̽��ֱ�� of Cambridge - trophoblast

Bioengineering, embryos and eggshells

cg605 — Wed, 17 May 2017 08:21:18 +0000

In 1999, Dr Michelle Oyen was a bioengineering student, working on a PhD project to measure the stiffness of bone, when the phone rang. It was Dr Steven Calvin, an obstetrician at the local hospital. “I’m trying to understand some issues around miscarriage and premature birth,” he said. “Is there someone there who has a machine that can stretch things, and make measurements of how strong something is?”

Calvin had a specific question: he was performing a procedure aimed at keeping a prematurely opening cervix closed by putting stitches around it. If a cervix opens too soon, it can result in premature birth. During the procedure, antiseptic is painted around the area, including the amniotic sac. He wanted to know if this substance changed the properties of the sac, making it more likely to rupture.

Oyen, now Reader in Bioengineering in Cambridge’s Mechanics and Materials Division and the Biomechanics research group, was fascinated by the idea of applying engineering thinking to this problem. “I was carrying out my experiments in a housekeeping cupboard in the hospital,” she remembers. “I had a rig for strength-testing the amniotic sac. I’d get a call from Dr Calvin that a woman in labour was happy for us to use the sample, I’d grab my rig and set it up in a cupboard down the hall from the delivery room.”

Their first investigation into this question resulted in a paper published in the Journal of Material Science: Materials in Medicine, and sparked what Oyen calls her life’s work: finding out why pregnancies go wrong. “Three per cent of the time, the amniotic sac breaks for no reason that we know,” she says. “That can cause miscarriage, or stillbirth if it’s before viability. Even after that, babies born between 25 and 30 weeks are very premature and so their outcomes are very poor. Even babies born after 30 weeks are still not fully ‘cooked’: you have to get to 37 weeks before we consider you to have made it to the end line. These problems happen in the developed world, even when we have so much technology around us. In the developing world, there’s a whole other set of issues. So when you talk about problems in pregnancy, you’re talking about a big chunk of humanity.”

There’s a long and honourable history of collaborations between engineering and medical science, from designing cutting-edge prosthetics to creating technology for robot-assisted surgery. Yet, says Oyen, looking at pregnancy in this way is an area that’s 20 or 30 years behind, say, orthopaedics. “Most of the time, pregnancy kind of works and doctors know how to manage something that goes wrong – but they don’t always understand why it’s happening. It’s something that we fundamentally don’t know about. And that really excites me.”

What makes pregnancy problems so ripe for exploration by engineers? ̽��ֱ��tools, says Oyen – namely, computers. “You can’t do experiments on pregnant women,” she points out. “It is completely unethical. But with computers, we can make a virtual model of the placenta. There’s potential for huge progress there.” One of her team’s recent projects, which gave rise to a paper published in the journal Placenta, is based around images of real placentas taken using a confocal microscope at a very high resolution. These images are then turned into 3D computational models. Oyen and her team can then model how the blood flows through the capillaries of the placenta, bringing oxygen from the mother to the baby. This will aid understanding of why the placenta sometimes malfunctions and fails to bring enough oxygen to the baby, meaning its growth is restricted.

That’s studying the placenta at full term: but its beginnings are also a rich area for research. When a fertilised egg implants into the uterus wall, specialised cells called trophoblasts must migrate in to help form the placenta, a biological process similar to how cancer cells metastasize. In collaboration with the Cambridge Centre for Trophoblast Research, which this year celebrates its tenth anniversary, Oyen’s team is studying how trophoblasts move, a unique cross-departmental group of pregnancy researchers. “ ̽��ֱ��collaboration with others from the Centre has just been amazing,” says Oyen. “That’s the thing about Cambridge. You don’t find such a wealth of expertise anywhere else.”

