The mission of the Merkle Lab is to improve human health by using a multidisciplinary array of approaches to illuminate the molecular and cellular basis of disease.
PhD/MPhil projects available within the Merkle team
Techniques we use
- Human pluripotent stem cell (hPSC) differentiation into neurons, astrocytes, and other disease-relevant cell types, and their co-culture.
- CRISPR/Cas9-based gene editing to introduce disease-associated genetic variants and generate knock-in reporter cell lines to permit the isolation and study of cell types of interest.
- Transcription factor-based forward programming, to broaden the repertoire of human cell types that can generated and studied in vitro.
- Single-cell and single nucleus RNA sequencing to profile the transcriptome of different mouse and human cell types under steady-state or perturbed conditions.
- Electrophysiology and calcium imaging to functionally characterise the responses of hPSC-derived neurons to drugs, hormones, and other factors.
- Targeted CRISPR screens to test the effects of disease-associated genes in disease-relevant human cell types.
- Whole genome sequencing to assess the genomic stability of hPSCs.
- High-content confocal imaging to quantify cellular features in cultured cells in order to measure the effects of genetic and cellular perturbations.
- Proximity proteomics to reveal proteins resident in neuronal primary cilia.
- Bulk transcriptomics, lipidomics, and peptidomics for the multimodal characterisation of mouse and human tissues under steady-state or perturbed conditions.
- Histology and immunostaining of tissues and cultured cells to reveal patterns of gene expression and cell type distribution.
- Machine learning analysis of videos of mouse behaviour for the unbiased assessment of neurodegenerative state.
- Computational drug prediction to reveal candidate neuroprotective drugs from transcriptomic data.
Poster prizes – Andrian Yang and Cortina Chen (2022 IMS-MRL retreat); Viviana Macarelli (2022 IMS-MRL student symposium); Simone Mazzaferro (2022 European Incretin Study Group, Lausanne).
Travel award – Viviana Macarelli (EMBO Cilia 2022 conference).
Pilot grants – Ed Harding – connecting us to the Cambridge Centre for Data-Driven Discovery to support the exploration of artificial intelligence and machine learning (AI/ML) approaches for drug discovery and unbiased mouse phenotyping.
Alumni achievements – Theresa Bartels for her successful PhD thesis defence, Julia Becker for submitting her PhD thesis, and Amit Chouhan, Andrea Halsey, Ryan Patterson-Cross, Sanya Aggarwal, and Sophie Austin for all landing great jobs after their time in the lab.
Our highlight publication
First author: Caroline Pantazis
In this pre-print (currently resubmitted for publication), we coordinated a large-scale collaborative effort in order to identify a common reference human induced pluripotent stem cell (iPSC) line to facilitate reproducibility in the stem cell field. We deeply characterised candidate cell lines by whole genome and single-cell sequencing, and tested their gene editing potential and ability to be differentiated to multiple lineages in head-to-head competitions with other iPSC lines. The identified reference iPSC line (KOLF2.1J), the associated datasets, and the lightweight MTA and website we helped develop to promote its widespread distribution promise to have a lasting impact on the stem cell field. Our vision is that KOLF2.1J will become one of a handful of widely-used iPSCs, much as C57Bl6/J mice are a commonly used strain.
Other publications we are proud of
Florian T. Merkle, Sulagna Ghosh, Giulio Genovese, Robert E. Handsaker, Seva Kashin, Daniel Meyer, Konrad J. Karczewski, Colm O’Dushlaine, Carlos Pato, Michele Pato, Daniel G. MacArthur, Steven A. McCarroll, Kevin Eggan. Cell Stem Cell, Volume 29, Issue 3, 2022, Pages 472-486.e7
We analysed 143 readily available human embryonic stem cell (hESC) lines at a resolution from whole chromosomes down to individual bases and identified several new recurrently culture-acquired mutations, as well as genetic variants associated with cancer and other diseases. Other groups may want to consider using these when selecting cell lines for a given purpose so we created a user-friendly, web-based portal summarising our findings.
Julie Jerber, Daniel D. Seaton, Anna S. E. Cuomo, Natsuhiko Kumasaka, James Haldane, Juliette Steer, Minal Patel, Daniel Pearce, Malin Andersson, Marc Jan Bonder, Ed Mountjoy, Maya Ghoussaini, Madeline A. Lancaster, HipSci Consortium, John C. Marioni, Florian T. Merkle, Daniel J. Gaffney & Oliver Stegle. Nature Genetics 53, 304–312 (2021).
A collaborative study to pool together and differentiate over 200 hiPSC lines in addition to mapping expression quantitative trait loci (eQTL) across specific cell types and development. We found molecular correlates that predict whether an iPSC line will differentiate well into neurons or not, that are of widespread practical utility to the stem cell field.
Outreach and widening participation
During COVID our team organised a series of international webinars with the UK Dementia Research Institute (UKDRI), supported by the CZI Neurodegeneration Challenge Network (NDCN) to bring together ECRs and established PIs interested in neurodegeneration in the UK, US, and elsewhere. These efforts culminated in an in-person day for individuals suffering from Parkinson’s Disease and their families, which we organised together with Prof. Roger Barker and Caroline Williams-Grey.
We enjoyed hosting a fantastic undergraduate student Hubert Ziebicki (summer 2022) as part of the University’s Experience Postgrad Life Sciences programme. Hubert accomplished a lot in his time, and we all wish him well. More details.
We are hosting Ukrainian PhD student Dmytro Shepilov from November 2022 to allow him to continue his studies which have been disrupted by war.
Thanks to the University as well as the IMS for generously helping us support him!