̽��ֱ�� of Cambridge - placenta

Surviving birth

lw355 — Thu, 10 Dec 2020 09:00:28 +0000

Researchers at one of the busiest maternity hospitals in the world aim to help more women survive complications giving birth.

‘Mini-placentas’ could provide a model for early pregnancy

cjb250 — Wed, 28 Nov 2018 18:00:49 +0000

Many pregnancies fail because the embryo does not implant correctly into the lining of the womb (uterus) and fails to form a placental attachment to the mother. Yet, because of the complexities of studying this early period of our development, very little is understood about what is happening normally and what can go wrong. Animals are too dissimilar to humans to provide a good model of placental development and implantation.

“ ̽��ֱ��placenta is absolutely essential for supporting the baby as it grows inside the mother,” says Dr Margherita Turco, the study’s first author, from the Departments of Pathology and Physiology, Development and Neuroscience at the ̽��ֱ�� of Cambridge. “When it doesn’t function properly, it can result in serious problems, from pre-eclampsia to miscarriage, with immediate and lifelong consequences for both mother and child. But our knowledge of this important organ is very limited because of a lack of good experimental models.”

Efforts to grow human placental cells started over 30 years ago in the Pathology department where Professors Ashley Moffett and Charlie Loke were studying cellular events in the first few weeks of pregnancy. With their chief technician, Lucy Gardner, they found ways to isolate and characterise placental trophoblast cells. These techniques, combined with the organoid culture system, enabled the generation of miniature functional models of the early placenta – or ‘mini-placentas’.

In the past few years, a new field of research has blossomed that uses these organoids – often referred to as ‘mini-organs’ – enabling insights into human biology and disease. At the ̽��ֱ�� of Cambridge, one of the world leaders in organoid research, scientists are using organoid cultures to grow everything from ‘mini-brains’ to ‘mini-livers’ to ‘mini-lungs’.

In a study funded by Wellcome and the Centre for Trophoblast Research, the Cambridge team was able to grow organoids using cells from villi – tiny frond-like structures – taken from placental tissue. These trophoblast organoids are able to survive long-term, are genetically stable and organise into villous-like structures that secrete essential proteins and hormones that would affect the mother’s metabolism during the pregnancy. Further analysis showed that the organoids closely resemble normal first-trimester placentas. In fact, the organoids so closely model the early placenta that they are able to record a positive response on an over-the-counter pregnancy test.

Professor Graham Burton, a co-author and Director of the Centre for Trophoblast Research, which last year celebrated its tenth anniversary, says: “These ‘mini-placentas’ build on decades of research and we believe they will transform work in this field. They will play an important role in helping us investigate events that happen during the earliest stages of pregnancy and yet have profound consequences for the life-long health of the mother and her offspring. ̽��ֱ��placenta supplies all the oxygen and nutrients essential for growth of the fetus, and if it fails to develop properly the pregnancy can sadly end with a low birthweight baby or even a stillbirth.”

In addition, the organoids may shed light on other mysteries surrounding the relationships between the placenta, the uterus and the fetus: why, for example, is the placenta able to prevent some infections passing from the mother’s blood to the fetus while others, such as Zika virus, are able to pass through this barrier? ̽��ֱ��organoids may also be used for screening the safety of drugs to be used in early pregnancy, to understand how chromosomal abnormalities may perturb normal development, and possibly even provide stem cell therapies for failing pregnancies.

Last year, the same team supported by Cambridge’s Centre for Trophoblast Research reported growing miniature functional models of the uterine lining.

“Now that we’ve developed organoid models of both sides of the interface – maternal tissue and placental tissue – we can start to look at how these two sides talk to each other,” adds Professor Ashley Moffett.

Professor Moffett also co-directed a recent study published in Nature that used genomics and bioinformatics approaches to map over 70,000 single cells at the junction of the uterus and placenta. This study revealed how the cells talk to each other to modify the immune response and enable the pregnancy, presenting new and unexpected cell states in the uterus and placenta, and showing which genes are switched on in each cell.

References

Turco, MY et al. Trophoblast organoids as a model for maternal-fetal interactions during human placentation. Nature; 28 Nov 2018; DOI: 10.1038/s41586-018-0753-3

Vento-Tormo, R, et al. Single-cell reconstruction of the early maternal–fetal interface in humans. Nature; 14 Nov 2018; DOI: 10.1038/s41586-018-0698-6

Researchers say that new ‘mini-placentas’ – a cellular model of the early stages of the placenta – could provide a window into early pregnancy and help transform our understanding of reproductive disorders. Details of this new research are published today in the journal Nature.

