24 October 2021

A new anti-viral therapy for SARS-CoV-2 was predicted twenty years ago by evolutionary biologist Mark Ridley

 

Corona update    
24 October 2021    

#36
  

"We just need to increase the viral mutation rate and they’ll collapse under their own copying errors. The treatment would need selectively to increase the viral, and not the host's, mutation rate, but that should be feasible." Mark Ridley (2000) Mendel's Demon, page 89. [7]

Ridley wrote about his second favourite cure for AIDS. So, this was not about SARS-CoV-2. SARS-CoV-1 and SARS-CoV-2 did not exist in 2000. It was another RNA virus: HIV. But the same evolutionary calculations apply. Ridley did not make a wild guess. He based his claim on his own tentative conclusion that some RNA viruses have evolved near to the limit of complexity set by their copying error rates. That means they have the maximum copy error rate compatible with survival: about 1 copy error per 30,000 bases. At each replication cycle the complete virus is copied (all 30,000 bases). That means that with that error rate a virus of length 30,000 bases would produce 1 copy error at each replication cycle.

According to the recent research the mutation rate of SARS-CoV-2 appears to be 3.7 per million bases per replication cycle [3]. As it happens SARS-CoV-2 has a length of 30,000 bases. Ridley did not know that, but he was close with his estimate. If SARS-CoV-2 lives close to the point of mutational meltdown, than it is quite easy to 'mutate the virus to death'. By 'close to the point of mutational meltdown' I mean only a slight increase in mutation rate will kill the virus. The genetic information in the virus will be destroyed increasingly at each copy cycle. In other words: only a little push will throw the virus into the abyss.

pushing the virus over the edge in to mutational collapse

If the virus is close to the edge (B) only a little push is needed. When it is further away from the edge (A) a strong push is needed.

Nature 8 Oct 2021 [1],[2]

So far the theory. How does that translate into a drug? Molnupiravir is the proposed answer. Here is an abbreviated abstract of how the drug works:

Molnupiravir is a nucleoside analogue, which means it mimics some of the building blocks of RNA. When SARS-CoV-2 enters a cell, the virus needs to duplicate its RNA genome to form new viruses. Molnupiravir gets incorporated into burgeoning RNA strands and, once inside, wreaks havoc. The compound can shift its configuration, sometimes mimicking the nucleoside cytidine (C) and sometimes mimicking uridine (U). Those RNA strands become faulty blueprints for the next round of viral genomes. Anywhere the compound gets inserted and that conformational shift happens, a point mutation occurs. When enough mutations accumulate, the viral population collapses. That is lethal mutagenesis. The virus essentially mutates itself to death [1].

In fact this is a practical translation of Ridley's idea: increase the mutation rate and the virus will suffer a mutational meltdown (error catastrophe). How this is achieved is interesting. The base substitute has two configurations: one similar to C and one similar to U. If those configurations occur randomly when incorporated in a RNA sequence, they introduce random mutations when the sequence is copied. Exactly that is the reason that compound does not occur naturally in RNA. It would make the genetic code unreliable. Life cannot be built on an unreliable code.

How strong would be the effect? What dose of the base analogue do we need?  


It would be too optimistic to assume that all suitable bases in the virus genome would be replaced by the drug. Now, there are between 7000 and 8000 of each of the 4 bases U,C,A,G in the virus RNA sequence of 30,000 bases (the length of SARS-CoV-2). Suppose that 10% of the say 7500 C's of a virus genome are replaced by Molnupiravir, that is 750, and when this RNA strand is copied again 50% of the Molnupiravir bases have a different configuration. This would cause 375 new mutations in the copied virus genome. This is really a huge amount when compared with  1 mutation in 3-7 virus replication cycles [6]. Compare this also to an estimated 10-20 mutations in a SARS-CoV-2 variant [8]. This high number of 375 mutations should destroy the function of all produced viral proteins ... if they are produced at all! If too many mutations occur for example in the Spike protein, the virus can't enter a human cell. If too many mutations accumulate in viral RNA polymerase, the virus RNA cannot be copied. 

Further, the effect of the drug will depend on how many of the virus particles will be affected. It would be too optimistic to suppose that all replicating virus particles would be affected. I have no idea what percentage that would be. Anyhow, the unaffected virus particles will replicate at an unrestricted rate. So, it all depends on the dose of the drug. A higher dose should have a stronger effect on the percentage of affected viruses and the percentage of replaced bases in a virus genome. But a higher dose could be toxic to the patient.

