
2019-nCoV may contain a gain-of-function for efficient spreading - deweller
https://www.sciencedirect.com/science/article/pii/S0166354220300528
======
johnwheeler
Edit: 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.j...](https://www.cdc.gov/homepage/images/banner/covid-19-1330px.jpg)

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?

~~~
zimpenfish
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.

~~~
rolph
yes you have it this is the concept.

------
deweller
Noteable 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?

~~~
fxtentacle
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.

~~~
fabian2k
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.

~~~
gazsp
Indeed:
[https://en.wikipedia.org/wiki/Furin](https://en.wikipedia.org/wiki/Furin)

------
_eigenfoo
I'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).

~~~
pmoriarty
From the HN Guidelines[1]:

 _" 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."_

[1] -
[https://news.ycombinator.com/newsguidelines.html](https://news.ycombinator.com/newsguidelines.html)

------
avip
Suddenly, everybody is a physician. Your fellow developer, who yesterday
couldn't find her package.json, walks around saying case fatality rate and
asymptomatic.

~~~
whatshisface
"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.

------
SkyPuncher
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.

[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.

------
halfdeadcat
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.

------
dfsegoat
Nitpick 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.

------
CyanLite4
In the microbial world, the mildest strains will survive the longest. Ideally
it would even become symbiotic to help fight antibiotic resistant bacteria.

~~~
samcal
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.

~~~
pingyong
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.

------
peter_retief
I came to read the comments to find out what this means. Is there anyone who
can translate this into something more understandable?

~~~
vikramkr
I 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.

------
kaffeemitsahne
I flagged this because the title was edited w.r.t. the actual article in a way
that nobody here seems to understand.

~~~
anyanswers
from 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. "

------
vikramkr
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.

~~~
peter_retief
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?

~~~
vikramkr
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...](https://www.nytimes.com/2020/03/01/health/coronavirus-washington-
spread.html)

------
gumby
Note that this is not sars-cov-2 (the virus that causes COVID-19) though
closely related.

~~~
mlavin
SARS-CoV-2 is the later, official name of 2019-nCoV.

~~~
gumby
Thanks, I am completely wrong so thanks for that and good thing my comment is
being voted down as it's too late to delete.

I'll stick to my discipline, fungal infections, in future!

------
JohnJamesRambo
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.

~~~
vikramkr
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.

