Tag Archives: SARS-CoV-2

Some very disturbing pictures

Granted that these pictures look like microscope slides containing colored blobs, but once you understand what they show, the implications are quite frightening.

These images are biopsies of various portions of the gastrointestinal tract in a person who had become  symptomatic  three months earlier with COVID-19 from which the person  has now recovered).The green blobs represent fluorescent antibodies binding to the nucleocapsid protein of the pandemic virus (SARS-CoV-2).  They are found in the enterocyte cells which line the inside of the gut.  These are the enterocyte which live for just 5 days before they are shed.  

This is my first shot at getting pictures into my blog, and they do appear blurry (apologies !).  I will try to correct this. All you need view is in the first and second columns of rows a, c, and e as most  of the rest are controls. The pictures are from a Nature paper — here’s a link — https://www.nature.com/articles/s41586-021-03207-w.pdf

 

Why is this disturbing?  Because their presence implies that they have been made continually for the whole three months, as enterocytes are born and die. 

Well maybe it’s an artifact confined to one patient.  Unfortunately similar findings were present in 5/14 cases recovered COVID-19 patients who received GI tract biopsies for clinical reasons unrelated to COVID-19.  The 14 are from a larger series of recovered COVID19 patients (see the copy of the previous post below). Like Reverend Paley’s found watch, the presence of the viral nucleocapsid protein demands an explanation of what had to be present to put it there.

There are a series of requirement for this to happen.  The messenger RNA for the protein had to be made and present, which, in turn means at the least that the viral gene from which the mRNA for the nucleocapsid protein was made must also be present.  What mades nucleocapsid mRNA? The viral RNA dependent polymerase. So the polymerase must be present as well, along with the 3 genes coding for the 3 proteins making up the polymerase.  Not only that but all of the above must have been present in longer lived cells  than the enterocytes.

Defective viruses certainly appear during the course of viral infection (particularly as in AIDS), but it is very scary to realize just how much of the virus must be present and functioning to produce just these findings. Perhaps the fluorescent antibody was really binding to another protein, not from the virus at all.  After all, antibodies aren’t always as specific as we’d like them to be.  

However, the authors did something else which makes this much less likely. They wrote, “In addition, viral RNA was detected by in situ hybridization in biopsy samples from the two participants who were tested for it”

Further scariness:  Pictures e and f show the nucleocapsid protein is present at the far end of the terminal ileum (small intestine) a part of our GI tract which is 22 feet long

So this person although well, was literally crawling with both the viral protein and the machinery necessary to make it. 

Are many more, or all such people who are clinically recovered from clinical COVID-19 excreting infectious virus?  I’m sure people have looked, and if they haven’t they should be. 

I’m going to now insert the previous post on the subject.  It contains a link to the Nature paper, so feel free to follow it and look for yourself.  It contains a lot more detail. 

Is the virus still within you? Will it cause trouble?

Let’s say you’ve recovered from a bout with COVID-19. Is the virus still with you? Could it come back and cause trouble? Given the data in a recent paper [ Nature vol. 591 pp. 639 – 644 ’21 ] — https://www.nature.com/articles/s41586-021-03207-w.pdf, it’s quite possible.

But first a story about my grandmother.  She was born somewhere around the Baltic Sea in 1880 and came to America in 1893.  She died of undiagnosed (hence untreated) miliary Tuberculosis in a University Hospital in 1967.  Just about everyone in Europe in the 1880s was exposed to TB and just like SARS-CoV-2 many if not most were asymptomatic.  Their lungs walled off the organism in something called a Gohn complex — https://en.wikipedia.org/wiki/Ghon%27s_complex.  The organism didn’t die — and probably broke out of the complex as my grandmother aged and her immune system got weaker and weaker.  It is very unlikely that she picked it up by exposure in the 1960’s.  As they say TB is forgotten but not gone.  

Which brings me to the Nature paper.  At first I thought it was great and very optimistic.  Some 87 people from New York City who had symptomatic SARS-CoV-2 infection (proven by finding the viral genome using RT-PCR technique).  The authors studied the antibody responses at an average of 1.3 and 6.2 months after infection.  Although the antibody levels dropped (which always happens) they changed so they bound the virus more tightly.  This is called affinity maturation — https://en.wikipedia.org/wiki/Affinity_maturation.  

So that’s good? 

No that’s bad because it implies that the protein stimulating affinity maturation is still around. The authors note the persistent antigenic stimulation of the immune system is possible because an “antigen trapped in the form of immune complexes on follicular dendritic cells .. . . . can be long-lived, because follicular dendritic cells do not internalize immune complexes”.  

Well maybe, but the paper gives evidence for another mechanism of antigen persistence (which I find more persuasive). 14 of the people had intestinal biopsies for appropriate clinical indications (see Table 7 in the supplementary information of the article). In some of the biopsies they detect viral antigen in some of the enterocytes (cells which line the inside of the gut) — I’m assuming the antigen is the viral spike protein, but it’s hard to find exactly what it is. 

