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.
Five Memorable Animals Who Expanded the Scientific Frontier
Untold numbers of animals have contributed to science, in ways big and small. Studying cows and cowpox helped English doctor Edward Jenner create a smallpox vaccine; Ivan Pavlov's experiments on dogs' reactions to external stimuli heavily influenced modern behavioral psychology.
We have these five animals to thank for some of our most important scientific advancements, from space travel to better organ replacement options.
Scientists still work with rats, rabbits, and other mammals to test cosmetics and pharmaceuticals and to conduct infectious disease research. Most of these animals remain nameless and unknown to the public, but over the years, certain individuals have had an outsize effect. We have these five animals to thank for some of our most important scientific advancements, from space travel to better organ replacement options.
1) LAIKA THE DOG
Laika was the first living creature ever to orbit the Earth. In October 1957, the Soviet Sputnik I ship had made history as the first man-made object sent into Earth's orbit; Premier Nikita Khrushchev was keen to gain another Space Race victory by sending up a canine cosmonaut.
Laika ("barker" in Russian), was a stray dog, reportedly a husky-spitz mix, recruited among several other female strays for the trip. Although the scientists put extensive work into preparing Laika and the other canine finalists—evaluating their reactions to air-pressure variations, training them to adapt to pelvic sanitation devices meant to contain waste, and eventually having them live in pressurized capsules for weeks—there was no expectation that the dog would return to Earth, and only one meal's worth of food was sent up with her.
Laika the dog, with a mockup of her space capsule.
Sputnik II, six times heavier than its predecessor, launched on November 3, 1957. Soviet broadcasts reported that Laika, fitted out with surgically implanted devices to monitor her heart rate, blood pressure, and breathing rates, survived until November 12; the spacecraft stayed in orbit for five more months, burning up when it re-entered the atmosphere.
At the time, the Sputnik II team reassured the world that Laika had died painlessly of oxygen deprivation. It was only decades later, in the 1990s, that Oleg Gazenko—one of the scientists and dog trainers assigned to the mission—revealed that Laika had died 5 to 7 hours after launch from a combination of heat and stress. The capsule had overheated, probably as a result of the rushed preparation; after the fourth orbit, the temperature inside Sputnik was over 90 degrees, and it's doubtful she could have survived much past that. "The more time passes, the more I'm sorry about it. We shouldn't have done it," Gazenko said. "We did not learn enough from the mission to justify the death of the dog."
Yet even the four or five orbits that Laika did complete were enough to spur scientists to press on in the effort to send a human into space.
2) HAM THE CHIMP
Four years after Laika's ill-fated flight, a chimpanzee named Ham entered suborbital flight in the American Project Mercury MR-2 mission on January 31, 1961, becoming the first hominid in space—and unlike Laika, he returned to Earth, alive, after a 16-minute flight.
Even though Ham's flight was not destined for orbit, the spacecraft and booster used on his trip were the same combination intended for the first (human) American's trip later that year. If he came back unharmed, NASA's medical team would be prepared to okay astronaut Alan Shepard's flight.
Ham receives his well-deserved apple.
For approximately 18 months before liftoff, Ham was trained to perform simple tasks, like pushing levers, in response to visual and auditory cues. (If he failed, he received an electric shock; correct performance earned him a treat. Pavlov would have been pleased.)
At 37 pounds, Ham was also the heaviest animal to ever make it to space. His vital signs and movements were monitored from Earth, and after a light electric shock from the ground team reminded him of his tasks, he performed his lever-pushing just a bit slower than he had on Earth, verifying that motion would not be seriously impaired in space.
Less than three months after Ham returned to Earth, on April 12, 1961, Soviet cosmonaut Yuri Gagarin became the first human to complete an orbital flight; Shepard was close behind, successfully crewing the MR-3 mission on May 5. For his part, Ham "retired" to the National Zoo in Washington D.C. for 17 years, before being transferred to the North Carolina Zoological Park; he died of liver failure in 1983 at age 26. His grave is at the International Space Hall of Fame in New Mexico.
3) KOKO THE GORILLA
A western lowland gorilla born at the San Francisco Zoo, Hanabi-ko, or "Koko," became famous in the 1970s for her cognitive and communicative abilities. Psychologist Francine "Penny" Patterson, then a doctoral student at Stanford, chose Koko to work on a language research project, teaching her American Sign Language; by age four, Koko demonstrated the ability both to make up new words and to combine known words to express herself creatively, as opposed to simply mimicking her trainer.
Koko and Penny compare notes.
Koko's work with Patterson reflected levels of cognition that were higher than non-human primates had previously been thought to have; by the end of her life, her language skills were roughly equivalent to a young child's, with a vocabulary of around 1,000 signs and the ability to understand 2,000 words of spoken English.
