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
Gain-of-function literally only means the protein has, in some sense, gotten better at its "job" (or has taken on an additional "job"). In this case, the "job" of the protein is to infect organisms more effectively.
Some background: viruses primarily contain the genetic material and a protein coat. The Spike (S) protein is one of the proteins in the coat, and plays a role in whether an infection will take root.
From the paper:
> we identified a peculiar furin-like cleavage site in the Spike protein of the 2019-nCoV, lacking in the other SARS-like CoVs
Furin is a protease that is present in healthy humans. Some proteins aren't "active" until they're cut (cleaved) at specific sites along their sequence, so furin's "job" is to cleave these proteins - activating them. Notably, furin is highly expressed in the lungs.
2019-nCoV apparently has a "furin-like site" in its Spike protein - a sequence that furin can bind to and cleave. Notably, furin is the protease that cleaves one of the proteins in the protein coat of HIV, which then allows for viral replication [1]. The authors therefore hypothesize that this mutation which creates the furin-like cleavage site accounts for some of the pathogenicity of 2019-nCoV. They further hypothesize that furin inhibitors may be effective agents in combating the virus (which have shown some promise in combating other viruses, tumours, etc.).
Disclaimer: not a virologist, just a computational biologist with a bit of interest in structural biology. Also, the authors emphasize that further experimentation needs to be done to validate this claim.
Yeah, 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.
Gain of function describes a mutation in COVID-19 that causes it to do something new. This is different from most mutations, which are loss of function, causing it to stop doing something old.
The gain of function mutation is a cleavage site, which means that a new protein can be created, which could have some new activity. This cleavage site looks like a Furin cleavage site: Furin is associated with transporting proteins inside a cell, and thus with infection. So a drug targeting the Furin pathway may block the effect of this gain of function mutation, and make COVID-19 less infections to those taking it.
I think sampo gave a concise explanation- I tried to clarify the terminology and mechanics around gain of function-loss of function in my comment below (since I think function means different thing to different people) - basically, there's potentially a mutation in those spike proteins that makes the virus more infective if it turns out to be supported by lab experiements, gain of function just means that the mutation makes the protein work better or gives it a new functionality instead of breaking it.
tl;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).
> 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?
Some 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.
They 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.
The analysis they present doesn't require the integration of foreign RNA. 2019nCov has a SPRR motif, where other viruses has similar motifs (SRRK, KNRR, TPRS...). It can be explained with mutations, and in fact they talk about convergent evolution.
Small elaboration: it didn’t “merge in” this feature, it independently evolved it (“convergent evolutionary pathway”), which implies it’s a particularly handy feature for this virus to have. (For the virus, not so much for us.)
The 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.
> ...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
there 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.
Thank 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).
Yeah 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 :)
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).
"On-Topic: Anything that good hackers would find interesting. That includes more than hacking and startups. If you had to reduce it to a sentence, the answer might be: anything that gratifies one's intellectual curiosity."
also:
"Please don't complain that a submission is inappropriate. If a story is spam or off-topic, flag it. Don't feed egregious comments by replying; flag them instead. If you flag, please don't also comment that you did."
This 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.
It’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.
HN 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.
Suddenly, everybody is a physician. Your fellow developer, who yesterday couldn't find her package.json, walks around saying case fatality rate and asymptomatic.
"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.
I'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.
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.
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What that means for any of us on Hacker News? I don't know.
Interesting article.This virus apparently developed a trick where it uses host proteases to clean its own viral envelope, allowing better fusion with host cells.
In the microbial world, the mildest strains will survive the longest. Ideally it would even become symbiotic to help fight antibiotic resistant bacteria.
I 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.
I'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.
I 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.
This 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.
I tried to write up a longer comment breaking it down in laymans terms (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.
"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. "
I 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.
Thanks that was helpful.
I was wondering if the size of the virus population would increase the chance of further mutations with its "gain of function" mutation
Why do some viruses just seem to "disappear" - ie Spanish Flu?
Spanish flu didn't disappear, it broke out again in the 1970s and the 2009 flu pandemic was caused by another h1n1 strain of the flu. It died out initially because it had infected basically everyone it could reach (some 30% of the worlds population) and the survivors had developed immunity - as if they'd been vaccinated, and those sorts of viruses burn out fast. And to your point about further mutations, yes statistically having more viral particles out there does mean more chance for mutation to occur (the spanish flu is actually a good example of this, where a second wave of the same flu that had mutated to become deadly was actually responsible for most of the damage, and people that were exposed to the first strain before the deadly mutation were in general immunized against the second deadly strain). THere are concerns of coronavirus mutating as it spreads - there was some talk about having identified different subtypes of the current coronavirus pandemic with different lethalities but I don't remember off the top of my head if that ended up being the case. IN general, viruses will continue to mutate and accumulate genetic changes as they spread, and even though most of these changes will have no impact on infectivity/lethality (gain-of-function changes are rare, loss of function changes lead to a dead end, so the no-change mutations will pile up slowly), you can still use them to track disease spread/understand at what time people got the virus and where they got it from based on the substrain. Here's a NYT article on the coronavirus cases in washington where scientists used just that form of mutation tracking/evolutionary biology to figure out what the most likely explanation for how the virus made it to the state and how long it has been spreading is: https://www.nytimes.com/2020/03/01/health/coronavirus-washin...
While 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.
This 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.
Not 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.
IF 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.
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.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?