This is quite bad, as the lifetime of the enterocyte is 5 days.  This means that the antigen is being continually produced, which means that the mRNA for the antigen is being continually produced, which in turn means that the viral genome is still around.  The mean lifetime of cellular mRNAs is 10 hours although some hang around for days, however I doubt that the mRNA responsible for the viral antigen had lasted for 2.8 to 5.7 months which is the time after clinical infection when the biopsies were done. 

So it is possible, that like TB in the Gohn complex, the immune system has fought the virus to a draw, but that the intact organism could be still present.  As in my grandmother, it is possible that the virus will reappear as the immune system weakens with age (something that happens in all of us). 

In that case we wouldl have recrudescence not reinfection. 

PS:  My grandmother came to this country at age 13 alone and speaking no English.  Every time I feel sad at what the pandemic has put us all through, I think of that generation.  

PPS: When she got sick, I wanted to put her in the hospital where I was an intern, but our family GP (Dr. Richard A. Gove) told me taking care of my own family was a very bad idea and put her elsewhere.  I doubt that I’d have made the diagnosis, or that anyone at our hospital would have. 

PPPS:  I don’t know if they still do autopsies, but I was always able to get one after I’d tell families of the deceased about my grandmother.  It meant that my wife and I and our two little kids were all screened for TB. 

PPPPS — a friend brought up the following — Eleanor Roosevelt, who was thought to have aplastic anemia, was treated with prednisone and later found to have died of military tuberculous, probably the recurrence of tb acquired some 4 decades earlier.

 

 

Is the virus still within you? Will it cause trouble?

Let’s say you’ve recovered from a bout with COVID-19. Is the virus still with you? Could it come back and cause trouble? Given the data in a recent paper [ Nature vol. 591 pp. 639 – 644 ’21 ] — https://www.nature.com/articles/s41586-021-03207-w.pdf, it’s quite possible.

But first a story about my grandmother.  She was born somewhere around the Baltic Sea in 1880 and came to America in 1893.  She died of undiagnosed (hence untreated) miliary Tuberculosis in a University Hospital in 1967.  Just about everyone in Europe in the 1880s was exposed to TB and just like SARS-CoV-2 many if not most were asymptomatic.  Their lungs walled off the organism in something called a Gohn complex — https://en.wikipedia.org/wiki/Ghon%27s_complex.  The organism didn’t die — and probably broke out of the complex as my grandmother aged and her immune system got weaker and weaker.  It is very unlikely that she picked it up by exposure in the 1960’s.  As they say TB is forgotten but not gone.  

Which brings me to the Nature paper.  At first I thought it was great and very optimistic.  Some 87 people from New York City who had symptomatic SARS-CoV-2 infection (proven by finding the viral genome using RT-PCR technique).  The authors studied the antibody responses at an average of 1.3 and 6.2 months after infection.  Although the antibody levels dropped (which always happens) they changed so they bound the virus more tightly.  This is called affinity maturation — https://en.wikipedia.org/wiki/Affinity_maturation.  

So that’s good? 

No that’s bad because it implies that the protein stimulating affinity maturation is still around. The authors note the persistent antigenic stimulation of the immune system is possible because an “antigen trapped in the form of immune complexes on follicular dendritic cells .. . . . can be long-lived, because follicular dendritic cells do not internalize immune complexes”.  

Well maybe, but the paper gives evidence for another mechanism of antigen persistence (which I find more persuasive). 14 of the people had intestinal biopsies for appropriate clinical indications (see Table 7 in the supplementary information of the article). In some of the biopsies they detect viral antigen in some of the enterocytes (cells which line the inside of the gut) — I’m assuming the antigen is the viral spike protein, but it’s hard to find exactly what it is. 

This is quite bad, as the lifetime of the enterocyte is 5 days.  This means that the antigen is being continually produced, which means that the mRNA for the antigen is being continually produced, which in turn means that the viral genome is still around.  The mean lifetime of cellular mRNAs is 10 hours although some hang around for days, however I doubt that the mRNA responsible for the viral antigen had lasted for 2.8 to 5.7 months which is the time after clinical infection when the biopsies were done. 

So it is possible, that like TB in the Gohn complex, the immune system has fought the virus to a draw, but that the intact organism could be still present.  As in my grandmother, it is possible that the virus will reappear as the immune system weakens with age (something that happens in all of us). 

In that case we wouldl have recrudescence not reinfection. 

PS:  My grandmother came to this country at age 13 alone and speaking no English.  Every time I feel sad at what the pandemic has put us all through, I think of that generation.  

PPS: When she got sick, I wanted to put her in the hospital where I was an intern, but our family GP (Dr. Richard A. Gove) told me taking care of my own family was a very bad idea and put her elsewhere.  I doubt that I’d have made the diagnosis, or that anyone at our hospital would have. 

PPPS:  I don’t know if they still do autopsies, but I was always able to get one after I’d tell families of the deceased about my grandmother.  It meant that my wife and I and our two little kids were all screened for TB. 

PPPPS — a friend brought up the following — Eleanor Roosevelt, who was thought to have aplastic anemia, was treated with prednisone and later found to have died of military tuberculous, probably the recurrence of tb acquired some 4 decades earlier.

