COVID-19 Mutations

Scuttlebutt
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I readily admit that science doesn’t have firm answers yet for a LOT of questions about this relatively novel virus. And of course even the science can’t say anything for sure about a phenomenon that hasn’t yet happened. It can only make predictions based on past similar experience, which is exactly what informed people are doing in the case of “herd” immunity with this virus. And I note that your cited experts from J.H. didn’t have any quibble with the likelihood of herd immunity, just the cost in terms of morbidity, mortality and time required to achieve it

But we can be pretty sure from clinical observations and reporting so far that a large number of people fully recover and stop shedding live infectious virus after a variable period of time that usually does not exceed 2 weeks (it’s a gaussian curve and a noteworthy few are still shedding virus at a month). And this clinical recovery and eventual end to virus shedding is accompanied at about 2 wks post infection with a sharp rise in the Ig M (immunodeficiency-globulin M) curve. And at about the time that peaks the Ig G curve begins to rise and can rise for several weeks to a month…somewhat correlating with how long it takes to purge the virus. These are all observed facts AND are very much consistent with just about every other virus infection/recovery cycle that we’ve ever seen.

Now we don’t have enough data yet to say with absolute certainty that, in the majority of these cases, the patient’s Ig G is “neutralizing” and kills the virus in cell culture. But we do have some small number of good clinical observations that it kills the virus in OTHER PATIENTS, because the small pilot studies done so far on convalescent plasma treatment have mostly resulted in improvement. So based on all the fragmentary and incomplete data and past observations, it appears that very likely that infection with this virus DOES indeed cause immunity in the person infected. And immunity that can even be transferred acutely by means of convalescent plasma.

The other piece of evidence from past experience is that viruses that don’t confer good immunity on their hosts do not go away (eg: HIV, Hep C, Herpes simplex) in the absence of strong anti-viral therapy. So far there have been only a few anecdotal cases of people shedding virus for an extremely extended period or recurrently after testing negative. In none of those cases or small series that I’ve seen (and I’m following the JAMA & NEJM every few days) have any serous investigations yet been done to establish whether these were continuing or new virus infections (can be told from the virus RNA) or what the immune status of the patients was (immune deficiencies lead to weak or no immunity.

And of course there’s no evidence yet of this immunity that appears to be developing will be very durable. It MIGHT only last a period of months, which would not be good for herd immunity to develop. But the more common short end of the range of naturally acquired viral immunities is usually at least a year or so (and the long end of the rang is lifetime).

So, all in all, at this point it appears very likely that there will be SOME immunity out there in the “herd” of people who’ve had this infection and recovered (the VAST majority of those infected). But just how good, and how long we just won’t know for quite awhile.

Meanwhile, barring herd immunity, and barring artificial immunity conferred by vaccine (will be awhile) or immune globulin (probably not practical for the masses), this virus will continue to infect humans until either it reaches a level where potential remaining victims are just too sparse (“herd” immunity) OR the virus changes by means of genetic drift. The virologists are telling us that this virus appears relatively stable (compared to, say, “common cold” viruses and maybe even influenza viruses) so the first would appear more likely than the second.

As they say, “time will heal all wounds and answer all questions.” I’d say the two leading horses in this race are a successful, widely available vaccine racing against herd immunity.

PS: By the way, I saw Trump on TV strongly suggesting that “we’ll have a vaccine by the end of the year.” NOTHING YET published in the medical literature or even medical “news” via professional source would support THAT much optimism. I HOPE he’s right, both for our sake and his. Even though, if you listened carefully, he didn’t guarantee it, people will remember it and say “he promised us a vaccine by now” if we get to the end of the year without one.

PS: I went back and read this a couple of days later and I caught an unintentional error (reversal!) that probably doesn’t mean much to most people, but anyone up on their virus immunology would think I didn’t know what I was talking about if they read it. That is, I reversed Ig G & Ig M in talking about when the immune globulins produced by the body start to appear. “M” comes first and may be somewhat non-specific for the particular virus. “G” comes up later and is pretty virus specific and, hopefully, “neutralizing” which means is kills the virus (makes it unable to reproduce or spread). Sorry, I hope I didn’t confuse anyone or make anyone’s kid make an error on his hi-school biology report! I just reversed it due to a mental slip! I have made the correction above.

