̽��ֱ�� of Cambridge - developmental biology

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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Scientists develop mouse ‘embryo-like structures’ with organisation along body’s major axes

cjb250 — Wed, 03 Oct 2018 17:00:21 +0000

̽��ֱ��definitive architecture of the mammalian body is established shortly after the embryo implants into the uterus. This body plan has spatial references, or axes, that guide the emergence of tissues and organs: an antero-posterior axis defined by the head at one end and the tail at the other, an orthogonal dorso-ventral axis and a medio-lateral axis, which orientates the arrangement of internal organs like the liver, pancreas or the heart.

Studying the processes orchestrating the formation of early mammalian embryos is hampered by the difficulty in obtaining them. Earlier findings from the Cambridge group had shown that embryonic stem cells could self-organise in culture into structures with an antero-posterior polarity.

Now, in collaboration with researchers from the ̽��ֱ�� of Geneva and the Swiss Federal Institute of Technology Lausanne (EPFL), they have extended the cultures to reveal a capacity of mouse stem cells to produce ‘pseudo-embryos’ that display some of the important characteristics of a normal mouse embryo. Established from only 300 embryonic stem cells, these structures, called ‘gastruloids’, exhibit developmental features and organisation comparable to the posterior part of a six to ten day-old embryo.

̽��ֱ��study shows that gastruloids organise themselves with regard to the three main body axes, as they do in embryos, and follow similar patterns of gene expression. One example of this is the pattern of expression of Hox genes, an ensemble of genes that are expressed in a precise sequential order in the embryo and act as landmarks for different aspects of the body, including the position of different vertebrae or of limbs. This degree of organisation makes gastruloids a remarkable system for the study of the early stages of normal or abnormal embryonic development in mammals.

“These results significantly extend our earlier findings. We were surprised to see how far gastruloids develop, their complex organisation and the presence of early-stage tissues and organ,” says Professor Alfonso Martinez Arias, leader of the ̽��ֱ�� of Cambridge team, at its Department of Genetics.

Professor Denis Duboule from the ̽��ֱ�� of Geneva and at the EPFL explained, “To determine whether gastruloids organise themselves into bona fide embryonic structures, we characterised their level of genetic activity at different stages of development”.

̽��ֱ��researchers identified and quantified the RNA transcribed from gastruloids and compared the expressed genes with those of mouse embryos at comparable stages of development, which showed there was a high degree of similarity.

“Gastruloids form structures similar to the posterior part of the embryo, from the base of the brain to the tail, whose development program is somewhat different from that of the head,” says Dr Leonardo Beccari, co-first author of the study, from the ̽��ֱ�� of Geneva.

These embryo-like structures express genes characteristic of the various types of progenitor cells necessary for the constitution of future tissues.

“ ̽��ֱ��complexity of gene expression profiles increases over time, with the appearance of markers from different embryonic cell lineages, much like the profiles observed in control embryos,” adds Dr Naomi Moris from the Cambridge team, co-first author of the article.

“ ̽��ֱ��implementation of the Hox gene network over time, which mimics that of the embryo, particularly confirms the remarkably high level of self-organisation of gastruloids,” explains Mehmet Girgin, co-first author of the study and PhD student at the Institute of Bioengineering at EPFL.

̽��ֱ��researchers say that these pseudo-embryos will allow an alternative method to animal research, in accordance with the principle of the ‘3Rs’ (the reduction, replacement and refinement of the use of animals in research). ̽��ֱ��finding that so much of the development of an embryo can be recapitulated using stem cells will also increase researchers’ ability to study the genetic mechanisms underlying normal development and disease.

Earlier in the year, the group led by Professor Magdalena Zernicka-Goetz at the Department of Physiology, Development and Neuroscience at the ̽��ֱ�� of Cambridge reported embryo-like structures capable of generating an anteroposterior axis but which required additional, extra-embryonic, stem cells to generate anteroposterior polarity. ̽��ֱ��new work shows surprisingly that stem cells can self-organise the three axes independently of the extra-embryonic tissues.