 

 

 

600,000 Pandemic deaths in the United Kingdom ! ! !

Yes, 600,000 pandemic deaths in the UK given their attack rate of 182/100,000 and a population the size of the USA (328 million) actually it’s even worse than that because their case fatality rate is 2.9 % and ours is 1.8% — so multiply the 600,000 deaths by 1.6 and you get a million deaths in the UK given their attack rate and case fatality rate (and scaling their population to match ours).

Where are these numbers coming from — the same place that those in the previous post came from — https://coronavirus.jhu.edu/data/mortality, Johns Hopkins. 

Here are the top ten attack rates per 100,000 population from the previous post

181.70, 180.83, 158.39, 155.25, 152.49, 143.61. 142.73, 140.98, 124.72, 118.50

You were asked to guess where the USA, and the UK were.  No the USA is not at the top, but in the middle (hardly great but not as bad as the 500,000 headline would imply).  The UK is at the top. 

Here are the 10 countries (alphabetized) from which these rates were drawn

Czech Republic, France, Italy, Mexico, Peru, Portugal, Slovakia, Spain, United Kingdom, USA

Here are the case fatality rates (in percent) from the same 10 countries

8.8, 3.5, 3.4, 2.9, 2.3, 2.2, 2.1, 2.0, 1.8, 1.7

The UK is 2.9 and the US among the lowest at 1.8  

Not what you’ve likely been led to believe.  

There are worse problems afoot for the USA.  Granted the following  are 3 small and nonrandomized samples, but the minorities who need it the most aren’t getting the vaccine (and not because it is being withheld from them).

Sample #1 Yrs Trly and wife second shot yesterday —

My wife and I received the booster dose of the Pfizer vaccine today. We live in a town that is 45% Latino (mostly Puerto Rican). Both times we were there, the vaccinees were almost all Caucasian, a disaster in the making. The nurse I spoke with said that what we’d seen about Latinos not getting vaccinated was typical in her experience. She also noted misinformation going around among them, such that vaccination would make you sterile.

Sample #2 a friend who was vaccinated elsewhere (but in the same metro area)- “That was my experience at the State Curative site at XXXXXXX. Large African-American population in that area; however, only caucasians getting the vaccines on both occasions. Puzzling.”

Sample #3 a college classmate and friend –Welcome to the club. I received my vaccine through Hopkins as a practicing clinician. My wife received hers as a DC resident through the DC Government in a Black neighborhood; all of the vaccinees there were whites from Foggy Bottom and Georgetown. the DC Government then got smart and has been allocating vaccine by specific neighborhood.

Now there was a giant article in the 4 January New Yorker by Lawrence Wright blaming the magnitude of the pandemic on Trump’s not pushing mask wearing. 

Well here’s our Vice President — https://abc7ny.com/vice-presidential-debate-vp-2020-kamala-harris/6852144/

Harris was asked if Americans should take the vaccine and if she would. Harris says that if doctors “tells us that we should take it, I’ll be the first in line to take it, absolutely. But if Donald Trump tells us that we should take it, I’m not taking it.”  Well he did tell us exactly that. 

Is it her fault that minorities aren’t taking the vaccine?  Don’t wait for the New Yorker to take up the issue. 

 

Virus 1 Astra Zenica vaccine 0

It’s already happened. A mutated pandemic virus has rendered a vaccine useless. This is serious — the game of cat and mouse with the mutating pandemic virus (otherwise known as natural selection) has begun. You can read all about it here

For a leisurely stroll through the background needed to understand the Science and Nature articles I’m going to essentially republish (and refurbish) a very recent  post — trying to make things as accessible as possible. 

The human species as a culture medium for the pandemic virus

Creationists or not, we are all about to get an unwanted lesson in natural selection and evolution, courtesy of the current pandemic virus (SARS-CoV-2).  This is going to be a long post, which will contain an incredible case of meningitis, thoughts on selfish genes in viruses, evolution, natural selection and why we’re in for a very, very long haul with the pandemic virus.

As you probably know, mutant pandemic viruses (all different) have emerged (in England, South Africa, Brazil).  Even worse they appear to be more infectious, and some are more resistant to our vaccines (all of which were made before they appeared).  

Here is lesson #1 in natural selection.  Viruses have no brains, they barely have a genome.  The human genome contains 3 billion positions, the pandemic virus 30,000.  So we have 100,000 times more information in our genome than the virus does. 100,000 is about the number of inches in a mile and half.  

So how is the virus outsmarting us?  Simply by reproducing like mad.  The molecular machines that copy our genome are very accurate, making about 1 mistake per 100,000,000 positions copied — that’s still enough for the average newborn to have 30 new mutations (more if the parents are older).  The viral machine is much less accurate.  So lots of genome mutations are made (meaning that the viral proteins made from the genome change slightly).  Those that elude the vaccines and antibodies we’re throwing at them survive and reproduce, most don’t.  This is natural selection in action. Survival of the fittest.  Darwin wasn’t kidding.

What is so remarkable about the British and the South African variants, is that they contain multiple mutations (23 in the British variant, at least 3 in the South African variant).  Usually its just one or two.

