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.
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 this 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 earlier this 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.”
Medical staff rushing organs to a surgery for transplantation.
Thanks to the remarkable evolution of organ transplantation, it's now possible to replace genitals that don't work properly or have been injured. Surgeons have been transplanting ovarian tissue for more than a decade, and they're now successfully transplanting penises and wombs too.
Rules and regulations aren't keeping up with the rapid rise of genital transplants.
Earlier this year, an American soldier whose genitals were injured by a bomb in Afghanistan received the first-ever transplant of a penis and scrotum at Johns Hopkins Medicine.
Rules and regulations aren't keeping up with the rapid rise of genital transplants, however, and there's no consensus about how society should handle a long list of difficult and delicate questions.
Are these expensive transplants worth the risk when other alternatives exist? Should men, famously obsessed with their penises, be able to ask for a better model simply because they want one? And what happens when transplant technology further muddles the concept of biological parenthood?
"We need to remember that the human body is not a machine with interchangeable parts," says bioethicist Craig M. Klugman of DePaul University. "These are complicated, difficult and potentially dangerous surgeries. And they require deep consideration on a physical, psychological, spiritual, and financial level."
From Extra Testicles to Replacement Penises
Tinkering with human genitalia -- especially the male variety -- is hardly a new phenomenon. A French surgeon created artificial penises for injured soldiers in the 16th century. And a bizarre implant craze swept the U.S. in the 1930s when a quack physician convinced men that, quite literally, the more testicles the merrier – and if the human variety wasn't available, then ones from goats would have to do.
Now we're more sophisticated. Modern genital transplants are designed to do two things: Treat infertility (in women) and restore the appearance and function of genitals (in men).
In women, surgeons have successfully transplanted ovarian tissue from one woman to another since the mid-2000s, when an Alabama woman gave birth after getting a transplant from her identical twin sister. Last year, for the first time in the U.S., a young woman gave birth after getting a uterus transplant from a living donor.
"Where do you draw the line? Is pregnancy a privilege? Is it a right?"
As for men, surgeons in the U.S. and South Africa have successfully transplanted penises from dead men into four men whose genitals were injured by a botched circumcision, penile cancer or a wartime injury. One man reportedly fathered a child after the procedure.
The Johns Hopkins procedure was the first to include a scrotum. Testicles, however, were not transplanted due to ethical concerns. Surgeons have successfully transplanted testicles from man-to-man in the past, but this procedure isn't performed because the testes would produce sperm with the donor's DNA. As a result, the recipient could father a baby who is genetically related to the donor.
Are Transplants Worth the Expense and Risk?
Genital transplants are not simple procedures. They're extremely expensive, with a uterus transplant estimated to cost as much as $250,000. They're dangerous, since patients typically must take powerful drugs to keep their immune systems from rejecting their new organs. And they're not medically necessary. All have alternatives that are much less risky and costly.
Dr. Hiten D. Patel, a urologist at Johns Hopkins University, believes these types of factors make penis transplants unnecessary. As he wrote in a 2018 commentary in the journal European Urology, "What in the world are we doing?"
There are similar questions about female genital transplants, which allow infertile women to become pregnant instead of turning to alternatives like adoption or surrogacy. "This is not a life-saving transplant. A woman can very well live without a uterus," says McGill University's Dr. Jacques Balayla, who studies uterine transplantation. "Where do you draw the line? Is pregnancy a privilege? Is it a right? You don't want to cause harm to an individual unless there's an absolute need for the procedure."
But Johns Hopkins urologist Dr. Arthur L. Burnett II, who served on the surgical team that performed the penis-and-scrotum procedure, says penis transplants can be appropriate when other alternatives – like a "neophallus" created from forearm skin and tissue – aren't feasible.
It's also important to "restore normalcy," he says. "We want someone to be able to have sense of male adequacy and a normal sense of bodily well-being on both physical and psychological levels."
Surgical team members who performed the penis transplant, including W. P. Andrew Lee, director of the department of plastic and reconstructive surgery, center.
As for the anonymous recipient, he's reportedly doing "very well" five months after the transplant. An update on Johns Hopkins' website states that "he has normal urinary functions and is beginning to regain sensation in the transplanted tissues."
When the Organ Donors Do It Live
Some peculiar messages reached Burnett's desk after his institution announced it would begin performing penis transplants. Several men wanted to donate their own organs. But for now, transplanted penises are only coming from dead donors whose next of kin have approved the donation.
Burnett doesn't expect live donors to enter the penis transplant picture. But there are no guidelines or policies to stop surgeons from transplanting a penis from a live donor or, for that matter, a testicle.
