Hello, everybody. Today we have the long-awaited episode of Filth in America podcast on syphilis. I say the long-awaited because in conversations that I have with listeners to this particular show and other folks working in public health, in health departments and clinics around the country, this has been a topic that has been requested over and over again. Partly because I think this is something that health departments and public health personnel, both clinically and administratively, have had to deal with more in recent years than perhaps when they came into the field. It is also a disease difficult to study, but we have in very recent history actually some new data that I think has pretty much clarified the origin study. And like so many other public health issues that we deal with these days, it is a disease, an entity that we know quite a lot about, that we have good solutions, but yet the incidence of syphilis in America and indeed the world today is going up. There has been a syphilis spike. Some have argued that it's been brewing for decades. Between 2018 and 2022, kind of the pandemic bookends, the reported cases of syphilis actually rose 80%. By 2022, cases of congenital syphilis were 10 times higher than they were in 2012. So there's a lot going on in the syphilis world. So we're going to dive into that today and talk about syphilis, one of the long-standing public health problems and scourges of humanity. Now, syphilis, of course, as most people are aware, is a sexually transmitted disease caused by a spiral or corkshoe-shaped bacterial called trypenema palladium. It is a spirochete, and there are at least three more known species that cause disease from this family, what we call trypenemal disease. There's one trypenema pertinu, which causes another disease, which has probably been around longer, called yaws. There's trypenema caridium, which causes a disease referred to as pinta. But of course, it's very difficult to distinguish pinta from some of the other diseases. There is endemic syphilis, which is called is caused from a strain of trypenopalladium endemitium. But one of the challenges that has come up with this organism and the study of this disease is that the four members of this bacterial family that cause disease really are tough to differentiate. It's nearly impossible to differentiate them with morphological or chemical or even immunological methods. DNA methods do work, but it's really hard. Of all of these four, however, syphilis is the sole sexually transmitted trimemal disease. The other diseases are transmitted via direct contact with an individual who is infected. They tend to infect skin and bone and other tissues superficially. And it is a disease that has occupied the minds of folks outside of maybe traditional public health and medical disciplines, because it seems to have a little bit different story as humanity develops, right? with respect to diseases. And that's, you know, here comes the Europeans, and they get into what is now the Dominican Republic and the Caribbean, and they move into the Americas in different iterations and bring with them a lot of European diseases that, of course, the native populations that were indigenous to these regions had never seen before as a population and had no natural immunity to. And these diseases take a horrific toll on the Native peoples, on the indigenous peoples in this area, and are largely responsible for the Europeans' activities in early colonization in the New World. Syphilis, however, really appears to work backwards. It goes the other way running counter. It is the disease that goes back. It appears to have been endemic in a couple of different forms that I'll talk about here in just a second in the New World. And it does appear that as early as Columbus's voyages, the disease got into those that had traveled with Columbus. And some historians have argued even Columbus himself and went back to the New World, causing significant problems. And this coincided with wars and other things that were going on in Europe at the time. Now, from the beginning of its descriptions in Europe, which kind of inform and shape a lot of what early syphilis thinking, it was very much a kind of a stigmatized and disgraceful disease against a poorly initially understood sexual disease. Now we understand it quite a bit more. Different populations tended to use it to blame each other, typically blaming it on whoever they happened to be fighting at the time or whoever they didn't like. There are different references to it starting in the late 15th century, again, coinciding with the time of Columbus's expeditions. And of course, different European countries fight each other differently. So the inhabitants of today's Italy, Germany, and the UK called syphilis the French disease or the French pox. The French call it the Neapolitan disease. The Russians call it the Polish disease, and the Polish call it the German disease. The Danish, the Portuguese, and a lot of inhabitants of Northern Africa call it the Spanish disease or the or the Castilian disease. The Turks, Turkish physicians start referring to it as the Christian disease. In Northern India, the Muslims blame the Hindus for the outbreak, and the Hindus blame the Muslims for it, but both of them also blame the Europeans. So from the earliest descriptions of this disease, which really comes to us by 1530, this disease is associated with a lot of finger pointing and a lot of issues trying to stigmatize other populations. It is, as we'll see in a minute, also very much associated with military activities and large-scale wars, which I think is important for us today. Now, as I said, there are some debates that have taken place up through recent years about the origins of syphilis. Triponemal disease itself probably does have an African origin and it's brought around. But as I said, there are multiple diseases caused by tryponemal bacteria. Not all of them are syphilis. There are the sexual and non-sexual, and the three of the four species we now know to these non-sexual diseases, which are described and have spread across the world. There was a movement really starting in the early 2000s and on to kind of dispute this idea, looking at skeletal remains, partly because this disease leaves hallmark signs on certain skeletons. So let's dig into what syphilis actually does, and then we'll talk about kind of these understandings of the origin. The hallmark lesions of syphilis are in the primary phase, right? And it has a chancre or a lesion, which typically is found on the genitals, but it can be found in other parts of the body. Earliest detections can be around the genital region. It's not uncommon for the first lesions to be