July 23, 2015

Dear Art and other classmates:
Of course I was thrilled to learn you have written a book (Arthur Boylston MD Defying Providence, Smallpox and the Forgotten 18th Century Medical Revolution Createspace Independent Publishing Platform, North Charleston, South Carolina 2012) and looked forward eagerly to reading it.  As usual in my mind, when an idea strikes me another voice immediately contradicts it.  Unfortunately it is frequently the second voice that speaks first, to the consternation of my friends.  In this case the voice said, “A history book.  How quaint.”  That bit of condescension was driven down my imaginary throat to a fare-you-well.  What a book.  There are so many remarkable things about it.

It is very readable.  It employs deftly narrative techniques I usually neglect such as foreshadowing, repetition for emphasis, inserting puzzles to rivet the reader’s mind and later resolving those puzzles.  It is, pardon me if you don’t like the comparison, more like scripture than like the news.  In the news you learn what people have done and that is generally incomplete; they are up to important things you don’t learn about.  In scripture you know the relevant things a character knows, know what was done and why and know how it plays out. 

Thus the characters are well developed.  And the drama includes conflicts between high courage and intelligence plus a desire for the common good against closed minds, misguided greed, political interests that should be unrelated to the question at hand but which distort the conversation and raw untrammeled stupidity.  This clash plays out over the grotesquely dying bodies of uncountable numbers of those with confluent smallpox. 

You bring to your task, as no other historian of your caliber possibly could, a state of the art, authoritative understanding of the immunology at the base of the fact that smallpox given by rubbing contaminated material on the skin (regardless of whether that skin has been first incised) almost invariably causes a clinically mild case of the disease while the same small pox acquired by brushing against the clothing of the same sufferer causes catastrophic illness, frequently and horribly lethal.  As we used to say, “Wow.” 

And your scholarship is so exhaustive that I truly believe it is complete.  I’d not say anything so absolute about many things in my life. 

So much for the appeal of the book to the general reader.  For me personally there is more. 

I think I remember you are related to Zabdiel Boylston, that early hero in your story whose meticulous and courageous work saved so many and who contributed to the ongoing intellectual development of the 18th century, whose success quite probably turned the American Revolution from a piteous catastrophe to a triumph that astonishes the world.  Is that true?   

Another point is that the part of the story that concerns Zabdiel is played out in Boston.  Since we went to school there I was smitten with a sort of pleasant nostalgia, remembering walking the same streets where heroes trod in a time now almost mythical in the common mind. 

Again for me personally, there is the recounting of debates in the Royal Society of Britain.  Given what was available to them, their judgment was often remarkably good.  From my end, there is a paper – John Calhoun, Death Squared: The Explosive Growth and Demise of a Mouse Population Proceedings of the Royal Society of Medicine vol. 66, January 1973 page 80 – presented to the same august body more recently.  My own work largely consists of stitching together far flung articles in top refereed journals.   Calhoun’s experiment cuts to the chase.  (Of course neither he, I nor anybody else had at the time any suspicion of the question of what epigenetic change causes a population of mammals to die out if they are permitted to increase without limit.)  He simply created a mouse utopia with ample room, food and bedding, well protected from outside threat and added four healthy males and four healthy females and then counted mice for years.  Their fertility collapsed.  The mice that gave birth on one day contributed to a rise in the population on that day.  On the next day there were no births, nor did births ever resume.  It is a pity they have not kept that paper in mind as Britain’s birth rate has fallen below replacement along with the rest of the developed world.  I get the feeling that although funding was less in those days the quality of mind of members of the Society then exceeded that of the Society or any similar body of scientists today.  But they did publish this immensely important paper.

There is one dark corner that even you treat as a minor embarrassment.  Jenner

[I mean of course Edward Jenner, whose work started the “vaccination” movement (standing as it were on the shoulders of the giant “inoculation movement”) that ultimately wiped clinical smallpox from the earth, (And of course by now has left the world 100% susceptible to smallpox since the last benefit of vaccination has long since worn off. gI imagine the DNA code for smallpox is public property and any loon with the knowledge and rather cheap tools can make his own so don’t spend any more time than you must hanging around airportsg).  Of course if you Google “Jenner” your results will be quite different from what you would have got not so many years ago.]

… back from digressions … Jenner supported using the relatively mild cowpox virus to protect people against the dreadful smallpox rather than raw, unreconstructed smallpox virus.  For this he is duly honored.  But he thought cowpox itself was “grease,” a disease of horse hooves, that had got into cows.  We forgive him for his silly … STOP.  Think about that again.  We have this “thing.”  Germs haven’t been discovered yet, but there is this thing.  It has a characteristic effect in horses.  So it is a specific thing.  So it is a species.  We took this species from its usual environment, a horse, and put it in a new environment, sheep, and now it behaves in a different characteristic way.  Right?  Since cowpox is just as specific as “grease,” we have a new species.  So when you put a species into a new environment it can change into a species appropriate to that environment.

