Trading syphilis for malaria: How doctors treated one deadly disease by infecting patients with another
If you had lived one hundred years ago, syphilis – a bacterial infection spread by sexual contact – would likely have been one of your worst nightmares. Even though syphilis still exists, it can now be detected early and cured quickly with a course of antibiotics. Back then, however, before antibiotics and without an easy way to detect the disease, syphilis was very often a death sentence.
To understand how feared syphilis once was, it’s important to understand exactly what it does if it’s allowed to progress: the infections start off as small, painless sores or even a single sore near the vagina, penis, anus, or mouth. The sores disappear around three to six weeks after the initial infection – but untreated, syphilis moves into a secondary stage, often presenting as a mild rash in various areas of the body (such as the palms of a person’s hands) or through other minor symptoms. The disease progresses from there, often quietly and without noticeable symptoms, sometimes for decades before it reaches its final stages, where it can cause blindness, organ damage, and even dementia. Research indicates, in fact, that as much as 10 percent of psychiatric admissions in the early 20th century were due to dementia caused by syphilis, also known as neurosyphilis.
Like any bacterial disease, syphilis can affect kids, too. Though it’s spread primarily through sexual contact, it can also be transmitted from mother to child during birth, causing lifelong disability.
The poet-physician Aldabert Bettman, who wrote fictionalized poems based on his experiences as a doctor in the 1930s, described the effect syphilis could have on an infant in his poem Daniel Healy:
I always got away clean
when I went out
With the boys.
The night before
I was married
I went out,—But was not so fortunate;
And I infected
My bride.
When little Daniel
Was born
His eyes discharged;
And I dared not tell
That because
I had seen too much
Little Daniel sees not at all
Given the horrors of untreated syphilis, it’s maybe not surprising that people would go to extremes to try and treat it. One of the earliest remedies for syphilis, dating back to 15th century Naples, was using mercury – either rubbing it on the skin where blisters appeared, or breathing it in as a vapor. (Not surprisingly, many people who underwent this type of “treatment” died of mercury poisoning.)
Other primitive treatments included using tinctures made of a flowering plant called guaiacum, as well as inducing “sweat baths” to eliminate the syphilitic toxins. In 1910, an arsenic-based drug called Salvarsan hit the market and was hailed as a “magic bullet” for its ability to target and destroy the syphilis-causing bacteria without harming the patient. However, while Salvarsan was effective in treating early-stage syphilis, it was largely ineffective by the time the infection progressed beyond the second stage. Tens of thousands of people each year continued to die of syphilis or were otherwise shipped off to psychiatric wards due to neurosyphilis.
It was in one of these psychiatric units in the early 20th century that Dr. Julius Wagner-Juaregg got the idea for a potential cure.
Wagner-Juaregg was an Austrian-born physician trained in “experimental pathology” at the University of Vienna. Wagner-Juaregg started his medical career conducting lab experiments on animals and then moved on to work at different psychiatric clinics in Vienna, despite having no training in psychiatry or neurology.
Wagner-Juaregg’s work was controversial to say the least. At the time, medicine – particularly psychiatric medicine – did not have anywhere near the same rigorous ethical standards that doctors, researchers, and other scientists are bound to today. Wagner-Juaregg would devise wild theories about the cause of their psychiatric ailments and then perform experimental procedures in an attempt to cure them. (As just one example, Wagner-Juaregg would sterilize his adolescent male patients, thinking “excessive masturbation” was the cause of their schizophrenia.)
But sometimes these wild theories paid off. In 1883, during his residency, Wagner-Juaregg noted that a female patient with mental illness who had contracted a skin infection and suffered a high fever experienced a sudden (and seemingly miraculous) remission from her psychosis symptoms after the fever had cleared. Wagner-Juaregg theorized that inducing a high fever in his patients with neurosyphilis could help them recover as well.
Eventually, Wagner-Juaregg was able to put his theory to the test. Around 1890, Wagner-Juaregg got his hands on something called tuberculin, a therapeutic treatment created by the German microbiologist Robert Koch in order to cure tuberculosis. Tuberculin would later turn out to be completely ineffective for treating tuberculosis, often creating severe immune responses in patients – but for a short time, Wagner-Juaregg had some success in using tuberculin to help his dementia patients. Giving his patients tuberculin resulted in a high fever – and after completing the treatment, Wagner-Jauregg reported that his patient’s dementia was completely halted. The success was short-lived, however: Wagner-Juaregg eventually had to discontinue tuberculin as a treatment, as it began to be considered too toxic.