Live women have already donated wombs and ovarian tissue, forcing them to face their own risks from transplant surgery. "You're putting the donor at risk because she has to undergo pretty expensive surgery for a procedure that is not technically lifesaving," McGill University's Balayla says.
When it comes to uterus transplants, the risk spreads even beyond donor and recipient. Balayla notes there's a third person in the equation: The fetus. "Immunosuppressant medication may harm the baby, and you're feeding the baby with a [uterine] blood vessel that's not natural, held together by stitches," he says.
It's up to each medical institution that performs the procedures to set its own policies.
Bioethicists are talking about other issues raised by genital transplants: How should operations for transgender people fit in? Should men be able to get penis transplants for purely cosmetic reasons? And then there's the looming question of genetic parenthood.
It's up to each medical institution that performs the procedures to set its own policies.
Let's say a woman gets a transplant of ovarian tissue, a man gets a testicle transplant, and they have a baby the old-fashioned way.* The child would be genetically linked to the donors, not the parents who conceived him or her.
Call this a full-employment act not just for bioethicists but theologians too. "Catholicism is generally against reproductive technologies because it removes God from the nature of the procreative act. This technology, though, could result in conception through the natural act. Would their concern remain?" DePaul University's Klugman asked. "Judaism is concerned with knowing a child's parentage, would a child from transplanted testes be the child of the donor or the recipient? Would an act of coitus with a transplanted penis be adultery?"
Yikes. Maybe it's time for the medical field or the law to step in to determine what genital transplants surgeons can and can't -- or shouldn't -- do.
So far, however, only uterus transplants have guidelines in place. Otherwise, it's up to each medical institution that performs the procedures to set its own policies.
"I don't know if the medical establishment is in the position to do the best job of self-regulation," says Lisa Campo-Engelstein, a bioethicist with Albany Medical College. "Reproductive medicine in this country is a huge for-profit industry. There's a possibility of exploitation if we leave this to for-profit fertility companies."
And, as bioethicist Klugman notes, guidelines "aren't laws, and people can and do violate them with no effect."
He doesn't think laws are the solution to the ethical issues raised by genital transplants either. Still, he says, "we do need a national conversation on these topics to help provide guidance for doctors and patients."
[Correction: The following sentence has been updated: "Let's say a woman gets a transplant of ovarian tissue, a man gets a testicle transplant, and they have a baby the old-fashioned way." The original sentence mistakenly read "uterus transplant" instead of "ovarian tissue."]
The award-winning New York Times science writer Carl Zimmer.
Carl Zimmer, the award-winning New York Times science writer, recently published a stellar book about human heredity called "She Has Her Mother's Laugh." Truly a magnum opus, the book delves into the cultural and scientific evolution of genetics, the field's outsize impact on society, and the new ways we might fundamentally alter our species and our planet.
"I was only prepared to write about how someday we would cross this line, and actually, we've already crossed it."
Zimmer spoke last week with editor-in-chief Kira Peikoff about the international race to edit the genes of human embryos, the biggest danger he sees for society (hint: it's not super geniuses created by CRISPR), and some outlandish possibilities for how we might reproduce in the future. This interview has been edited and condensed for clarity.
I was struck by the number of surprises you uncovered while researching human heredity, like how fetal cells can endure for a lifetime in a mother's body and brain. What was one of the biggest surprises for you?
Something that really jumped out for me was for the section on genetically modifying people. It does seem incredibly hypothetical. But then I started looking into mitochondrial replacement therapy, so-called "three parent babies." I was really surprised to discover that almost by accident, a number of genetically modified people were created this way [in the late 90s and early 2000s]. They walk among us, and they're actually fine as far as anyone can tell. I was only prepared to write about how someday we would cross this line, and actually, we've already crossed it.
And now we have the current arms race between the U.S. and China to edit diseases out of human embryos, with China being much more willing and the U.S. more reluctant. Do you think it's more important to get ahead or to proceed as ethically as possible?
I would prefer a middle road. I think that rushing into tinkering with the features of human heredity could be a disastrous mistake for a lot of reasons. On the other hand, if we completely retreat from it out of some vague fear, I think that we won't take advantage of the actual benefits that this technology might have that are totally ethically sound.
I think the United Kingdom is actually showing how you can go the middle route with mitochondrial replacement therapy. The United States has just said nope, you can't do it at all, and you have Congressmen talking about how it's just playing God or Frankenstein. And then there are countries like Mexico or the Ukraine where people are doing mitochondrial replacement therapy because there are no regulations at all. It's a wild west situation, and that's not a good idea either.
