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Delving deeply into development

Dr Peter Rugg-Gunn talks about the challenges of studying early human development, his group’s groundbreaking discoveries, and why he believes the Human Development Biology Initiative – a five year, £10m project funded by Wellcome – will lead to a step change in the field.

As far as biological questions go, the origins of human life are as fundamental as they get. How – from one fertilised egg – do our bodies pattern into a mosaic of hundreds of different cell types that enable us to think, feel and do? It’s a question Dr Peter Rugg-Gunn, a senior group leader in the ̨��swag’s Epigenetics programme and chief investigator of the Human Developmental Biology Initiative (HDBI), finds fascinating.

His work focuses on the first 14 days of our existence when the embryo undergoes extraordinary change, transforming from a uniform ball of cells into something poised to establish the embryonic body plan. During this early period, the embryo forms the progenitor cells of the placenta, which enable it to implant into the uterus and without which development cannot happen. At the same time, it must conserve special pluripotent cells at its core that will diverge at a later stage in development into the dozens of different cell lineages which become our diverse tissues with myriad functions.

“It’s an absolutely fascinating period in our lives, especially when you consider the challenges the early embryo must overcome. As well as being an extremely busy period of development, when so many things are going on, it’s also a time of great epigenetic change, which is why it’s such an interesting system for us to study,” he explains.

Epigenetics describes the additional layer on our genetic code that ensures the correct genes are switched on and off at the correct times and in the correct cells. Precisely how the embryo orchestrates such complex changes are at the heart of Rugg-Gunn’s research, as it’s a part of human development that science knows relatively little about.

“We know a reasonable amount about the first seven days of development, because of all the work that has been carried out on in-vitro fertilisation (IVF). We also have some understanding about embryos from about eight weeks post-conception from studying embryos donated for research purposes by women who have had abortions,” he explains. “But, in between these stages, once an embryo implants in the uterus at the end of the first week, we don’t know what happens next. You can’t see them, you can’t study them, and this is a real gap in our understanding.”

There are many reasons why addressing this gap matters. Around 50% of embryos fail to develop past the first three weeks of development, and this figure is even higher following IVF. So understanding more about how embryos develop after implantation could increase the success rate of IVF, alleviating the heartache caused by infertility and recurrent miscarriage. This developmental period is also when several serious congenital disorders first arise; the origins of which we know very little about. More widely, investigating these early stages would also expand our knowledge of embryonic stem cells, which are pluripotent cells with similar properties to those in early embryos.

Embryonic stem cells are widely used in research and are part of the development of stem cell therapies with potential applications in a wide range of diseases.

A good example is work from Rugg-Gunn’s group, which in 2022 published new discoveries about the amnion lineage, cells that form the membrane envelope which cushions the developing embryo. “It’s a critical tissue during development, the origins of which were largely unknown in humans,” he says. “As well as protecting the embryo, amnion cells have special properties that can promote wound healing. For this reason, amnion tissue donated after childbirth has been used to treat wounds for over 100 years. Our discovery on the origins of amnion cells means we can now convert embryonic stem cells into amnion cells and culture these cells in the lab, instead of having to rely on donated tissues. This allows us to work with much more standardised cells and scale them up to the numbers that might one day be compatible with helping to treat chronic wounds.”

His group has also developed a groundbreaking new in vitro culture system that mimics the implantation of early human embryos into the uterus. The system means that for the first time ever, researchers can study the crosstalk between the embryo and endometrium until day 14 – the legal limit for culturing human embryos for research.

Most exciting of all for Rugg-Gunn and his group is being part of the Wellcome-funded HDBI. The initiative involves dozens of research teams across the UK who work together to try to understand how cell lineages are established at different stages of development.

Embedded into the science is an exciting public engagement programme which aims to explore society’s views on human embryo research and to find out whether hopes and concerns might have changed since the UK’s Human Fertilisation and Embryology Act came into force more than 30 years ago. During 2023, the ̨��swag is leading a public dialogue focused on early embryo research, and in particular the 14-day limit on culturing embryos.

For both science and society, HDBI will have far-reaching impacts on the field of human development, Rugg-Gunn believes: “It’s a really exciting initiative: it’s ambitious in its questions and its scale; it’s timely because we now have powerful imaging and single-cell molecular technologies, several of which were developed at the ̨��swag; and because HDBI will set up new experimental platforms that will enable more researchers to do high quality human developmental biology research, it will move the field on further and faster.”

Looking ahead for the group’s wider research, progress also looks promising with the award of a Wellcome ̨��swagy Award to Rugg-Gunn in 2022. “With all the tools at our disposal, I feel that we’re on the cusp of filling these critical knowledge gaps and really unlocking a new level of understanding that will support healthy development, healthy pregnancies and stem cell technologies that will mean healthier lives for everyone.”