discovered in the lip or mouth. They can be around. Obviously, given the difference in genital anatomy, the disease where this lesion appears manifests quite differently in males versus females. I think it is fair to say that detection, especially in the early days of syphilis, was more difficult or less common because of where those lesions occurred than on men. So there was that. With these lesions, there is an abundance of spirochetes of these bacteria that are detectable in these lesions. But the spirochete itself is capable of infecting almost any organ or tissue in the body. It can cause a wide variety of clinical manifestations as it moves through. In fact, William Osler, the generally thought of as the father of internal medicine in 1897, really says that the medical student should study syphilis. If you study syphilis, you study all its manifestations, the rest of clinical understanding and understanding how to both assess and evaluate the clinical condition of patients will follow. It's that level of diversity of tissues and important clinical pathological manifestations at that time. And it's actually, and uh, of course, at that time, as we'll see in a second, it was a very, very common disease. So it would be, it would be out there, and it's actually probably more common than I think many people are aware of throughout history. Uh transmission occurs most frequently during sexual contact, although it can also not uncommonly be transmitted via the placenta from other fetus in so-called congenital syphilis. The risk of acquiring of acquiring syphilis after unprotected sex with an individual who has infectious syphilis is about 30 to 50 percent. Rarely it can be transmitted through some nonsexual contact or blood transfusion. The immunologic response is very complex, but that's generally how in the modern era we clinically diagnose. There are a lot of different antibodies that are produced, and there are a lot of immune reactions in untreated syphilis that fail to eradicate the existing infection and then later contribute to tissue degeneration. Unfortunately, patients that are treated early in the natural history of the disease are susceptible to re-infection. Generally, we think of syphilis these days in two major groups: early syphilis, which is less than one year in duration and infectious, and late syphilis, which is syphilis that is present in a person for more than a year, but less in and less infectious than others. So again, the initial tissue reaction is minimal, but the chancers are noticeable. Traditionally, we do think of it as primary, secondary, and either early latent or tertiary syphilis. Primary syphilis are those lesions that we talked about, oftentimes in the genital area, but also possible in other tissue types, and they are accompanied by regional swelling of the lymph nodes, lymptonopathy. There is usually an immunological response at that point, which can help and in some cases rid the body of the disease manifestations at that point. But generally speaking, untreated individuals do not clear the disease from their body as a whole. So you may have had these lesions, and in some cases, they do get better with time. It's not a fast process, but it can get better. But that does not mean you have cleared the spirochete from the body, and several people, a good proportion of people, not 100%, but a good proportion of people will progress on. Secondary syphilis also has lesions that were that typically involve the skin and mucous membranes. Occasionally, in this stage, you will see bone CNS, liver manifestations. And then again, sometimes those lesions do heal on their own, but even when that happens, that doesn't necessarily mean that the spirochete is eliminated from the body, and they can move on to a latent disease period where there's not really signs and symptoms, although lesions may relapse periodically. Finally, you'll get a tertiary disease. You'll get some granulatomous lesions in the skin, mucous membranes. At this point, bones and just about any organ can be involved. However, we do see, in addition to the bone, which different studies put it at maybe 10 to 15 percent of others say about 20 percent of patients get it. It's not an uncommon thing in people that progress to tertiary syphilis, but there is also cardiovascular syphilis, which is an unfortunate complication that can be fatal or lead to too early death and neuro syphilis. Um, but you can definitely get kind of a meningiovascular issue going on. You can cause, you can have in the cardiovascular manifestations some aoritic problems, aortic regurgitation and aneurysms, and all of these things can be really, really problematic. Again, the infectiousness uh does vary as you are in these different phases with the open lesions. You're the most infectious. And unfortunately, that's when these things are spread. Famously, several people in the Americas and around the world that we uh you might be familiar with have had this. Al Capone here in the U.S., the notorious gangster, uh, appears to have died of neuro syphilis. But several artists and authors, Keats was thought to have had it. Uh Dostoevsky and Oscar Wilde were writers that were suffering from syphilis, different folks. Frederick Nietzsche was thought to have had syphilis. In fact, the famous Casanova figure, right, who was known for his so-called excellent techniques of seduction, definitely was thought to have had uh syphilis, among many other sexually transmitted diseases. Famous painters, Moneg, again, Van Gogh, Goya, were thought to have had syphilis. There are those that have argued that Beethoven and Franz Schubert had syphilis. There are other political leaders. Tsar Ivan IV, also known as Ivan the Terrible, was thought to have contracted syphilis uh after the death of his wife. Some authors have actually blamed syphilis and later stages of syphilis for his brutal behavior. Uh King Henry III, Charles V of France, some have argued Henry VIII and George IV, and all kinds of other folks. So this, again, is a disease that has affected a lot. And I think its effect on human history from both a population health and individuals who have had it really can't be overstated. It's really, really not only something that has been a difficult problem to study, but also one that has had numerous manifestations, as many manifestations on human history as I think we can see in clinical history. Now, the debate had gone on for years about both this kind of Columbian theory and this pre-Columbian theory. The Columbian theory is, of course, that it was first contact with Europeans and the indigenous people of the New Worlds in 1492, and that started the spread of syphilis into Europe. Now, there are