(Bicentenary) Understanding congenital heart disease using single cell genomics and machine learning The University of Manchester in United Kingdom

This interdisciplinary PhD project will combine research on human pluripotent stem cell biology, single cell genomics and computational biology to deliver deep new insight into the mechanisms of human cardiac cell development and congenital heart disease (CHD). CHD is the most common birth defect, but its molecular causes remain poorly understood despite a burgeoning amount of new patient genome sequencing data. A major roadblock to clinical progress is the present lack of suitable models to connect genotype to human developmental phenotype – hundreds of genes have been implicated in CHD, but the predicted molecular consequences of most variants remain largely opaque.

This project aims to solve this by using data from a human embryonic stem cell model of cardiac development – including single cell genomics and CRISPR-Cas9 gene knockout library screening – plus data from animal models of heart development (mouse and zebrafish), and leveraging the latest methods in computational biology e.g. machine learning and AI. Together this will enable us to discover how human heart cell development is coordinated and the consequences of errors in its regulatory mechanisms. The project will take advantage of many recent datasets but will also include a wet lab component of data acquisition.

Supporting this research, the supervisory team includes experts in human stem cell biology, heart development, animal models of development, and computational biology – enabling the student to gain comprehensive training in all disciplines of the project. We expect this interdisciplinary partnership will create a synergism for research productivity that will reveal privileged new understanding of human biology. It will also provide a systematic approach to support the effective diagnosis and management of CHD. A key objective of the project is to translate this new understanding into a user-friendly web app, as a tool to interface with clinical researchers and as a foundation for integrating new layers of knowledge.

Successful PhD research necessitates a strong and dynamic research environment. The University of Manchester was recently awarded Centre of Research Excellence status by the British Heart Foundation, highlighting its strength in this area. Moreover, the Birket lab (supported by UKRI funding) has recently published an extensive study of human cardiac cell development in a 3D embryonic stem cell organoid model ( https://doi.org/10.1101/2024.08.15.607916 ), which includes single cell genomics data that will support this PhD project. The Hentges lab will provide expertise in heart development in animal models as well as machine learning techniques ( https://doi.org/10.1038/s41598-023-38110-z ). Finally, the Iqbal group is pioneering new machine learning-based methodologies for the analysis of single cell multi-modal (RNA and chromatin combined) datasets ( https://doi.org/10.1101/2023.09.25.559293 ). The environment is therefore optimal for a highly motivated candidate to succeed and thrive, while gaining training and expertise in the very latest biomedical research technologies.

Eligibility

Applicants must have obtained or be about to obtain a minimum Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant discipline such as (but not limited to) genetics, molecular biology, mathematics or computer science.  Research experience in bioinformatics / computational biology is desirable.

Before you Apply

Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.

How to Apply

To be considered for this project you MUST submit a formal online application form – on the application form you must select FBMH Bicentenary PhD Programme - Full-time. If you select the incorrect programme your application cannot be considered. Full details on how to apply can be found on the Bicentenary Website

Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered.  If you have any queries regarding making an application, please contact our admissions team .

Equality, Diversity and Inclusion

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website.