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.
Fungus is the ‘New Black’ in Eco-Friendly Fashion
A natural material that looks and feels like real leather is taking the fashion world by storm. Scientists view mycelium—the vegetative part of a mushroom-producing fungus—as a planet-friendly alternative to animal hides and plastics.
Products crafted from this vegan leather are emerging, with others poised to hit the market soon. Among them are the Hermès Victoria bag, Lululemon's yoga accessories, Adidas' Stan Smith Mylo sneaker, and a Stella McCartney apparel collection.
The Adidas' Stan Smith Mylo concept sneaker, made in partnership with Bolt Threads, uses an alternative leather grown from mycelium; a commercial version is expected in the near future.
Adidas
Hermès has held presales on the new bag, says Philip Ross, co-founder and chief technology officer of MycoWorks, a San Francisco Bay area firm whose materials constituted the design. By year-end, Ross expects several more clients to debut mycelium-based merchandise. With "comparable qualities to luxury leather," mycelium can be molded to engineer "all the different verticals within fashion," he says, particularly footwear and accessories.
More than a half-dozen trailblazers are fine-tuning mycelium to create next-generation leather materials, according to the Material Innovation Initiative, a nonprofit advocating for animal-free materials in the fashion, automotive, and home-goods industries. These high-performance products can supersede items derived from leather, silk, down, fur, wool, and exotic skins, says A. Sydney Gladman, the institute's chief scientific officer.
That's only the beginning of mycelium's untapped prowess. "We expect to see an uptick in commercial leather alternative applications for mycelium-based materials as companies refine their R&D [research and development] and scale up," Gladman says, adding that "technological innovation and untapped natural materials have the potential to transform the materials industry and solve the enormous environmental challenges it faces."
In fewer than 10 days in indoor agricultural farms, "we grow large slabs of mycelium that are many feet wide and long. We are not confined to the shape or geometry of an animal."
Reducing our carbon footprint becomes possible because mycelium can flourish in indoor farms, using agricultural waste as feedstock and emitting inherently low greenhouse gas emissions. Carbon dioxide is the primary greenhouse gas. "We often think that when plant tissues like wood rot, that they go from something to nothing," says Jonathan Schilling, professor of plant and microbial biology at the University of Minnesota and a member of MycoWorks' Scientific Advisory Board.
But that assumption doesn't hold true for all carbon in plant tissues. When the fungi dominating the decomposition of plants fulfill their function, they transform a large portion of carbon into fungal biomass, Schilling says. That, in turn, ends up in the soil, with mycelium forming a network underneath that traps the carbon.
Unlike the large amounts of fossil fuels needed to produce styrofoam, leather and plastic, less fuel-intensive processing is involved in creating similar materials with a fungal organism. While some fungi consist of a single cell, others are multicellular and develop as very fine threadlike structures. A mass of them collectively forms a "mycelium" that can be either loose and low density or tightly packed and high density. "When these fungi grow at extremely high density," Schilling explains, "they can take on the feel of a solid material such as styrofoam, leather or even plastic."
Tunable and supple in the cultivation process, mycelium is also reliably sturdy in composition. "We believe that mycelium has some unique attributes that differentiate it from plastic-based and animal-derived products," says Gavin McIntyre, who co-founded Ecovative Design, an upstate New York-based biomaterials company, in 2007 with the goal of displacing some environmentally burdensome materials and making "a meaningful impact on our planet."
After inventing a type of mushroom-based packaging for all sorts of goods, in 2013 the firm ventured into manufacturing mycelium that can be adapted for textiles, he says, because mushrooms are "nature's recycling system."
The company aims for its material—which is "so tough and tenacious" that it doesn't require any plastic add-on as reinforcement—to be generally accessible from a pricing standpoint and not confined to a luxury space. The cost, McIntyre says, would approach that of bovine leather, not the more upscale varieties of lamb and goat skins.
Already, production has taken off by leaps and bounds. In fewer than 10 days in indoor agricultural farms, "we grow large slabs of mycelium that are many feet wide and long," he says. "We are not confined to the shape or geometry of an animal," so there's a much lower scrap rate.
Decreasing the scrap rate is a major selling point. "Our customers can order the pieces to the way that they want them, and there is almost no waste in the processing," explains Ross of MycoWorks. "We can make ours thinner or thicker," depending on a client's specific needs. Growing materials locally also results in a reduction in transportation, shipping, and other supply chain costs, he says.
