IF THEY HAD ONLY LISTENED, December 27, 2021

Chapter 1 Why Aren’t We All Dead?

There are 10^23 stars in the Universe. There are 10 ^31 viruses on Earth. That’s 100 million viruses for every star in the Universe.  Why aren’t we all dead?

With the enormous number of viruses surrounding us all the time, looking for hosts with vulnerable replication machinery to hijack, you’d think we’d be fighting millions of pandemics at any given time. We would be if not for our secret weapon; mathematics.

We’re going to go on a fascinating journey together; of riches and beauty beyond our wildest imagination, of ugliness, greed and gluttony on a biblical scale, of unimaginable evil. We will learn about the breathtaking intricacies of the human immune system, pitted in a life and death struggle with invading pathogens every millisecond of the day. Always there, lurking in the shadows, at times when no hope is left, the unassailable bulwark that is mathematics will come to our rescue again and again, in starkly different ways, exposing lie after lie.

The difference between an epidemic and a pandemic is largely one of breadth but this distinction belies a critical difference between the two. Epidemics become pandemics because of massive spread, due to efficient viral transmission between humans. Because efficient human-to-human transmissibility is so rarely effected, epidemics are far more common than pandemics.

Pandemics are incredibly rare, given the number of viruses on Earth, because a number of hurdles must be successfully negotiated- some extremely unlikely- before an actual pandemic can be said to exist.

A few of those steps require mutations in the form of copying errors at precisely this or that spot in the genome (and nowhere else nearby). Mutations are copying errors that occur randomly during replication of the pathogen. They must occur in a way that makes a new three base-pair codon that maps to a different amino acid- a specific amino acid- that will change the shape and charge densities of the new protein translated from the sequence of codons on the viral RNA, including the newly-minted one. The new protein must be formed just so, such that its configuration is now able to very efficiently accomplish something (such as bind to the receptor of a different species) that it could not accomplish before.

There are 20 different amino acids. Only one will make the necessary change in shape and charge density. There are 64 different unique combinations (4 x 4 x 4 = 64) of three nucleotide bases when each base could have one of four configurations; adenine, guanine, cytosine or uracil. Considering that a typical, garden variety mid-sized standard globular protein is composed of around 1200 amino acids and that that some steps require multiple mutations at only those specific locations and no others, it is easy to see how the numbers quickly become astronomical, on the order of, or comparable to, the number of viruses laying in wait for us. 

Pandemics can occur due to a large variety of those viruses. We know about respiratory viruses like corona and influenza viruses causing pandemics but what about something like Ebola? Since Ebola is not a respiratory virus and requires contact with the infected person’s body fluids in order to get infected, the kind of wide, uncontrollable spread characteristic of pandemics, is very unlikely.

Hantavirus is something in between these two. The infected person does, indeed, breathe in the virus and hantavirus pulmonary syndrome (HPS) ensues causing rapid death, frequently. But it’s not a respiratory-transmitted virus per se because it occurs when people breathe in the virus as it aerosolizes when mouse saliva, urine, or feces dry. (It can also get into humans if they touch urine or feces and then touch their eyes or mouth or other mucus membranes).

In 1993, in the four corners region of the southwest U.S., a large number of people fell ill with a fatal respiratory syndrome that turned out to be a hantavirus carried by the deer mouse. Because of lots of snow and rain earlier in the year in that dry region of the southwest, where there had been minimal precipitation for years, abundant plants grew and the mice had plenty to eat. The deer mouse population swelled to ten times what it was in 1992, causing more humans to come into contact with the mice and that is why such a large outbreak occurred that year. The virus had been around since 1938, it turns out, but never discovered and isolated since it killed so rarely that it was not noticed in the way that sudden outbreaks are.  

Human-to-human transmission of the deadly “1993” hantavirus was never established and a pandemic did not occur even though sporadic hantavirus infections occurred during the year in Louisiana, called ‘Bayou virus’ (from the rice rat), Florida, called ‘Black Creek Canal virus‘ (from the cotton rat), and New York, from the Sin Nombre-like (Four square) virus (this time compliments of the white-footed mouse). Hanta virus is extremely deadly and we are very fortunate that it failed human-to-human transmission.

