Cross-Disciplinary Fellowships (XDF)

Notable outcomes & achievements

Publications, awards and other achievements.

Note that on 1 April 2021 the Institute of Genetics and Molecular Medicine (IGMM) has been renamed the Institute of Genetics and Cancer (IGC) to emphasise its scientific strengths in genetics and cancer research.

scMET: Bayesian modeling of DNA methylation heterogeneity at single-cell resolution

Single-cell DNA methylation assays can currently profile hundreds to thousands of DNA methylomes, with increasingly complex experimental designs. The high resolution of these measurements enables researchers to evaluate cell-to-cell epigenetic variability, as well as uncover the regulatory features that modulate it. However, the noise and biases intrinsic to such technologies create a need for computational frameworks that can systematically interrogate the data generated, dissecting genuine variability and quantifying uncertainties.

One of our XDF Programme Fellows, Dr Chantriolnt-Andreas Kapourani, is the first author on a study titled “scMET: Bayesian modeling of DNA methylation heterogeneity at single-cell resolution”. The study, published by the journal “Genome Biology” on the 20 April 2021, presented scMET - a Bayesian hierarchical approach to robustly quantify epigenetic heterogeneity using high-throughput single-cell DNA methylation datasets. The performance of scMET was extensively evaluated using synthetic data and recent large-scale assays in the context of the mouse brain cortex and during early development. The investigators also introduced a novel differential methylation framework which, unlike existing approaches, fully exploits the cellular resolution of the data to identify changes in epigenetic variability. scMET can overcome data sparsity and improve the quantification of genuine epigenetic cell-to-cell heterogeneity.

Graphical outline for scMET – for details see Kapourani A et al. Genome Biol. 2021 Apr 20;22(1):114.
Graphical outline for scMET – for details see Kapourani A et al. Genome Biol. 2021 Apr 20;22(1):114.

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New insights into how severe brain cancer evades immune attack

Graphical abstract and serial transplantation strategy of the work published in “Cell”
Graphical abstract and serial transplantation strategy of the work published in “Cell”

Glioblastoma multiforme (GBM) (also called glioblastoma) is a fast-growing tumour type that develops from star-shaped glial cells (astrocytes and oligodendrocytes) that support the health of the nerve cells within the brain. Treatment options are limited and just a quarter of glioblastoma patients survive more than one year.

One of the reasons glioblastoma is so hard to treat is because it has many distinct types, in terms of the genetic makeup and how those genes are expressed (transcriptional profile). In one of these distinct tumour subtypes (mesenchymal glioblastoma), the tumour supresses the immune environment around the cancer cells making it harder for the body to defend itself against those invasive cells.

Dr Chantriolnt-Andreas Kapourani, XDF Programme Fellow class of 2018, contributed to a study titled “Glioblastomas acquire myeloid-affiliated transcriptional programs via epigenetic immunoediting to elicit immune evasion” which identified the way in which glioblastoma can evade the body’s own immune response by using signals normally found in immune cells. The study involving investigators from the University of Edinburgh, the University College London and the Brown University was published in the journal “Cell” on 14 April 2021.

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Parameter-free molecular super-structures quantification in single-molecule localization microscopy

Single-molecule localization microscopy (SMLM) is a set of fluorescence microscopy techniques that have enabled visualization of small biological structures that was previously considered impossible due to the resolution limit. They do this by repeatedly imaging a small random subset of fluorescent molecules in the sample, creating images with sparse support and thereby allowing extremely high accuracy in determining the locations of the molecules. SMLM is quickly becoming an indispensable tool for studying biological structures but SMLM datasets can only be useful if properly quantified and interpreted. A group of researchers from University of Edinburgh and University of Strathclyde, with one of our XDF Programme Fellows - Dr Mattia Marenda - as a lead author, developed a parameter-free algorithm to quantify super-structures and connected clusters in SMLM datasets. Their algorithm, SuperStructure, can be used to analyse and explore complex SMLM data and extract functionally relevant information. They demonstrated the capabilities of SuperStructure on simulated and experimental datasets showing that it can be used as an unbiased tool to extract information beyond simple clustering. These findings were published on 18 March 2021 in the Journal of Cell Biology.

Working principle of SuperStructure analysis [for details see Marenda et al. J Cell Biol. 2021 May 3;220(5):e202010003].
Working principle of SuperStructure analysis [for details see Marenda et al. J Cell Biol. 2021 May 3;220(5):e202010003].

