Unwanted pregnancy can now be added to the list of preventions that antibodies may be fighting in the near future. For decades, really since the 1980s, engineered monoclonal antibodies have been knocking out invading germs — preventing everything from cancer to COVID. Sperm, which have some of the same properties as germs, may be next.
Not only is there an unmet need on the market for alternatives to hormonal contraceptives, the genesis for the original research was personal for the then 22-year-old scientist who led it. Her findings were used to launch a company that could, within the decade, bring a new kind of contraceptive to the marketplace.
It’s Suruchi Shrestha’s research — published in Science Translational Medicine in August 2021 and conducted as part of her dissertation while she was a graduate student at the University of North Carolina at Chapel Hill — that could change the future of contraception for many women worldwide. According to a Guttmacher Institute report, in the U.S. alone, there were 46 million sexually active women of reproductive age (15–49) who did not want to get pregnant in 2018. With the overturning of Roe v. Wade last year, Shrestha’s research could, indeed, be life changing for millions of American women and their families.
Now a scientist with NextVivo, Shrestha is not directly involved in the development of the contraceptive that is based on her research. But, back in 2016 when she was going through her own problems with hormonal contraceptives, she “was very personally invested” in her research project, Shrestha says. She was coping with a long list of negative effects from an implanted hormonal IUD. According to the Mayo Clinic, those can include severe pelvic pain, headaches, acute acne, breast tenderness, irregular bleeding and mood swings. After a year, she had the IUD removed, but it took another full year before all the side effects finally subsided; she also watched her sister suffer the “same tribulations” after trying a hormonal IUD, she says.
For contraceptive use either daily or monthly, Shrestha says, “You want the antibody to be very potent and also cheap.” That was her goal when she launched her study.
Shrestha unshelved antibody research that had been sitting idle for decades. It was in the late 80s that scientists in Japan first tried to develop anti-sperm antibodies for contraceptive use. But, 35 years ago, “Antibody production had not been streamlined as it is now, so antibodies were very expensive,” Shrestha explains. So, they shifted away from birth control, opting to focus on developing antibodies for vaccines.
Over the course of the last three decades, different teams of researchers have been working to make the antibody more effective, bringing the cost down, though it’s still expensive, according to Shrestha. For contraceptive use either daily or monthly, she says, “You want the antibody to be very potent and also cheap.” That was her goal when she launched her study.
The problem with contraceptives for women, Shrestha says, is that all but a few of them are hormone-based or have other negative side effects. In fact, some studies and reports show that millions of women risk unintended pregnancy because of medical contraindications with hormone-based contraceptives or to avoid the risks and side effects. While there are about a dozen contraceptive choices for women, there are two for men: the condom, considered 98% effective if used correctly, and vasectomy, 99% effective. Neither of these choices are hormone-based.
On the non-hormonal side for women, there is the diaphragm which is considered only 87 percent effective. It works better with the addition of spermicides — Nonoxynol-9, or N-9 — however, they are detergents; they not only kill the sperm, they also erode the vaginal epithelium. And, there’s the non-hormonal IUD which is 99% effective. However, the IUD needs to be inserted by a medical professional, and it has a number of negative side effects, including painful cramping at a higher frequency and extremely heavy or “abnormal” and unpredictable menstrual flows.
The hormonal version of the IUD, also considered 99% effective, is the one Shrestha used which caused her two years of pain. Of course, there’s the pill, which needs to be taken daily, and the birth control ring which is worn 24/7. Both cause side effects similar to the other hormonal contraceptives on the market. The ring is considered 93% effective mostly because of user error; the pill is considered 99% effective if taken correctly.
“That’s where we saw this opening or gap for women. We want a safe, non-hormonal contraceptive,” Shrestha says. Compounding the lack of good choices, is poor access to quality sex education and family planning information, according to the non-profit Urban Institute. A focus group survey suggested that the sex education women received “often lacked substance, leaving them feeling unprepared to make smart decisions about their sexual health and safety,” wrote the authors of the Urban Institute report. In fact, nearly half (45%, or 2.8 million) of the pregnancies that occur each year in the US are unintended, reports the Guttmacher Institute. Globally the numbers are similar. According to a new report by the United Nations, each year there are 121 million unintended pregnancies, worldwide.
