Full episode transcript below. Beware of typos!
Nick Jikomes
Dr. Blanche Capel, Thank you for joining me.
Blanche Capel 2:40
You're welcome. I'm glad to be here. Thank you for inviting me.
Nick Jikomes 2:44
Can you start off by just telling everyone a little bit about who you are and what kind of scientific research you do?
Blanche Capel 2:50
Yes, well, I'm I'm Blanche Capel. I'm a professor in the Department of cell biology at Duke University Medical Center. I did my my graduate training at the University. First of all, I did my undergraduate training at Hollins, which used to be Hollins college, it's now Hollins University in Virginia. It's an all women's college. It was at the time well known for its because we had produced a lot of really great writers. And I thought I wanted to write the Great Southern novels. So I initially involved really in science, my degree, there was an art history and, and literature. And then later after much after my children were born and started grade school, I went back to pick up some courses in science. I was always been really interested in genetics, but I'd never really thought I wanted to dig into it until quite a bit later. And then I decided it would be fun to just learn a bit more about genetics. So I went back to pick up some courses at Bryn Mawr College and Haverford College, I was at that time living outside Philadelphia. And I got really, really excited about science and eventually decided to go back to graduate school at the University of Pennsylvania, where I did my PhD. I was part of the genetics program. But I was loaned for, to Beatrice Mintz as my graduate advisor, she is a real was a real giant and in engineering mouse techniques, she was involved in creating some of the first time mirik mice and some of the first transgenics she just did a tremendous amount of, of work to to make the mouse the model organism that is today and she was a really innovative thinker. Very one of the brightest people I have ever met even today, and very interesting to work with temperamental and difficult and very demanding But I was a was a great treasure for me to have had the opportunity to work with her. For my PhD at the time I was working on a medical Edik stem cells. This was a time before, we were just beginning to think that there was probably a meta and meta poetic stem cell that could give rise to all the other lineages. And I was doing transplantation studies to see if we marked individual cells with a retroviral insert, whether we could see that same retroviral insert turn up in all the hematopoietic lineages in the adult. And I was transplanting fetal liver cells and bone marrow cells between mice at the time taking advantage of mutations in the mouse that deplete the hematopoietic compartment, which allowed engraftment of blood cells anyway, I she be be Miss had a real strong interest in sex determination and germ cell biology. Even though we didn't work on it in her lab, she had come from a lab, where she did a lot of work on on germ cell biology, and she was always fascinated by germ cells. And somehow I think she transferred that interest to me, even though I didn't work on that in her lab. And when I was looking for a postdoc, I found the level batch lab in London was really interesting to me. So Robin level batch had just set his lab up maybe four years before, and he was working on sex determination in mice. And he had a strong history in mouse genetics. And I admired that and I thought I had been working with a very strong and will shatter her finger in every pie, you know. And so I thought it might be nice to work with somebody who was just starting out, and where I wouldn't be on a more equal footing, and have a better chance to drive my own fate. And so, I applied to Robin for a postdoc position. And he took me by this time, I was pretty old. You know, I was, I don't know, 39 or 40, something like that. So it seemed like, you know, I didn't, I didn't know how easy it would be to get a postdoc position. But he took me and I went to London and just fell in love with sex determination and germ cell biology. It was a really exciting time in his lab.
We had, he had been working on on trying to identify the sex determining gene for many years by various methods, one of which was to use retroviruses to indiscriminately target embryonic stem cells, and then produce mice to see if if he had managed to hit the sex determining gene and cause sex reversal. And he and Elizabeth Robertson had done this project earlier. And in fact, they got a mouse it was sex reversed. But when they looked for the insertion site of the retrovirus, which was meant to mark the sex determining gene, it turned out that the retrovirus had jumped around and, and, and was no longer where it originally caused the damage on the Y chromosome. So they were not allowed, they were not able to identify the sixth determining gene from that experiment. And it was about the same time that David Paige who was working at MIT, identified a gene on the Y chromosome that he thought was the sex determining gene. It he called it well, we knew it is Zed F why? Because I was in England, so we were saying Zed instead of z. But um, and that was a real disappointment, both to Robin slab and also Peter Goodfellows lab who is also working in London, but working mainly on human tissue. And Peter Goodfellow had been walking down the human Y chromosome using probes from the junction with a region that pairs with the X chromosome, so he had probes at the time, we weren't sequencing, you know, so you had to do everything using tiling probes walking down the chromosome to see where the chromosome was disrupted was his plan. And when Paige published said if y is the sex determining gene, everybody was very crestfallen in England. But then we had some data in in the mouse in Robins lab, that showed that the gene that Paige had discovered was actually expressed in germ cells and not in the somatic cells in the mouse. And we knew that germ cells were not required for sex determination in the mouse, because you could eliminate the germ cells completely and still get male sex determination. So it could not be that the gene controlling insects determination was only expressed in the germ cells. So that made us think this is not the right gene, something's wrong here. So we began, you know, looking with Peter Goodfellows probes, sort of walking down the Y chromosome to see if we could identify another candidate gene. And we came across the SR YG. And it was a very, it was very interesting, because then when we use the mouse that Robin Lovell badge and Elizabeth Robertson had been had originally use the retroviral insertion to try to find the right gene, we discovered in that strain, the there was a gene on the Y chromosome that was completely deleted. And those mice were sex reverse to female. And that region that was deleted, covered this gene, SR y. So we were pretty sure that we had a correct gene. We also had a group of candidate humans from Algeria, that had deletions of the Y chromosome, at varying from, so there's a boundary with the X the region that pairs with the x, which is called the PAR, and from the PAR, downward, we had probes so that we could walk down the chromosome and see what was there and what was not. And a lot of these patients who were x y individuals that were sex reverse to female, white, no the other way around, sorry, there were x x patients that were sex reverse to male, we look to see what part of the Y chromosome those individuals carry.
And we sorted them. So when you get humans that are sex, reverse to male vary, it can be a hormone problem, or that is not really the involving the fundamental switch and sex determination. But if it's the gene on the Y chromosome, then the individuals that are of interest are the ones that have that boundary between the pairing region with the x and a bit of the Y chromosome, because it was known that the sex determining gene was somewhere not too far from that boundary. The the gene that David Paige had identified that if y was located about 200 KB down the Y chromosome from that boundary, but the gene that we were focusing on was located only about 40 KB. And the the patients that were sex reverse, because they had a piece of the Y chromosome all had breakpoints before you get to this F YG. Which was further evidence that said f y was not the right gene.
Nick Jikomes 12:43
I see. So So you were involved in the the identification of this very important gene that we'll talk about. And part of part of that identification came from sort of triangulating where it was on a particular chromosome based on these, these people from Algeria that had a rare genetic sex reversal condition.
Blanche Capel 13:03
Yeah, it's very, it was very exciting when we were able to, and I think in Peter Goodfellows lab, they had had these probes because they had been working on cloning regions of the Y chromosome. So they were able to basically walk down the chromosome and say, what's missing here? So it was really exciting finding,
Nick Jikomes 13:23
I think there's going to be a lot for us to unpack here. And roughly speaking, before we get to the how questions around the developmental biology of sex, I thought it would be good for people to kind of paint paint sort of a, a context for people by asking the why and the wind questions. And I was thinking maybe we could start with what might be a deceptively simple question. But what is biological sex? And when did it first of all?
Blanche Capel 14:00
I don't know when it first evolved, but it's very, very old. And I think two sexes. You know, of course, it really important for reproductive viability. I mean, hermaphrodites have existed also for an in many animal families for a long, long time. But there's limited genetic variability through selfing. That is through self fertilization. And the ability to have two sexes introduces a lot more genetic variability into the population. And so I think this is really was an important innovation. And I don't know the date for when people argue that two sexes first evolved.
Nick Jikomes 14:48
But admit, it's like hundreds of millions of
Blanche Capel 14:50
years, right? Yes, yes. Very long time.
