Tempting fate: How to get a head in embryo development

“Colour for me is at the core of beauty. And beauty and harmony with their occasional imperfections inspire me. They give me energy. In my mind they unite art with science” — Professor Magdalena Zernicka-Goetz

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Blastocyst embryo — winner of a Wellcome Image Award in 2011 (Credit: Agnieszka Jedrusik and Magdalena Zernicka-Goetz, University of Cambridge)

The journey from a single fertilised egg cell through to a baby delivered crying into the arms of its mother is one of the most beautiful and complex processes to occur in nature. We are only just beginning to understand the very earliest stages of life — when we are nothing more than a cluster of cells.

Professor Magdalena Zernicka-Goetz is interested in our fate: not in an existential sense, but rather in the fate of cells at the earliest stages of life. “We look at how cells decide their fate,” she explains. “All of the cells initially look the same, and yet we know that they will go on to make different parts of the body — our hands, our head, the left and right side of our bodies. How do the cells know where to go?”

She runs a lab in the Department of Physiology, Development and Neuroscience, having moved to Cambridge 20 years ago from Poland to join the lab of Professor Martin Evans. She kept good company — Professor Evans went on to be knighted and to receive a Nobel Prize, and she worked closely with Professor John Gurdon, another Knight of the Realm and future Nobel laureate.

When I meet her, she is temporarily housed in the Department of Anatomy. Her office is not like an ordinary researcher’s office. It is luxurious in its use of colour. An Ashanti doll sculpture, a fertility goddess reminding her of the time she lived in Africa, sits on a shelf above a bold magenta sofa, which coordinates magnificently with a large print on the wall. This beautiful purple and red image, set on a jet black background, is of a blastocyst, a very early stage embryo after fertilisation, but before it implants itself in the womb. The image was one of the winners of a Wellcome Image Award in 2011 — it’s not hard to see why.

“Colour for me is at the core of beauty,” she says. “And beauty and harmony with their occasional imperfections inspire me. They give me energy. In my mind they unite art with science.”

Professor Zernicka-Goetz has just been awarded 2.5 million Euros from the European Research Council (ERC) for her work, which builds upon research she started 5 years ago but published just last year in which she “cracked open the ‘black box’” of embryo development, allowing researchers to observe these early life stages for the first time.

Once an egg has been fertilised by a sperm, it divides several times to generate a small, free-floating ball of stem cells. These stem cells change their state from one of ‘totipotency’ to one of ‘pluripotency’. Totipotency is the state at which a stem cell can divide and grow and produce everything — every single cell of the whole body and the placenta, to attach the embryo to the mother’s womb. When they change to a pluripotent state, their development is restricted to generating the cells of the whole body.

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Blastocysts (Credit: Mubeen Goolam, Magdalena Zernicka-Goetz group, University of Cambridge)

“The classical definition of totipotency is that if you split a two-cell stage embryo into two halves, you can make two bodies. But when you do it with the four-cell stage embryo — by which time you have pluripotency — you won’t get four bodies. But nowadays, we can also define totipotency and pluripotency differently depending on the pattern of gene activity. There are several distinct states of pluripotency and understanding the journey between these different states is our current passion.”

Professor Zernicka-Goetz’s lab is looking at how genes regulate this change from totipotency to pluripotency and then on to the next stage, ‘differentiation’, where the embryo begins to take shape.

Around day three, the pluripotent embryonic cells cluster together inside the embryo towards one side. This stage is known as the blastocyst, the image on Professor Zernicka-Goetz’s wall. The blastocyst comprises three cell types: a small number of pluripotent stem cells that will develop into the future body, cells that will develop into the placenta and allow the embryo to attach to the womb, and cells that form the primitive endoderm, the ‘sac’ that will hold all of this together.

So far so good: scientists already understand a lot about the cellular and molecular events that result in the formation of these three cell types. But then the blastocyst implants itself in the wall of the womb — and enters a “black box”.

“We can culture embryos to the blastocyst stage in a dish, but they need to attach to the womb for the next stages of development to occur. When you implant the embryo back into the mother, you lose sight of it — and when you look at it two or three days later, it looks completely different. Then, it’s called an egg cylinder and it’s totally transformed. Something important has clearly happened.”