By 1917, Wagner-Juaregg’s theory about syphilis and fevers was becoming more credible – and one day a new opportunity presented itself when a wounded soldier, stricken with malaria and a related fever, was accidentally admitted to his psychiatric unit.
When his findings were published in 1918, Wagner-Juaregg’s so-called “fever therapy” swept the globe.
What Wagner-Juaregg did next was ethically deplorable by any standard: Before he allowed the soldier any quinine (the standard treatment for malaria at the time), Wagner-Juaregg took a small sample of the soldier’s blood and inoculated three syphilis patients with the sample, rubbing the blood on their open syphilitic blisters.
It’s unclear how well the malaria treatment worked for those three specific patients – but Wagner-Juaregg’s records show that in the span of one year, he inoculated a total of nine patients with malaria, for the sole purpose of inducing fevers, and six of them made a full recovery. Wagner-Juaregg’s treatment was so successful, in fact, that one of his inoculated patients, an actor who was unable to work due to his dementia, was eventually able to find work again and return to the stage. Two additional patients – a military officer and a clerk – recovered from their once-terminal illnesses and returned to their former careers as well.
When his findings were published in 1918, Wagner-Juaregg’s so-called “fever therapy” swept the globe. The treatment was hailed as a breakthrough – but it still had risks. Malaria itself had a mortality rate of about 15 percent at the time. Many people considered that to be a gamble worth taking, compared to dying a painful, protracted death from syphilis.
Malaria could also be effectively treated much of the time with quinine, whereas other fever-causing illnesses were not so easily treated. Triggering a fever by way of malaria specifically, therefore, became the standard of care.
Tens of thousands of people with syphilitic dementia would go on to be treated with fever therapy until the early 1940s, when a combination of Salvarsan and penicillin caused syphilis infections to decline. Eventually, neurosyphilis became rare, and then nearly unheard of.
Despite his contributions to medicine, it’s important to note that Wagner-Juaregg was most definitely not a person to idolize. In fact, he was an outspoken anti-Semite and proponent of eugenics, arguing that Jews were more prone to mental illness and that people who were mentally ill should be forcibly sterilized. (Wagner-Juaregg later became a Nazi sympathizer during Hitler’s rise to power even though, bizarrely, his first wife was Jewish.) Another problematic issue was that his fever therapy involved experimental treatments on many who, due to their cognitive issues, could not give informed consent.
Lack of consent was also a fundamental problem with the syphilis study at Tuskegee, appalling research that began just 14 years after Wagner-Juaregg published his “fever therapy” findings.
Still, despite his outrageous views, Wagner-Juaregg was awarded the Nobel Prize in Medicine or Physiology in 1927 – and despite some egregious human rights abuses, the miraculous “fever therapy” was partly responsible for taming one of the deadliest plagues in human history.
Ever since he was a baby, Sharon Wong’s son Brandon suffered from rashes, prolonged respiratory issues and vomiting. In 2006, as a young child, he was diagnosed with a severe peanut allergy.
"My son had a history of reacting to traces of peanuts in the air or in food,” says Wong, a food allergy advocate who runs a blog focusing on nut free recipes, cooking techniques and food allergy awareness. “Any participation in school activities, social events, or travel with his peanut allergy required a lot of preparation.”
Peanut allergies affect around a million children in the U.S. Most never outgrow the condition. The problem occurs when the immune system mistakenly views the proteins in peanuts as a threat and releases chemicals to counteract it. This can lead to digestive problems, hives and shortness of breath. For some, like Wong’s son, even exposure to trace amounts of peanuts could be life threatening. They go into anaphylactic shock and need to take a shot of adrenaline as soon as possible.
Typically, people with peanut allergies try to completely avoid them and carry an adrenaline autoinjector like an EpiPen in case of emergencies. This constant vigilance is very stressful, particularly for parents with young children.
“The search for a peanut allergy ‘cure’ has been a vigorous one,” says Claudia Gray, a pediatrician and allergist at Vincent Pallotti Hospital in Cape Town, South Africa. The closest thing to a solution so far, she says, is the process of desensitization, which exposes the patient to gradually increasing doses of peanut allergen to build up a tolerance. The most common type of desensitization is oral immunotherapy, where patients ingest small quantities of peanut powder. It has been effective but there is a risk of anaphylaxis since it involves swallowing the allergen.
