Advisor Spotlight: Embryology
Words from our advisors on early development, stem cell models, and the potential of artificial wombs.
In our quest for reproductive freedom, we seek out advice from the very best. The scientists we consult with have expertise from multiple areas, enabling us to obtain input to tackle the toughest challenges.
For this piece, we chatted with two of our advisors: Alejandro Aguilera Castrejón, a Group Leader at Virginia’s Howard Hughes Medical Institute Janelia Campus, and Guojun Sheng, a Professor at Kumamoto University in Japan. Each contributes a different kind of expertise, from Aguilera Castrejón’s pioneering work with roller-culture machines that can keep mouse embryos alive at the very earliest stages to Sheng’s broad perspective on evolution of embryo development informed by decades of experience working with bird embryos.
What follows is an edited and curated version of our discussions.
Let’s start with a question for both of you. What drives your interest in embryology?
Sheng: I like seeing things change from simple to complicated. I can play a movie of how embryos develop for any organism, and I can make sense out of it, from one single cell, a fertilized egg, to a complicated organism. I’m interested in trying to figure out, essentially, how to make an embryo survive from simple to complicated, and how each different tissue and organ type evolves and connects to each other. So a sort of holistic view of embryogenesis.
Aguilera Castrejón: When I started, I studied biology because I like animals. I didn’t know that you can be a scientist on the bench, inventing technology. I was thinking more of watching animals in the jungle, something like that. But then during my bachelor’s degree, I discovered molecular biology, and then developmental biology, in particular, the potential of stem cells. The biological mechanisms of how the cell has the ability to form a body is very interesting for me.
Professor Sheng, can you say a bit about how the research you do in your lab differs from the research of other labs in the embryology field? What makes your lab special?
Sheng: We study a process called gastrulation, that’s the transition from pluripotency. When you have fertilization you have cells which are actually pluripotent, meaning they can become every part of your body, but at some point they have to decide to not stay pluripotent, so they have to differentiate, and there is a sort of stereotypical way of differentiation, so that the whole thing can evolve as an organism rather than a cell in the cell culture. So gastrulation is the most important kind of developmental process, transitioning from pluripotency to three germ layers: ectoderm, mesoderm and endoderm, and then from each germ layer you have more specific lineage differentiation, eventually giving rise to the lung, kidney, eye, brain, whatever.
Dr. Aguilera Castrejón, the pluripotency of stem cells is also very important to your work using mice to study embryology. In particular, it enables a powerful research tool, stem cell embryo models. Can you say a bit about what they are, and what kinds of research they are enabling that couldn’t be done before?
Aguilera Castrejón: In general, to get an embryo you need to put together a male and a female mouse, they mate, and then the egg is fertilized and you can study this fertilized egg. But of course the source is always the mice, right? So there is an ethical limitation on the number of mice that you can use.
In the case of stem cell embryo models, by aggregating different populations of stem cells that you grow in a petri dish under specific conditions, these cells will talk to each other. Then they will self-assemble into a structure that really looks very similar to an embryo. The advantage of this is that you can study the process of how the embryo self-assembles just from cells in the dish.
You had an important role in the development of the roller culture machine, used to grow both mouse embryos and stem cell embryo models. Tell us about the impact that has had on the field.
Aguilera Castrejón: Before, it was basically impossible to test whether stem cell embryo models can grow to more advanced stages, because there was not a stable protocol to grow even natural embryos. Now we know that we can culture these natural embryos to very advanced stages, which open a window for mechanistic studies of live mammalian embryo development during gastrulation and organogenesis. So this allows us to test whether the stem cell embryo models have the same capacity to grow as a natural embryo.
Curiosity-driven research is important, as is helping patients. What are some of the ways that a better understanding of how embryos develop can advance reproductive medicine?
Aguilera Castrejón: Now, if you see that there is a fetus or a baby with a specific disease, it is impossible to correct it, especially while the embryo is developing. In the future, if we create systems that allow you to maintain the fetus alive until term in vitro, if you detect a fetus or an embryo that has some genetic defects, then you can take it out of the womb and treat it to correct the disease. We know that it’s impossible to put it back in the womb, but maybe you can keep it alive in this ex utero system and then this will allow you to have a healthy human being in the end. So, I think that’s a very long-term goal, but it could make a big impact. Besides, the basic research for understanding organ formation during development that ex utero culture allows will certainly help for regenerative medicine purposes.
Professor Sheng, while Dr. Aguilera Castrejón’s lab works with mouse embryos, your lab studies bird embryos. Birds can do something that most mammals currently can’t: gestate outside their mother’s body. How well do we understand that process?
Sheng: That’s a very interesting thing.
Even in chickens you have the interface between embryo and environment. You need oxygen the same way the embryo needs oxygen, and the organ that you use to get oxygen is called the chorioallantoic membrane. Then you would imagine that whatever signal is being secreted from this tissue for an oviparous animal like a chick, there’s no maternal tissue to stimulate, right? So it can only stimulate the embryonic growth itself. And if it’s in a viviparous animal [an animal, like a mammal, that bears live young], then you have signals which can influence both the fetal side as well as the maternal side. So if you look at the genes involved in some of these, signaling is actually quite conserved there. Which means that what we think of as essential for fetal-maternal interaction in humans or in mammals, it’s probably built upon some system which was already present in the ancestor of mammals, and we’re building upon this already-existing kind of signal to strengthen the fetal-maternal interaction.
From a comparative embryology point of view, the placentation process, the fact that development needs maternal input, looks like it’s a novel thing for so-called eutherian mammals, placentals like us. But if you really think from a comparative embryology point of view, it’s actually not new. There are all sorts of intermediate things. Many reptiles have so-called live birth, and many reptiles also have nutritional absorption from uterine secretions from the mother, which is more or less like what we know of mammals. And you have mammals which have a minimal amount of the nutritional acquisition, like monotremes for example, and also not a very robust kind of fetal-maternal interaction. You have different ways of getting the maternal nutrition, uterine histotroph, which is to get the nutrition from uterine secretions, or hemotroph, meaning that you get nutrition from maternal circulation, but in a way that is different from the human cases, so-called hemochorial placentation mediating the fetal-maternal interaction. For example in pigs and horses they have very superficial implantation, they don’t have invasive implantation. So it’s a whole spectrum of things. Meaning that everything is okay as long as you meet some basic needs. Essentially, the embryo needs food and the embryo needs oxygen. The embryo needs an aqueous environment, and the embryo needs some way of getting rid of metabolic waste. And amniotes [a clade containing mammals, birds, and reptiles] can do it in a more or less conserved way.
As advisors for e184, you bring your expertise to advance our research. What attracted each of you to work with e184?
Aguilera Castrejón: I think that e184 is very realistic. There are many companies in the ex utero field but a lot of them are already trying to sell that they have machines for humans. And I think in order to see something like this in humans we need to do a lot of tests first in animal models. So I like that from e184, that it’s setting goals to establish a solid background for the field first in animal models, in order to be able to translate it later to humans. I think that’s something that attracted me to work with e184.
Sheng: For me as a more holistic view, I tend to be skeptical. “Interesting, but can it really work?” right? But thinking about it another way, a lot of things can work. You can have a cell from plant tissue and grow the whole plant out of it. So it’s not impossible: multicellular systems can start from a cell and then can recapitulate the whole thing. Then the challenge is, is it really possible for humans, or for some primate, or for eutherian mammals to achieve that…and I feel that the time is kind of right.
It takes a combination of the right mixture of people, that’s very important, and I think most individual labs or individual universities or individual schools of thinking, it’s probably not enough. It takes something that can lift a little bit up, from a slightly higher perspective.