̽��ֱ�� of Cambridge - embryology

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

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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.

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Deeper origin of gill evolution suggests 'active lifestyle' link in early vertebrates

fpjl2 — Thu, 09 Feb 2017 17:02:27 +0000

A new study has revealed that gills originated much deeper in evolutionary history than previously believed. ̽��ֱ��findings support the idea that gills evolved before the last common ancestor of all vertebrates, helping facilitate a "lifestyle transition" from immobile filter-feeder to actively swimming predator.

̽��ֱ��research, published today in the journal Current Biology, shows that gills develop from the same embryonic tissue in both jawed and jawless vertebrates - a lineage that split very early in our ancestral tree.

Jawed vertebrates - such as fish, birds and mammals - make up 99% of all living vertebrates, including us. Jawless vertebrates include the parasitic lamprey and scavenging hagfish: eel-like creatures that diverged from the ancestral line over 400 million years ago.

Previous work in this area involved slicing thin sections of fish embryos to chart organ growth. These "snapshots" of development led scientists to believe that gills were formed from different tissues: the internal 'endoderm' lining in jawless vertebrates, and the 'ectoderm' outer skin in the jawed.

As a result, since the mid-20th century it was thought that the ancient jawed and jawless lines evolved gills separately after they split, an example of 'convergent evolution' - where nature finds the same solution twice (such as the use of echolocation in both bats and whales, for example).

Biologists at the ̽��ֱ�� of Cambridge used fluorescent labelling to stain cell membranes in skate embryos, and tracked them through the dynamic development process. Their experiment has now shown that the gills of jawed vertebrates emerge from the same internal lining cells as their jawless relatives.

̽��ֱ��researchers say this is strong evidence that gills evolved just once, much earlier in evolutionary history - before the jawless divergence - and that the "crown ancestor" of all vertebrates was consequently a more anatomically complex creature.

̽��ֱ��findings pull the invention of gills closer to the "active lifestyle" shift in our early ancestors: the evolution from passive filter feeders to self-propelled ocean swimmers. Scientists say that gill development may have been a catalyst or consequence of this giant physiological leap.

"These findings demonstrate a single origin of gills that likely corresponds with a key stage in vertebrate evolution: when some of our earliest relatives transitioned from filtering particles out of water pumped through static bodies to actively swimming through the oceans," says lead author Dr Andrew Gillis, a Royal Society ̽��ֱ�� Research Fellow in Cambridge's Department of Zoology, and a Whitman Investigator at the Marine Biological Laboratory in Woods Hole, US.

"Gills provided vertebrates with specialist breathing organs in their head, rather than having to respire exclusively through skin all over the body. We can't say whether these early animals became more active and needed to evolve a new respiratory mechanism, or if it was gill evolution that allowed them to move faster.

"However, whether by demand or opportunity, our work suggests that the physiological innovation of gills occurred at the same time as the lifestyle transition from passive to active in some of our earliest ancestors."

While the jawed vertebrate lineage spawned the majority of vertebrate life that exists on Earth today - "evolutionarily speaking, we are all bony fish," says Gillis - lamprey and hagfish are the living remnants of a once extensive assemblage of primitively predatory jawless vertebrates.

"Lamprey are eel-like parasites that use their tooth-like organs and raspy tongue to latch onto fish and suck out the blood, while hagfish scavenge by taking bites out of dead matter," he says.

Gillis and colleagues used embryos of the little skate to track early gill development through cell tracing. ̽��ֱ��skate is a cartilaginous fish - an early-branching lineage of jawed vertebrates that includes the sharks and stingrays.

This made skate an excellent comparison point to try and infer the primitive anatomical and developmental conditions in the last common ancestor of jawed and jawless vertebrates.

̽��ֱ��embryonic work of the Gillis laboratory neatly complements paleontological research from their Cambridge colleague Prof Simon Conway Morris, who has spent much of his career studying fossils of the Cambrian period of rapid evolution - when most major animal groups originated.

In 2014, Conway Morris was part of the team that discovered Metaspriggina: one of the oldest-known vertebrate fossils, perhaps over 500 million years old, which displayed hints of a gill structure, as well as the muscle arrangement of an active swimmer.

"Our embryological research helps us understand exactly how the gill structures in early vertebrates such as Metaspriggina relate to the gills of living forms," says Gillis.

"Embryology can tell us about the evolutionary relationship between anatomical features in living animals, while palaeontology can pinpoint precisely when these features first appear in deep time. I think that this work nicely illustrates how these two areas of research can inform one another."

Fish embryo study indicates that the last common ancestor of vertebrates was a complex animal complete with gills – overturning prior scientific understanding and complementing recent fossil finds. ̽��ֱ��work places gill evolution concurrent with shift to self-propulsion in our earliest ancestors.