 You’ve probably heard about the mutation changing just one of the 147 amino acids  in hemoglobin to cause sickle cell anemia. Here’s another.  APOE is a 299 amino acid protein.  It comes in 3 variants  — due to changes at 2 positions.  One variant greatly increases the risk of Alzheimer’s disease, another decreases it.  So even single mutations can be quite powerful. 

So how did these multiple mutations come about?  We likely now have an answer due to one very well studied case [ Cell vol. 183 pp. 1901 – 1912 ’20 ] in an immunocompromised patient with chronic lymphatic leukemia (CLL). She shed the virus for 70 days.  Even so, she wasn’t symptomatic, but because the patient had enough immune system to fight the virus to a draw, it persisted, and so its genome was always changing.  The authors were smart enough to continually sequence the viral genome throughout the clinical course and watch it change.  So that’s very likely how the virus accumulates mutations, it lived for a long time in a patient who lived a long time with a weakened immune system allowing the virus to merrily mutate without being killed and allowing the weakened immune system to effectively select viruses it can’t kill. 

Could this happen again? Of course.   There are some 60,000 new cases of CLL each year in the USA.  Many of them have abnormal immune systems even before chemotherapy begins.

Here is an example from my own practice. The patient was a 40 year old high school teacher who presented with severe headache, stiff neck and drowsiness.  I did a spinal tap to get cerebrospinal fluid (CSF) for culture so we could find the best possible antibiotic to treat the organism.  This was 30+ years ago, and we had no DNA testing to tell us immediately what to do.  We had to wait 24 hours  while the bugs grew in culture to form enough that we could identify the species and determine  the antibiotics it was sensitive to. . 

As the fluid came out, I had a sinking feeling; as it was cloudy, implying lots of white cells fighting the infection. Enough white cells to make CSF cloudy (it normally looks like water) is a very bad sign. So after starting the standard antibiotic to be used in the first 24 hours before the cultures came back, I called the lab for the cell count.  They said there weren’t any.  I thought they’d seriously screwed up maybe losing what I’d sent or mislabeling it and looking at the wrong sample, and I unpleasantly stormed down to the lab (as only an angry physician can do) to see the spinal fluid.  They were right.  The cloudiness of the CSF was produced by hordes of bacteria not white cells.  This was even worse as clearly the bacteria were winning and the patient’s immune system was losing, and I never expected the patient to survive.  But survive he did and even left the hospital.  

Unfortunately, the meningitis turned out to be  the first symptom of an abnormal immune system due to a blood malignancy — multiple myeloma. 

****

Addendum 2 February — I sent this post to an old friend and college classmate who is now a hematology professor at a major med school.  He saw a similar case —

“When I was a medical student I saw a pediatric sickle anemia patient (asplenic) with fever and obtundation. When I looked at the methylene-blue stained CSF, I thought that stain had precipitated. So I obtained a fresh bottle of stain and it looked the same. Only this time, I looked more closely and what I thought was precipitated stain were TNTC pneumococci.

I urge all my immunosuppressed patient to get vaccinated for covid-19. I worry that if many people don’t get vaccinated,  those who do will not be that better off.”

Addendum 3 February– I asked him if his patient had survived like mine —

answer 

“Unfortunately, no. With the pneumococcus, If antibiotics are not started within 4 hours after recognition, the train has left the station.”

 

****

So there are millions of active cases of the pandemic, and tons of people with medical conditions (leukemia, multiple myeloma, chemotherapy for other cancer) with abnormal immune systems, just waiting for the pandemic virus to find a home and proliferate for days to weeks.  Literally these people are culture media for the virus. Not all of them have been identified, so don’t try to prevent this by withholding vaccination from the immunocompromised — they’re the ones who need it the most. 

I think we’re in for a very long haul with the pandemic.  We’re just gearing up to stay on top of the viral sequence du jour.   Genome sequencing is not routine (it should be).  The South African and British mutations were picked up because a spike in cases led people to sequence the virus from these patients.  Viral genome sequencing and surveillance should be routine in most countries and should not wait for an infection spike to occur. 

You may come across the terms B.1.351 and  507Y.V2 — they are different names for the South African virus which beat Astra Zenica.  The British variant is also called B.1.1.7

The human species as a culture medium for the pandemic virus

Creationists or not, we are all about to get an unwanted lesson in natural selection and evolution, courtesy of the current pandemic virus (SARS-CoV-2).  This is going to be a long post, which will contain an incredible case of meningitis, thoughts on selfish genes in viruses, evolution, natural selection and why we’re in for a very, very long haul with the pandemic virus.

As you probably know, mutant pandemic viruses (all different) have emerged (in England, South Africa, Brazil).  Even worse they appear to be more infectious, and some are more resistant to our vaccines (all of which were made before they appeared).  

Here is lesson #1 in natural selection.  Viruses have no brains, they barely have a genome.  The human genome contains 3 billion positions, the pandemic virus 30,000.  So we have 100,000 times more information in our genome than the virus does. 100,000 is about the number of inches in a mile and half.  

