How thousands of first- and second-graders saved the world from a deadly disease
Although Jonas Salk has gone down in history for helping rid the world (almost) of polio, his revolutionary vaccine wouldn't have been possible without the world’s largest clinical trial – and the bravery of thousands of kids.
Exactly 67 years ago, in 1955, a group of scientists and reporters gathered at the University of Michigan and waited with bated breath for Dr. Thomas Francis Jr., director of the school’s Poliomyelitis Vaccine Evaluation Center, to approach the podium. The group had gathered to hear the news that seemingly everyone in the country had been anticipating for the past two years – whether the vaccine for poliomyelitis, developed by Francis’s former student Jonas Salk, was effective in preventing the disease.
Polio, at that point, had become a household name. As the highly contagious virus swept through the United States, cities closed their schools, movie theaters, swimming pools, and even churches to stop the spread. For most, polio presented as a mild illness, and was usually completely asymptomatic – but for an unlucky few, the virus took hold of the central nervous system and caused permanent paralysis of muscles in the legs, arms, and even people’s diaphragms, rendering the person unable to walk and breathe. It wasn’t uncommon to hear reports of people – mostly children – who fell sick with a flu-like virus and then, just days later, were relegated to spend the rest of their lives in an iron lung.
For two years, researchers had been testing a vaccine that would hopefully be able to stop the spread of the virus and prevent the 45,000 infections each year that were keeping the nation in a chokehold. At the podium, Francis greeted the crowd and then proceeded to change the course of human history: The vaccine, he reported, was “safe, effective, and potent.” Widespread vaccination could begin in just a few weeks. The nightmare was over.
The road to success
Jonas Salk, a medical researcher and virologist who developed the vaccine with his own research team, would rightfully go down in history as the man who eradicated polio. (Today, wild poliovirus circulates in just two countries, Afghanistan and Pakistan – with only 140 cases reported in 2020.) But many people today forget that the widespread vaccination campaign that effectively ended wild polio across the globe would have never been possible without the human clinical trials that preceded it.
As with the COVID-19 vaccine, skepticism and misinformation around the polio vaccine abounded. But even more pervasive than the skepticism was fear. The consequences of polio had arguably never been more visible.
The road to human clinical trials – and the resulting vaccine – was a long one. In 1938, President Franklin Delano Roosevelt launched the National Foundation for Infantile Paralysis in order to raise funding for research and development of a polio vaccine. (Today, we know this organization as the March of Dimes.) A polio survivor himself, Roosevelt elevated awareness and prevention into the national spotlight, even more so than it had been previously. Raising funds for a safe and effective polio vaccine became a cornerstone of his presidency – and the funds raked in by his foundation went primarily to Salk to fund his research.
The Trials Begin
Salk’s vaccine, which included an inactivated (killed) polio virus, was promising – but now the researchers needed test subjects to make global vaccination a possibility. Because the aim of the vaccine was to prevent paralytic polio, researchers decided that they had to test the vaccine in the population that was most vulnerable to paralysis – young children. And, because the rate of paralysis was so low even among children, the team required many children to collect enough data. Francis, who led the trial to evaluate Salk’s vaccine, began the process of recruiting more than one million school-aged children between the ages of six and nine in 272 counties that had the highest incidence of the disease. The participants were nicknamed the “Polio Pioneers.”
Double-blind, placebo-based trials were considered the “gold standard” of epidemiological research back in Francis's day - and they remain the best approach we have today. These rigorous scientific studies are designed with two participant groups in mind. One group, called the test group, receives the experimental treatment (such as a vaccine); the other group, called the control, receives an inactive treatment known as a placebo. The researchers then compare the effects of the active treatment against the effects of the placebo, and every researcher is “blinded” as to which participants receive what treatment. That way, the results aren’t tainted by any possible biases.
But the study was controversial in that only some of the individual field trials at the county and state levels had a placebo group. Researchers described this as a “calculated risk,” meaning that while there were risks involved in giving the vaccine to a large number of children, the bigger risk was the potential paralysis or death that could come with being infected by polio. In all, just 200,000 children across the US received a placebo treatment, while an additional 725,000 children acted as observational controls – in other words, researchers monitored them for signs of infection, but did not give them any treatment.