Got it?  You can throw around words like “selection,” “survival of the fittest,” “evolution” and “speciation” all you like.  Jenner got there first.  You have an interest in how remarkable the 18th century was for scientific advance, and here’s another.  Of course we now believe it didn’t happen.  And Jenner’s experiment might have needed hundreds or thousands of generations to pan out if it was going to work.  But he thought of it, and that’s not an embarrassing dark corner.  He anticipated Alfred Russel Wallace and Charles Darwin. 

Again on a personal note the champions of your tale save lives, including the lives of babies.  Let me give you my own, rather idiosyncratic definition of a baby.  Traditionally an impending baby would have been diagnosed when the mother missed a period.  This has been pushed back by many to the moment when the embryo implants on the uterine wall.  “Life begins at implantation,” so to speak. It is quite logical to push it back farther to, “Life begins at fertilization.”  The zygote is the first stage of personhood.  But there are popular birth control measures that prevent implantation, and lots of people would rather call those methods ways or preventing rather than ways of terminating a pregnancy.  I push it back farther.  I say when a healthy sperm from a man hoping for a pregnancy reaches a healthy ovum from a woman intending a pregnancy that is a baby.  At that moment the DNA complement of the person in ensuing life is established.  If you have done anything to present the sperm and ovum from forming a zygote, you have killed a baby.  The only way of doing that I know of is to have insufficient consanguinity between the couple.  Anything that prevents the zygote from developing, assuming standard environmental needs, into a viable independent organism, has also killed a baby.  Again, lack of consanguinity is the keystone need.  I do not demand anybody else agree to this definition, although I find it quite logical.  But you need to understand it when I say, “I have devoted many years and expect to devote my remaining proactive time to saving babies.

We know that vaccination with cowpox virus or inoculation with smallpox virus can preempt the development of the dreaded disease of smallpox if it is encountered in the environment.  So at what age can it be done?  If there is a chance that the mother is immune, then ideally it should not be done on a newborn.  It may have inherited antibodies from the mother that prevent the vaccination or inoculation from taking.   The current recommendation, so far as I can learn, for chicken pox is that the first shot can be given between the ages of 12 and 18 months.  I would imagine that if clinical smallpox were still in the environment, that would be a reasonable time for inoculation or vaccination.  So for immunization purposes, “Life begins at 12 months.”  Still the difference is less than about two years, so I have a feeling of common interest although I cannot claim similar brilliance, courage or success.

There is also the issue of mothers.  Women generally don’t die from not getting pregnant although there are exceptions in benighted parts of the world where her life may be in danger from others in the tribe and I imagine, without ever hearing of a case, that women have committed suicide for that reason.  While your paladins were saving lives, one of the most vulnerable were pregnant women.  They could not even be inoculated without developing the ghastly consequences of full blown smallpox.  The women I pity are the untold millions who will cry themselves to sleep tonight because they can’t get pregnant. 

Again on a personal note, when I look at the drama I see strong men, of course at the time it was pretty much men, screaming and cursing and demonizing each other over disagreements on whether inoculation was good or harmful and then years later whether vaccination was better or worse than inoculation.  I writhe with envy.  If I can’t have friends at least send me people to revile me and persecute me and say all manner of evil against me falsely.  That seems to be the usual way ahead.  Ah for a hundred of the best minds in medicine, recently reached retirement age so their experience is maximal and current, their networks still in place, their prestige mind boggling and best of all they are for the first time in their lives no threat to anybody, not scoping out somebody else’s job, neither to be stabbed in the back nor motivated to stab anyone in the back, not importuned by sycophantic grad students trying to wangle a position, well aware that this years golden wisdom maybe next year’s trap.  Surely then I would need but say, “Marry in or Die Out,” it’s Robin Fox’s chapter in Handbook on Evolution and Society.  I can lend you a copy if your librarian won’t buy it or can’t find it or if you are so mired in penury you can’t cough up a couple hundred smackers for Amazon,” Truly, truly I say then they would check the references, fire messages back and forth to each other, judge the matter on its merits and not on my pathetic presentation and then together consolidate into an ad hoc honorary society and tell the world.  Oh, I’m sorry.  I’ve got those things.  It’s you.  Well maybe soon, eh what? 

Clinging to personal perspective before descending into madness in the next section, the fact is I’ve got the shingles.  Last year I was saying, “What’s wrong with me?  I’ve undertaken the most important task since humans began.  It’s going very badly.  I should have some sort of psychological malfunction or a psychosomatic disease.  I’d be crazy if I didn’t.”

Then came the bronchospasm.  Never had it in my life.  It was so bad I got asphyxiation arousal.  I knew such a thing existed.  There are people who do it to themselves, I ken not why.  But with the help of fistfuls of pills, an inhaler and a bunch of stuff done by the friendly ER doc it went away.  I was almost feeling decent when the shingles descended, and terrible was its wrath.  It lasted, and lasted, and lasted … it hit me in February and here it is July.  It still hurts, but the sores are all healed.  I was feeling good enough to set up with some friends to get pictures of Florida Man.  I’m sure you are keeping an eye on nobabies.net so as to be able to follow his adventures about once a month.  Did the shoot.   Read the book.  Got a relapse while reading the book.  Yesterday I called in sick to work.  Can’t work with running sores. Well I could do it, but it’s volunteer work at the health department where little indigent babies are brought in for their chickenpox shots.  Of course the part about current knowledge of immunity against viruses was, shall we say, of more than ordinary interest to me.  You might not be so eager.  Goodness knows I hope it doesn’t give anybody else shingles.  Maybe this is the end of my psychosomatic catastrophe.  There’s hope.