So how is the virus outsmarting us?  Simply by reproducing like mad.  The molecular machines that copy our genome are very accurate, making about 1 mistake per 100,000,000 positions copied — that’s still enough for the average newborn to have 30 new mutations (more if the parents are older).  The viral machine is much less accurate.  So lots of genome mutations are made (meaning that the viral proteins made from the genome change slightly).  Those that elude the vaccines and antibodies we’re throwing at them survive and reproduce, most don’t.  This is natural selection in action. Survival of the fittest.  Darwin wasn’t kidding.

What is so remarkable about the British and the South African variants, is that they contain multiple mutations (23 in the British variant).  Usually its just one or two.

 You’ve probably heard about the mutation changing just one of the 147 amino acids  in hemoglobin to cause sickle cell anemia. Here’s another.  APOE is a 299 amino acid protein.  It comes in 3 variants  — due to changes at 2 positions.  One variant greatly increases the risk of Alzheimer’s disease, another decreases it.  So even single mutations can be quite powerful. 

So how did these multiple mutations come about?  We likely now have an answer due to one very well studied case [ Cell vol. 183 pp. 1901 – 1912 ’20 ] in an immunocompromised patient with chronic lymphatic leukemia (CLL). She shed the virus for 70 days.  Even so, she wasn’t symptomatic, but because the patient had enough immune system to fight the virus to a draw, it persisted, and so its genome was always changing.  The authors were smart enough to continually sequence the viral genome throughout the clinical course and watch it change. 

Could this happen again.  Of course?   There are some 60,000 new cases of CLL each year in the USA.  Many of them have abnormal immune systems even before chemotherapy begins.

Here is an example from my own practice. The patient was a 40 year old high school teacher who presented with severe headache, stiff neck and drowsiness.  I did a spinal tap to get cerebrospinal fluid (CSF) for culture so we could find the best possible antibiotic to treat the organism.  This was 30+ years ago, and we had no DNA testing to tell us immediately what to do.  We had to wait 24 hours  while the bugs grew in culture to form enough that we could identify the species and determine  the antibiotics it was sensitive to. . 

As the fluid came out, I had a sinking feeling; as it was cloudy, implying lots of white cells fighting the infection. Enough white cells to make CSF cloudy (it normally looks like water) is a very bad sign. So after starting the standard antibiotic to be used in the first 24 hours before the cultures came back, I called the lab for the cell count.  They said there weren’t any.  I thought they’d seriously screwed up maybe losing what I’d sent or mislabeling it and looking at the wrong sample, and I unpleasantly stormed down to the lab (as only an angry physician can do) to see the spinal fluid.  They were right.  The cloudiness of the CSF was produced by hordes of bacteria not white cells.  This was even worse as clearly the bacteria were winning and the patient’s immune system was losing, and I never expected the patient to survive.  But survive he did and even left the hospital.  

Unfortunately, the meningitis turned out to be  the first symptom of an abnormal immune system due to a blood malignancy — multiple myeloma. 

****

Addendum 2 February — I sent this post to an old friend and college classmate who is now a hematology professor at a major med school.  He saw a similar case —

“When I was a medical student I saw a pediatric sickle anemia patient (asplenic) with fever and obtundation. When I looked at the methylene-blue stained CSF, I thought that stain had precipitated. So I obtained a fresh bottle of stain and it looked the same. Only this time, I looked more closely and what I thought was precipitated stain were TNTC pneumococci.

I urge all my immunosuppressed patient to get vaccinated for covid-19. I worry that if many people don’t get vaccinated,  those who do will not be that better off.”

Addendum 3 February– I asked him if his patient had survived like mine —

answer 

“Unfortunately, no. With the pneumococcus, If antibiotics are not started within 4 hours after recognition, the train has left the station.”

 

****

So there are millions of active cases of the pandemic, and tons of people with medical conditions (leukemia, multiple myeloma, chemotherapy for other cancer) with abnormal immune systems, just waiting for the pandemic virus to find a home and proliferate for days to weeks.  Literally these people are culture media for the virus. Not all of them have been identified, so don’t try to prevent this by withholding vaccination from the immunocompromised — they’re the ones who need it the most. 

I think we’re in for a very long haul with the pandemic.  We’re just gearing up to stay on top of the viral sequence du jour.   Genome sequencing is not routine (it should be).  The South African and British mutations were picked up because a spike in cases led people to sequence the virus from these patients.  Viral genome sequencing and surveillance should be routine in most countries  — not waiting on an infection spike. 

 

 

A non-coercive way to get people to accept vaccination for the pandemic virus

Many people are afraid of being vaccinated (for anything, not just the pandemic flu). Yelling at them won’t help. Calling them stupid won’t help. You can’t pass a law to coerce them, but here’s a law that would likely convince them that it is a good idea.

Can you think of it?

I’m not sure if congress could do it, or whether it would have to be done state by state.

Just require all death certificates for people dying with COVID-19 to state whether they’d been vaccinated or not. Certainly now all of the deaths will be in unvaccinated people, but as time passes (say 3 – 6 months) and 95% of them remain in the unvaccinated (as studies of the vaccine have shown) and 1/3 to half of the population is vaccinated, people will take notice.

