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.
The unprecedented scale and impact of the COVID-19 pandemic has caused scientists and engineers around the world to stop whatever they were working on and shift their research toward understanding a novel virus instead.
"We have confidence that we can use our system in the next pandemic."
For Guangyu Qiu, normally an environmental engineer at the Swiss Federal Laboratories for Materials Science and Technology, that means finding a clever way to take his work on detecting pollution in the air and apply it to living pathogens instead. He's developing a new type of biosensor to make disease diagnostics and detection faster and more accurate than what's currently available.
But even though this pandemic was the impetus for designing a new biosensor, Qiu actually has his eye on future disease outbreaks. He admits that it's unlikely his device will play a role in quelling this virus, but says researchers already need to be thinking about how to make better tools to fight the next one — because there will be a next one.
"In the last 20 years, there [have been] three different coronavirus [outbreaks] ... so we have to prepare for the coming one," Qiu says. "We have confidence that we can use our system in the next pandemic."
"A Really, Really Neat Idea"
His main concern is the diagnostic tool that's currently front and center for testing patients for SARS-Cov-2, the virus causing the novel coronavirus disease. The tool, called PCR (short for reverse transcription polymerase chain reaction), is the gold standard because it excels at detecting viruses in even very small samples of mucus. PCR can amplify genetic material in the limited sample and look for a genetic code matching the virus in question. But in many parts of the world, mucus samples have to be sent out to laboratories for that work, and results can take days to return. PCR is also notoriously prone to false positives and negatives.
"I read a lot of newspapers that report[ed] ... a lot of false negative or false positive results at the very beginning of the outbreak," Qiu says. "It's not good for protecting people to prevent further transmission of the disease."
So he set out to build a more sensitive device—one that's less likely to give you a false result. Qiu's biosensor relies on an idea similar to the dual-factor authentication required of anyone trying to access a secure webpage. Instead of verifying that a virus is really present by using one way of detecting genetic code, as with PCR, this biosensor asks for two forms of ID.
SARS-CoV-2 is what's called an RNA virus, which means it has a single strand of genetic code, unlike double-stranded DNA. Inside Qiu's biosensor are receptors with the complementary code for this particular virus' RNA; if the virus is present, its RNA will bind with the receptors, locking together like velcro. The biosensor also contains a prism and a laser that work together to verify that this RNA really belongs to SARS-CoV-2 by looking for a specific wavelength of light and temperature.
If the biosensor doesn't detect either, or only registers a match for one and not the other, then it can't produce a positive result. This multi-step authentication process helps make sure that the RNA binding with the receptors isn't a genetically similar coronavirus like SARS-CoV, known for its 2003 outbreak, or MERS-CoV, which caused an epidemic in 2012.
It could also be fitted to detect future novel viruses once their genomes are sequenced.
The dual-feature design of this biosensor "is a really, really neat idea that I have not seen before with other sensor technology," says Erin Bromage, a professor of infection and immunology at the University of Massachusetts Dartmouth; he was not involved in designing or testing Qiu's biosensor. "It makes you feel more secure that when you have a positive, you've really got a positive."
The light and temperature sensors are not in themselves new inventions, but the combination is a first. The part of the device that uses light to detect particles is actually central to Qiu's normal stream of environmental research, and is a versatile tool he's been working with for a long time to detect aerosols in the atmosphere and heavy metals in drinking water.
Bromage says this is a plus. "It's not high-risk in the sense that how they do this is unique, or not validated. They've taken aspects of really proven technology and sort of combined it together."
This new biosensor is still a prototype that will take at least another 12 months to validate in real world scenarios, though. The device is sound from a biological perspective and is sensitive enough to reliably detect SARS-CoV-2 — and to not be tricked by genetically similar viruses like SARS-CoV — but there is still a lot of engineering work that needs to be done in order for it to work outside the lab. Qiu says it's unlikely that the sensor will help minimize the impact of this pandemic, but the RNA receptors, prism, and laser inside the device can be customized to detect other viruses that may crop up in the future.
"If we choose another sequence—like SARS, like MERS, or like normal seasonal flu—we can detect other viruses, or even bacteria," Qiu says. "This device is very flexible."
It could also be fitted to detect future novel viruses once their genomes are sequenced.