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ISSF award to study transcriptome-chromatin dynamics and regulation of cell state in early eye development

Drawing of sagittal section of eye of human embryo of six weeks. [from Henry Vandyke Carter and Henry Gray “Anatomy of the Huma
Drawing of sagittal section of eye of human embryo of six weeks. [from Henry Vandyke Carter and Henry Gray “Anatomy of the Human Body” (1918)]

In January 2021 one of our XDF Programme Fellows, Dr Andrew Papanastasiou, has been awarded a Wellcome Trust's Institutional Strategic Support Fund (ISSF) award to support a project titled “Coupled transcriptome-chromatin dynamics and regulation of cell state in early eye development”. The funds will enable the generation of joint single-cell RNA sequencing (RNA-seq) and Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) data from optic-cup organoid differentiation which will be used to model eye-field formation ex vivo. These unique datasets will be used to identify molecular events underlying eye-field formation and support computational-methods development. The formation of the eye field, a centrally located group of neural plate cells defined by the expression of a specific set of transcription factors (TF), is the earliest known stage of mammalian eye development. Perturbations of eye-field specification are thought to be the most common cause of severe eye malformations, so the proposed research might shed some new light on these conditions. The proposed research aims to address two fundamental questions:

(1) What are the necessary cellular state transitions required for successful establishment of the eye-field, and are these driven by changes in gene expression or chromatin accessibility?

(2) At the level of individual gene-regulatory mechanisms, are key changes in mean levels and variability of TF expression preceded by dynamic changes in chromatin accessibility of specific cis-regulatory regions (enhancers and promoters)?

Wellcome Trust's Institutional Strategic Support Fund 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.

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XDF Programme Fellow became an Associate Editor of “Biochemistry and Biophysics Reports”

BB Reports Logo

In January 2021, one of the XDF Programme fellows - Dr Didier Devaurs, joined the Editorial Board of the journal “Biochemistry and Biophysics Reports” (BB Reports). This open access Elsevier journal publishes original research in all aspects of biochemistry, biophysics and related areas like molecular and cell biology. In his role as an Editor, Didier contributes knowledge in the areas of quantitative biomedical research, structural bioinformatics, computational structural biology, molecular modelling, molecular dynamics, molecular docking, protein-ligand interactions, protein-peptides interactions, protein-protein interactions, hydrogen exchange monitoring - including hydrogen deuterium exchange mass spectrometry (HDX-MS) and hydrogen deuterium exchange NMR spectroscopy (HDX-NMR), and small-angle scattering - including small-angle X-ray scattering (SAXS) and small-angle neutron scattering (SANS).

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“Genetics Needs Non-geneticists” – reflections on migrating between disciplines and lessons learned from the XDF Programme

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. 

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XDF Programme Fellow contributed to a “Nature” paper describing how chemicals cause complex cell mutations

Schematic showing segregation of DNA lesions
Schematic showing segregation of DNA lesions

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.

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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 IGC.

Graphical abstract of the work proposed by Dr Khamseh
A comprehensive experimental design: Simultaneously generates multiomics, temporal & population data in early oncogenesis to: i) Capture/classify mutational and corresponding gene expression trajectories of pre-neoplastic cells over time ii) Develop mathematical/computations models to infer how different sets of driver mutations interact, both within and between different pathways, leading to cell competition/cooperativity

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XDF Programme Fellow contributed to a “Nature” paper on multi-omics profiling of gastrulation

The process of gastrulation
The process 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.

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XDF Programme Fellow published papers in physics and biomedicine journals

Zebrafish MITF-low melanoma models of human MITF-low melanoma (MITF is a transcription factor essential for melanocyte development and survival). While the bulk of the tumour is dependent on MITF activity, MITF-independent cells pre-exist and arise de novo in residual disease.
Zebrafish MITF-low melanoma models of human MITF-low melanoma (MITF is a transcription factor essential for melanocyte development and survival). While the bulk of the tumour is dependent on MITF activity, MITF-independent cells pre-exist and arise de novo in residual disease.

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).

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Super-resolved image of SAF-A protein in cell nucleus (Credit: Dr Mattia Marenda).
Super-resolved image of SAF-A protein in cell nucleus (Credit: Dr Mattia Marenda).

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.

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Melissa Model Overview
Melissa Model Overview

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.    

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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