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.
Could a tiny fern change the world — again?
More than 50 million years ago, the Arctic Ocean was the opposite of a frigid wasteland. It was a gigantic lake surrounded by lush greenery brimming with flora and fauna, thanks to the humidity and warm temperatures. Giant tortoises, alligators, rhinoceros-like animals, primates, and tapirs roamed through nearby forests in the Arctic.
This greenhouse utopia abruptly changed in the early Eocene period, when the Arctic Ocean became landlocked. A channel that connected the Arctic to the greater oceans got blocked. This provided a tiny fern called Azolla the perfect opportunity to colonize the layer of freshwater that formed on the surface of the Arctic Ocean. The floating plants rapidly covered the water body in thick layers that resembled green blankets.
Gradually, Azolla colonies migrated to every continent with the help of repeated flooding events. For around a million years, they captured more than 80 percent of atmospheric carbon dioxide that got buried at the bottom of the Arctic Ocean as billions of Azolla plants perished.
This “Arctic Azolla event” had devastating impacts on marine life. To date, scientists are trying to figure out how it ended. But they documented that the extraordinary event cooled down the Arctic by at least 40 degrees Fahrenheit — effectively freezing the poles and triggering several cycles of ice ages. “This carbon dioxide sequestration changed the climate from greenhouse to white house,” says Jonathan Bujak, a paleontologist who has researched the Arctic through expeditions since 1973.
Some farmers and scientists, such as Bujak, are looking to this ancient fern, which manipulated the Earth’s climate around 49 million years ago with its insatiable appetite for carbon dioxide, as a potential solution to our modern-day agricultural and environmental challenges. “There is no other plant like Azolla in the world,” says Bujak.
Decoding the Azolla plant
Azolla lives in symbiosis with a cyanobacterium called Anabaena that made the plant’s leaf cavities its permanent home at an early stage in Earth's history. This close relationship with Anabaena enables Azolla to accomplish a feat that is impossible for most plants: directly splitting dinitrogen molecules that make up 78 percent of the Earth’s atmosphere.
A dinitrogen molecule consists of two nitrogen atoms tightly locked together in one of the strongest bonds in nature. The semi-aquatic fern’s ability to split nitrogen, called nitrogen-fixing, made it a highly revered plant in East Asia. Rice farmers used Azolla as a biofertilizer since the 11th century in Vietnam and China.
For decades, scientists have attempted to decode Azolla’s evolution. Cell biologist Francisco Carrapico, who worked at the University of Lisbon, has analyzed this distinctive symbiosis since the 1980s. To his amazement, in 1991, he found that bacteria are the third partner of the Azolla-Anabaena symbiosis.
“Azolla and Anabaena cannot survive without each other. They have co-evolved for 80 million years, continuously exchanging their genetic material with each other,” says Bujak, co-author of The Azolla Story, which he published with his daughter, Alexandra Bujak, an environmental scientist. Three different levels of nitrogen fixation take place within the plant, as Anabaena draws down as much as 2,200 pounds of atmospheric nitrogen per acre annually.
“Using Azolla to mitigate climate change might sound a bit too simple. But that is not the case,” Bujak says. “At a microscopic level, extremely complicated biochemical reactions are constantly occurring inside the plant’s cells that machines or technology cannot replicate yet.”
In 2018, researchers based in the U.S. managed to sequence Azolla’s complete genome — which is four times larger than the human genome — through a crowdfunded study, further increasing our understanding of this plant. “Azolla is a superorganism that works efficiently as a natural biotechnology system that makes it capable of doubling in size within three to five days,” says Carrapico.
Making Azolla mainstream again in agriculture
While scientific groups in the Global North have been working towards unraveling the tiny fern’s inner workings, communities in the Global South are busy devising creative ways to return to their traditional agricultural roots by tapping into Azolla’s full potential.
Pham Gia Minh, an entrepreneur living in Hanoi, Vietnam, is one such citizen scientist who believes that Azolla could be a climate savior. More than two decades after working in finance and business development, Minh is now focusing on continuing his grandfather’s legacy, an agricultural scientist who conducted Azolla research until the 1950s. “Azolla is our family’s heritage,” says Minh.
Pham Gia Minh, an entrepreneur and citizen scientist in Hanoi, Vietnam, believes that Azolla could be a climate savior
Pham Gia Minh
Since the advent of chemical fertilizers in the early 1900s, farmers in Asia abandoned Azolla to save on time and labor costs. But rice farmers in the country went back to cultivating Azolla during the Vietnam War after chemical trade embargoes made chemical fertilizers far too expensive and inaccessible.