You are beginning to get a feel for the necessary steps in creating a pandemic so let’s go over those steps in full, and in some detail as they apply to the SARS-2 coronavirus pandemic.

The Steps Required for a Pandemic to Occur:

1. The virus must not kill the host. Generally, the virus maintains a symbiotic relationship with its host and, at most, displays only a very mild pathogenicity. In the case of SARS-2, the host did not exist because the virus was made in a lab (more on this very important issue below) but for its close coronavirus relatives, the horseshoe bat serves as host.

2. The host must shed the virus. Through urine, feces, saliva, etc.

3. Humans or an intermediate host must come in contact with the sheddings.

4. The virus must jump the species barrier to humans and evade the immune response (“zoonotic spillover”).This usually requires a mutation in the spike protein so that it can successfully interact with the ACE-2 receptors found on human cells and thereby gain entry into the cytoplasm of the cell.

5. The virus must engage in efficient replication while evading immune capture.

   This involves commandeering the host cell’s replication machinery in the cytoplasm and translating its RNA into the various proteins necessary to make copies of itself.

6. The virus must be able to accomplish efficient human-to-human transmission.This depends largely on the rate of fusion of the viral capsule with the host cell which itself depends on precise cleavage between the S1 and S2 subunits of the spike protein by a protease present on the surface of the host cells next to the ACE-2 receptor. As mentioned above, Ebola fails here because contact with infected body fluids is necessary to transmit Ebola and it is easy to recognize the sick and avoid them. This is fortunate, because Ebola’s Infection Fatality Rate (IFR) is exceedingly high at 50% plus. “SARS-1” (SARS) fails here because its fusion rate is low.

7. The virus must cause significant morbidity +/- low to moderate late mortality.

   You don’t want significant early mortality, as in Ebola, because the host will die before spreading the virus about, taking the virus with it. You don’t want insignificant morbidity as in the common cold because negligible disease results, not worthy of being called a pandemic.

What are the odds all of this would happen without help from a lab? The odds are very long. That’s why we’ve had only 20 pandemics since 164 AD; 20 in 1857 years or about one every 93 years. Note also that since the advent of antibiotics, all pandemics have been due to viruses and almost all of those of the respiratory type.

I’ve already explained why pandemics are so rare from the viewpoint of the unlikelihood of getting the precise viral genetic mutations to occur. There are just too many ways to get it wrong. Allow me to drive this concept home because we are going to use it over and over again.

Suppose a student takes the SAT test twice. One of the two times, she scores a 600 on the SAT Math because she got 75 questions right out of 100 and the other time she scored an 800, getting all 100 questions right. Which score should the college admissions officers use to most accurately assess her true ability or should they simply average them and think a 700 (80 correct questions) most accurately represents her potential. The answer? They should use the 800. This is because if her true ability was at 600 or even 700, it would be virtually impossible to “get lucky” and guess the correct answer on all of the remaining 30 or 20 problems she did not know how to solve.  It’s easy to calculate. The chance of guessing correctly on 30 questions in a row where each question has five possible choices is 1/5^30.  The likelihood of guessing correctly on 20 questions is 1/5^20. These are virtually zero. Just take four questions. Guessing correctly occurs 1/5 x 1/5 x 1/5 x 1/5 or only one time in 625. Imagine how remote the odds are at 20 guesses or 30.

Now that we’ve established that the 800 wasn’t a fluke (the result of lucky guessing), what about the 600? Could it be a fluke? Sure! Maybe her boyfriend broke up with her the week before the test and she was too upset to concentrate. Maybe her mind was on her grandmother’s illness or her family’s financial troubles or that ugly thing one of her classmates said to her going into the exam center. There are lots of possible reasons the 600 might not represent her true aptitude.

We all have an intuitive sense that this is right. Moleculecular bonds are always vibrating in different directions, say, in the materials used to build an airplane engine or in its fuselage. It probably wouldn’t be a good thing if all the bonds vibrated in the exact same direction at the same time, six miles up in the air but we all feel comfortable sitting in that plane because the likelihood of that happening is infinitesimally small. There are just too many ways for the bonds to vibrate in oblique directions mostly cancelling each other out and only one way for them to all vibrate in the same direction. The odds of it happening, one divided by the gozillion different ways the bonds could vibrate at all angles to each other, are too low for it to be feared.