some people that we said we have questioned this, but that is really, I think, the leading uh theory today, and we'll talk about why. So, you know, the navigators in Columbus's fleet would have brought this affliction back to the New World in 1493. Uh, there are several documents, especially some belonging to some Spanish physicians that were uh there when Columbus returns from America. You know, and that those documents confirm that the disease was encountered for the first time in Europe right around that. And some folks may have actually gotten off the boat with uh symptoms, but one of the physicians specifically acknowledges it as an unknown disease, so far not seen and never described. They see have onsets in 1493 in Barcelona. There are some folks that say that thought at the time he came from Espanola Island, uh, which is in the Galapagos. There are others, uh, other documents at that time that talk about members of the crew already suffering from syphilis at that point. Importantly, another aspect of things that was going on was a conflict in Central Europe. Uh, in 1489, Pope Innocent VIII was in conflict with Ferdinand I of Naples because the Italian king really didn't want to pay his debts to the Pope. And so the Pope offers the Kingdom of Naples to Charles VIII, who was the affable France, and to a certain extent, you know, he had some claims to it. Um in 1494, Ferdinand I dies, and as a successor, Alfonso II, who declares allegiance where he lines up with the Duchy of Milan. And so this prompts a war because you have in Milan the Sforza family, these folks. And at the end of 1494, just one year after the return of Columbus from his first expedition to America, Charles VIII enters Italy with an army of 25,000 men, most of whom are mercenaries. Uh they're Swiss and Spanish, Italian mercenaries, Flamin' mercenaries, and they enter Rome. And most sources, both of the invaders and the invaded, say that there was just a life of limited depravity among these mercenaries. By 1495, February 1495, Charles VIII's army enters Naples without really a whole lot of resistance, and they they have about a thousand German and Spanish mercenaries, too, that are uh defending Naples, including about a thousand Italians too. The French army was received well for people wanting to kind of clean all this up, but there too, this depravity and thefts and all of this goes on, and then Charles VIII, uh, when he starts getting power, so the Italians all line up and defeat Charles VIII in the Battle of Forniveau in July 1495. Now, it is during this 1495 Battle of Forniveau that Italian physicians describe for the first time. This disease that they see on the French soldiers' bodies manifested as a generalized eruption consisting of pustules. And they said it was more terrifying than leprosy, more terrifying than elephantiasis, and that it could be lethal, and that it was transmitted through sexual intercourse. And of course, this is very consistent with what we now call syphilis, although, as we said, the initial descriptions did not call it syphilis. And the French army gets blamed for spreading this throughout Italy. So, you know, these war conditions really represent a favorable feel for the first outbreak of syphilis. You have large populations on the move, engaging in a lot of sexual contact, a lot of things going on up and down. You know, all these different uh powers of Europe are going for, and of course, the armies are made up of mercenaries. So you have all kinds of people mixing all kinds of things, and you have marriages, but also rapes and prostitution, and all these different things go on. Um, and the disease is described in this period as a disease of great severity, a rapid spreading, atypical to what they were used to seeing. And, you know, this is consistent with a disease new to a population, which is one of the folks of the supporters of this Colombian hypothesis say, like this is the this really supports the idea it was new, and you don't have a whole lot of natural immunity in the European population, and it rapidly becomes endemic uh across Europe. There are other social activities that happen. There are there is the expulsion of the Jews from Spain, uh, and they really say the individuals of Hebrew origins that refuse to convert to Catholicism. So you have a huge number of Jews, about 200,000, uh, that moved to North Africa and Southern Europe on their way. Several of them settled at Rome. They weren't really allowed in Rome, but there is uh an outbreak there, and there is a quite a lot of death during what really appears to be syphilis. So, of course, uh, as with lots of other things, you have this new group of people, so people tend to blame the Jews for that. But really, you see looking at it a pretty discernible path. Now, people have questioned this, and so how do we know uh looking back beyond these kinds of descriptions about it? Well, as I mentioned, there are quite a lot of manifestations of syphilis as it goes. One of those is very distinct in that its uh effect on bone. Now, the other tryponemal diseases also affect bone, but syphilis' effect as the disease progresses, if untreated, uh, is pretty distinct, although a lot of the distinctions were not necessarily easy to say from just gross large-scale visual examination of bones. There were some hallmark distinctions. There's a very distinct thing that you see in the back of skulls and some other bones around that are that are definitely distinctive for syphilis, but it wasn't as clear as you as you might think. And uh it wasn't really until kind of in the early 2000s that there were some additional refinements to the ability to study bone, microscopic evaluations, and so on, that really clarified. So when you look at older records where they're looking at evidence from bones to see where this disease is, there is a little bit of error that comes into it that has been recently clarified. Most historians and anthropologists and whatnot started looking back to see if there was evidence of the disease in Europe before 1492. There is ample evidence uh from all over the New World of the disease, quite a lot from Peru, but it goes all the way up to Alaska, in what is now the United States, in Mexico. So syphilis was a fairly known and widespread disease. We we have evidence for tryponemal disease in the New World from certainly as long ago as 8,000 years ago, maybe 9,000 years ago. We see evidence uh of tryponemal disease and more recently syphilis. There were those that looked at skeletal remains in Europe and appeared to see uh some evidence of syphilis before 1492. And so they said, well, look, this is this kind of would debunk the idea of a New World disease back. However, that