“It makes things much simpler for research,” says Professor Martinez Arias. “Not only do gastruloids self-organise to generate the three axes, but they also mimic the spatial and temporal patterns of embryos, without extra-embryonic tissue. This suggests that gastruloids can become a useful tool, particularly in understanding gene expression during development.”

This work was largely funded by the Biotechnology and Biological Sciences Research Council (BBSRC), the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), the Engineering and Physical Sciences Research Council (EPSRC) and the European Research Council.

Adapted from a press release from the ̽��ֱ�� of Geneva.

Reference
Beccari, L, Moris, N, Girgin, M, et al. Multi-axial self-organisation properties of mouse embryonic stem cells into gastruloids. Nature; 3 Oct 2018; DOI: 10.1038/s41586-018-0578-0

Image caption
Seven-day old gastruloid. ̽��ֱ��cell nuclei are marked in blue. Neural progenitor cells (green) are distributed along the antero-posterior axis. Progenitor cells of the tail bud (pink) are confined to the posterior extremity of the gastruloid and indicate the direction of its elongation. © Mehmet Girgin, EPFL

A team of scientists at the ̽��ֱ�� of Cambridge has developed an artificial mouse embryo-like structure capable of forming the three major axes of the body. ̽��ֱ��technique, reported today in the journal Nature, could reduce the use of mammalian embryos in research.

We were surprised to see how far gastruloids develop, their complex organisation and the presence of early-stage tissues and organ

Alfonso Martinez Arias

Mehmet Girgin, EPFL

Seven-day old gastruloid

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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!”

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Ancient fish scales and vertebrate teeth share an embryonic origin

fpjl2 — Mon, 20 Nov 2017 20:05:34 +0000

In biology, one long-running debate has teeth: whether ancient fish scales moved into the mouth with the origin of jaws, or if the tooth had its own evolutionary inception.

Recent studies on species such as zebrafish showed scales and teeth developing from distinctly different clusters of cells in fish embryos, pouring cold water on ‘teeth from scales’ theories.

However, while most fish in the sea have bones, one ancient lineage – sharks, skates and rays – possess skeletons made entirely of cartilage.

These cartilaginous fish retain some primitive characteristics that have been lost in their bony counterparts, including small spiky scales embedded in their skin called ‘dermal denticles’ that bear a striking resemblance to jagged teeth.

Now, researchers at the ̽��ֱ�� of Cambridge have used fluorescent markers to track cell development in the embryo of a cartilaginous fish – a little skate in this case – and found that these thorny scales are in fact created from the same type of cells as teeth: neural crest cells.

̽��ֱ��findings, published in the journal PNAS, support the theory that, in the depths of early evolution, these ‘denticle’ scales were carried into the emerging mouths of jawed vertebrates to form teeth. Jawed vertebrates now make up 99% of all living vertebrates, from fish to mammals.

“ ̽��ֱ��scales of most fish that live today are very different from the ancient scales of early vertebrates,” says study author Dr Andrew Gillis from Cambridge’s Department of Zoology and the Marine Biological Laboratory in Woods Hole.

“Primitive scales were much more tooth-like in structure, but have been retained in only a few living lineages, including that of cartilaginous fishes such as skates and sharks.

“Stroke a shark and you’ll find it feels rougher than other fish, as shark skin is covered entirely in dermal denticles. There’s evidence that shark skin was actually used as sandpaper as early as the Bronze Age,” says Gillis.

“By labelling the different types of cells in the embryos of skate, we were able to trace their fates. We show that, unlike most fish, the denticle scales of sharks and skate develop from neural crest cells, just like teeth.

“Neural crest cells are central to the process of tooth development in mammals. Our findings suggest a deep evolutionary relationship between these primitive fish scales and the teeth of vertebrates.

“Early jawless vertebrates were filter feeders – sucking in small prey items from the water. It was the advent of both jaws and teeth that allowed vertebrates to begin processing larger and more complex prey.”

̽��ֱ��very name of these scales, dermal denticles, alludes to the fact that they are formed of dentine: a hard calcified tissue that makes up the majority of a tooth, sitting underneath the enamel.

̽��ֱ��jagged dermal denticles on sharks and skate – and, quite possibly, vertebrate teeth – are remnants of the earliest mineralised skeleton of vertebrates: superficial armour plating.

