Notable outcomes & achievements
Publications, awards and other achievements.
“Genetics Needs Non-geneticists” – reflections on migrating between disciplines and lessons learned from the XDF Programme
On 25 July 2020 the journal “Trends in Genetics” published a short article from XDF Programme Director Professor Chris Ponting. The text titled “Genetics Needs Non-geneticists” was invited by the journal editors and focuses on challenges facing fellows moving to genetics from other disciplines. It also describes lessons learned from the XDF Programme to date.
XDF Programme Fellow contributed to a “Nature” paper describing how chemicals cause complex cell mutations
One of our cross-disciplinary fellows, Dr Ava Khamseh, contributed to a study titled “Pervasive lesion segregation shapes cancer genome evolution” that has been published in the journal “Nature” on the 24 June 2020. Researchers tracked the impact of diethylnitrosamine, a toxic substance similar to compounds found in tobacco, exhaust and some plants, to better understand how chemicals cause mutations in cells’ DNA and how DNA lesions segregate, unrepaired, into daughter cells for multiple cell generations, resulting in the chromosome-scale phasing of subsequent mutations. They also demonstrated that lesion segregation is a unifying property of exogenous mutagens, including UV light and chemotherapy agents in human cells and tumours, which has profound implications for the evolution and adaptation of cancer genomes. The study was performed by a multidisciplinary team of scientists from the United Kingdom, Germany and Spain.
ISSF award for an XDF Programme Fellow
Wellcome Trust's Institutional Strategic Support Fund (ISSF) enables universities in the UK and Ireland to invest in areas that are of mutual strategic importance to Wellcome and the individual institutions. These are within and across medical and clinical sciences, public health, social sciences and medical humanities. At the University of Edinburgh particular emphasis is placed on supporting early career researchers and interdisciplinary projects.
In January 2020 one of our XDF Programme Fellows, Dr Ava Khamseh, has been awarded an ISSF grant to carry out an interdisciplinary study that should improve a quantitative understanding of the necessary and sufficient early conditions and steps required for the evolution of normal cells into cancer cells. The project titled “Recurrent clonal expansion trajectories and mutational competition in a model of very early oncogenesis” will use a tractable somatic mouse model of hepatocellular carcinoma (HCC) - the most common form of primary liver cancer - to trace clonal evolution at cellular resolution, over hours and days, via targeted single cell DNA and RNA sequencing. It will also develop a novel statistical approach to robustly quantify interactions between different mutations that lead to competition and/or cooperativity of cell populations. Using DNA and RNA profiles from the same cells will help determine how these mutational signatures relate to transcriptional trajectories, leading to evolution of pre-neoplastic cell populations. The work will be undertaken in close collaboration with Luke Boulter and Catalina Vallejos laboratories in the IGMM.
- University of Edinburgh Institutional Strategic Support Fund (ISSF3) website
- Interesting review article on clonal heterogeneity and tumour evolution
XDF Programme Fellow contributed to a “Nature” paper on multi-omics profiling of gastrulation
December 19th, 2019 issue of a highly acclaimed multidisciplinary journal “Nature” provides a good example of positive outcomes resulting from collaborative approaches encouraged by the XDF Programme. One of our cross-disciplinary fellows recruited in 2018, Dr Chantriolnt-Andreas Kapourani, contributed to a study published in the journal. The work titled “Multi-omics profiling of mouse gastrulation at single cell resolution” involved researchers from the United Kingdom, Germany, China and Canada, and provided a single-cell resolution multi-omics map of chromatin accessibility, DNA methylation and RNA expression during the onset of gastrulation in mouse embryos. Gastrulation is a phase early in the embryonic development of most animals, during which the single-layered blastula is reorganized into a multilayered structure known as the gastrula. The process of gastrulation is of fundamental importance for subsequent tissue formation and organ development and the results published in “Nature” have important implications for the role of the epigenome (chemical changes to the DNA and histone proteins of an organism) in defining cell-lineage commitment. Future studies that use multi-omics approaches to investigate cell populations have the potential to transform our understanding of cell-fate decisions, with important implications for stem cell biology.
XDF Programme Fellow published papers in physics and biomedicine journals
One of the main objectives of the XDF Programme is to train the fellows in biomedical sciences while at the same time helping them to nourish knowledge and skills they had already gained from their previously studied disciplines. This is hoped to be achieved through carefully designed collaborations and joint projects with people from informatics, physics and similar fields of research. In Summer/Autumn 2019, one of the XDF Programme Fellows, Dr Ava Khamseh, published two very interesting papers in high impact journals from different disciplines – physics and cancer research. She achieved it by working with two separate teams on very different topics using both numerical and biomedical methodologies - suggesting perhaps, that the XDF Programme approach to cross-disciplinarity might be working well.
