̽��ֱ�� of Cambridge - Magdalena Zernicka-Goetz

Human embryo-like models created from stem cells to understand earliest stages of human development

cjb250 — Tue, 27 Jun 2023 15:00:04 +0000

Published today in the journal Nature, this embryo model is an organised three-dimensional structure derived from pluripotent stem cells that replicate some developmental processes that occur in early human embryos.

Use of such models allows experimental modelling of embryonic development during the second week of pregnancy. They can help researchers gain basic knowledge of the developmental origins of organs and specialised cells such as sperm and eggs, and facilitate understanding of early pregnancy loss.

“Our human embryo-like model, created entirely from human stem cells, gives us access to the developing structure at a stage that is normally hidden from us due to the implantation of the tiny embryo into the mother’s womb,” said Professor Magdalena Zernicka-Goetz in the ̽��ֱ�� of Cambridge’s Department of Physiology, Development and Neuroscience, who led the work.

She added: “This exciting development allows us to manipulate genes to understand their developmental roles in a model system. This will let us test the function of specific factors, which is difficult to do in the natural embryo.”

In natural human development, the second week of development is an important time when the embryo implants into the uterus. This is the time when many pregnancies are lost.

̽��ֱ��new advance enables scientists to peer into the mysterious ‘black box’ period of human development – usually following implantation of the embryo in the uterus – to observe processes never directly observed before.

Understanding these early developmental processes holds the potential to reveal some of the causes of human birth defects and diseases, and to develop tests for these in pregnant women.

Until now, the processes could only be observed in animal models, using cells from zebrafish and mice, for example.

Legal restrictions in the UK currently prevent the culture of natural human embryos in the lab beyond day 14 of development: this time limit was set to correspond to the stage where the embryo can no longer form a twin.

Until now, scientists have only been able to study this period of human development using donated human embryos. This advance could reduce the need for donated human embryos in research.

Zernicka-Goetz says the while these models can mimic aspects of the development of human embryos, they cannot and will not develop to the equivalent of postnatal stage humans.

Over the past decade, Zernicka-Goetz’s group in Cambridge has been studying the earliest stages of pregnancy, in order to understand why some pregnancies fail and some succeed.

In 2021 and then in 2022 her team announced in Developmental Cell, Nature and Cell Stem Cell journals that they had finally created model embryos from mouse stem cells that can develop to form a brain-like structure, a beating heart, and the foundations of all other organs of the body.

̽��ֱ��new models derived from human stem cells do not have a brain or beating heart, but they include cells that would typically go on to form the embryo, placenta and yolk sac, and develop to form the precursors of germ cells (that will form sperm and eggs).

Many pregnancies fail at the point when these three types of cells orchestrate implantation into the uterus begin to send mechanical and chemical signals to each other, which tell the embryo how to develop properly.

There are clear regulations governing stem cell-based models of human embryos and all researchers doing embryo modelling work must first be approved by ethics committees. Journals require proof of this ethics review before they accept scientific papers for publication. Zernicka-Goetz’s laboratory holds these approvals.

“It is against the law and FDA regulations to transfer any embryo-like models into a woman for reproductive aims. These are highly manipulated human cells and their attempted reproductive use would be extremely dangerous,” said Dr Insoo Hyun, Director of the Center for Life Sciences and Public Learning at Boston’s Museum of Science and a member of Harvard Medical School’s Center for Bioethics.

Zernicka-Goetz also holds position at the California Institute of Technology and is NOMIS Distinguished Scientist and Scholar Awardee.

̽��ֱ��research was funded by the Wellcome Trust and Open Philanthropy.

Reference
Weatherbee, B A T et al.: A model of the post-implantation human embryo derived from pluripotent stem cells. Nature; 27 June 2023. DOI: 10.1038/s41586-023-06368-y

Cambridge scientists have created a stem cell-derived model of the human embryo in the lab by reprogramming human stem cells. ̽��ֱ��breakthrough could help research into genetic disorders and in understanding why and how pregnancies fail.

Our human embryo-like model gives us access to the developing structure at a stage that is normally hidden from us due to the implantation of the tiny embryo into the mother’s womb

Magdalena Zernicka-Goetz

̽��ֱ�� of Cambridge

Day 4 embryoid showing an inner epiblast like domain in magenta that has apico-basal polarity (yellow apical, blue basal), similar to the epiblast of the human embryo just after implantation

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

Yes

Licence type:

Attribution

‘Synthetic’ embryo with brain and beating heart grown from stem cells

jg533 — Thu, 25 Aug 2022 15:03:28 +0000

New model embryo, using mouse stem cells, reaches a further point in development than has been achieved in any other stem cell-derived model.