I don’t know any legislators, but maybe you do, and you should suggest it to them.

Why the news about SARS-CoV-2 mutations is actually good

How can the latest news about mutations in the pandemic virus be good?   Simply this — there are so many known ones, that it’s almost certain that nearly every possible mutations has been formed out there, and since not much has changed about the lethality of the virus, none of them are that bad.  Not only that, but the ones that haven’t occurred must be lethal to the virus and will give us new ideas about how to attack it.

Here is a link to an article (vol. 585 pp. 174 – 177 ’20) in the current 10 September Nature — https://media.nature.com/original/magazine-assets/d41586-020-02544-6/d41586-020-02544-6.pdf.  Hopefully not behind a paywall. It’s definitely worth a read

You’ve probably heard about the D614G mutation in the spike protein of the virus.  It came out of nowhere and has taken over worldwide, even in areas where different forms of the viral genome were previously established.  D is the one letter abbreviation for aspartic acid, one of the twenty amino acids, and G stands for another one glycine.  This immediately makes bells ring for the chemist, because glycine is the smallest amino acid, having a single hydrogen atom for its side chain, while the side chain of aspartic acid contains 2 carbons 4 hydrogens one oxygen and one nitrogen atom.  So there’s a lot more room for the protein where aspartic acid used to be.

Whether or not the mutation made the virus more infectious still isn’t known.  It appears to be more infectious in studies using pseudoviruses.  Not everyone has a high level containment facility, so people work with the AIDS virus (HIV1) which doesn’t need one and simply change one of its proteins to the spike protein of the pandemic virus (yes we have the technology to do that).  Then they infect cells with the pseudovirus.  Translating this to whole organisms (us) with the real virus requires a leap of faith.  It’s a long leap, but pseudoviruses are the best thing we have at present.

Here are three quotes from the article ”

“More than 90,000 isolates have been sequenced and made public (see http://www.gisaid.org). ”

“Two SARS-CoV-2 viruses collected from anywhere in the world differ by an average of just 10 RNA letters out of 29,903,”

“Researchers have catalogued more than 12,000 mutations in SARS-CoV-2 genomes. ”

How many mutations are possible in the  viral genome?  Just 29,903 times 3, because at each position, the element normally there can change to only 3 others — the viral genome is made of RNA is a linear chain of only 29,003 nucleotides, and each nucleotide can be uracil (U), adenine (A) guanosine  (G) or cytosine (C).  That’s it.  Proteins can have 20 different amino acids at each position.

So 13% of all possible mutations have been found in the virus, out of only 90,000 completely sequenced genomes. There are now 28,000,000 cases out there, so it’s almost certain with 1,000 times more virus out there to sequence, that nearly all the other 44,000 or so possible mutations have already occurred somewhere in the world.

How can this be good news?  Because if any of them were truly horrible, we’d know about it.  It would have taken over just the way the D614D mutation did.

But there’s even more to be gleaned from this work.  Hopefully http://www.gisaid.org is continuing to accumulate more and more sequences from all over the world.  Suppose certain mutations don’t show up.   This means they are fatal to an infectious virus.  Since we know exactly what proteins the virus is making and what stretch of the genome makes each one, this should suggest  clear lines of attack into the virus.

Why do some socially isolate and some don’t

The current flare in US cases (and deaths) are likely due to a failure in social isolation, rather than a loosening of restrictions on activity.  Georgia loosened its restrictions back in April.  Following this, new cases dropped for two months, and deaths dropped for nearly 3 months, before rising again to pre-lockdown levels and above.  The number of new ‘cases’ can partially be attributed to more testing, but the number of deaths can not.  For links and the exact numbers see the copy of the previous post after the ***

I think the rise is partially explainable by a failure of social distancing. Have a look at this  https://nypost.com/2020/07/18/video-shows-people-in-queens-flooding-streets-without-masks/.   It may not be a COVID party in name, but it is in fact.

That being the case, wouldn’t it be nice to know why some people social distance and others do not.

Incredibly, a paper just came out looking at exactly that Proc. Natl. Acad. Sci. vol. 117 pp. 17667 – 17674 ’20 (28 July).  It’s likely behind a paywall so let me explain what they did.

The work was conducted in the first two weeks after the 13 March declaration of a national emergency.  Some 850 participants from the USA had their working memory tested using the Mechanical Turk from Amazon — https://en.wikipedia.org/wiki/Amazon_Mechanical_Turk.  Essentially they are volunteers.  I leave it to you to decide how characteristic of the general population at large these people are.   My guess is that they aren’t.

Then the 850 were subsequently asked how much they had complied with social distancing.

But first, a brief discussion of working memory — more is available at https://en.wikipedia.org/wiki/Working_memory

Working memory is tested in a variety of methods, but it basically measures how many objects you can temporarily hold in your head at one time.  One way to test it, is to give you a series of digits, and then ask you to repeat them backwards (after a lag of a second or so).  Here’s what the authors used —

“Participants performed an online visual working memory task, in which they tried to memorize a set of briefly presented color squares for  half a second and after a 1 second delay tried to identify a changed color in the test display by clicking on it using a computer mouse.”