Nick Jikomes 14:53
Okay, so it's been around a long time, and you get so the idea and I've heard this articulated before, but the idea for why it like why would why would organisms even evolve sexual reproduction? Asexual reproduction has many convenient features, right? You don't need to go find a partner, you know exactly what you're getting, because you're gonna have a clone. But basically, you're saying that one of the things that that lineages get so to speak, or why sexual reproduction might have adaptive advantages, has to do with creating extra genetic diversity.
Blanche Capel 15:23
Yes. Because when you are selfing, then you're just creating, you know, gametes with your own genome that's going to combine with gametes with your own genome. So there really is no chance for for, you know, mixing up the genome. And there's a lot of evidence that genetic variability is more adaptive, in particularly in changing environments that, you know, so one, even if some members of the population are disadvantaged in a changed environment, there will likely be members of the population that can continue the species because they will be adaptive.
Nick Jikomes 16:02
Yeah, that makes a lot of sense. Especially. I mean, you know, when you think about humans and other animals, you know, one thing that we can do very well is adapt to very different ecological contexts
Blanche Capel 16:13
we can and as a population, we can do that extremely well.
Nick Jikomes 16:18
So is it do most or all animals have sexual reproduction? Are there any animal species that do asexual reproduction or anything like that?
Blanche Capel 16:28
Yes, there are. There are many animals that do a sexual reproduction. I think the, for example, the worm C. elegans, which is a common laboratory model, the the species that makes oocytes also can make sperm, they're hermaphrodites, and they breed of as hermaphrodites or they can mate with males. So they can do either. And in some ways, that makes them an easy genetic model, if you want them to just self so that you don't have to change the genome. You don't get, you know, an altered genome and the offspring. But, but they can do either and they I think they're do they typically are hermaphrodites early in their life, and then they are, they have been they made later with males. They first produce sperm, which goes into a organ called a sperm or Theca. And it's at the end of the uterus, this organ. And so there are a lot of sperm in this sperm a Theca. And as the x come down, the oocytes come down the uterus, they have to go through the sperm a Theca, where they're fertilized, and then I think the sperm DECA can be refilled with by mating.
Nick Jikomes 17:58
Interesting. So there are there are some animal species that are that are capable of hermeticism. And additionally, they also still engage in sexual reproduction.
Blanche Capel 18:09
Yes. And lizards, some lizards are are hermaphrodites as well. So I mean, I think it's, I think many species use that method.
Nick Jikomes 18:19
I see I see and hermaphrodite here, what? What's the actual definition? Is that just when you have individuals that can produce both sperm and egg,
Blanche Capel 18:26
yes. A true hermaphrodite has a testis and an ovary, and it can have it at the same time or at different times in their life cycle.
Nick Jikomes 18:39
Interesting. And that's, I think one of the maybe one of the things that we'll talk about a little bit here is, you know, I was going to ask, you know, did did sexual reproduction evolve wants, like, is there one sort of way that sex is determined that evolved, and we all inherited that from a single common ancestor? Or is is the picture different?
Blanche Capel 19:01
So sex is involved evolved many different times, and the mechanisms are very, very different in different species. One interesting thing is that there are, we have sex chromosomes, so we have to go home with chromosomes that are hetero morphic. So they have different they're obviously different. If you do a chromosomal spread, you can find the X and Y chromosomes because they're the two chromosomes that don't match any other chromosome. The Y is much smaller than the X, but part of the Y and part of the X pair up together so that at meiosis, those chromosomes align together and then segregate an x to one cell and a y to the other. So we have XY chromosomes. There's also a different system of, of sex chromosomes referred to as z and w. And and these are by convention, z w systems have a female that carries the two different sex chromosomes and then the male is called a homo gametic sex, meaning that he has just two y's.
Nick Jikomes 20:18
I see. So that's like, it's like the opposite of mammals and humans.
Blanche Capel 20:21
Yes, opposite of humans. So, in the, in the in the XY system, males have an x and a y. So they are the heterochromatic sex meaning their gametes segregate with one of either of two types of chromosomes and X or Y. And the females are the HOMO gametic sets, meaning they only make one kind of Gimme that only if they all have an X. In chickens and, and other birds and bearded dragons, for example, their system is ZEW. And the female is the heterochromatic sex, so she's z w, and the male is z z. And just by convention, we call systems in which the male is the heterochromatic, sex as a x, y system, and systems in which the female as the heterochromatic sex as z w system. So interact.
Nick Jikomes 21:20
So evolution figured out at least two different ways to use sex chromosomes to give rise to males and females. And this happened this sort of happens in different ways in the bird lineage versus the mammal lineage.
Blanche Capel 21:33
Yes, and what's more, even in other animals that have an x y system, the sex chromosomes come from an ordinary pair of autosomes that just acquire a gene that influences sex determination. And once that occurs, that chromosome tends to acquire more genes that favor that sex. So for example, the gene SR y, which is on the Y chromosome and mammals see seems to have arisen by some changes in the promoter region, that allowed it to be expressed in the Indigo Natl somatic cells. So in the cells of the early gonet, where it began when fluence their fate, and to turn them into sertoli cells and turn the gonads into a testis. And the the mammalian sex chromosomes evolved from one ancestral autosomal pair, but the bird sex chromosomes derived from a completely different autosomal pair, as did the the bearded dragon. So they all come from different autosomes initially, and the gene that causes sex determination is different in different species.
Nick Jikomes 22:58
I see. So sort of like, I think, correct me if I'm wrong, what you're saying is, at some point in evolution, one of one of the chromosomes in in an animal will acquire some ability to do something to do with sex determination. And once that happens, the sex determining genes tend to concentrate in that chromosome and move literally to that chromosome, such that you end up getting what we now see a sex chromosomes
Blanche Capel 23:25
chromosome, and they can evolve and they can also disappear. They can erode. But you can imagine that if one if, for example, a sex determining gene lands on a chromosome, and that chromosome makes embryos that inherited male, then it the system will be propagated by the acquisition of genes around that gene on that Y chromosome that chromosome that produce more sperm or produce stronger sperm. So that means that that chromosome will be transmitted more often, because more individuals will be fathered by the individual that acquire that change. So sex determining genes tend to gather together when they promote the one sex or the other.
Nick Jikomes 24:22
Interesting, okay, so the sex determining genes tend to cluster on the same chromosome. If one gene helps turn you into a male anatomical plan versus a female plan. You'll also tend to get other genes such as those involved, I mean, presumably like sperm proteins and things that affect sperm motility and all that stuff. Yes. Interesting. And
Blanche Capel 24:43
that can happen in theory on any original pair of autosomes.
Nick Jikomes 24:47
I see. And so that was, yeah, that would explain why. In mammals and humans, you get x y for male, the heterochromatic sexes male, but it's flipped in birds and other animals. And so That. That brings us to an interesting question, I think so, you've got sex chromosomes playing an important role in the bird and mammal lineages. But you know what determines what determines whether or not you're a male is not whether or not you're the hetero comedic sex per se, because in one case in mammals it is and the other case in birds it isn't. So what determines male or female miss if it's not the sex chromosomes that you have?
Blanche Capel 25:29
Well, it can be determined by many things, it can be determined by environmental factors, if some species that don't have sex chromosomes, or have no sex chromosomes that we've identified. There sexist control by environmental factors that could mean population. In some fish, its population density, it can be ah, in the water, it can be. Other environmental cues like temperature is a common determinant of sex. And interestingly, these things can be superimposed. So in the bearded dragon, there are sex chromosomes there are there are ZEW sex chromosomes. But that species is sensitive to temperature. So at very high temperatures, dragons, that would be males ZZ dragons that would normally develop as a male. If they are developing at a very high temperature, they'll turn into females, the temperature can override the signal on the sex chromosome in this case. And this has been shown for a couple of species that even though they have sex chromosomes, environmental factors. In chicken, for example, they have sex chromosomes, they have CW six chromosomes. But if you put estrogen on a chicken egg, regardless of its sex chromosome constitution, it will turn into a female. Interesting. Yeah, so there's several intersecting pathways. Yeah,
Nick Jikomes 27:09
what's the system? One? Um, so one thing maybe we should do upfront here is we've already used some terms that maybe people aren't familiar with. Can you explain the difference for people between gametes, gonads and genitalia? The three G's here?
