6 ms·
2019-nCoV may contain a gain-of-function for efficient spreading
- deweller 7y agoNoteable quote from the study: > This furin-like cleavage site...may provide a gain-of-function to the 2019-nCoV for efficient spreading in the human population compared to other lineage b beta- coronaviruses. Can somebody who understands this please elaborate on the implications?
- webdevatlurk 7y agoThe phrase "gain of function" seems to mean the virus differs in some way that makes it more contagious or deadly.
- zaroth 7y agoThank you, that makes a lot more sense than some sort of “gain” (as in, increasing output levels) of “function” (as in, a mathematical calculation where each input has exactly one output). I’m thinking what the heck is a Gainof Function?
- webdevatlurk 7y agoHeh, It makes more sense if you think about it medically. Like, the gain or loss of function in a limb or organ. For a virus I suppose this would be function in reproduction.
- vikramkr 7y agoYeah the function here is not a mathematical function - it just means functionality, like the thing that it can do. Sometimes we biologists can be spectacularly uncreative in naming things :)
- codekilla 7y agoYes, and here is a good overview of it in the context of some contentious research [1]. [1] https://journals.sagepub.com/doi/abs/10.1177/0306312716666420 https://journals.sagepub.com/doi/abs/10.1177/030631271666642...
- webdevatlurk 7y agoSeems interesting, but I can't read that without paying, and I probably lack the background necessary for it to be understandable.
- codekilla 7y agoType the DOI into sci-hub.tw
- webdevatlurk 7y agoThanks. Didn't know this existed.
- rolph 7y agoyou can copy it like a link as well and paste it in
- esahione 7y agoIt means someone edited it. As everyone knows by now.
- trenchgun 7y agoIt does not mean that.
- blattimwind 7y agoTheir previous comment > Humans are notoriously good at coming up with bullshit explanations for both random/statistical & deterministic phenomena. Apt.
- wyxuan 7y agoThis has been a debunked conspiracy theory.
- fxtentacle 7y agoThey talk about a "cleavage site", meaning a 3D shape with the chemical properties necessary to cut something. And apparently, that ability to cut molecules similar to furin enables this virus to more efficiently enter cells, i.e. successfully infecting someone with a lower dose of live viruses. Where this new shape came from, they do not know. But since viruses tend to mutate a lot and integrate RNA snippets floating around in their host's blood stream, it is likely that they picked it up from some other virus simultaneously infecting the same individual. In short, the new nCoV seems to be so contagious because it merged in a new feature from a different virus species. The implication is that by specifically blocking this thing that nCov has but older Cov do not have, one might be able to drastically reduce its contagiousness.
- fabian2k 7y agoThe cleavage site is the target that gets cleaved, not the part that does the cutting. So in this case the virus has a site that can be cleaved by certain enzymes like Furin.
- gazsp 7y agoIndeed: https://en.wikipedia.org/wiki/Furin https://en.wikipedia.org/wiki/Furin
- webdevatlurk 7y agoFrom the Wiki page for Furin > ...must be cleaved by furin or furin-like proteases to become fully functional. Anthrax toxin, pseudomonas exotoxin, and papillomaviruses must be processed by furin during their initial entry into host cells. From the sound of this: - the site on the virus gets cleaved - Furin enables the cleaving - Furin exists in hosts cells What I think I understand is, the cleaving makes it easier for the virus to reproduce inside the cell? edit: turns out I have no idea how to format things on HN
- rolph 7y agothe cleaving prepares the virus to be able to enter the cell
- sampo 7y agoSome proteins are inactive first after they have been synthesized. Furin is an enzyme that targets certain sites in certain biomolecules and cuts a piece off, activating these proteins. Apparently some furin is floating around in the human body for this purpose. The article suggest that there is a furin target site (binding site) in the surface "spikes" of the coronavirus. And when furin cuts piece off the spikes, the resulting, or remaining, part then assists the entry of the virus into cells. Here is a review article from 2019 on furin. Apparently several viruses use this "trick" as part of their entry mechanism. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682551/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682551/ (I have some biology studies from long ago, I am not professional in molecular biology.)