Concluding, we could state that 20 yeas ago evolutionary biologist Mark Ridley correctly predicted the possibility of an error catastrophe causing drug such as Molnupiravir.

In June 2021 Molnupiravir received an emergency use authorization of the U.S. Food and Drug Administration (FDA) for therapy of COVID-19 patients. The European Medicines Agency (EMA) is reviewing Molnupiravir.


Thoughts about first RNA replicating molecules ...

The 'RNA world' is a well-known hypothesis about the Origin of Life. I am tempted to think that unreliable, unstable bases could have been used by the very first RNA replicators. By a process of natural selection for stability, the more stable bases would end up in the successful replicators. The unstable bases would become extinct. The 5 bases we now have A,C,T,G,U must have been selected for their stability and became dominant. A personal hypothesis. Data have to be collected and experiments have to be done!


Postscript

20 Nov 2021:  Molnupiravir has been approved by The European Medicines Agency (EMA).


Sources

  1. How antiviral pill molnupiravir shot ahead in the COVID drug hunt, Nature, 8 Oct 2021 
  2. The Merck pill, which could become the first oral antiviral COVID treatment, forces the coronavirus SARS-CoV-2 to mutate itself to death, Scientific American 12 Oct 2021
  3. Vítor Borges et al Mutation rate of SARS-CoV-2 and emergence of mutators during experimental evolution, biorxiv.org (not yet peer-reviewed)
  4. Molnupiravir (wikipedia)
  5. Error catastrophe (wikipedia); Mutational meltdown (wikipedia)
  6. The total number and mass of SARS-CoV-2 virions, PNAS June 22, 2021.
  7. This book is one of the most insightful books about evolution I have ever read. It is reviewed on my website. 
  8. 24 November 2021: a new SARS-CoV-2 variant has been discovered in South Africa: the Omnicron variant (wikipedia). The variant has 51 mutations in total including deletions and 1 insertion. Added Dec 1 2021

 

 



14 October 2021

Dutch educator Kees Boeke (1884-1966) was the inspiration for the very popular video Powers of Ten

Picknick: the Powers of Ten opening scene (2010)

This is the opening scene of the legendary Powers of Ten educational movie that was produced in 1977 and published in 2010 on youtube. Since its publication on youtube it received more than 7 million views! In the description of the video on youtube there is no mention of Kees Boeke who invented the idea of using steps of 10x as an educational device. An unfriendly omission. However, his name is present in the last second in the Credits section of the movie: "With much gratitude to Kees Boeke". Okay, but this is rather vague. Exactly, what did he contribute? It is not clear that the film was based on his book Cosmic View (1957). Boeke deserves more than this. Hence this blog.


Kees Boeke was a Dutch teacher and education reformer. His idea was a method to teach schoolchildren relative sizes. In 1927 he made his first attempts to use steps of 10x. Much later he also tried steps in powers of two, but quickly returned to the powers of ten. He called them 'jumps of ten' because he started jumping upwards.

First page of Kees Boeke (1959,2021)
'Wij in het heelal, een heelal in ons'.
(Dutch edition)


Boeke started with a picture of a girl [1] with a frustrated cat on her bosom. The rest of the book contains drawings, some color, some black and white. From the first picture he starts zooming out by jumps of 10x. Higher and higher above the ground. Village (Bilthoven), region, country (The Netherlands), Europe, Earth, Solar system, etc. And then back to the micro world. For a historical context: the famous Earthrise photo was taken on
December 24, 1968. The book appeared 12 years before Neil Armstrong became the first human to step on the moon (1969).

A year later another video appeared on youtube: Powers of Ten - Ultimate Zoom (micro-macro - Imax combined) 815,989 views 12 Feb 2011:

Powers of Ten video (2011)
(screenshot from the video)

 

The video starts with a display of the cover of Cosmic View. The universe in 40 jumps and two previous videos. That is the good news. The bad news is that only the upper half of the cover is shown. So, the name of the author Kees Boeke is not visible! What a pity! His name is also absent in the description of the video and in the Credits at the end of the video. I find the music irritating and superfluous. It would have been better to have a voice-over or at least display the steps of the power of ten in the bottom left corner.