̽��ֱ��placenta is absolutely essential for supporting the baby as it grows inside the mother. When it doesn’t function properly, it can result in serious problems

Margherita Turco

Title: Image reproduced with the permission of SPD Swiss Precision Diagnostics GmbH (SPD)

Researcher profile: Dr Margherita Turco

Dr Margherita Turco began her career studying the development of embryos in domestic animals during her studies for Veterinary Biotechnology at the ̽��ֱ�� of Bologna, in Italy. During her PhD in Molecular Medicine at the European Institute of Oncology in Milano, she became interested in how early cell lineage decisions are made and began using various stem cells models to address this question.

This led Margherita to come to Cambridge in 2012 to carry out her postdoctoral work on human trophoblast stem cells at Cambridge’s Centre for Trophoblast Research (CTR), during which time she was awarded a Marie Curie Fellowship. She now has a Royal Society Dorothy Hodgkin Fellowship that has enabled her to build up her own research group.

Margherita’s goal is to understand how the human placenta grows and develops during pregnancy.

“ ̽��ֱ��placenta is a remarkable organ that is formed early in pregnancy. It plays the crucial role of nourishing and protecting the baby throughout its development before birth,” she says.

There is a lot that can go wrong during this period, however.

“Complications occurring during pregnancy, such as pre-eclampsia, fetal growth restriction, stillbirth, miscarriage and premature birth, are principally due to defective placental function. These conditions, which collectively affect around one in five pregnancies, can pose a risk to both the baby and mother’s health. Understanding early placental development is the key to understanding successful pregnancy.”

Human placental development has been a ‘black box’ for ethical and practical reasons. “ ̽��ֱ��lack of reliable experimental models that accurately mimic how placental cells behave has hindered our ability to ask even quite basic questions,” she says.

To address this issue, Margherita was funded by the CTR to develop models of the human placenta.. Her mentors have included Professors Ashley Moffett and Graham Burton from the Centre, and Dr Myriam Hemberger from the Babraham Institute, bringing together different a wide range of expertise to this challenging project.

Margherita uses a type of model known as an ‘organoid’ and has now managed to generate organoid models from both the mother’s uterus and the placenta, the two sides of the maternal-fetal interface.

“As their name suggests, organoids are essentially mini-organs grown in the laboratory that preserve the normal cellular architecture and function,” she says. “They have proved to be powerful tools in investigating development and biological functions in many other organ systems – the heart, gut, liver, kidney and brain. They can also be used for screening drugs and studying how pathogens affect tissues. I believe they will be equally transformative for the investigation of early pregnancy and the origin of later complications.”

Cambridge has been the ideal place for Margherita to carry out her research because of the unique concentration of placental and stem cell biologists within the CTR.

“There is no other place in the world with such a combination of skills, knowledge and resources,” she says.

“I hope to be able to uncover the mysterious events that occur early in human pregnancy that previously were not possible to study. In the longer term, I hope this will alleviate the suffering experienced by couples affected by infertility or complications of pregnancy.”

̽��ֱ��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

Placenta plays pivotal “umpire” role to influence pregnancy outcomes

tdk25 — Mon, 12 Sep 2016 19:00:56 +0000

Researchers have shown for the first time how the placenta “umpires” a fight for nutrients between a pregnant mother and her unborn baby. ̽��ֱ��study suggests that the placenta will adjust the amount of nutrients transported to the foetus for growth in line with the mother’s physical ability to supply.

̽��ֱ��findings, published in the journal PNAS, suggest that if the bodily environment that a mother provides for her baby is unfavourable, for example through small body size or metabolic dysfunction, the placenta will change the flow of nutrients to the foetus relative to her own state. This can affect foetal development, resulting in complications at birth.

It is the first time that scientists have been able to provide clear evidence that the placenta plays the decisive role in this delicate balancing act, rather than merely acting as a passive interface which enables the transfer of nutrients from mother to foetus.

̽��ֱ��study, by researchers at the ̽��ֱ�� of Cambridge, involved making a precise genetic change in mice, which caused poor growth and changed the mother’s bodily environment. They then observed how the placenta developed and acted in response, finding that in mothers in which this alteration had been made, the structure of the placenta was different, and fewer nutrients reached the foetus.

A better understanding of how the placenta manages the trade-off will eventually enable researchers to reduce pregnancy complications in both humans and other mammals.

̽��ֱ��study was led by Dr Amanda Sferruzzi-Perri, a Research Associate at St John’s College, ̽��ֱ�� of Cambridge, and is part of a five-year project in the Department of Physiology, Development and Neuroscience examining the relationship between the placenta and pregnancy complications.

“During pregnancy there is a kind of ‘tug-of-war’ going on between the mother and the foetus over who gets the nutrients that the mother ingests,” Sferruzzi-Perri said. “This work shows for the first time that the placenta is the umpire which controls that fight. Understanding more about the placenta’s role is extremely important. If nutrients cannot be divided correctly during pregnancy, it can lead to life-threatening complications for expectant mothers, and long-term health consequences for both mother and child.”

At least one in every eight pregnancies in the UK is affected by complications stemming from impairment of the placenta. In the developing world the rate is even higher, with at least one in every five pregnant women affected. ̽��ֱ��potential consequences include abnormal birth weight, premature delivery, pre-eclampsia, and maternal diabetes.