Study identifies trigger for ‘head-to-tail’ axis development in human embryo

jg533 — Thu, 17 Jun 2021 09:06:13 +0000

̽��ֱ��second week of gestation represents a critical stage of embryo development, or embryogenesis. Failure of development during this time is one of the major causes of early pregnancy loss. Understanding more about it will help scientists to understand how it can go wrong, and take steps towards being able to fix problems.

̽��ֱ��pre-implantation period, before the developing embryo implants into the mother’s womb, has been studied extensively in human embryos in the lab. On the seventh day the embryo must implant into the womb to survive and develop. Very little is known about the development of the human embryo once it implants, because it becomes inaccessible for study.

Pioneering work by Professor Magdalena Zernicka-Goetz and her team developed a technique, reported in 2016, to culture human embryos outside the body of the mother beyond implantation. This enabled human embryos to be studied up to day 14 of development for the first time.

In a new study, the team collaborated with colleagues at the Wellcome Sanger Institute to reveal what happens at the molecular level during this early stage of embryogenesis. Their findings provide the first evidence that a group of cells outside the embryo, known as the hypoblast, send a message to the embryo that initiates the development of the head-to-tail body axis.

When the body axis begins to form, the symmetrical structure of the embryo starts to change. One end becomes committed to developing into the head end, and the other the ‘tail’.

̽��ֱ��new results, published today in the journal Nature Communications, reveal that the molecular signals involved in the formation of the body axis show similarities to those in animals, despite significant differences in the positioning and organisation of the cells.

“We have revealed the patterns of gene expression in the developing embryo just after it implants in the womb, which reflect the multiple conversations going on between different cell types as the embryo develops through these early stages,” said Professor Magdalena Zernicka-Goetz in the ̽��ֱ�� of Cambridge’s Department of Physiology, Development and Neuroscience, and senior author of the report.

She added: “We were looking for the gene conversation that will allow the head to start developing in the embryo, and found that it was initiated by cells in the hypoblast – a disc of cells outside the embryo. They send the message to adjoining embryo cells, which respond by saying ‘OK, now we’ll set ourselves aside to develop into the head end.’”

̽��ֱ��study identified the gene conversations in the developing embryo by sequencing the code in the thousands of messenger RNA molecules made by individual cells. They captured the evolving molecular profile of the developing embryo after implantation in the womb, revealing the progressive loss of pluripotency (the ability of the embryonic cells to give rise to any cell type of the future organism) as the fates of different cells are determined.

“By creating an atlas of the cells involved in human development and how they communicate with other cells, we can start to understand more about the cellular processes and mechanisms behind very early embryo growth, which has been much harder to study compared to other mammals. This freely available information can now be used by researchers around the world to help inform future studies,” said Dr Roser Vento-Tormo, one of the senior authors and Group Leader at the Wellcome Sanger Institute.

“Our goal has always been to enable insights to very early human embryo development in a dish, to understand how our lives start. By combining our new technology with advanced sequencing methods we have delved deeper into the key changes that take place at this incredible stage of human development, when so many pregnancies unfortunately fail,” said Zernicka-Goetz.

This research was funded by Wellcome. It was carried out with the oversight of the UK Human Fertilisation and Embryology Authority, and with permission from a local research ethics committee.

Reference: Mole, M.A. et al: ‘A single cell characterisation of human embryogenesis identifies pluripotency transitions and putative anterior hypoblast centre.’ Nature Communications, June 2021. DOI: 10.1038/s41467-021-23758-w

Scientists have identified key molecular events in the developing human embryo between days 7 and 14 - one of the most mysterious, yet critical, stages of our development.

We have revealed the patterns of gene expression in the developing embryo just after it implants in the womb

Magdalena Zernicka-Goetz

Human embryo in the lab 9 days after fertilisation.

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

Yes

Study suggests embryos could be susceptible to coronavirus as early as second week of pregnancy

cjb250 — Tue, 04 Aug 2020 23:22:16 +0000

̽��ֱ��researchers say this could mean embryos are susceptible to COVID-19 if the mother gets sick, potentially affecting the chances of a successful pregnancy.

While initially recognised as causing respiratory disease, the SARS-CoV-2 virus, which causes COVID-19 disease, also affects many other organs. Advanced age and obesity are risk factors for complications but questions concerning the potential effects on fetal health and successful pregnancy for those infected with SARS-CoV-2 remain largely unanswered.

