I don't know if you appreciate what to me is one of the most fascinating facts in the world, which is, regardless our cell body and how we look like. Regardless if an animal looks like that and it has tusks, or it swims in the ocean and has stripes and gills, or it has wings and lays eggs, and lives as a worm for a while, or the woman and man's body which are slightly different. All these diversity was generated at some point because we all came from a single cell. So, at some point, we all were one cell, nothing but one cell. And that one cell had to grow in number, because clearly we're composed now for more than one cell. And on top of that, these cells that were generated out of this one cell, and we'll see what that is and where it's come from, had to differentiate to form the different organs and the different parts of our body. Whatever they had to do that at the right place, at the right time. Grow enough food on your head, it's only good if you are an octopus, but it's kind of useless if you're a human. So, all that has to happen somehow out of this one single cell. And what I'm going to show you it's a movie that I don't know how many times I show this, because I show it also in my undergrad class, but I don't get tired of seeing it. What you're going to see on the screen are these little balls. And these little balls are nothing but an embryo that is a two-cell stage. So, it's one stage later than this one single cell I show you. So, for example, this is one cell and that's one cell. So, this was an egg that was fertilized, was allowed to divide once. And what you're going to see now, it's how these two cells become an animal with an eye, with muscles, with something that swims. So, you will see this marvelous process right now. And I have to say, I have to thank Ali Brivanlou from Rockefeller University, which is the person that provided this slide. Okay, are you ready? So, what you're going to see at the beginning is nothing changes in size. What happens is there's a rapid increase in the cell number. So, you will see these dividing into little squares, little squares, little square. Then, it's going to move, it's the process called gastrulation. And out of gastrulation, there are the three germ layers, she mentioned one of them. And out of that, you get organogenesis, organs form. And out of that, you get a tadpole. So, pay attention, it's important. This goes fast. But this is to me, the most fascinating problem in biology. So, this is dividing, dividing, dividing, dividing, dividing. Now, soon it will start gastrulation, you will see they have some streaks. Gastrulation, a lot of cell movement, see that's where the neural tube is going to be. Now, this is shaped into something that you're familiar with. And these things go out, and they're still swimming, and they have an eye, and they have a brain, and they have muscle, and they have gut, and they're done. So, we, as humans went through a very similar process. And there's a quote in embryology that it's not married, it's not graduation, the most important part on your life was going through that. And I think it's true. Without that there is nothing else. And we did it successfully because we're here. The issue that becomes obvious now is that we want to do that again in the lab. And that was where I was saying that it's so difficult. And it's frustrating because a tadpole can do it. But, it doesn't matter how smart we think we are, it's extremely hard to reproduce and control in the lab. So, the question in stem cell biology now that we can isolate stem cells, it's how to get them to do these at will. The day we learn how to do this and control it at will in the lab, we will have a chance of generating cells or organs to study, or maybe replace in the future. So that is the motivation for this. That's why we have to understand developmental biology, that's how we can apply developmental biology. So, to me, the distinction between applied science and basic science doesn't make any sense. If you're studying embryology, which could be as basic as understanding why did you get a eye, it became absolutely necessary to apply stem cell technologies to the clinic. So let's revise. And the first part of the talk, we're going to see how these things happened. What can we do? And what happens in IVF clinics, which are important for the beginning of this process. We get into a window of what we do in the lab. And we're going to end on a controversial topic I guarantee you from now. But, I will give you all the background you need to know to then make your own judgment. This is where the story starts. There is a sperm that meets an egg. Each of these contain half of the genetic material. They fertilize. They form this one single cell where we all come from. And what you saw it's basically from the cell, a lot of growth in cell number and differentiation into cells that combine to form tissues and organs. An organ, it's a combination of tissues that it's a combination of multiple cell types. So, for therapies, sometimes we will like to make a particular cell to study. Sometimes, even for transplantation, we wil like to make a particular cell. But sometimes, that's not enough. And when it's failing for example, in a patient, what we're interested to study is how these cells interact with each other in a particular organ, or we need to replace that organ. So, there's an extra layer of complexity. Making a neural is not making a brain, just making a neural. So keep that in mind, please. And also, because we are at the American Museum of Natural History, I think it's important to also consider some historical aspects of science. And particularly, after this march for science and this question of what science means. And science is the best explanation we have right now for the reality we perceive. And the beauty about