"By the end of the trial, my son tolerated approximately 1.5 peanuts," Sharon Wong says.
DBV Technologies, a company based in Montrouge, France has created a skin patch to address this problem. The Viaskin Patch contains a much lower amount of peanut allergen than oral immunotherapy and delivers it through the skin to slowly increase tolerance. This decreases the risk of anaphylaxis.
Wong heard about the peanut patch and wanted her son to take part in an early phase 2 trial for 4-to-11-year-olds.
“We felt that participating in DBV’s peanut patch trial would give him the best chance at desensitization or at least increase his tolerance from a speck of peanut to a peanut,” Wong says. “The daily routine was quite simple, remove the old patch and then apply a new one. By the end of the trial, he tolerated approximately 1.5 peanuts.”
How it works
For DBV Technologies, it all began when pediatric gastroenterologist Pierre-Henri Benhamou teamed up with fellow professor of gastroenterology Christopher Dupont and his brother, engineer Bertrand Dupont. Together they created a more effective skin patch to detect when babies have allergies to cow's milk. Then they realized that the patch could actually be used to treat allergies by promoting tolerance. They decided to focus on peanut allergies first as the more dangerous.
The Viaskin patch utilizes the fact that the skin can promote tolerance to external stimuli. The skin is the body’s first defense. Controlling the extent of the immune response is crucial for the skin. So it has defense mechanisms against external stimuli and can promote tolerance.
The patch consists of an adhesive foam ring with a plastic film on top. A small amount of peanut protein is placed in the center. The adhesive ring is attached to the back of the patient's body. The peanut protein sits above the skin but does not directly touch it. As the patient sweats, water droplets on the inside of the film dissolve the peanut protein, which is then absorbed into the skin.
The peanut protein is then captured by skin cells called Langerhans cells. They play an important role in getting the immune system to tolerate certain external stimuli. Langerhans cells take the peanut protein to lymph nodes which activate T regulatory cells. T regulatory cells suppress the allergic response.
A different patch is applied to the skin every day to increase tolerance. It’s both easy to use and convenient.
“The DBV approach uses much smaller amounts than oral immunotherapy and works through the skin significantly reducing the risk of allergic reactions,” says Edwin H. Kim, the division chief of Pediatric Allergy and Immunology at the University of North Carolina, U.S., and one of the principal investigators of Viaskin’s clinical trials. “By not going through the mouth, the patch also avoids the taste and texture issues. Finally, the ability to apply a patch and immediately go about your day may be very attractive to very busy patients and families.”
Brandon Wong displaying origami figures he folded at an Origami Convention in 2022
Sharon Wong
Clinical trials
Results from DBV's phase 3 trial in children ages 1 to 3 show its potential. For a positive result, patients who could not tolerate 10 milligrams or less of peanut protein had to be able to manage 300 mg or more after 12 months. Toddlers who could already tolerate more than 10 mg needed to be able to manage 1000 mg or more. In the end, 67 percent of subjects using the Viaskin patch met the target as compared to 33 percent of patients taking the placebo dose.
“The Viaskin peanut patch has been studied in several clinical trials to date with promising results,” says Suzanne M. Barshow, assistant professor of medicine in allergy and asthma research at Stanford University School of Medicine in the U.S. “The data shows that it is safe and well-tolerated. Compared to oral immunotherapy, treatment with the patch results in fewer side effects but appears to be less effective in achieving desensitization.”
The primary reason the patch is less potent is that oral immunotherapy uses a larger amount of the allergen. Additionally, absorption of the peanut protein into the skin could be erratic.
Gray also highlights that there is some tradeoff between risk and efficacy.
“The peanut patch is an exciting advance but not as effective as the oral route,” Gray says. “For those patients who are very sensitive to orally ingested peanut in oral immunotherapy or have an aversion to oral peanut, it has a use. So, essentially, the form of immunotherapy will have to be tailored to each patient.” Having different forms such as the Viaskin patch which is applied to the skin or pills that patients can swallow or dissolve under the tongue is helpful.
The hope is that the patch’s efficacy will increase over time. The team is currently running a follow-up trial, where the same patients continue using the patch.
“It is a very important study to show whether the benefit achieved after 12 months on the patch stays stable or hopefully continues to grow with longer duration,” says Kim, who is an investigator in this follow-up trial.
"My son now attends university in Massachusetts, lives on-campus, and eats dorm food. He has so much more freedom," Wong says.