To examine the risks, a team of researchers used technology developed by Professor Magdalena Zernicka-Goetz at the ̽��ֱ�� of Cambridge to culture human embryos through the stage they normally implant in the body of the mother to look at the activity – or ‘expression’ – of key genes in the embryo. Their findings are published today in the Royal Society’s journal Open Biology.

On the surface of the SARS-CoV-2 virus are large ‘spike’ proteins. Spike proteins bind to ACE2, a protein receptor found on the surface of cells in our body. Both the spike protein and ACE2 are then cleaved, allowing genetic material from the virus to enter the host cell. ̽��ֱ��virus manipulates the host cell’s machinery to allow the virus to replicate and spread.

̽��ֱ��researchers found patterns of expression of the genes ACE2, which provide the genetic code for the SARS-CoV-2 receptor, and TMPRSS2, which provides the code for a molecule that cleaves both the viral spike protein and the ACE2 receptor, allowing infection to occur. These genes were expressed during key stages of the embryo’s development, and in parts of the embryo that go on to develop into tissues that interact with the maternal blood supply for nutrient exchange. Gene expression requires that the DNA code is first copied into an RNA message, which then directs the synthesis of the encoded protein. ̽��ֱ��study reports the finding of the RNA messengers.

Professor Magdalena Zernicka-Goetz, who holds positions at both the ̽��ֱ�� of Cambridge and Caltech, said: “Our work suggests that the human embryo could be susceptible to COVID-19 as early as the second week of pregnancy if the mother gets sick.

“To know whether this really could happen, it now becomes very important to know whether the ACE2 and TMPRSS2 proteins are made and become correctly positioned at cell surfaces. If these next steps are also taking place, it is possible that the virus could be transmitted from the mother and infect the embryo’s cells.”

Professor David Glover, also from Cambridge and Caltech, added: “Genes encoding proteins that make cells susceptible to infection by this novel coronavirus become expressed very early on in the embryo’s development. This is an important stage when the embryo attaches to the mother’s womb and undertakes a major remodelling of all of its tissues and for the first time starts to grow. COVID-19 could affect the ability of the embryo to properly implant into the womb or could have implications for future fetal health.”

̽��ֱ��team say that further research is required using stem cell models and in non-human primates to better understand the risk. However, they say their findings emphasise the importance for women planning for a family to try to reduce their risk of infection.

“We don’t want women to be unduly worried by these findings, but they do reinforce the importance of doing everything they can to minimise their risk of infection,” said Bailey Weatherbee, a PhD student at the ̽��ֱ�� of Cambridge.

Reference
Weatherbee, BAT, et al. Expression of SARS-CoV-2 receptor ACE2 and the protease TMPRSS2 suggests susceptibility of the human embryo in the first trimester. Open Biology; 5 Aug 2020; DOI: 10.1098/rsob.200162

Image
Image of a human embryo cultured in vitro through the implantation stages and stained to reveal OCT4 transcription factor, magenta; GATA6 transcription factor, white; F-actin, green; and DNA, blue. Analysis of patterns of gene expression in such embryos reveals that ACE2, the receptor for the SARS-CoV-2 virus, and the TMPRSS2 protease that facilitates viral infection are expressed in these embryos, which represent the very early stages of pregnancy. (Credit: Zernicka-Goetz Lab)

Genes that are thought to play a role in how the SARS-CoV-2 virus infects our cells have been found to be active in embryos as early as during the second week of pregnancy, say scientists at the ̽��ֱ�� of Cambridge and the California Institute of Technology (Caltech).

COVID-19 could affect the ability of the embryo to properly implant into the womb or could have implications for future fetal health

David Glover

Zernicka-Goetz Lab

human embryo cultured in vitro

Yes

Scientists generate key life event in artificial mouse ‘embryo’ created from stem cells

cjb250 — Mon, 23 Jul 2018 15:00:29 +0000

̽��ֱ��team, led by Professor Magdalena Zernicka-Goetz at the ̽��ֱ�� of Cambridge, previously created a much simpler structure resembling a mouse embryo in culture, using two types of stem cells – the body’s ‘master cells’ – and a 3D scaffold on which they can grow.

Now, in a study published today in Nature Cell Biology, Professor Zernicka-Goetz and colleagues have developed the embryo-like structures further, using not just two but three types of stem cells which let them reconstruct a process known as gastrulation, an essential step in which the embryonic cells being self-organising into the correct structure for an embryo to form.

