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They tell us that
We lost our tails
Evolving up
From little snails
I say it’s all
Just wind in sails

Are we not men?
We are Citrate!
Are we not men?
D-E-V-O

Monkey men all
In business suits
Teachers and critics
All dance the poot

Are we not men?
We are Megaplates!
Are we not men?
D-E-V-O

Are we not men?
We are Devo!

We must repeat
D-E-V-O

Homo Jocko by Devo. Sort of. That brings back memories. Saw Devo back in medical school. When I was in medical school, not Devo. Fun show. My brother bought an Energy Dome Hat, since, unfortunately, lost.

Monkeypox. I know Dr. Novella discussed the pox lately, but I feel like a little idle speculation on the topic. Emphasis on speculation. Monkeypox, chickenpox, smallpox. Ever wonder that the Great Pox was? Syphilis. So horrible it was worse than the Small Pox. From reports, syphilis was quite the disease when it hit Europe in the 15th century, different clinically and more virulent than the three stages of Lues we have today. Why the difference? Did the spirochete evolve? Did we evolve? Some combination? No one knows.

The standard model is that the Old World gave smallpox to the New and the New World returned the favor with the great pox. Or was syphilis circulating in Europe before Columbus and took an evolutionary jump into virulence? It might be the case.

The researchers managed to recover and sequence Treponemal DNA from four samples and compared the sequences with a modern syphilis strain…the diversity of strains around the time of Columbus’s crossing offers additional evidence that the pathogen had already made a home in Europe.

Syphilis or a pox, understanding infectious diseases is, at its core, applied evolution.1

As an aside, I have always liked the word pox and it is a shame that pox is not more widely used. Medicine has a lot of archaic language that we are poorer for no longer using. And I thought it was “a pox on both your houses”, and had this whole Romeo and Juliet theme plotted when I discovered it was “A plague o’ both your houses! They have made worms’ meat of me”, a quote worthy of any of the plagues of the last 40 years. With over a million dead, COVID-45 has been making worms’ meat of far too many.

An ID consultation has, at its heart, three components: what infection does the patient have, why do they have that infection, and how best to treat it. It is the “why” that is usually the most enjoyable to tease out of the case and the most interesting. Why at the molecular level, the human level, and the societal level. ID docs, as I have said before, are the only truly holistic doctors.

Infections first have to spread. There are three ways to acquire infections: eat it, touch it, or breathe it. If you are a splitter, you could say food or water are subsets of eating and sex as a subset of touching, and breathing has the spectrum from droplets to aerosols. And there are all the odd ways of getting infections: injection drugs or insect bites or transfusions; all subsets of touch. But I will be a lumper for simplicity’s sake.

Then organisms have to adhere to something. The pathogen has to stick to a cell, a protein, a sugar, a receptor. Without binding to something, gaining some toe hold, infections cannot start. I find the adherence of pathogens endlessly interesting. Which is part of why I am never invited to parties. I spent three years of my life trying, and failing, to determine how Candida adhered to endothelial cells. I may have been the world’s worst bench researcher.

COVID has its ACE 2 receptors. HIV, its CD4/Chemokine receptors. Interestingly, these receptors have high density on foreskins which is part of why circumcision is one way to decrease HIV spread. Influenza starts by binding to sugar residues that are common in the upper airway of humans. The good news is that bird flu binds to different sugars, which humans do not have. The bad news? Bird flu is three mutations, or an unfortunate recombination, away from being able to use human upper airway sugars. S. bovis has enhanced ability to adhere to the matrix of bowel cancer which is why bacteremia with that organism warrants an evaluation for gastrointestinal malignancy.

And on and on. Each organism has its preferred binding site, its staging site, from which it can launch its invasion.

Of course, there is the yin of receptors to the yang of pathogen binding. We are all different, a mass of polymorphisms and inherited genetic quirks that may increase or decrease a pathogen’s ability to adhere to us. Most of the polymorphisms that show up in my feeds concern the immune system, but my favorite, and yes I have favorites,2 is mutant snot. If you have the wrong snot, you are at increased risk for invasive Meningococcal disease. Or as a scientist would put it,

A mutation in SPLUNC1 affecting mucosal attachment, biofilm formation, and invasion of mucosal epithelial cells is a new genetic cause of meningococcal disease.