The team is further ahead in the phase 3 follow-up trial for 4-to-11-year-olds. The initial phase 3 trial was not as successful as the trial for kids between one and three. The patch enabled patients to tolerate more peanuts but there was not a significant enough difference compared to the placebo group to be definitive. The follow-up trial showed greater potency. It suggests that the longer patients are on the patch, the stronger its effects.
They’re also testing if making the patch bigger, changing the shape and extending the minimum time it’s worn can improve its benefits in a trial for a new group of 4-to-11 year-olds.
The future
DBV Technologies is using the skin patch to treat cow’s milk allergies in children ages 1 to 17. They’re currently in phase 2 trials.
As for the peanut allergy trials in toddlers, the hope is to see more efficacy soon.
For Wong’s son who took part in the earlier phase 2 trial for 4-to-11-year-olds, the patch has transformed his life.
“My son continues to maintain his peanut tolerance and is not affected by peanut dust in the air or cross-contact,” Wong says. ”He attends university in Massachusetts, lives on-campus, and eats dorm food. He still carries an EpiPen but has so much more freedom than before his clinical trial. We will always be grateful.”
Scientists aim to preserve donkeys, one frozen embryo at a time
Every day for a week in 2022, Andres Gambini, a veterinarian and senior lecturer in animal science at the University of Queensland in Australia, walked into his lab—and headed straight to the video camera. Trained on an array of about 50 donkey embryos, all created by Gambini’s manual in vitro fertilization, or IVF, the camera kept an eye on their developmental progress. To eventually create a viable embryo that could be implanted into a female donkey, the embryos’ cells had to keep dividing, first in two, then in four and so on.
But the embryos weren’t cooperating. Some would start splitting up only to stop a day or two later, and others wouldn’t start at all. Every day he came in, Gambini saw fewer and fewer dividing embryos, so he was losing faith in the effort. “You see many failed attempts and get disappointed,” he says.
Gambini and his team, a group of Argentinian and Spanish researchers, were working to create these embryos because many donkey populations around the world are declining. It may sound counterintuitive that domesticated animals may need preservation, but out of 28 European donkey breeds, 20 are endangered and seven are in critical status. It is partly because of the inbreeding that happened over the course of many years and partly because in today’s Western world donkeys aren’t really used anymore.
“That's the reason why some breeds begin to disappear because humans were not really interested in having that specific breed anymore,” Gambini says. Nonetheless, in Africa, India and Latin America millions of rural families still rely on these hardy creatures for agriculture and transportation. And the only two wild donkey species—Equus africanus in Africa and Equus hemionus in Asia—are also dwindling, due to losing their habitats to human activities, diseases and slow reproduction rates. Gambini’s team wanted to create a way to preserve the animals for the future. “Donkeys are more endangered than people realize,” he says.
There’s much more to donkeys' trouble though. For the past 20 or so years, they have been facing a huge existential threat due to their hide gelatin, a compound derived from their skins by soaking and stewing. In Chinese traditional medicine, the compound, called ejiao, is believed to have a medicinal value, so it’s used in skin creams, added to food and taken in capsules. Centuries ago, ejiao was a very expensive luxury product available only for the emperor and his household. That changed in the 1990s when the Chinese economy boomed, and many people were suddenly able to afford it. “It went from a very elite product to a very popular product,” says Janneke Merkx, a campaign manager at The Donkey Sanctuary, a United Kingdom-based nonprofit organization that keeps tabs on the animals’ welfare worldwide. “It is a status symbol for gift giving.”
Having evolved in the harsh and arid mountainous terrains where food and water were scarce, donkeys are extremely adaptable and hardy. But the Donkey Sanctuary documented cases in which an entire village had their animals disappear overnight, finding them killed and skinned outside their settlement.
The Chinese donkey population was quickly decimated. Unlike many other farm animals, donkeys are finicky breeders. When stressed and unhappy, they don’t procreate, so growing them in large industrial settings isn’t possible. “Donkeys are notoriously slow breeders and really very difficult to farm,” says Merkx. “They are not the same as other livestock like sheep and pigs and cattle.” Within years the, the donkey numbers in China dropped precipitously. “China used to have the largest donkey population in the world in the 1990s. They had 11 million donkeys, and it's now down to less than 3 million, and they just can't keep up with the demand.”