Blanche Capel 27:27
Yeah, so Okay, gametes are the cells that are produced that give rise to sperm and eggs. And they are a special cell lineage that is usually formed early in the embryo. And then those cells migrate to their position in the embryo, which is in the gonad. And they are they developed into sperm or eggs. The gonad is an organ that arises early in embryogenesis. And it's the only by potential organ. That is to say, it is an organ that arises and can develop into two different completely different organs, it can become a testis or an ovary, the same cells and the same initial little structure. So this is unlike other organs like kidneys, when a kidney forms, the cells that make up the kidney can only become a kidney, they don't have the chance to decide how they're going to be another organ. And it's true for the heart. But for the gonad, the gonad arises, this is unique by potential structure, which is what makes it so interesting to study from the point of view of Organogenesis. So trying to understand how our early organs form, the gonad is very unique, because it can follow one of these two pathways. And the pathway it follows typically controls the sexual phenotype of the organism. So it's the first at least one of the first dimorphic meaning different between the sexes, structure. And once it forms, it begins to produce hormones typical of what it has become if it becomes an ovary, it'll make estrogen. If it becomes a testis, it'll make testosterone and then the, the rest of the body responds to the hormone that is produced by the gonad. So the rest of the the or the animal will be feminized or masculinized, by the hormones produced by the gonet once the gonad makes the choice,
Nick Jikomes 29:41
alright, so So the gametes are basically the sex cells, the certain type of cell like sperm or egg.
Blanche Capel 29:48
They're a cell that's produced that that gives rise to eggs and sperm and the they migrate that they're called germ cells. That that form the guy meats eventually. But when they're just germ cells, they are also by potential and they'll migrate to the gonad. And the gonad has little niches little compartments to put them in. And then the gonad takes care of those cells, it surrounds the cells in the gonad, surround those special germ cells, and allow them to develop into eggs or sperm.
Nick Jikomes 30:21
I see. So the gonad is the special organ that you said it has by potential. So it can turn into either one thing or another thing, it can turn to either ovary or test this and make it unique compared to other organs, like the heart or the intestines are whatever, in that way. And I guess what determines which one it turns into is just some combination of sex chromosomes and genetic factors together with environmental factors, and the combination probably varies from species to species.
Blanche Capel 30:50
That's right. But that initial second decision within the gonad is referred to within the field as primary sex determination.
Nick Jikomes 30:58
I see. And it's primarily because it happens. It happens early. And then basically, you said that that then that then changes the internal environment based on the hormones that get released from from that organ.
Blanche Capel 31:10
Yeah. And the genitalia begins as a structure that's also by potential. It's not really in the same way, but that what happens is that it can either turn into female genitalia or male genitalia, but that typically depends on the hormones from the gonad. I see. There are a couple of known cases where it depends on the sex chromosomes and not the hormones. That's true in kangaroos and tammar Wallaby. So some marsupial's, the genitalia development is dependent on the sex chromosome constitution and not sex hormones. It may be that as things go forward, we will find more cases of structures or changes in development that are not dependent on the gonads but are dependent on sex chromosomes. Right now, we don't have a lot of examples of that. But I think there are some coming along.
Nick Jikomes 32:12
Interesting. Well, what about in humans? So what's the primary factor driving? Whether you develop ovaries or testis? In humans? Is that mostly a sex chromosome thing?
Blanche Capel 32:25
Yes, that's the SR y gene on the Y chromosome, same as in mouse. And my son humans are relatively are in fact, all of placental mammals are relatively insensitive to environmental factors. As far as we know, I mean, they are because development occurs in the uterus, they are protected from temperature changes, you know, pH differences, unaffected by population density, you know, they're, they're really protected from other factors that really influence the fate of other organisms, for example, that live in that are aquatic, where, you know, there may be a high level of estrogens and water.
Nick Jikomes 33:09
I see. So there's this natural buffering there just because of the internal fertilization that placental mammals have, has anyone done experiments where, you know, in mice where you just alter the in utero environment in some dramatic way?
Blanche Capel 33:25
Well, uterine environment is hard to modify. I mean, they can't change the temperature. And the placenta basically mediates a lot of the hormone balance to the Maria Excuse me, but I think that we have tried and others have tried to take out to take gonads out of embryos and culture them in a dish with extra hormones to see whether we can influence her fate. And a colleague of mine, Andy pasque, has found some evidence for this, but we found it very difficult to get any any convincing data from this. And it could be that we just the, the mammalian, the placental mammalian system is strongly buffered against against this in marsupial's, you marsupials, as you may know, only spent half of their gestation period in the uterus. They're born at mid gestation, and then they go into the pouch. When they're born. Their front end of the animal is very well developed. They have good claws, and they can, when they're born, they climb up the fur into the pouch, dragging the the back end of them, which is barely developed at all. I mean, their hind limbs are just tiny at the time that they're born. And then they develop from a sort of an equal period in the pouch before they're actually able to be independent. And if you introduce estrogens at the time they're born if when they're born a little early, so you have to hatchet with just the right time, but you can influence the fate of the gonads in marsupial's. Interesting, interesting, suggesting that, you know, maybe mammals are not completely resistant to estrogen, but it's difficult.
Nick Jikomes 35:13
Yeah, certainly much harder than than some of the fish and amphibians.
Blanche Capel 35:19
From most most egg laying species, particularly aquatic species, if you add estrogen to the water or estrogen mimics, for example, environmental toxicants there have been many studies, for example, in lakes in Florida, we are in the lakes near Disney World, there's a very high incidence of genital abnormalities and and defects in alligators and other species that develop in waters where a lot of plastic and yeah, and but whereas if you go to some of the lakes deep in the Everglades, you don't see that.
Nick Jikomes 35:57
Um, so one one question here that I think is interesting, and that maybe we take for granted is, you know, you've spoken about these by potential organs. And we talked about sexual dimorphism. But very simple question that that I've heard children ask before actually is, what why is it? Why does sexual reproduction involve two sexes? Why is it three or four or five? And where does this sort of buy potentiality come from?
Blanche Capel 36:29
I don't have an answer for that. But I think that our sexual phenotypes are a lot more diverse, than we've sort of appreciated in the past. We tended to think of sex as to bell shaped curve out on the end of a spectrum. So one pile of females over here in one pile of males over here. But actually, I think there's much more overlap between males and females. The more we learn about sex determination, the more we find that there are many factors that influence the outcome, many genes and that are segregating in the population. And so there's a all females are not. There's a lot of variation among females and a lot of variation among males. And there's probably a tremendous amount of overlap between these two bell shaped curves in the middle, where we have sexes that we are beginning to appreciate is just different Not, not we, it's reflected in the terminology. So we used to refer to DSD, we now speak of them as differences in sexual development, but we used to call them defects and sexual development. And I think that this kind of terminology is much more inclusive of what we actually see that, that sex is not such a bipolar principle.
Nick Jikomes 38:00
I see. And how many? So when we think about sex cells, you've got sperm and egg? Is there ever? Are there ever intermediate sex cell phenotypes? Are there ever separate ones? Or is it just those
Blanche Capel 38:13
two? There's just those two. And in fact, you know, in mammals, in most species, we have developed an elaborate internal organ system for managing the ductile tracks from the gonads to get the gonads out to the outside world, right? I mean, to get the germ cells out to the outside world, the gametes are, are protected inside the gonad as they grow into eggs or sperm. And then we develop elaborate sex ducts that take them from the testis of the ovary, outward in the world. So you know, the ovary ovulate, so sites, they're picked up by the oviduct, and carry to the, through the oviduct, where they're fertilized, and then into the uterus where they implant and grow. And in males, there are elaborate ducts around the testis, in which the sperm that's released from the test is travels and is modified as it goes through all the mail ductal system, until it can swim fast and and has a highly modal tail and so forth. So there are many. There's a lot of development that goes on in the sperm, as it travels through the male ductal system, until it's ready for ejaculation and is competitive to fertilize and OSI. I see. You know, these systems are highly evolved for mammals and for every other species, though, many of them work differently.