A major cause appears to be the placenta’s response to unfavourable biological changes in the mother herself. These may, for example, be the result of poor nutrition, high stress levels, metabolic dysfunction, or obesity.

How the placenta allocates nutrients in these situations, however, and the hormonal signals that the placenta may be releasing while doing so, is not fully understood. By understanding these processes better, researchers hope to identify both the biological early warning signals that a problem has arisen, and their relationship to specific causes, enabling them to develop therapeutic interventions that reduce the number of complications overall.

̽��ֱ��new study represents a step towards those aims because researchers were able to directly influence the balancing act that the placenta performs and observe it in relation to both the physiology of the mother, and the actual growth and nutrient supply of the foetus.

To achieve this they used a model system where an enzyme called p110 alpha was genetically modified in mice. In a healthy mother, this enzyme is activated by hormones like insulin and insulin-growth factors (IGFs), kick-starting a relay race within cells which stimulates nutrient uptake and, as a result, normal growth and metabolic function. By altering this enzyme, the team reduced the mother’s overall responsiveness to such hormones, creating an unfavourable environment.

̽��ֱ��results showed that in mothers which carried the altered form of p110 alpha, the placenta’s growth and structure was impaired. As well as being physically different, it was also found to be transporting fewer nutrients to the unborn offspring.

Because of the way in which the experiments were set up, the team were also able to see what would happen to the placenta if the foetus carried the altered form of p110 alpha, but the mother was normal. They found that in these cases, the placenta also showed defects, but was able to compensate for this by transporting more nutrients to the foetus, and thus optimising nutrition.

This shows that the placenta will fine-tune the distribution of nutrients between the mother and foetus, in response to the circumstances in which it finds itself. It also indicates that, because the mother needs to be able to support her baby both during pregnancy and after birth, the placenta will do its best to judge how much nutrition the foetus receives, so that the mother’s health is not compromised.

“ ̽��ֱ��placenta is taking in signals all the time from the mother and the foetus,” Sferruzzi-Perri explained. “If the mother has some sort of defect in her ability to grow, the placenta will limit the amount of nutrients it allocates to the foetus to try and preserve her health.”

“What this tells us is that the mother’s environment is a very strong, modifiable characteristic to which we should be paying more attention, in particular to see if there are specific factors that we can change to improve the outcome of pregnancies. Being able to influence the mother’s environment through changes in p110 alpha gives us a means to study this in a controlled way, and to work out what those critical factors are.”

̽��ֱ��next stage of the research will involve examining the signals that the placenta sends to the mother to affect the way she uses the nutrients she ingests, potentially providing important clues about biomarkers which provide an early warning of pregnancy complications.

Dr Sferruzzi-Perri’s research is supported by a Dorothy Hodgkin Fellowship from the Royal Society. Her paper, Maternal and fetal genomes interplay through phosphoinositol 3-kinase(PI3K)-p110α signalling to modify placental resource allocation, is published in PNAS. ̽��ֱ��work was supported by a Next Generation Fellowship from the Centre for Trophoblast Research.

New research provides the first clear evidence that the amount of nutrients transported to the foetus by the placenta adjusts according to both the foetal drive for growth, and the mother’s physical ability to provide.

During pregnancy there is a kind of ‘tug-of-war’ going on between the mother and the foetus over who gets the nutrients that the mother ingests. This work shows for the first time that the placenta is the umpire which controls that fight

Amanda Sferruzzi-Perri

Free stock image via Pexels.

"Pregnant".

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

Yes

Rethinking the secrets of life: a code upon a code

bjb42 — Sun, 04 Jan 2009 15:29:25 +0000

Cracking the DNA structure in the early 1950s revolutionised the study of genetics in providing key information on how cells transmit information to the next generation. Five decades later, upon the publication of the draft human genome sequence, we entered the so-called post-genomic era. ̽��ֱ��ability to interrogate our complete DNA sequence has allowed a field of genomic medicine to emerge that has had profound promise for our understanding of genetic disease.

But our genomes constitute more than just the linear DNA blueprint. DNA is bundled into three-dimensional chromosome structures. This packaging is influenced by molecular flags known as epigenetic modifications that are attached to the DNA and to the proteins that organise it into chromosomes. These chemical modifications (including methylation and acetylation) determine whether parts of chromosomes are tightly or loosely packaged, which in turn influences whether a gene has the potential to be switched on or off.

Remarkably, during cell division, cells acquire the same epigenetic modifications as their parent cell, resulting in the heritable transmission of these epigenetic states and a ‘memory’ of a cell’s identity. Epigenetic states, however, have inherent flexibility because they can undergo normal regulated change in response to particular stimuli, to modulate gene expression as the need arises; for example, during the development of stem cells into particular organ systems. If these natural epigenetic processes occur improperly, major adverse health and behaviours can ensue. Epigenetic modifications therefore render our genomes functionally flexible, adaptable and vulnerable.