The Long-Term Vision: Hospitals and Transit Hubs
The device has been designed to connect with two other systems: an air sampler and a microprocessor because the goal is to make it portable, and able to pick up samples from the air in hospitals or public areas like train stations or airports. A virus could hopefully be detected before it silently spreads and erupts into another global pandemic. In the case of SARS-CoV-2, there has been conflicting research about whether or not the virus is truly airborne (though it can be spread by droplets that briefly move through the air after a cough or sneeze), whereas the highly contagious RNA virus that causes measles can remain in the air for up to two hours.
"They've got a lot on the front end to work out," Bromage says. "They've got to work out how to capture and concentrate a virus, extract the RNA from the virus, and then get it onto the sensor. That's some pretty big hurdles, and may take some engineering that doesn't exist right now. But, if they can do that, then that works out really quite well."
One of the major obstacles in containing the COVID-19 pandemic has been in deploying accurate, quick tools that can be used for early detection of a virus outbreak and for later tracing its spread. That will still be true the next time a novel virus rears its head, and it's why Qiu feels that even if his biosensor can't help just yet, the research is still worth the effort.
It could also be fitted to detect future novel viruses once their genomes are sequenced.
The dual-feature design of this biosensor "is a really, really neat idea that I have not seen before with other sensor technology," says Erin Bromage, a professor of infection and immunology at the University of Massachusetts Dartmouth; he was not involved in designing or testing Qiu's biosensor. "It makes you feel more secure that when you have a positive, you've really got a positive."
The light and temperature sensors are not in themselves new inventions, but the combination is a first. The part of the device that uses light to detect particles is actually central to Qiu's normal stream of environmental research, and is a versatile tool he's been working with for a long time to detect aerosols in the atmosphere and heavy metals in drinking water.
Bromage says this is a plus. "It's not high-risk in the sense that how they do this is unique, or not validated. They've taken aspects of really proven technology and sort of combined it together."
This new biosensor is still a prototype that will take at least another 12 months to validate in real world scenarios, though. The device is sound from a biological perspective and is sensitive enough to reliably detect SARS-CoV-2 — and to not be tricked by genetically similar viruses like SARS-CoV — but there is still a lot of engineering work that needs to be done in order for it to work outside the lab. Qiu says it's unlikely that the sensor will help minimize the impact of this pandemic, but the RNA receptors, prism, and laser inside the device can be customized to detect other viruses that may crop up in the future.
"If we choose another sequence—like SARS, like MERS, or like normal seasonal flu—we can detect other viruses, or even bacteria," Qiu says. "This device is very flexible."
It could also be fitted to detect future novel viruses once their genomes are sequenced.
The Long-Term Vision: Hospitals and Transit Hubs
The device has been designed to connect with two other systems: an air sampler and a microprocessor because the goal is to make it portable, and able to pick up samples from the air in hospitals or public areas like train stations or airports. A virus could hopefully be detected before it silently spreads and erupts into another global pandemic. In the case of SARS-CoV-2, there has been conflicting research about whether or not the virus is truly airborne (though it can be spread by droplets that briefly move through the air after a cough or sneeze), whereas the highly contagious RNA virus that causes measles can remain in the air for up to two hours.
"They've got a lot on the front end to work out," Bromage says. "They've got to work out how to capture and concentrate a virus, extract the RNA from the virus, and then get it onto the sensor. That's some pretty big hurdles, and may take some engineering that doesn't exist right now. But, if they can do that, then that works out really quite well."
One of the major obstacles in containing the COVID-19 pandemic has been in deploying accurate, quick tools that can be used for early detection of a virus outbreak and for later tracing its spread. That will still be true the next time a novel virus rears its head, and it's why Qiu feels that even if his biosensor can't help just yet, the research is still worth the effort.
Spina Bifida Claimed My Son's Mobility. Incredible Breakthroughs May Let Future Kids Run Free.
When our son Henry, now six, was diagnosed with spina bifida at his 20-week ultrasound, my husband and I were in shock. It took us more than a few minutes to understand what the doctor was telling us.
When Henry was diagnosed in 2012, postnatal surgery was still the standard of care – but that was about to change.
Neither of us had any family history of birth defects. Our fifteen-month-old daughter, June, was in perfect health.
But more than that, spina bifida – a malformation of the neural tube that eventually becomes the baby's spine – is woefully complex. The defect, the doctor explained, was essentially a hole in Henry's lower spine from which his spinal nerves were protruding – and because they were exposed to my amniotic fluid, those nerves were already permanently damaged. After birth, doctors could push the nerves back into his body and sew up the hole, but he would likely experience some level of paralysis, bladder and bowel dysfunction, and a buildup of cerebrospinal fluid that would require a surgical implant called a shunt to correct. The damage was devastating – and irreversible.
