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 patient tilts back her head and winces as the long swab stick pushes six inches up her nose. The tip twirls around uncomfortably before it's withdrawn.
"Our saliva test can detect the virus in asymptomatic and pre-symptomatic cases."
A gloved and gowned healthcare worker wearing a face shield and mask tells the patient that she will learn whether she is positive for COVID-19 as soon as the lab can process her test.
This is the typical unpleasant scenario for getting a coronavirus test. But times are rapidly changing: Today, for the first time, the U.S. Food and Drug Administration cleared one company to sell saliva collection kits for individuals to use at home.
Scientists at the startup venture, RUCDR Infinite Biologics at Rutgers University in New Jersey, say that saliva testing offers an easier, more useful alternative to the standard nasal swab.
"Our saliva test can detect the virus in asymptomatic and pre-symptomatic cases," said Dr. Andrew Brooks, chief operating officer at RUCDR.
Another venture, Darwin BioSciences in Colorado, has separately developed an innovative method of testing saliva for the coronavirus that causes COVID-19.
Saliva testing can allow earlier detection to identify people who may not know they are contagious, say scientists at both companies. In addition, because patients spit into a tube or cup, saliva testing is safer for healthcare workers than taking swabs. This frees up scarce personal protective equipment (PPE) for use elsewhere. Nasal swabs themselves have been in scarce supply.
Saliva testing, if it becomes widespread, potentially could mean opening society sooner. The more ubiquitous testing becomes across the population, experts say, the more feasible it becomes for public health officials to trace and isolate contacts, especially of asymptomatic cases. Testing early and often will be essential to containing emerging hot spots before a vast outbreak can take root.
Darwin Biosceiences is preparing to seek an FDA Emergency Use Authorization (EUA) this month for its patented "CoVScreen" testing system, which potentially could be available to labs nationally by mid-summer.
Meanwhile, Infinite Biologics will now begin selling kits to consumers for home collection, upon order by a physician. The FDA said that the company's saliva test was as accurate as the nasal swab method used by health care professionals. An FDA summary documenting the company's data reported: "There was 100% positive and negative agreement between the results obtained from testing of saliva and those obtained from nasopharyngeal and oropharyngeal swabs."
The greatest scientific advantage, said Dr. Brooks, is that nasal and oral swabs only collect the surface area where the swab goes, which may not be the place with most viral load. In contrast, the virus occurs throughout a saliva sample, so the test is more trustworthy.
The lab at Rutgers can process 20,000 tests a day, with a 48-hour turnaround. They have 75,000 tests ready to ship now.
The Leap: Detecting Sickness Before You Feel It
"We wanted to create a device that could detect infections before symptoms appeared," explained Nicholas Meyerson, co-founder and CEO of Darwin.
For more than 300 years, he said, "the thermometer was the gold standard for detecting disease because we thought the first sign of illness was a fever. This COVID-19 pandemic has proven that not all pathogens cause a fever. You can be highly contagious without knowing it."
"The question is whether we can scale up fast enough to meet the need. I believe saliva testing can help."
Therefore, Meyerson and co-founder Sara Sawyer from the University of Colorado began to identify RNA biomarkers that can sense when a pathogen first enters a molecule and "sets off alarms." They focused on the nucleic acids concentrated in saliva as the best and easiest place to collect samples for testing.
"The isothermal reaction in saliva takes place at body or room temperature," he said, "so there's no need for complicated testing machinery. The chemical reaction can be read out on a paper strip, like a pregnancy test -- two stripes if you're sick, and one stripe if you're okay."
Before the pandemic, limited but successful human trials were already underway at CU in Boulder and at the CU Anschutz Medical Campus east of Denver. "This was our proof of concept," he said.
Darwin was founded in March and has secured enough venture capital to concentrate protype development on detecting the virus causing COVID-19. So far, said Meyerson, "Everything works."
A small double-blind test of 30 samples at CU produced 100 percent accuracy. "I'm not sure if that will hold true as we go into clinical trials," he said, "but I'm confident we will satisfy all the requirements for at least 95 percent clinical validation."