Nick Jikomes 39:41
And so in terms of like, how some of the stuff happens, focusing on humans and mammals, so humans have the x y system, x y is associated with male development xx is associated with female development, and that has something to do with which of the two You gonads develops out of this by by potential primordial origin that you spoke about. So can you start to describe in simple terms how that actually happens, like what does it have to do with a Y chromosome and where to learn to some of these interesting genes start to come in.
Blanche Capel 40:16
Okay, so as our y, it turns out, is a transcription factor. Now, transcription factors are proteins that bind somewhere on a chromosome and activate another gene. So it triggers when fry is expressed, it binds the region around another gene called Sox nine. And that gene has a lot of targets that are involved in causing the cell is active and to differentiate as a sertoli cell sertoli cells are the key cell in the testis, they lined the inside of seminiferous cords, which are characteristic of the tests. And so expression of socks nine and the genes it act it's also a transcription factor that activates a lot of other genes. And so there's a cascade of gene expression from SR y coming on to sucks nine coming on and then sucks nine, activating five or six other genes, maybe more, we don't know yet. But that causes those cells to commit to a sertoli fate. If S R y does not come on, those same cells will commit to a granulosa cell fate that's the cell in the ovary that forms ovarian follicles that surround Oh sites. I see. So the cells that the by potential stage seem to be primed to develop as cells in the ovary. So they seem to be on a track to become granulosa cells in the ovary. But if the SROI gene turns on in those cells, it will divert their development towards sertoli. Cell.
Nick Jikomes 42:00
I see. Okay, so So you've got this bio potential organ, it's inherently able to go one way or the other, turn it to either ovary or test this? Yes, yeah, if this one gene is around, which is on the Y chromosome, which which, which is associated with being male and mammals, this protein is transcription factors present, that's sort of like a master switch that turns on a bunch of other genes or turns off a bunch of other genes. And that pushes you towards becoming testers rather than ovaries. And if you don't have that, there's just sort of some kind of bias to become ovaries by default.
Blanche Capel 42:33
Yeah, might be involved. We're not sure of that yet. But that's kind of what it looks like. And at the moment, and it turns out that the gonad is itself by potential. But it turns out that the cells within the gonad each cell type is also by potential. So that's what makes the whole organ by potential, but there are at least three general cell types in that early organ, one of them can become either a sertoli cell or a granulosa cell in the ovary. Another one of them is called the steroidogenic Progenitor, it's the cell that can give rise to cells that make testosterone or cells that make estrogen. And then there are the germ cells that I've already told you about that that can become either sperm or oocytes. And it turns out that the donor site, the early germ cells, take on the fate of the organ they find themselves in. So that means that if they, regardless of their sex chromosome constitution, if they migrate into a structure that's forming an ovary, they'll become oocytes. Whereas if they migrate into structure forming a testis, they'll start developing along the sperm pathway.
Nick Jikomes 43:48
I see. So so is the reason that so when we identify a mammal as male versus bird, that's male, you know, in the one in the mammalian case, the male will be hetero comedic. So x y in the bird case, it would be z z, z, z z. But what makes them both male would be the identity of the gonad that develops,
Blanche Capel 44:13
yes, I see identity develops, yes.
Nick Jikomes 44:18
And then the gonads starts to develop, and the gonads are producing themselves sex hormone. So is that where sex hormones really start to come in and play a role here?
Blanche Capel 44:27
Yes. And then the sex, the sex hormones will influence the development of the genitalia the sex ducts. So initially, mammals are born with to completely not born so are they formed with two completely different sex duct systems. And they are present in animals that are x x and x y. The same, the same two ducks are present in both. But if you're, if you're gonna and begins to develop as a testis, then the testers will produce factors that cause them, the duck that's going to become the male ductal system to form properly, but it will cause the other ductal system that would be the female ductal system to degenerate completely. And the reverse is true in animals that are xx and form an ovary. In that case, the male ductal system is not supported, and so it degenerates and the ductal system that can become the female ducts, that is the oviduct in the uterus, will will grow because of inflammation from the ovary.
Nick Jikomes 45:36
When we start to talk about sex hormones, like everyone has heard of sex hormones, everyone has heard of testosterone and estrogen, I don't think a lot of people know exactly what they are. So what are sex hormones? And what do they actually do at the cellular level? How do they actually like exert their effects?
Blanche Capel 45:54
Well, they're usually small molecules that bind to a receptor on the surface of a cell. So many cells have receptors that sit on their surface and stick out into the environment. And when secreted factors come along, they can bind, they can recognize their right receptor, and get transported into the cell. And then once they're in the cell, they often in combination with their receptor, also act as a transcription factor that can go into the nucleus and bind the DNA somewhere and activate more genes.
Nick Jikomes 46:27
Okay, so so some of these sex hormones, at least they actually bind to a receptor, and then that that whole structure can actually go into the nucleus and determine whether or not different genes come on or off. That's right. Interesting. So what I mean, are there any major? Why is it so important? That? How is it that like the ratios of the sex hormones are important for determining the subsequent development of different aspects of sexual phenotype? Is it because the balance of say testosterone estrogen makes different genes come out enough?
Blanche Capel 47:05
Yes, that's right. So if many, for example, the, your the cells that form your genitalia initially, before it's become male or female, they are responsive to hormones, and in most species, and they have receptors on their surface, so they can detect estrogen or androgens, and they will differentiate in a different way the cells will express different genes and turn into something different, depending or not, on whether or not they sense those hormones. Interesting. And the balance between them. I'm not sure that's understood so well, at the level of the whole organism. There must be some sort of competition going on, between receptors that detect one hormone or the other, or perhaps even the binding sites on the chromosomes. It's, I don't think it's completely clear how competition between the two hormones works.
Nick Jikomes 48:07
And in the beginning, when you were talking about some of the history of some of the discoveries here, you mentioned that you had these interesting people from Algeria, that had some kind of interesting phenotype that had to do with the sex chromosomes, can you can you actually explain that a little bit more and what was actually going on there?
Blanche Capel 48:28
So we we had access to a group of patients from for some reason, there's a high incidence of sex reversal among these patients, and we receive samples, just DNA samples from the patients. But the patients had been identified as x x. So they had the chromosomal phenotype of a female, but they had developed with at least some testis tissue. And as I said earlier, that that can occur, we had about 200 samples to start with, was sent to us. The trouble is that, that sort of development so if you come into a clinic, and you have some aspect of male development, for example, your genitalia is not clearly associated with male, classic male or female genitalia is what usually seen first or females that don't go through menses, so they don't start menstruating. And so the mothers take the children to the doctor, and they find out well, actually, there's some sexual variation here. Anyway, so these females had, or would have been female xx individuals had differentiated with some testis, like parts of their gonads. And so they came to our attention, and we initially, we needed to sort through them a whole stack of 200 samples to figure out which ones might be informative for our purpose, which was to find the SR YG. So we, we hypothesized that some of these individuals were sex reverse to male because they had a piece of the Y chromosome that carried the gene, the sex determining gene. And we wanted to find among the 200 samples, the ones that we might look at more closely and find out what region of the Y they add.
Nick Jikomes 50:30
I see. So somehow these individuals had some piece of the Y chromosome, even though they were otherwise in chromosomal terms have the female configuration? Yes. Right. And how common is this type of thing where you have a sex chromosomal abnormalities, like one 101 and 1001 a
Blanche Capel 50:48
million? I'm terrible at these kinds of numbers, but it's not that common. I think this is maybe one in 1000 or so for this sort of sex chromosome abnormality.
