Can ovaries make new eggs?

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It's unexplainable.

I'm Noam Hassenfeld.

Roughly half the human population has ovaries.

Researchers know they generally come in pairs, that they're about the size of kumquats, shaped like almonds, and that they hold eggs that, if they're fertilized, can eventually turn into children.

But as our reporter Bird Pinkerton learned, there's a whole lot researchers don't know about ovaries.

And in order to answer those questions, they might need to roll back the clock on decades of assumptions.

Here's Berg.

If you took high school biology, you probably read in your biology textbook somewhere some version of a specific story we tell about our ovaries.

So the story starts in utero.

Rachel Gross is my favorite human biology textbook.

She's a friend, but also a reproductive health reporter.

And she gave me a refresher course.

She said that in utero, a fetus is developing limbs and eyes, but also a bunch of eggs.

Until the baby is born with maybe around one to two million.

And as the story goes, that is all the eggs that this new little person will ever have.

From the beginning, those eggs start dying off.

A few of them are disappearing even as the baby becomes a child, though most of them are just sort of hanging out, not doing a whole lot.

Until the hormone surges and cycles of puberty start that monthly cycle that many of us know called ovulation and menstruation.

And in that cycle, there's kind of a cohort of these sleeping tiny eggs that are recruited.

These recruits then start growing.

And at one point one egg is ahead of the pack and starts helping inhibit the other eggs which all die.

The winning egg then takes a little trip through the fallopian tubes.

Maybe it gets fertilized.

Probably not.

And if not, it gets ejected in the delightfully bloody, sometimes crampy, usually pretty annoying phase of menstruation known as a period.

Each month or so, the ovaries are losing a bunch of eggs this way, and then other eggs are also just dying on their own.

In your 30s and 40s, the process of eggs actually dying or degenerating speeds up.

So we know that some force accelerates and that a lot of these eggs aren't even making it to the growth phase.

A lot of them have this death wish before they even get started.

And eventually the menstruation cycle stops.

At the point that you are at what we call menopause, which is between 45 and 55.

And it's known as when you,

about when you run out of eggs, and when you also stop having this monthly hormonal cycle that results in your period.

This is the story that scientists have been telling about ovaries for decades now.

And it relies on two fundamental assumptions.

So, one, the ovary's most important function is to hold and develop eggs.

And two, that those eggs are only disappearing over the course of a lifetime.

We've got this limited cache of eggs that's just tick, tick, ticking ever closer to empty until the body runs out.

And so, this is kind of wondrous and crazy to contemplate, but it's also maybe wrong.

On today's show, what if we've gotten the the story of ovaries wrong?

And what would a new story look like?

So first, where did this textbook story about ovaries and their dwindling eggs even come from?

It kind of starts gestating in the late 1800s and it keeps developing throughout the early 1900s.

But Rachel says if we're going to give it like a birthday or a birth decade, she would pick the 1950s.

It goes back to this British scientist named Sir Sally Zuckerman.

He was trained as an anatomist and he did a lot of his own experiments.

Including experiments about eggs, because Zuckerman got interested in this debate that had been going back and forth for a few decades at this point.

It was this debate about whether whether or not female animals could generate new eggs, just like male animals can generate new sperm.

And he decided to really dig into this question and figure out once and for all who was right.

Zuckerman and his team started doing all kinds of experiments on rats and on monkeys to see what they could learn from their ovaries.

So the most basic thing they did was to take ovaries from rats and monkeys in different stages of their lives and count up the numbers of eggs that they had.

They'd also do stuff like remove one ovary from a rat to see if the other ovary would make more eggs to compensate.

And over and over again, Zuckerman was finding the same thing.

Basically, the takeaway that he kept coming to was that over time, the number of eggs either stay the same or they go down.

They never went back up.

And in 1951, Zuckerman announced these findings to the world.

And this is the moment where the story of the dwindling eggs that we all know and love or like feel somewhat ambivalent about is the moment when it really took over.

It really becomes the backbone of the field of reproductive biology.

So it's in every textbook and it's the first line in hundreds of papers that you read.

It basically says, everyone knows that this is how the ovary works, that a female is born with all the eggs she'll ever have, and they degenerate throughout her lifetime up until the menopause.

The story has made its way into TV.

Researchers used a complicated math formula to show that after the teenage years, it's all downhill in terms of how many eggs a woman has left in her ovaries.

My personal favorite is the news broadcast where a reporter decides to go to a gym to ask random women who really are just trying to work out how they feel about the rapid decline of their eggs.