- rolph 7y agothere is a protien on the virus that is called S [spike]. there is a protien [protease] in the extracellular space of your tissues that cleaves other protiens these are called Furins. Furins activate enzymes where they are needed by cleaving [cutting away all the shipping wrap]. The S protien of the nCoV SARS 2 virus has a cleavage site that is cut by the furin class of protiens. this seems to be a modification as the SARS CoV does not have this cleavage site as far as can be seen for the time. so what does this do? the S protien is specific to a binding site [ACE2] and that will be found in high prevalence in the lungs, but is found elsewhere. the corona virus does not seem to shed through the skin but through mucous and sputum so the virus that is efficient at lung infection will win when this is its transmission mode. if the virus doesnt make it to the lungs it is in a less than optimal place for survival compared to the lungs. so the virus has a specific tag recognition sequence to find ACE2 and stick. this is where the Furin comes in. The S protien is in shipping state until it reaches the lungs and is cleaved by Furin, this is when the S protien become S1; S2. the S1 stays bound to ACE2, the S2 does some work and wrenches the cell membrane open then inserts its nucleocapsid---this is now an infection. the exact details are not entirely worked out such as is there an absolute requirement for S binding or S cleavage in any particular order. and does anything else participate in the process. the authour suggests some correlation of furin cleavage sites with increased pathogenicity [potential to cause disease] based on observations of other unrelated virus having a newly acquired cleavage site correlated with increased proclivity to cause a disease process in humans. there may be some undercurrent regarding these molecular feature as a general theme in biology, however there is not a firm scientific consensus that this is the case. the articel referenced is a preproof meaning it is close to being accepted for publishing so it isnt science yet. [PDF] here : https://sci-hub.se/10.1016/j.antiviral.2020.104742 https://sci-hub.se/10.1016/j.antiviral.2020.104742
- _eigenfoo 7y agoI'm not sure why this is circulating HN. Most of us here are not medical or epidemiological experts at all, and most of the comments here are just people asking for an layman's explanation of this paper. Trying to ascribe meaning to highly technical results seems futile (at best) or irresponsible (at worst).
- swsieber 7y agoThis particular study though doesn't have any impact on how we personally react to the virus though, so it falls into the realm of intellectually stimulating.
- deleted 7y ago[deleted]
- vl 7y agoIt’s a typical geek bait: a lot of smart words, some obscure info that needs to be superficially researched first to be understandable. At the age of the attention economy this specific specimen of information is highly engaging for this specific slice of population.
- allovernow 7y agoHN is disproportionately composed of multidisciplinary generalists with backgrounds in a range of fields, including virology and molecular biology. There is no harm in having smart people reading breakthrough literature in other fields. Even if we don't understand every detail, often with enough experience in other fields you can still get the gist and there's always opportunity for cross-pollination. >Trying to ascribe meaning to highly technical results seems futile (at best) or irresponsible (at worst). I'd like to point out that this is primarily how grad school on the cutting edge works. You pick a subject and start reading papers until piece by piece things start to make sense. Frequently people do so by jumping into a graduate topic that can be quite different from their undergrad, and this is still a valid way to learn for a subset of the population. Frankly given the gravity of the pandemic I don't think any published article is inappropriate for HN right now.
- pmoriarty 7y ago
- peter_retief 7y agoI came to read the comments to find out what this means. Is there anyone who can translate this into something more understandable?
- armatav 7y agoI guess gain-of-function == new-feature.
- vikramkr 7y agoI tried to write up a longer comment breaking it down in laymans terms (https://news.ycombinator.com/item?id=22536734 https://news.ycombinator.com/item?id=22536734), not sure if it's helpful but I figured I'd at least give it a go. It basically boils down to there is a mutation in this strain of virus that seems to give it an ability to infect cells better (gain of function = new feature or enhanced feature of a protin, nothing to do with mathematical functions or the lambda calculus), and this paper discusses what it is and how it's hypothesized to work.
- CyanLite4 7y agoIn the microbial world, the mildest strains will survive the longest. Ideally it would even become symbiotic to help fight antibiotic resistant bacteria.
- whatshisface 7y agoSwitching from humans to human-infecting bacteria would be a very unlikely species jump.