The early work on antibodies as a contraceptive had been inspired by women with infertility. It turns out that 9 to 12 percent of women who are treated for infertility have antibodies that develop naturally and work against sperm. Shrestha was encouraged that the antibodies were specific to the target — sperm — and therefore “very safe to use in women.” She aimed to make the antibodies more stable, more effective and less expensive so they could be more easily manufactured.
Since antibodies tend to stick to things that you tell them to stick to, the idea was, basically, to engineer antibodies to stick to sperm so they would stop swimming. Shrestha and her colleagues took the binding arm of an antibody that they’d isolated from an infertile woman. Then, targeting a unique surface antigen present on human sperm, they engineered a panel of antibodies with as many as six to 10 binding arms — “almost like tongs with prongs on the tongs, that bind the sperm,” explains Shrestha. “We decided to add those grabbers on top of it, behind it. So it went from having two prongs to almost 10. And the whole goal was to have so many arms binding the sperm that it clumps it” into a “dollop,” explains Shrestha, who earned a patent on her research.
Suruchi Shrestha works in the lab with a colleague. In 2016, her research on antibodies for birth control was inspired by her own experience with side effects from an implanted hormonal IUD.
UNC - Chapel Hill
The sperm stays right where it met the antibody, never reaching the egg for fertilization. Eventually, and naturally, “Our vaginal system will just flush it out,” Shrestha explains.
“She showed in her early studies that [she] definitely got the sperm immotile, so they didn't move. And that was a really promising start,” says Jasmine Edelstein, a scientist with an expertise in antibody engineering who was not involved in this research. Shrestha’s team at UNC reproduced the effect in the sheep, notes Edelstein, who works at the startup Be Biopharma. In fact, Shrestha’s anti-sperm antibodies that caused the sperm to agglutinate, or clump together, were 99.9% effective when delivered topically to the sheep’s reproductive tracts.
Going forward, Shrestha thinks the ideal approach would be delivering the antibodies through a vaginal ring. “We want to use it at the source of the spark,” Shrestha says, as opposed to less direct methods, such as taking a pill. The ring would dissolve after one month, she explains, “and then you get another one.”
Engineered to have a long shelf life, the anti-sperm antibody ring could be purchased without a prescription, and women could insert it themselves, without a doctor. “That's our hope, so that it is accessible,” Shrestha says. “Anybody can just go and grab it and not worry about pregnancy or unintended pregnancy.”
Her patented research has been licensed by several biotech companies for clinical trials. A number of Shrestha’s co-authors, including her lab advisor, Sam Lai, have launched a company, Mucommune, to continue developing the contraceptives based on these antibodies.
And, results from a small clinical trial run by researchers at Boston University Chobanian & Avedisian School of Medicine show that a dissolvable vaginal film with antibodies was safe when tested on healthy women of reproductive age. That same group of researchers last year received a $7.2 million grant from the National Institute of Health for further research on monoclonal antibody-based contraceptives, which have also been shown to block transmission of viruses, like HIV.
“As the costs come down, this becomes a more realistic option potentially for women,” says Edelstein. “The impact could be tremendous.”
This article was first published by Leaps.org in December, 2022. It has been lightly edited with updates for timeliness.
Creamy milk with velvety texture. Dark with sprinkles of sea salt. Crunchy hazelnut-studded chunks. Chocolate is a treat that appeals to billions of people worldwide, no matter the age. And it’s not only the taste, but the feel of a chocolate morsel slowly melting in our mouths—the smoothness and slipperiness—that’s part of the overwhelming satisfaction. Why is it so enjoyable?