So, when I say that, what runs through your head?

That's shocking.

Yeah, it makes me nervous.

I think that sounds a little extreme.

But the idea that we're always only losing eggs has also had a deeper impact in that it's really fundamentally shaped how researchers have approached the ovaries for decades now.

Dr.

Yi is examining Elaine to see whether she has produced enough eggs for an in vitro procedure this month.

Take in vitro fertilization, for example, which helps people get pregnant.

The whole IVF process really hinges on this idea that the ovary has a finite number of disappearing eggs.

They're the limiting factor.

So for IVF, you basically want to force the ovaries to produce as many eggs as possible out of their limited number.

In an in vitro cycle, ovulation drugs are used to cause a number of eggs to ripen rather than the normal one per cycle.

It treats them as this finite resource.

These eggs are a very limited resource.

And you want to get as many as possible to combine with a sperm and then reimplant the embryo.

The new options also mean women who face medical treatments that may threaten fertility can freeze their eggs for later use.

And if you look at something like egg freezing, for example, where people put aside their eggs to use later, the fundamental premise there is that the ovaries only lose eggs and that egg freezing clinics can help save some eggs for later.

Experts say freezing eggs can help address the conflict between the biological clock and career timeline.

So Rachel, as a reproductive health reporter, she had learned this textbook story, she had accepted it, and then she started reporting out a book about reproductive organs.

And as she was looking into the ovaries specifically, she stumbled across this whole body of research that really calls this story into question.

This was research that started around 20 years ago, at the end of the 1990s.

So there's this guy, this reproductive biologist.

His name is John Tilley.

He was researching eggs and ovaries, trying to figure out how fast they die off and

why they die off.

And to figure that out, he was looking at mouse ovaries and basically trying to count up their eggs to figure out how fast they were then degenerating.

So when he's running these numbers, he calls it like his accounting phase, he basically finds that they don't add up.

The eggs were dying off at such a rapid rate that it was like 1,200 a day, which made no sense.

And a mouse would be completely out of eggs within weeks if that were the case.

And that's not how a mouse works.

So Tilly had this problem.

Like he needed to balance his egg books and figure out a way that mice could be losing a ton of eggs and yet still have eggs down the line.

And meanwhile, in the 1990s.

After more than a decade of work, researchers said today they have isolated and grown basic human stem cells.

A stem cell is a type of cell that is full of potential and can usually become any type of cell in the body.

Unlike other adult cells which die, these stem cells can grow and divide indefinitely.

And stem cells we now know hang out in the body making new cells for us.

So they are in our bone marrow, for example, but they're also in the testicles.

And in the testicles, they go through a process that's specific to making sex cells, this process called meiosis.

Basically, the stem cells divide and then sperm is created.

So Tilly, back in the day, he gets curious.

He starts poking around in his mouse ovaries.

And lo and behold, he's seeing signs of meiosis happening.

That same kind of cell division that's happening in the testicles to make new sperm.

He's pretty sure he's just found it happening in these ovaries as well.

And that wouldn't really make sense if it was just a bunch of sleeping eggs or a bunch of eggs degenerating.

It suggested that eggs were being formed.

This was huge potentially.

Like, for the first time in 50 years, there was a sign that Zuckerman might have been wrong, that maybe eggs weren't just dying off in ovaries, but that there were actually stem cells in the ovaries that were creating new eggs.

Obviously, this is,

it's like extraordinary claims take extraordinary evidence.

Unfortunately, right off the bat, Tilley started making big claims about his research.

You have the lead researcher, John Tilley, and then the media really grabbing onto this and making a huge deal of it and making this huge leap saying this will revolutionize reproductive technology.

This is probably happening in humans.

The Telegraph ran this article that was like, scientists learn how to beat the menopause.

A lot of Tilley's fellow ovarian researchers didn't really love the hype that was surrounding this.

And they also had problems with the findings as well.

People would say, you are misinterpreting the data.

These are not necessarily stem cells.

and kind of the markers you're using to say they're stem cells are under question.

So, I think the way that Tilly says it a lot is he was basically eaten alive.

Tilly started trying to gather more evidence to back up his case.

He was running a lot of experiments, actually.

Like, he used chemotherapy, for example, to sterilize mice, and then he put the stem cells from bone marrow into their ovaries.

They were then able to have babies again, which suggested that maybe the stem cells were reviving their eggs somehow.