As with the COVID-19 vaccine, skepticism and misinformation around the polio vaccine abounded. But even more pervasive than the skepticism was fear. President Roosevelt, who had made many public and televised appearances in a wheelchair, served as a perpetual reminder of the consequences of polio, as an infection at age 39 had rendered him permanently unable to walk. The consequences of polio had arguably never been more visible, and parents signed up their children in droves to participate in the study and offer them protection.
The Polio Pioneer Legacy
In a little less than a year, roughly half a million children received a dose of Salk’s polio vaccine. While plenty of children were hesitant to get the shot, many former participants still remember the fear surrounding the disease. One former participant, a Polio Pioneer named Debbie LaCrosse, writes of her experience: “There was no discussion, no listing of pros and cons. No amount of concern over possible side effects or other unknowns associated with a new vaccine could compare to the terrifying threat of polio.” For their participation, each kid received a certificate – and sometimes a pin – with the words “Polio Pioneer” emblazoned across the front.
When Francis announced the results of the trial on April 12, 1955, people did more than just breathe a sigh of relief – they openly celebrated, ringing church bells and flooding into the streets to embrace. Salk, who had become the face of the vaccine at that point, was instantly hailed as a national hero – and teachers around the country had their students to write him ‘thank you’ notes for his years of diligent work.
But while Salk went on to win national acclaim – even accepting the Presidential Medal of Freedom for his work on the polio vaccine in 1977 – his success was due in no small part to the children (and their parents) who took a risk in order to advance medical science. And that risk paid off: By the early 1960s, the yearly cases of polio in the United States had gone down to just 910. Where before the vaccine polio had caused around 15,000 cases of paralysis each year, only ten cases of paralysis were recorded in the entire country throughout the 1970s. And in 1979, the virus that once shuttered entire towns was declared officially eradicated in this country. Thanks to the efforts of these brave pioneers, the nation – along with the majority of the world – remains free of polio even today.
In 2010, a 67-year-old former executive assistant for a Fortune 500 company was diagnosed with mild cognitive impairment. By 2014, her doctors confirmed she had Alzheimer's disease.
As her disease progressed, she continued to live independently but wasn't able to drive anymore. Today, she can manage most of her everyday tasks, but her two daughters are considering a live-in caregiver. Despite her condition, the woman may represent a beacon of hope for the approximately 44 million people worldwide living with Alzheimer's disease. The now 74-year-old is among a small cadre of Alzheimer's patients who have undergone an experimental ultrasound procedure aimed at slowing cognitive decline.
In November 2020, Elisa Konofagou, a professor of biomedical engineering and director of the Ultrasound and Elasticity Imaging Laboratory at Columbia University, and her team used ultrasound to noninvasively open the woman's blood-brain barrier. This barrier is a highly selective membrane of cells that prevents toxins and pathogens from entering the brain while allowing vital nutrients to pass through. This regulatory function means the blood-brain barrier filters out most drugs, making treating Alzheimer's and other brain diseases a challenge.
Ultrasound uses high-frequency sound waves to produce live images from the inside of the human body. But scientists think it could also be used to boost the effectiveness of Alzheimer's drugs, or potentially even improve brain function in dementia patients without the use of drugs.
The procedure, which involves a portable ultrasound system, is the culmination of 17 years of lab work. As part of a small clinical trial, scientists positioned a sensor transmitting ultrasound waves on top of the woman's head while she sat in a chair. The sensor sends ultrasound pulses throughout the target region. Meanwhile, investigators intravenously infused microbubbles into the woman to boost the effects of the ultrasound. Three days after the procedure, scientists scanned her brain so that they could measure the effects of the treatments. Five months later, they took more images of her brain to see if the effects of the treatment lasted.
Promising Signs
After the first brain scan, Konofagou and her team found that amyloid-beta, the protein that clumps together in the brains of Alzheimer's patients and disrupts cell function, had declined by 14%. At the woman's second scan, amyloid levels were still lower than before the experimental treatment, but only by 10% this time. Konofagou thinks repeat ultrasound treatments given early on in the development of Alzheimer's may have the best chance at keeping amyloid plaques at bay.
