Overview
Matt Guille grew up on the Island of Guernsey before his degree and PhD in Biochemistry at King’s College London. Post-doctoral research at the Imperial Cancer Research Fund (now the Crick) and the University of London’s Developmental Biology Research Centre followed before moving to the Biophysics unit at Portsmouth to start his own lab. During all of this period Matt worked on how genes are controlled and on their functions. In 2006 Matt established the European Xenopus Resource Centre for the research community, it is now the “go to” facility in the world for research using the clawed frogs. Nowadays his research focuses on diagnosis and understanding of rare genetic diseases.
This presentation will start by introducing genes and their function very briefly and then describe why Xenopus frogs are such powerful “model organisms”. followed by what the Resource Centre does. We will then move onto the rare disease programme. Although these are called rare diseases, around 7000 of these have been discovered and 1 in 17 people in the UK has one of these. Recent advances in DNA sequencing and analysis driven by the 100 000 genomes project have allowed the potential disease-causing variations in patient genomes to be identified. Despite this fewer than half of patients have a diagnosis. Five years ago we started to use the tadpole to test the link between potential disease-causing patient gene variants and their disease. We continue to develop this technology but have already identified some 30 new diseases.
Lynn’s Review
I think many of us were unsure of what we would discover from today’s presentation. I once looked after a xenopus for a few years, so I knew a little about the African, clawed frog, but today, I discovered so much more.
Matt Guille is professor of Developmental Genetics at Portsmouth University, where he set up an independent lab working on gene regulation in Xenopus, and in 2006 this led to the inception of the European Xenopus Resource Centre funded by the Wellcome Trust.
Xenopus, since the 1940s, was used for pregnancy testing: urine from a pregnant woman, if injected under the skin of the frog, would cause it to produce eggs. However, for over 50 years, Xenopus, has been a model for biomedical research, leading to many ground- breaking discoveries.
At first xenopus was used to discover the basics of biology, such as: what makes blood form; and what networks are used by genes, later, building upon those discoveries, has led to the use of xenopus as a model for diseases.
Various model organisms having a similar genome to humans, have been used over the years, and the ethics of using these models has long been debated. More consideration for the ethics of animal research has prevailed in the 21st century. In recent years, the mouse was generally most favoured, having close similarities to the human genome, but the frog, which also has a similar genome, is considered less sentient than a mouse and so is widely used as a model. Xenous laevis is also very hardy. It can live in extreme environments and is nocturnal. It can produce eggs all year round, and it is these embryos that are generally employed for research.
Big data and mathematical modelling form a part of research as do Organoids (cell cultures), but though organoids may be the tool of the future, the advancement in this technique is slow, and mathematical modelling can only result from data achieved through the use of animal models.
An early breakthrough in the understanding of how molecules can cause change, was through an experiment worked on by Hilda Mangold under the direction of Hans Spemann. She transplanted cells from the dorsal lip of a newt embryo onto its ventral side, and discovered that transplanted cells were instructing, or inducing, neighbouring cells to migrate and adopt specific cell fates. she observed that an entire neural tube and brain would form at the site of the transplant; effectively creating a new newt embryo. In 1990 Richard Harland discovered the molecules that caused this change. The process led to the creation of what is termed an “Organiser.”
Portsmouth University now has 1024 tanks full of frogs (these can live for at least 15 years), and freezers full of cells from organisms. The Resource centre, which supplies frogs to other countries, is well funded at present and has some top of the range technology in the form of microscopes with zeiss lenses which also act similarly to CT scanners.
The “100,000 genome project,” helped cement the NHS’s position as one of the most advanced healthcare systems in the world, and helped lay the foundation for a new era of personalised medicine. Along with cancer, the Project looked at the whole genomes of people affected by rare disease to try and identify any genetic variations that might be causing symptoms.
Xenopus can quickly be genetically altered to study rare genetic diseases. One in seventeen people are born with a rare genetic disease and one in twenty have a rare gene variant. This year, two new therapies have emerged from gene sequencing and research using xenopus.
For one child, Jessica, who suffered from severe epileptic fits, it was discovered that a change in diet was all that was required.
In the past, the cost of multiple tests to detect disease in a child might cost £345,000; now gene sequencing and the use of CRISPR techniques with RNA injected into frogs can bring results in just over 2 days at very little cost.
Xenopus laevis and the smaller xenopus tropicalis are now at the forefront of research and are beginning to be used clinically.
Science research criteria is changing. In the past, the top requisite was: “Scientific excellence,” but now it’s: “Value for money.”
Britain has the lead in this.
There is so much more to discover in this field, particularly the use of viral vectors for targeting disease.
Below I put links to sites I have referred to in writing this. I hope you find them useful.
https://researchportal.port.ac.uk/en/persons/matt-guille
https://www.sciencedirect.com/science/article/abs/pii/B9780128030776000229
https://www.jax.org/news-and-insights/jax-blog/2016/october/women-in-science-hilde-mangold#
https://news.berkeley.edu/2016/10/20/lab-frog-dna-shows-what-happens-when-genomes-collide/
https://www.england.nhs.uk/genomics/genomic-research/100000-genomes-project/
https://www.genome.gov/sites/default/files/media/files/2021-08/NHGRI_T2T_Infographic.pdf