- moyix 7y agoThis is commonly repeated but not really true, see http://www.iayork.com/MysteryRays/2007/08/26/rabbits-1-virus-1-evolution-of-viral-virulence/ http://www.iayork.com/MysteryRays/2007/08/26/rabbits-1-virus...
- samcal 7y agoI'm not sure that your first sentence is true. The symptomatic effect that a not-mild virus strain has can help it spread, for obvious reasons. It seems like there's an optimization problem there, with a sweet spot where the virus doesn't kill its host, but makes them cough and sneeze to spread to other hosts.
- pingyong 7y agoI could imagine that not causing symptoms would probably be ideal if the virus could survive endlessly and not get eventually killed by our immune system. But anything that does get killed by our immune system is kind of on the clock and needs to spread relatively quickly.
- ajross 7y agoThis is sort of true, in a Darwinian sense. But it's true because viruses which kill their hosts inhibit their own propagation! It doesn't help us at all if our goal is to prevent those people from being killed in the first place.
- vikramkr 7y agoI mean, it might not survive the longest if it's more infective, but evolution doesn't work like that, and we're worried about short term impacts. Yeah if it's really bad we'll eventually make it go extinct just like we made smallpox go extinct, but smallpox didn't adapt and survive and become less wild. We are the evolutionary pressure driving it to exinction - the virus right now is plenty happy surviving as the more virulent strain it is. It's survival of the good enough, not survival of the fittest, and a deadly strain is good enough to keep surviving.
- gumby 7y agoNote that this is not sars-cov-2 (the virus that causes COVID-19) though closely related.
- kaffeemitsahne 7y agoI flagged this because the title was edited w.r.t. the actual article in a way that nobody here seems to understand.
- anyanswers 7y agofrom the paper: "This furin-like cleavage site, is supposed to be cleaved during virus egress (Mille and Whittaker, 2014) for S-protein “priming” and may provide a gain-of-function to the 2019-nCoV for efficient spreading in the human population compared to other lineage b betacoronaviruses. This possibly illustrates a convergent evolution pathway between unrelated CoVs. "
- johnwheeler 7y agoEdit: found this below https://news.ycombinator.com/item?id=22535930 https://news.ycombinator.com/item?id=22535930 (see sampo’s response in comments) I am completely baffled to the meaning of this given the scientific nomenclature used, but I would really like to know what it means and why it is front page HN. What I imagine it means is that the red things on this picture https://www.cdc.gov/homepage/images/banner/covid-19-1330px.jpg https://www.cdc.gov/homepage/images/banner/covid-19-1330px.j... have some sort of indentation, or cleavage, that makes them either more or less dangerous. Am I close? Can someone who understands explain for the layman?
- jforman 7y agotl;dr any unique feature of this virus may be explanatory for its demonstrably increased virulence, and may be targetable by existing therapeutics as well. This particular feature is a candidate finding of this type — the specific molecular biology involved isn't particularly important for non-molecular biologists (I was one in a past life).
- conspiracyjoe 7y agoNo idea. Only other context I've come across this as a lay person is in describing gain of function research. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996883/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996883/ Not sure that's what the other intended though, would appreciate someone with technical understanding interpreting.
- zimpenfish 7y agoYeah, I think it's the "peculiar furin-like cleavage site in the Spike protein" that's the new mutation which might make this variant more efficient in spreading. As best I can tell as a biological layman.
- rolph 7y agoyes you have it this is the concept.
- unchocked 7y ago
- ohmanjjj 7y agoWhen will world governments finally admit we are dealing with a bio weapon engineered in a lab by a rogue group or nation.
- JohnJamesRambo 7y agoNot to be tinfoil hat but isn’t this exactly the sort of thing you would add to it if you were making a bioweapon in the only BSL-4 lab in China which is a few meters from the wet market they are saying was the epicenter? > Strikingly, the 2019-nCoV S-protein sequence contains 12 additional nucleotides upstream of the single Arg↓ cleavage site 1 (Fig. 1, Fig. 2) leading to a predictively solvent-exposed PRRAR↓SV sequence, which corresponds to a canonical furin-like cleavage site (Braun and Sauter, 2019; Izaguirre, 2019; Seidah and Prat, 2012). This furin-like cleavage site, is supposed to be cleaved during virus egress (Mille and Whittaker, 2014) for S-protein “priming” and may provide a gain-of-function to the 2019-nCoV for efficient spreading in the human population compared to other lineage b betacoronaviruses. This possibly illustrates a convergent evolution pathway between unrelated CoVs.