This armour would have perhaps peaked some 400 million years ago in now-extinct jawless vertebrate species, as protection against predation by ferocious sea scorpions, or even their early jawed kin.

̽��ֱ��Cambridge scientists hypothesise that these early armour plates were multi-layered: consisting of a foundation of bone and an outer layer of dentine – with the different layers deriving from different types of cells in unborn embryos.

These layers were then variously retained, reduced or lost in different vertebrate linages over the course of evolution. “This ancient dermal skeleton has undergone considerable reductions and modifications through time,” says Gillis.

“ ̽��ֱ��sharks and skate have lost the bony under-layer, while most fish have lost the tooth-like dentine outer layer. A few species, such as the bichir, a popular fish in home aquariums, have retained aspects of both layers of this ancient external skeleton.”

Latest findings support the theory that teeth in the animal kingdom evolved from the jagged scales of ancient fish, the remnants of which can be seen today embedded in the skin of sharks and skate.

This ancient dermal skeleton has undergone considerable reductions and modifications through time

Andrew Gillis

Andrew Gillis, Gillis Lab.

Dermal denticles on the tail of the Little Skate, as used in the latest research.

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

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Breath of life: how your risk of heart disease may stem back to your time in the womb

cjb250 — Tue, 11 Jul 2017 08:00:07 +0000

̽��ֱ��history of science is littered with self-experimenters so passionate about their work that they used themselves as human guinea pigs, however ill-advisedly.

Sir Joseph Barcroft (1872–1947) was one such character. Professor of Physiology at Cambridge, he was best known for his studies of the oxygenation of blood. He also led mountain expeditions where he analysed the oxygen content of his blood and that of other expedition members.

In the middle of his career, Barcroft built an airtight glass chamber in his laboratory in Cambridge. There, he could live and exercise at oxygen levels equivalent to 16,000 feet. Like many self-experimentation stories, things did not always go to plan: in one experiment, he had to be rescued by colleagues after spending six days in the chamber and reportedly turning blue.

Despite his occasional misguided venture, Barcroft’s scientific legacy was significant and so, in his honour, the ̽��ֱ�� of Cambridge has recently opened a new state-of-the-art facility in his name. Research at the Barcroft Centre focuses on farm animals – mainly sheep and chickens, but also pigs – to model important aspects of human physiology.

̽��ֱ��Centre’s work spans several areas including Professor Jenny Morton’s studies on understanding fatal neurodegenerative diseases such as Huntington’s disease and a similar childhood disease, Batten disease, and Dr Frances Henson’s work on bone diseases such as osteoarthritis.

However, a significant amount of its work focuses on how we develop in the womb and how this programmes us for increased risk of heart disease in later life. This seems fitting as, in later years, Barcroft became interested in fetal development, and in particular the effects of low levels of oxygen on the unborn baby in the womb.

Carrying on this legacy are Professor Dino Giussani and his postdocs Dr Kim Botting and Dr Youguo Niu. All are also members of the Centre for Trophoblast Research (CTR), which this year celebrates its tenth anniversary and focuses on the interactions between the pregnant mother and the fetus, as mediated by the placenta.

Low levels of oxygen – or hypoxia – can occur in high-altitude pregnancies. But, as Giussani explains, there are far more common causes. “Smoking, pre-eclampsia, even maternal obesity – these all increase the risk of hypoxia for the mother’s baby, as do inherited genetic variants,” he says.

Housed in the Barcroft Centre is a suite of hypoxia chambers – superficially similar, perhaps, to that in which Barcroft placed himself, but nowadays far more sophisticated (and much safer). These are not intended for humans, but rather for animals, each of which is very closely monitored, often remotely using technology developed by the team.

̽��ֱ��smallest of these chambers doubles as an incubator for fertilised hens’ eggs. Scientists can watch the development of the fetus directly. They can see how the heart grows, for example, how it is affected by hypoxia, and what effect potential drugs have in ameliorating possible complications.