He also put stem cells that were genetically modified to glow green into mouse ovaries, and then the mice ended up having glowing green mouse pups as a result, which suggests that the stem cells made eggs and then those eggs became babies.

And in the meantime, Other researchers were doing their own work to try and verify this.

They were using their own methods.

they were working with other animals, and some of them were finding similar results, which kind of brings us to where we are today.

So at this point, there's more than 80 papers that show evidence of ovarian stem cells in rats, cows, monkeys, and eventually humans.

There's still a lot of remaining questions, especially for humans.

Like, it is...

not clear how many eggs these stem cells make, and these ovaries are also being manipulated in experimental lab conditions.

We just don't know if they naturally produce eggs throughout someone's lifetime or if they can just be triggered to do this by like damage or aging.

But as it stands, we can at least begin to rewrite like the middle of our textbook story, right?

We can consider the possibility that on the journey from sort of baby to menopause, the ovaries might be regenerating eggs at some point.

And if we rewrite that middle part, it also opens up new ways for our textbook story about ovaries to potentially end.

It opens up all these new avenues that might allow us to solve problems related to fertility.

Like, let's say that researchers can find a way to reliably make new human eggs using stem cells outside the body.

That is a new tool of intervention for people that are concerned with fertility or who have conditions that threaten their fertility.

Think about our IVF example again.

So with IVF, you are really getting only a few eggs per IVF cycle.

And people that have gone through this know that it's incredibly expensive and painful and time consuming and often not covered by insurance.

It's just a really not efficient way to do this.

So if you have the ability to have as Tilly says, eggs on demand, which is to say you remove some stem cells and you just produce new eggs outside the body or culture new eggs, then that takes off that limiting factor of going through all of that pain and effort for just a few eggs.

These kinds of treatments are still like way far off in the distance.

There's obviously ethical issues whenever it comes to making a human life using a new experimental technology.

But there is research being done now to start exploring this space.

One of the first applications that researchers are actually testing now is how to help young cancer patients who have had these really brutal treatments that kind of blast their ovaries and kill off the eggs and presumably stem cells.

So, if you can actually recruit out some of the stem cells beforehand and then reimplant them afterwards so they're not damaged by chemotherapy, then that should give them both ovarian function, like hormone function, and the ability to get pregnant later on.

This is not like a novel idea.

In the past, chemo patients have had pieces of their ovaries reimplanted to do this kind of work.

But the idea is that stem cells will be more powerful and resilient.

So this is already a lot of new, hopeful research, like this new story leading to new ideas.

But as Rachel was researching her book, reporting all this out, She realized something else about the story that we tell about ovaries.

It is hyper-focused on all the ways that ovaries contribute to babies and baby making.

But I was finding that they were doing so much else.

After the break, what else Ovaries can do?

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Huge implications in a country where millions of career women put off marriage and children while their biological clocks are unexplainable.

Unexplainable, we're back.

I'm Bird Pinkerton.

And before the break, Rachel Gross was explaining that the story we tell ourselves about ovaries, this story that they are forever losing eggs and never gaining any of them back, that story might be incorrect.

But in the process of kind of reconsidering that story, she also started to reconsider a more basic cultural story that we tell about the ovaries.

A lot of people think of them as egg baskets, which is sort of what the word means, is just like keeper of eggs.

But the researchers that Rachel was speaking to were starting to think of ovaries as more than just egg keepers.

Each egg is surrounded by this halo of little bubbles that are cells that are called granulosa cells.

And they're the ones that are producing hormones communicating with the egg, affecting the entire body.

And for a long time, some reproductive scientists sort of ignored these granulosa cells, these bubbles that were surrounding the egg, because they were so focused on getting at the eggs themselves.

IBF researchers, for instance, like pick off all of those cells on the outside because they're kind of in the way when they want to fertilize.

It's kind of wild to think about, but it does make sense.

Like if you think that the focus of ovaries is to make eggs, everything else is kind of secondary.

But now the scientists that Rachel is speaking to are refocusing their research.

Like they are starting to study those hormone-producing granulosa cells instead of just picking them off.

And then there's all these cells that we don't know what they're doing.

Literally, other mysterious cells in the ovary that have barely been researched yet.

So it's kind of a black box because we focused again so much on the eggs that we're not sure what the other tissue in there is doing.

And Rachel says that this new interest in hormonal cells could also lead to new avenues of treatments that are related to the ovaries, but that are not about fertility or making babies.

It's like

by

kind of unlearning this assumption that we're born with all the eggs we ever have, it opened these new possibilities for like, whoa, what can the ovaries do?