Once a mammalian egg has been fertilised by a sperm, it divides multiple times to generate a small, free-floating ball comprising three types of stem cells. At the stage of development known as the ‘blastocyst’ stage, the particular stem cells that will eventually make the future body – the embryonic stem cells (ESCs) – cluster together inside the embryo towards one end. ̽��ֱ��other two types of stem cell in the blastocyst are the extra-embryonic trophoblast stem cells (TSCs), which will form the placenta, and primitive endoderm stem cells (PESCs) that will form the yolk sac, ensuring that the foetus’s organs develop properly and providing essential nutrients.

In March 2017, Professor Zernicka-Goetz and colleagues published a study that described how, using a combination of genetically-modified mouse ESCs and TSCs, together with a 3D ‘jelly’ scaffold known as an extracellular matrix, they were able to grow a structure capable of assembling itself and whose development and architecture very closely resembled the natural embryo. There was a remarkable degree of communication between the two types of stem cell: in a sense, the cells were telling each other where in the embryo to place themselves.

However, a key step in the life of the embryo – gastrulation, described by the eminent biologist Lewis Wolpert as “truly the most important time in your life” – was missing. Gastrulation is the point at which the embryo transforms from being a single layer to three layers: an inner layer (endoderm), middle layer (mesoderm) and outer layer (endoderm), determining which tissues or organs the cells will then develop into.

“Proper gastrulation in normal development is only possible if you have all three types of stem cell. In order to reconstruct this complex dance, we had to add the missing third stem cell,” says Professor Zernicka-Goetz. “By replacing the jelly that we used in earlier experiments with this third type of stem cell, we were able to generate structures whose development was astonishingly successful.”

By adding the PESCs, the team was able to see their ‘embryo’ undergo gastrulation, organising itself into the three body layers that all animals have. ̽��ֱ��timing, architecture and patterns of gene activity reflected that of natural embryo development.

Image: Synthetic embryo like structure with embryonic part generated from the embryonic stem cells (pink) and and extra-embryonic tissues in blue. (Credit: Zernicka-Goetz lab, ̽��ֱ�� of Cambridge)

“Our artificial embryos underwent the most important event in life in the culture dish,” adds Professor Zernicka-Goetz. “They are now extremely close to real embryos. To develop further, they would have to implant into the body of the mother or an artificial placenta.”

̽��ֱ��researchers say they should now be in a position to better understand how the three stem cell types interact to enable the embryo to develop, by experimentally altering biological pathways in one cell type and seeing how this affects the behaviour of one, or both, of the other cell types.

“We can also now try to apply this to the equivalent human stem cell types and so study the very earliest events in human embryo development without actually having to use natural human embryos,” says Professor Zernicka-Goetz.

By applying these studies side-by-side, it should be possible to learn a great deal about the fundamental aspects of the first stages of mammalian development. In fact, such comparisons should enable scientists to study events that happen beyond day 14 in human pregnancies, but without using 14-day-old human embryos; UK law permits embryos to be studied in the laboratory only up to this period.

“ ̽��ֱ��early stages of embryo development are when a large proportion of pregnancies are lost and yet it is a stage that we know very little about,” says Professor Zernicka-Goetz. "Now we have a way of simulating embryonic development in the culture dish, so it should be possible to understand exactly what is going on during this remarkable period in an embryo’s life, and why sometimes this process fails.”

̽��ֱ��research was funded by the European Research Council and Wellcome.

Reference
Sozen, B et al. Self-assembly of embryonic and two extra-embryonic stem cell types into gastrulating embryo structures. Nature Cell Biology; 23 Jul 2018; DOI: 10.1038/s41556-018-0147-7

̽��ֱ��creation of artificial embryos has moved a step forward after an international team of researchers used mouse stem cells to produce artificial embryo-like structures capable of ‘gastrulation’, a key step in the life of any embryo.

Our artificial embryos underwent the most important event in life in the culture dish. They are now extremely close to real embryos

Magdalena Zernicka-Goetz

Zernicka-Goetz lab, ̽��ֱ�� of Cambridge

Synthetic embryo-like structure made of three stem cells types in yellow, pink and green

Researcher Profile: Dr Berna Sozen

Dr Berna Sozen is living the dream.

Originally from Turkey, she came to Cambridge to join Professor Magdalena Zernicka-Goetz’s team. “During my MSc, as a young passionate researcher-to-be, I was fascinated by her research, which resolves the puzzles in early mammalian life,” she says. “My dream has come true and I have spent several years at Cambridge now.”