Of course, we grow in a womb, with a placenta connecting us to our mother and controlling our nutritional intake. Mice and rats are the most commonly used mammals in research, but to model mammalian development in longer-living species with similar rates of development to humans, it is necessary to turn to larger animals. Sheep make a good model. Not only is their gestation – and postnatal life – more comparable to a human’s than to a rat’s, but a newborn lamb’s physiology is also similar in a crucial way to a newborn baby’s: its heart is mature at birth. By comparison, a newborn rat’s heart is still very immature.

For part of gestation, the sheep are placed in hypoxia chambers, which contain finely controlled, lower-than-normal levels of oxygen. “This reduces the amount of oxygen in the blood of the pregnant sheep and thereby in her fetus,” explains Botting. “This mimics conditions where the placenta is not working appropriately, as in pregnancy complicated by pre-eclampsia or maternal obesity.”

̽��ֱ��pregnant ewes deliver outside the chambers in normal ambient air. Once born, most of the lambs are put out to pasture in the paddocks adjacent to the Centre, where they grow to adulthood.

“ ̽��ֱ��lambs which were hypoxic in the womb are not noticeably different,” says Giussani. “ ̽��ֱ��sheep will effectively live a normal life. That is the very point, because underneath, a silent killer is brewing; we want to investigate what happens as they grow because there is a theory that a complicated pregnancy may increase the risk of heart disease in the offspring later in life.”

Professor Abby Fowden, Head of the School of the Biological Sciences, and another CTR member and user of the Barcroft Centre, says that the facilities are unique. “It’s probably the only centre in the UK that has the capacity – the surgical and care facilities – to do these kinds of long-term developmental and neurodegenerative studies,” she explains.

Like Giussani, Fowden and her collaborator Dr Alison Forhead are interested in how the early environment in the womb programmes us for disease in later life. They are particularly interested in the role of hormones – in both the mother and the fetus – and how they affect growth and development.

There are some conditions, such as hypothyroidism – whereby the body produces insufficient thyroid hormones – and maternal stress, that probably affect normal fetal development, but about which surprisingly little is understood. To model these conditions, Fowden and Forhead again turn to a range of mammals including sheep and pigs.

As Forhead explains, normal development of the fetus is crucial for health in later life. “In the case of many organs, you’re born with a certain number of functional units, and in postnatal life you don’t have the capacity to change that number. So the number you’re born with has long-lasting consequences.”

Take nephrons, for example. These are functional units of our kidneys that filter the blood and are responsible for how much salt and water is excreted into the urine. “If you’re born with fewer nephrons, this has consequences for how much salt you retain, setting you up in later life to be at greater risk of developing high blood pressure.”

What is apparent from this work is just how much of disease in later life is programmed in the womb. While our lifestyle – our diet, how much we exercise after birth – plays an important role in whether we develop heart disease or type 2 diabetes, for example, much of the risk is present before we are even born, programmed during pregnancy into how our DNA and tissues function.

And these effects don’t necessarily stop at the next generation, as Giussani is discovering in his parallel work with rodents, which allows two or more generations to be studied in a comparably short time.

“If we look at the ‘grandchildren’ of pregnant rats that had a hypoxic pregnancy, we see this disease risk being passed on again, but in a really interesting way,” he says. “A male ‘child’ passes on the cardiovascular risk to the ‘grandchild’, but female offspring confer protection. This is really exciting as inheritable protection against a future risk of heart disease has never been demonstrated in mammals.”

In other words, while we must still recognise our own contribution to our risk of developing certain diseases, some of this risk was programmed into us before we were born: in fact, even before our parents were born. Work at the Barcroft Centre – in monitoring animals for not just one generation but several – will be vital for understanding the consequences of pregnancy not only for our children but also for their children – and even their children’s children.

Inset image: Joseph Barcroft.

Smoking, lack of exercise, bad diet and our genes are all well-known risk factors for heart disease, cancer and diabetes. But, as researchers are beginning to understand, the environment in the womb as we first begin to grow may also determine our future.

Underneath, a silent killer is brewing... there is a theory that a complicated pregnancy may increase the risk of heart disease in the offspring later in life.