This reduction in amyloid appeared to halt the woman's cognitive decline, at least temporarily. Following the ultrasound treatment, the woman took a 30-point test used to measure cognitive impairment in Alzheimer's. Her score — 22, indicating mild cognitive impairment — remained the same as before the intervention. Konofagou says this was actually a good sign.
"Typically, every six months an Alzheimer's patient scores two to three points lower, so this is highly encouraging," she says.
Konofagou speculates that the results might have been even more impressive had they applied the ultrasound on a larger section of the brain at a higher frequency. The selected site was just 4 cubic centimeters. Current safety protocols set by the U.S. Food and Drug Administration stipulate that investigators conducting such trials only treat one brain region with the lowest pressure possible.
The Columbia trial is aided by microbubble technology. During the procedure, investigators infused tiny, gas-filled spheres into the woman's veins to enhance the ultrasound reflection of the sound waves.
The big promise of ultrasound is that it could eventually make drugs for Alzheimer's obsolete.
"Ultrasound with microbubbles wakes up immune cells that go on to discard amyloid-beta," Konofagou says. "In this way, we can recover the function of brain neurons, which are destroyed by Alzheimer's in a sort of domino effect." What's more, a drug delivered alongside ultrasound can penetrate the brain at a dose up to 10 times higher.
Costas Arvanitis, an assistant professor at Georgia Institute of Technology who studies ultrasonic biophysics and isn't involved in the Columbia trial, is excited about the research. "First, by applying ultrasound you can make larger drugs — picture an antibody — available to the brain," he says. Then, you can use ultrasound to improve the therapeutic index, or the ratio of the effectiveness of a drug versus the ratio of adverse effects. "Some drugs might be effective but because we have to provide them in high doses to see significant responses they tend to come with side effects. By improving locally the concentration of a drug, you open up the possibility to reduce the dose."
The Columbia trial will enroll just six patients and is designed to test the feasibility and safety of the approach, not its efficacy. Still, Arvantis is hopeful about the potential benefits of the technique. "The technology has already been demonstrated to be safe, its components are now tuned to the needs of this specific application, and it's safe to say it's only a matter of time before we are able to develop personalized treatments," he says.
Konofagou and her colleagues recently presented their findings at the 20th Annual International Symposium for Therapeutic Ultrasound and intend to publish them in a scientific journal later this year. They plan to recruit more participants for larger trials, which will determine how effective the therapy is at improving memory and brain function in Alzheimer's patients. They're also in talks with pharmaceutical companies about ways to use their therapeutic approach to improve current drugs or even "create new drugs," says Konofagou.
A New Treatment Approach
On June 7, the FDA approved the first Alzheimer's disease drug in nearly two decades. Aducanumab, a drug developed by Biogen, is an antibody designed to target and reduce amyloid plaques. The drug has already sparked immense enthusiasm — and controversy. Proponents say the drug is a much-needed start in the fight against the disease, but others argue that the drug doesn't substantially improve cognition. They say the approval could open the door to the FDA greenlighting more Alzheimer's drugs that don't have a clear benefit, giving false hope to both patients and their families.
Konofagou's ultrasound approach could potentially boost the effects of drugs like aducanumab. "Our technique can be seamlessly combined with aducanumab in early Alzheimer's, where it has shown the most promise, to further enhance both its amyloid load reduction and further reduce cognitive deficits while using exactly the same drug regimen otherwise," she says. For the Columbia team, the goal is to use ultrasound to maximize the effects of aducanumab, as they've done with other drugs in animal studies.
But Konofagou's approach could transcend drug controversies, and even drugs altogether. The big promise of ultrasound is that it could eventually make drugs for Alzheimer's obsolete.
"There are already indications that the immune system is alerted each time ultrasound is exerted on the brain or when the brain barrier is being penetrated and gets activated, which on its own may have sufficient therapeutic effects," says Konofagou. Her team is now working with psychiatrists in hopes of using brain stimulation to treat patients with depression.
The potential to modulate the brain without drugs is huge and untapped, says Kim Butts Pauly, a professor of radiology, electrical engineering and bioengineering at Stanford University, who's not involved in the Columbia study. But she admits that scientists don't know how to fully control ultrasound in the brain yet. "We're only at the starting point of getting the tools to understand and harness how ultrasound microbubbles stimulate an immune response in the brain."