- vikramkr 7y agoIF you were making a bioweapon, you'd probably try and do the opposite so you can try and target it better. This is a really dumb bioweapon because it infects you worse too - in general bioweapons are just a terrible weapon for non=suicidal nation-states because you can at least aim nuclear weapons, but you can't aim a virus. This mutation is exactly the sort of boring everyday mutation viruses pick up in the process of being viruses - they mutate quicker than our DNA and picking up something like this is with a dna replication error leading to a little stutter is not hard at all. HIV, influenza, etc are all examples of how effective good old fashioned natural selection and random mutation is at advancing viral capabilities and evasion strategies without any help from humans needed.
- dfsegoat 7y agoNitpick title based on dense verbiage [1]: 2019-nCov may contain a mutation for efficient spreading 1 - Gain-of-function mutation: A mutation that confers new or enhanced activity on a protein.
- avip 7y agoSuddenly, everybody is a physician. Your fellow developer, who yesterday couldn't find her package.json, walks around saying case fatality rate and asymptomatic.
- antocv 7y agoThe worst part of being a software developer, is being around other software developers. Seriously, the most know-it-alls ever.
- whatshisface 7y ago"Asymptomatic" means "not coughing," surely even a developer could understand that. You should be glad they're taking this opportunity to learn the basics of a very important field.
- jacobra2 7y agoGiven that: * Almost none of the commenters understand what this post is about * It spiked to the top of HN, despite that * There are a handful of comments suggesting covid-19 is a bio weapon I can't help but wonder if this very post is manufactured to spread the bio weapon conspiracy.
- Benmcdonald__ 7y agoI know the Russian government is pushing a covid-19 conspiracies. Plus Iranian govt somewhat too
- vl 7y agoWhile discussing outbreak with the guy who works in computational biology, he told me a simple idea: most engineered bio-weapons are not as successful as normal viruses because viruses go through massive parallel evolution process constantly, and you can’t just engineer as effectively.
- vikramkr 7y agoThis is a very good article and sound science - I don't know how the linked article itself would try and spread bio-weapon conspiracy. I tried writing up an explanation, and I'm sure other biologists will come in with more concise and better understandable ones over the next few minutes - the terminology might be confusing because it overlaps with words used in a CS context, but I think it's relevant to HN and is a high quality article, jsut in a different technical field than what you might usually see so you might need a different set of commenters to work their way out of the woodwork and try and clarify/engage in the discussion.
- deweller 7y agoI'm the poster. Yes, I've heard the bio weapon conspiracies. They tend to say that this "gain-of-function" property is proof of a bio weapon. I posted this because a) It was interesting to me b) I was hoping the HN community might be able to help shine some intellectual light on what gain-of-function actually means in this context. c) It is an article in what appears to be a reputable journal But I see it is now flagged. So perhaps it is too much of a hot-button topic.