Dino Giussani

Ryan Melaugh

IMG_1331

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

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Human reproduction likely to be more efficient than previously thought

cjb250 — Tue, 13 Jun 2017 10:23:54 +0000

Dr Gavin Jarvis from Cambridge’s Department of Physiology, Development and Neuroscience re-examined data going back to the 1940’s and concluded that previous claims about natural embryo mortality are too often exaggerated. His report is published in F1000Research.

“Trying to determine whether a human embryo survives during the first days after fertilisation is almost impossible,” says Dr Jarvis. “A woman can only suspect that she is pregnant, at the earliest, two weeks after fertilisation, when she misses a period. Using sensitive laboratory tests, embryos can be detected as they implant into the womb about one week after fertilisation. What happens before then under natural circumstances is anyone’s guess.”

In 1938, two doctors in Boston, Dr Arthur Hertig and Dr John Rock, became the first people to see a human embryo when they examined wombs removed from women during surgery. They estimated that a half of human embryos die in the first two weeks after fertilisation. However, Dr Jarvis’s re-analysis of this data shows that this figure is so imprecise as to be of little value.

“I think it is fair to say that their data show that embryos can and do fail at these early stages, and also that many do just fine, but we could say that even without the data,” he adds. “Hertig’s samples, whilst descriptively informative, are quantitatively unhelpful. It doesn’t take us much further than where we would be without the data.”

Pregnancies are also lost after the first two weeks and currently published estimates of total embryo loss from fertilisation through to birth range from less than 50% to 90%. Embryo mortality of 90% implies that only 10% of embryos survive to birth, implying that human reproduction is highly inefficient.

Since 1988, several studies on women trying to get pregnant have provided a more consistent picture. ̽��ֱ��earliest point at which pregnancy can be detected is one week after fertilisation when the embryo starts to implant into the womb of the mother. At this point the hormone hCG, which is used in regular pregnancy tests, becomes detectable. Among implanting embryos, about one in five fail very soon and the woman will have a period at about the expected time, never suspecting that she conceived. Once a period is missed and pregnancy confirmed, about 10-15% will be lost before live birth, mostly within the first few months. In total, once implantation starts, about two thirds of embryos survive to birth. ̽��ֱ��number of embryos that survive and die before implantation remains unknown.

Modern reproductive technologies have enabled fertilisation to be observed directly in the laboratory. Poor survival of in vitro embryos may have contributed to the pessimistic view about natural human embryo survival, says Dr Jarvis.

“Fertilising human eggs and culturing human embryos in the laboratory is not easy. A large proportion of eggs fertilised in vitro do not develop properly even for a week. Of those that do and are transferred into women undergoing IVF treatment, most do not become a new-born baby.”

This failure of in vitro embryos may reflect the natural situation. Alternatively, the artificial environment of reproductive treatments may contribute to the high failure rate of IVF embryos. Dr Jarvis’s re-analysis of the data suggests that the latter is the case.

“It’s impossible to give a precise figure for how many embryos survive in the first week but in normal healthy women, it probably lies somewhere between 60-90%. This wide range reflects the lack of relevant data. Although we can’t be precise, we can avoid exaggeration, and from reviewing the studies that do exist, it is clear that many more survive than is often claimed,” concludes Dr Jarvis.

Reference
Gavin E Jarvis. Early embryo mortality in natural human reproduction: What the data say. f1000research; DATE; DOI: 10.12688/f1000research.8937.2

Gavin E Jarvis. Estimating limits for natural human embryo mortality. f1000research; DATE; DOI: 10.12688/f1000research.9479.2

How difficult is it to conceive? According to a widely-held view, fewer than one in three embryos make it to term, but a new study from a researcher at the ̽��ֱ�� of Cambridge suggests that human embryos are not as susceptible to dying in the first weeks after fertilisation as often claimed.

It’s impossible to give a precise figure for how many embryos survive in the first week but in normal healthy women, it probably lies somewhere between 60-90%

Gavin Jarvis

Esparta Palma

Dos rayitas

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Similarities in human and pig embryos provide clues to early stages of development

cjb250 — Wed, 07 Jun 2017 17:00:39 +0000

In research published today in Nature, researchers at the ̽��ֱ�� of Cambridge and the ̽��ֱ�� of Nottingham demonstrate how pig embryos and human embryonic cells show remarkable similarities in the early stages of their development. By combining these two models, they hope to improve our understanding of the origins of diseases such as paediatric germ cell tumours and fetal abnormalities.