That’s what an interdisciplinary research team of chocolate lovers from the University of Leeds School of Food Science and Nutrition and School of Mechanical Engineering in the U.K. resolved to study in 2021. They wanted to know, “What is making chocolate that desirable?” says Siavash Soltanahmadi, one of the lead authors of a new study about chocolates hedonistic quality.
Besides addressing the researchers’ general curiosity, their answers might help chocolate manufacturers make the delicacy even more enjoyable and potentially healthier. After all, chocolate is a billion-dollar industry. Revenue from chocolate sales, whether milk or dark, is forecasted to grow 13 percent by 2027 in the U.K. In the U.S., chocolate and candy sales increased by 11 percent from 2020 to 2021, on track to reach $44.9 billion by 2026. Figuring out how chocolate affects the human palate could up the ante even more.
Building a 3D tongue
The team began by building a 3D tongue to analyze the physical process by which chocolate breaks down inside the mouth.
As part of the effort, reported earlier this year in the scientific journal ACS Applied Materials and Interfaces, the team studied a large variety of human tongues with the intention to build an “average” 3D model, says Soltanahmadi, a lubrication scientist. When it comes to edible substances, lubrication science looks at how food feels in the mouth and can help design foods that taste better and have more satisfying texture or health benefits.
There are variations in how people enjoy chocolate; some chew it while others “lick it” inside their mouths.
Tongue impressions from human participants studied using optical imaging helped the team build a tongue with key characteristics. “Our tongue is not a smooth muscle, it’s got some texture, it has got some roughness,” Soltanahmadi says. From those images, the team came up with a digital design of an average tongue and, using 3D printed molds, built a “mimic tongue.” They also added elastomers—such as silicone or polyurethane—to mimic the roughness, the texture and the mechanical properties of a real tongue. “Wettability" was another key component of the 3D tongue, Soltanahmadi says, referring to whether a surface mixes with water (hydrophilic) or, in the case of oil, resists it (hydrophobic).
Notably, the resulting artificial 3D-tongues looked nothing like the human version, but they were good mimics. The scientists also created “testing kits” that produced data on various physical parameters. One such parameter was viscosity, the measure of how gooey a food or liquid is — honey is more viscous compared to water, for example. Another was tribology, which defines how slippery something is — high fat yogurt is more slippery than low fat yogurt; milk can be more slippery than water. The researchers then mixed chocolate with artificial saliva and spread it on the 3D tongue to measure the tribology and the viscosity. From there they were able to study what happens inside the mouth when we eat chocolate.
The team focused on the stages of lubrication and the location of the fat in the chocolate, a process that has rarely been researched.
The artificial 3D-tongues look nothing like human tongues, but they function well enough to do the job.
Courtesy Anwesha Sarkar and University of Leeds
The oral processing of chocolate
We process food in our mouths in several stages, Soltanahmadi says. And there is variation in these stages depending on the type of food. So, the oral processing of a piece of meat would be different from, say, the processing of jelly or popcorn.
There are variations with chocolate, in particular; some people chew it while others use their tongues to explore it (within their mouths), Soltanahmadi explains. “Usually, from a consumer perspective, what we find is that if you have a luxury kind of a chocolate, then people tend to start with licking the chocolate rather than chewing it.” The researchers used a luxury brand of dark chocolate and focused on the process of licking rather than chewing.
As solid cocoa particles and fat are released, the emulsion envelops the tongue and coats the palette creating a smooth feeling of chocolate all over the mouth. That tactile sensation is part of the chocolate’s hedonistic appeal we crave.
Understanding the make-up of the chocolate was also an important step in the study. “Chocolate is a composite material. So, it has cocoa butter, which is oil, it has some particles in it, which is cocoa solid, and it has sugars," Soltanahmadi says. "Dark chocolate has less oil, for example, and less sugar in it, most of the time."