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Does that mean that the range of mutation as reported in this article is not large enough to be considered significant, or are you talking about something entirely different?

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Well, mutation technically means any change in the genetic code (in the case of coronaviruses, their code is “written” or recorded in repeating cycles of “bits” of data in the form of 3 “nucleotides” (the “N” in RNA). Without getting too far into the technical weeds, the code is written w. 4 repeating letters: A, C, G & U for RNA (A,C,G,T for DNA) grouped into groups of 3. EACH “bit” of 3 letters specifies one particular amino acid of the 20 possible amino acids that can be linked into polymer chains to form a protein.

SO, if you get ONE letter changing, in a group of 3 (out of thousands and thousands of groups of 3 in the viruses RNA genome), technically you’ve got a mutation. But changing ONE amino acid in a protein polymer that can have thousands and thousands MAY (often, usually) will NOT significantly change the physical or functional characteristics of the virus in any detectible way, But changes of even just one letter out of many thousands CAN BE DETECTED by doing what’s called a “full RNA sequencing” of an intact virus.

These single letter change mutations (called “SNPs” for "single nucleotide polymorphisms) can and do occur every few to many generations (locations on the genome vary in stability) in humans the same ls likely true for most viruses. It’s one way humans can trace their ancestry back with DNA to see how far back they have a common ancestor with another person. And ditto for viruses. But remember you’re going to have a least a couple of hundred generations of a virus pass thru your body during one episode of infection!! But tracing these SNPs is one way that the virologists can tell us things like the predominant virus “strain” (RNA pattern) on the West Coast appears to have come (directly) from China and the predominant strain on the East Coast appears to have come from Europe (on the way from China). (not sure if that’s still the prevailing hunch but it WAS a week or so back).

The other kind of “mutation” or RNA/DNA change that occurs is in “repeats” (“STRs” or short tandem repeats in humans because our DNA, in the inactive state, is stored with a mirror image chain of duplicate code “paired up” as two chains; in a single stranded RNA virus like a coronavirus there’s no paring of the codes but there can still be, and are, short segments of code that seem to repeat over and over. The function of this repetitive code is not at all clear in many cases. But it appears that it is part of the exceedingly complex set of mechanisms that our genetic code has to have “backups and repair abilities.” At least that’s what some think. Other’s think it may be just junk from a copy/backup system working overtime. (personally, I’d bet on the former).

ANYWAY, these SR’s (short repeats) can be COUNTED in a give set of RNA. And individual generations vary in the COUNT or number of repeats. In humans, the STR count can vary up to every generation and will almost certainly vary (increases) every few generations. Again, they vary according to location on the genome.

So the most common mutations (short repeats & single nucleotide (letter) variations) are VERY common and usually just make succeeding generations identifiable from one-another without making them significantly physically (phenotypically is the techie word) different or functionally different.

But at these mutations accumulate, EVENTUALLY enough micro change in the amino acids of key proteins accumulates that the organism begins to “drift” into being SOMETHING ELSE. And that something else may be enough different that your immune system, which had the mug shots and fingerprints of the first perp, DOESN’T recognize the thug after his RNA has had “plastic surgery.”!! (you get the point).

Sometimes the process happens slowly, sometimes it can happen VERY rapidly. After the fact, like with the influenza viruses, the virologists can go back and SEE EXACTLY what the change or changes were in the genetic code that made it a “new virus”, but they are virtually impossible to predict. Although certain families of viruses are very “unstable” in this way and changing frequently (common cold viruses have this rep.), but this SARS branch of the coronaviruses (SARS, MERS, SARS-2) has been tentatively pronounced “relatively stable” genetically by the guys who should know. One can only hope they’re not just doing wishful thinking!!