Primordial germ cells, the precursors of eggs and sperm, are among the earliest cells to emerge in human embryos after implantation, appearing around day 17, while the surrounding cells go on to form the rest of the human body. However, little is understood about how they originate. Currently, the law prohibits culture of human embryos beyond 14 days, which prevents investigations on this and subsequent events such as gastrulation, when the overall body plan is established.

Now, researchers have used a combination of human and pig models of development to shed light on these events. They have shown for the first time that the interplay between two key genes is critical for the formation of the germline precursors and that this ‘genetic cocktail’ is not the same in all species.

First, by using human pluripotent embryonic stem cells in vitro, scientists led by Professor Azim Surani at the Wellcome Trust/Cancer Research UK Gurdon Institute established a model that simulates genetic and cellular changes occurring up to gastrulation. Human pluripotent embryonic stem cells are ‘master cells’ found in embryos, which have the potential to become almost any type of cell in the body.

As these stem cells can be multiplied and precisely genetically manipulated, the model system provides a powerful tool for detailed molecular analysis of how human cells transform into distinct cell types during early development, and which changes might underlie human diseases.

̽��ֱ��work shows that when an embryo progresses towards gastrulation, cells temporarily acquire the potential to form primordial germ cells, but shortly afterwards lose this potential and instead acquire the potential to form precursors of blood and muscle (mesoderm) or precursors of the gut, lung and the pancreas (endoderm). ̽��ֱ��model also tells us that while the genes SOX17 and BLIMP1 are critical for germ cell fate, SOX17 subsequently has another role in the specification of endodermal tissues.

For an accurate picture of how the embryo develops, however, it is necessary to understand how cells behave in the three-dimensional context of a normal embryo. This cannot be achieved by studies on the most commonly used mouse embryos, which develop as egg ‘cylinders’, unlike the ‘flat-disc’ human embryos. Pig embryos, on the other hand, develop as flat discs (similar to human embryos), can be easily obtained, and are ethically more acceptable than working with non-human primate (monkey) embryos.

Researchers from the ̽��ֱ�� of Nottingham dissected whole flat discs from pig embryos at different developmental stages and found that development of these embryos matches with the observations on the in vitro human model, as well as with non-human primate embryonic stem cells in vitro. For example, pig germ cells emerge in the course of gastrulation just as predicted from the human model, and with the expression of the same key genes as in human germ cells. Human and pig germ cells also exhibit key characteristics of this lineage, including initiation of reprogramming and re-setting of the epigenome – modifications to our DNA that regulate its operations and have the potential to be passed down to our offspring – which continues as germ cells progress towards development into sperm and eggs.

̽��ֱ��combined human-pig models for early development and cell fate decisions likely reflect critical events in early human embryos in the womb. Altogether, knowledge gained from this approach can be applied to regenerative medicine for the derivation of relevant human cell types that might be used to help understand and treat human diseases, and to understand how mutations that perturb early development can result in human diseases.

Dr Ramiro Alberio, from the School of Biosciences at the ̽��ֱ�� of Nottingham, says: “We’ve shown how precursors to egg and sperm cells arise in pigs and humans, which have similar patterns of embryo development. This suggests that the pig can be an excellent model system for the study of early human development, as well as improving our understanding of the origins of genetic diseases.”

Dr Toshihiro Kobayashi in the Surani lab at the Gurdon Institute, adds: “We are currently prevented from studying human embryo development beyond day 14, which means that certain key stages in our development remain a mystery. ̽��ֱ��remarkable similarities between human and pig development suggest that we may soon be able to reveal the answers to some of our long-held questions.”

̽��ֱ��research was supported by Wellcome.

Reference
Kobayashi, T et al. Principles of early human development and germ cell program from conserved model systems. Nature; 7 June 2017; DOI: 10.1038/nature22812

Scientists have shown how the precursors of egg and sperm cells – the cells that are key to the preservation of a species – arise in the early embryo by studying pig embryos alongside human stem cells.