The more you can hold in your head for a short period of time, the more working memory you have.  There is a lot of contention about just what intelligence is and how to measure it, but study after study shows that the greater your working memory, the more intelligent you are.

To cut to the chase — here are their results.

The greater their working memory, the greater the degree of compliance with social distancing.

Here is the author’s explanation –what’s yours?

“We find that working memory capacity contributes unique variance to individual differences in social distancing compliance, which may be partially attributed to the relationship between working memory capacity and one’s ability to evaluate the true merits of the recommended social distancing guidelines. This association remains robust after taking into account individual differences in age, gender, education, socioeconomic status, personality, mood-related conditions, and fluid intelligence.”

Talk about currency and relevance ! !   If failure of social distancing explains the rise in cases, studies like this will help us attack it.

Here is the older post with numbers and links

***

The News is Bad from Georgia

This is an update on a series of post about Georgia and the effect of relaxing restrictions on activity.  If you’ve been following the story, this post is somewhat repetitive, but I’d rather not leave newcomers behind. As of 14 July Georgia seemed to be bucking the trend of increasing deaths (but not of increasing ‘cases’ however defined).  No longer.

 https://dph.georgia.gov/covid-19-daily-status-report.  Page down past the map to the chart with 3 tabs —  cases (which means daily newly diagnosed cases), cumulative cases, and death.  Clicking on the tabs will move you back and forth (or better if your screen is big enough open the link twice and compared cases vs. deaths.

Georgia has changed the way it reports cases, no longer waiting 14 days before result are secure.  I also think they changed some of the older numbers.  I don’t recall seeing over 70 deaths in a day in May and June, yet the current chart shows 4 of them.  There is no way to get the old reports from the Georgia department of health, by clicking on the links in the old posts on the subject.  They all take you to the current one.

The 7 day average of deaths back in 25 April was 35, new cases  740 based on detection of viral genome or antibodies to it — not sick people

Sadly now the 7 day average of death is now 45 and new cases 3700.

The charts allow you to see when both new cases and deaths began to rise.  The number of new cases began to spike 16 June and the number of death began to increase 19 July (eyeball the charts, and you’ll see that these are not precise numbers.  So there was about a 1 month lag between the increases.

So were the doom and gloom sayers correct?  Here they are again to refresh your memory.

From The Atlantic — “Georgia’s Experiment in Human Sacrifice — The state is about to find out how many people need to lose their lives to shore up the economy.” — https://www.theatlantic.com/health/archive/2020/04/why-georgia-reopening-coronavirus-pandemic/610882/

Possibly they were right, but deaths actually decreased for a month or two after 25 April hitting a low of 13 daily deaths on 2 July.   I don’t think any of them predicted a lag of 2 months before the apocalypse.

Most likely it was a change in behavior.  Have a look at this  https://nypost.com/2020/07/18/video-shows-people-in-queens-flooding-streets-without-masks/.   It may not be a COVID party in name, but it is in fact.

At first glance it appears that they are trying for a Darwin award, but on second glance, based purely on a cost benefit analysis (to them only) the chances of a healthy 18 – 20 year old dying from COVID19 are less than 1 in a thousand.  Libido is incredibly intense at that age.   I’m not sure what I would have done in their shoes.  Here are some statistics from Florida with numbers large enough to be significant

Here is some older data from Florida  (from their department of health) — http://ww11.doh.state.fl.us/comm/_partners/covid19_report_archive/state_reports_latest.pdf

Age  Range     Number of Cases  Number of Hospitalizations Deaths

14 – 24              54,815                                503                                    12

25 – 34             70,030                              1,315                                    34

This is a risk of death if you are a ‘case’ however defined of less than 1/2,000.

This is age range of most of folks in the video. Further more recent examples are lifeguards in NY and on Cape Cod.

Think of all the gay men who knew full well how AIDS was transmitted, still got it and died.  Libido is powerful.  The classic example is Randy Shilts who wrote the magnificent “And the Band Played On” in 1987 about the early days of the epidemic.  He knew everything there was to know about the way the AIDS virus (HIV1) was transmitted yet he himself died of AIDS.

Further examples are lifeguards in NY and on Cape Cod.

 

The presidential election will be decided in the next month — revision for clarity

Apologies to all for the previous post which was far murkier than it could have been.  The problem was that a ‘case’ of the pandemic coronavirus can mean 3 very different things.  These distinctions are tedious but crucial.

Meaning #1 — COVID19 — People who are clinically ill with the virus (official name SARS-CoV-2).  These are the people that  may die of the illness, although most do not.

Meaning #2 — The viral genome has been found in your saliva.

Meaning #3 — You have antibodies to the virus in your blood.

Here is the distinction between #2 and #3 — Antibodies (proteins) and genomes (RNA) are completely different chemically. Finding the actual genome (RNA in this case) of a virus in an individual  is like seeing a real bear up close and personal.  This can do you some damage.  In contrast, antibodies to the virus are made by an individual who has been infected by the virus in the past.       Antibodies are like seeing the tracks of the bear without the bear itself. You can’t see tracks without the bear having been present at some point in the past.  Antibodies mean you were infected at some point whether you knew it or not.

