Elvan Böke, 36, is the daughter of a physics professor and a metallurgical engineer. Born in Karabük, Turkey, her life has been marked by two major events.
The first was having grown up watching Teenage Mutant Ninja Turtles on TV. Looking back at her childhood, the molecular biologist realizes that, at the age of five, she was already interested in mutant animals, which are essential for conducting scientific research.
At the age of 12, Böke learned that her mother was pregnant. She was 38-years-old: it was a risky pregnancy. Elvan accompanied her mother to the doctor many times, learning from a very young age about the numerous risks of having children later in life, which include higher chances of a miscarriage or congenital defects in newborns.
Böke was particularly struck by a specific fact: at the time of birth, women – like the vast majority of mammals – already carry all the eggs they will have for the rest of their lives in their ovaries. There are between one and two million… enough to populate a medium-sized city.
At puberty, these oocytes – or immature eggs – begin to mature. By this point in time, there are only about 300,000 left. Only about 400 mature eggs are released during a lifetime, usually one per menstrual cycle. When there are only 1,000 oocytes left, menopause will begin and reproductive life will be over. Tens of thousands of oocytes are lost along the way, without ever reaching maturity. But nobody knows why.
“When I explain this at conferences full of biologists – very smart and prestigious people – I’m very surprised that they don’t know [the answer],” Böke explains. In other words: we humans live without knowledge about the fascinating cells that have made human life possible.
After studying genomics in Turkey and receiving a doctorate in the United States and the United Kingdom, Böke has directed the Oocyte Biology Group at the Barcelona Center for Genomic Regulation (CRG) since 2017. She has just received a prestigious grant from the European Research Center – worth $2.2 million – to research the basic biology of oocytes and their maturation.
These cells are the only ones in the body that, for decades, are immune to aging… but it’s largely unknown as to why. Understanding this could alleviate the enormous demographic problem in several developed countries, as mothers are getting older and fewer children are being born.
Question. Of all the cells in the body, why did you decide to focus on the eggs?
Answer. Because oocytes are the most interesting cells in the body. They’re in charge of giving life to the new generation – they’re the largest cells in the body and also some of the oldest. And they’re really beautiful, too. In fact, I think that, next to neurons, they’re the most beautiful. Despite all this, they’re [understudied]. As a woman, I’m disappointed with how little we research and understand our own [reproductive system].
Q. Why do we know so little about eggs?
A. It’s difficult to work with them. In other fields of biology, you can grow cells in a laboratory… but oocytes don’t multiply, nor do we know how to create them from scratch. You have to sacrifice an animal to remove its ovaries and get those cells. Also, in each animal, there aren’t many oocytes. It’s not like the cells number in the millions – [there are] only a few thousand in a mouse. Historically, there has been a shocking lack of funding for this type of research. There isn’t much interest.
A. In 1980 – in a developed country like the United States – the majority of mothers were between the ages of 18 and 22. But by 2016, more and more women were having their children in their thirties. [This trend] continues: mothers are getting older. For a long time, governments and [science-funding] bodies didn’t feel like this was a topic worth investing in, because there wasn’t really a fertility problem. Now there is. This isn’t just a female health problem… it’s a demographic emergency that affects us all.
Q. You have just received the equivalent of $2.2 million from the European Union. What exactly do you want to study with these funds?
A. Any type of cell in the body ages (including neurons), showing signs of wear and tear with age. If the ovules (eggs) accumulated the same damage, we would basically become extinct as a species in two or three generations. But the reality is that they don’t accumulate defects with age. They don’t age! So, when a woman has a child at 38, that child is no different than that of a 20-year-old mother, because the [cell] from which it came [didn’t] age. In fact, demographic studies suggest that the children of older mothers tend to be healthier and achieve higher levels of education.
Q. How come?
A. It’s unclear. In part, older mothers tend to have a higher educational level. It may also be that they’re more aware of the first signs of illness in their children and know how to identify them better. [In 2016, a study by the Max Planck Institute for Demography in Germany argued that, at the population level, children born to older mothers were healthier and more educated. On the one hand, pregnancies in mothers aged 35 or over tend to have more complications… but, according to the paper, the benefits of having children later in life outweigh the risks].
Q. So having children later in life makes sense?
A. Sure. I had my daughter [when I was] 34-years-old. I wanted to finish my education first, build a career, find a partner. It’s logical that, more and more often, we’re having our first child [while entering] our thirties. But it’s important that we’re aware of what this involves. I know women my age or younger who take fertility tests and discover that their ovaries [are like] a 40-year-old’s – they have very few eggs left. One thing we could do now, as a society, is have a widespread fertility testing program. [This would mean that] by the age of 18, a woman could have an approximate idea about their fertility and better plan their lives.
Q. When does the health of the ovaries begin to deteriorate?
A. It’s a gradual process. Around the age of 35, a considerable decline begins… but this number varies a lot. Fertility clinics sometimes explain it as if there’s a certain age beyond which you’ll never be able to have children… but this isn’t true.