̽��ֱ��study of the epigenetic control of genome function has led to the dawn of a new revolution that some have coined the ‘epigenomic era’. Professor Anne Ferguson-Smith (Department of Physiology, Development and Neuroscience), Dr Miguel Constância (Department of Obstetrics and Gynaecology) and Dr Sue Ozanne (Metabolic Research Laboratories at the Institute of Metabolic Science) are studying epigenetic processes that confer long-term memory to genes under the influence of the cellular environment, with far-reaching implications for human reproduction and health.

An epigenetic voyage in space and time

Epigenetic mechanisms of gene regulation are important throughout development, from when the sperm first meets the egg (fertilisation), through early lineage decisions, to fetal development and postnatal life. Somatic epigenetic modifications need to be ‘reprogrammed’ in germ cells and also in early embryos so as to achieve developmental pluripotency, whereby cells can give rise to all the cells needed in the developing fetus. This normally results in epigenetic marks that are different in some locations on chromosomes inherited from eggs compared with those inherited from sperm.

For 99% of genes inherited by the embryo, gene expression can occur from both the maternally and paternally inherited versions. But the remaining 1% are ‘imprinted’, which means that only one of the two gene copies is expressed after fertilisation. ̽��ֱ��teams of Professor Ferguson-Smith and Dr Constância use imprinted genes as tractable experimental systems for studying the epigenetic control of genome function and its role in mammalian development. Recently, Professor Ferguson-Smith’s team showed that a DNA-binding protein plays a key role in the programming of imprints, providing a link between the underlying DNA sequence and the regulation of epigenetic marks.

Parent power

Why do we need imprinting and what are its evolutionary consequences? ̽��ֱ��Cambridge researchers have discovered that the functional epigenetic asymmetry that exists between the genomes of the parents has important influences during pregnancy and throughout life. These effects include contributions to the allocation of maternal resources – especially to the control of key aspects of mammalian physiology related to growth and adaptations to feeding and metabolism.

Dr Constância’s group has recently described the effects of one gene that is expressed only from the copy inherited from the father. ̽��ֱ��gene for insulin-like growth factor 2 (Igf2) operates in a vital area of the placenta where maternal and fetal blood mix and nutrients are exchanged, controlling the influx of nutrients to the fetus. Igf2 also operates in fetal tissues to control the level of demand for nutrients. These studies raise the novel concept that imprinted genes are key genetic regulators of the supply of, and genetic demand for, maternal nutrients to the mammalian fetus. This may have implications for our understanding of the selective forces that led to the evolution of the process of imprinting.

̽��ֱ��control of nutritional resources is now known to apply to many other epigenetically regulated imprinted genes controlling growth in the mother’s womb and also after birth. Work by Professor Ferguson-Smith’s group has looked in further detail at such genes and has shown that imprinted genes can also influence normal metabolism.

We are what we eat

̽��ֱ��diet of an individual has important health issues at any stage of life – ‘we are what we eat’ after all. There is growing evidence from studies both in humans and in animal models that maternal diet during pregnancy is particularly important as it has major long-term health consequences, including risk of developing type 2 diabetes, heart disease and obesity – so in some ways ‘we are also what our mothers ate’. This has been termed the developmental origins of health and disease hypothesis. It suggests that subtle differences in nutrition or other early environmental factors during fetal or early postnatal life lead to permanent alterations in the structure and function of important organs, leaving a legacy of disease susceptibility in later life.

Dr Ozanne’s group has shown that reducing the protein intake of pregnant rodents leads to type 2 diabetes, obesity and premature death in the offspring. This is accompanied by permanent changes in the expression of genes regulating insulin production and action. All three research teams are currently investigating what the molecular mechanisms could be that connect the effects of maternal diet during pregnancy with gene expression in the offspring many years later (i.e. after many rounds of cell division). Not surprisingly, permanent changes in the epigenetic marks on DNA, and therefore effects on gene programmes throughout development and into adult life, are emerging as a major player. For example, Dr Ozanne and Dr Constância have recently discovered that a reduction in protein intake during pregnancy alters the epigenetic marks on the regulatory regions of important genes in the pancreas, leading to differences in their expression.

DNA wears Prada

Epigenetic processes are not confined to nutrition and growth – many other systems under epigenetic influence are also now coming to light. These include the ability of plants to respond to seasons, the capacity of chromosomes to segregate properly during cell division, and many of the key changes that occur in cancer and neurological disorders. It seems that our genetic future lies not only in studying the skeleton that is our DNA, but also in understanding the epigenetic modifications that clothe it.