Nick Jikomes 50:58
And, I mean, presumably, this can happen in multiple different ways, because I know that you can be like, X X, Y, or have different different things. And does this does this tend to manifest in is this, this tends to manifest in in sexual phenotypes that are just not clearly associated with a classic male or female phenotypes,
Blanche Capel 51:23
they can manifest in that way. And many other differences in sex development can arise as a result. You know, for example, there are there's a problem called Congenital adrenal hyperplasia, where the adrenal gland produces just really high levels of androgens during gestation, and that can cause an XX embryo to be masculinized. So that when she's born based on genitalia, it would be hard to assign her as to a classic male or female genital formation. So that that's one of many other disorders. That is, that's not a chromosomal disorder that's genetic, one gene that causes that but there are many other cases where the sexual phenotype can be altered. Many of them are hormonal. So for example, the classic one is individuals that like black and androgen receptor, you know, I told you that there's a testosterone receptor, it's really called the androgen receptor. And if you have a mutation in the androgen receptor, even if your x y, and you develop a normal testis, the cells that normally differentiate based on the hormone environment can't sense the hormone they can, they don't recognize the testosterone. If without an androgen receptor on the surface of those genitalia cells, they develop female because they don't have any influence from the test. This is making testosterone but they can't sense it.
Nick Jikomes 53:03
Alright, so the detectors for the home hormone are absent. So even though the gonad has gone one route, the male route, the other cells that would normally respond to that testosterone level in, in the developing organism just can't respond.
Blanche Capel 53:19
No, they can't respond. So they go, they develop his female genitalia. And, but the tests but the gonad has become a testis. And in this kind of a mismatch it's you know, I think that the individuals usually infertile because the genitalia and the sex ducts don't match the sex of the gonads. So and as I said earlier, these systems are highly evolved to work together. gametes from the gonads out to the outside world. And so
Nick Jikomes 53:56
that makes sense. So if if the gonad develops on one route, but a lot of the secondary features that that develop downstream of the hormonal environment that set up by the gonad, if there's that mismatch, there, it often result results in infertility. That's right. I see. And then, um, one area that's fascinating to me, and I don't know if this is your expertise, but I have a neuroscience background too is these things can also affect the brain, right? I know that sex hormones are involved in you know, going inside of neurons and affecting how the neurons develop, can you start to talk about how, because because, you know, it's easy to think about two phases of development, I guess there's the early phase, where you're an embryo and then you're born, and then or two or three, and then there's, you know, in humans, we have a childhood where after we're born before we become sexually mature, and then of course, puberty happens, and then sexual maturity results. So how do these sort of different time time segments of development start to hook into each other and what for example, determines, like what and puberty starts or how that starts.
Blanche Capel 55:03
I don't think that's known very clearly. But I think there are a lot of people working on it are very interested in the whole issue of brain sex, to sort of put it in its broadest, broadest concept, that means maybe what your sexual identity is what you think your sexual identity is, there's also a part of brain sex that has to do with what partner preference you have. Those things are really not what I work on. They're sort of outside my expertise, I really just basically work on the initial sex determination step within the gonet. But but I'm also fascinated by these questions. And I think we don't actually know when brain sexual identity is, is acquired. Whether part of it is happens before birth, or whether it's, it's, it mostly happens after birth, I think we don't really know. There are some differences in the brains between males and females. But it's been very hard to decide which of these is influenced somehow by, for example, chromosomal sex, versus hormones, you know, so the hormones definitely have an influence on the development of some of the cells in the brain. And some of the preoptic cortex is no, yeah, pre pre optic areas is the region that I think is most Ben Smith strongly associated with differences in the cellular composition, and so forth, that that are associated with xx or XY individuals. But I don't think any of the evidence for brain development is, is really solid at the moment. So I think it's still people are still trying to figure figure this out. One interesting line of research that is currently being followed is, is what differences occur between XX and XY cells that might inherently tell them something about their identity. B beyond what the gonad is telling the whole organism. This has been highlighted by work in the chicken. That if you have a few more minutes, I'll tell you about oh, yeah, absolutely. Chickens can develop into what are called gynandra, morphs, which are individuals that are male on one side and female on the other. Many birds can do this and other arthropods like lobsters do this. And fruit flies do this, where one side of the animal is just it's bilateral. One side is an in birds, you'll see birds that have male plumage on one side and female plumage on the other. And this is a really unusual fate. And based on the ideas that I've been telling you, it's just that once the gonads decide what they are, and they make hormones that bathe the whole body and estrogen or testosterone, you would expect this kind of thing to be impossible. You know, you would think that the whole body would get behind one plant or the other. But it turns out that in gynandra, morphs, this doesn't happen. And there seems to be a divide down the middle. Recent work in these animals suggests that the side that they likely arise through meiotic defects that give rise to where an egg is fertilized by two sperm and you get a maybe fertilization after a division so that you have some animals that have that carry the Z chromosome and some animals that have two x's themselves that have this z XZW, and the others that are two ZZ. So it's been shown in birds that when this occurs, typically one side of the animal will have a predominance of one cell type and the other side of the animal will have a predominance of the other cell type. And it has been hypothesize that for example, Z zw cells can sense their environment, their hormone environment differently from z z cells. Interesting. And that might mean an intrinsic sensor system. Sensing System in in the cells, and people have been looking for this in mammals, but it's really been hard to understand. You know, there are experiments showing that xx or XY embryonic stem cells have different properties, and particularly in terms of their epigenetic regulation. So it could be that our our XX and XY cells have intrinsic differences that we don't understand yet.
Nick Jikomes 59:45
Interesting. So So there could be intrinsic differences, meaning that the cells are different irrespective of like the hormonal environment they're bathed in, but we really worked out what those details are.
Blanche Capel 59:58
And in mammals, even if You are an even if you are an individual that is a mosaic of XX and XY cells, your you will not have bilateral differentiation, it doesn't happen in mammals, or very, very rarely. So in that case, the whole body gets behind one plan to either have female characteristics or male characteristics. And so we don't quite understand how this is working. We know that, for example, you can make an X X, you can turn an x x animal into a male by expressing the SROI gene in the early embryo.
Nick Jikomes 1:00:39
Obviously, just that one gene,
Blanche Capel 1:00:40
just that one gene, right, all you need to do is introduce that one gene into an XX embryo when it first forms. And it will get expressed in the gonad. It will turn the gonet into a testis, and the testis will turn the animal into a male.
Nick Jikomes 1:00:57
Interesting, and that's been done in rodents.
Blanche Capel 1:00:59
That's been done in mice, right? It's now been done. I think in other species, I'm trying to think what but I think also in sheep or
Nick Jikomes 1:01:08
something like that, I see. Yes, that's goes back to what you were explaining before, you have this by potential Oregon. And it sort of inherently it can go either way. But it's kind of got this bias to become female. But if you have the SRR y gene, that sort of this master switch that makes you go in the other direction, right.
Blanche Capel 1:01:25
And in that case, you realize the whole body is x x, all the cells in the body are xx, and yet they follow a male differentiation program. So if the X and Y chromosomes in mammals are, are influential in how cells sense their fate, it can be overridden by hormones. I see. But this is a point that is worth I think, spending a few more minutes on. I think sex determination is very complex and reinforcing system with many feedback loops, autoregulatory loops and when a gonad embarks on the testis or the ovary pathway, many of the genes that are activated, their role is to suppress the other pathway. So once a gonad decides to become a test is that is the cells decide to become sertoli cells, those cells will shut down the granulosa cell pathway. And it's true at the individual cell gene network level. It's also true at the whole, all the cells in that organ will do the same thing. So there's there are a lot of feedback, root loops and self reinforcing loops that tend to what we call, we refer to it as canalization. But that means that you train the organ into one little canal. But basically, you're trying to get the organ to develop as either a testis or an ovary. And there can be intermediates. But the most reproductively advantageous is that you form either one
Nick Jikomes 1:03:09
thing or the other. I see. So you've got this by potential state. And you get these gene regulatory programs and cellular mechanisms that turn on such that, you know, the the term here is cannibalization, you become catalyzed towards one pathway or the other. And it sounds like what you're saying is because in a sexually reproducing species, you know, it doesn't really do much from from a reproductive standpoint to have like, half of one system and half of the other you kind of want to go down one pathway or the other one.
