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Self funded BMS Project: Understanding the population dynamics of haematopoietic stem cells during gene therapy for sickle cell disease


   York Biomedical Research Institute


About the Project

Applications accepted for PhD Only

Background: This project builds on the recent discovery that whole genome sequencing approaches in blood stem and progenitor cells can be used to estimate the number of actively contributing blood stem cells in humans (Lee-Six et al., Nature 2018). More than 100,000 spontaneous, genome-wide somatic mutations were identified across 140 single-cell-derived blood stem and progenitor colonies from a healthy 59-year-old man. This allowed a family tree of relatedness to be constructed and population genetics approaches were applied to estimate clonal dynamics of the stem cell pool. Our recent collaborative efforts between York, Boston Children’s Hospital and the Wellcome Sanger Institute and funded by the Bill and Melinda Gates Foundation has applied this technique to patient samples in sickle cell disease (SCD) gene therapy trials to understand the number of blood stem cells that are targeted, the pre- and post-gene therapy mutational burden, and the clonal dynamics of SCD stem cells.

Objectives:

1. Develop a detailed map of the genomic changes per stem cell lineage in pre- and post-gene therapy SCD patients.

2. Enumerate stem cells that can be targeted by gene therapy and determine whether there is heterogeneity in their contribution to mature blood cell production in patients

Novelty and Timeliness:

Our approach provides unprecedented insight into the genomic integrity of these patients with 100s of single cell-derived genomes sequenced per patient, revealing pre-existing mutations and comprehensively mapping newly expanding stem cell clones. In the wake of recent safety concerns in gene therapy trials, there is an urgent need for additional real world data related to the presence of pre-leukaemic driver mutations.

Experimental Approach:

The host lab has extensive experience in the clonal expansion of mouse and human single blood stem and progenitor cells and these expansion techniques are essential for getting enough DNA to monitor HSC population size and clonal dynamics by tracking acquired somatic mutations and avoiding the introduction of genetic markers. The project will involve flow cytometry, clonal stem cell assays and a significant computational biology component for data analysis which will be supported by the secondary supervisor as well as through collaboration with the Wellcome Sanger Institute.

The York Biomedical Research Institute at the University of York is committed to recruiting extraordinary future scientists regardless of age, ethnicity, gender, gender identity, disability, sexual orientation or career pathway to date. We understand that commitment and excellence can be shown in many ways and have built our recruitment process to reflect this. We welcome applicants from all backgrounds, particularly those underrepresented in science, who have curiosity, creativity and a drive to learn new skills.

Entry Requirements: Students with, or expecting to gain, at least an upper second class honours degree, or equivalent, are invited to apply. The interdisciplinary nature of this programme means that we welcome applications from students with backgrounds in any biological, chemical, and/or physical science, or students with mathematical backgrounds who are interested in using their skills in addressing biological questions. 

Programme: PhD in Biomedical Science (3 years)

Start Date: 1st October 2022

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Funding Notes

This is a self funded research project. Applicants need to have adequate funds to meet the costs of a self-funded research project including tuition fees and living expenses for the duration of the research programme.

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