Many women want non-hormonal birth control. A 22-year-old's findings were used to launch a company that could, within the decade, bring a new kind of contraceptive to the marketplace.
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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.
The genesis
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
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 science
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.
The future
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.
A child sits on the cracked earth, staring at the sun.
(© ittipol/Adobe)
When Rattan Lal was awarded the Japan Prize for Biological Production, Ecology in April—the Asian equivalent of a Nobel—the audience at Tokyo's National Theatre included the emperor and empress. Lal's acceptance speech, however, was down-to-earth in the most literal sense.
Carbon, in its proper place, holds landscapes and ecosystems together.
"I'd like to begin, rather unconventionally, with the conclusion of my presentation," he told the assembled dignitaries. "And the conclusion is four words: In soil we trust."
That statement could serve as the motto for a climate crisis-fighting strategy that has gained remarkable momentum over the past five years or so—and whose rise to international prominence was reflected in that glittering award ceremony. Lal, a septuagenarian professor of soil science at Ohio State University, is one of the foremost exponents of carbon farming, an approach that centers on correcting a man-made, planetary chemical imbalance.
A Solution to Several Problems at Once?
The chemical in question is carbon. Too much of it in the atmosphere (in the form of carbon dioxide, a potent greenhouse gas) is the main driver of global heating. Too little of it in the soil is the bane of farmers in many parts of the world, and a threat to our ability to feed a ballooning global population. Advocates say agriculture can mitigate both problems—by adopting techniques that keep more soil carbon from escaping skyward, and draw more atmospheric carbon down into fields and pastures.
The potential impacts go beyond slowing climate change and boosting food production. "There are so many benefits," says Lal. "Water quality, drought, flooding, biodiversity—this is a natural solution for all these problems." That's because carbon, in its proper place, holds landscapes and ecosystems together. Plants extract it from the air and convert it into sugars for energy; they also transfer it to the soil through their roots and in the process of decomposition. In the ground, carbon feeds microbes and fungi that form the basis of complex food webs. It helps soil absorb and retain water, resist erosion, and hold onto nitrogen and phosphorous—keeping those nutrients from running off into waterways and creating toxic algal blooms.
Government and private support for research into carbon-conscious agriculture is on the rise, and growing numbers of farmers are exploring such methods. How much difference these methods can make, however, remains a matter of debate. Lal sees carbon farming as a way to buy time until CO2 emissions can be brought under control. Skeptics insist that such projections are overly optimistic. Some allies, meanwhile, think Lal's vision is too timid. "Farming can actually fix the climate," says Tim LaSalle, co-founder of the Center for Regenerative Agriculture at California State University, Chico. "That should be our only focus."
Yet Can soil solve the climate crisis? may be not be the key question in assessing the promise of carbon farming, since it implies that action is worthwhile only if a solution is ensured. A more urgent line of inquiry might be: Can the climate crisis be solved without addressing soil?
A Chance Meeting Leads to the Mission of a Lifetime
Lal was among the earliest scientists to grapple with that question. Born in Pakistan, he grew up on a tiny subsistence farm in India, where his family had fled as refugees. The only one of his siblings who learned to read and write, he attended a local agricultural university, then headed to Ohio State on scholarship for his PhD. In 1982, he was working at the International Institute of Tropical Agriculture in Nigeria, trying to develop sustainable alternatives to Africa's traditional slash-and-burn farming, when a distinguished visitor dropped by: oceanographer Roger Revelle, who 25 years earlier had published the first paper warning that fossil fuel combustion could throw the climate dangerously off-kilter.
Rattan Lal, Distinguished University Professor of Soil Science at Ohio State, received the Japan Prize at a ceremony in April.
(Photo: Ken Chamberlain. CFAES.)
Lal showed Revelle the soil in his test plots—hard and reddish, like much of Africa's agricultural land. Then (as described in Kristin Ohlson's book The Soil Will Save Us), he led the visitor to the nearby forest, where the soil was dark, soft, and wriggling with earthworms. In the forest, the soil's carbon content was 2 to 3 percent; in Lal's plots, it had dwindled to 0.5 percent. When Revelle asked him where all that carbon had gone, Lal confessed he didn't know. Revelle suggested that much of it might have floated into the atmosphere, adding to the burden of greenhouse gases. "Since then," Lal told me, "I've been looking for ways to put it back."
Back at Ohio State, Lal found that the United States Department of Agriculture (USDA) and Environmental Protection Agency (EPA) were also interested in the connection between soil carbon and climate change. With a small group of other scientists, he began investigating the dimensions of the problem, and how it might be solved.
Comparing carbon in forested and cultivated soils around the globe, the researchers calculated that about 100 billion tons had vanished into the air since the dawn of agriculture 10,000 years ago. The culprits were common practices—including plowing, overgrazing, and keeping fallow fields bare—that exposed soil carbon to oxygen, transforming it into carbon dioxide. Yet the process could also be reversed, Lal and his colleagues argued. Although there was a limit to the amount of carbon that soil could hold, they theorized that it would be possible to sequester several billion tons of global CO2 emissions each year for decades before reaching maximum capacity.
Lal set up projects on five continents to explore practices that could help accomplish that goal, such as minimizing tillage, planting cover crops, and leaving residue on fields after harvest. He organized conferences, pumped out papers and books. As other researchers launched similar efforts, policymakers worldwide took notice.
