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.
Monnica Williams was stuck. The veteran psychologist wanted to conduct a study using psychedelics, but her university told her they didn't have the expertise to evaluate it via an institutional review board, which is responsible for providing ethical and regulatory oversight for research that involves human participants. Instead, they directed her to a hospital, whose reviewers turned it down, citing research of a banned substance as unethical.
"I said, 'We're not using illegal psilocybin, we're going through Health Canada,'" Williams said. Psilocybin was banned in Canada in 1974, but can now be obtained with an exemption from Health Canada, the federal government's health policy department. After learning this, the hospital review board told Williams they couldn't review her proposal because she's not affiliated with the hospital, after all.
It's all part of balancing bureaucracy with research goals for Williams, a leading expert on racial trauma and psychedelic medicine, as well as obsessive compulsive disorder (OCD), at the University of Ottawa. She's exploring the use of hallucinogenic substances like MDMA and psilocybin — commonly known as ecstasy and magic mushrooms, respectively — to help people of color address the psychological impacts of systemic racism. A prolific researcher, Williams also works as an expert witness, offering clinical evaluations for racial trauma cases.
Scientists have long known that psychedelics produce an altered state of consciousness and openness to new perspectives. For people with mental health conditions who haven't benefited from traditional therapy, psychedelics may be able to help them discover what's causing their pain or trauma, including racial trauma—the mental and emotional injury spurred by racial bias.
"Using psychedelics can not only bring these pain points to the surface for healing, but can reduce the anxiety or response to these memories and allow them to speak openly about them without the pain they bring," Williams says. Her research harnesses the potential of psychedelics to increase neuroplasticity, which includes the brain's ability to build new pathways.
"People of color are dealing with racism all the time, in large and small ways, and even dealing with racism in healthcare, even dealing with racism in therapy."
But she says therapists of color aren't automatically equipped to treat racial trauma. First, she notes, people of color are "vastly underrepresented in the mental health workforce." This is doubly true in psychedelic-assisted psychotherapy, in which a person is guided through a psychedelic session by a therapist or team of therapists, then processes the experience in subsequent therapy sessions.
"On top of that, the therapists of color are getting the same training that the white therapists are getting, so it's not even really guaranteed that they're going to be any better at helping a person that may have racial trauma emerging as part of their experience," she says.
In her own training to become a clinical psychologist at the University of Virginia, Williams says she was taught "how to be a great psychologist for white people." Yet even people of color, she argues, need specialized training to work with marginalized groups, particularly when it comes to MDMA, psilocybin and other psychedelics. Because these drugs can lower natural psychological defense mechanisms, Williams says, it's important for providers to be specially trained.
"People of color are dealing with racism all the time, in large and small ways, and even dealing with racism in healthcare, even dealing with racism in therapy. So [they] generally develop a lot of defenses and coping strategies to ward off racism so that they can function." she says. This is particularly true with psychedelic-assisted psychotherapy: "One possibility is that you're going to be stripped of your defenses, you're going to be vulnerable. And so you have to work with a therapist who is going to understand that and not enact more racism in their work with you."
Williams has struggled to find funding and institutional approval for research involving psychedelics, or funding for investigations into racial trauma or the impacts of conditions like OCD and post-traumatic stress disorder (PTSD) in people of color. With the bulk of her work focusing on OCD, she hoped to focus on people of color, but found there was little funding for that type of research. In 2020, that started to change as structural racism garnered more media attention.
After the killing of George Floyd, a 46-year-old Black man, by a white police officer in May 2020, Williams was flooded with media requests. "Usually, when something like that happens, I get contacted a lot for a couple of weeks, and it dies off. But after George Floyd, it just never did."
Monnica Williams, clinical psychologist at the University of Ottawa
Williams was no stranger to the questions that soon blazed across headlines: How can we mitigate microaggressions? How do race and ethnicity impact mental health? What terms should we use to discuss racial issues? What constitutes an ally, and why aren't there more of them? Why aren't there more people of color in academia, and so many other fields?
Now, she's hoping that the increased attention on racial justice will mean more acceptance for the kind of research she's doing.
In fact, Williams herself has used psychedelics in order to gain a better understanding of how to use them to treat racial trauma. In a study published in January, she and two other Black female psychotherapists took MDMA in a supervised setting, guided by a team of mental health practitioners who helped them process issues that came up as the session progressed. Williams, who was also the study's lead author, found that participants' experiences centered around processing and finding release from racial identities, and, in one case, of simply feeling wholly human without the burden of racial identity for the first time.
The purpose of the study was twofold: to understand how Black women react to psychedelics and to provide safe, firsthand, psychedelic experiences to Black mental health practitioners. One of the other study participants has since gone on to offer psychedelic-assisted psychotherapy to her own patients.
Psychedelic research, and psilocybin in particular, has become a hot topic of late, particularly after Oregon became the first state to legalize it for therapeutic use last November. A survey-based, observational study with 313 participants, published in 2020, paved the way for Williams' more recent MDMA experiments by describing improvements in depression, anxiety and racial trauma among people of color who had used LSD, psilocybin or MDMA in a non-research setting.
Williams and her team included only respondents who reported a moderate to strong psychoactive effect of past psychedelic consumption and believed these experiences provided "relief from the challenging effects of ethnic discrimination." Participants reported a memorable psychedelic experience as well as its acute and lasting effects, completing assessments of psychological insight, mystical experience and emotional challenges experienced during psychedelic experience, then describing their mental health — including depression, anxiety and trauma symptoms — before and after that experience.
Still, Williams says addressing racism is much more complex than treating racial trauma. "One of the questions I get asked a lot is, 'How can Black people cope with racism?' And I don't really like that question," she says. "I think it's important and I don't mind answering it, but I think the more important question is, how can we end racism? What can Black people do to stop racism that's happening to them and what can we do as a society to stop racism? And people aren't really asking this question."