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Development of the egg cylinder (Credit: Ivan Bedzhov, Magdalena Zernicka-Goetz group, University of Cambridge)

Professor Zernicka-Goetz, with her group at the University of Cambridge and with the help of colleagues in the School of Pharmacy at the University of Nottingham, developed substrate and culture conditions that trick the embryo into thinking it has been implanted in the woman, allowing it to continue to develop. The substrate and culture conditions have now been further enhanced by Professor Zernicka-Goetz’s team and patented by Cambridge Enterprise.

“This implantation stage is a crucial time in the embryo’s development. It’s when the overall body plan and the position of the head are decided and so many developmental defects can become acquired at this stage of pregnancy. Until we developed this technique there was just no way of directly seeing what happens and how all of this first starts and how to protect it from going wrong — we’ve now cracked open the black box and this feels as if the new world has opened in front of our eyes.”

Between implantation and the ‘egg cylinder’, the stem cells form ‘rosettes’ with a hole at the centre. As with a Polo mint, where the hole is as important as the mint, so it is with these rosettes: the hole will eventually become the cavity, in which the whole foetus is suspended and carefully protected. The hole was thought to arise through a process known as apoptosis, or programmed cell death, but up until now, no one could see how this important hole first opens. Having developed a way of observing these processes as they happen in living mouse embryos, Professor Zernicka-Goetz and her group found that the pluripotent cells do not die but instead they all organise themselves into this beautiful three-dimensional rosette structure. But why the rosette?

“One of our hypotheses is that it’s important that there is coordination amongst the multiple cells at this stage. If they’re chaotic, they won’t form just one hole, they’ll form lots of different holes. The coming together of cells into this single rosette structure ensure this doesn’t happen and the whole embryo, and so the baby, is normal.”

Professor Zernicka-Goetz’s postdoctoral researcher, Dr Anna Hupalowska, illustrates this with a rather beautiful analogy: synchronised swimming. If the erratically-arranged swimmers come together to form a rosette, they can easily and elegantly form a larger doughnut shape with a hole at the centre.

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Credit: Ania Hupalowska, Magdalena Zernicka-Goetz group, University of Cambridge

Another postdoctoral researcher in Professor Zernicka-Goetz’s team, Dr Marta Shahbazi, is currently testing the hypothesis and trying to unravel the regulation of this process and the regulation of the pluripotency state that again changes at this time.

This process can be seen in embryo development in mice and in monkeys, implying this should be the same in humans. Professor Zernicka-Goetz and her team will use the ERC grant to see if this is the case. This will be first time that anyone has been able to observe human rosettes to understand how they form and what is key for correct development of human embryos at the time of implantation, she says.

The grant will also allow research which is far more personal to her. When Professor Zernicka-Goetz was pregnant with her second child, Simon, she was already in her forties. Aware that this increases the risk of genetic abnormalities, she undertook a genetic test, which involves removing cells from the placenta — generated by the same egg that generated Simon’s body — to look at the number of chromosomes. A healthy individual has two copies of each chromosome (excluding the sex chromosomes X and Y); an extra copy can cause problems — Down’s syndrome, for example, is caused by an extra copy of chromosome 21.

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Illustration of part of a cell of patient with Down’s syndrome, showing an extra copy of chromosome 21 (Credit: Blausen gallery 2014. Wikiversity Journal of Medicine)

“It turned out that as much as a quarter of cells in the placenta showed abnormalities — they had three copies of chromosome 2, which can cause a much more severe condition than Down’s syndrome as the chromosome carries a large number of genes. This was very worrying.”

She chose to continue with the pregnancy and take further tests, which required removing foetal cells. Fortunately, it turned out well and the cells of Simon’s body had the correct complement of chromosomes and he is perfectly normal. But this made her realise how little we understand about how and when these abnormal cells, known as aneuploid cells, become eliminated; this personal experience inspired her to develop a mouse and stem cell models to study exactly how and when this happens.

“We need to know what happens to these abnormal cells — do they remain and potentially affect the child’s development, or do they somehow get overtaken by the healthy cells? Given that the average age at which women have their children is rising, this is a question that will become increasingly important.”

Find out more about research at the University of Cambridge here.

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