The specific "CoVStick" test strips will roll out soon, he said: "We hope before the second wave of the pandemic hits."
The broader saliva test-strip product from Darwin, "SickStick," is still one to two years away from deployment by the military and introduction into the consumer drugstore market for home use, said Meyerson. It will affordably and quickly detect a range of viral and bacterial infections.
An illustration of the "CoVStick."
(Darwin Biosciences)
A Potential Game Changer
Society needs widespread testing daily, said George Church, founding core faculty of the Wyss Institute for Biologically Inspired Engineering at Harvard University. Speaking at an online SynBioBeta webinar in April, he urged developing stockpiles of testing kits for home use.
As for any potential of false positives, Church said a much bigger risk is not having enough tests.
"Saliva testing is going to speed up the timeline for opening society a lot," said Meyerson. "People need to self-collect samples at home. A lot more people are going to be willing to spit into a tube than to push a swab six inches up their own nose."
Brooks, of Rutgers, addressed the big picture. "It's critical that we open society as soon as possible to minimize the economic impact of the pandemic. Testing is the surest and safest path. The question is whether we can scale up fast enough to meet the need. I believe saliva testing can help."
Earlier this year, biotech company Moderna broke world records for speed in vaccine development. Their researchers translated the genetic code of the coronavirus into a vaccine candidate in just 42 days.
We're about to expand our safety data in Phase II.
Phase I of the clinical trial started in Seattle on March 16th, with the already-iconic image of volunteer Jennifer Haller calmly receiving the very first dose.
Instead of traditional methods, this vaccine uses a new -- and so far unproven -- technology based on synthetic biology: It hijacks the software of life – messenger RNA – to deliver a copy of the virus's genetic sequence into cells, which, in theory, triggers the body to produce antibodies to fight off a coronavirus infection.
U.S. National Institute of Allergy and Infectious Diseases Director Anthony Fauci called the vaccine's preclinical data "impressive" and told National Geographic this week that a vaccine could be ready for general use as early as January.
The Phase I trial has dosed 45 healthy adults. Phase II trials are about to start, enrolling around 600 adults. Pivotal efficacy trials would follow soon thereafter, bankrolled in collaboration with the government office BARDA (Biomedical Advanced Research and Development Authority).
Today, the chief medical officer of Moderna, Tal Zaks, answered burning questions from the public in a webinar hosted by STAT. Here's an edited and condensed summary of his answers.
1) When will a vaccine become available?
We expect to have data in early summer about the antibody levels from our mRNA vaccine. At the same time, we can measure the antibody levels of people who have had the disease, and we should be able to measure the ability of those antibodies to prevent disease.
We will not yet know if the mRNA vaccine works to prevent disease, but we could soon talk about a potential for benefit. We don't yet know about risk. We're about to expand our safety data in Phase II.
In the summer, there is an expectation that we will be launching pivotal trials, in collaboration with government agencies that are helping fund the research. The trials would be launched with the vaccine vs. a placebo with the goal of establishing: How many cases can we show we prevented with the vaccine?
This is determined by two factors: How big is the trial? And what's the attack rate in the population we vaccinate? The challenge will be to vaccinate in the areas where the risk of infection is still high in the coming months, and we're able to vaccinate and demonstrate fewer infections compared to a placebo. If the disease is happening faster in a given area, you will be able to see an outcome faster. Potentially by the end of the year, we will have the data to say if the vaccine works.
Will that be enough for regulatory approval? The main question is: When will we cross the threshold for the anticipated benefit of a presumed vaccine to be worth the risk?
There is a distinction between approval for those who need it most, like the elderly. Their unmet need and risk/benefit is not the same as it is for younger adults.
My private opinion: I don't think it's a one-size-fits-all. It will be a more measured stance.
2) Can you speed up the testing process with challenge studies, where volunteers willingly get infected?
It's a great question and I applaud the people who ask it and I applaud those signing up to do it. I'm not sure I am a huge fan, for both practical and ethical reasons. The devil is in the details. A challenge study has to show us a vaccine can prevent not just infection but prevent disease. Otherwise, how do I know the dose in the challenge study is the right dose? If you take 100 young people, 90 of them will get mild or no disease. Ten may end up in hospital and one in the ICU.