An especially impactful study in 2012 showed that Koko had learned to play the recorder, revealing an ability for voluntary breath control that scientists had previously thought was linked closely to speech and could only be developed by humans. Barbara J. King, a biological anthropologist, suggested that Koko's immersion in a human environment may have helped her develop such a skill, and that it might be misleading to consider similar abilities "innate" or lacking in either humans or non-human primates.
Koko's displays of emotions also fascinated the public, especially those that seemed to closely mirror humans': she cared for pet kittens; appeared on Mr. Rogers' Neighborhood and untied the host's shoes for him; acted playfully with Robin Williams during a visit from him, and later expressed grief when told about the comedian's death. Koko died in her sleep in June 2018, at age 46. Patterson continues to run The Gorilla Foundation, which is dedicated to using inter-species communication to motivate conservation efforts.
4) DOLLY THE SHEEP
Dolly—named after country singer Dolly Parton—was the first mammal ever to be cloned from an adult somatic cell, using the process of nuclear transfer. She was born in 1996 as part of research by scientists Keith Campbell and Ian Wilmut of the University of Edinburgh.
Dolly the cloned sheep.
By taking a donor cell from an adult sheep's mammary gland, using it to replace the cell nucleus of an unfertilized, developing egg cell, and then bringing the resultant embryo to term, Campbell and Wilmut proved that even a mature cell (one that had developed to perform mammary gland functions) could revert to an embryonic state and go on to develop into any and all parts of a mammal.
Although cloned livestock are legal in the U.S.—the FDA approved the practice in 2008, after determining that there was no difference between the meat and milk of cattle, pigs, and goats—Dolly has had an even bigger impact on stem cell research. The successful test of nuclear transfer proved that it was possible to change a cell's gene expression by changing its nucleus.
Japanese stem cell biologist Shinya Yamanaka, inspired by the birth of Dolly, won the Nobel Prize in 2012 for his adaptation of the technique. He developed induced pluripotent stem cells (iPS cells) by chemically reverting mature cells back to an embryonic-like blank state that is highly desirable for disease research and treatment. This technique allows researchers to work with such stem cells without the ethically charged complication of having to destroy a human embryo in the process.
5) LAIKA THE PIG
Named in honor of the dog who made it to space, the second science-famous Laika was a genetically engineered pig born in China in 2015 as a result of gene editing carried out by Cambridge, MA startup eGenesis and collaborators.* eGenesis aims to create pigs whose organs—hearts, kidneys, lungs, and more—are safe to transplant into people.
Laika the gene-edited pig.
Using animal organs in humans (xenotransplantation) is tricky: the immune system is very good at recognizing interlopers, and the human body can start to reject an organ from another species in as little as five minutes. But pigs are otherwise exceptionally good potential donors for humans: their organs' sizes and functions are very similar, and their quick gestation and maturation make them attractive from an efficiency standpoint, given that twenty Americans die every day waiting for organ donors.
Perhaps unsurprisingly, Dolly the sheep helped move xenotransplantation forward. In the 1990s, immunologist David Sachs was able to use a similar cloning method to eliminate alpha-gal, an enzyme that is produced by most animals with immune systems, including pigs—but not humans. Since our immune systems don't recognize alpha-gal, attacks on that enzyme are a major cause of organ rejection. Sachs' experiments increased the survival time of pig organs in primates to weeks: a huge improvement, but not nearly enough for someone in need of a liver or heart.
The advent of CRISPR technology, and the ability to edit genes, has allowed another leap. In 2015, researchers at eGenesis used targeted gene-editing to eliminate the genes for porcine endogenous retroviruses from pig kidney cells. These viral elements are part of all pigs' genomes and pose a potentially high risk of infecting human cells. (After the HIV/AIDS crisis especially, there was a lot of anxiety about potentially introducing a new virus into the human population.)
The eGenesis lab used nuclear transfer to embed the edited nuclei into egg cells taken from a normal pig; and Laika was born months later—without the dangerous viral genes. eGenesis is now working to make the organs even more humanlike, with the goal of one day providing organs to every human patient in need.
*[Disclosure: In 2019, eGenesis received a series B investment from Leaps By Bayer, the funding sponsor of leapsmag. However, leapsmag is editorially independent of Bayer and is under no obligation to cover companies they invest in.]
[Correction, March 3, 2020: Laika the gene-edited pig was born in China, not Cambridge, and eGenesis is pursuing xenotransplant programs that include heart, kidney, and lung, but not skin, as originally written.]