science that we can challenge that, not only we can challenge, we should challenge it all the time, and we should come up with hypotheses. If I would have given you this talk few years ago, the process that goes from this to that would have the been following. The sperm contains a little human. And that little human that comes within the sperm, he's been fed by the woman, the egg, and host in the womb for nine months to develop. And that was science at the time. So, we were allowed to challenge that model. And I think it's important to understand that this fits the cosmovision at the time, woman could not be important at certain part in history. Thankfully, we changed that. But I think it's important to keep in mind that everything we do, it's our understanding our model of reality right now. So, let's go back to this. Let's see how we understand this process now. The sperm contains half of the genetic material we need, the other half is provided by the egg. The sperm for the purpose of this, it just delivery of half of genetic material. It's the least important player in this equation. We are becoming dispensable as a male, as the half of the gender. And at fertilization, there is this half of genetic material that you'll receive from your father, and half of genetic material that you'll receive from your mother. They combine and fertilization makes this zygote. And it's this zygote that will continue. So, keep in mind that to go from an egg to a zygote, you need a complete genetic complement. By the way, in nature, there are species that can go without a sperm and they will generate haploid animal, which contains half of the genetic material only from the mother. Do you know an example of that? Who had honey in the last three days? Yeah. So, what happened to the male? The drone comes from an unfertilized eggs, and there are sharks that can do that, and so on. So, again, we are, like I'm at home absolutely dispensable. So, what happens after these? There is fertilization, there is complete genetic material, and it's this zygote that starts differentiating and growing. And we're going to pause in another important stage in early development, which is called blastocyst. And this blastocyst that comes after the zygote, so the cell number increase. And now you can see it has two structures, an outer structure and an inner structure. The inner structure is called the inner cell mass, and the outer is a trophoblast. The inner cell mass, it's what will develop into the embryo that it's basically us. Does anybody know what trophoblast make? We all carry the scar from it. We all carry something that shows we had it at the time and we don't have it anymore. The placenta, exactly, we all carry the bellybutton. The scar of the umbilical cord on the placenta that we lost soon after birth. And this is an important distinction because, although this is a full embryo, only the inner cell mass contributes to our adult body. And that will become relevant when we think about where the stem cells come from. I'm going to make a little detour now, and we talk about something that we will link to stem cell derivation for a second. So, think about this. This is the whole embryo. So IVF clinics all the time do these. They get a sperm from a donor or from the father, they get an egg that they retrieve from a woman. They combine them in vitro, so they fertilize them in vitro. They allow them to develop up to this stage, blastocyst. And this is the stage that they transfer into a woman for a pregnancy. So a success IVF, the first step is doing this. And good quality blastocyst, and you might have heard that have two purposes. One is the transfer back to the female, and good quality ones that are not being used for transfer are being frozen to keep for the future. So, when women go back to get another one of these, they are retrieved from a freezer. So kind of a delayed twin, because there were fertilized at the same time. There's one trick that you may have heard in the news not long ago and I thought it was a good time to bring it, which is these mitochondrial replacement therapies or something like that. And so, one of the things that I was telling you, the sperm comes from a man and the egg comes from a woman, but Diego also carries these little organelles called mitochondria. And the mitochondria carry their own little genome. So, they have DNA in them. It's called mitochondrial DNA. And sometimes, that DNA carries a mutation, and because mitochondria are really important, they provide energy for the cells among other things. So, mitochondrial defect. It's kind of a nasty thing to have. So, if they would keep going and merge the sperm with the egg and lead this to develop, the cells that will produce the embryo, also the placenta, will inherit these defective mitochondria. So, IVF clinics can do this trick, like very special allowances, only about three times, as far as I know. They fertilize the sperm with the egg, they get the egg that has now the genetic material, that is the combination of this man and the woman that donated the egg. But this woman, also had a genetic following the mitochondria. So, the eggs carry these defective mitochondria and a trigger that can be applied you will see it applied a few times in this talk, you can take that nucleus with a genetic material that is combination of these two, take it out of these and now get a second female that donates an egg with normal mitochondria, in-nucleate that, remove the nucleus, and now you have the two pieces again. You have a full genetic complement, not half, because half plus half is one. And now you have an egg, that doesn't have any genetic material. So, combining these two, now you reconstitute an egg with the full genetic material, and now you allow this to develop, and now you will inherit the mitochondria for the healthy