The last stage of infection is the land rush. Pathogens want a wide-open vista with no competition that they can fill with their progeny. Competition comes in many forms: other organisms, immunity, cilia, diarrhea, cough. Get rid on the right type of competition and the organism can spread quickly and widely.

Spread, adhere, land rush.

How would that apply to monkeypox?

Monkeypox is spread by contact and droplets, with perhaps a bit of aerosols. Like smallpox. This is always a question from an infection control perspective. Spread by contact and droplet is the predominant method of spread. But there are always unique circumstances, often human behaviors, that will aid in the spread of disease by both its common route and by less common routes. Want to increase the transmission TB? Hotbox. Transmit more hepatitis C? Invent syringes and needles. Etc. Human behavior can lead to surprising ways to aid pathogen spread.

The smartest (see first footnote) way a pathogen can spread is to be a sexually transmitted disease. Sex brings close contact and is face to face as well as face to many other areas. Humans tend towards polymorphous perversity, although Freud is a crock. I prefer the idea that for humans there is nothing unnatural– just untried. Humans tend to try every possible behavior and with that behavior comes the potential for disease spread. Monkeypox, while not a true STD (yet), is apparently latching on to that method to help spread. But as noted above, sex is just a very intimate form of contact spread.

Being an STD is smart for many reasons. One is that I have noticed that people tend to repeat sexual contacts, giving a pathogen many opportunities to spread. Symptomatic pox may occur in and around an orifice that is not being examined by the afflicted and may not be noticed during passion in a darkened environment. Finally, people will often have sex even if they are not feeling well, i.e., when they are infectious. In the old days before the cause of AIDS was known (let alone HAART), and currently, people continue to have sex while symptomatic for HIV. And one of the risks for acquiring HIV is the presence of a genital ulcer. It was no surprise that that circumcision may have initially increased the acquisition to HIV because the patients did not wait until healed to have sex. I suspect that the presence of the pox, like that of an ulcer or circumcision scab, will not deter many people from having sex.

I have a memory from high school of a Lenny Bruce bit where he is in the ER with his leg cut off and he expresses a willingness to have sex at that moment. I can’t find the bit on the web, so maybe it is a false memory. But the concept is valid.

So if monkeypox is trying to go down the STD its route, this is a wise choice from a transmission perspective.

What about initial binding? For smallpox all I can find is:

The virus binds to host cell receptors via hemagglutinin antigens expressed on its outer surface. The exact mechanism of entry is not yet known.

And unlikely to be known. At least I hope no one is currently doing smallpox transmission studies.

For other pox viruses?

In general, poxviruses show species specificities that range from narrow to broad, but we still know little about the fundamental mechanisms that mediate the host tropism of individual poxviruses. Even if variola virus never again infects humans, there are other poxviruses that can cause serious human disease.

For monkeypox:

The genomes of monkeypox and variola viruses are about 96% similar in the central regions but differ in the terminal regions, the place where most of the virulence and host-range genes are located. Phylogenetic analysis has shown that the variola and monkeypox viruses have a common ancestor but have not evolved one from the other.

Monkeypox and smallpox seem different enough that the former is unlikly to take over the space once occupied by the latter. But there is always the worry given its “wide tissue tropism” that it could settle into humans to become the new syphilis. That would not surprise me.

And for that initial adherence:

…for poxviruses, no specific host-cell receptors have been identified…Therefore, poxviruses can probably bind to and enter a wide range of mammalian cells, but the ability of a given poxvirus to fully complete the replication cycle varies markedly between cells of different lineages or species origins.

So I can’t really glean from the basic starting point of infections for monkeypox if there is a potential for enhanced pathogenicity by increasing adherence in humans. Time will tell, as time is wont to do. But we do know that monkeypox can infect human cells, so it is already halfway there.