We returned home with June and spent the next few days cycling between disbelief and total despair. But within a week, the maternal-fetal medicine specialist who diagnosed Henry called us up and gave us the first real optimism we had felt in days: There was a new, experimental surgery for spina bifida that was available in just a handful of hospitals around the country. Rather than waiting until birth to repair the baby's defect, some doctors were now trying out a prenatal repair, operating on the baby via c-section, closing the defect, and then keeping the mother on strict bedrest until it was time for the baby to be delivered, just before term.
This new surgery carried risks, he told us – but if it went well, there was a chance Henry wouldn't need a shunt. And because repairing the defect during my pregnancy meant the spinal nerves were exposed for a shorter amount of time, that meant we'd be preventing nerve damage – and less nerve damage meant that there was a chance he'd be able to walk.
Did we want in? the doctor asked.
Had I known more about spina bifida and the history of its treatment, this surgery would have seemed even more miraculous. Not too long ago, the standard of care for babies born with spina bifida was to simply let them die without medical treatment. In fact, it wasn't until the early 1950s that doctors even attempted to surgically repair the baby's defect at all, instead of opting to let the more severe cases die of meningitis from their open wound. (Babies who had closed spina bifida – a spinal defect covered by skin – sometimes survived past infancy, but rarely into adulthood).
But in the 1960s and 1970s, as more doctors started repairing defects and the shunting technology improved, patients with spina bifida began to survive past infancy. When catheterization was introduced, spina bifida patients who had urinary dysfunction, as is common, were able to preserve their renal function into adulthood, and they began living even longer. Within a few decades, spina bifida was no longer considered a death sentence; people were living fuller, happier lives.
When Henry was diagnosed in 2012, postnatal surgery was still the standard of care – but that was about to change. The first major clinical trial for prenatal surgery and spina bifida, called Management of Myelomeningocele (MOMS) had just concluded, and its objective was to see whether repairing the baby's defect in utero would be beneficial. In the trial, doctors assigned eligible women to undergo prenatal surgery in the second trimester of their pregnancies and then followed up with their children throughout the first 30 months of the child's life.
The results were groundbreaking: Not only did the children in the surgery group perform better on motor skills and cognitive tests than did patients in the control group, only 40 percent of patients ended up needing shunts compared to 80 percent of patients who had postnatal surgery. The results were so overwhelmingly positive that the trial was discontinued early (and is now, happily, the medical standard of care). Our doctor relayed this information to us over the phone, breathless, and left my husband and me to make our decision.
After a few days of consideration, and despite the benefits, my husband and I actually ended up opting for the postnatal surgery instead. Prenatal surgery, although miraculous, would have required extensive travel for us, as well as giving birth in a city thousands of miles from home with no one to watch our toddler while my husband worked and I recovered. But other parents I met online throughout our pregnancy did end up choosing prenatal surgery for their children – and the majority of them now walk with little assistance and only a few require shunting.
Sarah Watts with her husband, daughter June, and son Henry, at a recent family wedding.
Even more amazing to me is that now – seven years after Henry's diagnosis, and not quite a decade since the landmark MOMS trial – the standard of care could be about to change yet again.
Regardless of whether they have postnatal or prenatal surgery, most kids with spina bifida still experience some level of paralysis and rely on wheelchairs and walkers to move around. Now, researchers at UC Davis want to augment the fetal surgery with a stem cell treatment, using human placenta-derived mesenchymal stromal cells (PMSCs) and affixing them to a cellular scaffold on the baby's defect, which not only protects the spinal cord from further damage but actually encourages cellular regeneration as well.
The hope is that this treatment will restore gross motor function after the baby is born – and so far, in animal trials, that's exactly what's happening. Fetal sheep, who were induced with spinal cord injuries in utero, were born with complete motor function after receiving prenatal surgery and PMSCs. In 2017, a pair of bulldogs born with spina bifida received the stem cell treatment a few weeks after birth – and two months after surgery, both dogs could run and play freely, whereas before they had dragged their hind legs on the ground behind them. UC Davis researchers hope to bring this treatment into human clinical trials within the next year.
A century ago, a diagnosis of spina bifida meant almost certain death. Today, most children with spina bifida live into adulthood, albeit with significant disabilities. But thanks to research and innovation, it's entirely possible that within my lifetime – and certainly within Henry's – for the first time in human history, the disabilities associated with spina bifida could be a thing of the past.