First glimpse into a vital developmental milestone opens new healthcare possibilities

• University of Leicester scientist develops first multiscale computer model that captures aspects of human gastrulation - the process that leads to the development of tissues and organs
• Once described as ‘the most important time in your life’
• Will allow scientists to design and test effects of engineered cells, and open new opportunities for personalised medicine

17 January 2023, Leicester, UK -- Computer modelling of our very first cells following conception has provided new insights that could lead to new ways of tackling disease through personalised medicine and cell therapy.

A scientist at the University of Leicester has created the first computer model that captures the gene networks involved in human gastrulation, the point at which our cells start to develop our tissues and organs, once dubbed ‘the most important time in your life’.

The process is detailed in a study recently published in print in the journal Stem Cell Reports.

Gastrulation is the process within an embryo that leads to the cells responsible for the development of tissues and organs in organisms. When a sperm fertilizes an egg cell, that cell divides into more cells that are largely identical to the original. When gastrulation occurs after around 14 days, those cells then begin to divide into three different types of cells which are then responsible for growing all the parts of the body: mesoderm, endoderm and ectoderm cells.

It was once referred to as ‘the most important time in your life’ by the scientist Lewis Wolpert.

Ethical and technical limitations prevent the study of human embryos at the point of gastrulation, but a University of Leicester researcher has now created a computer model that recreates the decision-making behind the process, and can allow scientists to predict how genetic changes affect specific cell fates.

It could allow scientists to engineer cell types on demand and conduct patient-specific modelling to tailor treatments to patients’ genomic profiles.

Lead researcher Dr Himanshu Kaul who heads the Laboratory for Multiscale Emergent Bioengineering in the School of Engineering at the University of Leicester said: “Most governments don't allow research with human embryos after 14 days due to the onset of gastrulation following this point. Gastrulation is a major first step that the body takes to create cells ready to help start forming organs, but we really did not have a window into human gastrulation, until the advent of technology that replicates aspects of gastrulation in a dish. While capturing the full complexity of human gastrulation remains some distance away, this technology has revealed unprecedented insights into this fascinating process.

“Still, this so-called peri-gastrulation is a complex process and I was quite encouraged by the accuracy of our predictions when compared against experimental observations. This was significant because it validated our technique to capture the multiscale decision-making, i.e. how gene interactions impact cell activity that in turn shapes the microenvironment of the cells, yielding ectoderm, mesoderm, and endoderm-like cells in the dish.

“The capability to show how the emergence of these cells can be tied to the gene networks and ultimately how you could control those is a critical novelty of our work. This sets the stage for programming specific multicellular outcomes on demand. This approach is also significant because of the role it could play in understanding disease mechanisms. For example, we do not understand diseases like asthma because multiple genes work in tandem. Now we have a tool or an approach that scientists can use to really tease apart the contribution of each of these genes.”

The computer model works by simulating how genes work together in a network. Genes both produce proteins and are activated by them, so scientists first need to understand how those genes work in concert to drive how the cell behaves. Dr Kaul could then make changes in the simulated genes and look at the effect on a virtual cell colony. The results were then verified using technology developed in Professor Peter Zandstra’s lab in the University of Toronto, Canada, that allows scientists to capture aspects of gastrulation outside of an embryo.

Many diseases emerge because of changes in these gene networks and this research now provides the missing link between what happens at the level of individual genes and with what happens at the organ or tissue level.

Dr Kaul added: “We are progressively moving towards an integrated understanding of biological processes, from the gene to the cell and tissue levels. This requires computational methods that can link interactions across these disparate scales. My work has presented a way to achieve this and I hope it will pave the way for more detailed insights and the next generation of models, including in my own lab, that will enable us to both understand human development and diseases more accurately and use the knowledge to develop personalised therapies.”

‘Virtual cells in a virtual microenvironment recapitulate early development-like patterns in human pluripotent stem cell colonies’ is published in Stem Cell Reports, DOI: /10.1016/j.stemcr.2022.10.004 Link: https://doi.org/10.1016/j.stemcr.2022.10.004