Yet another advantage to making things out of mycelium is its biodegradability at the end of an item's lifecycle. When a pair of old sneakers lands in a compost pile or landfill, it decomposes thanks to microbial processes that, once again, involve fungi. "It is cool to think that the same organism used to create a product can also be what recycles it, perhaps building something else useful in the same act," says biologist Schilling. That amounts to "more than a nice business model—it is a window into how sustainability works in nature."
A product can be called "sustainable" if it's biodegradable, leaves a minimal carbon footprint during production, and is also profitable, says Preeti Arya, an assistant professor at the Fashion Institute of Technology in New York City and faculty adviser to a student club of the American Association of Textile Chemists and Colorists.
On the opposite end of the spectrum, products composed of petroleum-based polymers don't biodegrade—they break down into smaller pieces or even particles. These remnants pollute landfills, oceans, and rivers, contaminating edible fish and eventually contributing to the growth of benign and cancerous tumors in humans, Arya says.
Commending the steps a few designers have taken toward bringing more environmentally conscious merchandise to consumers, she says, "I'm glad that they took the initiative because others also will try to be part of this competition toward sustainability." And consumers will take notice. "The more people become aware, the more these brands will start acting on it."
A further shift toward mycelium-based products has the capability to reap tremendous environmental dividends, says Drew Endy, associate chair of bioengineering at Stanford University and president of the BioBricks Foundation, which focuses on biotechnology in the public interest.
The continued development of "leather surrogates on a scaled and sustainable basis will provide the greatest benefit to the greatest number of people, in perpetuity," Endy says. "Transitioning the production of leather goods from a process that involves the industrial-scale slaughter of vertebrate mammals to a process that instead uses renewable fungal-based manufacturing will be more just."
Can Biotechnology Take the Allergies Out of Cats?
Amy Bitterman, who teaches at Rutgers Law School in Newark, gets enormous pleasure from her three mixed-breed rescue cats, Spike, Dee, and Lucy. To manage her chronically stuffy nose, three times a week she takes Allegra D, which combines the antihistamine fexofenadine with the decongestant pseudoephedrine. Amy's dog allergy is rougher--so severe that when her sister launched a business, Pet Care By Susan, from their home in Edison, New Jersey, they knew Susan would have to move elsewhere before she could board dogs. Amy has tried to visit their brother, who owns a Labrador Retriever, taking Allegra D beforehand. But she began sneezing, and then developed watery eyes and phlegm in her chest.
"It gets harder and harder to breathe," she says.
Animal lovers have long dreamed of "hypo-allergenic" cats and dogs. Although to date, there is no such thing, biotechnology is beginning to provide solutions for cat-lovers. Cats are a simpler challenge than dogs. Dog allergies involve as many as seven proteins. But up to 95 percent of people who have cat allergies--estimated at 10 to 30 percent of the population in North America and Europe--react to one protein, Fel d1. Interestingly, cats don't seem to need Fel d1. There are cats who don't produce much Fel d1 and have no known health problems.
The current technologies fight Fel d1 in ingenious ways. Nestle Purina reached the market first with a cat food, Pro Plan LiveClear, launched in the U.S. a year and a half ago. It contains Fel d1 antibodies from eggs that in effect neutralize the protein. HypoCat, a vaccine for cats, induces them to create neutralizing antibodies to their own Fel d1. It may be available in the United States by 2024, says Gary Jennings, chief executive officer of Saiba Animal Health, a University of Zurich spin-off. Another approach, using the gene-editing tool CRISPR to create a medication that would splice out Fel d1 genes in particular tissues, is the furthest from fruition.
"Our goal was to ensure that whatever we do has no negative impact on the cat."
Customer demand is high. "We already have a steady stream of allergic cat owners contacting us desperate to have access to the vaccine or participate in the testing program," Jennings said. "There is a major unmet medical need."
More than a third of Americans own a cat (while half own a dog), and pet ownership is rising. With more Americans living alone, pets may be just the right amount of company. But the number of Americans with asthma increases every year. Of that group, some 20 to 30 percent have pet allergies that could trigger a possibly deadly attack. It is not clear how many pets end up in shelters because their owners could no longer manage allergies. Instead, allergists commonly report that their patients won't give up a beloved companion.