Our work suggests that the physiological innovation of gills occurred at the same time as the lifestyle transition from passive to active in some of our earliest ancestors

Andrew Gillis

Left: Early skate embryo labeled with fluorescent dye. Right: Image of a hatchling skate

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Scientists develop human embryos beyond implantation stage for first time

cjb250 — Wed, 04 May 2016 15:55:47 +0000

Once an egg has been fertilised by a sperm, it divides several times to generate a small, free-floating ball of stem cells. Around day three, these stem cells cluster together inside the embryo towards one side; this stage is known as the blastocyst. ̽��ֱ��blastocyst comprises three cell types: cells that will develop into the future body (which form the ‘epiblast’), cells that will develop into the placenta and allow the embryo to attach to the womb, and cells that form the primitive endoderm that will ensure that the fetus’s organs develop properly and will provide essential nutrients.

This pre-implantation period – so-called as the blastocyst has yet to implant itself into the uterus – has been extensively studied in human embryos using in vitro culture methods. However, on the seventh day of development, the human embryo must implant into the uterus of the mother to survive and to develop further, even though UK law permits embryos to be studied in the laboratory for up to 14 days.

̽��ֱ��failure of an embryo to implant is a major cause of early pregnancy loss and yet the cellular and molecular changes that take place in the human embryo at this stage remain unknown. This is because it is impossible to carry out such studies on embryos developing in the womb, and until now there has been no system to culture human embryos in the laboratory beyond day seven.

Today, in parallel papers in Nature and Nature Cell Biology, two international teams report the development of a technique that allows them to culture human embryos outside the body of the mother for an additional six days, up to day 13 of development. This work builds on previous work by Professor Magdalena Zernicka-Goetz’s team from the ̽��ֱ�� of Cambridge on mouse and was funded by the Wellcome Trust.

Using the technique, the researchers have shown that the reorganisation of the embryo that normally takes place during early post-implantation development can be achieved in the lab given the right culture conditions.

Professor Zernicka-Goetz, who led the UK research and is an author on both studies, says: “Implantation is a milestone in human development as it is from this stage onwards that the embryo really begins to take shape and the overall body plans are decided. It is also the stage of pregnancy at which many developmental defects can become acquired. But until now, it has been impossible to study this in human embryos. This new technique provides us with a unique opportunity to get a deeper understanding of our own development during these crucial stages and help us understand what happens, for example, during miscarriage.”

“Embryo development is an extremely complex process and while our system may not be able to fully reproduce every aspect of this process, it has allowed us to reveal a remarkable self-organising capacity of human blastocysts that was previously unknown,” says Dr Marta Shahbazi one of the co-first authors of the study from the ̽��ֱ�� of Cambridge.

̽��ֱ��researchers established a system for the in vitro culture of human embryos and, using this technique, followed the development of the embryos up to day 13 of development. Immediately following ‘implantation’, the three cell types that comprise the blastocyst reorganise into a new configuration.

“ ̽��ֱ��stem cells in the epiblast that will form the future body have the remarkable ability to self-organise themselves and create a cavity that represent the basic structure of the early post-implantation human embryo,” says Professor Zernicka-Goetz. “Without this cavity, it would be impossible for the embryo to develop further as it is the basis for its future development. It is also a mechanism that we can study using human embryonic stem cells.”

This cavity was previously thought to arise through a process known as apoptosis, or programmed cell death, but using human embryonic stem cell models, the researchers were able to show that in fact cell death is not required for the cavity formation in human embryos.

“This process is similar to what we have recently observed in mouse embryos, despite the significant differences in the structure of post-implantation embryos in these different mammalian species”, says Professor Zernicka-Goetz. “This suggests it may be a fundamental process conserved across many species.”

Dr Simon Fishel, founder and President of CARE Fertility Group, adds: “This is about much more than just understanding the biology of implantation embryo development. Knowledge of these processes could help improve the chances of success of IVF, of which only around one in four attempts are successful.”

This research has been possible thanks to couples that underwent IVF treatment and decided to donate their surplus embryos to advance our understanding of the early phases of post-implantation human development. ̽��ֱ��research was licensed by the UK Human Fertilisation and Embryology Authority.

Left image: At day 10 of embryo development the pluripotent stem cells that will generate the future body self-organise to generate a cavity (the pro-amniotic cavity). This configuration is the basis for the subsequent developmental stages and the formation of the body plan. ̽��ֱ��immunofluorescence image shows a day 10 human embryo cultured in vitro through early post-implantation stages (purple-epiblast, red-nucleus, green-membrane).

Right image: At day 11 of embryo development the pluripotent stem cells that will generate the future body self-organiseto generate a cavity (the pro-amniotic cavity). This configuration is the basis for the subsequent developmental stages and the formation of the body plan. ̽��ֱ��immunofluorescence image shows a day 11 human embryo cultured in vitro through early post-implantation stages (while-epiblast, blue-nucleus, green-membrane).

Reference
Shahbazi, MN et al. Self-organisation of the human embryo in the absence of maternal tissues. Nature Cell Biology; 4 May 2016; DOI: 10.1038/ncb3347

Deglincerti, A et al. Self-organization of the in vitro attached human embryo. Nature; 4 May 2016

A new technique that allows embryos to develop in vitro beyond the implantation stage (when the embryo would normally implant into the womb) has been developed by scientists at the ̽��ֱ�� of Cambridge allowing them to analyse for the first time key stages of human embryo development up to 13 days after fertilisation. ̽��ֱ��technique could open up new avenues of research aimed at helping improve the chances of success of IVF.

