How wrong could I be ?

I wrote a post 13 September saying the SARS-CoV-19 virus mutations were nothing to worry about. Some 19,000 were already known, and anything bad should have happened already, so we were in the clear. You can find a copy of this post below the *****.

If there ever was a case of ‘absence of evidence is not evidence of absence’ this is it. A sample taken in England that month (but not reported until November) found the B 1.1.7 variant which is more infectious).

So it’s time to take stock about the future course of the pandemic. 

First — the new strain had all sorts of mutations (23 depending on how you count them).  This was unprecedented, and why I was so sanguine in the post.   We now understand how this might have happened due to one very well studied case [ Cell vol. 183 pp. 1901 – 1912 ’20 ] in an immunocompromised patient with chronic lymphatic leukemia, shed the virus for 70 days.  The patients wasn’t symptomatic, but because the patient had enough immune system to fight the virus to a draw, it persisted, and its genome was always changing.  Now we worry that infection in people getting just one dose of vaccine might show the same characteristics, being incubators for multiple mutations.

So it’s going to be cat and mouse with the virus for the forseeable future.  Fortunately as new mutations occur leading to more infectious and/or more virulent viruses, we’ll know exactly what they are, and can change the mRNA in the vaccine to exactly match them. 

Even better, research is now swinging into high gear to find out what the virus is doing inside cells. Several studies [ Cell vol. 184 pp. 92 – 105  ’21 ] have infected cells with the virus, and then used CRISPR to knock out a bunch of genes, the cells that survive have had a gene knocked out that the virus needs pointing to a line of attack.  Other studies (using other types of cells) have also found other  genes essential for the virus, but there is little overlap in the genes that they find.

This line of attack is good, particularly when you remember that despite 40 years of work we have no vaccine against AIDs, but we have all sorts of drugs inhibiting the virus inside the cell, so that AIDs has become a chronic manageable disease rather than a death sentence (as it was when I was in practice).

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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.

 

 

 

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