̽��ֱ��remarkable similarities between human and pig development suggest that we may soon be able to reveal the answers to some of our long-held questions

Toshihiro Kobayashi

Walfred Tang (Surani lab)

Developing human primordial germ cells (each small green and red cell is a PGC)

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Miniature ‘womb lining’ grown in lab could reveal secrets of menstrual cycle and early pregnancy

cjb250 — Mon, 10 Apr 2017 15:30:19 +0000

̽��ֱ��mucosal lining inside the uterus is called the endometrium. Over the course of the menstrual cycle, its composition changes, becoming thicker and rich with blood vessels in preparation for pregnancy, but if the woman does not conceive, the uterus sheds this tissue, causing the woman’s period.

A team from the Centre for Trophoblast Research, which this year celebrates its tenth anniversary, was able to grow the organoids in culture from cells derived from endometrial tissue and maintain the organoids in culture for several months, faithfully reproducing the genetic signature of the endometrium – in other words, the pattern of activity of genes in the lining of the uterus. They also demonstrated that the organoids respond to female sex hormones and early pregnancy signals, secreting what are collectively known as ‘uterine milk’ proteins that nourish the embryo during the first months of pregnancy.

̽��ֱ��findings of the study, funded by the Medical Research Council, the Wellcome Trust and the Centre for Trophoblast Research, are published today in the journal Nature Cell Biology.

̽��ֱ��organoids are capable of generating both secretory (red) and epithelial (cyan) cells of the uterus. Image: Centre for Trophoblast Research

“These organoids provide a major step forward in investigating the changes that occur during the menstrual cycle and events during early pregnancy when the placenta is established,” says Dr Margherita Turco, the study’s first author. “These events are impossible to capture in a woman, so until now we have had to rely on animal studies.”

“Events in early pregnancy lay the foundations for a successful birth, and our new technique should provide a window into this events,” adds Professor Graham Burton, Director of the Centre for Trophoblast Research, and joint senior author with Ashley Moffett of the study. “There’s increasing evidence that complications of pregnancy, such as restricted growth of the fetus, stillbirth and pre-eclampsia – which appear later in pregnancy – have their origins around the time of implantation, when the placenta begins to develop.”

Research in animal species such as mice and sheep has shown that factors secreted by the endometrial glands are critical for enabling a developing fertilised egg (known as the ‘conceptus’) to implant into the wall of the uterus. There is also strong evidence that the conceptus sends signals to the endometrial glands that then stimulate the development of the placenta. In this way, the conceptus is able to stimulate its own development through a ‘dialogue’ with the mother; if it fails, the result is loss of the pregnancy or severe growth restriction of the fetus.

Professor Burton and colleagues believe that using the organoids will allow them to investigate in greater detail how the conceptus communicates with the glands, identifying the full repertoire of factors released in response and testing their effects on placental tissues. His team will be collaborating with the Bourn Hall Clinic – a fertility clinic near Cambridge – to investigate whether parts of this circuitry are impaired or deficient in women experiencing difficulty in conceiving, and if so to devise potential new treatments.

̽��ֱ��technique also enables the researchers to grow organoids from endometrial cancer cells. As proof-of-principle, this will allow them to model and understand diseases of the endometrium, including cancer of the uterus and endometriosis.

Organoid cultures have proven to be powerful tools for investigating the behaviour of other organ systems. Members of the Centre for Trophoblast Research are confident that their new advance will provide a much-needed window on events during the earliest stages of pregnancy, when the conceptus and mother first physically interact.

Reference
Turco, MY et al. Long-term, hormone-responsive organoid cultures of human endometrium in a chemically defined medium. Nature Cell Biology; 10 April 2017; DOI: 10.1038/ncb3516

Scientists at the ̽��ֱ�� of Cambridge have succeeded in growing miniature functional models of the lining of the womb (uterus) in culture. These organoids, as they are known, could provide new insights into the early stages of pregnancy and conditions such as endometriosis, a painful condition that affects as many as two million women in the UK.

These organoids provide a major step forward in investigating the changes that occur during the menstrual cycle and events during early pregnancy

Margherita Turco

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