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.
Should You Bank Your Kid’s Teeth for Stem Cells?
When Karen Davis attended a presentation at a dental conference in 2013, she unexpectedly discovered a service that could help her daughter, Madeline: storing stem cells derived from her teeth that potentially could be used in the future to treat her Crohn's disease.
"Even though this isn't a viable option today, I know how rapidly things can change."
Throughout high school, Madeline suffered from the painful autoimmune disorder, which wreaks havoc on the gastrointestinal system and can lead to life-threatening complications.
"I leave no stone unturned when it comes to medical care and this resonated with me," says Davis, a Dallas-based dental hygienist who was encouraged by advances in stem cell research. Later that year, when Madeline got her wisdom teeth extracted, Davis shipped them off to the Store-A-Tooth company in Massachusetts, where they will be kept frozen until needed. "Even though this isn't a viable option today, I know how rapidly things can change," says Davis. "To me, this was a worthwhile investment—I didn't want to miss out on an opportunity that would provide a pathway to a cure."
Karen Davis pictured with her daughter Madeline.
(Courtesy of Karen Davis)
The process itself was straightforward. Madeline's newly extracted wisdom teeth--baby teeth can be saved, too—were bathed in a special solution, loaded into a Styrofoam container lined with cold packs and sent to the stem cell company. There, a team harvested the dental stem cells from the pulp, then grew them in culture and cryogenically preserved them. Store-A-Tooth charges $1500-1749 for tooth collection and $120 per year for storage, while other dental pulp stem cell tissue banks cost $500-$600 upfront and in the $120 range annually for storage.
The rationale here is that if you missed out on banking your baby's umbilical cord blood, this gives you another chance to harvest their stem cells. "If their child later develops an illness that could be managed or even cured with stem cell therapy, this is an insurance policy," says Amr Moursi, DDS, PhD, chair of the department of pediatric dentistry at New York University College of Dentistry.
But is there a genuine potential here for some effective treatments in the relatively near future—or is this just another trendy fad? Scientific opinion is decidedly mixed. Stem cells have been heralded as the next frontier in medicine because of their versatility: with a little chemical coaxing, they can be transformed into different cell types, such as heart, blood or brain cells, to create tissue that can mend damaged body parts. Because they're taken from your own body, there's little chance of rejection, which means patients don't have to take strong antirejection drugs that can have all sorts of unpleasant side effects for the rest of their lives.
However, while stem cells are immature cells found in different tissues, ranging from abdominal fat to bone marrow, there is a vast difference between the stem cells found in cord blood and in teeth. Cord blood, which is culled from the umbilical cord when a baby is born, contains what are called hematopoietic stem cells (HSCs), which can mature into other blood cells. These type of stem cells have already been approved by the U.S. Food and Drug Administration to treat patients—especially children--with blood cancers, such as leukemias and lymphomas, and certain blood disorders like sickle cell anemia.
In contrast, stem cells in teeth are called mesenchymal stem cells (MSCs), which are found in dental pulp, the tissue in the center of the tooth that's filled with nerves and blood vessels. MSCs are adult stem cells normally found in the bone marrow that can transform into bone, fat, and cartilage cells, and also aid in the formation of blood stem cells.
"Right now we just don't have rigorous evidence that they can be used in that fashion and have real benefit."
Small studies on lab animals suggest that MSCs secrete growth factors—hormonal steroids or proteins—that can nurture ailing cells, act as powerful anti-inflammatory agents that could tame autoimmune disorders like the one that plagues Karen Davis's daughter, and may even generate new nerve and muscle tissue. Preliminary research suggests they potentially could treat medical conditions as varied as heart disease, spinal cord injury and type 1 diabetes by generating new cells, which can replace damaged or dead cells.
But this is all very early research and there's a vast difference between how cells behave in the tightly controlled environment of a lab versus the real world in a diverse population of human patients. "Right now we just don't have rigorous evidence that they can be used in that fashion and have real benefit," says Pamela G. Robey, PhD, chief of the skeletal biology section at the National Institute of Dental and Craniofacial Research at the National Institutes of Health.
Robey should know—she headed the research team that discovered stem cells in human baby teeth and in wisdom teeth more than fifteen years ago. She believes prospects are better using these stem cells for tooth repair: research suggests they may be able to fix cracked teeth, repair bone defects caused by gum disease, or in root canal therapy, where they can be used to replace infected tissue with regenerated healthy pulp.
In the meantime, though, there are no clinical applications for MSCs. "These tooth banking companies aren't doing their own research," says Leigh Turner, a bioethicist at the University of Minnesota who monitors stem cell clinics. "They cobble together reports of early research in humans or from animal studies in an effort to provide a narrative to make it seem like it is evidence based."
Still, in all fairness, tooth banking companies aren't making the kind of extravagant claims made by stem cell clinics, which operate in a gray area of the law and purport to treat everything from chronic lung disease to Alzheimer's. "We don't know when therapies will be available using these cells because the pace of research is hard to predict," says Peter Verlander, PhD, a molecular geneticist and chief scientific officer of Provia Laboratories, the parent company of Store-A-Tooth. "But for parents who regretted not banking their child's cord blood, especially if they later develop a disease like diabetes, this is another opportunity."
But the jury is still out if this is truly a good investment. Moursi, a national spokesperson for the American Academy of Pediatric Dentistry who fields queries about this practice from a dozen or so families a year, concludes: "If you could afford it, and know the risks, benefits and current limitations, then it is something to consider."