By 1973, Azolla cultivation in rice paddy fields was established on half a million hectares in Vietnam. By injecting nitrogen into the soil, Azolla improves soil fertility and also increases rice yields by at least 27 percent compared to urea. The plants can also reduce a farm’s methane emissions by 40 percent.
“Unfortunately, after 1985, chemical fertilizers became cheap and widely available in Vietnam again. So, farmers stopped growing Azolla because of the time-consuming and labor-intensive cultivation process,” says Minh.
Minh has invested in a rural farm where he is proving that modern technology can make the process less burdensome. He uses a pump and drying equipment for harvesting Azolla in a small pond, and he deploys a drone for spraying insecticides and fertilizers on the pond at regular intervals.
As Azolla lacks phosphorus, farmers in developing countries still find it challenging to let go of chemical fertilizers completely. Still, Minh and Bujak say that farmers can use Azolla instead of chemical fertilizers after mixing it with dung.
In the last few years, the fern’s popularity has been growing in other developing countries like India, Palestine, Indonesia, the Philippines, and Bangladesh, where local governments and citizens are trying to re-introduce Azolla integrated farming by growing the ferns in small ponds.
Replacing soybeans with Azolla
In Ecuador, Mariano Montano Armijos, a former chemical engineer, has worked with Azolla for more than 20 years. Since 2008, he has shared resources and information for growing Azolla with 3,000 farmers in Ecuador. The farmers use the harvested plants as a bio-fertilizer and feed for livestock.
“The farmers do not use urea anymore,” says Armijos. “This goes against the conventional agricultural practices of using huge amounts of synthetic nitrogen on a hectare of rice or corn fields.”
He insists that Azolla’s greatest strength is that it is a rich source of proteins, making it highly nutritious for human beings as well. After growing Azolla on a small scale in ponds, Armijos and his business partner, Ivan Noboa, are now building a facility for cultivating the ferns as a superfood on an industrial scale.
According to Armijos, one hectare of Azolla in Ecuador can produce seven tons of proteins. Whereas soybeans produce only one ton of protein per hectare. “If we switch to Azolla, it could help in reducing deforestation in the Amazon. But taming Azolla and turning it into a crop is not easy,” he adds.
Henriette Schluepmann, a molecular plant biologist at Utrecht University in the Netherlands, believes that Azolla could replace soybeans and chemical fertilizers someday — only if researchers can achieve yield stability in controlled environments over long durations.
“In a country like the Netherlands that is surrounded by water with high levels of phosphates, it makes sense to grow Azolla as a substitute for soybeans,” says Schluepmann. “For that to happen, we need massive investments to understand these ferns’ reproductive system and how to replicate that within aquaculture systems on a large scale.”
Pollution control and carbon sequestration
Currently, Schluepmann and her team are growing Azolla in a plant nursery or closed system before transferring the ferns to flooded fields. So far, they have been able to continuously grow Azolla without any major setbacks for a total of 155 days. Taking care of these plants’ well-being is an uphill struggle.
Unlike most plants, Azolla does not grow from seeds because it contains female and male spores that tend to split instead of reproducing. To add to that, growing Azolla on a large scale in controlled environments makes the floating plants extremely vulnerable to insect infestations and fungi attacks.
“Even though it is easier to grow Azolla on a non-industrial scale, the long and tedious cultivation process is often in conflict with human rights,” she says. Farms in developing countries such as Indonesia sometimes use child labor for cultivating Azolla.”
History has taught us that the uncontrolled growth of Azolla plants deprives marine ecosystems of sunlight and chokes life underneath them. But researchers like Schluepmann and Bujak are optimistic that even on a much smaller scale, Azolla can put up a fight against human-driven climate change.
Schluepmann discovered an insecticide that can control Azolla blooms. But in the wild, this aquatic fern grows relentlessly in polluted rivers and lakes and has gained a notorious reputation as an invasive weed. Countries like Portugal and the UK banned Azolla after experiencing severe blooms in rivers that snuffed out local marine life.
“Azolla has been misunderstood as a nuisance. But in reality, it is highly beneficial for purifying water,” says Bujak. Through a process called phytoremediation, Azolla locks up pollutants like excess nitrogen and phosphorus and stops toxic algal blooms from occurring in rivers and lakes.
A 2018 study found that Azolla can decrease nitrogen and phosphorus levels in wastewater by 33 percent and 40.5 percent, respectively. While harmful algae like phytoplankton produce toxins and release noxious gases, Azolla automatically blocks any toxins that its cyanobacteria, Anabaena, might produce.