was a very small size. The methodology in some cases was questionable, in some cases was good, but they didn't have the benefit of some of the new anthropological techniques looking at bone. Nobody, I think, at the time thought that the uh skeleton remains from Europe that had these lesions were definitively syphilis. It was just they had similar things going on. And uh several authors began to really dig in and try to debunk this uh in the 2000s. Now, I don't think that the you know, the pre-Columbian concept, the idea that this was circulating widely all over, was ever the dominant theory. Scholars that were in this school of thought said, well, you know, that there are these diseases, but oftentimes it was pretty clear that we had a mix up with leprosy or other clinical diseases we can go back and find evidence of. The, like said, the samples, the number of remains found with lesions that some folks might argue were syphilis, not definitively, was very, very small. And there were issues with the radiocarbon dating that were that was used. A lot of these were coastal and therefore had a lot of uh seafood diet, which can affect some radiocarbon techniques for radiocarbon dating. Uh if you control for this, it definitely looks like the remains are not quite as old as some authors had originally found. But when you look at remains from Mexico, Chile, Argentina, Peru, uh, we definitely see syphilis. We definitely see various forms of this illness going on. I don't think anybody questions that it was there. We definitely have evidence of syphilis in the Dominica at the site where Columbus landed in the mid-2000s, around 2005. There were some revisions to the techniques for examining bone. Those authors very distinctly said that it was clear from their investigations that there really wasn't any evidence in Europe before 1492 of syphilis based on their examination of skeletal remains and re-examination of previously examined skeletal remains. But yet there was extensive evidence going way, way, way back to in the New World. Um the oldest artistic description we have of syphilis is actually on a jug or Voz from Peru, uh, where we see a mother and a baby that have what really clearly appears to be syphilis, and there are other jugs uh identifying different diseases. Leprosy in particular is in a separate jug, so it was clear that there was a differing disease. And by 2024, there was a a landmark publication that was out in science that showed that syphilis was, again, very prevalent in the New World prior to first contact with Europeans, but not really prevalent uh in Europe. These scientists used updated new, more sensitive DNA-based techniques, and they were able to find it. So now we have the skeletal data with advanced techniques that weren't previously available, and the most advanced DNA techniques, which are much, much better for this sort of thing than DNA techniques that had been previously available, and of course, only that's only been available for a little while, older, you know, historic, um, not a fit dependent of any DNA things. And they definitely find that there was a disease that was that started appearing in Europe after 1492 that coincides with these wars, where we see the first descriptions of uh syphilis going on. And it was a not uncommon disease, although different in the New World. Now, they also say that yaws, another manifestation of triponial disease that is not syphilis, that's caused a little bit differently from a different bacterial strain, is there. But the other thing that the newer DNA techniques allow is you can kind of work backwards, right? You can come up with a lineage. Where do we see this? What is it similar? You can come up with a tree, a phylogenetic tree of these things. And interestingly, the syphilis that we see today, and the syphilis that we saw for the last uh 100, uh 150 years or so, was different than Yaw. It wasn't as closely related to Yaws and some of these other dynamics um tryponemal diseases. It also was a little bit different than the syphilitic disease that you saw before 1500 in the New World. And working backwards, looking at you know, the rate of mutations and changes and so on, it appears that unfortunately for the world, and certainly for the European uh explorers, there was a new emergence of trypenebal disease just before 1500, right around the time Columbus gets to the New World. And it is the modern morviliant, sexually transmitted triple needle disease that we know as syphilis. So it may have been a different form of illness that was in the New World indigenous populations and spreading, and this new event, some sort of genetic event happened just before 1500, right around time of first contact with Europeans, that led to the emergence of this new disease, which then spread to Europe and spread all over Europe and then around. So you have multiple manifestations. So I think, while again, you never can say 100% without any sort of reason for further discussion uh about it, I think we're pretty close. I think we we pretty much know that it was this disease which emerged just before 1500 in the New World that was contracted by uh some of the sailors on Columbus's voyage and then was brought back to Europe and found very favorable conditions in the wars that were going on at the same time in Europe where a lot of these folks went. Now, our modern description of the disease of syphilis actually comes from 1530. In fact, the name syphilis comes from that description of an Italian physician. Now, at that same time, Europeans were already speculating that it was an imported disease from the Americans. So this is again not new that they recognized uh this particular uh illness as largely a new thing. But this was a description of this very virulent disease that is around certainly in Italian literature in 1530, in Italian medical discussions uh in 1530. And that's largely again a consequence of the really significant issues that are happening as a result of this particular disease. So it is named and it's actually looped in more at that point with diseases like uh gonorrhea and other sexually transmitted diseases that are going on. So I think we can look at that as our modern origin. Syphilis is the name of a shepherd in mythology who, and according to some of these mythological stories, curses Apollo, the god Apollo, and wants to worship the king. And Apollo then kind of curses the shepherd with this particular disease in uh this poem, The Allegory of Syphilis. And he ha, and that's where the name comes from, and then it goes around and actually ultimately affects the king in this poem, uh, and other figures like Telus and whatnot. And the there was kind of this imploring