But in the UK, they said alright, well let's talk about this, let's have a debate in Parliament, and they did, and then the government came up with a well thought-through policy. They decided that they were going to allow for this, but only in places that applied for a license, and would be monitored, and would keep track of the procedure and the health of these children and actually have real data going forward. I would imagine that they're going to very soon have their first patients.
As you mentioned, one researcher recently traveled to Mexico from New York to carry out the so-called "three-parent baby" procedure in order to escape the FDA's rules. What's your take on scientists having to leave their own jurisdictions to advance their research programs under less scrutiny?
I think it's a problem when people who have a real medical need have to leave their own country to get truly effective treatment for it. On the other hand, we're seeing lots of people going abroad to countries that don't monitor all the claims that clinics are making about their treatments. So you have stem cell clinics in all sorts of places that are making all sorts of ridiculous promises. They're not delivering those results, and in some cases, they're doing harm.
"Advances in stem cell biology and reproductive biology are a much bigger challenge to our conventional ideas about heredity than CRISPR is."
It's a tricky tension for sure. Speaking of gene editing humans, you mention in the book that one of the CRISPR pioneers, Jennifer Doudna, now has recurring nightmares about Hitler. Do you think that her fears about eugenics being revived with gene editing are justified?
The word "eugenics" has a long history and it's meant different things to different people. So we have to do a better job of talking about it in the future if we really want to talk about the risks and the promises of technology like CRISPR. Eugenics in its most toxic form was an ideology that let governments, including the United States, sterilize their own citizens by the tens of thousands. Then Nazi Germany also used eugenics as a justification to exterminate many more people.
Nobody's talking about that with CRISPR. Now, are people concerned that we are going to wipe out lots of human genetic diversity with it? That would be a bad thing, but I'm skeptical that would actually ever happen. You would have to have some sort of science fiction one-world government that required every new child to be born with IVF. It's not something that keeps me up at night. Honestly, I think we have much bigger problems to worry about.
What is the biggest danger relating to genetics that we should be aware of?
Part of what made eugenics such a toxic ideology was that it was used as a justification for indifference. In other words, if there are problems in society, like a large swath of people who are living in poverty, well, there's nothing you can do about it because it must be due to genetics.
If you look at genetics as being the sole place where you can solve humanity's problems, then you're going to say well, there's no point in trying to clean up the environment or trying to improve human welfare.
A major theme in your book is that we should not narrow our focus on genes as the only type of heredity. We also may inherit some epigenetic marks, some of our mother's microbiome and mitochondria, and importantly, our culture and our environment. Why does an expanded view of heredity matter?
We should think about the world that our children are going to inherit, and their children, and their children. They're going to inherit our genes, but they're also going to inherit this planet and we're doing things that are going to have an incredibly long-lasting impact on it. I think global warming is one of the biggest. When you put carbon dioxide into the air, it stays there for a very, very long time. If we stopped emitting carbon dioxide now, the Earth would stay warm for many centuries. We should think about tinkering with the future of genetic heredity, but I think we should also be doing that with our environmental heredity and our cultural heredity.
At the end of the book, you discuss some very bizarre possibilities for inheritance that could be made possible through induced pluripotent stem cell technology and IVF -- like four-parent babies, men producing eggs, and children with 8-celled embryos as their parents. If this is where reproductive medicine is headed, how can ethics keep up?
I'm not sure actually. I think that these advances in stem cell biology and reproductive biology are a much bigger challenge to our conventional ideas about heredity than CRISPR is. With CRISPR, you might be tweaking a gene here and there, but they're still genes in an embryo which then becomes a person, who would then have children -- the process our species has been familiar with for a long time.
"We have to recognize that we need a new language that fits with the science of heredity in the 21st century."
We all assume that there's no way to find a fundamentally different way of passing down genes, but it turns out that it's not really that hard to turn a skin cell from a cheek scraping into an egg or sperm. There are some challenges that still have to be worked out to make this something that could be carried out a lot in labs, but I don't see any huge barriers to it. Ethics doesn't even have the language to discuss the possibilities. Like for example, one person producing both male and female sex cells, which are then fertilized to produce embryos so that you have a child who only has one parent. How do we even talk about that? I don't know. But that's coming up fast.
We haven't developed our language as quickly as the technology itself. So how do we move forward?
We have to recognize that we need a new language that fits with the science of heredity in the 21st century. I think one of the biggest problems we have as a society is that most of our understanding about these issues largely comes from what we learned in grade school and high school in biology class. A high school biology class, even now, gets up to Mendel and then stops. Gregor Mendel is a great place to start, but it's a really bad place to stop talking about heredity.
[Ed. Note: Zimmer's book can be purchased through your retailer of choice here.]