Also, the timeline. Can it let you skip Phase II of large efficacy trial? The reality for us is that we are about to start Phase II anyway. It would be months before a challenge trial could be designed. And ethically: everybody agrees there is a risk that is not zero of having very serious disease. To justify the risk, we have to be sure the benefit is worth it - that it actually shrunk the timeline. To just give us another data point, I find it hard to accept.
This technology allows us to scale up manufacturing and production.
3) What was seen preclinically in the animal models with Moderna's mRNA vaccines?
We have taken vaccines using our technology against eight different viruses, including two flu strains. In every case, in the preclinical model, we showed we could prevent disease, and when we got to antibody levels, we got the data we wanted to see. In doses of 25-100 micrograms, that usually ends up being a sweet spot where we see an effect. It's a good place as to the expectation of what we will see in Phase I trials.
4) Why is Moderna pursuing an mRNA virus instead of a traditional inactivated virus or recombinant one? This is an untried technology.
First, speed matters in a pandemic. If you have tech that can move much quicker, that makes a difference. The reason we have broken world records is that we have invested time and effort to be ready. We're starting from a platform where it's all based on synthetic biology.
Second, it's fundamental biology - we do not need to make an elaborate vaccine or stick a new virus in an old virus, or try to make a neutralizing but not binding virus. Our technology is basically mimicking the virus. All life works on making proteins through RNA. We have a biological advantage by teaching the immune system to do the right thing.
Third, this technology allows us to scale up manufacturing and production. We as a company have always seen this ahead of us. We invested in our own manufacturing facility two years ago. We have already envisioned scale up on two dimensions. Lot size and vaccines. Vaccines is the easier piece of it. If everybody gets 100 micrograms, it's not a heck of a lot. Prior to COVID, our lead program was a CMV (Cytomegalovirus) vaccine. We had envisioned launching Phase III next year. We had been already well on the path to scale up when COVID-19 caught us by surprise. This would be millions and millions of doses, but the train tracks have been laid.
5) People tend to think of vaccines as an on-off switch -- you get a vaccine and you're protected. But efficacy can be low or high (like the flu vs. measles vaccines). How good is good enough here for protection, and could we need several doses?
Probably around 50-60 percent efficacy is good enough for preventing a significant amount of disease and decreasing the R0. We will aim higher, but it's hard to estimate what degree of efficacy to prepare for until we do the trial. (For comparison, the average flu vaccine efficacy is around 50 percent.)
We anticipate a prime boost. If our immune system has never seen a virus, you can show you're getting to a certain antibody level and then remind the immune system (with another dose). A prime boost is optimal.
My only two competitors are the virus and the clock.
6) How would mutations affect a vaccine?
Coronaviruses tend to mutate the least compared to other viruses but it's entirely possible that it mutates. The report this week about those projected mutations on the spike protein have not been predicted to alter the critical antibodies.
As we scale up manufacturing, the ability to plug in a new genetic sequence and get a new vaccine out there will be very rapid.
For flu vaccine, we don't prove efficacy every year. If we get to the same place with an mRNA vaccine, we will just change the sequence and come out with a new vaccine. The path to approval would be much faster if we leverage the totality of efficacy data like we do for flu.
7) Will there be more than one vaccine and how will they be made available?
I hope so, I don't know. The path to making these available will go through a public-private partnership. It's not your typical commercial way of deploying a vaccine. But my only two competitors are the virus and the clock. We need everybody to be successful.
Kira Peikoff was the editor-in-chief of Leaps.org from 2017 to 2021. As a journalist, her work has appeared in The New York Times, Newsweek, Nautilus, Popular Mechanics, The New York Academy of Sciences, and other outlets. She is also the author of four suspense novels that explore controversial issues arising from scientific innovation: Living Proof, No Time to Die, Die Again Tomorrow, and Mother Knows Best. Peikoff holds a B.A. in Journalism from New York University and an M.S. in Bioethics from Columbia University. She lives in New Jersey with her husband and two young sons. Follow her on Twitter @KiraPeikoff.