to repent and get rid of this scourge, apologize to Apollo, apologize to other things, which apparently does happen. And Telus provides humanity with a tree, uh, which produces a gum that was largely used as an early treatment for syphilis. Now, in the New World, there were several topical plant-based treatments that were available for syphilis. But yeah, there was an allegory of syphilis. That was a poem, and syphilis was the name of this shepherd in the poem. That's where the name comes from. And this this disease was described by 1530. So it goes forward. And again, we don't really see a whole lot of references in Europe before that, but we do see references in the Americas. Now, there are a lot of studies of syphilis going forward, right? There is the next big leap for us is in 1767. There's definitely an effort to distinguish between gonorrhea, canceroid syphilis as distinct maladies. There were several doctors who started treating gonorrhea as a separate entity. Uh, unfortunately, there was a physician in 1767 by the name of John Hunter, and he was a very famous kind of uh venereal disease physician, as they called it, or special disease physician. Um, and he conducted an experiment uh which consisted of inoculating the urethral secretion of a gonorrhea patient into a healthy patient. And then the last developed syphilis, and so he said gonorrhea and syphilis are the same disease, according to his mind. What Hunter misses out from, that we now know, was that the patient from whom this secretion was taken had both syphilis and gonorrhea. Uh, but that really delays the differential diagnosis. And again, remember, microbiologically, we can't see these things yet, and even today they're very difficult to do. In 1831, a guy by the name of Record did a larger study on syphilis and gonorrhea and showed definitively that the gonorrhea only occurs after contact with gonorrhea patients, and syphilis only occurs after sexual contact with syphilis patients. So that is really the definitive moment when there's really no doubt that this is separate from other sexually transmitted diseases, despite the fact that disease has been described for 300 years or so at that point. It wasn't, though, until 1905 that Sheldon and Hoffman discover the etiologic agent, which they named asparakeet. They find it in uh the syphilis lesions. They prove it's exemption both in fresh and then stained and colored with GIMSA. So they then changed the name of that bacteria to Trimponemopalladium that we still have today. By 1906, Landsteiner uses dark field microscopy for the detection of the spirochete. So this is the first time we're really able to start seeing this in a diagnostically practical method. By 1910, German bacteriologist, um guy by the name of August Wassermann, comes up with the first serologic test, right? So doing serology to test it. And by 1949, Nelson and Mayer conceived the TPI, the tryponema palladium immolization test, which is the first specific test for trypenema. Trypenema palladium. So all of these things are really slow progressions of diagnosis. I mean, think about a disease that has been described in medical literature since 1530, but we don't really get a truly specific test until 1949. That's one of the struggles with this particular illness, right? As common as it is, as much as as many people who um are affected with it, right, we don't really till 1949 truly have a very good practical test. Today we have a variety of other anybody's tests, RPR is very common, and other tests can be definitive and are fairly fast. So when you're you you have all these issues, whether it's the bone things or the DNA things or the microbiological aspect that make it a little tougher, it has delayed our understanding and given rise to other ways of looking at syphilis. And this is a good connection you see there between the basic science developments and the public health and clinical medicine developments. Now, initially there were treatments, of course, there were lots of different ones that may have not been all that effective. They might have been painful, might have had adverse reactions. You know, obviously some of the first treatments were plants that were in the New World, the guac tree, again, uh, and there's references of this going way, way, way back. Um, that guag tree, uh, guacum officinale, which is also known as the sassafras or willow. That was the most widely recognized treatment in the early parts. And of course, those trees were brought back from the New World to Europe. Um, now those plants were kind of purgitive agents. Uh they did lead to diarrhea, increasing urinary debt, and they were really thought of as blood cleansers for this bad blood. So you get this connection of syphilis to bad blood, and these were treatments that were not only advocated by physicians, but also priests, really saying that this is um something that should go on, should go on. There was also early uh uses of mercury. You know, there were very, very early on, and in fact, some people uh really liked the glyacree treatments because mercury was so problematic. Of course, it's been used in Arabic medicine for the treatment of dermatomes as well as leprosy. Uh it was widely used in Europe, and as the Europeans came to the Americas, it was widely used there. It's a very potent diuretic, uh, which of course causes excessive salivation too when it gets up to toxic doses. But at the time, it was thought that you could eliminate this pestilence from the body through sweat, salivation, and diuresis. So mercury that causes these things to happen is a logical choice. So they mix it with grease and typically would administer it topically in high doses. Of course, this leads to ulcerations, but it is widely used for sexually transmitted diseases in a long, in a long, long way up until the antibiotic era in the early 20th century. So there is also something developed called the Barbarossa pill, which is named after a Turkish admiral who gave the pill to his soldiers. He he also apparently had syphilis. There was that particular pill form, had mercury and some perfumes and fruit. And again, you might have had some efficacy. The mercury, being so toxic, did kill the bacteria. But of course, it had the set effect of possibly killing the person too. So that's not so great. But it was used. Merculus chloride or calomel was administered orally or topically. They also did therapeutic fumigation with it. And patients, you know, they might like it, but they may not like it, but they did seem to tolerate it. But you did get a lot of systemic intoxications with these particular. Particular treatments. So mercury isn't ideal. There are some other treatments that are approached