But before long, recalls Colorado State University soil scientist Keith Paustian (a fellow carbon-farming pioneer, who served with Lal on the UN's International Panel on Climate Change), official attention "kind of faded away. The bigger imperative was to cut emissions." And because agriculture accounted for only about 13 percent of greenhouse gas pollution, Paustian says, the sectors that emitted the most—energy and transportation—got the bulk of funding.
A Movement on the Rise
In recent years, however, carbon farming has begun to look like an idea whose time has come. One factor is that efforts to reduce emissions haven't worked; in 2018 alone, global CO2 output rose by an estimated 2.7 percent, according to the Global Carbon Project. Last month, researchers from the Scripps Institute of Oceanography reported that atmospheric CO2—under 350 ppm when Lal began his quest—had reached 415 ppm, the highest in 3 million years. And with the world's population expected to approach 10 billion by 2050, the need for sustainable technologies to augment food production has grown increasingly pressing.
Today, carbon-conscious methods are central to the burgeoning movement known as "regenerative agriculture," which also embraces other practices aimed at improving soil health and farming in an ecologically sound (though not always strictly organic) manner. In the United States, the latest Farm Bill includes $25 million to incentivize soil-based carbon sequestration. State and local governments across the country are supporting such efforts, as are at least a dozen nonprofits. The Department of Energy's Advanced Projects Research Agency (ARPA-e) is working to develop crops and technologies aimed at increasing soil carbon accumulation by 50 percent. General Mills recently announced plans to advance regenerative farming on 1 million acres by 2030, and many smaller companies have made their own commitments.
The toughest challenge, Lal suggests, may be persuading farmers to change their ways.
Internationally, the biggest initiative is the French-led "4 per 1,000" initiative, which aims to increase the amount of carbon in the soil of farms and rangelands worldwide by 0.4 percent per year—a rate that the project's website contends would "halt the increase of CO2 (carbon dioxide) concentration in the atmosphere related to human activities."
Given the current pace of research, Lal believes that goal—which equates to sequestering 3.6 billion tons of CO2 annually, or 10 percent of global emissions—is doable. The toughest challenge, he suggests, may be persuading farmers to change their ways. Although carbon farming can reduce costs for chemical inputs such as herbicides and fertilizers, while building rich topsoil, agriculturalists tend to be a conservative lot.
And getting low-income farmers to leave crop residue on fields, instead of using it for fuel or animal feed, will require more than speeches about melting glaciers. Lal proposes a $16 per acre subsidy, totaling $64 billion for the world's 4 billion acres of cropland. "That's not a very large amount," he says, "if you're investing in the health of the planet."
Experimental Methods Attract Supporters and Skeptics
Some experts question whether enough CO2 can be stashed in the soil to prevent the rise in average global temperature from surpassing the 2º C mark—set by the 2016 Paris Agreement as the limit beyond which climate change would become catastrophic. But others insist that carbon farming's goal should be to reverse climate change, not just to put it on pause.
"That's the only way out of this predicament," says Tim LaSalle, whose Center for Regenerative Agriculture supports the use of experimental methods ranging from multi-species cover cropping to fungal-dominant compost solutions. Using such techniques, a few researchers and farmers claim to be able to transfer carbon to the soil at rates many times higher than with established practices. Although several of these methods have yet to be documented in peer-reviewed studies, LaSalle believes they point the way forward. "We can't fix the climate, or even come close to it, using Rattan's numbers," he says, referring to Lal. "If we can replicate these experiments, we can fix it."
Even scientists sympathetic to regenerative ag warn that relying on unproven techniques is risky. "Some of these claims are beyond anything we've seen in agricultural science," says Andrew McGuire, an agronomist at Washington State University. "They could be right, but extraordinary claims require extraordinary evidence."
Still, the assorted methods currently being tested—which also include amending soil with biochar (made by heating agricultural wastes with minimal oxygen), planting long-rooted perennial crops instead of short-rooted annuals, and deploying grazing animals in ways that enrich soil rather than depleting it—offer a catalogue of hope at a time when environmental despair is all too tempting.
Last October, the National Academy of Sciences, Engineering, and Medicine issued a report acknowledging that it was too late to stave off apocalyptic overheating just by reducing CO2 emissions; removing carbon from the atmosphere would be necessary as well. The document laid out several options for doing so—most of which, it cautioned, had serious limitations.
"Soil is a bridge to the future. We can't do without it."
One possibility was planting more forests. To absorb enough carbon dioxide, however, trees might have to replace areas of farmland, reducing the food supply. Another option was creating biomass plantations to fuel power plants, whose emissions would be stored underground. But land use would be a problem: "You'd need to cover an area the size of India," explains Paustian, who was a co-author of the report. Yet another alternative was direct-air capture, in which chemical processes would be used to extract CO2 from the air. The technology was still in its infancy, though—and the costs and power requirements would likely be astronomical.
The report took up agriculture-based methods on page 95. Those needed further research as well, the authors wrote, to determine which approaches would be most effective. But of all the alternatives, this one seemed the least problematic. "Soil carbon is probably what you can do first, cheapest, and with the most additional co-benefits," says Paustian. "If we can make progress in that area, it's a huge advantage."
In any case, he and other researchers agree, we have little choice but to try. "Soil is a bridge to the future," Lal says. "We can't do without it."