Just over a decade ago, an fantastical creature was introduced to the world: Sam, an animal that was a rooster on their left half and a hen on their right half. The scientists who investigated them, from the University of Edinburgh, baptized the animal Sam for both Samantha and Samuel. The geneticist Irene Miguel Aliaga usually shows a photograph of the chimera in her talks. Sam demonstrated that cells, at least bird cells, had an intrinsic sexual identity: a cell is male or female.
Miguel Aliaga’s groundbreaking research has revealed previously unknown differences between the sexes, with implications for diet, fertility and susceptibility to cancer. The geneticist at Imperial College London has illuminated these enigmatic mechanisms with bold experiments on flies. Her research on intestines led her to state that the viscera harbor “a second brain,” which differs between males and females. As a result of her research. on July 15, Miguel Aliaga and fellow geneticist Carola García de Vinuesa will become the first Spanish scientists to join the Royal Society of the United Kingdom, an exclusive society founded in 1660 whose members have included Isaac Newton, Charles Darwin, Albert Einstein and Rita Levi-Montalcini.
Question. What does that half-rooster, half-chicken animal tell us?
Answer. Those experiments were quite revealing. When we think of differences between the sexes, we always think of the ovaries and the testicles: I have estrogen, you have testosterone, and that is why we are different. What those experiments showed is that the size of the male half was totally different from that of the female half. If everything depended on hormones, which are floating around everywhere, why would one part be smaller than the other? Those experiments showed that there are more factors in sex than just hormones. This is what we are investigating: the sex of the organs, the sex of the cells. There is an intrinsic component of sexual identity in cells.
Q. In any biology book, the only organs that are differentiated by sex are the penis and testicles in males and the vulva and ovaries in females, but you show that all the organs differ by sex.
A. Yes. We work with the intestines, but it is also seen in the pancreas and the liver. There are a lot of sexual differences, and they can also change during adult life. The plasticity of adult organs is not well-researched.
Q. In your talks you usually show the image of a python eating a crocodile, an exaggerated case that illustrates the ability of the organs to change shape and volume.
A. It’s an extreme case of how much adult organs can change. You are born with a gut and you think, “This is my gut for life.” But what the python illustrates is that the intestine can grow a lot and then shrink in adult life. And you think, “Well, this is a python that just ate a huge crocodile.” But, in reality, this happens in all the animals that we are researching. We initially saw it in flies, but mice’s guts also grow a lot during pregnancy and lactation. Now we’re starting to examine humans, and it seems to happen with us too. The organs change inside us. They grow and shrink, and that matters.
Q. Can you give an example?
A. In flies and mice, the length of the intestine grows up to 20%. The ability to reproduce goes down if you interfere with that process and don’t let the mother’s intestine grow during pregnancy and lactation, or, in the case of flies, when they’re laying eggs. It is important that the intestine grows so that these species can reproduce. In humans we’re looking at it now, and it seems to grow a bit during pregnancy and lactation as well. We don’t know yet if it’s important.
Q. You lament the confusion between sex and gender. What is one and what is the other?
A. Sex is a biological variable: you can be male, female or intersex. Gender is a social construct: as a society we assign values of men and women. Now there are several categories, because being a social construct, it is not a fixed thing. I am a woman and a female, but sex and gender do not always coincide. Potentially, both biological factors and this social construct can have an impact on physiology and pathophysiology, for example, if you develop a certain cancer. The social construct can be associated with one gender tending to eat a certain diet, and that can influence the cancer that you end up developing.
Q. You also research sex differences in the human brain.
A. Yes, it is a complicated subject. With a fly or a mouse, there is no gender. There is only sex. Many people have a hard time seeing the difference between sex and gender, including many scientists. In my flies or in my mice, gender doesn’t matter. I can say that there is always a difference between the male fly and the female fly. And that difference is of sex, clearly. In humans there are many differences between males and females, between men and women, but it is more difficult to find out if they are due to sex (biological) or gender (social) differences. Therein lies the complication, but people are quite dogmatic. Normally you have people who believe everything is sex and people who believe everything is gender. And the reality is that it is difficult to separate them.