Meanwhile, the 74-year-old woman who received the ultrasound treatment last year, goes on about her life, having "both good days and bad days," her youngest daughter says. COVID-19's isolation took a toll on her, but both she and her daughters remain grateful for the opportunity to participate in the ultrasound trial.
"My mother wants to help, if not for herself, then for those who will follow her," the daughter says. She hopes her mother will be able to join the next phase of the trial, which will involve a drug in conjunction with the ultrasound treatment. "This may be the combination where the magic will happen," her daughter says.
Naked Mole Rats Defy Aging. One Scientist Has Dedicated Her Career to Finding Out How.
Naked mole rats have extraordinarily long lifespans and are extremely resistant to cancer.
Rochelle "Shelley" Buffenstein has one of the world's largest, if not the largest, lab-dwelling colonies of the naked mole rat. (No one has done a worldwide tabulation, but she has 4,500 of them.) Buffenstein has spent decades studying the little subterranean-dwelling rodents. Over the years, she and her colleagues have uncovered one surprising discovery after another, which has led them to re-orient the whole field of anti-aging research.
Naked mole rats defy everything we thought we knew about aging. These strange little rodents from arid regions of Africa, such as Kenya, Ethiopia and Somalia, live up to ten times longer than their size would suggest. And unlike virtually every other animal, they don't lose physical or cognitive abilities with age, and even retain their fertility up until the end of life. They appear to have active defenses against the ravages of time, suggesting that aging may not be inevitable. Could these unusual creatures teach humans how to extend life and ameliorate aging?
Buffenstein, who is senior principle investigator at Calico Life Sciences, has dedicated her life to finding out. Her early interest in the animals of what is now Zimbabwe led to her current position as a cutting-edge anti-aging researcher at Calico, the Google-funded health venture launched in 2013. The notoriously secretive company is focused on untangling the mysteries of why animals and people age, and whether there are ways to slow or temporarily arrest the process.
The small, wrinkly animal, which lives in underground burrows in the hot, arid regions of Africa, is hardly the beauty queen of the mammalian kingdom. Furless, buck-toothed and tiny-eyed, the creatures look like they could use a good orthodontist, a protective suit of clothes and possibly, some spectacles to enhance their eyesight. But these rats more than make up for their unimpressive looks with their superlative ability to adapt to some of the most inhospitable conditions on earth.
Based on the usual rule that body size predicts lifespan, naked mole rats shouldn't live that long. After all, similarly-sized rodents like mice have a life expectancy of two years or less. But Buffenstein was one of the first scientists to recognize that naked mole rats live an extraordinarily long time, with her oldest animal approaching 39 years of age. In addition, they never become geriatric in the human sense, defying the common signs of aging — age-related diseases, cognitive decline and even menopause. In fact, the queens, or females that do all the breeding in a bee-like underground colony, remain fertile and give birth to healthy pups up until what would be considered very old age in humans. And the naked mole rat has other curious abilities, such as the ability to endure extreme low-oxygen, or hypoxic, conditions like those they encounter in their underground nests.
"One thing we've learned from these animals is that they stay healthy until the very end."
It's not that the naked mole rat isn't subject to the vicissitudes of life, or the normal wear and tear of biological processes. Over the years, Buffenstein and her colleagues have discovered that, while the process of oxidative stress — thought for 50 years to be the main cause of aging — occurs in the naked mole rat just as in any other animal, its damage does not accumulate with age. Oxidative stress occurs during normal cell metabolism when oxygen "free radicals" with one or more unpaired electrons wreak havoc on large cellular molecules, leaving microscopic debris in their wake that clogs up the gears of healthy cell function. Somehow, naked mole rats have an enhanced ability to clear out the damaged cells and molecules before they can set off the usual chain reaction of cell dysfunction and death, according to a 2013 paper in which Buffenstein is the lead author.
Oxidative stress is not the only factor known to be problematic in aging. Slowly accumulating damage to DNA typically leads to protein malfunction and improper folding. In humans and most other animals, these protein fragments can accumulate in cells and gum up the works. Only not so much in naked mole rats, which are able to maintain normal protein folding throughout their long life. After years of discoveries like these, Buffenstein has gradually reframed her focus from "what goes wrong to produce aging?" to "what goes right in the naked mole rat to help it defy the normal wear and tear of life?" Buffenstein's research suggests that the tiny mammals have a unique ability to somehow clear out damaged protein fragments and other toxic debris before they can cause disease and aging.