For more information, please contact the authors Professor Anne Ferguson-Smith (afsmith@mole. bio.cam.ac.uk; Department of Physiology, Development and Neuroscience), Dr Miguel Constância (jmasmc2@cam.ac.uk; Department of Obstetrics and Gynaecology) and Dr Sue Ozanne (seo10@cam.ac.uk; Metabolic Research Laboratories, Institute of Metabolic Science).

Epigenetics is taking the biomedical research world by storm; three Cambridge scientists use examples from their own research to explain why.

Stefanie Reichelt, Cancer Research UK

large chromosomes

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Yes

Prenatal origins of heart disease

bjb42 — Sun, 04 Jan 2009 15:27:10 +0000

Heart disease is the greatest killer in the UK today, accounting for four in every 10 deaths and imposing a substantial burden on the nation’s health and wealth. ̽��ֱ��concept is familiar to us all that traditional risk factors, such as smoking and obesity, and genetic makeup increase the risk of heart disease. However, it is now becoming apparent that a third factor is at play – a developmental programming that is predetermined before birth, not only by our genes but also by their interaction with the quality of our prenatal environment.

A biological trade-off

Pregnancies that are complicated by adverse conditions in the womb, such as happens during pre-eclampsia or placental insufficiency, enforce physiological adaptations in the unborn child and placenta. While these adaptations are necessary to maintain viable pregnancy and sustain life before birth, the adaptations come at a cost, claiming reduced growth as a biological trade-off. In fact it’s more than just growth that is affected – we now know that the trade-off extends to the development of key organs and systems such as the heart and circulation, which increases the risk of cardiovascular disease in adult life. Overwhelming evidence in more than a dozen countries has linked development under sub-optimal intrauterine conditions leading to low birth weight with increased rates in adulthood of coronary heart disease and its major risk factors – hypertension, atherosclerosis and diabetes.

̽��ֱ��idea that a fetus’ susceptibility to disease in later life could be programmed by the conditions in the womb has been taken up vigorously by the international research community, with considerable efforts focusing on nutrient supply across the placenta as a risk factor. But nutrient supply is just part of the story. How much oxygen is available to the fetus is also a determinant of growth and the risk of adult disease. Dr Dino Giussani’s research group in the Department of Physiology, Development and Neuroscience is asking what effect reduced oxygen has on fetal development by studying populations at high altitude.

Lessons from high altitude

Bolivia lies at the heart of South America, split by the Andean Cordillera into areas of very high altitude to the west and areas at sea-level to the east, as the country extends into the Amazon Basin. At 400 m and almost 4000 m above sea-level, respectively, the Bolivian cities of Santa Cruz and La Paz are striking examples of this difference.

Pregnancies at high altitude are subjected to a lower partial pressure of oxygen in the atmosphere compared with those at sea-level. Women living at high altitude in La Paz are more likely to give birth to underweight babies than women living in Santa Cruz. But is this a result of reduced oxygen in the womb or poorer nutritional status?

̽��ֱ��research team studied birth weight records from healthy term pregnancies in La Paz and Santa Cruz, especially from obstetric hospitals and clinics selectively attended by women from either high- or low-income backgrounds. High-altitude babies showed a pronounced reduction in birth weight compared with low-altitude babies, even in cases of high maternal nutritional status. Babies born to low-income mothers at sea-level also showed a reduction in birth weight, but the effect of under-nutrition was not as pronounced as the effect of high altitude on birth weight; clearly, fetal oxygenation was a more important determinant of fetal growth within these communities

Remarkably, although one might assume that babies born to low-income mothers at high altitude would show the greatest reduction in birth weight, these babies were actually heavier than babies born to high-income mothers at high altitude. It turns out that the difference lies in ancestry. ̽��ֱ��lower socio-economic groups of La Paz are almost entirely made up of Aymara Indians, an ancient ethnic group with a history in the Bolivian highlands spanning two millennia. On the other hand, individuals of higher socio-economic status in Bolivia represent a largely European and North American admixture, relative newcomers to high altitude. It seems therefore that an ancestry linked to prolonged high-altitude residence confers protection against reduced atmospheric oxygen.

Do these early influences of oxygenation feed through to increased risk of cardiovascular disease? A large-scale, five-year study to determine this has been initiated in the two cities that will link birth weight data with measurements of cardiovascular health and disease in Bolivian high- and lowlanders. But an early indication has been supplied by a somewhat unlikely source: Bolivian hen eggs.

Mountain chicks

Dr Giussani’s group has discovered that they can replicate the results found in Andean pregnancies in eggs: fertilised eggs from Bolivian hens native to sea-level show growth restriction when incubated at high altitude, whereas eggs from hens that are native to high altitude show a smaller growth restriction. Using hen eggs has allowed the researchers to accomplish something that would take generations of migration in human populations to demonstrate: moving fertilised eggs from hens native to high altitude down to sea-level. This not only restored growth, but the embryos were actually larger than sea-level embryos incubated at sea-level. And, importantly, when looking for early markers of cardiovascular disease, it was discovered that growth restriction at high altitude was indeed linked with cardiovascular defects – shown by an increase in the thickness of the walls of the chick heart and aorta.