Blanche Capel 1:03:39
Yeah. Because if you form a testis, but you don't have an epidemis and a vas deferens to direct the sperm out for fertilization, it's not going to do any good. So I think that that individual won't propagate.
Nick Jikomes 1:03:54
So interesting. Yeah, that makes a lot of sense. I know. I know, there's a lot of interesting examples in like fish and other animals were in the adults, if I'm not mistaken, at least under the right environmental conditions, they can actually do a sex reversal. Is that true? And what? Like, how does that actually work in those
Blanche Capel 1:04:15
organisms? Isn't that amazing? So yes, this is true. And many fish do this many reef fish. It's very common. And they can either develop first as males, which is called Pro Tan dras. Or they can develop first as females which is called protagonists. And in that case, they exist as males, for example, for some part of their life and then they switch to females, they can switch as a normal sort of process of their development. A common laboratory animal is zebrafish and zebrafish develops all zebrafish, first produce oocytes, and then some of them switch to producing are. So they're protagonists, they start as females, but many other fish start as male, and then they either switch or they don't switch depending on the cues from their environment. And this can be triggered by lots of things. But very often, fish maintain their sex based on their hierarchy and their school. Typically, there's a very dominant male, who subdues the other fish in the school, the females are, are fertile producing oocytes, and laying, but the males, the other male fish in the school are not developed. So they remain teenagers. And if the male disappears from from their view, then one of them will, one of the either the males or the females will differentiate into a dominant male. And that usually depends on the size and the dynamics in the school. So if it's a female, it will be a very large female who has a dominant role in the school so she can become the male. Or one of the immature males can develop into a sperm producing male and dominate the school.
Nick Jikomes 1:06:11
And you said that switch can happen when the dominant male is hidden from view. Now, my question there is, is it really the view, my naive guess, would have been that there's some kind of hormone secreted, but is it actually the visual system here, that's
Blanche Capel 1:06:25
your right, everybody thought it was probably hormones, he was, you know, some fear mode that he was secreting into the water. The key experiment was putting fish in cages, luring them into tanks where there's a cage in front with the dominant male, and there's cage in the back that contains all the other fish in the school. And so then they and everybody was performing like they should be. But then they lowered a curtain between the dominant male and the cage of fish in the back. And when those fish couldn't see the dominant male, one of them sex reversed. They're all in the same water, still in the same water, but they can't see the male. So this is the experiment that led us to the conclusion that the dominant male is dominant, because he is doing, he's performing in some way that suppresses the development of the other fish, they, they see him and they know he's dominant entry challenge him, by the way, in many species, sort of, for example, African cichlids, those males are really, really busy because they guard the nest. And they're being challenged all the time by other males. So males have a cyclic hormone surge every day. And when the other males in the group have hormone surges, they'll challenge the dominant male. And so he asked to keep running out to tell them no, no, I'm still the dominant male, and, and sort of beat them back. And then one day he loses control. I guess he gets worn out, he's got to guard the nest to he's busy guy.
Nick Jikomes 1:08:05
Interesting. Yeah. So what what does it mean? Like what does it mean, at a high level for? I mean, we've got sexual reproduction has evolved so many different times in across the animal kingdom. And yet, you've got all of these different ways of determining sex, all of these different mechanisms that have evolved. What does it mean that on the one hand, sexual reproduction is is so common, and has evolved so many times, but and yet, it's it's sort of different in all these different lineages?
Blanche Capel 1:08:36
I think it's the I think it's the nature of the of the way the system is a balance between two competing networks. That can be driven by minor differences in one of the if you think of it as factors piled on a fulcrum on a scale, you have a pile of male factors over here and a pile of female factors over here. And when something evolves, some mutation that causes a very dominant gene to emerge. It can wait one side, so it goes towards male, for example, and it represses the female pathway. But then you could have another gene evolve that's stronger than this one that pushes toward the female side. And it outcompetes and now the female pathway is triggered. I think it's easy in a system like that, where there are a lot of reinforcing loops, and a whole network of genes that's driving either side. And new new genes emerge all the time and evolution and they can cause a shift in the way this balance behaves. But since it's self reinforcing, and there's so many genes in the network, and they are also repressing the alternative pathway, I think it's just a fertile ground for the emergence of new genes that can influence the system.
Nick Jikomes 1:09:55
I see. Yeah. And if I sort of play with that analogy, you know, I can imagine that Uh, you know, if the lineage is committed to sexual reproduction, meaning asexual reproduction is not possible. If you know, you have to keep the fulcrum balanced because if it goes one way, or then you've got all males or all females and the lineage is going to die. So it sort of makes sense in evolutionary terms. I think that to keep it balanced, you sort of need many different nodes that can be tweaked and played with in order to prevent it from getting too lopsided.
Blanche Capel 1:10:26
Yeah, I think that's true. But I think it also really is permissive for the emergence of the new genes and fish you see this all the time, many fish have very different systems with different genes at the top of the Cascade. But something else that's interesting that we haven't, we haven't understood yet really is even downstream in the network. So I should tell you that the, the structure of an ovary and the structure of, of a testis are pretty similar across species. Like if you do a section of a testis in a pig and compare it to a human, you wouldn't really see that much difference. Even in a turtle a test, this looks like a testis. And yet, the way of getting it is so different. And you would think that the formation of organs would be, you know, stereotypically it would be very highly conserved, the gene cascade that gives you those structures should be similar. It turns out that there are many of the same genes involved, but they're expressed in a different order. So it's as though somebody shuffled the genes. But they're still working. So I think this also suggests this very complex network system with lots of nodes, lots of so that, you know, there may be one prominent node in one species, but another node may be prominent in another species. And I don't really understand the reason for this.
Nick Jikomes 1:12:01
Interesting. So you were mentioning how like, you've got all these species of fish and other critters, that can have a strongly that our second termination pathways are strongly sensitive to environmental components, that could be the social structures that the fish are in, it could be pH of the water, or temperature, with certain reptiles and things. And the reason that's not the case in mammals made a lot of sense, the I mean, we have internal fertilization, the environment is made purpose and placental mammals to be constant. So you just you have a constant environment, it's sort of engineered in from the beginning. One thing that's interesting about humans and primates, I suppose, and maybe a couple other creatures is, we have not only long periods of extended development that happened after birth, but also, in the case of humans, right? Like we can manipulate our environments in ways that other organisms, that doesn't even occur to them, they just can't do it. So like, for example, we can use things like exogenous steroid hormones, we can use things like puberty blockers, do we know anything about how those things affect development that happens in humans after birth?
Blanche Capel 1:13:20
Um, it will, it depends on when they're given. You know, I think the original development of your sex ducks and your genitalia occurs in utero. And then it is amplified a bit in puberty. So depending on exactly when you get these treatments, it will have a greater or lesser effect. I don't think we really understand quite how they fit into the whole cascade very well, as I said, I'm not sure we understand puberty, except that we know some of the things that trigger it, but I don't think we really understand how that works very much yet. So I think we we are using these blockers as you know, but this is very common in medicine, that we use something that works along before we really know why it works, or how it works. But I think we have a greater appreciation for the range of sexual phenotype than we used to. And a greater, I don't know, tolerance, for lack of a better word of this kind of variability. You know, we used to judge we used to judge very harshly individuals that were not clearly in the male or female pile. And now I think we appreciate their differences. And usually they are associated with often with very high creativity and all kinds of other features that are really good things. So I think, you know, and increasingly there will be ways to do achieve reproduction or achieve fertility. Even when you don't have the classic development of a testes or an ovary. I mean, lots of people are working on the formation of synthetic gametes. So maturing eggs and sperm in vitro, or even building a testis or an ovary as an organoid. That can then be in culture, which might even someday be able to house and mature the germ cells into eggs or sperm. That is a goal of a field called synthetic embryology. Or a lot of people are trying to figure out how we can do that in vitro. This, of course, associated with a lot of ethical considerations, that I'm not really qualified to get into at the moment. But, you know, I don't want you to think that scientists are blind to the ethical concerns if we begin to make eggs and sperm in vitro.