The Death Predictor: A Helpful New Tool or an Ethical Morass?
Whenever Eric Karl Oermann has to tell a patient about a terrible prognosis, their first question is always: "how long do I have?" Oermann would like to offer a precise answer, to provide some certainty and help guide treatment. But although he's one of the country's foremost experts in medical artificial intelligence, Oermann is still dependent on a computer algorithm that's often wrong.
Doctors are notoriously terrible at guessing how long their patients will live.
Artificial intelligence, now often called deep learning or neural networks, has radically transformed language and image processing. It's allowed computers to play chess better than the world's grand masters and outwit the best Jeopardy players. But it still can't precisely tell a doctor how long a patient has left – or how to help that person live longer.
Someday, researchers predict, computers will be able to watch a video of a patient to determine their health status. Doctors will no longer have to spend hours inputting data into medical records. And computers will do a better job than specialists at identifying tiny tumors, impending crises, and, yes, figuring out how long the patient has to live. Oermann, a neurosurgeon at Mount Sinai, says all that technology will allow doctors to spend more time doing what they do best: talking with their patients. "I want to see more deep learning and computers in a clinical setting," he says, "so there can be more human interaction." But those days are still at least three to five years off, Oermann and other researchers say.
Doctors are notoriously terrible at guessing how long their patients will live, says Nigam Shah, an associate professor at Stanford University and assistant director of the school's Center for Biomedical Informatics Research. Doctors don't want to believe that their patient – whom they've come to like – will die. "Doctors over-estimate survival many-fold," Shah says. "How do you go into work, in say, oncology, and not be delusionally optimistic? You have to be."
But patients near the end of life will get better treatment – and even live longer – if they are overseen by hospice or palliative care, research shows. So, instead of relying on human bias to select those whose lives are nearing their end, Shah and his colleagues showed that they could use a deep learning algorithm based on medical records to flag incoming patients with a life expectancy of three months to a year. They use that data to indicate who might need palliative care. Then, the palliative care team can reach out to treating physicians proactively, instead of relying on their referrals or taking the time to read extensive medical charts.
But, although the system works well, Shah isn't yet sure if such indicators actually get the appropriate patients into palliative care. He's recently partnered with a palliative care doctor to run a gold-standard clinical trial to test whether patients who are flagged by this algorithm are indeed a better match for palliative care.
"What is effective from a health system perspective might not be effective from a treating physician's perspective and might not be effective from the patient's perspective," Shah notes. "I don't have a good way to guess everybody's reaction without actually studying it." Whether palliative care is appropriate, for instance, depends on more than just the patient's health status. "If the patient's not ready, the family's not ready and the doctor's not ready, then you're just banging your head against the wall," Shah says. "Given limited capacity, it's a waste of resources" to put that person in palliative care.
The algorithm isn't perfect, but "on balance, it leads to better decisions more often."
Alexander Smith and Sei Lee, both palliative care doctors, work together at the University of California, San Francisco, to develop predictions for patients who come to the hospital with a complicated prognosis or a history of decline. Their algorithm, they say, helps decide if this patient's problems – which might include diabetes, heart disease, a slow-growing cancer, and memory issues – make them eligible for hospice. The algorithm isn't perfect, they both agree, but "on balance, it leads to better decisions more often," Smith says.
Bethany Percha, an assistant professor at Mount Sinai, says that an algorithm may tell doctors that their patient is trending downward, but it doesn't do anything to change that trajectory. "Even if you can predict something, what can you do about it?" Algorithms may be able to offer treatment suggestions – but not what specific actions will alter a patient's future, says Percha, also the chief technology officer of Precise Health Enterprise, a product development group within Mount Sinai. And the algorithms remain challenging to develop. Electronic medical records may be great at her hospital, but if the patient dies at a different one, her system won't know. If she wants to be certain a patient has died, she has to merge social security records of death with her system's medical records – a time-consuming and cumbersome process.
An algorithm that learns from biased data will be biased, Shah says. Patients who are poor or African American historically have had worse health outcomes. If researchers train an algorithm on data that includes those biases, they get baked into the algorithms, which can then lead to a self-fulfilling prophesy. Smith and Lee say they've taken race out of their algorithms to avoid this bias.
Age is even trickier. There's no question that someone's risk of illness and death goes up with age. But an 85-year-old who breaks a hip running a marathon should probably be treated very differently than an 85-year-old who breaks a hip trying to get out of a chair in a dementia care unit. That's why the doctor can never be taken out of the equation, Shah says. Human judgment will always be required in medical care and an algorithm should never be followed blindly, he says.
Experts say that the flaws in artificial intelligence algorithms shouldn't prevent people from using them – carefully.
Researchers are also concerned that their algorithms will be used to ration care, or that insurance companies will use their data to justify a rate increase. If an algorithm predicts a patient is going to end up back in the hospital soon, "who's benefitting from knowing a patient is going to be readmitted? Probably the insurance company," Percha says.
Still, Percha and others say, the flaws in artificial intelligence algorithms shouldn't prevent people from using them – carefully. "These are new and exciting tools that have a lot of potential uses. We need to be conscious about how to use them going forward, but it doesn't mean we shouldn't go down this road," she says. "I think the potential benefits outweigh the risks, especially because we've barely scratched the surface of what big data can do right now."