The researchers determined that the oral processing of chocolate begins as soon as it enters a person’s mouth; it starts melting upon exposure to one’s body temperature, even before the tongue starts moving, Soltanahmadi says. Then, lubrication begins. “[Saliva] mixes with the oily chocolate and it makes an emulsion." An emulsion is a fluid with a watery (or aqueous) phase and an oily phase. As chocolate breaks down in the mouth, that solid piece turns into a smooth emulsion with a fatty film. “The oil from the chocolate becomes droplets in a continuous aqueous phase,” says Soltanahmadi. In other words, as solid cocoa particles and fat are released, the emulsion envelops the tongue and coats the palette, creating a smooth feeling of chocolate all over the mouth. That tactile sensation is part of the chocolate’s hedonistic appeal we crave, says Soltanahmadi.
Finding the sweet spot
After determining how chocolate is orally processed, the research team wanted to find the exact sweet spot of the breakdown of solid cocoa particles and fat as they are released into the mouth. They determined that the epicurean pleasure comes only from the chocolate's outer layer of fat; the secondary fatty layers inside the chocolate don’t add to the sensation. It was this final discovery that helped the team determine that it might be possible to produce healthier chocolate that would contain less oil, says Soltanahmadi. And therefore, less fat.
Rongjia Tao, a physicist at Temple University in Philadelphia, thinks the Leeds study and the concept behind it is “very interesting.” Tao, himself, did a study in 2016 and found he could reduce fat in milk chocolate by 20 percent. He believes that the Leeds researchers’ discovery about the first layer of fat being more important for taste than the other layer can inform future chocolate manufacturing. “As a scientist I consider this significant and an important starting point,” he says.
Chocolate is rich in polyphenols, naturally occurring compounds also found in fruits and vegetables, such as grapes, apples and berries. Research found that plant polyphenols can protect against cancer, diabetes and osteoporosis as well as cardiovascular ad neurodegenerative diseases.
Not everyone thinks it’s a good idea, such as chef Michael Antonorsi, founder and owner of Chuao Chocolatier, one of the leading chocolate makers in the U.S. First, he says, “cacao fat is definitely a good fat.” Second, he’s not thrilled that science is trying to interfere with nature. “Every time we've tried to intervene and change nature, we get things out of balance,” says Antonorsi. “There’s a reason cacao is botanically known as food of the gods. The botanical name is the Theobroma cacao: Theobroma in ancient Greek, Theo is God and Brahma is food. So it's a food of the gods,” Antonorsi explains. He’s doubtful that a chocolate made only with a top layer of fat will produce the same epicurean satisfaction. “You're not going to achieve the same sensation because that surface fat is going to dissipate and there is no fat from behind coming to take over,” he says.
Without layers of fat, Antonorsi fears the deeply satisfying experiential part of savoring chocolate will be lost. The University of Leeds team, however, thinks that it may be possible to make chocolate healthier - when consumed in limited amounts - without sacrificing its taste. They believe the concept of less fatty but no less slick chocolate will resonate with at least some chocolate-makers and consumers, too.
Chocolate already contains some healthful compounds. Its cocoa particles have “loads of health benefits,” says Soltanahmadi. Dark chocolate usually has more cocoa than milk chocolate. Some experts recommend that dark chocolate should contain at least 70 percent cocoa in order for it to offer some health benefit.Research has shown that the cocoa in chocolate is rich in polyphenols, naturally occurring compounds also found in fruits and vegetables, such as grapes, apples and berries. Research has shown that consuming plant polyphenols can be protective against cancer, diabetes and osteoporosis as well as cardiovascular and neurodegenerative diseases.
“So keeping the healthy part of it and reducing the oily part of it, which is not healthy, but is giving you that indulgence of it … that was the final aim,” Soltanahmadi says. He adds that the team has been approached by individuals in the chocolate industry about their research. “Everyone wants to have a healthy chocolate, which at the same time tastes brilliant and gives you that self-indulging experience.”