donor and not the one. So, that it's basically what you've heard the news not long ago about mitochondrial replacement therapies. They're going to see a couple of tricks with these, so that's why it's important that we introduce one step at a time. The normal protocol is the one now, in IVF clinics. Sperm, egg, zygote, blastocyst. And we say that these it's what it's transferred to females and the embryo itself, as will be generated for some that is called "the inner cell mass". And the inner cell mass it's right before this very important step called gastrulation that you saw in the movie with cells start moving around, and this is the first big big big big differentiation of cells into different layers. Basically it's like a commitment's tech. And so, importantly, at this stage there was not a huge commitment, into what part of the body each cell would generate. And it's from there, that two things can happen. This is allowed to develop and forms an embryo, or these. It's taken into a tissue culture dish. The inner cell masses amplify, and that's an embryonic stem cell. So, now you know how to get embryonic stem cells from a research, for example. They come from IVF clinics. So, this will be the protocol. That's called the moral, this is the blastocyst, the inner cell mass, taking out these are disintegrated and they are played in wonderful conditions and goodies that took a lot of time to develop. Because if you think about it, these cells can become everything, can become every cell in our body, and they would like to do that. You can grow them forever, as long as you're careful and you grow them in the right conditions. The moment you're not careful, they will differentiate into whatever they want to be. So, it's an in vitro artifact. We are freezing, artificially freezing this step in development, this inner cell must state in the line. That's a whole trick and we can cultivate those and we can keep them frozen in this state. And because they are frozen in that state, at some point, 0 is saying, we can give them the right conditions to see if we can aim or we can differentiate them into different cells of the body. So, the task now, you already know the logic how to derive embryonic stem cells. The big task now is how to make these embryonic stem cells to do something we want. Short disclaimer and I'm going aside, where these blastocysts is coming from. Where, you know, they are coming from IVF clinics. And we already mentioned that this good quality blastocyst are being frozen or transferred into females. The rest are discarded. So, there are two ways that can be discarded. They can just be discarded or they can be just discarded in the process of generating and Vernick stem cell lines. These can, for example, be either just bad quality blastocyst and nobody would transfer, or it could be blastocysts that were screened because both parents carry a mutation and they wanted to be sure that their child doesn't curry that mutation. So, out of all the blastocyst they produced in vitro, maybe some of them carry a mutation that will cause a severe disease. So, they choose not to transfer that back into the woman, because they choose not to have a baby with that disease. That blastocyst becomes an invaluable resource for the scientific community, because now we can derive an embryonic stem cell with the genetic makeup of a human disease. And it's been used to study what goes wrong, what could go wrong and what can be done to improve the survival of a given organ or cell. So, the blastocysts that are used to the right embryonic stem cells, would have been discarded anyway. And for the people in the audience that are old enough to remember some of the controversies a few years ago, where make believe that they were, how was the sentence he was used, "They create life to destroy it". That's not true. It's illegal to do that. One side note and I'm not going to make a judgment of what you consider life or not. She's going to say that we should have. And this is more. I'm preparing for what I'm going to tell you at the end, which we didn't learn much from the past, we let things go too fast before we all engage in this conversation and we engage in the conversation as a scientist. We take the fall. After that was outrageous tainment. Now you generate creating life to destroy. People will ask me "Would you put babies in the blender? What do you do in the lab?" And the answer is no, you use embryos that were destined to be destroyed anyway this blastocyst. That will never generate a baby, because they are so defective. That will be a miscarriage. So, those things happen normally. And everybody old enough knows people that 50% of the women may have had a miscarriage at one point. So, this is one of the things that doesn't go wrong. So, nature does it all the time. No, it's not a lab, f reak thing happened. The other one is, when you consider what's a life or what's not, when a life start. One of the things to consider is the legal implications of that. And please remember this, because we're going to come back with that. Once something is legally defined as a human life, it has a consequence. The easiest thing to explain is the firefighter. There's a building on fire. There's a kindergarten in the fourth floor. 400 toddlers. There is a IVF clinic on the second floor. This is life. Human life. The IVF clinic has a thousand of these in a liquid nitrogen tank. The firefighter is forced by law to take the action that will save the greatest number of life. If he or she has to choose to the one of the two. 400 life, toddlers, a thousand lives, freezer. By law, he's forced to save the greatest number of life. So, what we call life or not, has not only moral, but also legal implications. Keep that in mind. We're going to come back to what we call human life at the end in an unexpected way.