And finally the promised insanity.  You mention two locations where inoculation may have been the most ancient; that is to say North Africa and Wales.  Your study, as I have suggested, is so thorough that I am happy to rule our Tierra del Fuego and Ulan Bator from consideration right off the bat.  Now inoculation is most strange in that it is counterintuitive that it might work (Usually we deal with contagious disease by avoiding it, smallpox as you say being the only one where it is helpful under the right circumstances it actually helps) and it only works for smallpox.  Might it have been invented only once?   What contact has there been between North Africa and Wales?  Not so very much in historical times.  But the Rh negative blood type has a rather strange distribution in that it can be traced from Sudan and across North Africa, particularly among the Berbers, up to the Basque country then northern Ireland and Scotland and finally there is a little blip in Bergen in Norway.  Alas my reference is an ancient Scientific American article – I think it may have been by Cavelli-Sforza – that I cannot lay a hand on any longer, but which if memory serves contained a map of the distribution of Rh negative blood.  The allele is widespread in Europe, Africa and the Middle East but tapers off strongly as one proceeds eastward.   There was no inclusion of the Western Hemisphere so I am forced to think that it was very rare here before the advent of the European. 

My most recent understanding of human prehistory is that some tens of thousands of years ago we were reduced to the equivalent of a single band.  So was that band Rh negative or positive?  It is quite likely that it was one or the other.  In a small group, unless the allelic frequency is nicely balanced the majority type will drive the minority to extinction.  The danger of the locus of course is that an Rh positive fetus carried by an Rh negative mother, unless it be the first such pregnancy, is likely to be injured or killed by the mother’s immune reaction.  This involves something about the relevant antibodies being able to cross the placenta while the anti blood type A and anti blood type B antibodies cannot.  The fetus of course has to carry the Rh (yes, I know, that’s archaic terminology but I’m in an archaic mind set just now) positive allele since it is itself is Rh positive and must also carry the Rh negative allele since the mother must be homozygous Rh negative at the site in order to be phenotypically Rh negative.  So the dead offspring always carries off one of each type of allele and slowly reduces the minority type until it is lost.

I am given to understand that there are a large number of different alleles that are Rh negative and clinically indistinguishable.  I have never heard whether there are a similar number of Rh  positive alleles.  It would seem logical that whichever type has the most alleles is our ancestral type going back to that night around the campfire when we were all siblings and close cousins.  Then there was a mutation that either knocked out the function of an allele or restored the function of a previously silenced allele (Apes are, I think, Rh positive, so it is not implausible that the allele had been silenced but was sitting around to be awakened by a single mutation.) 

So whatever we were at that family gathering the mutation later entered and both types went in all directions although once entering Asia the negative type lost the genetic lottery.  The coastwise trail across the Mediterranean and up the west coast of Europe was but one of many. 

Also in Sudan there is evidence of megalithic architecture.  Such architecture is found worldwide, but there is a hint that it is disproportionately traceable up through Egypt, across the Mediterranean, this time a bit more conspicuous in Malta but still present in North Africa, up the west coast of Europe, including Wales and on to Scotland and certain islands, the Faroe Islands seeming to be the end of the spoor.  So one might well hypothesize that the megalithic migration and the Rh negative migration were one and the same.  And, hold your hat, that migration might have carried knowledge of inoculation.  In that case the invention must be quite old indeed. 

I told you this was crazy.  Anyway, thanks for producing your splendid book.  It has caused my brain to stretch and feel good.

I find I am left with one more thought.  You explain clearly how smallpox contracted through the skin induces a superb immune response and minimal, for that disease, symptoms while smallpox contracted through the airway produces a poor immune response and terrible symptoms.  You tell us that smallpox is the only disease for which this is true.  Are you quite sure?  Has it indeed been tried on the common cold and the flu?  Preparing the flu vaccine takes many months so that you can wind up with a vaccine that is directed toward the wrong virus as happened last year.  If inoculation through the skin would be effective then a bunch of Band-Aids impregnated with the bug should be quick and easy to produce.  Once it was quite clear what the virus d’année was then immunization could outpace the infection. 

Class at large: I put this question to Art and he was kind enough to send the following clarification.

”A point about why it worked is that the virus was epidermotrophic ie it infected skin cells and began to replicate. Cells sense foreign DNA and begin making a range of cytokines which attract inflammatory cells and trigger an immune response. Chickenpox virus would probably do the same thing, but other viruses which do not penetrate and replicate in skin cells probably would not. Hence inoculation would probably only work for members of the pox virus family and perhaps a few other minor viruses. Still, if you were into working with camels I think that camelpox would work.” Best wishes,

And best wishes to you all,

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