The Scientist Behind the Pap Smear Saved Countless Women from Cervical Cancer
For decades, women around the world have made the annual pilgrimage to their doctor for the dreaded but potentially life-saving Papanicolaou test, a gynecological exam to screen for cervical cancer named for Georgios Papanicolaou, the Greek immigrant who developed it.
The Pap smear, as it is commonly known, is credited for reducing cervical cancer mortality by 70% since the 1960s; the American Cancer Society (ACS) still ranks the Pap as the most successful screening test for preventing serious malignancies. Nonetheless, the agency, as well as other medical panels, including the US Preventive Services Task Force and the American College of Obstetrics and Gynecology are making a strong push to replace the Pap with the more sensitive high-risk HPV screening test for the human papillomavirus virus, which causes nearly all cases of cervical cancer.
So, how was the Pap developed and how did it become the gold standard of cervical cancer detection for more than 60 years?
Born on May 13, 1883, on the island of Euboea, Greece, Georgios Papanicolaou attended the University of Athens where he majored in music and the humanities before earning his medical degree in 1904 and PhD from the University of Munich six years later. In Europe, Papanicolaou was an assistant military surgeon during the Balkan War, a psychologist for an expedition of the Oceanographic Institute of Monaco and a caregiver for leprosy patients.
When he and his wife, Andromache Mavroyenous (Mary), arrived at Ellis Island on October 19, 1913, the young couple had scarcely more than the $250 minimum required to immigrate, spoke no English and had no job prospects. They worked a series of menial jobs--department store sales clerk, rug salesman, newspaper clerk, restaurant violinist--before Papanicolaou landed a position as an anatomy assistant at Cornell University and Mary was hired as his lab assistant, an arrangement that would last for the next 50 years.
Papanikolaou would later say the discovery "was one of the greatest thrills I ever experienced during my scientific career."
In his early research, Papanikolaou used guinea pigs to prove that gender is determined by the X and Y chromosomes. Using a pediatric nasal speculum, he collected and microscopically examined vaginal secretions of guinea pigs, which revealed distinct cell changes connected to the menstrual cycle. He moved on to study reproductive patterns in humans, beginning with his faithful wife, Mary, who not only endured his almost-daily cervical exams for decades, but also recruited friends as early research participants.
Writing in the medical journal Growth in 1920, the scientist outlined his theory that a microscopic smear of vaginal fluid could detect the presence of cancer cells in the uterus. Papanikolaou would later say the discovery "was one of the greatest thrills I ever experienced during my scientific career."
At this time, cervical cancer was the number one cancer killer of American women but physicians were skeptical of these new findings. They continued to rely on biopsy and curettage to diagnose and treat the disease until Papanicolaou's discovery was published in American Journal of Obstetrics and Gynecology. An inexpensive, easy-to-perform test that could detect cervical cancer, precancerous dysplasia and other cytological diseases was a sea change. Between 1975 and 2001, the cervical cancer rate was cut in half.
Papanicolaou became Emeritus Professor at Cornell University Medical College and received numerous awards, including the Albert Lasker Award for Clinical Medical Research and the Medal of Honor from the American Cancer Society. His image was featured on the Greek currency and the US Post Office issued a commemorative stamp in his honor. But international acclaim didn't lead to a more relaxed schedule. The researcher continued to work seven days a week and refused to take vacations.
After nearly 50 years, Papanicolaou left Cornell to head and develop the Cancer Institute of Miami. He died of a heart attack on February 19, 1962, just three months after his arrival. Mary continued to work in the renamed Papanicolaou Cancer Research Institute until her death 20 years later.
The annual pap smear was originally tied to renewing a birth control prescription. Canada began recommending Pap exams every three years in 1978. The United States followed suit in 2012, noting that it takes many years for cervical cancer to develop. In September 2020, the American Cancer Society recommended delaying the first gynecological pelvic exam until age 25 and replacing the Pap test completely with the more accurate human papillomavirus (HPV) test every five years as the technology becomes more widely available.
Not everyone agrees that it's time to do away with this proven screening method, though. The incidence rate of cervical cancer among Hispanic women is 28% higher than for white women, and Black women are more likely to die of cervical cancer than any other racial or ethnicities.
Whether the Pap is administered every year, every three years or not at all, Papanicolaou will always be known as the medical hero who saved countless women who would otherwise have succumbed to cervical cancer.
More than 20 percent of American adults suffer from chronic pain. And as many as one in four of those prescribed opioids to manage that pain go on to misuse – or abuse – them, often with devastating consequences. Patients afflicted by both chronic pain and opioid addiction are especially difficult to treat, according to Eric Garland, PhD, Director of the University of Utah’s Center on Mindfulness and Integrative Health Intervention Development, because opioid overuse increases pain sensitivity, and pain promotes relapse among those being treated for addiction.
A new study, however, shows that a mindfulness-based therapy can successfully tackle both problems at once, pointing to a tool that could potentially help in fighting the opioid crisis. “This is the first large-scale clinical trial to show that any psychological intervention can reduce opioid misuse and chronic pain for the long term,” says Garland, lead author of the study, published February 28th in JAMA Internal Medicine.