Implantation is a milestone in human development as it is from this stage onwards that the embryo really begins to take shape and the overall body plans are decided

Magdalena Zernicka-Goetz

Magda Human Embryo

Zernick-Goetz lab, ̽��ֱ�� of Cambridge

Imaging a human embryo in the absence of maternal tissues - day 10 (left) and day 11 (right)

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Early-stage embryos with abnormalities may still develop into healthy babies

cjb250 — Tue, 29 Mar 2016 09:00:29 +0000

Researchers at the Department of Physiology, Development and Neuroscience at Cambridge report a mouse model of aneuploidy, where some cells in the embryo contain an abnormal number of chromosomes. Normally, each cell in the human embryo should contain 23 pairs of chromosomes (22 pairs of chromosomes and one pair of sex chromosomes), but some can carry multiple copies of chromosomes, which can lead of developmental disorders. For example, children born with three copies of chromosome 21 will develop Down’s syndrome.

Pregnant mothers – particular older mothers, whose offspring are at greatest risk of developing such disorders – are offered tests to predict the likelihood of genetic abnormalities. Between the 11th and 14th weeks of pregnancy, mothers may be offered chorionic villus sampling (CVS), a test that involves removing and analysing cells from the placenta. A later test, known as amniocentesis, involves analysing cells shed by the foetus into the surrounding amniotic fluid – this test is more accurate, but is usually carried out during weeks 15-20 of the pregnancy, when the foetus is further developed.

Professor Magdalena Zernicka-Goetz, the study’s senior author, was inspired to carry out the research following her own experience when pregnant with her second child. “I am one of the growing number of women having children over the age of 40 – I was pregnant with my second child when I was 44,” says Professor Zernicka-Goetz.

At the time, a CVS test found that as many as a quarter of the cells in the placenta that joined her and her developing baby were abnormal: could the developing baby also have abnormal cells? When Professor Zernicka-Goetz spoke to geneticists about the potential implications, she found that very little was understood about the fate of embryos containing abnormal cells and about the fate of these abnormal cells within the developing embryos.

Fortunately for Professor Zernicka-Goetz, her son, Simon, was born healthy. “I know how lucky I was and how happy I felt when Simon was born healthy,” she says.

“Many expectant mothers have to make a difficult choice about their pregnancy based on a test whose results we don’t fully understand,” says Professor Zernicka-Goetz. “What does it mean if a quarter of the cells from the placenta carry a genetic abnormality – how likely is it that the child will have cells with this abnormality, too? This is the question we wanted to answer. Given that the average age at which women have their children is rising, this is a question that will become increasingly important.”

“In fact, abnormal cells with numerical and/or structural anomalies of chromosomes have been observed in as many as 80-90% of human early stage embryos following in vitro fertilization,” says Professor Thierry Voet from the Wellcome Trust Sanger Institute, UK, and the ̽��ֱ�� of Leuven, Belgium, another senior author of this paper, “and CSV tests may expose some degree of these abnormalities.”

In research funded by the Wellcome Trust, Professor Zernicka-Goetz and colleagues developed a mouse model of aneuploidy by mixing 8-cell stage mouse embryos in which the cells were normal with embryos in which the cells were abnormal. Abnormal mouse embryos are relatively unusual, so the team used a molecule known as reversine to induce aneuploidy.

In embryos where the mix of normal and abnormal cells was half and half, the researchers observed that the abnormal cells within the embryo were killed off by ‘apoptosis’, or programmed-cell death, even when placental cells retained abnormalities. This allowed the normal cells to take over, resulting in an embryo where all the cells were healthy. When the mix of cells was three abnormal cells to one normal cell, some of abnormal cells continued to survive, but the ratio of normal cells increased.

“ ̽��ֱ��embryo has an amazing ability to correct itself,” explains Professor Zernicka-Goetz. “We found that even when half of the cells in the early stage embryo are abnormal, the embryo can fully repair itself. If this is the case in humans, too, it will mean that even when early indications suggest a child might have a birth defect because there are some, but importantly not all abnormal cells in its embryonic body, this isn’t necessarily the case.”

̽��ֱ��researchers will now try to determine the exact proportion of healthy cells needed to completely repair an embryo and the mechanism by which the abnormal cells are eliminated.

Reference
Bolton, H et al. Mouse model of chromosome mosaicism reveals lineage-specific depletion of aneuploid cells and normal developmental potential. Nature Comms; 26 March 2016; DOI: 10.1038/ncomms11165

Abnormal cells in the early embryo are not necessarily a sign that a baby will be born with a birth defect such as Down’s syndrome, suggests new research carried out in mice at the ̽��ֱ�� of Cambridge. In a study published today in the journal Nature Communications, scientists show that abnormal cells are eliminated and replaced by healthy cells, repairing – and in some cases completely fixing – the embryo.

What does it mean if a quarter of the cells from the placenta carry a genetic abnormality – how likely is it that the child will have cells with this abnormality, too? This is the question we wanted to answer

Magdalena Zernicka-Goetz

Zappys Technology Solutions

Chromosomes (cropped)

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