Two-and-a-half year-old Huckleberry, a blue merle Australian shepherd, pulls hard at her leash; her yelps can be heard by skiers and boarders high above on the chairlift that carries them over the ski patrol hut to the top of the mountain. Huckleberry is an avalanche rescue dog — or avy dog, for short. She lives and works with her owner and handler, a ski patroller at Breckenridge Ski Resort in Colorado. As she watches the trainer play a game of hide-and-seek with six-month-old Lume, a golden retriever and avy dog-in-training, Huckleberry continues to strain on her leash; she loves the game. Hide-and-seek is one of the key training methods for teaching avy dogs the rescue skills they need to find someone caught in an avalanche — skier, snowmobiler, hiker, climber.
Lume’s owner waves a T-shirt in front of the puppy. While another patroller holds him back, Lume’s owner runs away and hides. About a minute later — after a lot of barking — Lume is released and commanded to “search.” He springs free, running around the hut to find his owner who reacts with a great amount of excitement and fanfare. Lume’s scent training will continue for the rest of the ski season (Breckenridge plans operating through May or as long as weather permits) and through the off-season. “We make this game progressively harder by not allowing the dog watch the victim run away,” explains Dave Leffler, Breckenridge's ski patroller and head of the avy dog program, who has owned, trained and raised many of them. Eventually, the trainers “dig an open hole in the snow to duck out of sight and gradually turn the hole into a cave where the dog has to dig to get the victim,” explains Leffler.
By the time he is three, Lume, like Huckleberry, will be a fully trained avy pup and will join seven other avy dogs on Breckenridge ski patrol team. Some of the team members, both human and canine, are also certified to work with Colorado Rapid Avalanche Deployment, a coordinated response team that works with the Summit County Sheriff’s office for avalanche emergencies outside of the ski slopes’ boundaries.
There have been 19 avalanche deaths in the U.S. this season, according to avalanche.org, which tracks slides; eight in Colorado. During the entirety of last season there were 17. Avalanche season runs from November through June, but avalanches can occur year-round.
High tech and high stakes
Complementing avy dogs’ ability to smell people buried in a slide, avalanche detection, rescue and recovery is becoming increasingly high tech. There are transceivers, signal locators, ground scanners and drones, which are considered “games changers” by many in avalanche rescue and recovery
For a person buried in an avalanche, the chance of survival plummets after 20 minutes, so every moment counts.
A drone can provide thermal imaging of objects caught in a slide; what looks like a rock from far away might be a human with a heat signature. Transceivers, also known as beacons, send a signal from an avalanche victim to a companion. Signal locators, like RECCO reflectors which are often sewn directly into gear, can echo back a radar signal sent by a detector; most ski resorts have RECCO detector units.
Research suggests that Ground Penetrating Radar (GPR), an electromagnetic tool used by geophysicists to pull images from inside the ground, could be used to locate an avalanche victim. A new study from the Department of Energy’s Sandia National Laboratories suggests that a computer program developed to pinpoint the source of a chemical or biological terrorist attack could also be used to find someone submerged in an avalanche. The search algorithm allows for small robots (described as cockroach-sized) to “swarm” a search area. Researchers say that this distributed optimization algorithm can help find avalanche victims four times faster than current search mechanisms. For a person buried in an avalanche, the chance of survival plummets after 20 minutes, so every moment counts.
An avy dog in training is picking up scent
While rescue gear has been evolving, predicting when a slab will fall remains an emerging science — kind of where weather forecasting science was in the 1980s. Avalanche forecasting still relies on documenting avalanches by going out and looking,” says Ethan Greene, director of the Colorado Avalanche Information Center (CAIC). “So if there's a big snowstorm, and as you might remember, most avalanches happened during snowstorms, we could have 10,000 avalanches that release and we document 50,” says Greene. “Avalanche forecasting is essentially pattern recognition,” he adds--and understanding the layering structure of snow.
However, determining where the hazards lie can be tricky. While a dense layer of snow over a softer, weaker layer may be a recipe for an avalanche, there’s so much variability in snowpack that no one formula can predict the trigger. Further, observing and measuring snow at a single point may not be representative of all nearby slopes. Finally, there’s not enough historical data to help avalanche scientists create better prediction models.
That, however, may be changing.