Pregnancy problems are one of the Oyen Lab’s four main strands of research, the others being more traditional areas of bioengineering, including the creation of synthetic materials using inspiration from the natural world – studying materials such as eggshell and bone to find an equally strong and light material, for example. As any cook knows, Oyen says, an eggshell is actually pretty robust. If you want to break it, you need to hit it hard against your glass bowl. Yet it starts off as a squishy, watery membrane filled with yolk.

Given the right conditions – usually a chicken with average body temperature – it becomes a full egg with a hard shell in about 18 hours. This is a material that is 97per cent ceramic but forms naturally in close to ambient conditions, and therefore is not energy-intensive – unlike concrete, which always involves high temperatures to process. These materials could have medical applications, such as replacing the metal and plastic currently used for new hip and knee joints, or they could even be scaled up to create anything from furniture to buildings: the lab’s current project on eggshell-inspired materials is funded by the US Army Corps of Engineers.

“Materials inspired by bone and eggshell are really good structural materials: why limit them to medicine?” Oyen says. “We can make bone-like material now, but only in lab quantities. It would take a big company to scale it up. Natural materials are really interesting. We build things out of steel and concrete now, but before we started getting the idea to do that, we built things with whatever was around us – wood or stone. People don’t really appreciate what impact this could have on global warming: in 2007, the creation of steel and concrete was responsible for more CO2 emissions than the aviation industry worldwide. We demonise airlines without realising that building a skyscraper also makes a big contribution.”

Looking at the scope of her work, it’s hardly surprising that a glimpse at Oyen’s office bookshelf reveals a dizzying array of interests, from clouds to Russian dictionaries to Cary Grant – not to mention the electronic piano keyboard that stands next to it. “Yes, I have broad interests, which I think is normal for someone in such an interdisciplinary field,” she says. “A lot of my work is synthesising and bringing people together. Most of my students are co-supervised, most of my work is collaborative. I spend very little time sitting in a room, typing on a computer. I get people together. I talk to engineers and medics, I get biologists talking to engineers. I’m the traffic cop in the middle, translating from engineering language to biomedical language.”

Her chosen path is partly personal, she says – Oyen has juvenile arthritis, which began in her teens. Her father worked in an engineering company and had her solving problems from the start. “My motivation is completely selfish,” she says with a grin. “My first degree was in Materials Science and Engineering, and while I was doing that, I twigged that there were medically related engineering applications. I was doing very traditional metallurgy. I had nothing to do with medicine. But when I was having a particularly bad bout with my joints, I started getting interested. I started coming across some of the very traditional approaches to solving medical problems, like total joint replacement, which goes back to the 1950s. You replace living tissue, which is 75 per cent water, with metal and plastic. That’s a very 1950s solution and yet we haven’t come up with anything better.”

There is a word in bioengineering – bioinspiration – which, within the context of the discipline, means a method of solving engineering problems using natural approaches. A bioengineer will systematically study how nature has solved problems and then try to map that method on to a current problem. Perhaps it’s not too much of a stretch to say that a kind of bioinspiration is at the root of everything Oyen does: taking both nature’s design flaws and extraordinary abilities – to regrow, renew and create life – as a starting point for making things work better, from carrying a child to creating a city.

“There is so much potential in all our work, but in the pregnancy work, I feel like it’s really just getting started,” she says. “High risk, high reward – and the reward is better outcomes for mothers and babies. It’s what engineering is all about: problem-solving. It’s creative. After all, the root of the word engineer is not engine, but ingenuity.”

Dr Oyen is a Fellow at Homerton College.

Article by Lucy Jolin. This article first appeared in CAM - the Cambridge Alumni Magazine, edition 80. Find out more about Dr Oyen's work.

Homerton Fellow Dr Michelle Oyen explains why she has dedicated her working life to investigating why pregnancies go wrong.

I spend very little time sitting in a room, typing on a computer. I get people together. I talk to engineers and medics, I get biologists talking to engineers. I’m the traffic cop in the middle

Dr Michelle Oyen

Anna Huix

Michelle Oyen

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

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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