Scientists Grow “Synthetic” Embryo With Brain and Beating Heart – Without Eggs or Sperm

From mouse stem cells, researchers from the University of Cambridge have built model embryos with a brain, a heart that beats, and the building blocks for every other organ in the body. It represents a fresh way to recreate the beginnings of life.

The embryo model was created by the study team without the use of eggs or sperm, under the direction of Professor Magdalena Zernicka-Goetz. Instead, they made use of stem cells, which are the body's master cells and may differentiate into practically any form of cell.

"How we've come this far is absolutely astounding. Our community has long held this as a goal, and after ten years of hard effort, we have finally achieved it. (Magdalena Zernicka-Goetz)

The researchers imitated natural processes in the lab by directing the three varieties of stem cells that are present in early mammalian development to the point where they begin interacting. By increasing the expression of a certain set of genes and creating a special environment for their interactions, the researchers were able to induce the stem cells to "speak" to one another.

The stem cells self-organized into structures that developed through the various phases of development until they had beating hearts and the brain's structural components. They also contained the yolk sac, which provides nutrition to the embryo during its early weeks of development. The Cambridge-developed models, in contrast to earlier synthetic embryos, progressed to the stage where the complete brain, including the anterior region, began to form. In comparison to other stem cell-derived models, this represents a further stage of development.

The team believes that their findings could aid in the understanding of why some embryos do not grow into healthy pregnancies while others do. The outcomes could also be utilized to direct the production and repair of artificial human organs for transplantation. The study was published on August 25, 2022, in the magazine Nature. It is the outcome of more than ten years of research that has steadily produced increasingly complicated embryo-like structures.

According to Zernicka-Goetz, a professor in the Department of Physiology, Development, and Neuroscience at Cambridge University who specializes in mammalian development and stem cell biology, "our mouse embryo model not only develops a brain but also a beating heart, all the components that go on to make up the body." "How we've come this far is absolutely astounding. Our community has long held this as a goal, and after ten years of hard effort, we have finally achieved it.                                                                                       

A healthy development of a human embryo requires a "dialog" between the tissues that will create the embryo and the tissues that will connect the embryo to the mother. In the first week after fertilization, three distinct stem cell types start to emerge; one of these will eventually develop into the body's tissues, while the other two aid in the growth of the embryo. The placenta, which connects the fetus to the mother and supplies oxygen and nourishment, will develop from one of these extraembryonic stem cell varieties. The yolk sac is the second, where the embryo develops and receives its initial nutrition.                                                     

When the three different stem cell types start communicating with one another and giving instructions to the embryo on how to develop appropriately, many pregnancies end prematurely.

The majority of women don't even recognize they are pregnant at this point, according to Zernicka-Goetz, a professor of biology and biological engineering at Caltech. "This stage of pregnancy serves as the building block for everything that comes after. It will fail, and the pregnancy won't succeed.

Over the past ten years, the Cambridge research team of Professor Zernicka-Goetz has been examining these first few weeks of pregnancy in an effort to comprehend why some pregnancies end in failure and others in success.

The stem cell embryo model is crucial, according to Zernicka-Goetz, since it provides access to the developing structure at a stage that is typically inaccessible to us due to the implantation of the tiny embryo into the mother's womb. This accessibility enables us to modify genes in a model experimental setting to comprehend their developmental roles.

The researchers assembled cultivated stem cells that represented each of the three tissue types in the proper ratios and environments to encourage their growth and communication with one another, finally self-assembling into an embryo.

In order to guide the development of the embryo, extraembryonic cells communicate with embryonic cells not just chemically but also mechanistically, or through touch.

"This stage of human life is so enigmatic, so to be able to watch how it develops in a dish — to have access to these specific stem cells, to understand why so many pregnancies fail and how we might be able to prevent that from happening — is pretty extraordinary," said Zernicka-Goetz. "We examined the conversation that needs to take place between the various stem cell types at that time - we've showed how it happens and how it might go awry."

The capacity to synthesize the full brain, especially the anterior portion, which has been a primary aim in the development of synthetic embryos, represents a significant advancement in the field. Because this area of the brain needs signals from one of the extraembryonic tissues to develop, this is effective in Zernicka-technique. Goetz's From their 2018 and 2021 trials, which used the same component cells to develop into embryos at a somewhat earlier stage, the scientists hypothesized that this might be happening. They can now declare with certainty that their model is the first to indicate growth of the anterior, and in fact the entire brain, by delaying development by just one day.

According to Zernicka-Goetz, "this gives new opportunities to research the mechanics of neurodevelopment in an experimental model." In reality, by disrupting a gene already known to be crucial for the development of the neural tube, a forerunner to the nervous system, as well as the brain and eyes, we show the confirmation of this notion in the work. The synthetic embryos exhibit the same recognized problems in brain development as an animal with this mutation when this gene is absent. As a result, we can start using this method on the numerous genes whose role in brain development is unknown.

While the current study used mouse models, analogous human models are being created by the researchers with the capacity to generate certain organ types. This will help them understand the mechanisms underlying critical processes that would otherwise be hard to investigate in real embryos. Up to the 14th day of development, human embryos may only be researched in the lab under current UK law.

The techniques created by Zernicka-team Goetz's could also be used to direct the creation of synthetic organs for patients awaiting transplants if they are later demonstrated to be effective with human stem cells.

"There are so many individuals waiting for organ transplants all across the world," said Zernicka-Goetz. The possibility of using the knowledge gained from our research to develop accurate synthetic human organs to save lives that are currently being lost is what makes our work so thrilling. Using our understanding of how adult organs are created, it should also be possible to influence and heal those organs.