The educational value of The powers of Ten in general is far more than teaching schoolchildren relative sizes. I think the true value lies in placing all the natural sciences on the same scale of sizes: biology, chemistry, physics, geography, earth-sciences, cosmology. Because humans are in the middle of the micro- and the macro world, it helps to see the places of all sciences on the scale of powers of ten. It would be a suitable introductory film for a Big History course because Big History is trying to integrate all sciences including social sciences.

Recently his original book in Dutch (1959) has been reprinted (see previous blog) and two former teachers of the school Kees Boeke founded, published a book about Kees Boeke and the origin of the powers-of-ten-idea. The school he founded, the Werkplaats Kindergemeenschap, Bilthoven, still exists.


  • youtube: Powers of Ten™ (1977) (length: 9 min)
  • book: Kees Boeke:  'Cosmic View: The Universe in Forty Jumps' (1957)
  • book: Kees Boeke: 'Wij in het heelal, een heelal in ons' (1959)
  • wikipedia: Kees Boeke (1884-1966)
  • previous blog (Dutch): De Tiendesprongen van Kees Boeke (10 Oct)



[1] According to one of the authors,  Jos Heuer, the girl is Mirjam Freudenthal. [19 Oct 2021].

10 October 2021

De Tiendesprongen van Kees Boeke

Jos Heuer, Henk Willems (2021)
Tiendesprongen,
Walburgpers

Kees Boeke: Wij in het heelal, Een heelal in ons.
heruitgave
2021, Walburgpers

De Tiendesprongen van Kees Boeke (1884-1966) zijn wereldberoemd geworden, maar weinigen weten dat ze van Kees Boeke afkomstig zijn. Robbert Dijkgraaf en Vincent Icke, beide natuurkundigen, hebben hun enthousiasme uitgesproken. Kees Boeke was een leraar, onderwijshervormer, pedagoog, activist, Quacker-pacifist en revolutionair denker. De Engelse titel van zijn boek dat alles in gang zette is Cosmic View, The Universe in 40 Jumps (1957), de Nederlandse titel Wij in het heelal, Een heelal in ons (1959). Recent is er een heruitgave verschenen van Wij in het heelal (2021) (foto boven). Het is interessant om te zien hoe Boeke te werk ging. Twee oud-docenten zijn in diverse archieven gedoken om een reconstructie te maken van hoe het idee ontstond en zich ontwikkeld heeft (Tiendesprongen, zie afbeelding boven).

Er is een film gebaseerd op het idee verschenen: 'Powers of Ten' (1977) die in 2010 op youtube (9 min) is gepubliceerd onder dezelfde naam. Nu: meer dan 7 miljoen hits! Het werd een klassieker. Als je die bekijkt krijg je de beste visuele indruk van het idee. Uiteraard kon Boeke toen hij zijn idee publiceerde niet beschikken over moderne animatietechnieken. De eerste scene in de film is de bekende picknick scene van een man en een vrouw met afmetingen van 1x1m. 1 meter = 100 of: 10 tot macht 0. In het Engels is macht power, vandaar de titel Powers. De film zoomt uit met niet minder dan 24 stappen van 10. Bij de laatste stap ben gekomen tot: 1024 x 1024 meter. Dat is de werkelijke afmeting van wat je op de foto ziet (lengte x breedte). Daarna zoomt het weer in met grote snelheid naar de picknick scene en daarna verder inzoomen met 16 stappen van 10. Uiteindelijk heeft het vierkant een onvoorstelbare kleine afmeting van 10-16 meter. Technisch is de film zeer knap gedaan. Misschien zijn we tegenwoordig te veel verwend met Google Earth en animatietechnieken. Maar dat bestond in die tijd nog niet!

Helaas zie ik in de beschrijving van Powers of Ten op youtube geen vermelding dat het originele idee van Kees Boeke was! Echt een misser. Wel staat op de allerlaatste seconde van de aftiteling "With much gratitude to Kees Boeke". Dat dan weer wel. Maar wie ziet dat nu?


 

I heb geprobeerd deze post te publiceren op 10-10 10:10:10 maar Blogger laat het tijdstip niet (meer) zien :-(


PS 19 Okt: met dank aan Jos Heuer voor correcties in de tekst!