Nick Jikomes 1:15:58
But do you think that's it's scientifically possible that like, within, within a human lifetime, we could have the knowledge and the technology to essentially create an embryo a fully viable embryo that grows and develops into a baby, and a completely engineered external environment, it's external to an actual human body? Well, I
Blanche Capel 1:16:21
don't know about a whole baby. But I think an Oregon is achievable. I mean, we already have methods that are, have taken us a long way. And a lot of people are working on a generation of a gonet. Because it seems that germ cells need to go in that environment. And we don't understand, we don't understand all the reasons why. So in the absence of the knowledge of what to add to them, to make them feel comfortable, or at home, and in a dish, the best approach seems to be to produce the cells that give rise to a test a certain ovary and, and then give the germ cells to those cells and say, Okay, you take care of them, you obviously know how to do it. So the idea is to build the cells of the gonads, and then see if we can introduce germ cells, we can already generate germ cells, or germ like cells from induced pluripotent cells or from embryonic stem cells through a series of molecular steps. So we know how to generate the germ cells. And then it's a question of maturing them. And so far that I would say that has been. I'm not yet convinced that we've got, we're there. But I think we probably will be there in another 1010 or 15 years.
Nick Jikomes 1:17:39
I see. And so you said we don't really know much about the mechanics of how puberty is happening. But we do we know, we do know something about like, what triggers it? Is it like a hormonal levels thing? Or what do we actually know there?
Blanche Capel 1:17:54
Well, it's, it's triggered by estrogen in, in females rises in estrogen. But I what I mean to say is that I'm not sure anybody really understands why it occurs when it occurs. At least I don't like but I don't I mean,
Nick Jikomes 1:18:13
I see so but it has something to do with with sex hormone levels reaching a certain level. Yes. Yes. I see. I see. And so when, like, when when people use something like a puberty blocker, what are those drugs actually do? Is it preventing? Is it like a receptor antagonist for the sex hormones? Or what's the actual mechanism of action there?
Blanche Capel 1:18:34
I don't know what people are using. I know people are using hormones or hormone treatments. But I don't actually know what the what the puberty blocker they're using is. And probably gonadotropin from, you know, because the pituitary the hypothalamus is probably what's controlling all of this. And so I think it blocks messages from the hypothalamus.
Nick Jikomes 1:19:00
I see. I see. And you mentioned that, you know, this might be a burgeoning area of study, but there's potentially some some interesting epigenetics going on, in terms of epigenetic regulation of cells with based on which sex chromosomes they have. And I've been talking about epigenetics, broadly speaking with with a variety of speakers recently in different different contexts, metabolism, aging, and things like that. But what's you know what's going on right now, in terms of epigenetic regulation of sex determination in mammals? Are there any exciting questions being asked?
Blanche Capel 1:19:35
Yeah, lots. So we found a few years back that turtle sex determination, which depends on temperature, is controlled by an epigenetic enzyme that regulates whether or not the male pathway is activated. So I don't know whether our listeners are familiar with epigenetic regulation but it base simply means that the chromosomal DNA is modified in some way. So that when transcription factors come, they can either bind the site that activates a gene or that site is blocked by modifications to the DNA. What we found in the turtle is that a gene that controls the removal of those modifications to free up a site for transcription factor to bind. That gene is regulated by temperature and the turtle. It's, it's a very interesting pathway, where temperature actually influences channels in the cell that open and close. They're called trip channels, and they open and close in response to the temperature the cell is in. And when they open, they can like calcium into the cell. And when calcium comes in, it starts a network that activates this gene. And the gene then goes and modifies the chromosomes. And that's what allows the male pathway to turn on and turtles. In mammals, the gene also has a role. We haven't actually published this yet, but we get partial sex reversal when we reverse when we disrupt the gene in mammals. So we're following this up to figure out whether it has co activators? Or why it's partial.
Nick Jikomes 1:21:20
Interesting. Yeah, I mean, there's so much diversity here. That's amazing. Yeah. And like with, you know, with the reptiles and the fish and stuff, it makes sense. I mean, it just makes perfect sense that you have all these environmental inputs, just because right there, eggs are external, they're touching the environment in a way, the external environment in a way that that mammalian embryos don't. So pH sensitivity, temperature sensitivity, you mentioned also, I mean, this is another sort of, I guess, environmental concern, like you mentioned, and I think you said in Florida, where there's a lot of human activity and human stuff that gets into the water that can actually affect things like alligator development.
Blanche Capel 1:21:57
Again. It's worrying, yeah. Along with climate change.
Nick Jikomes 1:22:04
Yeah. Yeah, that's another big one, too. Yeah, is that actually has that been documented or like, in places where the temperature is clearly rising, for example, like that, you know, if all the reptiles are now boys or something,
Blanche Capel 1:22:17
they're all girls, girls. Among sea turtles, I think they haven't found a male and a nest in Florida in the last two or three years. Oh, wow. So the temperature is just too warm for males, they develop at a lower temperature. And in the in the turtles, and the temperature has just been too warm. It's true in Australia as well. But what's been seen in Austria studied in Australia, which is interesting is that males from the very southern tip of Australia, have now started swimming up to the breeding grounds for the females in the north, where the temperature is very warm. As there aren't any, there's no competition up there. So the males are swimming up from the south to to fertilize the females in the northern part. And maybe they'll bring a different gene load that will just say, maybe, in this sort of recombination, amazing recombination system we have in, in, in bisexual reproduction, we will generate animals that can adapt to the temperature. That is to say, a new gene will involve in the network that can cause males to develop even at high temperatures.
Nick Jikomes 1:23:29
Interesting. Yeah, that's, that's fascinating. Yeah, so the seat of the male sea turtles in some parts of the world have discovered, they've discovered the ultimate vacation spot. That's right. So in, in mammals, in placental mammals, especially, we've got this sort of amazing buffering system in the uterus, you've got the placenta that's that regulates work and kind of go in and out of the in utero environment. Are you? Do you have any concerns at all about like, the modern human environment based on our diet and based on pollutants affecting human development and sexual development? Or do you think that the placenta protects us mostly?
Blanche Capel 1:24:13
Oh, we haven't studied at much in terms of sex determination, a little bit. People in the fields of toxicology are looking at this. But there certainly is a lot known, for example, about the effect on germ cell biology, so men who drink a lot of alcohol, it affects the epigenetic regulation in their germ cells. And so a lot of this work is going on right now. It's called determinants of I don't remember the name of it, but anyway, it's just looking at how environmental impact from smokers or from people who have a lot of alcohol or are obese how that affecting the development of they're often the most pronounced effects are in the germ cells. So for some reason, the germ cells of their embryos are being affected. So that means not the generation that is currently developing in the uterus, but their offspring will be affected.
Nick Jikomes 1:25:21
I see so so a lot of the the sounds like a lot of the details are to be worked out. But it seems like it's we're getting fairly clear signals that there's some kind of epigenetic mechanism at work with all these kinds of things.
Blanche Capel 1:25:31
That's right. And it's, it's clear that the environment does influence the development of mammals in utero, it's just a little more subtle and difficult to get out than it is in a pond system, you know, with aquatic species.