- vikramkr 7y agoI noticed there's some confusion around the biological terms here (function in biology does not necessarily equal programming functions, this has nothing to do with mathematical functions or the lambda calculus), and this is my area of expertise, so I figured I'll try to do my best to clarify some of the biology here in laymans terms. I might be overexplaining some parts and underexplaining others, please let me know if it's clear. Here's what gain of function means in a biological context. When you have a mutation occur to a protein coding gene, one of two overall things can happen - nothing or something. Genetic code has some built in redundancies that mean that you can swap out some DNA base pairs and end up with the same protein in the end. If something happens, there's broadly two types of thing that could happen to the resulting protein. You could have a loss of function - where the gene basically breaks, or a gain of funciton - where the gene either works better or gains the ability to do something new. (Of course "nothing much happens" is also an option here if the new protein is similar to the old one). One important context this comes up in is cancer. You have genes in your genome that are actively stopping cancer from forming and spreading (tumor suppressor genes) as well as genes that would, if allowed to work unrestrained ( think a gene that signals for cell growth) would cause cancer (proto-oncogenes). A gain of function mutation in a proto-oncogene turns it into a cancer-driving oncogene, and a loss of function gene in tumor suppressors opens the door for oncogenes to do their work unrestrained. In the context of this virus, the authors identified a mutation in the spike protein (one of the important proteins in the virus involved in a lot of its biological processes including infeting a cell) that is not present in it's evolutionary cousins. Basically, this particular coronavirus spreading right now, even though it is very closely related to previous coronaviruses, seems to ahve this one bit in its genetic code that is starkly different, suggesting that this strain/subspecies/species picked up this mutation recently. Now, seeing that the new coronavirus has this genetic feature could indicate one of two things. Either, it's just an artifact of the founders effect where the small population of viruses that jumped from that bat or snake or pangolin to a human would have genetic differences just by chance, and because that small population got blown up to a huge population, the mutation is just along for a ride. Or, it could be a factor in allowing this species to succeed in the first place. OK, now to the actual mutation. The authors argue the latter - that this mutation might be important in the virus finding the success that it did. They basically found that this mutation leads to that part of the spike protein being more easily able to be cleaved (cut) by the protein Furin. This cleaving of the protein would better prime the virus to be able to infect cells and allow it to infect humans more specifically, and they note that Furin is highly expressed in the lungs as well. They note that a lot of experimental work has to be done to validate this, so it looks like they identified this computationally/with sequence analysis, but it could prove an important lead in terms of figuring out why is this coronavirus more infective than others in humans and provide a new therapeutic target for tackling this strain of the virus. So to summarize, there are many species of coronaviruses out there, including many related to this particular strain. In this strain, however, there's a mutation that seems to be unique to it. THis mutaiton is a "gain of function" mutation, meaning that it allows the spike protein the mutation is in to work better or get new functionalities compared to SARS/MERS viruses. (If it was a loss of function mutation - then you could reason that you would get something less infective since the protein wouldn't be able to work). The hypothesized mechanism of gain of function in volves of protein highly expressed in the lung that could help explain why it's so much more contagious than previous coronaviruses and also provide a target for therapeutic intervention. More experimental work needs to be done to validate it. I hope that was clear and noot too detailed or too high level - please let me know if any aspect was confusing and if that was a helpful explanation.
- halfdeadcat 7y agoInteresting article.This virus apparently developed a trick where it uses host proteases to clean its own viral envelope, allowing better fusion with host cells.
- SkyPuncher 7y agoI'm married to a doctor and have had some brief discussions about nCov with her over the past few weeks. This typically means sending her an article to have to explain it to me (not the case here). Here is my non-doctor take in non-doctor words - and possibly wrong. I've tried to source where possible. * Betacoronaviruses have four lineages (A-D). This is actually sourced. [0] * 2019-nCov is lineage B, which is the same as original SARS. MERS is lineage C. This is sourced as well. [0] * 2019-nCov has a "furin-like" cleavage site, which other lineage B betacoronaviruses do not. Sourced as the article for this thread. * I believe a cleavage site plays a role in how a virus binds to and enters a cell. Personal interpretation - could be wrong. * Based on Wikipedia, "Furin". I believe this means either (1) that the 2019-nCov has a cleavage site that requires modification to activate or (2) 2019-nCov has a cleavage site that resembles the human FURIN gene. I'm clearly out of my territory on this statement so fact check it yourself. * People developing treatments should consider this "furin-like" cleavage site for therapies as they "may" have implications on the virus lifecycle. From the source article. [0]https://www.nature.com/articles/s41564-020-0688-y https://www.nature.com/articles/s41564-020-0688-y ----- My personal take is identifying viruses treatments is a bit like writing a very complex pattern match in software. It needs to be specific enough to not kill good cells, but general enough handle uniqueness among individual virus cells. This articles seems to be identifying a unique pattern within 2019-nCov that people developing treatments should consider this. It may also be suggesting that the "unique" factor is hidden in some way. ---- What that means for any of us on Hacker News? I don't know.