“In our labs, we observed that Azolla works effectively in treating wastewater,” explains Schluepmann. “Once we gain a better understanding of Azolla aquaculture, we can also use it for carbon capture and storage. But in Europe, we would have to use the entire Baltic Sea to make a difference.”
Planting massive amounts of these prehistoric ferns in any of the Northern great water bodies is out of the question. After all, history has taught us that the uncontrolled growth of Azolla plants deprives marine ecosystems of sunlight and chokes life underneath them. But researchers like Schluepmann and Bujak are optimistic that even on a much smaller scale, Azolla can put up a fight against human-driven climate change.
Traditional carbon capture and storage methods are not only expensive but also inefficient and could increase air pollution. According to Bujak’s estimates, Azolla can sequester 10 metric tonnes of carbon dioxide per hectare annually, which is 10 times the average capacity of grasslands.
“Anyone can set up their own DIY carbon capture and storage system by growing Azolla in shallow water. After harvesting and compressing the plants, carbon dioxide gets stored permanently,” says Bujak.
He envisions scaling up this process by setting up “Azolla hubs” in mega-cities where the plants are grown in shallow trays stacked on top of each other with vertical farming systems built within multi-story buildings. The compressed Azolla plants can then be converted into a biofuel, fertilizer, livestock feed, or biochar for sequestering carbon dioxide.
“Using Azolla to mitigate climate change might sound a bit too simple. But that is not the case,” Bujak adds. “At a microscopic level, extremely complicated biochemical reactions are constantly occurring inside the plant’s cells that machines or technology cannot replicate yet.”
Through Azolla, scientists hope to work with nature by tapping into four billion years of evolution.
A new virus has emerged and stoked fears of another pandemic: monkeypox. Since May 2022, it has been detected in 29 U.S. states, the District of Columbia, and Puerto Rico among international travelers and their close contacts. On a worldwide scale, as of June 30, there have been 5,323 cases in 52 countries.
The good news: An existing vaccine can go a long way toward preventing a catastrophic outbreak. Because monkeypox is a close relative of smallpox, the same vaccine can be used—and it is about 85 percent effective against the virus, according to the World Health Organization (WHO).
Also on the plus side, monkeypox is less contagious with milder illness than smallpox and, compared to COVID-19, produces more telltale signs. Scientists think that a “ring” vaccination strategy can be used when these signs appear to help with squelching this alarming outbreak.
How it’s transmitted
Monkeypox spreads between people primarily through direct contact with infectious sores, scabs, or bodily fluids. People also can catch it through respiratory secretions during prolonged, face-to-face contact, according to the Centers for Disease Control and Prevention (CDC).
As of June 30, there have been 396 documented monkeypox cases in the U.S., and the CDC has activated its Emergency Operations Center to mobilize additional personnel and resources. The U.S. Department of Health and Human Services is aiming to boost testing capacity and accessibility. No Americans have died from monkeypox during this outbreak but, during the COVID-19 pandemic (February 2020 to date), Africa has documented 12,141 cases and 363 deaths from monkeypox.
Ring vaccination proved effective in curbing the smallpox and Ebola outbreaks. As the monkeypox threat continues to loom, scientists view this as the best vaccine approach.
A person infected with monkeypox typically has symptoms—for instance, fever and chills—in a contagious state, so knowing when to avoid close contact with others makes it easier to curtail than COVID-19.
Advantages of ring vaccination
For this reason, it’s feasible to vaccinate a “ring” of people around the infected individual rather than inoculating large swaths of the population. Ring vaccination proved effective in curbing the smallpox and Ebola outbreaks. As the monkeypox threat continues to loom, scientists view this as the best vaccine approach.
With many infections, “it normally would make sense to everyone to vaccinate more widely,” says Wesley C. Van Voorhis, a professor and director of the Center for Emerging and Re-emerging Infectious Diseases at the University of Washington School of Medicine in Seattle. However, “in this case, ring vaccination may be sufficient to contain the outbreak and also minimize the rare, but potentially serious side effects of the smallpox/monkeypox vaccine.”
There are two licensed smallpox vaccines in the United States: ACAM2000 (live Vaccina virus) and JYNNEOS (live virus non-replicating). The ACAM 2000, Van Voorhis says, is the old smallpox vaccine that, in rare instances, could spread diffusely within the body and cause heart problems, as well as severe rash in people with eczema or serious infection in immunocompromised patients.
To prevent organ damage, the current recommendation would be to use the JYNNEOS vaccine, says Phyllis Kanki, a professor of health sciences in the division of immunology and infectious diseases at the Harvard T.H. Chan School of Public Health. However, according to a report on the CDC’s website, people with immunocompromising conditions could have a higher risk of getting a severe case of monkeypox, despite being vaccinated, and “might be less likely to mount an effective response after any vaccination, including after JYNNEOS.”