Understanding the very early stages of embryo development is important because it may help explain why a significant number of human pregnancies fail at around the time the embryo implants into the wall of the uterus. Key events after implantation stage of embryo development are largely inaccessible to science because they occur in the ‘black box’ of the human uterus even before most women know that they are pregnant.

̽��ֱ��research is not always easy, of course – her work with Professor Zernicka-Goetz, growing embryo-like structures from mouse stem cells, really is at the cutting-edge of research – but it can be hugely satisfying.

“Observing these self-developing embryo-like structures under the microscope is so exciting that I do not care even if there is a need to be in lab in the middle of night!” she says. “I still clearly remember the moment that I and my co-author saw these structures for the first time. It was a breath-taking moment. Those moments are what we live for in science.”

Berna is helping contribute to the immense legacy that Cambridge has to offer in embryology and stem cell research.

“I work in the same building where Nobel Laureate Bob Edwards succeeded in fertilising a human egg in vitro. Another Nobel Laureate Sir Martin Evans was the first to culture mouse embryonic stem cells and cultivate them in a laboratory at ̽��ֱ�� of Cambridge,” she says. “These works revolutionised treatments for fertility and laid the foundations for human stem cell research. These great scientists paved the way for Magdalena’s pioneering research in embryology. I feel I couldn’t have been in any better place for my research than this.”

̽��ֱ��beautiful images of early embryos produced by Professor Zernicka-Goetz’s team no doubt help inspire Berna’s other passion in life, photography. “Colours and patterns become glamorous behind the lens and I always find the beauty in everything,” she says. “I think this makes me a better biologist!”

Yes

Licence type:

Attribution

Postgraduate Pioneers 2017 #2

ta385 — Wed, 25 Oct 2017 12:39:35 +0000

Second in the series is Sarah Harrison, a final year PhD student in the Department of Physiology, Development and Neuroscience, whose research highlights the importance of extra-embryonic cells and cell interactions.

My research sets out to

My research tries pick apart what takes you from a single fertilized egg through to a body with head, tail and limbs and internal organs through embryonic development. And we mostly look at the mouse embryo to answer these questions and look at changes in cell shape, cell behavior and cell fate decisions along the way.

Day-to-day

Rather than using whole mouse embryos to answer these questions about development, I derive stem cell populations from the embryos and maintain these in culture. What this means is that most of the time I’m standing in a small tissue culture room with my arms underneath a tissue culture hood to keep the cells happy and sterile. And then we grow the cells up and perform assays on how gene expression is changing when we change their culture conditions and try and plate them in scaffolds of 3D to generate embryo like structures. When I’m not in the culture room, I’m dissecting embryos, I’m down at the animals house looking after our transgenic mouse colonies and some of the time I’m sitting down doing data analysis. I’m in quite a collaborative group, so it’s rare that it’s just one person working on one question. Actually we’ve got lots of questions and we try to use all of our tools and expertise to answer them most effectively.

My best days

My favourite period in the lab was when I was just starting to put together the work that went on to get us a first author publication. That was when I was combining embryonic stem cells with stem cells that I’d derived from extra embryonic tissues, so tissues that would go on to form the placenta. Combining these two cell types in a dish started to generate, through self-organisational processes, structures that looked like embryos. And when I first saw this I couldn’t believe my eyes, it was amazing, and I couldn’t wait to tell my supervisor. And even though it was still quite early days, it showed that our hypothesis about interactions between embryonic and extra-embryonic cells being really important in generating a body, was working, so that was great.

I hope my work will lead to

I hope my PhD research will help the mouse embryology field at least to see the importance of cell interactions, and that it’s not just about the cells that go on to make the body but also the extra-embryonic cells that nourish the embryo. So hopefully it will provide a new slant on early embryology. For me personally, I feel I’ve drilled right down into an incredibly precise area of life science. Now I’d like to broaden out a little bit and perhaps go into science publishing to be able to communicate these really interesting discoveries, many of which are happening right here in Cambridge.

It had to be Cambridge because

In terms of developmental biology, there is nowhere like Cambridge. ̽��ֱ��building I’m in now is where scientists pioneered IVF, for instance. So that history is a major factor for people, but it’s not just about past breakthroughs, it’s about what’s going on now. I can go across the road to another building and chat to someone who is developing ways to encapsulate cells in tiny beads of gel, and really high tech, high through-put methods are being developed all around. And so it’s a great place to develop your research, not just in the techniques you know and love, but to expand and be more collaborative. On top of that, socially it’s great. We can go to lots of different institutes, and develop not just professional collaborations but also social collaborations, where we share ideas and results to get feedback. Having all these clever people around is a big benefit for developing.

