Magdalena Zernicka-Goetz is the Bren Professor of Biology and Biological Engineering at the California Institute of Technology and a Professor of Stem Cell Biology and Development at the University of Cambridge.
In this interview, we discuss recent advances in technologies that allow us to use stem cells to create embryo-like structures with a brain and even a beating heart in a dish. We explore how these ‘synthetic’ embryos are built and the limits of their similarity to natural embryos grown from fertilized eggs. She also explains how they can help us understand why pregnancies fail, how to build organs from scratch, and even how to rejuvenate aging bodies. But first, she reveals the key insight that has allowed us to grow these embryo models in a dish longer than ever before: that the cells that will make up the body cannot do it alone.
What is a synthetic embryo, and what can it be used for?
FUTURE: To start off, can you explain what a synthetic embryo is?
MAGDALENA ZERNICKA-GOETZ: I actually don’t like that term much, to be honest. It’s confusing because people will wonder, what is this made of?
But we use it because it’s a shortcut to say that we’ve synthesized an embryo-like structure from building blocks. In our lab, we use three types of building blocks. One building block reflects the stem cell for every single type of cell that will build our adult body. It’s called the embryonic stem cell. And the other two building blocks are stem cells for so-called extraembryonic structures. One of them is famous, it’s the placenta. This is the one that connects the baby with the body of the mother through which the baby will be fed. The second one of these extraembryonic structures is less famous, but it’s called the yolk sac. That’s a kind of sack in which the embryo will grow.
Broadly, what are some of the things we might want to do with synthetic embryo models?
So, for example we’ve shown that these models can be used to understand the function of specific genes that are critical for some stages of development. We know, for example, there’s a gene that’s important for brain and eye development. But we do not know exactly how it functions from real mouse embryo models, because we cannot follow the whole process from the beginning to the end so precisely. So now you can use embryonic stem cells, in which you can eliminate that gene and find out more about the stage of development this gene is important and for what. You can also eliminate these genes at different time points and see the consequences.
It will not be able to grow and develop as we do, but it can give us important insight into the fragments of life that at this moment are a total mystery.
We can also look at the role of a particular environment or particular metabolites. For instance, pregnant women are advised to take folic acid as it helps neural development. But at which stage exactly it is important, what does this really do?
Is there an opportunity to better understand why so many pregnancies end very early, given these models simulate the same early development stages?
Yes, absolutely. It’s very important to realize that the majority of pregnancies fail at the time when we don’t even know we are pregnant. The first two weeks of development are very fragile because there are major milestones that have to be achieved at the right time.
First, we have to produce stem cells for these three tissues that I mentioned, two extraembryonic, one embryonic. We have to create them in the right way, and then those tissues have to interact with each other. But time also matters. You cannot extend pregnancy to, say, 15 months. This shows that particular milestones have to be achieved at particular time points.
Only one stem cell type really builds the body, but the other two are guiding forces, a little like a mother and father.
So when these developmental milestones are not occurring correctly, or they’re delayed, or occur too early, embryos are aborted. Or when the communication between those three types of cells is somehow abnormal, or not happening at all, again, embryos become aborted. That’s why so many pregnancies fail. So now, with these models, we are able to look into how we can protect the baby within the body of the mother. That’s the hope and that’s a very important motivation for me.
I wish to stress though that right now we are talking about synthetic mouse embryo models. But obviously, this is a sort of prototype for building human embryo three-dimensional models but even then it would not really be a human embryo. It will not be able to grow and develop as we do, but it can give us important insight into the fragments of life that at this moment are a total mystery.
So where are we with human synthetic embryo models or even culturing in vitro human embryos?
So, human embryo models are not yet there. There is not yet a whole embryo-like structure built from human stem cells, to my knowledge. When we started to build stem cell-derived mouse embryo models many people asked why we aren’t doing it with human stem cells, and I’m sure that many of my colleagues are trying to build a similar model using human stem cells. But it’s not trivial. First off, human stem cells and mouse stem cells do not develop in the same way. They need different conditions to be maintained in culture. To really make sure that we know how to do it, the mouse model will be a prototype.
Nevertheless, many people, including us, use human stem cells in culture to build three-dimensional tissues or fragments of embryos. We use them to understand, for example, how the amniotic cavity (the closed sac that contains the amniotic fluid), forms. Would we be able to correct its development when it goes wrong?
But it’s only a fragment of the human embryo, a model at the early stages of implantation in the uterine wall. Right now, we can culture human embryos only until so-called day 14, this is the limit where we cannot pass.
Creating embryo-like structures in the lab
That’s fascinating. So, how do you create the mouse synthetic embryo?
The way we build these synthetic embryo models in our lab is kind of unique. We developed this approach through understanding how the embryo builds itself in natural life, and we use the lessons from the embryo to mimic that process in the lab in a petri dish.
So we use the three types of stem cells. We try to put them together in the right proportions, create the right environment so that the three types of cells, and the cells that will arise from them, are happy and wish to communicate with each other.
That’s what’s essential: to use three types of cells–not one–because normally development happens through interactions between three types of cells. Only one stem cell type really builds the body, but the other two are guiding forces, a little like a mother and father.
I’ve never described it like that before, but you could think about it this way because these two other types of cells provide instructions and signaling information, but they also build a sort of a home for the embryo to be nourished.