In the late 1960s, the ring vaccination strategy became part of the WHO’s mission to globally eradicate smallpox, with the last known natural case described in Somalia in 1977. Ring vaccination can also refer to how a clinical trial is designed, as was the case in 2015, when this approach was used for researching the benefits of an investigational Ebola vaccine in Guinea, Kanki says.
“Since Monkeypox spreads by close contact and we have an effective vaccine, vaccinating high-risk individuals and their contacts may be a good strategy to limit transmission,” she says, adding that privacy is an important ethical principle that comes into play, as people with monkeypox would need to disclose their close contacts so that they could benefit from ring vaccination.
Rapid identification of cases and contacts—along with their cooperation—is essential for ring vaccination to be effective. Although mass vaccination also may work, the risk of infection to most of the population remains low while supply of the JYNNEOS vaccine is limited, says Stanley Deresinski, a clinical professor of medicine in the Infectious Disease Clinic at Stanford University School of Medicine.
Other strategies for preventing transmission
Ideally, the vaccine should be administered within four days of an exposure, but it’s recommended for up to 14 days. The WHO also advocates more widespread vaccination campaigns in the population segment with the most cases so far: men who engage in sex with other men.
The virus appears to be spreading in sexual networks, which differs from what was seen in previously reported outbreaks of monkeypox (outside of Africa), where risk was associated with travel to central or west Africa or various types of contact with individuals or animals from those locales. There is no evidence of transmission by food, but contaminated articles in the environment such as bedding are potential sources of the virus, Deresinski says.
Severe cases of monkeypox can occur, but “transmission of the virus requires close contact,” he says. “There is no evidence of aerosol transmission, as occurs with SARS-CoV-2, although it must be remembered that the smallpox virus, a close relative of monkeypox, was transmitted by aerosol.”
Deresinski points to the fact that in 2003, monkeypox was introduced into the U.S. through imports from Ghana of infected small mammals, such as Gambian giant rats, as pets. They infected prairie dogs, which also were sold as pets and, ultimately, this resulted in 37 confirmed transmissions to humans and 10 probable cases. A CDC investigation identified no cases of human-to-human transmission. Then, in 2021, a traveler flew from Nigeria to Dallas through Atlanta, developing skin lesions several days after arrival. Another CDC investigation yielded 223 contacts, although 85 percent were deemed to be at only minimal risk and the remainder at intermediate risk. No new cases were identified.
How much should we be worried
But how serious of a threat is monkeypox this time around? “Right now, the risk to the general public is very low,” says Scott Roberts, an assistant professor and associate medical director of infection prevention at Yale School of Medicine. “Monkeypox is spread through direct contact with infected skin lesions or through close contact for a prolonged period of time with an infected person. It is much less transmissible than COVID-19.”
The monkeypox incubation period—the time from infection until the onset of symptoms—is typically seven to 14 days but can range from five to 21 days, compared with only three days for the Omicron variant of COVID-19. With such a long incubation, there is a larger window to conduct contact tracing and vaccinate people before symptoms appear, which can prevent infection or lessen the severity.
But symptoms may present atypically or recognition may be delayed. “Ring vaccination works best with 100 percent adherence, and in the absence of a mandate, this is not achievable,” Roberts says.
At the outset of infection, symptoms include fever, chills, and fatigue. Several days later, a rash becomes noticeable, usually beginning on the face and spreading to other parts of the body, he says. The rash starts as flat lesions that raise and develop fluid, similar to manifestations of chickenpox. Once the rash scabs and falls off, a person is no longer contagious.
“It's an uncomfortable infection,” says Van Voorhis, the University of Washington School of Medicine professor. There may be swollen lymph nodes. Sores and rash are often limited to the genitals and areas around the mouth or rectum, suggesting intimate contact as the source of spread.
Symptoms of monkeypox usually last from two to four weeks. The WHO estimated that fatalities range from 3 to 6 percent. Although it’s believed to infect various animal species, including rodents and monkeys in west and central Africa, “the animal reservoir for the virus is unknown,” says Kanki, the Harvard T.H. Chan School of Public Health professor.
Too often, viruses originate in parts of the world that are too poor to grapple with them and may lack the resources to invest in vaccines and treatments. “This disease is endemic in central and west Africa, and it has basically been ignored until it jumped to the north and infected Europeans, Americans, and Canadians,” Van Voorhis says. “We have to do a better job in health care and prevention all over the world. This is the kind of thing that comes back to bite us.”