To keep the ejiao conveyor going, some producers turned to the illegal wildlife trade. Poachers began to steal and slaughter donkeys from rural villages in Africa. The Donkey Sanctuary documented cases in which an entire village had their animals disappear overnight, finding them killed and skinned outside their settlement. Exactly how many creatures were lost to the skin trade to-date isn’t possible to calculate, says Faith Burden, the Donkey Sanctuary’s director of equine operations. Traditionally a poor people’s beast of burden, donkey counts are hard to keep track of. “When an animal doesn't produce meat, milk or eggs or whatever edible product, they're often less likely to be acknowledged in a government population census,” Burden says. “So reliable statistics are hard to come by.” The nonprofit estimates that about 4.8 million are slaughtered annually.
During their six to seven thousand years of domestication, donkeys rarely got the full appreciation for their services. They are often compared to horses, which doesn’t do them justice. They’re entirely different animals, Burden says. Built for speed, horses respond to predators and other dangers by running as fast as they can. Donkeys, which originate from the rocky, mountainous regions of Africa where running is dangerous, react to threats by freezing and assessing the situation for the best response. “Those so-called stubborn donkeys that won’t move as you want, they are actually thinking ‘what’s the best approach,’” Burden says. They may even choose to fight the predators rather than flee, she adds. “In some parts of the world, people use them as guard animals against things like coyotes and wolves.”
Scientists believe that domestic donkeys take their origin from Equus africanus or African wild ass, originally roaming where Kenya, Ethiopia and Eritrea are today. Having evolved in the harsh and arid mountainous terrains where food and water were scarce, they are extremely adaptable and hardy. Research finds that they can go without water for 72 hours and then drink their fill without any negative consequences. Their big jaws let them chew tough desert shrubs, which horses can’t exist on. Their large ears help dissipate heat. Their little upright hooves are a perfect fit for the uneven rocky or other dangerous grounds. Accustomed to the mountain desert climate with hot days and cold nights, they don’t mind temperature flux.
“The donkey is the most supremely adapted animal to deal with hostile conditions,” Burden says. “They can survive on much lower nutritional quality food than a cow, sheep or horse. That’s why communities living in some of the most inhospitable places will often have donkeys with them.” And that’s why losing a donkey to an illegal skin trade can devastate a family in places like Eritrea. Suddenly everything from water to firewood to produce must be carried by family members—and often women.
Workers unloading donkeys at the Shinyanga slaughterhouse in Tanzania. Fearing a future in which donkeys go extinct, scientists have found ways to cryopreserve a donkey embryo in liquid nitrogen.
TAHUCHA
One can imagine a time when worldwide donkey populations may dwindle to the point that they would need to be restored. That includes their genetic variability too. That’s where the frozen embryos may come in handy. We may be able to use them to increase the genetic variability of donkeys, which will be especially important if they get closer to extinction, Gambini says. His team had already created frozen embryos for horses and zebras, an idea similar to a seed bank. “We call this concept the Frozen Zoo.”
Creating donkey embryos proved much harder than those of zebras and horses. To improve chances of fertilization, Gambini used the intracytoplasmic sperm injection or ICSI, in which he employed a tiny needle called a micropipette to inject a donkey sperm into an egg. That was a step above the traditional IVF method, in which the egg and a sperm are left floating in a test tube together. The injection took, but during the incubating week, one after the other, the embryos stopped dividing. Finally, on day seven, Gambini finally spotted the exact sight he was hoping to see. One of the embryos developed into a burgeoning ball of cells.
“That stage is called a blastocyst,” Gambini says. The clump of cells had a lot of fluids mixed within them, which indicated that they were finally developing into a viable embryo. “When we see a blastocyst, we know we can transfer that into a female.” He was so excited he immediately called all his collaborators to tell them the good news, which they later published in the journal of Theriogenology.
The one and only embryo to reach that stage, the blastocyst was cryopreserved in liquid nitrogen. The team is waiting for the next breeding season to see if a female donkey may carry it to term and give birth to a healthy foal. Gambini’s team is hoping to polish the process and create more embryos. “It’s our weapon in the conservation ass-enal,” he says.
Lina Zeldovich has written about science, medicine and technology for Popular Science, Smithsonian, National Geographic, Scientific American, Reader’s Digest, the New York Times and other major national and international publications. A Columbia J-School alumna, she has won several awards for her stories, including the ASJA Crisis Coverage Award for Covid reporting, and has been a contributing editor at Nautilus Magazine. In 2021, Zeldovich released her first book, The Other Dark Matter, published by the University of Chicago Press, about the science and business of turning waste into wealth and health. You can find her on http://linazeldovich.com/ and @linazeldovich.