With our Postgraduate Open Day fast-approaching (3 Nov), we introduce five PhD candidates who are already making waves at Cambridge.

I couldn’t believe my eyes, it was amazing, and I couldn’t wait to tell my supervisor.

Sarah Harrison, final year PhD student

Sarah Harrison

Postgraduate Open Day

For more information about the ̽��ֱ��'s Postgraduate Open Day on 3rd November 2017 and to book to attend, please click here.

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

Yes

Of mice and women

cg605 — Fri, 04 Aug 2017 14:01:53 +0000

Walk into Professor Magdalena Zernicka-Goetz’s laboratory and it is her sofa that catches your eye. A gaudy pink-purple, it is easily visible through the glass that separates the benches, fridges and microscopes from the office where she draws the threads of her thinking together. It converts into a bed – handy for all-night experiments. And it’s where her team sat, last year, when, during a regular update meeting, they realised that they’d made a world-changing discovery. They had created a structure resembling a mouse embryo, entirely in the laboratory, using stem cells: a world first.

“I still remember that moment,” says Zernicka-Goetz, Professor of Mammalian Development and Stem Cell Biology and group head of the Zernicka-Goetz Laboratory. “It is one of the most happy moments in your life, when your dreams come true. You work on something, very intensively. You often have to inspire and motivate people in the lab to work on it. These are super-intelligent people. They do it because they see a value in it, not because you are telling them to. And the result is very much a team success.”

Until she was four, Zernicka-Goetz lived in her father’s scientific laboratories. Her family had lost everything during the war, including their home. Now, growing up in Warsaw, behind the Iron Curtain, the laboratory was home: a lab converted into the family’s apartment, with the kitchen installed in a corridor. Zernicka-Goetz would walk to her pre-school, hand in hand with her father, Professor Boguslaw Zernicki and together they would discuss his passion: the brain. How do we think? Why do we think? Where do our dreams come from? ̽��ֱ��young Zernicka-Goetz was encouraged to dig deep, to probe cause and effect.

“At the time, I didn’t realise it was inspirational,” she says. “Now, tracing my steps back, I can see the connection. At school, my biology teacher wasn’t so great. I wouldn’t have been so fascinated by science if I hadn’t had this charismatic father, motivated not by career progression, but by pure science.”

She came to Cambridge in 1995 as an EMBO Fellow, supervised by Professor Sir Martin Evans (who discovered embryonic stem cells). Her fascination, nurtured during her PhD at the ̽��ֱ�� of Warsaw under the supervision of Professor Andrzej Tarkowski, was around the plasticity of embryos. They are gloriously flexible, she says: remove one cell from an embryo and the rest will develop normally. “We know that they can recover from their different perturbations in early life, but how does that work? How do they recover? Embryos of many other animals can’t do this, but mammalian embryos can. Why? ̽��ֱ��process fascinated me.”

She deliberately chose a different specialisation to her father’s, not wanting to be directly compared to him. But when it comes down to it, she says, both areas are all about cells. “I was fascinated by our thoughts and where they come from, and how it can all be narrowed down to the function of individual cells within the brain,” she says. “I like painting and sculpture, which somehow translates into playing with embryos and stem cells. Making shapes with them – that’s what helps me to think and sometimes inspires me.”

Zernicka-Goetz’s playful and imaginative attitude to the astonishingly complex structure that is the mammalian embryo has given rise to some extraordinary work. In 2016, Nature and Nature Cell Biology published her papers outlining a new technique for allowing human embryos to develop in the lab for up to 13 days. Previously, embryos could survive in vitro for only seven days (the point at which an embryo would normally implant into the womb).

̽��ֱ��new technique is vital for studying early pregnancy loss. Under UK law, researchers are permitted to study human embryos in the lab for up to 14 days, but as no method existed for keeping them alive after seven days there was no way to study the changes which might be taking place. Then came Zernicka-Goetz’s technique, which involves creating a system in the lab which allows embryo cells to organise themselves to form a basis for future development, just as they do in the womb.