PS: I wrote that off the top of my head w/o reading your article first. Excellent article! The graphics sure help explain a lot that is hard to get across with just words!! I don’t think that article and I disagree on any major point. They kind of answer your question toward the end without coming right out and saying it. But YES, nobody’s finding enough change (yet anyway) in the viruses harvested from this epidemic to think that natural acquired immunity (from having it) or acquired immunity (from a vaccine) won’t be reasonably durable. It SOUNDS like it might be MORE durable than influenza immunity but it will be a long, long time before things settle down enough that a level playing field comparison of that could be properly done.

PPS: Thinking about my post after re-reading it. And some of you guys are tough editors and don’t miss stuff. So, someone’s gonna ask: “Are those the ONLY two ways mutations occur.” And the answer is NO. Those are the common everyday variety. But there are numerous other, less frequent screw-ups that can occur in the reproductive machinery of the virus (which is just a fraction of what’s needed to make new virus). Basically, the virus has just enough “command and control code” to take over and co-opt the host cells machinery which is what actually makes the new viruses. Most major foul-ups in setting up the machinery and doing th copying result in death of the host cell and the invading virus with it, with no offspring. But there definitely is some middle ground between “minor” and “fail” that can once in awhile result in a major change in the end product.

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Thank you for your well crafted explanation and welcome back after a long absence. Hope you’re doing well in these ‘interesting times’.

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At 78, my own advice to myself is to keep hidin’ out! This CAN be bad stuff for people my age. BUT I’ve had one med. school buddy who thought it was just a cold until he got tested. He said he’d barely call it “sick.”

THAT is the REALLY BIG unsolved mystery of this virus. It’s NOT JUST age, or any particular health aberration or infirmity that predicts who does bad. There is no answer yet, but based on the informed speculation I’ve been reading, I’m guessing that a HOST genetic factor (or combination of genetic factors) is going to prove to be an important key to the mystery. Something that isn’t a big issue when you’re young and healthy but becomes much more dangerous when you aren’t. Possibly something that accumulates in the body with aging, but maybe to a variable degree.

One thing that is tied up in this in some way is our blood vessel muscle regulation (vasoconstriction muscles). That is predictable because the viruses’ target attachment point is a receptor that normally functions in the system of internal chemicals (hormones) that regulate blood pressure and blood flow to the kidneys. Time will tell.

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I’ve read about a marathon runner in his 40’s who was put on a ventilator & people with no underlying health problems dying with covid19. But there’s plenty of stories like your elderly friend, centenarians & obesed smokers who only had minor symptoms. Only time will tell what’s the mystery with covid19 but considering HIV/AIDS has been around for 40 years & it hasn’t been eradicated yet we might have a long wait. I wouldn’t be surprised if different strands are more deadlier than others? That would explain why different cities in the same country with similar standards, equipment & practices would have higher & lower mortality rates than others.

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Now I’m reading that the strain that mutated in Europe and is the prevalent version in the US is more contagious.

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Well there’s plenty of evidence of many “strains” identifiable by the small mutations we were talking about. But as far as I’ve seen in the professional stuff in the couple of major journals I follow (JAMA & NEJM, which do a pretty good job of publishing the major stuff and reporting things published elsewhere if they think they’re significant), no one has published any convincing data of a strain that DIVERGES, clinically (ie in the way if behaves in disease causation).

But there is LOTS & LOTS of speculation out there, a good bit of it from well trained physicians on the front lines treating patients but not necessarily collecting data in a research way, that SOME of the great VARIATION that we see in the course and severity of the disease MIGHT be due to variation in the virus. And some of that speculation is being picked up by reporters talking to a lot of potential SOURCES for a story.

But there COULD be good alternate explanations for the variations even if it’s not due to variation in the virus (eg: environmental and community differences causing variation in how it spreads, “host factors” or differences in people causing variation in how it affects people and how well the deal with it).

So far, I have not seen anything convincing out there that shows we’re dealing with divergence into 2 or more kinds of coronavirus.