What are their limits?

And one of the most promising of these new possibilities is exploring how the ovaries affect menopause, this dramatic systemic change that a lot of bodies undergo.

So basically, menopause is associated with with loss of bone density, heart problems, cognitive problems like Alzheimer's, and a host of other things.

We don't know for sure whether hitting menopause causes all of these things or whether they're associated because your body is aging.

But if there is a relationship between these declines and the big hormonal shifts around menopause, researchers are now wondering, are there secrets hidden away in our ovaries that could help delay these declines?

Could the regeneration of eggs, for example, actually have bigger implications?

If the ovary is regenerating, it's also regenerating cells that make new hormones and that help keep the body going and maintain health.

And these researchers actually are interested in tapping into that by creating a form of kind of artificial ovary.

And their actual goal is not to have women have babies later.

It's to delay the negative effects of menopause.

They want to see if they can take some stem cells from the ovary and use them to make more of the hormone producing cells instead of just the eggs.

Basically to bioengineer like a bit of ovary in a dish.

And they were describing to me as it could be, you know, it doesn't need to look like an ovary.

It could be like a silver dollar or something and you don't need to implant it in the abdomen.

You could implant it under your arm skin because one of the crazy cool things about all your glands is that they work everywhere.

This silver dollar thing is just in the idea phase right now, but other researchers are working on actual real-world experiments.

So there are several doctors who will take tiny strips of your ovarian cortex out when you're younger, keep them, and re-implant them as you grow older with the idea that it will sort of jumpstart your ovary.

There isn't great data yet on whether that's actually working at all or whether it's even helping with the potential side effects of menopause.

But

that's kind of the direction in which some treatments are moving.

Whether or not these treatments wind up helping people to combat the declines that they experience in older age, Rachel says she's just excited by all of this because she sees it as the first steps towards a whole new field of research.

I think the bigger point here is that when you have a simple narrative that seems to explain a body part really well, a narrative like ovaries come with all the eggs they're ever going to have, that really closes the lid on other explanations and other questions that could give you a ton more insight into those organs.

Ovaries are one example, but they're certainly not the only example.

This kind of story is something I would find over and over again when I was working on my book, which looks at all sorts of pelvic organs, from the uterus to the ovaries to the vagina to the clitoris.

And there would be this dominant narrative of what this body part was for and what it represented.

And then there would be scientists coming up and saying, wait, we've never considered this.

Or what if you look at it like this?

Take the clitoris, for example.

It has been called a minuscule phallus or an underdeveloped penis or a tiny nub for hundreds and hundreds of years.

And science has sort of minimized it in many ways.

Then a female researcher poked around and realized that the clitoris was actually a much, much bigger organ than people had realized.

It's just that it's sort of under the surface waiting to be better studied.

Or take the vagina, for example.

Like the word literally means sheath.

It's been treated as kind of this like tube for people's penises, or as this place that needs to be kept, like really pure and really clean.

Whereas in reality, the vagina has many incredible qualities, including self-lubrication and housing this ecosystem, this vaginal microbiome that helps protect the space between you and not you.

And it's really an extension of your immune system.

The stories that we tell about our organs they shape what we know, they shape what we research, and they shape what gets funded.

And this was something scientists were telling me over and over again.

When you study the human body, even though the human body is not changing, it has been around for centuries and centuries, and you've seen these organs before, you really see what you expect to see, and you see what you are looking for.

You kind of blur out the rest.

And what I think we need is people that can fill in that background and can focus on the parts that have been blurred out.

If you want to read more about the researchers and scientists who are studying the parts of the pelvic organs that have been blurred out, I cannot recommend Rachel Gross's book enough.

It is called Vagina Obscura, An Anatomical Voyage.

This episode was produced by me, Bird Pinkerton.

It was edited by Catherine Wells and Meredith Hodnott with more editing help from Brian Resnick.

Noam Hasenfeld scored the episode, Christian Ayala mixed and sound designed it, and the inimitable Richard Seema checked the facts.

Seriously, Richard is just a fact-checking king, and I want him to know that I appreciate him deeply.

I also appreciate Manding Wen's Pigeon, Sonny, who loves to take over Zoom meetings.

If you have thoughts about this episode or ideas for the show, please email us.

We're at unexplainable at Vox.com.

We read every email,

and we'd also love it if you left us a review or a rating, even.

Unexplainable is part of the Vox Media Podcast Network, and we'll be back next week.

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