Zernicka-Goetz had wanted to develop just such a system from her very early days as a scientist. “I very much wanted to grow these embryos beyond the so-called ‘blastocyst’ stage – the fourth day of their life in the culture dish. This is when the transformation of an embryo’s architecture happens. Nature looks very different before the embryo is implanted, and afterwards.” Her supervisors discouraged her. Far too difficult, they said. “Lots of famous scientists had tried it and failed, so they told me I should not be wasting my time. But seven years ago, I decided to return to my dream. And it worked.” That work resonated around the world, winning the People’s Choice award for Science magazine’s ‘Breakthrough of the Year 2016’.

Then, this spring, came her work on growing mouse embryo-like structures. Zernicka-Goetz was on her way to Paris to make a speech when she heard of the paper’s publication (authors are not told in advance when their papers will be published in scientific journals). Interest was phenomenal – the world’s media descended on her. “It was a very important speech, which I was honoured to have been asked to give, and I didn’t want to cancel,” she remembers. “So I spent the whole journey on the Eurostar on the phone to journalists. It was actually more stressful than happy as I wanted to be part of it, but had to delegate it to people in the lab, and to everybody who I knew I could rely on reporting the story accurately and say: please go to the TV studio and speak about it, because I can’t do it! I have to give this speech!”

How did her team achieve this landmark when all other efforts failed? Like many discoveries, it came about through a new way of thinking about the problem, says Zernicka-Goetz. ̽��ֱ��key to her success lay in the use of two different kinds of stem cells. “ ̽��ֱ��first type of cell, pluripotent embryonic stem cells, make the mouse baby. ̽��ֱ��second type, multipotent trophoblast stem cells, make the placenta,” she explains. “We allowed these two types of stem cells to interact with each other by providing an extra-cellular matrix to help them communicate – a kind of 3D scaffold. We hoped that they would self-organise to create an embryonic structure – and they did.”

It is important to understand that this is not ‘creating life’. Her team will not be attempting to ‘grow’ baby mice in the lab. Rather, Zernicka-Goetz says, this work is providing a system to enable scientists to better understand development. Using actual mouse embryos in research is not ideal: they are complex structures which aren’t easy to grow at the life stage that is of interest to Zernicka-Goetz’s team. Mimicking the developmental processes taking place in these embryos using stem cells is far more convenient. “And this is of enormous importance,” she says. “This is the stage where many human pregnancies fail. Human and mouse development at this time have a lot of common elements. So using this system, we will be able to identify the role of specific genes and processes, and the communication between different kinds of cells in order to build the organism.”

Two world-changing discoveries in a year is an astonishing record, but Zernicka-Goetz says she doesn’t necessarily feel proud. “Often, in life, things are mixed,” she says. “You have to deal with happy moments and difficult moments. ̽��ֱ��difficulty for me is still mastering my balance between my life as a scientist and teacher and mother and friend and wife. During the normal day, I often run to keep up with it all – all those different lives. So when the unusual happens, it is overwhelming and you feel not proud but rewarded. Rewarded for all this effort, and training, and forgetting about your own feelings and life for what you are trying to achieve.”

It’s hard for her to predict the future, she says. Her lab is currently working on 17 different projects. Her ideas develop as they go along, she says, but behind them, always, lurk the biggest of big questions: where does life come from? How does it start? And why do we still know so little about it? “I often wake up with ideas,” she says. “Perhaps I see something during the day, or I think of something in conversation, or when I am discussing something with my kids. Sometimes I go for a run and I think about how we might solve a specific problem. But the important question for me is to find a way to address those big questions. We know there are many things we don’t know, so how do we find out about them?”

Article by Lucy Jolin. This article first appeared in CAM - the Cambridge Alumni Magazine, issue 81.

Last year, Magdalena Zernicka-Goetz, Professor of Mammalian Development and Stem Cell Biology, made not one, but two world-changing discoveries.

Lots of famous scientists had tried it and failed, so they told me I should not be wasting my time. But seven years ago, I decided to return to my dream. And it worked.

Professor Magdalena Zernicka-Goetz

Art meets science by Kate Peters

Magdalena Zernicka-Goetz is a Fellow of Sidney Sussex. She was photographed in the Heong Gallery, at Downing.

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

Scientists create artificial mouse ‘embryo’ from stem cells for first time

cjb250 — Thu, 02 Mar 2017 19:00:06 +0000

Understanding the very early stages of embryo development is of interest because this knowledge may help explain why a significant number of human pregnancies fail at this time.