later, particularly in the U.S., you see the addition of bismuth into the treatment regiment. So you're giving these two heavy metals to get the best. And you do get resolution, particularly primary syphilis doing this. And in fact, these are widely and very common used treatments, commonly used treatments in the U.S. up through, again, the advent of penicillin, really before 1943. These are the treatments that are standard, right? And there are lots of discussions and lots of writings about how to do this. This was a standard thing that was part of medical education. And it was very, it was thought as a very straightforward thing. This is you give mercury and we balance it and we manage all of the symptoms, but we can get resolution. Now, again, there's a lot of problems. It wasn't as effective as you might think, but it did, it did work. And it was, you know, right kind of at the end of its utilization with the advent of penicillin, uh, something that most physicians could do pretty well. There were large syphilis clinics around, and they would manage these things and get very good results managing other things. One of the other treatments that that comes up is a fever-based treatment. Now, the spirochete is somewhat sensitive to heat. It does not do particularly well with fevers. So you get people looking at ways to induce fevers. So you have people looking at that. You have known microbiologic names like Paul Ehrlich. He actually got the Nobel Prize in Physiology and Medicine in 1908 for his discovery of arsphenamine, salversan. He discovered it, which kind of acts like an antibiotic, but he kind of develops it somewhat by accident when he's looking at finding a cure for other things. He's the first one who's really trying to look for this magical bullet, so a drug trying to do something to a bacteria without causing all these toxic effects. Uh salversan was actually called compound 606 because it was discovered after 606 failed experiments. There was then a safer novel drug that came right after it called neosarvarsin, which was an uh an arsenic-based compound. So those two compounds with bismuth and mercury were really the treatment from the 1880s until 1940, 43, somewhere in there. The fever was an interesting story. Um, again, syphilis is so widespread, particularly in Europe and the Americas, and they're looking at it, and it's very difficult to treat, and not everybody could tolerate these toxic heavy metals, because even civil certain is safer, but it's still arsenic-based. So they don't really have at this point a true antibiotic. So it was discovered that because the spirocheg is so sensitive to heat, that if you induce malaria, that is to say, you take blood or other fluids from a patient who has malaria at a time when they have apparent malarial parasites in the blood. You can see them in a microscope, they're having a kind of a relapsing malarial crisis, and you inject that into a patient with syphilis, that the high relapsing fevers that occur, the hallmark of malaria, actually will kill the syphilis spirochene. And then, of course, by certainly the early as early 20th century, but throughout the 19th century, quinine had been known and discovered and was very effective at eliminating malaria. So we had a treatment for malaria. So you take your syphilis person, we don't have great treatments for, give them malaria, the malaria fevers then will kill the syphilis, and then you give them quinine to kill the malaria that you gave them, which is very effective, particularly at that time, and off you go. And this was so effective that he too received the Nobel Prize for Physiology Medicine in 1927. And that therapy was used. Now, uh later, certainly by the late 30s, 1940s, a lot of physicians were really more interested in trying to optimize the heavy metal doses and do it that rather than the febra, but it was definitely used. It was definitely used here at Vanderbilt, definitely used other places. So you have all these different approaches until the hallmark discovery of penicillin. And unless you know the story of the penicillin with Alexander Fleming and others, looking in the molds, it was developed and widely used around World War II. During that period, the drug was tested against the syphilis bacterium and was found to be very effective. That is to say the trypenema was very susceptible to penicillin. But initially, penicillin was largely reserved for trauma cases, burns, things like that, and wartime needs. So there's a lot of discussion in the mid-40s during World War II about the need to do larger trials looking at syphilis and penicillin. And those are not done till later. But when they are done, they see that penicillin is extremely effective. You don't have all the issues you do with giving somebody heavy metals and these other topicals. You don't have the issues ethically with infecting somebody with a different disease to fix the first disease. So that became the standard, and it is the standard today. And as we said earlier on, despite using this widely since certainly the 1950s, very little, if any, resistance to penicillin among trypenema has occurred. So we have a way to deal with this, and that had allowed a decrease. But it's important to understand, right, that as we've said, syphilis long has an association with wars. There was a large increase in syphilis during the American Civil War as patients move around and prostitution is utilized and other things goes on, so that goes up. And of course, those are chronic, so that really kind of moves to almost an endemic sexual syphilis. World War II and World War I both, particularly World War II, dramatically increases. But prior to World War II, in the 30s, this is a really, really big problem. There are studies done that showed as many as 10 percent, depending on which sampling you look at, of Americans had syphilis of one form or another at any given time. 10 percent. In some European countries, it was as high as 20 percent in some samples. There were really a lot of concern, and that's where these clinics, of which Vannabilt, here where I am, had one, but others, the public health service starts creating syphilis centers around to deal with this, where you could have specialized folks. There was a field of medicine, dermatocephilitology, so you're kind of a syphilis dermatologist who specialized in the treatment of syphilis wherever it happened to occur. And these were oftentimes in academic medical centers where you would have various specialists, because again, as we said, this bacteria can affect so many different tissues throughout the body, and there's different things that have to be done. And of course, the later manifestations would require lots of