Nick Jikomes 1:25:50
I see. I see. And it is, are there any general records, the plus I don't really know much about placental biology at all. Obviously, there's a lot of stuff. You don't want to get through there. But some stuff has to get through. So what are the kinds of things that generally get through the placenta?
Blanche Capel 1:26:08
nutrients, it's an exchange system from waste from the embryo gets out that way, and nutrients come in water. immunity from the mother, all kinds of things do get through the placenta. But it it I think it does filter the hormone environment considerably. So I think some hormones get into the embryo, if you over overload the mother, but I think very, it's hard to do that. I see it as acts as a break,
Nick Jikomes 1:26:42
I think, yeah, so so it's a filter, but it's probably not a perfect filter, like there's probably stuff that we're eating or drugs that we take prescription drugs, like there's probably some stuff that gets through.
Blanche Capel 1:26:53
And, you know, pregnant females can't take a lot of different drugs that do seem to get through the placenta. And it's pretty clear that metabolic influences also happen. So obese females, there are effects on on offspring also, effects on setting the metabolism of the offspring. Based on the mother's metabolism,
Nick Jikomes 1:27:22
RC, so aspects of metabolism can get set, which are not based on genetics, but they're based on the in utero environment. And that would mean that, you know, from the moment of birth, you know, the child's metabolism has been sort of biased in one way or the other based on the mother's previous diet. That's right.
Blanche Capel 1:27:39
Wow. Yeah. I mean, this is this was found kind of a long time ago with when studies were done of women who were starved during pregnancy during the war. And it was found that their offspring had metabolism setpoints, I believe that allowed them to exist on very small amounts of food. Wow. So I think that now, you know, obese women have offspring that whose metabolism is set by their previous experience in the in the womb. So I think it really is going to give us a lot of food for thought about what can happen to our embryos. Yeah. And often it skips a generation and moves to them. Because if the germ cells are, so the germ cells, I think I told you earlier, germ cells migrate to the gonads, while the gonad is still forming, and that's during fetal life. So your baby that's developing, if you're pregnant, your baby is going to be forming their gonads, and their germ cells are going to be there, all through their fetal development. And so those germ cells, which are going to form your grandchildren, will be affected by whatever you're doing during your pregnancy.
Nick Jikomes 1:29:02
Okay, so there is really something to think skipping a generation, at least in some cases. Interesting. One of the things that I thought was interesting that you mentioned at the very beginning, this, I'm always interested when people switch, like switch from science to non science or the other way or kind of switch careers and do two different things. You mentioned something interesting at the beginning, you said you were an art history major. And you wanted to be a novelist. And then you became a scientist. What can you talk about that a little bit more? What actually triggered that? What actually what actually prompted you to make that transition?
Blanche Capel 1:29:38
Oh, I don't. I think that you know, for some reason, I guess when I graduated from college, I thought it was going to be easy to just sit down and write a novel. But it turns out that's really, really hard to do. And especially if you have a couple of toddlers crawling around. And I think that you I sort of you know, I had children when I was pretty young. And then I just got involved in in their nursery schools. And then, you know, up until about first grade when I was so involved every day, I didn't have time to think about anything else. And I think then by then I was really ready for a different experience. And I had gotten over the idea that I was going to sit down and just write a novel any any day now. And I thought, you know, it would be really interesting to pursue something like science. But even then, I didn't really think of it as a career, I thought of it as an avocation, I would do that just because I needed something really interesting to be doing with my time. I've often told a story about volunteering for a, it was some sort of an event where we were meant to bring things for the tea room, and we sold them, you know, with tea to patrons and earn some money for the school, I can't remember what we were doing. But anyway, I had brought some brownies to donate. And there was this very officious woman there who was trying to show me how to cut the brownies. Because I apparently wasn't cutting them into exactly even squares, and she thought the clients would complain. And so she was giving me very precise instructions about you know, that I needed to cut them this way. And I was thinking, I'm not doing this anymore. Do this, I can't do this with my life, you know, I just, if somebody's going to tell me how to do something, it needs to be something important to you know, teach me surgery or something, don't tell me how to cut the brownies. So I decided I was going to do something else. And I and I just enrolled in a genetics class at Bryn Mawr, but had a fantastic teacher. And he kind of woke me up again and made me think, so much fun to be thinking, you know, to have to think about things. It's such a lot of fun. And you feel really alive. And I think after you know, eight years or so with toddlers, you anyone would recognize that feeling is just really welcome. And I just got more and more involved. By the time I went back to school, my children were in past first grade. So they were in school until three in the afternoon. So I had most of the day free. And then things just went on from there. I kept really liking it, I would take the next class and I think, Oh, this is great. Maybe I'll take another one. And then at some point, somebody said, Look, why don't you go to graduate school? And oh, you know, what do I want with graduate school? I mean, I did not imagine that I was headed toward a career. In fact, it took me a really long time to decide that I was actually going to go for a career in academic science.
Nick Jikomes 1:32:47
Yeah, you. I mean, in many ways, you did things the opposite. Like when I was in grad school, a major dilemma I would hear about from female students was, you know, if they wanted to have kids, they would think about having them like later because they wanted to get through. They want to get through all the schooling and stuff first, but you actually did it in the opposite direction. And it kind of worked out seemed like,
Blanche Capel 1:33:08
it did work out. But it was an accident. I mean, you know, I didn't know I was gonna go to school when I had to. But it was a good thing, really. Because by the time I got into graduate school, you know, one was in high school, and the other one was, I don't know. I don't know. 11. So it wasn't as though I had very small children. Yeah, that makes sense. Yeah. And I was lucky, I was able to get help during the day, to pick up people from school and stuff like that, it is definitely challenging to, you know, keep all the balls in the air. Because, you know, you've got, you still have to take care of the children after school, like, you know, and often experiments don't work that way. But I was really lucky, I was able to work it all out. And, and, and I loved it. I just loved it. So it was really, it was a matter of just continuing with something that I found so exciting and rewarding. And, you know, fun, fun, really fun thing to do with my life. I really think you should go to graduate school if you really, if you really enjoy doing it. And not if you don't, you know, it's it's a commitment. And most of the time things don't work. You know, I don't know what you would say, but I guess maybe 70 or 75% of experiments don't work. Yeah. And it can be really discouraging and frustrating.
Nick Jikomes 1:34:35
What, what are is there? Like, are there one or two exciting projects that you're working on right now? Or one or two big questions that that you don't like to ask people? Like, is there a big question right now that you're working on or that some of the people in your field are working on that we don't know the answer to but maybe in the next two or three or four years we will probably learn something
Blanche Capel 1:34:59
um Well, I, we have several really exciting projects from my point of view. But one of the things we're trying to understand is is what controls the female pathway in the gonads. So we know that as I said earlier, the gonads seems to have a bias toward female development. And then S R Y comes along and turns it into a testis. But we don't really know what's at the top of the female pathway. And I think we're really interested in seeing if we can figure that out. It's been hard to get at. And so it's not, it's not yet really clear what that is. But we're excited about that project. In turtles, were really, we've been looking at germ cell biology and the turtle, and we're really interested in how germ cells are affecting the sex determination pathway and turtles. And we've been working on that. And also lately. We're also very interested in male germ cells in the mouse. We have some evidence for post transcriptional regulation, that means RNA binding proteins that are involved in controlling germ cell fate, developing sperm, we're interested in that process too. So I think we have a lot of we have a lot of things, different things happening in the lab that that I'm very excited about.
Nick Jikomes 1:36:21
Interesting. Well, this has been fascinating. Dr. Capel, you know, this is an area I think we probably could have talked for even longer because I know there's a lot of different stuff, especially with all the diversity between all the different animal types. But I think this is an area to that, that people want to learn more about, and I definitely learned a lot. So thank you for your time.
Blanche Capel 1:36:39
Thank you, Nick. It was really fun to talk with you. I'm so glad you called me about this.
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