Once a mammalian egg has been fertilised by a sperm, it divides multiple times to generate a small, free-floating ball of stem cells. ̽��ֱ��particular stem cells that will eventually make the future body, the embryonic stem cells (ESCs) cluster together inside the embryo towards one end: this stage of development is known as the blastocyst. ̽��ֱ��other two types of stem cell in the blastocyst are the extra-embryonic trophoblast stem cells (TSCs), which will form the placenta, and primitive endoderm stem cells that will form the so-called yolk sac, ensuring that the foetus’s organs develop properly and providing essential nutrients.

Previous attempts to grow embryo-like structures using only ESCs have had limited success. This is because early embryo development requires the different types of cell to coordinate closely with each other.

However, in a study published today in the journal Science, Cambridge researchers describe how, using a combination of genetically-modified mouse ESCs and TSCs, together with a 3D scaffold known as an extracellular matrix, they were able to grow a structure capable of assembling itself and whose development and architecture very closely resembled the natural embryo.

“Both the embryonic and extra-embryonic cells start to talk to each other and become organised into a structure that looks like and behaves like an embryo,” explains Professor Magdalena Zernicka-Goetz from the Department of Physiology, Development and Neuroscience, who led the research. “It has anatomically correct regions that develop in the right place and at the right time.”

Image: Stem cell-modelled embryo at 96 hours (embryonic (magenta) and extra-embryonic (blue) tissue with surrounding extracellular matrix (cyan)). Credit: Berna Sozen, Zernicka-Goetz Lab, ̽��ֱ�� of Cambridge

Professor Zernicka-Goetz and colleagues found a remarkable degree of communication between the two types of stem cell: in a sense, the cells are telling each other where in the embryo to place themselves.

“We knew that interactions between the different types of stem cell are important for development, but the striking thing that our new work illustrates is that this is a real partnership – these cells truly guide each other,” she says. “Without this partnership, the correct development of shape and form and the timely activity of key biological mechanisms doesn’t take place properly.”

Comparing their artificial ‘embryo’ to a normally-developing embryo, the team was able to show that its development followed the same pattern of development. ̽��ֱ��stem cells organise themselves, with ESCs at one end and TSCs at the other. A cavity opens then up within each cluster before joining together, eventually to become the large, so-called pro-amniotic cavity in which the embryo will develop.

While this artificial embryo closely resembles the real thing, it is unlikely that it would develop further into a healthy foetus, say the researchers. To do so, it would likely need the third form of stem cell, which would allow the development of the yolk sac, which provides nourishment for the embryo and within which a network of blood vessel develops. In addition, the system has not been optimised for the correct development of the placenta.

Professor Zernicka-Goetz recently developed a technique that allows blastocysts to develop in vitro beyond the implantation stage, enabling researchers to analyse for the first time key stages of human embryo development up to 13 days after fertilisation. She believes that this latest development could help them overcome one of the main barriers to human embryo research: a shortage of embryos. Currently, embryos are developed from eggs donated through IVF clinics.

“We think that it will be possible to mimic a lot of the developmental events occurring before 14 days using human embryonic and extra-embryonic stem cells using a similar approach to our technique using mouse stem cells,” she says. “We are very optimistic that this will allow us to study key events of this critical stage of human development without actually having to work on embryos. Knowing how development normally occurs will allow us to understand why it so often goes wrong.”

̽��ֱ��research was largely funded by the Wellcome Trust and the European Research Council.

Dr Andrew Chisholm, Head of Cellular and Developmental Science at Wellcome, said: “This is an elegant study creating a mouse embryo in culture that gives us a glimpse into the very earliest stages of mammalian development. Professor Zernicka-Goetz’s work really shows the importance of basic research in helping us to solve difficult problems for which we don’t have enough evidence for yet. In theory, similar approaches could one day be used to explore early human development, shedding light on the role of the maternal environment in birth defects and health.”

Reference
Harrison, SE et al. Assembly of embryonic and extra-embryonic stem cells to mimic embryogenesis in vitro. Science; 2 March 2017; DOI: 10.1126/science.aal1810

Scientists at the ̽��ֱ�� of Cambridge have managed to create a structure resembling a mouse embryo in culture, using two types of stem cells – the body’s ‘master cells’ – and a 3D scaffold on which they can grow.

We knew that interactions between the different types of stem cell are important for development, but the striking thing that our new work illustrates is that this is a real partnership – these cells truly guide each other

Magdalena Zernicka-Goetz

Sarah Harrison and Gaelle Recher, Zernicka-Goetz Lab, ̽��ֱ�� of Cambridge

Stem cell-modelled embryo at 96 hours (left); Embryo cultured in vitro for 48 hours from the blastocyst stage (right)

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

Yes

Licence type:

Attribution