different specialized care if you can even treat a patient who has that far progressed. So there was a lot going on before the advent. By the 50s, with the advent of penicillin, there's a lot of descriptions of a very high prevalence of syphilis. Again, World War II in this case significantly increases the prevalence of syphilis globally. When you have these huge migrations of populations and the other things that come with war, this association between syphilis and war is very, very clear. So much so that coming out of World War II into the 50s, the Surgeon General of the United States argued that syphilis was among the most important public health problems, if not the primarily important public health problem. And so you really see this emphasis on treating syphilis, getting folks in, and a tremendous large-scale public health activity. A lot of clinics, a lot of funding. The Surgeon General in the 50s, a guy by Navy Perrin, who himself knew quite a lot about syphilis, devotes a huge amount of public health resources to dealing with it. It is one of the primary public health issues at that time, and really had been from the first half of the 20th century. Unfortunately, some of that leads to some of the dark chapters in medical and public health history, and certainly in syphilis history. And that is the Tuskegee, Tuskegee syphilis study. Officially, it was the Tuskegee study of untreated syphilis in the Negro Male, also referred to as the Tuskegee experiment. This was a study that was conducted between 1932 and 1972 by the Public Health Service and the U.S. C DC on a group of 400 African-American men with syphilis, as well as a crow group control group without. Importantly, some of this came up because of the exceedingly high prevalence of syphilis observed in black men at the time. And while the incidence by the 1930s, as we said, was very high across the U.S. population, it was highest in black men. It may have been as much as double what it was in white men. So there was this need to do it, to look at different things. And so the Public Health Service started this study in collaboration with Tuskegee University. At that time, it was called the Tuskegee Institute, which was in Alabama. And the study enrolled 600 improvis African-American sharecroppers from Macon County, Alabama. Of them, 399 had latent syphilis and 201 were not infected. There were private funding, in addition to government funding, that went on. They were definitely trying to design this particular study to be a companion of a 1928 study called the Oslo Study of Untreated syphilis that reported on the pathologic manifestations of untreated syphilis in several hundred white males. So there, you know, there had been this study on white males, but not on black males. And so it was an effort to try to clarify the natural history of the disease in black males. Importantly, tertiary syphilis, the longer-term manifestation, does show a pretty distinctive difference in that cardiovascular manifestations of tertiary syphilis are more common in blacks than neuro syphilis is, the neurological, and the neurological are likewise more common in whites. So there was this thought that there was something different that needed to go on as an incentive for participation in this study. The men were promised free medical care and ultimately promised funeral expenses. The men in this study did receive medical care and mental health care that they wouldn't have otherwise received. But importantly, and I think the long-term problem with this is that they were deceived by the public health service, who never really told them their syphilis status. They provided disguised placebos, ineffective treatments, did diagnostic procedures, some of which were very invasive, like lumbar punctures, and kind of told them as a treatment for just bad blood. The men were initially told that this experiment is only going to last about six months, but it was extended to 40 years. The private funding for the study was actually lost, but the Public Health Service continued the study without telling these men that they would never be treated. None of the infected men were treated with penicillin, despite the fact, you know, certainly after World War II, when penicillin, which had, as we've talked about, really conclusively proven to be the gold standard by 1947 was widely available and was no longer being reserved just for trauma or military use. Uh, that antibiotic was widely available and become the standard treatment. And it went on until 1972, with none of the participants ever actually having been given penicillin. So this went on, I mean, this is uh I think about as egregious a violation of ethical standards. A lot of authors cited as the most infamous biomedical research study in U.S. history. It was only stopped after a whistleblower, after a leak. There were a hundred folks of this group that died from complications of syphilis, 28 died from these direct late-stage syphilis. There were 19 children born to these men that had congenital syphilis. It was only, like we said, uh a result of some whistleblower activity. Uh it actually was publishing clinical data as early as 1934 and 1936. Some of these folks actually were uh were drafted or attempted to be drafted into World War II. Uh they were diagnosed at having syphilis at military induction in order to get it, but the PHS prevented those specific individuals that were diagnosed by the Army from getting the treatment, uh, depriving them of a cure. So you have just really everything going wrong. In fact, they would send these participants letters, last chance for free special treatment, and all of this. By the end of the study, only 74 of the subjects were still alive. Forty of these men's wives had been infected. There was a whistleblower, a guy by the name of Peter Buxton. I was a 29-year-old whistleblower in 1972. Um, and he he really blows the lid off this study and shows what all is going on. And the study was ended almost immediately after he'd done this. The remaining men were taken care of. There were legal settlements and so on. However, there were widespread publicity around this, and a lot of folks truly um, you know, attribute this to modern hesitancy among uh African Americans to seek out care, certainly from government health agencies, but medical care in general. If you ask it, ask those things. There's numerous surveys that show this Tuskegee experiment, or they were experimenting on this and and didn't tell folks. Ultimately, President Clinton apologizes for this. And like I said, there were legal sediments funding the families and the remaining survivors. This not only had this sociocultural impact, right, of increasing hesitancy and