That said, I did see a medical news report last evening (and it was on Fox news too) about a virologist, I believe at the U. of AZ, who identified ONE VIRUS (out of thousands he sequenced and gazillions of ones out in “the wild”) that showed a MUTATION at a very specific point in the virus that is know to affect a very specific enzyme crucial to the viruses ability to infect a cell. AND, confirmed that this is the SAME mutation that they THINK may be the mutation that widely spread with the SARS virus that caused it to suddenly die out.

Now that sound exciting, but it’s not as significant as it sounds. Every patients infected produces millions and millions of new viruses (most of which die). The total number of COVID-19 viruses out there, each of them POTENTIALLY infective…at least for a time…must be a number with a LOT of zeros behind it. Something like the number of silicon atoms on a few miles of sandy beach!!

So, finding ONE virus that showed, with RNA sequencing (writing out the entire genome of the virus), this suspected key mutation that could end the career of this virus suddenly is NOT a big deal in and of itself. It DOES SHOW that this potentially damaging mutation that they suspect truncated the SARS epidemic is CAPABLE of occurring in this COVID-19 (SARS-2) virus. But the mutation would have to happen WIDELY in the population of the virus to make it go extinct (near extinct would be good enough).

Remember the old story about getting “enough monkeys sitting at enough typewriters and you’ll eventually have one of them produce…” (fill in here what you want: The Lord’s Prayer, a Shakespeare sonnet, whatever).

The point being, we now appear to have evidence that this virus is, like its cousin SARS, vulnerable to some degree to this mutation that they THINK may have been the Achille’s heel of SARS. How likely that is to happen, at least in time to save SOME of our bacon, is ANYBODY’S GUESS!!

PS: I’ll just add a footnote that I find interesting and that MAY OR MAY NOT be related to the subject of the virus mutating into something less virulent. Some time ago I saw a mention of this Israeli scientist Yitzhak (or Isaac) Ben Israel, who is an Israeli academic and government advisor in the filed of physics and mathematical analysis & modeling. HE said, fairly early on, that his mathematical analysis of the growth curves of the new case rates of COVID-19 in EACH of the countries of the world that were reporting suggested the SAME EXACT mathematical pattern of rise, plateau and fall (though of course of different magnitudes) REGARDLESS of whether or not they had taken mitigation measures or, if they had, how strong they were. He said the pattern suggested that after 60-70 days, the curves all showed signs of downtrends to extinction.

He published this in a paper (in Hebrew but also wrote his own English translation) where he admitted he was not a biologist and had NO CLUE as to WHY the virus behavior curves all had the same mathematics. But he suggested the virologists ought to look into it. His paper was mostly greeted with guffaws by the professional virologist community and the epidemiologists. I watched for the US media to pick up on it but never saw it. Some of the US physician’s newsletters picked it up, which is how I saw it. Googling on it produced mainly article in the Israeli press.

This came out fairly early in the course of the US epidemic and a lot has happened since then. Watching, I have not seen any more of Dr. Ben Israel, either to confirm or retract. But a few days ago, I saw a US academic (theoretical chemist, again outside his field) who advanced a similar idea, less specific about time course but based on much more up to date data. He didn’t mention Ben Israel’s paper, but said he was seeing a similarity in the downturn curves across a WIDE variety of areas with a WIDE spectrum of control measures. Here’s the original (news) article by Ben Israel (from Israeli Times) and the US article by the chemist.

https://www.timesofisrael.com/the-end-of-exponential-growth-the-decline-in-the-spread-of-coronavirus/

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The tentative conclusions I read about suggested that the Euro/US strain was not more virulent than the original, only more infectious.

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I’m not prone to quibble about terminology at all. But that word “virulent” has an interesting usage. If you look in the dictionary online, you’ll see that it has special definitions in “medicine” and “microbiology” (which includes virology). In medicine, it implies severity of a disease, but in microbiology it implies “highly infective.” I think I instinctively use it that way, but I had never actually looked it up before. When I used it in that post, I really meant BOTH.

I have seen that same thought expressed early on from the Chinese, but from your link is sounds like the Los Alamos people have narrowed it down to some sense of WHAT the mutation did (make the spike protein more effective at binding to the target cell), which is new information for me.