Q. Where do you stand?
A. What I can say is that, in all the animals that I have looked at, there are differences due to sex. In all of them. So I can’t believe that humans have no sex differences. In any tissue, in all the organs I have looked at, there are obvious sex differences. Sometimes these differences are seen as an attack on equality, but the fact that there are differences does not mean that one sex is better and the other is worse.
Q. If I showed you a woman’s brain and a man’s brain, would you know which is which?
A. If you look at the genes that are activated, wherever you look, you will see differences between the sexes. Where do those differences come from and what do they mean? I do not know. The brain is the most controversial case, obviously.
Q. Whether it’s a brain or a liver, you take any cell and you know if it’s male or female.
A. Obviously, yes.
Q. That isn’t controversial.
A. No, that cannot be questioned. It is a fact. If I look at which genes are turned on or I look at the chromosomes, I can tell if the cell is male or female.
Q. How is the biological sex of a human cell noted, besides the XX or XY sex chromosomes?
A. The sex chromosomes, for example, will dictate the type of genes that are turned on in the cell. And the activation of genes will also depend on the environment in which the cell is found: hormones, nutrients…
Q. And a male or female cell is neither better nor worse.
A. Exactly. In a talk I was showing that female fly gut stem cells proliferate more, and I explained that this is important for the mother fly when it reproduces, because it needs the gut to grow. When the intestine grows, that helps fertility, the fecundity of the fly. And a boy in the audience got angry and said to me: “But how can you say that the intestine of the females is better?” And I replied: “No, I’m not telling you which is better, I’m just telling you that their stem cells proliferate more.” The fly is a good example of how something can be good in one context, but bad in another. For example, gut stem cells that proliferate more in the female fly is a good thing during reproduction, but if you genetically induce tumors, the female fly develops larger tumors, because those cells proliferate much more. There is never a better and a worse. It’s always a yin and yang thing, in a way.
Q. Your research with intestines has revealed that the organs of males and females are more different than we thought.
A. Yes, we did not expect to find so many differences. We are seeing that they are very different and that how they communicate with other organs is also very different. For example, communication between the gut and the brain can be quite different between males and females. It is an amazing thing.
Q. What are the implications of these differences?
R. They have made us aware that we have to consider sex in all research. We should not assume that the physiology and pathophysiology of animals, or of humans, will be the same. For example, in humans, susceptibility to cancer is different in men and women. It is due to a combination of many factors: diet, environment, genetic variants. But our research says that you also have to consider the intrinsic sex of the cells. It used to be assumed that sex differences in cancer were due to male or female hormones. We have seen that there is also an intrinsic component of the cell, of the sex of the cell, at least in the fly.
Q. Your research with fruit flies has won six Nobel Prizes.
A. Yes, flies are very powerful in discovering new processes, because they allow you to do experiments without necessarily having an a priori hypothesis. If you want to see which genes control a process, you can remove different genes in different flies. To see differences between the sexes, you can take stem cells from the intestine of an adult female fly and make them male. And you can do it very quickly. On the fly all these tests can be done in a couple of months, while in mice it takes a year or two.
Q. Do we have a second brain in the gut?
A. Yes, we have a lot of neurons in the gut, and the gut is connected to the brain by neurons that can sense nutrients and affect physiology and behavior, at least in model organisms like the mouse. We are also seeing that even the non-neuronal digestive cells of the intestine can detect nutrients such as zinc. So the “gut feelings” thing is justified.
Q. How should society understand these differences between the sexes?
A. In ecology, an ecosystem’s diversity is important for it to survive any external challenge. I see society the same way. The diverse society—at the level of sex, gender, ethnicity or whatever—is the one that can best survive challenges. We are stronger that way. I don’t see sex and gender differences, or different needs, as a problem. I always see it as a good thing. There is nothing wrong with admitting these differences.