like a fog.
Corticosteroids also kickstart healing process (not really in COVID) and regrowth - you also race against tissue destruction. Most importantly they barely reduce scar formation. And they actually improve breathing via action on alveoli as well as reduce swelling.
The specific two to use are hydrocortisone and dexamethasone based on studies thus far, in critical patients - ones put on respirators. (Prednisolone could also work.)
In a nutshell, SARS-CoV-2 (COVID-19) does block interferon response by using molecular mimics. Some of the proteins encoded in the virus are really similar to proteins in the interferon pathway, so this is not surprising. Still pretty unexplored and a nice route towards finding treatments.
Now, the interesting part is that the dynamics of interferon is very non-linear. Cells exchange interferon signals with other cells in the same tissue to pass information and coordinate with the immune system. There are fairly sophisticated models (using stochastic message passing!) that confirm lab observations on regular non-infected cells [1].
My hypothesis is that by blocking interferon in a sufficient number of cells on individuals with already disrupted innate immunity (due to ageing, insulin resistance, etc.) the system becomes chaotic. Infection by e.g. pneumococci is tolerated because the signaling is perturbed and then, all of a sudden, you get a massive amount of proinflammatory molecules secreted and cells decide to undergo apoptosis. That's the cytokine storm that everyone talks about.
Sadly, pursuing these ideas within academia is hard as most (but not all) biology labs are really hostile to mathematical models, even if they explain or predict things they can't using hand waving. Perhaps I should seek VC funding.
When you start to find essential elements, they get mathified (look at DNA) but look how much experimental work it takes to do that? Scaling up experiments can also take some math, but once you figure out the trick, you just have a lot of experiments to run....
It’s so long.. after 10 minutes I wanted to know the point of it, so I skipped aggressively to the middle, found a few points, then skipped to the end.
I wonder if there’s any value to so many words in this day and age with so many other things to read on the internet.
There are many books being written every year, yet the classics remain so -- they aren't pushed away into non-existence.
If you have trouble finding the value in the literature blame the author, not the word-count.
If the question is 'Does short content generate more hits on the internet?', then undeniably yes.
If New Yorker articles are not for you, then do not try to read New Yorker articles. Really! Read other things you will actually like. If you want a quick rundown of the topic, Wikipedia is only a click away, and gets right to the point.
Those of us who like New Yorker articles appreciate them when they appear. We know there will be an investment of time, and we know that a board of Editors has ensured that, for those of us who like the format, our time will not be wasted. Those who don't, know in advance that they will just be frustrated and bored, and can skip past instead. You are not even obliged to "upvote" the post.
Really, nobody is keeping track. Nobody will think ill of you for skipping past the moment you notice "New Yorker" in the URL. If you ever become ready for New Yorker articles, New Yorker articles will be there for you.
If you are hoping that people will discuss the novel aspects of the coronavirus's impact on the immune system then you might choose an article that focuses on that.
Instead, if you choose an article that spends a large amount of time discussing tangential points, creating lengthy analogies for the workings of the immune system and discussing other forms of immune response then probably you are hoping people will discuss those too.
But people will appreciate as well as criticise. That there are people who appreciate the analogies are apparent in the discussion here where people do just that. That there are people who would prefer a focused article and find that the tangents detract from the underlying store is just the flip side of that discussion that the op decided to have.
I personally wish that long form journalist articles would have an outline at the beginning so that I know what I am about to read. Otherwise it often just feels like the author is rambling and going nowhere. Some stories actually have a lot of moving parts and require long form journalism to paint a realistic and balanced picture. Instead, a lot of "long form" journalism just adds filler analogies and tangential factoids that may be interesting but often don't add anything to the underlying story or are unnecessary for understanding.
[1]: https://en.wikipedia.org/wiki/Antibody-dependent_enhancement
https://sciencebasedmedicine.org/hcqtrial-com-astroturf-and-...
Ok, that doesn't look good… (Still, I would have preferred that doctors would be free to decide by themselves which drug to prescribe for a new disease. After all, they have skin in the game !)