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

https://www.sciencemag.org/news/2021/02/south-africa-suspends-use-astrazenecas-covid-19-vaccine-after-it-fails-clearly-stop?utm_source=Nature+Briefing&utm_campaign=6ada806177-briefing-dy-20210208&utm_medium=email&utm_term=0_c9dfd39373-6ada806177-46043190

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. 

 

 

The neuropharmacological brilliance of the meningococcus

The meningococcus can kill you within 12 hours after the spots appear — https://en.wikipedia.org/wiki/Waterhouse–Friderichsen_syndrome.  Who would have thought that it would be teaching us neuropharmacology.   But it is —  showing us how to make a new class of drugs, that no one has ever thought of.

One of the most important ways that the outside of a cell tells the inside what’s going on and what to do is the GPCR (acronym for G Protein Coupled Receptor).  Our 20,000 protein coding genome contains 826 of them. 108 G-protein-coupled receptors (GPCRs) are the targets of 475 Food and Drug Administration (FDA)-approved drugs (slightly over 1/3).   GPCRs are embedded in the outer membrane of the cell, with the protein going back and forth through the membrane 7 times (transmembrane segment 1 to 7 (TM1 – TM7). As the GPCR sits there usually the 7 TMs cluster together, and signaling molecules such as norepinephrine, dopamine, serotonin etc. etc. bind to the center of the cluster.   This is where the 475 drugs try to modify things.

Not so the meningococcus. It binds to the beta2 adrenergic receptor on the surface of brain endothelial cells lining cerebral blood vessels, turning on a signaling cascade which eventually promotes opening junctions of the brain endothelial cells with each other, so the bug can get into the brain.  All sorts of drugs are used to affect beta2 adrenergic receptors, in particular drugs for asthma which activate the receptor causing lung smooth muscle to relax.  All of them are small molecules which bind within the 7 TM cluster.

According to Nature Commun. vol 10 pp. 4752 –> ’19, the little hairs (pili) on the outside of the organism bind to sugars attached to the extracellular surface of the receptor, pulling on it activating the receptor.

This a completely new mechanism to alter GPCR function (which, after all,  is what our drugs are trying to do).  This means that we potentially have a whole new class of drugs, and 826 juicy targets to explore them with.

Here is one clinical experience I had with the meningococcus.  A middle aged man presented with headache, stiff neck and fever.  Normally spinal fluid is as clear as water.  This man’s was cloudy, a very bad sign as it usually means pus (lots of white blood cells).  I started the standard antibiotic (at the time)  for bacterial meningitis — because you don’t wait for the culture to come back which back then took two days.  The lab report showed no white cells, which I thought was screwy, so I went down to the lab to look for myself — there weren’t any.  The cloudiness was due to a huge number of meningococcal bacteria.  I though he was a goner, but amazingly he survived and went home. Unfortunately his immune system was quite abnormal, and the meningitis was the initial presentation of multiple myeloma.