A Surprising Breakthrough Will Allow Tiny Implants to Fix—and Even Upgrade—Your Body
Imagine it's the year 2040 and you're due for your regular health checkup. Time to schedule your next colonoscopy, Pap smear if you're a woman, and prostate screen if you're a man.
"The evolution of the biological ion transistor technology is a game changer."
But wait, you no longer need any of those, since you recently got one of the new biomed implants – a device that integrates seamlessly with body tissues, because of a watershed breakthrough that happened in the early 2020s. It's an improved biological transistor driven by electrically charged particles that move in and out of your own cells. Like insulin pumps and cardiac pacemakers, the medical implants of the future will go where they are needed, on or inside the body.
But unlike current implants, biological transistors will have a remarkable range of applications. Currently small enough to fit between a patient's hair follicles, the devices could one day enable correction of problems ranging from damaged heart muscle to failing retinas to deficiencies of hormones and enzymes.
Their usefulness raises the prospect of overcorrection to the point of human enhancement, as in the bionic parts that were imagined on the ABC television series The Six Million Dollar Man, which aired in the 1970s.
"The evolution of the biological ion transistor technology is a game changer," says Zoltan Istvan, who ran as a U.S. Presidential candidate in 2016 for the Transhumanist Party and later ran for California governor. Istvan envisions humans becoming faster, stronger, and increasingly more capable by way of technological innovations, especially in the biotechnology realm. "It's a big step forward on how we can improve and upgrade the human body."
How It Works
The new transistors are more like the soft, organic machines that biology has evolved than like traditional transistors built of semiconductors and metal, according to electric engineering expert Dion Khodagholy, one of the leaders of the team at Columbia University that developed the technology.
The key to the advance, notes Khodagholy, is that the transistors will interface seamlessly with tissue, because the electricity will be of the biological type -- transmitted via the flow of ions through liquid, rather than electrons through metal. This will boost the sensitivity of detection and decoding of biological change.
Naturally, such a paradigm change in the world of medical devices raises potential societal and ethical dilemmas.
Known as an ion-gated transistor (IGT), the new class of technology effectively melds electronics with molecules of human skin. That's the current prototype, but ultimately, biological devices will be able to go anywhere in the body. "IGT-based devices hold great promise for development of fully implantable bioelectronic devices that can address key clinical issues for patients with neuropsychiatric disease," says Khodagholy, based on the expectation that future devices could fuse with, measure, and modulate cells of the human nervous system.
Ethical Implications
Naturally, such a paradigm change in the world of medical devices raises potential societal and ethical dilemmas, starting with who receives the new technology and who pays for it. But, according clinical ethicist and health care attorney David Hoffman, we can gain insight from past experience, such as how society reacted to the invention of kidney dialysis in the mid 20th century.
"Kidney dialysis has been federally funded for all these decades, largely because the who-gets-the-technology question was an issue when the technology entered clinical medicine," says Hoffman, who teaches bioethics at Columbia's College of Physicians and Surgeons as well as at the law school and medical school of Yeshiva University. Just as dialysis became a necessity for many patients, he suggests that the emerging bio-transistors may also become critical life-sustaining devices, prompting discussions about federal coverage.
But unlike dialysis, biological transistors could allow some users to become "better than well," making it more similar to medication for ADHD (attention deficit hyperactivity disorder): People who don't require it can still use it to improve their baseline normal functioning. This raises the classic question: Should society draw a line between treatment and enhancement? And who gets to decide the answer?
If it's strictly a medical use of the technology, should everyone who needs it get to use it, regardless of ability to pay, relying on federal or private insurance coverage? On the other hand, if it's used voluntarily for enhancement, should that option also be available to everyone -- but at an upfront cost?
From a transhumanist viewpoint, getting wrapped up with concerns about the evolution of devices from therapy to enhancement is not worth the trouble.
It seems safe to say that some lively debates and growing pains are on the horizon.
"Even if [the biological ion transistor] is developed only for medical devices that compensate for losses and deficiencies similar to that of a cardiac pacemaker, it will be hard to stop its eventual evolution from compensation to enhancement," says Istvan. "If you use it in a bionic eye to restore vision to the blind, how do you draw the line between replacement of normal function and provision of enhanced function? Do you pass a law placing limits on visual capabilities of a synthetic eye? Transhumanists would oppose such laws, and any restrictions in one country or another would allow another country to gain an advantage by creating their own real-life super human cyborg citizens."
In the same breath though, Istvan admits that biotechnology on a bionic scale is bound to complicate a range of international phenomena, from economic growth and military confrontations to sporting events like the Olympic Games.
The technology is already here, and it's just a matter of time before we see clinically viable, implantable devices. As for how society will react, it seems safe to say that some lively debates and growing pains are on the horizon.