How She Got Here
Buffenstein ascribes her initial acquaintance with the naked mole rat to serendipity. Back in 1979, her postgraduate mentor Jenny Jarvis at the University of Cape Town in South Africa kept a small colony of rats in her office while studying the mechanisms that lead to the animals' unusual adaptive capabilities. It was Buffenstein's job to take care of them. Working with Jarvis, Buffenstein focused on understanding their unique adaptations to the extreme conditions of their natural habitat.
They studied the unusual behaviors regulating the rat colonies. For instance, they observed that designated "workers" dig the entire colony's underground tunnels and a single reproducing female breeds with only a small number of males. Buffenstein also examined how these animals are able to survive without the "sunshine hormone" — vitamin D — and their unusual modes of regulating their internal temperatures and converting food into energy. Though classified as mammals, the rodents simply don't conform to the mammalian handbook, having found ingenuous ways to alter their bodies and behavior that is fine-tuned to the scorching heat and aridity of their environment.
To escape the heat, they simply burrow underground and live in elaborate tunnels. To cope with the low-oxygen conditions underground, they slowed their metabolism and learned to live for extended periods of time in such hypoxic conditions that an ordinary animal would quickly suffocate. But it was slowly dawning on Buffenstein that the small creatures were exceptional in additional ways.
When Buffenstein got her first academic position at the University of Witwatersrand in Johannesburg, Jarvis said she could take some of the naked mole rats with her. When she did, Buffenstein noticed that the animals were living far longer than similarly sized rodents. "At that stage, they were about ten years old. Little did I know how long they would eventually show us they could live," she says.
In 1997, after accepting a position at the City College of New York, Buffenstein moved to the U.S. and took her rat colony with her. There she was able to pursue an evolving narrative about the humble naked mole rat that continued to defy expectations. As the years passed, it was becoming more and more evident that her observations could have major implications for aging research. Eventually, she took a position at the Barshop Institute for Aging and Longevity Studies in San Antonio, Texas.
One early observation of Buffenstein's suggested that the species most often used in aging research—mice, roundworms, fruit flies and yeast—have short lifespans and poor defenses against aging. These animals provide important insights into how aging works, and have revealed possible targets for intervention. But they don't show what goes right in apparently non-aging animals like the naked mole rat.
Buffenstein's years of studying the rats has laid the foundation for a whole new perspective in aging research.
"My hypothesis," she says, "is that naked mole rats are very good at removing damaged macromolecules and cells, thereby maintaining homeostasis and cell and tissue function. All the repair pathways examined by us and others in the field point to more efficient repair and more rapid responses to damaging agents." These include things like free radicals and radiation.
Buffenstein’s Legacy
Some researchers today are building on Buffenstein's foundational discoveries to home in on possible anti-aging mechanisms that lead to the extraordinary resilience of naked mole rats. University of Cambridge researcher and co-founder of the institution's Naked Mole-Rat Initiative, Ewan St. John Smith, is studying the animal's resistance to cancer.
In a 2020 paper published in Nature, Smith and his colleagues established that naked mole rats harbor cancer-causing genes, and these genes occasionally create cancer cells. But something in the rats shuts the multiplication process down before the cells can grow out of control and form tumors. Now, scientists want to know what mechanisms, exactly, are at play in preventing the cells from invading healthy tissues. Smith has hypothesized that the answer is somehow embedded in interactions in the cells' microenvironment.
He also thinks the animal's immune system could just be very effective at seeking out and destroying cancer cells. Several current cancer therapies work by boosting the body's immune system so it can attack and eliminate the toxic cells. It's possible that the naked mole rat's immune system naturally goes into hyper-drive when cancer cells appear, enabling it to nip the disease in the bud before tumors can form. A pharmacologist by training, Smith thinks that if there is some chemical mediator in the naked mole rat that supercharges its immune cells, perhaps that mediator can be synthesized in a drug to treat humans for cancer.
