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How to build a human: Babraham Institute to unlock secrets of early human development

A £10million project will reveal the secrets of early human development.

Bringing together researchers across the country, and using cutting-edge techniques, the Wellcome-funded Human Developmental Biology Initiative (HDBI) will peer into the ‘black box’ of the days and weeks following conception.

Scientists from Babraham Institute, from left, Gavin Kelsey, Wolf Reik and Peter Rugg-Gunn will contribute to the project, using their expertise in epigenetics, single-cell analysis and stem cells. Picture: Keith Heppell
Scientists from Babraham Institute, from left, Gavin Kelsey, Wolf Reik and Peter Rugg-Gunn will contribute to the project, using their expertise in epigenetics, single-cell analysis and stem cells. Picture: Keith Heppell

Uncovering how cells divide and specialise, how tissues and organs form – and how the process sometimes goes wrong – the project will ultimately create a kind of instruction manual for growth.

The research will create ‘family histories’ of cells in four areas of focus: the early human embryo, the brain and spinal cord, the blood and immune system and the heart and lungs.

At the Babraham Institute, Professor Wolf Reik, Dr Gavin Kelsey and Dr Peter Rugg-Gunn, all group leaders in the epigenetics research programme, will contribute their expertise in studying the earliest stages.

“It will bring really cutting-edge methods, both experimental and computational, to human development,” Prof Reik tells the Cambridge Independent.

After a sperm cell fuses with an egg cell, or ‘ovum’, their genetic material combine in a single cell called a zygote, and the ‘germinal’ stage of development begins, which covers the early stage up to the implantation of the embryo in the uterus.

In this phase, the zygote divides in a process called cleavage, with one cell becoming two, then two becoming four, and so on.

A ball of 16 cells is called the morula. At this stage, the cells start to bind more firmly together and the process of cellular differentiation begins, by which different types of cells form.

An outer layer of cells known as the trophoblast develops, which goes on to form the foetal placenta, while the rest form the inner cell mass, which is the source of embryonic stem cells that give rise to the three germ layers in the human body.

Prof Reik said: “What’s particularly exciting to discover in early human development is how the first cell states are established and how the first lineages diverge, and the underlying gene expression changes and epigenetic changes.”

Gene expression is the process by which a gene produces a functional product, such as a protein, while epigenetic changes describes factors that influence whether genes are switched on or off, and which drive the formation of different cell types.

But how much do we know about what drives cells to differentiate?

Prof Wolf Reik in the sequencing lab. Picture: Keith Heppell
Prof Wolf Reik in the sequencing lab. Picture: Keith Heppell

“Actually very little,” says Prof Reik. “We know many of the components – transcription factors [proteins that convert DNA into RNA], epigenetic regulation and signalling influences from the outside are very important. But how they are all integrated to tip the cell one way or another is pretty unknown. It is a hugely exciting opportunity to get some real insights into that.”

Understanding such processes could give us clues to why they sometimes go wrong. About three in 100 babies are born with developmental defects. Some of these – such as heart defects, spina bifida and cleft palate – start very early in pregnancy, but we have a very limited understanding of how and why they occur.

A key reason for this is the sheer challenge of studying embryos and foetuses.

“Human development is difficult to study – getting the samples and the right stages are quite challenging,” notes Prof Reik.

Collaborating with Prof Jennifer Nichols, of the MRC Cambridge Stem Cell Institute, the Babraham work will use donated embryos from IVF treatments which, with the appropriate licence, can be used for research up to day 14 of development.

The initiative will operate within the UK’s strong regulatory and legal framework and will also actively consider the ethical issues raised by this growing area of research. Ethics and public engagement programmes are part of the project.

Prof Reik will apply an advanced technique his lab has developed with Dr Kelsey known as single cell multi-omics sequencing.

Like genome sequencing, this approach unlocks a code, but in this case it is applied to different levels of information within a single cell, namely:

  • the transcriptome – the messenger RNA molecules expressed by genes;
  • the methylome – details of all the methyl groups added to DNA within a cell to change its activity; and
  • chromatin accessibility – which describes how the cellular machinery that controls genes is able to contact and interact with DNA.

Carrying out this process at different points in time enables changes to be identified.

Prof Wolf Reik in the sequencing lab. Picture: Keith Heppell
Prof Wolf Reik in the sequencing lab. Picture: Keith Heppell

Dr Kelsey explains: “Being able to map these layers of information in single cells gives us an unprecedented opportunity to establish real links between genes and their controlling elements.”

Prof Reik adds: “Another method is to try computationally to understand the connections, which is obviously quite challenging. There is a huge amount of data in every cell.

“We work very closely with computational biologists to detect the meaningful connections between these layers.”

Some of the layers unlocked by this method contain millions of data points, so the process of assessing how they change and are connected requires the use of statistical algorithms and machine learning.

One of Prof Reik’s hopes is that through these methods the research will detect the early signs of the next major stage in embryonic development, when the inner cell mass of what is called the blastocyst goes through a process called gastrulation. This is when it becomes organised into the germ layers – the three distinct cell layers that go on to form the skin and hair, the organs and the inner lining of the organs.

“What is also exciting is to see if we can detect close to the day 14 window what we call priming – that foreshadowed event of gastrulation in the three major germ layers,” says Prof Reik.

“In the mouse we have found we can detect cells ‘thinking’ about making a cell state change before they actually do so.

“We hope to find similar patterns of cells beginning to ‘think’ about the future in the human embryo as well.”

Dr Kelsey adds: “We have learnt a huge amount in animal models, but we know that there are some important distinctions from other mammals in how human embryos develop and the mechanisms they use to control genes at these very early stages.”

For Dr Rugg-Gunn, group leader of a team studying human stem cells and the establishment of cell identity, the initiative represents a fascinating opportunity to explore how stem cells give rise in the developing embryo to all of the tissues and organs that make up the human body.

“Our research over the last few years has uncovered new ways in which gene activity is controlled as human stem cells specialise towards particular tissues,” he says.

At the Babraham Institute are, from left, Gavin Kelsey, Wolf Reik and Peter Rugg-Gunn. Picture: Keith Heppell
At the Babraham Institute are, from left, Gavin Kelsey, Wolf Reik and Peter Rugg-Gunn. Picture: Keith Heppell

“The HDBI provides a tremendous opportunity for us to discover how these control mechanisms work directly in human embryos so that we can learn how these tissues are formed during development and why this process sometimes goes wrong.

“In turn, this information will help us to improve our stem cell models so that we can produce more accurate cell types for applications in regenerative biology.”

Other researchers involved in the project will explore later stages of development using foetal tissue, donated following abortions. Again, strict ethical frameworks operate to guide such research, which will explore how the developing organs and tissues are organised.

“How do they change shape, move around, organise together into little or bigger families and begin to talk to each other and develop functions that complement and work together? Those are interesting ideas and they will come out in the later stage work on defined organ systems,” says Prof Reik.

The technology developed by scientists on the project will be a great resource to the wider research community.

Andrew Chisholm, head of cellular and developmental science at Wellcome, said: “This new initiative brings together a diverse group of biologists from across the country to share their expertise and work together to build a ‘family tree’ of how different cells and tissues come together to form organs. This will create a treasure trove of data and technologies that will be made available to the community.

“Thanks to new techniques and technologies to study human development, the HDBI will provide insights that could help our understanding of developmental disorders.”

The HDBI, which is earmarked as a five-year programme but could be extended if successful, involves researchers from the University of Cambridge, UCL, the Francis Crick Institute, the University of Oxford, the University of Dundee and the University of Newcastle.

It will partner closely with the MRC-Wellcome Human Developmental Biology Resource.

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