Poison to Protection

If you’re paranoid of being poisoned, one possibility is to build immunity. Folklore suggests one king Mithridates of Pontus did just that. He’d take small doses of arsenic amongst other poisons and build up to larger doses, all while fighting Pompey and the Roman empire. An internet search for “arsenic eaters” will lead you to several articles about the famed Styrian arsenic eaters, a small community of Austrian peasants who were tested by consuming arsenic on food and seemed not to suffer any ill effects.

 

If you’re interested in the history, there is a very readable and relatively short article available on JSTOR by John Parascandola: “Pharmacology and Folkore: The Arsenic Eaters of Styria” (Pharmacy in History, 2015, vol. 57, no.1-2, pp. 3-16). I learned that arsenic was considered a possible medicine and cosmetic. I suppose that in low doses it would kill pathogenic bacteria and other microbes that might cause skin blemishes. I learned that the “Styrian defense” was used in murder trials: claiming that the victim regularly consumed arsenic, and perhaps took too much in a fatal dose. I learned that some indigenous populations in the Andes had an arsenic-metabolizing gene, likely from long-term generational exposure to higher arsenic concentrations in the water. And folklore-wise, I learned about a legend of “poison maidens” from India – assassins who could kill you with a kiss, having been “fed poisonous plants and venomous snakes form infancy, becoming immune…”

 

Since I’m interested in the origin of life, and I taught a special topics class on “Metals and Biochemistry” last spring semester, I now pay attention to chemical evolution arguments on why certain substances arrived “later” on the scene. New signaling pathways came into play as eukaryotes and multicellularity came into the story of life on Earth. Why is Mg²⁺ mainly internal and associated with phosphates and nucleic acids, while Ca²⁺ is mainly involved in extracellular signaling? Why are zinc and copper latecomers in various enzymes, nickel and iron are early, and molybdenum shows up somewhere in between? One of the reference books I used in class was The Biological Chemistry of the Elements by R. J. P. Williams and J. J. R. Frausto da Silva. So, I decided to read selections from their companion book, The Natural Selection of the Chemical Elements.

 

While skimming the book, I started to be intrigued by the idea that certain substances that were poisonous and deleterious to early organisms, eventually became incorporated into living systems. This popped up throughout the book, but comes together in the final summary chapter in a section (16.3) on “The environment and evolution”. The authors pose the question: “Did the change in environment drive the evolution or was there just random searching?” They provide a compromise answer in two parts: “(1) a poison, of necessity, gives rise to protection from it; (2) a protection can give rise to functional use so as to increase survival.”

 

Here's my summary of their argument using quotes from the text: “The protection against the poison involves at first greater production of the protein system most useful in handling this poison…” Inorganic poisons result in “sequestration and rejection” by pumping out the bad stuff. Organic poisons are destroyed by enzymes. “Thus, a poison increases the turnover of certain RNA (and proteins) and therefore of exposure of local regions of DNA.” This “exposed” DNA is “more liable to mutation, [thus] selection could drive improved protection… [locally] within that short section of the code… with little effect elsewhere on the DNA. The step from protection to functional use follows the same pattern since protection involves handling the elements and requires knowledge of poisons within the cell. The obvious step is to make the poison an extracellular messenger or part of an enzyme.”

 

As I’ve studied autocatalytic cycles to understand how proto-metabolism arises, I had mainly focused on what substances are favorably incorporated and why. I’ve thought about evolution and system expansion from the point of view of protometabolites acting as catalysts, crummy at first but with increased selection better catalysts persist. I had considered molecular parasites – things that reduce the stoichiometric factor to maintain autocatalysis – but I hadn’t thought about the role of molecular poisons. What if certain nitrogenous compounds were initially “poisonous” in some way (as many are still today)? Perhaps some of these compounds, as they were recognized as such, were then turned into messenger-type molecules which catalyze other reactions to allow system expansion? This is an interesting idea fomenting at the edges of my thought process. I’m not quite sure whether this idea will lead to something concrete I can test, but I’m now reciting the mantra “poison to protection”. And now I get to do more research!