Many of the articles mention that DNA viruses do not mutate with the abandon of RNA viruses. I somehow do not find that reassuring. Monkeypox is mutating, as it should:

The genomes from the current outbreak share 40-some mutations with each other that distinguish them from their closest relatives…

Although the significance of these mutations is uncertain.

I keep two studies always in my mind when it comes to organisms mutating for increased fitness in a new environment. The first was by Richard Lenski who grew:

E. coli continuously for about twenty years in his Michigan State lab. For the fast-growing bug, that’s over 40,000 generations!

After 30,000 generations the organisms developed the ability to metabolize citrate as an energy source:

The major point Lenski emphasizes in the paper is the historical contingency of the new ability. It took trillions of cells and 30,000 generations to develop it, and only one of a dozen lines of cells did so. What’s more, Lenski carefully went back to cells from the same line he had frozen away after evolving for fewer generations and showed that, for the most part, only cells that had evolved at least 20,000 generations could give rise to the citrate-using mutation. From this he deduced that a previous, lucky mutation had arisen in the one line, a mutation which was needed before a second mutation could give rise to the new ability. The other lines of cells hadn’t acquired the first, necessarily, lucky, “potentiating” mutation, so they couldn’t go on to develop the second mutation that allows citrate use.

The other study is the megaplate. I will pause here while you watch the video. It’s only two minutes long and it’s the whole picture/thousand words thing. Or maybe video/thousand words. Back? Cool, huh? And scary.

My take home? Humans are citrate. Humans are a megaplate. Since monkeypox has found a nice home in humans, I will not be surprised if it rearranges itself, and us, to make itself more comfortable. Cable. A good chair. High-speed internet. Why wouldn’t it? All it will need is time and replication.

Vaccinia is still circulating in South and Central America in humans and cows. What happens if a monkey pox and a vaccinia infect the same human?

Recombination between co-infecting poxviruses provides an important mechanism for generating the genetic diversity that underpins evolution.

Or monkeypox jumps into US rodents? Congress would be doomed. And it would become endemic in parts of the US. Given:

In New York City, the rat population is about 25% the size of human population – that’s about 2 million rats!

Then ratpox would be a better term for the virus; I hope WHO is paying attention. Or maybe Cagneypox.

Probably nothing will happen. But. To paraphrase the Borg:

We are the microorganisms. Lower your immunity and surrender your cells. We will add your biological and technological distinctiveness to our own. Your biochemistry will adapt to service us. Resistance is futile.

Smallpox vaccination stopped in the US in 1972 and every year since has added a new cohort of monkeypox-susceptible humans. Humans are Oklahoma circa 1889, the monkeypox are lined up waiting to grab their acreage.

So will monkeypox settle into humans for the long haul? It seems a reasonable possibility. HIV did it. COVID-45 did it. Hell, measles did it, by way of rinderpest from cows, about 900 years ago.

Given a chance, it’s what pathogens do.


1 Throughout the essay I am going to use language that will drive real evolutionists crazy, with adjectives that suggest organisms have evolutionary agency. I know they don’t. Maybe it’s sloppy, but I lean towards the colloquial and away from the formal. The Oregon way, where formal dress is tucking your tee shirt into your hiking pants.

2 Part of that whole “not invited to parties” thing.

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  • Mark Crislip, MD has been a practicing Infectious Disease specialist in Portland, Oregon, from 1990 to 2023. He has been voted a US News and World Report best US doctor, best ID doctor in Portland Magazine multiple times, has multiple teaching awards and, most importantly,  the ‘Attending Most Likely To Tell It Like It Is’ by the medical residents at his hospital. His multi-media empire can be found at edgydoc.com.

Posted by Mark Crislip

Mark Crislip, MD has been a practicing Infectious Disease specialist in Portland, Oregon, from 1990 to 2023. He has been voted a US News and World Report best US doctor, best ID doctor in Portland Magazine multiple times, has multiple teaching awards and, most importantly,  the ‘Attending Most Likely To Tell It Like It Is’ by the medical residents at his hospital. His multi-media empire can be found at edgydoc.com.