The naked mole rat's extreme tolerance to hypoxia could also play a role. "Interestingly," he says, "when cells become cancerous, they also become hypoxic, and naked mole rats are known to be very resistant to hypoxia.
He notes that a form of low-level hypoxia is also present in the bodies and brains of both aged mice and older humans. It's commonly seen in the brains of humans with Alzheimer's disease and other forms of age-related dementia. This suggests that hypoxia in humans — and in other mammals — may have a role to play in Alzheimer's and the aging process itself. Resistance to hypoxia could be why the naked mole rat, in Smith's words, "chugs along quite happily" in conditions that in humans are associated with disease and decline.
Smith cheerfully acknowledges his debt to Buffenstein for laying so much of the groundwork in a field rife with possible implications for anti-aging. "Shelley is amazing," he says. "Naked mole rats have a queen and I always refer to her as the queen of the naked mole rat world." In fact, Buffenstein gave Smith his first colony of rats, which he's since grown to about 150. "Some of them will still be around when I retire," he jokes.
Vera Gorbunova, a professor of biology and oncology at the University of Rochester who studies both longevity and cancer in naked mole rats, credits Buffenstein with getting others to study the animals for anti-aging purposes. Gorbunova believes that "cancer and aging go hand-in-hand" and that longer-lived animals have better, more accurate DNA repair.
Gorbunova is especially interested in the naked mole rat's ability to secrete a superabundance of a "super-sugar" molecule called hyaluronan, a ubiquitous additive to skin creams for its moisturizing effect. Gorbunova and others have observed that the presence of high concentrations of hyaluronan in the naked mole rat's extracellular matrix — the chemical-rich solution between cells — prevents the overcrowding of cells. This, perhaps, could be the key to the animal's ability to stop tumors from forming.
Hyaluronan is also present in the extracellular matrix of humans, but the naked mole rat molecule is more than five times larger than the versions found in humans or mice, and is thought to play a significant part in the animal's DNA repair. But just rubbing a cream containing hyaluronan over your skin won't stop cancer or aging. High concentrations of the substance in the extracellular matrix throughout your body would likely be needed.
Gorbunova notes that the naked mole rat offers a multitude of possibilities that could eventually lead to drugs to slow human aging. "I'm optimistic that there are many different strategies, because the naked mole rat likely has many processes going on that fight aging," she says. "I think that in a relatively short time, there will be bonafide treatments to test in animals. One thing we've learned from these animals is that they stay healthy until the very end."
So if naked mole rats don't become frail with age or develop age-related diseases, what does kill them? The answer, unfortunately, is usually other naked mole rats. Buffenstein has long noted that even though they live in highly cooperative colonies, they can be quite cantankerous when there's a disruption in the hierarchy, a sentiment echoed by Gorbunova. "Sometimes there are periods of peace and quiet, but if something happens to the queen, all hell breaks loose," she says. "If the queen is strong, everybody knows their place," but if the queen dies, the new queen is inevitably decided by violent competition.
To the casual observer, a strange, wrinkly rodent like the naked mole rat might seem to have little to teach us about ourselves, but Buffenstein is confident that her discoveries could have major implications for human longevity research. Today, at Calico's labs in San Francisco, she's focused entirely on the determining how anti-aging defense mechanisms in the rats could lead to similar defenses being stimulated or introduced in humans.
"The million-dollar question is, what are the mechanisms protecting against aging, and can these be translated into therapies to delay or abrogate human aging, too?"
Buffenstein fired up a new generation of scientists with multiple discoveries, especially the fundamental one that naked mole rats are subject to the same wear and tear over time as the rest of us, but somehow manage to reverse it. These days, the trailblazer is at work on untangling the molecular mechanisms involved in the animal's resistance to cardiac aging. On top of everything else, the small creature has a unique ability to fight off the scourge of heart disease, which is the leading cause of death in the industrialized world.
After all, the point is not to extend old age, but to slow down aging itself so that frailty and disability are compressed into a brief period after a long-extended period of vitality. By switching the focus from what goes wrong to mechanisms that defend against aging in the first place, the discoveries of Buffenstein and a new generation of researchers who are building on her groundbreaking research promise to be a driving force in the quest to extend not only life, but healthy, vigorous life in humans.
This article was first published by Leaps.org on June 23, 2021.