Q. It’s possible to measure the ovarian reserve, correct?
A. Yes, but it’s just an estimate. Reproductive biologists [have] discovered that oocytes that begin to mature and grow release a hormone. The levels of this [hormone] in the blood are related to the number of eggs you have left. This is the system that fertility clinics use to measure ovarian reserve. But it’s important to know that [this is] an indirect approximation. It doesn’t tell you what happens in the reserve, which is where your unripe oocytes (eggs) are.
Q. Do fertility clinics properly explain these limitations to patients?
A. I don’t think they’re [omitting] the truth… but they embellish a lot. An example of this is with egg-freezing. The approximate success rate – that is, a healthy baby being born from a frozen egg – is less than 5%. I don’t think many clinics talk about this with their patients.
Q. Can it be known from birth when you’ll stop being fertile?
A. No, because there’s no data to estimate it reliably. We would need data [from] many females at birth. Even if we started [logging it], we would only have the model 60 years from now.
Q. How do the eggs stay young?
A. We’ve just made this discovery – we’ll publish [our findings] in the journal Science soon. In almost all other types of cells, this topic has been studied for many decades, but until recently, no one has been interested in how oocytes generate energy. What we have seen in mice is that these cells are special. Inside the cytoplasm of the cells (the jelly-like substance inside them), many proteins are generated that do their job. They’re then discarded. With age, these cleaning mechanisms stop working well… this is what happens in neurons with Alzheimer’s, for example.
What we have discovered is that the oocytes also generate this waste, but they keep it in a special compartment – like an airtight garbage can that is kept insulated. In this way, the waste doesn’t cause [the cells] problems or aging. And the most interesting thing is that, just before being fertilized by a sperm, the ovules expel that garbage can, probably so that it doesn’t cause complications when [it’s time] to form an embryo.
Q. Why is waste accumulated until then?
A. We think it’s because they don’t want to waste energy [by disposing of it].
Q. And if they can stay young, why do they suddenly grow old at a certain age?
A. We really don’t know. It’s like our car broke down. We know it’s broken, but not why.
Q. What kind of experiments are you going to do to find out?
A. Much of our work is done with animal oocytes. Human oocytes are provided to us by the Hospital Clinic of Barcelona. They basically come from women who have to have their ovaries removed.
Last year, we published a study that showed that mitochondria – the cellular organelles responsible for producing energy – have to be turned off to avoid generating harmful waste. So, we’ll compare young and not-so-young oocytes to see when they start to go bad. We’ll do the same with those new compartments of protein aggregates. We’ll see when the engine starts to [malfunction]. Because it’s brutal that, for decades, it’s simply been accepted that after 40 years, the system stops working, just like that. The problem is that we [don’t even] know what parts the engine has.
Q. Could all this basic knowledge allow women to have children at later ages?
A. It’s enough for me to know that this can help women have children in their fourth decade of life. At about 60, women enter menopause. What I do think we can do is slow down the decline of the eggs until reaching menopause. So, instead of starting the deterioration at 33, [it could] start at 42, for example.
Q. What do you think human reproduction will be like in 50 years?
A. I’m optimistic – I would like to think that not much will change. But it probably will, it’ll be much more technological than now. The percentage of children born through assisted fertilization is skyrocketing and will probably be much higher in 50 years.
Q. You’ve commented on another surprising fact: one in four women is infertile and we don’t know why.
A. Exactly. We have no medical explanation. In men, the rate is one in ten. And we don’t really know why either.
Q. Is there more research on male fertility problems than female fertility problems?
A. Yes, much more. If we look at the main repository of studies on biomedicine, in the year 2019, for example – the last year of normal science before the pandemic, so to speak – twice as many papers were published on sperm than on eggs. If we restrict it to studies of these cells exclusively in humans, the difference is seven times more work on sperm than on oocytes. The latter are represented by 28 studies. That same year, 1,157 papers on erectile dysfunction were published. Much more research is done on erectile dysfunction than on female reproduction.
Despite this, the situation is improving. More and more people are studying this topic. A curious thing is that the vast majority of teams are led by women. There are some exceptions – but the majority of us are women. I don’t know why there are so few men in this field.
Q. Is there any relationship between diet and female fertility?
A. Both obesity and malnutrition drastically reduce female fertility. We’ve seen that oocytes produce their energy in a different way than other cells. And this method uses only fat and protein for energy. Zero carbs. And this probably tells us something about the mother’s diet and her fertility.
Q. Why are most mammals already born with all their ovules? Is there an advantage to this?
A. Nobody knows. I believe that the womb is the safest place in which a person can be. There, we’re much [better] protected from any environmental interference than after we’re born. It makes sense that we develop the most important cells in our bodies – the ones that will give rise to the next generation – when we’re most safe. We then expend a lot of energy and effort to ensure that these cells stay healthy for years.
If women continuously formed oocytes and, for example, had a high fever or drank a lot of alcohol, it would be very dangerous, because the oocytes contain almost all the cytoplasm of the future embryo. Spermatozoa, on the other hand, are very numerous and hardly contribute to the cytoplasm.
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