No one can completely avoid Fel d1, which clings to clothing and lands everywhere cat-owners go, even in schools and new homes never occupied by cats. Myths among cat-lovers may lead them to underestimate their own level of risk. Short hair doesn't help: the length of cat hair doesn't affect the production of Fel d1. Bathing your cat will likely upset it and accomplish little. Washing cuts the amount on its skin and fur only for two days. In one study, researchers measured the Fel d1 in the ambient air in a small chamber occupied by a cat—and then washed the cat. Three hours later, with the cat in the chamber again, the measurable Fel d1 in the air was lower. But this benefit was gone after 24 hours.
For years, the best option has been shots for people that prompt protective antibodies. Bitterman received dog and cat allergy injections twice a week as a child. However, these treatments require up to 100 injections over three to five years, and, as in her case, the effect may be partial or wear off. Even if you do opt for shots, treating the cat also makes sense, since you could protect more than one allergic member of your household and any allergic visitors as well.
An Allergy-Neutralizing Diet
Cats produce much of their Fel d1 in their saliva, which then spreads it to their fur when they groom, observed Nestle Purina immunologist Ebenezer Satyaraj. He realized that this made saliva—and therefore a cat's mouth--an unusually effective site for change. Hens exposed to Fel d1 produce their own antibodies, which survive in their eggs. The team coated LiveClear food with a powder form of these eggs; once in a cat's mouth, the chicken antibody binds to the Fel d1 in the cat's saliva, neutralizing it.
The results are partial: In a study with 105 cats, the level of active Fel d1 in their fur had dropped on average by 47 percent after ten weeks eating LiveClear. Cats that produced more Fel d1 at baseline had a more robust response, with a drop of up to 71 percent. A safety study found no effects on cats after six months on the diet. "Our goal was to ensure that whatever we do has no negative impact on the cat," Satyaraj said. Might a dogfood that minimizes dog allergens be on the way? "There is some early work," he said.
A Vaccine
This is a year when vaccines changed the lives of billions. Saiba's vaccine, HypoCat, delivers recombinant Fel d1 and the coat from a plant virus (the Cucumber mosaic virus) without any vital genetic information. The viral coat serves as a carrier. A cat would need shots once or twice a year to produce antibodies that neutralize Fel d1.
HypoCat works much like any vaccine, with the twist that the enemy is the cat's own protein. Is that safe? Saiba's team has followed 70 cats treated with the vaccine over two years and they remain healthy. Again the active Fel d1 doesn't disappear but diminishes. The team asked 10 people with cat allergies to report on their symptoms when they pet their vaccinated cats. Eight of them could pet their cat for nearly a half hour before their symptoms began, compared with an average of 17 minutes before the vaccine.
Jennings hopes to develop a HypoDog shot with a similar approach. However, the goal would be to target four or five proteins in one vaccine, and that increases the risk of hurting the dog. In the meantime, allergic dog-lovers considering an expensive breeder dog might think again: Independent research does not support the idea that any breed of dog produces less dander in the home. In fact, one well-designed study found that Spanish water dogs, Airedales, poodles and Labradoodles--breeds touted as hypo-allergenic--had significantly more of the most common allergen on their coat than an ordinary Lab and the control group.
Gene Editing
One day you might be able to bring your cat to the vet once a year for an injection that would modify specific tissues so they wouldn't produce Fel d1.
Nicole Brackett, a postdoctoral scientist at Viriginia-based Indoor Biotechnologies, which specializes in manufacturing biologics for allergy and asthma, most recently has used CRISPR to identify Fel d1 genetic sequences in cells from 50 domestic cats and 24 exotic ones. She learned that the sequences vary substantially from one cat to the next. This discovery, she says, backs up the observations that Fel d1 doesn't have a vital purpose.
The next step will be a CRISPR knockout of the relevant genes in cells from feline salivary glands, a prime source of Fel d1. Although the company is considering using CRISPR to edit the genes in a cat embryo and possibly produce a Fel d1-free cat, designer cats won't be its ultimate product. Instead, the company aims to produce injections that could treat any cat.
Reducing pet allergens at home could have a compound benefit, Indoor Biotechnologies founder Martin Chapman, an immunologist, notes: "When you dampen down the response to one allergen, you could also dampen it down to multiple allergens." As allergies become more common around the world, that's especially good news.