Certainly makes sense that being more effective at binding to the target would make the virus more effective at spreading. And that would cause it to gradually out-compete its ancestor virus that had the less effective binding. Darwin in action right before our very eyes!!

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A good summary, published in the past 24 hrs., of the notable (as opposed to minor and common) mutations detected in SARS-2 coronavirus causing COVID-19. Note the comment about the argument for and against the improved spreading with the mutation we’ve been discussing. But it IS becoming more common, so something is making it reproduce itself faster. The ORF7a & ORF8 gene deletions (which is included in “mutations”) are MAYBE potentially more significant in terms the virus (bad for it/good for us!)

The whole idea if a virus mutating so as to kill itself off is an iffy one. Evolutionary selection SHOULD make the virus evolve to be better and better at reproducing itself. Fortunately, the may include mutations that may make it less likely to kill it’s host (but still infect and reproduce efficiently). But there’s a LOT we don’t know or fully understand about the details or reproductive genetics.

Something sometimes makes mutations that are clearly harmful nevertheless remain in or even rarely spread in a population. We also don’t understand a LOT about how our immune memory works and is stored. There is one theory that SOME immune memories could be passed between generations.

Certainly populations that have contended with certain infections for many generations are more resistant, in ways we don’t fully understand, to infections that can devastate historically sheltered populations. Just ask the Native Americans about how they handled measles and smallpox. That MIGHT apply going the other way to syphilis and the Europeans, but that controversy has NEVER been settled.

As an interesting footnote for those who care: there ARE in fact viruses that infect bacteria and kill them. Called bacteriophages (because something was eating the bacteria in the lab’s culture!). They are typically VERY large viruses (on the threshold of visible with light microscope) and were the first viruses that were directly “discovered”, although the presence of invisible infectious agents was suspected by some for a long time.

Another interesting thing that sheds some light on today’s situation as far as how we THINK we KNOW things that later turn out to be 180 deg. wrong. At the time of the 1918 flu epidemic, “virus” meant an invisible infectious agent that was still infectious after passing the fluid (or whatever) from an infected person through a filter that removed all (then known and visible) infectious agents.

Viruses were thought by some to be LIQUIDS rather than the protein “crystals” that they actually are. around 1910 smallpox virus had been rudimentarily “cultured” or grown on some fresh pig tissue with living cells (ie: cell death suggested that the virus was reproducing). But other than that, viruses had not been identified, seen, cultured or characterized chemically AT ALL.

However, a German bacteriologist name Pfeiffer had isolated a bacteria (with great difficulty of reliable recovery and culture) from cases of “influenza.” It was initially called Pfeiffer’s bacillus but, when it was frequently (but not always) found in cases of influenza, it came to be named “Hemophilus influenzae” (“H. flu” nowadays, your kids get vaccinated for it).

H. flu was also known to cause meningitis and other infections. Certain strains of streptococcus were also frequently found in cases of influenza, especially those that died with pneumonia. In the absence of knowing anything about the Influenza Virus, the “EXPERTS” were pretty sure that one of these two bacteria was the CAUSE of most cases of influenza.

During the epidemic, vaccines and immune serums were made specifically using pure cultures of these bacteria (which would induce immunity only to those bacteria) and were urgently and widely distributed. Many, many reports of “cures” and “only 2 case out of 1200 sailors on a warship” with a flu outbreak were widely reported. Turns out, those bacteria were what is called “opportunistic secondary invaders.” Many times they may well have played a role in driving a few nails into the coffin of influenza fatalities. But we know from modern experience and antibiotic treatment of bacteria that pure flu alone CAN kill you.

The POINT of the whole story is that we are, in SOME ways, almost as ignorant about SARS-2 virus today as the EXPERTS were in 1918 about the influenza virus. Fortunately, we’ve got a good leg up on them, and the tools we have to work with are so far beyond what they even dreamed of in 1918 that they would think it was science fiction. But we are made of the same stuff that they were. We can be thankful that we stand on their shoulders!

(influenza virus was first “discovered” in the early '30’s in pigs and cultured from a human case a few years later; an early killed virus vaccine was developed for the Army in 1944)

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