skepticism of government public health efforts and government clinical medical efforts, particularly uh in certain minority groups, but also because it was so egregious that there were several different uh things that are the standard of medical ethics that were passed in its aftermath. Starting in 1974, this Tuskegee syphilis experiment directly leads to the passage of the National Research Act. There's a commission that's created at the time to look at regulations governing studies. So within HHS, the Office of Human Research Protection, so HRP, uh, was established to oversee clinical trials, which still does. New studies require informed consent. And in fact, anybody who's been working in clinical trials understands the informed consent is really one of the most important aspects of properly structured clinical trials, one of the most audited and looked at by all kinds of things. They do require communication of diagnosis, accurate reporting of test results, all in the OHRP regulations. Uh IRBs, which include both clinicians, scientists, and lay people, are established and are required for all human subjects research now as a result of the Tuskegee. And all of these types of things, which are really part of it, you know, ensuring the participants are formed, the informants and things are a hallmark of modern clinical trials. All come from this Tuskegee syphilis study. Now, it's fair to say, you know, there was a lot of things in the wake of War II and Nazi experimentation that gave rise to these bioethics comments. That's all true. But the precipitating event for these modern things was, in fact, the Tuskegee experiment, which people did compare to these kind of unaauthorized and horrible things that the Nazis were doing. So this really shapes today. However, despite all of this, you know, we did actually make quite a lot of progress with effective treatment, so much so that the kind of the dermatosphilitology specialty doesn't really exist anymore. We went from these very high numbers of cases in the 1950s steadily downward, uh, with some gaps, some outbreaks, but folks are uh were able to get this treatment. And again, resistance hasn't emerged. Syphilis screening, potentially penicillin treatment is a standard part of prenatal care because the disease can definitely lead to miscarriage or still birth. And in about 40% of cases, babies bored women with untreated syphilis will die from that infection. So they did it. And the infant manifestations are really horrifying, and skin peeling and hepatosplenomegaly, CNS. You know, unfortunately, newborns may only present years later, so that it is a standard part of prenatal care if we have people that get prenatal care. Brittle bones. But it's really a this you know has been a black mark on public health since the Tuskegee. Yeah, we've, you know, the public health kind of regrouped and powered through and has gotten a lot of these things. And syphilis rates typically decreased until 1999. And then in 2000, things start changing, and we start seeing increase. And again, uh a resurgence of discussion about the Tuskegee experiment and others, um, other governmentally supported experiments definitely started coming out. This overall kind of hesitancy about medical interventions coincides with the rise of social media and the spreading of information that isn't necessarily accurate, uh, that a lot of us are dealing with, starts going on. And so, you know, from the late 1990s when there was this belief that the U.S. was on track to beat syphilis, and you know, this this activity around sexually transmitted disease spawned by HIV, you started getting more and more, but all of a sudden it starts changing. And, you know, there this is a disease that screening uh is useful for, but it's kind of inaccurate, right? I mean, not inaccurate, but uh um limited because even if I clear it in the primary stages, you could get it again. It doesn't give you lifelong immunity. So we have to kind of keep working. And then we started seeing a big increase following the 2000s, right? Before that, you know, there was a lot of inference on barrier protections, which will of course help with syphilis transmission as well. But a lot of these things you started seeing an initial increase in men who have sex with men, uh dramatic re-resurgence, and then you start seeing a parallel rise uh in in heterosexuals, which is linked to drug use. We start seeing more and more in women. So it's really having a pretty broad swath of ways that people are getting syphilis. Unfortunately, it is very, very common now. As we said, uh from 2018 to 2022, uh reported cases rose 80 percent in the U.S. Also in 2022, cases of congenital syphilis uh among newborns were 10 times higher, 3,700 cases than they were in 2012. The new applicant does still include a very high proportion of blacks, but also American Indians have been disproportionately affected by this rise. Women are making up a much higher proportion of syphilis cases that we find now. There are really broad based increases. Later studies showed that after 2022 until the present, we have kind of plateaued, right? So there was uh an increase in overall incidence of 1.26 cases per 100,000 person years in January 2017 to 4.88 per 100,000 person years in July 22. That peak has declined by October 2024. It was down nationally to 2.47 cases per 100,000 uh person years. But you think about this is a huge number of people uh out there uh getting it. And so you know a lot of our public health resources are now drawn back into dealing with this uh this particular issue that goes on, even though we have a very effective therapy and a very effective ways of dealing. So I think again, we are at another public health crossroads, uh. certainly in the U.S., where we can decide to engage and beat back these illnesses, or we can decide not to. And the diseases have proven time and time again that they will continue on if we don't do anything about it. So it is one of these interesting diseases that we now have a treatment for. There's no real vaccine or anything, but there is a treatment for it that does work and works better than some treatments for other diseases out there, widely available, inexpensive, but it only works if we use it. And that's really the story of a lot of public health interventions. It only works if we get out there and do the education. It only works if we get out there and administer the interventions that we know how to do. It only works if we tell people about these things and let them know what's going on, what we can do about it, what we know, and importantly what we don't know. So, with that, we'll see you next time on the Filth America podcast. Thank you very much.