Bringing the Andes to Cambridge

To have hopes of clinical intervention, we need to understand why reduced oxygen should be a trigger for a prenatal origin of heart disease. Towards this goal, the group’s most recent data studying rat pregnancy complicated with reduced fetal oxygenation have indicated that the adverse effects on cardiovascular development may be secondary to a disturbance known as oxidative stress. ̽��ֱ��body normally produces by-products of oxygen called free radicals and, unless these are neutralised by antioxidants, they cause damage to cells. If oxidative stress is the underlying cause of cardiovascular defects, this offers the highly interesting possibility of using antioxidants to treat pregnancies complicated by reduced oxygen delivery to the fetus, be it at sea-level or high altitude. This may halt the development of heart disease at its very origin, bringing preventive medicine back into the womb.

For more information, please contact the author Dr Dino Giussani (dag26@cam.ac.uk) at the Department of Physiology, Development and Neuroscience. Research described here was sponsored by the British Heart Foundation, Biotechnology and Biological Sciences Research Council (BBSRC), Lister Institute of Preventive Medicine, Royal Society and Wellcome Trust. Dr Giussani is a member of the Centre for Trophoblast Research.

Studies in La Paz, the highest city in the world, are helping to uncover a link between prenatal conditions and heart disease in later life.

High-altitude babies showed a pronounced reduction in birth weight compared with low-altitude babies, even in cases of high maternal nutritional status.

Kristin Gussani

La Paz, Chile

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Yes

Collagen mechanics: learning from nature

bjb42 — Mon, 01 Sep 2008 15:37:11 +0000

Mention the word ‘biology’ and most people think immediately about cells. However, large portions of the human body are non-cellular and are made instead from an extracellular matrix (ECM) that provides much of the structural support around cells. This supportive function of the ECM is especially evident in the connective tissues of the body. Many load-bearing structures such as bones, teeth and ligaments are connective tissues and these have been the focus of recent bioengineering research in Cambridge.

Dr Michelle Oyen, Lecturer in the new Engineering for Life Sciences programme in the Department of Engineering, is studying the mechanical functions of connective tissues. Her research ranges from fundamental science and engineering projects through to collaborative projects with clinicians for developing mechanics-based tools for use in medical practice. ̽��ֱ��unifying theme of this research lies with the primary component of many connective tissues: the structural protein collagen.

Building blocks of natural materials

Collagen is ubiquitous; this triple-helical protein makes up a quarter of all proteins in the body. It self-assembles from the molecular scale up to large fibre-like structures, creating a hierarchical material with remarkable physical properties. Collagen combines with other ECM components – mainly water, non-collagenous proteins and sugars – and, in mineralised tissues, with bioceramics analogous to earth minerals. These non-living, but cell-derived, materials combine with cells to form living yet mechanically robust tissues.

Collagen takes on different roles in different parts of the body. In structural tissues, like bones and ligaments, it’s found in rope-like fibres that provide resistance to stretching and tearing forces. In cartilage, which is mostly loaded in compression, collagen has more of a ‘holding’ function, with the fibres arranged rather like a basket, retaining other hydrated proteins and sugars. In the lens of the eye, collagen is crystalline, organised precisely for optical transparency. In fact, there are over 20 different types of collagen in the body, and it is not even known precisely what functions they all fulfil.

Mechanics in medicine

̽��ֱ��study of the biomechanical properties of collagen and ECM is a particularly exciting and fast-growing field in reproductive medicine. One aspect of Dr Oyen’s research has been to examine the physical properties of the ECM in the amniotic sac, the membrane that ruptures (the ‘breaking of waters’), signalling imminent birth.

Rupture occurring before full-term gestation results in approximately a third of all premature births. Following the first-ever set of rigorous bioengineering studies on placental membranes, Dr Oyen and clinical colleagues at the ̽��ֱ�� of Minnesota concluded that the phenomenon is due to localised damage, not widespread overall membrane deterioration, and that diagnostic techniques may be developed to detect localised thinning and ECM damage for intervention into premature birth.

This project is taking a new direction since Dr Oyen’s arrival in Cambridge. By teaming up with researchers at the newly opened Centre for Trophoblast Research (www.trophoblast.cam.ac.uk), she will be able to examine placental development from an engineering and mechanics perspective.

Mimicking nature

Nature clearly creates dynamic, mechanically functional tissues that are different from anything engineers have made. As an example, cartilage, which forms the gliding surface that permits joint movement, is approximately 75% water and only 25% collagen, sugar and other proteins, and yet its stiffness and shock-absorbing capability make it comparable to solid rubber. Moreover, the cartilage-on-cartilage sliding interface has lower friction than ice sliding on ice.