Last year, an international group of researchers created computer simulations of snow cover using 16 years of meteorological data to forecast avalanche hazards, publishing their research in Cold Regions Science and Technology. They believe their models, which categorize different kinds of avalanches, can support forecasting and determine whether the avalanche is natural (caused by temperature changes, wind, additional snowfall) or artificial (triggered by a human or animal).
With smell receptors ranging from 800 million for an average dog, to 4 billion for scent hounds, canines remain key to finding people caught in slides.
With data from two sites in British Columbia and one in Switzerland, researchers built computer simulations of five different avalanche types. “In terms of real time avalanche forecasting, this has potential to fill in a lot of data gaps, where we don't have field observations of what the snow looks like,” says Simon Horton, a postdoctoral fellow with the Simon Fraser University Centre for Natural Hazards Research and a forecaster with Avalanche Canada, who participated in the study. While complex models that simulate snowpack layers have been around for a few decades, they weren’t easy to apply until recently. “It's been difficult to find out how to apply that to actual decision-making and improving safety,” says Horton. If you can derive avalanche problem types from simulated snowpack properties, he says, you’ll learn “a lot about how you want to manage that risk.”
The five categories include “new snow,” which is unstable and slides down the slope, “wet snow,” when rain or heat makes it liquidly, as well as “wind-drifted snow,” “persistent weak layers” and “old snow.” “That's when there's some type of deeply buried weak layer in the snow that releases without any real change in the weather,” Horton explains. “These ones tend to cause the most accidents.” One step by a person on that structurally weak layer of snow will cause a slide. Horton is hopeful that computer simulations of avalanche types can be used by scientists in different snow climates to help predict hazard levels.
Greene is doubtful. “If you have six slopes that are lined up next to each other, and you're going to try to predict which one avalanches and the exact dimensions and what time, that's going to be really hard to do. And I think it's going to be a long time before we're able to do that,” says Greene.
What both researchers do agree on, though, is that what avalanche prediction really needs is better imagery through satellite detection. “Just being able to count the number of avalanches that are out there will have a huge impact on what we do,” Greene says. “[Satellites] will change what we do, dramatically.” In a 2022 paper, scientists at the University of Aberdeen in England used satellites to study two deadly Himalayan avalanches. The imaging helped them determine that sediment from a 2016 ice avalanche plus subsequent snow avalanches contributed to the 2021 avalanche that caused a flash flood, killing over 200 people. The researchers say that understanding the avalanches characteristics through satellite imagery can inform them how one such event increases the magnitude of another in the same area.
Avy dogs trainers hide in dug-out holes in the snow, teaching the dogs to find buried victims
Lifesaving combo: human tech and Mother Nature’s gear
Even as avalanche forecasting evolves, dogs with their built-in rescue mechanisms will remain invaluable. With smell receptors ranging from 800 million for an average dog, to 4 billion for scent hounds, canines remain key to finding people caught in slides. (Humans in comparison, have a meager 12 million.) A new study published in the Journal of Neuroscience revealed that in dogs smell and vision are connected in the brain, which has not been found in other animals. “They can detect the smell of their owner's fingerprints on a glass slide six weeks after they touched it,” says Nicholas Dodman, professor emeritus at Cummings School of Veterinary Medicine at Tufts University. “And they can track from a boat where a box filled with meat was buried in the water, 100 feet below,” says Dodman, who is also co-founder and president of the Center for Canine Behavior Studies.
Another recent study from Queens College in Belfast, United Kingdom, further confirms that dogs can smell when humans are stressed. They can also detect the smell of a person’s breath and the smell of the skin cells of a deceased person.
The emerging avalanche-predicting human-made tech and the incredible nature-made tech of dogs’ olfactory talents is the lifesaving “equipment” that Leffler believes in. Even when human-made technology develops further, it will be most efficient when used together with the millions of dogs’ smell receptors, Leffler believes. “It is a combination of technology and the avalanche dog that will always be effective in finding an avalanche victim.”