Let’s rewind a little bit. This field has made a lot of progress in the last few years. Can you tell me what the really important landmarks have been in terms of making progress towards building this embryo model?
I have to say two facts that are well known. First, is that embryonic stem cells can be maintained in culture and propagate in culture indefinitely. This was the discovery of Martin Evans, who got the Nobel Prize for it. We knew that if you take a few of those cells, and put them together with an embryo, they would be able to contribute to adult tissues.
So we knew that stem cells have this magical potential. But what we did not know, and what was a breakthrough about 10 years ago, was whether we would be able to build embryos from those cells exclusively, without the host embryo. It was not like a sudden thing, of course, it was step by step. But the way we learned how to do it was by first observing how the embryo does it.
There is a stage of development that is very early, called the stage of embryo implantation, that we know very little about, particularly for humans. The first few days of development before this stage are pretty well worked out. The three types of cells I talked about arise within these first few days.
[These] models are not only important for us to understand embryogenesis, but also important to understand the genesis of particular tissues that build our adult organs. We are trying to identify the basic rules that have to be fulfilled.
After these three types of cells are formed, they start to talk to each other. But how they communicate was not well known, because this is the time when the embryo invades the body of the mother, during the process called implantation. We couldn’t mimic this process in vitro, so we couldn’t observe it. So, our first step was to develop a way of culturing real embryos, mouse and humans, through that stage in the lab.
As soon as we were able to achieve that, we were able to follow the cells, label them, and track them to identify the time when they multiply and interact with each other. When we followed those events, we realized that now we knew enough to be able to mimic these events with stem cells representing the three tissues.
It was a journey, and the first, most important milestone was to work out how the embryo does it. In particular, realizing that the embryo takes instructions from the two extraembryonic tissues. So far, we’ve built five models by adding different combinations of extraembryonic cells to the embryonic ones. The first model was published in 2014, and the last model was just published.
Tell me about this next step. What has been achieved with this new model in terms of how far the embryos progress and what you can see in them? And, how do they look compared to a fertilized egg that develops into an embryo?
The last model now develops until the moment that the head, heart and somites (segments along the body axes) form. This is incredible, because we were not sure whether these embryo-like structures would be good enough to achieve these milestones. All the progenitors of the brain are there, and the heart structure beats and pumps blood.
The lessons from the early embryo can also teach us how to rejuvenate tissues, because embryonic tissues are young tissues.
So how similar are they to natural embryos? They are very similar, but not identical. This is very interesting, because then you can follow the development of the models that are nearly identical, and those that are not, to understand the basic principles that we have to fulfill to make a particular type of tissue or organ perfect.
That’s why those models are not only important for us to understand embryogenesis, but also important to understand the genesis of particular tissues that build our adult organs. We are trying to identify the basic rules that have to be fulfilled for these events to be accomplished properly. You can start to work out what’s going on, and since you are allowing the embryo to build itself, you can work out the mechanisms of that process and when they go wrong.
Where synthetic embryos might lead
Tell me a little bit more about what you, personally, want to do with these models. Are there particular questions or challenges that you want to address?
My major interests are twofold. Number one is to understand how life is created. So, I use this model to try to really understand this mysterious phase of life when the cells communicate with each other, for the first time, to build something as complex as ourselves. But this is also the time when the majority of pregnancies fail. If we can understand this, we would be able, in the future, to help prevent those failures. This is our hope.
It’s a little bit like how to build a house, right? You don’t rely on the building blocks to sort themselves out.
The lessons from the early embryo can also teach us how to rejuvenate tissues, because embryonic tissues are young tissues. So it teaches us about building our organs and building tissues. Hopefully the knowledge from these studies — step by step — will be used for transplantation of organs or repairing organs in our adult bodies, when they fail.
Are there existing roadblocks, either technical or in our scientific understanding, that are holding back the development and use of these models?
Yeah, there are, mainly around the technology of creating the embryo-like structures. When we put these three types of stem cells together, we rely on the forces between them to create the proper embryo. Sometimes that goes well, sometimes that doesn’t go well. We see this variability of structures. So, we will have to develop tools to better control these events.
For instance, at this conference I’m currently attending, I spent time discussing optogenetics with a colleague. Using light, he can stimulate particular responses of the cell. So, can we use these optogenetic approaches to help us guide the process of self-organization?
To guide the process in what way?
To engineer specific events. For example, when we think about creating tissues and organs that can replace damaged ones, to do it efficiently we would need to understand how we can engineer them. It’s a little bit like how to build a house, right? You don’t rely on the building blocks to sort themselves out. Or, if a building was less than perfect, that would be unnacceptable. We’d like to guide the building process to give quality control.
So, we are not capable of being engineers or architects yet. We are instead trying to create an environment for the embryo to build itself and understand this process and follow it, and help it or perturb it. But we are not yet in the process of tissue engineering. Tissue engineering is very, very important, and it will be the future of organ replacements. So many patients wait for liver transplants, or other organs that are failing, and this is really tragic. If we can create and repair those organs by using the knowledge that comes from our studies, it will be absolutely incredible. What we do and what many of my colleagues do–so called bioengineering of tissue–is where it’s going to go in the future.