"I never imagined we'd reach to this point. This is a great stride forward and it required ten years of arduous labor from many of my team members. Your dreams have come true, even though you never thought they would.

The result of a decade's worth of research is the development of synthetic mouse embryos that grow in a test tube and build hearts and brains using only embryonic stem cells.

The enigma surrounding the operation of embryos fascinates me. Every embryo goes through the same process: from one cell to many, they multiply, communicate, and organize into a structure that serves as the model for all adult body parts. However, how do embryonic cells decide what to do with their lives, where to go, and how to behave? How do they create the correct components at the right time and place?

The process of creating the initial "synthetic embryo" models was one we completed piece by piece. When we started, we were aware that embryonic stem cells could be cultivated in the lab forever and that, when injected into an embryo, they might be able to form any tissue in the adult creature. The difficult part was directing them to grow into a full embryo. We used two types of extraembryonic tissue in addition to embryonic stem cells: one kind produces the placenta, and the other is a pouch in which the embryo develops. These tissues are crucial because they act as messengers, telling the embryo when and where to develop each of its parts.

Combining stem cells from each of these three different tissue types is more difficult than it sounds. We needed to find a setting where all three different cell types could develop and interact. Additionally, we had to determine the proper ratios of each cell type and add them in the proper order. Once these fundamental concepts were established, the stem cells took care of the rest. They self-organized to advance through a series of developmental phases until they had beating hearts and the building blocks for brains.

Our success was largely a result of thinking outside the box. Studies using embryo models most often concentrate on embryonic stem cells without taking into account the important role of extraembryonic cells. The appropriate ratios of extraembryonic and embryonic stem cells were combined. Extraembryonic cells communicate with embryonic cells using a variety of methods, including chemical messages and mechanically "by touch." Our research is assisting in the comprehension of these signaling events.

In order to understand the mechanics underlying critical events that would otherwise be impossible to examine, we are creating a comparable model of the human embryo. This is significant since the vast majority of human pregnancies end in miscarriage at this point of development for unknown reasons. Additionally, it will enable us to pinpoint the conditions necessary for the formation of healthy human tissues into various organs.

We've learned a lot about the processes by which the embryo creates itself thanks to the new "synthetic embryo," which was created. We learned how cells move between compartments as the multi-layered body plan emerges, how the extraembryonic tissues direct embryonic stem cells along the proper pathways to signal formation of the correct structures, and how this appropriately sets the stage for neurulation — the process where tissue folds to form the neural tube and, in turn, the brain and spinal cord.

When the small embryo implants into the mother's womb, a stage that is typically concealed from us, this model allows us access to the developing structure. We are able to see the embryo's development as it moves through that stage because our model does not need to implant in order to grow. Because of this accessibility, we can work with genes to determine how they affect development in a model experimental setting.

It is unquestionably true that perseverance and enthusiasm are necessary for this kind of activity. In the communist-run Poland where I was raised, travel was prohibited and unconventional thinking was discouraged. Many of us rebelled against the intense social pressure to fit in, which was present. This had the benefit of inspiring a desire to think for oneself and to persevere in the face of setbacks. That also affected how I became a scientist.

I developed methods to analyze the "developmental black box" — the embryo's development at the time of implantation — when I founded my research group in Cambridge. During my PhD, my advisors had discouraged me from pursuing it because they thought it could be challenging to beam light inside this "box." However, I was so intrigued by the topic of how the embryo self-organizes that I persisted because we have made progress little by little.

I would advise all aspiring scientists to follow their hearts. Study a subject that interests you, and select a professor who can accommodate your working style. Young scientists should be mentored in the lab, but they should also be given room to express their uniqueness. According to my observations, when women in science advance in their jobs, they face more difficulties. It's crucial to have mentors who understand how to balance science with ordinary life, including starting a family, at later stages.

I was astonished when an early test revealed anomalies during my own pregnancy. I awaited the amniocentesis, which collects fetal cells that have gotten into the amniotic fluid because the sampling was of extraembryonic cells. These were typical, which helped to calm my concerns. My research on mosaic aneuploidy, a condition in which chromosomally normal cells coexist with cells with the incorrect number of chromosomes, was sparked by this event. Amazingly, we discovered that by removing these defective cells, the regular, healthy cells were able to fill their place. We're still attempting to figure out why and how this system doesn't work in the tissues that form the placenta.

Science is difficult, labor-intensive, and consumes the majority of your waking hours. I unwind by watching movies. I watch a lot of documentaries, art films, and international films in Polish, French, and Danish. But I watch dramas when I want to lose myself in a different story. I recently became a convert to gardening, where I can support the growth of other living forms!

Being able to see the beginnings of a new life up close and personal is an amazing feeling and a privilege. It's similar like finding a brand-new planet that we were unaware even existed.

See Scientists Grow "Synthetic" Mouse Embryo With Brain and Beating Heart for more information on this study.

Synthetic embryos fully develop from gastrulation to neurulation and organogenesis, according to a study published in Nature on August 25, 2022, by Gianluca Amadei, Charlotte E. Handford, Chengxiang Qiu, Joachim De Jonghe, Hannah Greenfeld, Martin Tran, Beth K. Martin, Dong-Yuan Chen, Alejandro Aguilera-Castrejon, Jacob H. Hanna, Michael Elowitz, Florian Holl

By UNIVERSITY OF CAMBRIDGE