OK, so here’s another shot at what was I saying in the previous post.

I find it very sad that loosening the restrictions on activity has become so political. The left says that it will be a disaster and that cases and deaths will spike (meaning #1). As far as I’ve seen, they never say they hope they’re wrong.  The right says that deaths will continue, but the rate won’t increase.  There is evidence for both sides, but in the coming months we’ll actually have data one way or the other.

One thing is certain.  The number of cases of positive viral culture (meaning #2) will increase.  It has to because more people will be tested. So far, we’ve only studied around 1/1,000 of the population.  No one has ever said the lockdown will prevent new infection.  It hasn’t, but it has slowed things down.

I’m hoping that cases of COVID19 and death will not explode.  Not because I want Trump to win, but because getting people back to work  would be good for the country.  Should that happen, the anger of those who lost their jobs or businesses during the shutdown will be formidable.  Trump will win.

Should deaths from COVID19 explode (meaning #1) as restrictions are lifted, Trump is toast.

We should also get some idea of the percentage of the population who have been infected (manifest by antibodies to the pandemic virus meaning #3).  It almost certainly will increase, unless those already showing the antibodies lose them (which is unheard of happening this fast inFor  the antibodies we’ve studied in the past).

I’m cautiously optimistic that not much will happen when restrictions are eased. Here’s why.  All the studies on antibodies (meaning #3) done so far show they are 10 – 100 times more prevalent than cases where the virus is cultured (meaning #2).  For example 20% of Manhattan sampled population have the antibodies.  This implies that most infections with the pandemic coronavirus are asymptomatic.  

Another viral disease with a high prevalence of antibodies is infectious mononucleosis.  90% of adults in the USA have antibodies to mono, but far fewer than 90% were ever sick.

So the number of cases with positive culture (meaning #2)  isn’t what’s important.  It’s how many of them get sick with COVID19 (meaning # 1).  I think we have very good past statistics on the number of deaths and cases of COVID19   It will be clear if there is a spike in COVID19.

However be careful not to read too much into the first week’s statistics after restrictions are lifted, as there is a lag period of 2 – 11 days between infection and clinical illness.  Also try to understand which of the 3 meanings of “case” the article you are reading is talking about — this won’t always be possible.

 

Covid19* could be coming for you — take 2

Flattening the curve (by social isolation) was never about completely preventing new infections.  It was about slowing the rate of rise in new infections so hospitals wouldn’t be overwhelmed.  That was the state of play when I wrote the following post 29 March (seems like ages ago doesn’t it?)

A friend and his wife are getting 3 days of meals delivered to their room in their retirement home.  Clearly a great way to socially isolate themselves.  This will help ‘flatten the curve’.  What that means is that the peak won’t be as high, so we won’t run out of beds and respirators.

But look at the curve in this article — https://www.flattenthecurve.com

Now integrate the area under the curve.  Looks like the number of cases is comparable (more actually under the flattened curve).

Add this to the extreme likelihood that covid19 will become endemic in the population (given the number of cases out there).  This means that absent a vaccine or a treatment, you will meet it sooner or later with whatever biologic resources you have.

On the positive side, the amount of research into the way virus kills is only matched by the number of therapeutic trials underway (both enormous).  The way the journals have opened up so results are widely available gratis and freely shared is impressive.

There is no question that the virus has become endemic, with no study of the presence of antibodies to the virus coming in at less than 4%, and that in Manhattan coming in at 20%.

So those unhappy about loosening restrictions have essentially shifted the goals of social isolation from slowing the rate of new infections (which has happened) to preventing new infections, something that I think is impossible.  We’re about to see if there will be a massive explosion of new cases of covid19 (which is symptomatic infection with SARS-CoV-2 rather than just the presence of its genome) or not, in the 15 or so states starting to loosen restrictions.

The studies showing antibody prevalence greater than 3 – 4% (which is essentially all of them that I’m aware of) argue that we won’t see an explosion in symptomatic infections.  That’s just about everyone’s hope (even those predicting disaster) and it’s what I think will happen.   Nothing like data to prove you right or wrong.  We’re about to find out.

As always, watch out for premature celebrations of rightness or wrongness — see https://luysii.wordpress.com/2020/04/29/watch-the-press/

  • Actually the title is incorrect, but the first post in the series was written 5 weeks ago, when most people knew what COVID19 was, the point of these posts being communication.  The virus itself is not COVID19 which stands for the illness the virus produces.  A variety of names have been applied to the virus — Chinese flu, Wuhan virus, coronavirus2.  The correct name is SARS-CoV-2 — hardly rolls trippingly off the tongue does it?  One should also distinguish finding the genome of the virus (RNA) which implies active infection, from antibodies to the virus which imply a past infection (the difference between seeing a bear and seeing its tracks).  So the correct title is really SARS-CoV-2 is coming for you – take 2 (if you’re a pedant)