In fact, when engineers design materials, uniformity and simplicity are often prized. Engineering materials do not always feature the multi-level hierarchical organisations found in protein-based materials, nor do they exemplify the dramatic spatial non-uniformity that has been found to strengthen natural materials. So, by learning from nature, novel engineering systems might be developed that utilise the principles found in natural materials – a field of technology that has been termed biomimetics.

In some instances, biomimetics takes the form of direct imitation, as in the case of a nanocomposite of mineral and proteins similar to natural bone. For cases of major bone defects, such as occurs through trauma or cancer, a bone-like material that is biocompatible can be seeded with cells to form a ‘tissue-engineered’ construct and implanted within the body. However, if you consider just how lightweight, yet stiff, strong and tough, a bone-like material is, why not use it for other structural applications such as architecture? This is a challenge that Dr Oyen is investigating.

To do this, you need to go back to first principles – how the material forms. With funding from the Royal Society, Dr Oyen is examining biomineralisation and the formation of mechanically robust bone-like materials. ̽��ֱ��work differs from tissue-engineering approaches in that there is no cellular component and the end applications are viewed as being remote from medicine. Although a large number of groups have considered the synthesis of biomimetic materials, far fewer have taken a primary angle associated with the measurement of mechanical properties. Dr Oyen views the materials as successful when they replicate both bone composition and mechanical behaviour.

Inspirational materials

It is also possible to abstract ideas from nature without directly imitating the materials themselves. As examples, key concepts that could guide the formation of ‘bone-inspired’ materials include: composite materials with a very large stiffness mismatch between the phases; materials that form from room-temperature deposition of a ceramic onto a self-assembled polymer; materials with up to seven different levels of hierarchical organisation; and materials that are self-healing. Each of these concepts could be applied to a system that is not protein based, and ongoing research both at Cambridge and across the world is incorporating these types of principles for materials development.

Compared with many branches of engineering, biomimetic engineering is comparatively new. In this rapidly expanding field, the lessons learnt from the physical and mechanical properties of natural materials such as collagen and bone offer great promise within an engineering framework. Not only is this sure to make a difference to 21st-century healthcare, but there are also ways in which engineering will itself benefit from the abstraction of ideas from nature.

For more information, please contact the author Dr Michelle Oyen (mlo29@cam.ac.uk)

at the Department of Engineering.

Because of their unique structure, biological tissues exhibit physical and mechanical properties that are unlike anything in the world of engineering.

So, by learning from nature, novel engineering systems might be developed that utilise the principles found in natural materials – a field of technology that has been termed biomimetics.

Dr Jon Heras, Equinox Graphics

collagen

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Great expectations in pregnancy research

amb206 — Fri, 01 Feb 2008 00:00:00 +0000

Complications in pregnancy represent a persistent and major problem in public health. ̽��ֱ��first three months after conception are known to be the most critical, with as many as 20% of pregnancies lost during this time. For pregnancies that develop beyond 24 weeks, between 0.5 and 1% result in death of the baby, either in the womb or in the first four weeks of life. Premature birth can incur major complications associated with delivery, immediate care of the infant, childhood diseases, and educational and social problems in later life. Not only is there an emotional cost to families, but an economic assessment in the USA reported that the cumulative subsequent healthcare and social costs associated with one year’s worth of pre-term deliveries was $26 billion. Understanding and intervening to prevent these events is clearly crucial.

Although some advances have been made, the dismaying fact is that the rates of stillbirth have generally remained static over the past 20–30 years. This partly reflects an incomplete understanding of the biological events that lead to these complications of pregnancy. Determining what these mechanisms might be is essential for devising new strategies of intervention, and applying in-depth scientific studies to human pregnancy is now seen as vital.

Two multidisciplinary initiatives in Cambridge have recently embarked on improving our understanding of pregnancy and its outcomes: a large antenatal screening of women at the Rosie Maternity Hospital in Cambridge and the recent endowment of a Centre for Trophoblast Research within the School of Biological Sciences. Both initiatives build on the wealth of expertise in the biology of pregnancy that exists across Cambridge.

Screening for adverse outcomes

A four-year research project that aims to monitor 5000 pregnant women commenced in 2007 under the leadership of Professor Gordon Smith in the ̽��ֱ��’s Department of Obstetrics and Gynaecology. A multidisciplinary team of translational researchers in both the School of Clinical Medicine and the School of Biological Sciences are participating in the project, which is funded under the Women’s Health theme of the UK Department of Health’s Cambridge Comprehensive Biomedical Research Centre.

Women enrolling in the study are scanned and give blood samples at 12, 20, 28 and 36 weeks of gestation, allowing detailed characterisation of the baby’s growth and development. Thanks to an industrial collaboration with GE Healthcare, the long-term loan of two state-of-the-art scanners will enable real-time three-dimensional scanning of the babies in utero. At birth, samples of placenta and cord blood will be obtained and stored.