Garland’s study focused on 250 adults who had received opioid therapy for chronic pain for 90 days or longer, randomly assigning them to eight weeks of either a standard psychotherapy support group or Mindfulness-Oriented Recovery Enhancement (MORE) therapy, which combines mindfulness training, cognitive-behavioral therapy (CBT) and positive psychology. Nine months after getting these treatments in primary care settings, 45 percent of patients in the MORE group were no longer misusing opioids, compared to 24 percent of those in group therapy. In fact, about a third of the patients in the MORE group were able to cut their opioid dose in half or reduce it even further.
Patients treated with MORE also experienced more significant pain relief than those in support groups, according to Garland. Conventional approaches to treating opioid addiction include 12-step programs and medically-assisted treatment using drugs like methadone and Suboxone, sometimes coupled with support groups. But patients with Opioid Use Disorder (OUD) – the official diagnosis for opioid addiction – have high relapse rates following treatment, especially if they have chronic pain.
While medically-assisted treatments help to control drug cravings, they do nothing to control chronic pain, which is where psychological therapies like MORE come in.
“For patients suffering from moderate pain and OUD, the relapse rate is three times higher than in patients without chronic pain; for those with severe chronic pain, the relapse rate is five times higher,” says Amy Wachholtz, PhD, Director of Clinical Health Psychology and associate professor at University of Colorado in Denver. “So if we don’t treat the chronic pain along with the OUD addiction simultaneously, we are setting patients up for failure.”
Unfortunately, notes Garland, the standard of care for patients with chronic pain who are misusing their prescribed painkillers is “woefully inadequate.” Many patients don’t meet the criteria for OUD, he says, but instead fall into a gray zone somewhere between legitimate opioid use and full-blown addiction. And while medically-assisted treatments help to control drug cravings, they do nothing to control chronic pain, which is where psychological therapies like MORE come in. But behavioral therapies are often not available in primary care settings, and even when clinicians do refer patients to behavioral health providers, they often prescribe CBT. A large scale study last year showed that CBT – without the added components of mindfulness training and positive psychology – reduced pain but not opioid misuse.
Psychotherapist Eric Garland teaches mindfulness.
University of Utah
Reward Circuitry Rewired
Opioids are highly physiologically addictive. Repeated and high-dose drug use causes the brain to become hypersensitive to stress, pain, and drug-related cues, such as the sight of one’s pill bottle, says Garland, while at the same time becoming increasingly insensitive to natural pleasures. “As an individual becomes more and more dependent on the opioids just to feel okay, they feel less able to extract a healthy sense of joy, pleasure and meaning out of everyday life,” he explains. “This drives them to take higher and higher doses of the opioid to maintain a dwindling sense of well-being.”
The changes are not just psychological: Chronic opioid use actually causes changes in the brain’s reward circuitry. “You can see on brain imaging,” says Garland. “The brain’s reward circuitry becomes more responsive when a person is viewing opioid related images than when they are viewing images of smiling babies, lovers holding hands, or sunsets over the beach.” MORE, he says, teaches “savoring” – a tenet of positive psychology – as a means of restructuring the reward processes in the brain so the patient becomes sensitive to pleasure from natural, healthy rewards, decreasing cravings for drug-related rewards.
Mindfulness and Addiction
Mindfulness, a form of meditation that teaches people to observe their feelings and sensations without judgement, has been increasingly applied to the treatment of addiction. By observing their pain and cravings objectively, for example, patients gain increased awareness of their responses to pain and their habits of opioid use. “They learn how to be with discomfort, whether emotional or physical, in a more compassionate way,” says Sarah Bowen, PhD, associate professor of psychology at Pacific University in Oregon. “And if your mind gives you a message like ‘Oh, I can’t handle that,’ to recognize that that’s a thought that might not be true.”
Bowen’s research is focused on Mindfulness-Based Relapse Prevention, which addresses the cravings associated with addiction. She has patients practice what she calls “urge surfing”: riding out a craving or urge rather than relying on a substance for immediate relief. “Craving will happen, so rather than fighting it, we look at understanding it better,” she says.
MORE differs from other forms of mindfulness-based therapy in that it integrates reappraisal and savoring training. Reappraisal is a technique often used in CBT in which patients learn to change negative thought patterns in order to reduce their emotional impact, while savoring helps to restructure the reward processes in the brain.
Mindfulness training not only helps patients to understand and gain control over their behavior in response to cravings and triggers like pain, says Garland, but also provides a means of pain relief. “We use mindfulness to zoom into pain and break it down into its subcomponents – feelings of heat or tightness or tingling – which reduces the impact that negative emotions have on pain processing in the brain.”
Eric Garland examines brain waves.
University of Utah
Powerful interventions
As the dangers of opioid addiction have become increasingly evident, some scientists are developing less addictive, non-opioid painkillers, but more trials are needed. Meanwhile, behavioral approaches to chronic pain relief have continued to gain traction, and researchers like Garland are probing the possibilities of integrative treatments to treat the addiction itself. Given that the number of people suffering from chronic pain and OUD have reached new heights during the COVID-19 pandemic, says Wachholtz, new treatment alternatives for patients caught in the relentless cycle of chronic pain and opioid misuse are sorely needed. “We’re trying to refine the techniques,” she says, “but we’re starting to realize just how powerful some of these mind-body interventions can be.”
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.