The first study, titled “Machine learning determination of dynamical parameters: The Ising model” and published in the journal “Physical Review B”, was performed in collaboration with investigators from Higgs Centre for Theoretical Physics at the University of Edinburgh, Alan Turing Institute in London and Ascent Robotics in Tokyo. The study uses machine learning (training of a set of restricted Boltzmann machines on one- and two- dimensional Ising spin configurations at various values of temperature, generated using Monte Carlo simulations) to develop new approaches for data distribution analysis. It forms the foundation for further investigations of interactions between variables in biological systems. Notably Ava has been designated one of the corresponding authors for this work.
The second study, titled “Zebrafish MITF-low melanoma subtype models reveal transcriptional subclusters and MITF-independent residual disease” and published in the journal “Cancer Research”, identified novel cell states in melanoma progression and residual disease. Melanoma is the deadliest type of skin cancer with almost 16,000 new cases every year in the UK and the study used state-of-the-art high-resolution imaging combined with single cell gene expression analysis to understand these new cell states for the first time in a complex living system. The study, led by Dr Elizabeth Patton from IGMM, involved research institutions from Australia, Belgium, Iceland, USA and UK (including IGMM’s MRC Human Genetics Unit and CRUK Edinburgh Centre).
First successful research grant application with an XDF Programme Fellow as the Lead Applicant
Ability to secure research funding represents one of the essential skills for successful scientists in today’s highly competitive research environment and the XDF Programme places strong emphasis on providing its Fellows with education and training opportunities in this area with the overarching aim of facilitating their transition to independence.
Summer 2019 was notable in this respect as it marked the first successful outcome of a grant application led by an XDF Programme Fellow - Dr Mattia Marenda. In May 2019 – less than a year from the beginning of the XDF Programme - Mattia and his colleagues from IGMM (Prof Nick Gilbert, Dr Dimitrios Papadopoulos), the University of Edinburgh’s School of Physics and Astronomy (Dr Davide Michieletto) and the Department of Physics of the Strathclyde University (Dr Sebastian van de Linde) submitted an application titled “Investigating the Bio-Physical Properties of SAF-A Assembly via Live-Cell Super-Resolution Microscopy, Machine Learning and Molecular Dynamics Simulations” for consideration by the SULSA Technology Seed Funding scheme. The application had been deemed highly innovative and funds were awarded to enable its implementation.
Understanding the three-dimensional organisation of the genome in eukaryotic cells represents one of the greatest challenges in Life Sciences and the cross-disciplinary team assembled will use a broad spectrum cutting-edge technologies to characterise and understand the biophysical principles with which SAF-A, a protein with structural and functional roles in chromatin organisation, organises the genome.
- Scottish Universities Life Sciences Alliance (SULSA) website
- Information on genome organisation -the 3D genome review collection
First research publication attributed to the XDF Programme
The 21st of March 2019 was a notable date for the Programme as it marked the first scientific-research journal publication that acknowledges the XDF Programme support. In a study titled “Melissa: Bayesian clustering and imputation of single-cell methylomes” published in the journal “Genome Biology”, Dr Chantriolnt-Andreas Kapourani (one of the Fellows recruited in 2018) and Prof Guido Sanguinetti describe a new computational method - Methylation Inference for Single Cell Analysis (Melissa) – to aid single cell DNA methylation studies in biomedicine.
DNA methylation is a process by which methyl groups are added to the DNA molecule. It belongs to so called epigenetic modifications – modifications that do not involve changes to the underlying DNA sequence. Methylation can change the activity of a DNA segment. In mammals DNA methylation is essential for normal development and is associated with a number of key processes including genomic imprinting, X-chromosome inactivation, repression of transposable elements, aging, and carcinogenesis. Yet its role in gene regulation and the molecular mechanisms underpinning its association with diseases are still imperfectly understood. DNA methylation measurements at single-cell level are rapidly becoming a major tool to understand epigenetic gene regulation in individual cells, however all available technologies are plagued by intrinsically low coverage in terms of numbers of assayed methylated DNA stretches (so called CpGs). The authors propose Melissa as a way of addressing low coverage issue by sharing information between CpGs with local smoothing and between cells with Bayesian clustering prior. This methodology should have significant impact on future methylation studies.
Article in “Genome Biology”: https://genomebiology.biomedcentral.com/articles/10.1186/s13059-019-1665-8
General information about DNA methylation: https://en.wikipedia.org/wiki/DNA_methylation
“Training multi-discipline scientists can fight disease” – article in “The Scotsman” by Professor Chris Ponting
On the 27th of August 2018, just after a successful completion of the first ever XDF Programme Induction Week (20-24 August 2018), “The Scotsman” newspaper published an article by the XDF Programme lead Prof. Chris Ponting. The article entitled “Training multi-discipline scientists can fight disease” explains to a lay audience reasons behind training new generation of data-savvy multi-disciplinary scientists. It was intended to inform general public about the Medical Research Council – University of Edinburgh Cross-Disciplinary Post-Doctoral Fellowships and trigger some reflection on the challenges facing contemporary biomedical sciences.
Link to the article: https://www.pressreader.com/uk/the-scotsman/20180827/281930248842677