̽��ֱ��study is prospective; for those women whose pregnancies sadly have complications or adverse outcomes (such as pre-eclampsia, spontaneous pre-term birth, stillbirth or low-birth-weight babies), the stored samples will be retrieved and compared with controls. These samples then become the focus of extensive clinical and biological analyses to try to establish the cause. Studies will analyse the development and function of the placenta and the effect of oxidative stress; the expression or silencing of genes in relation to whether they came from the mother or the father (known as genomic imprinting); the maternal–foetal immune interaction; and the genes that are expressed in the placenta. ̽��ֱ��MRC Epidemiology Unit will conduct follow-up studies of the growth and development of the babies who have been carefully monitored during the pregnancy.

̽��ֱ��hope is that this detailed characterisation of foetal development, on such a large scale, will lead to mechanistic studies on the causes of common clinical problems in pregnancy. As well as providing refined risk assessment, novel treatments might be identified that could improve the outcome of pregnancies in women deemed to be at higher risk.

Centre for Trophoblast Research

̽��ֱ��recent endowment of the Centre for Trophoblast Research, due to be launched on 9 July 2008, is a highly innovative initiative aimed at promoting research into trophoblast biology both within Cambridge and on the wider national and international stages. ̽��ֱ��trophoblast is the cell type that forms the interface between the foetus and its mother, supplying nutrients to support the growth of the foetus. It is fundamental to successful pregnancy and must interact intimately with the maternal cells lining the uterus, leading to the formation of the placenta.

In humans, this interaction is particularly invasive and, during the first few weeks of pregnancy, the foetus becomes completely embedded within the wall of the uterus. This form of placentation, seen only among the great apes, poses unique immunological and haemodynamic challenges. ̽��ֱ��invading trophoblast cells, which are genetically related to, but distinct from, those of the mother, must negotiate passage with her immune system to allow them to reach their target – the specialised blood vessels in the wall of the uterus. As a result of this invasion, the vessels undergo major structural changes that ensure the placenta has a plentiful and continuous supply of blood in later pregnancy.

There is now abundant evidence that the major complications of pregnancy are associated with deficient trophoblast invasion, resulting in aberrant maternal blood flow to the placenta. Research performed in Cambridge has demonstrated that, paradoxically, too much flow in early pregnancy results in miscarriage, whereas too little in later pregnancy is associated with low birth weight and pre-eclampsia. These new insights have radically changed our understanding of human pregnancy and have helped to explain why miscarriage and pre-eclampsia are virtually unique to humans. Studying trophoblast biology is therefore not only of basic scientific interest but is also key to understanding the root causes of these pregnancy disorders.

Raising hopes for future pregnancies

̽��ֱ��aim of these multidisciplinary initiatives across Cambridge is to arrive at a better understanding of the biology of normal and complicated human pregnancy. Only by doing so can scientists hope to develop new diagnostic tests to identify women at increased risk of complications and, potentially, new interventions that might prevent the life-long effects of these complications on mothers and their children.

Participating researchers

Antenatal screening initiative (Principal Investigator: Prof Gordon Smith)

Dr Steve Charnock-Jones and Dr Miguel Constância (Dept of Obstetrics and Gynaecology); Prof Graham Burton, Prof Abby Fowden, Dr Dino Giussani and Dr Anne Ferguson-Smith (Dept of Physiology, Development and Neuroscience); Dr Ashley Moffett (Dept of Pathology); Prof David Dunger (Dept of Paediatrics); Dr Ian White (MRC Biostatistics Unit); Dr Ken Ong (MRC Epidemiology Unit).

̽��ֱ��project is within the Women’s Health theme of the Cambridge Comprehensive Biomedical Research Centre – a partnership between Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust and the ̽��ֱ�� of Cambridge, and created by the National Institute for Health Research (NIHR). These themes focus on translating advances in basic medical research from the laboratory to the hospital clinic.

Centre for Trophoblast Research (Director: Prof Graham Burton)

Participating researchers will be announced in 2008. ̽��ֱ��Centre will facilitate research by providing flexible and responsive funding for seminars, workshops and visiting scholars, as well as laboratory space in the Department of Physiology, Development and Neuroscience. ̽��ֱ��Centre also aims to encourage the next generation through graduate studentships and postdoctoral fellowships.

For more information, please contact the authors Professor Gordon Smith at the Department of Obstetrics and Gynaecology (gcss2@cam.ac.uk) or Professor Graham Burton at the Department of Physiology, Development and Neuroscience (gjb2@cam.ac.uk). Please go towww.trophoblast.cam.ac.ukfor more information about the Centre for Trophoblast Research.

Most pregnancies develop normally but when complications arise they can have devastating effects. Two recent initiatives in Cambridge hope to deliver a new understanding of events during this critical period of human life.

Thanks to an industrial collaboration with GE Healthcare, the long-term loan of two state-of-the-art scanners will enable real-time three-dimensional scanning of the babies in utero.

Professor Graham Burton

Human placental villi showing signs of oxidative stress

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