When Lynne Maquat, who leads the Center for RNA Biology at the University of Rochester, became interested in the ribonucleic acid molecule in the 1970s, she was definitely in the minority. The same was true for Joan Steitz, now professor of molecular biophysics and biochemistry at Yale University, who began to study RNA a decade earlier in the 1960s.
"My first RNA experiment was a failure, because we didn't understand how things worked," Steitz recalls. In her first undergraduate experiment, she unwittingly used a lab preparation that destroyed the RNA. "Unknowingly, our preparation contained enzymes that degraded our RNA."
At the time, scientists pursuing genetic research tended to focus on DNA, or deoxyribonucleic acid — and for good reason. It was clear that the enigmatic double-helix ribbon held the answers to organisms' heredity, genetic traits, development, growth and aging. If scientists could decipher the secrets of DNA and understand how its genetic instructions translate into the body's functions in health and disease, they could develop treatments for all kinds of diseases. On the contrary, the prevailing dogma of the time viewed RNA as merely a helper that passively carried out DNA's genetic instructions for protein-making — so it received much less attention.
But Maquat and Steitz weren't interested in heredity. They studied biochemistry and biophysics, so they wanted to understand how RNA functioned on the molecular level — how it carried instructions, catalyzed reactions, and helped build protein bonds, among other things.
"I'm a mechanistic biochemist, so I like to know how things happen," Maquat says. "Once you understand the mechanism, you can think of how to solve problems." And so the quest to understand how RNA does its job became the focus of both women's careers.
"People can now appreciate why some of us studied RNA for such a long time."
Half a century later, in 2021, their RNA work has earned two prestigious recognitions only months from each other. In February, they received the Wolf Prize in Medicine, followed by the Warren Alpert Foundation Prize in May, awarded to scientists whose achievements led to prevention, cure or treatments of human diseases.
It was the development of the COVID-19 vaccines that made RNA a household name. Made by Moderna and Pfizer, the vaccines use the RNA molecule to deliver genetic instructions for making SARS-CoV-2's characteristic spike protein in our cells. The presence of this foreign-looking protein triggers the immune system to attack and remember the pathogen. As the vaccines reached the finish line, RNA took center stage, and it was Maquat's and Steitz's research that helped reveal how these molecular cogwheels drive many biological functions within cells.
If you think of a cell as a kingdom, the DNA plays the role of a queen. Like a monarch in a palace, DNA nestles inside the cell's nucleus issuing instructions needed for the cell to function. But no queen can successfully govern without her court, her messengers, and her soldiers, as well as other players that make her kingdom work. That's what RNAs do — they act as the DNA's vassals. They carry instructions for protein assembly, catalyze reactions and supervise many other processes to make sure the cellular kingdom performs as it should.
There are a myriad of these RNA vassals in our cells, and each type has its own specific task. There are messenger RNAs that deliver genetic instructions for protein synthesis from DNA to ribosomes, the cells' protein-making factories. There are ribosomal RNAs that help stitch together amino acids to make proteins. There are transfer RNAs that can bring amino acids to this protein synthesis machine, keeping it going. Then there are circular RNAs that act as sponges, absorbing proteins to help regulate the activity of genes. And that's only the tip of the iceberg when it comes to RNA diversity, researchers say.
"We know what the most abundant and important RNAs are doing," says Steitz. "But there are thousands of different ones, and we still don't have a full knowledge of them."
Critical to RNA's proper functioning is a process called splicing, in which a precursor mRNA is transformed into mature, fully-functional mRNA — a phenomenon that Steitz's work helped elucidate. The splicing process, which takes place in cellular assembly lines, involves removing extra RNA sequences and stringing the remaining RNA pieces together. Steitz found that tiny RNA particles called snRNPs are crucial to this process. They act as handy helpers, finding and removing errant genetic material from the mRNA molecules.
A dysfunctional RNA assembly line leads to diseases, including many cancers. For instance, Steitz found that people with Lupus — an autoimmune disorder — have antibodies that mistakenly attack the little snRNP helpers. She also discovered that when snRNPs don't do their job properly, they can cause what scientists call mis-splicing, producing defective mRNAs.
Fortunately, cells have a built-in quality-control process that can spot and correct these mistakes, which is what Maquat studied in her work. In 1981, she discovered a molecular quality-control system that spots and destroys such incorrectly assembled mRNA. With the cryptic name "nonsense-mediated mRNA decay" or NMD, this process is vital to the health and wellbeing of a cellular kingdom in humans — because splicing mistakes happen far more often than one would imagine.
"We estimate that about a third of our mRNA are mistakes," Maquat says. "And nonsense-mediated mRNA decay cleans up these mistakes." When this quality-control system malfunctions, defective mRNA forge faulty proteins, which mess up the cellular machinery and cause disease, including various forms of cancer.
Scientists' newfound appreciation of RNA opens door to many novel treatments.
Now that the first RNA-based shots were approved, the same principle can be used for create vaccines for other diseases, the two RNA researchers say. Moreover, the molecule has an even greater potential — it can serve as a therapeutic target for other disorders. For example, Spinraza, a groundbreaking drug approved in 2016 for spinal muscular atrophy, uses small snippets of synthetic genetic material that bind to the RNA, helping fix splicing errors. "People can now appreciate why some of us studied RNA for such a long time," says Maquat.
Steitz is thrilled that the entire field of RNA research is enjoying the limelight. "I'm delighted because the prize is more of a recognition of the field than just our work," she says. "This is a more general acknowledgment of how basic research can have a remarkable impact on human health."