A 2024 Crick PhD project with Silvia Santos.
Project background and description
The Santos lab studies two fundamental cellular decisions: cell division and cellular differentiation in the context of early development and disease, using 2D and 3D (organoid) human embryonic stem cell-based models.
A potential project is to understand the interplay between cell division and cell identity during human development, reprogramming and disease using hESC and organoid models. Please note: this is just one example of the sort of project that is available in the Santos lab. The precise project will be decided on in consultation with the supervisor
Proper development of an organism requires careful coordination between the cell cycle machinery and cellular behaviour. Divisions in the embryo are clocklike, fast, short and synchronous with no checkpoints or gap phases. With time, during lineage specification, these divisions become longer and asynchronous. The resulting somatic like cycles have checkpoint control and long gap phases, and the initiation of events is dependent on completion of early events, just like a falling domino. The question, thus, arises on how do the same cell cycle regulators self-organize and adapt to drive different cell division cycles? And how does a fast cell cycle, such as that of an embryonic cell or a cancer cell, adapts to become a slow, well-controlled cell division cycle?
While it has been established that the cell cycle remodels with cellular differentiation, increasing evidence also suggests that cell cycle regulators might bias fate choices, enforce cell identity and have an unanticipated role in driving lineage specification.
We will investigate these questions in the context of reprogramming and cellular differentiation.
The potential student will use multi-disciplinary approaches including live cell imaging of embryonic stem cells expressing cell cycle and fate biosensors, genome editing techniques and multi-omics single cell RNAseq approaches to gain mechanistic understanding into how the cell cycle remodels during embryonic stem cell differentiation and contributes to lineage specification in the developing embryo.
In this project, some of the specific aims include but are not limited to:
- To use genome editing technologies to perturb the cell cycle-cell fate cross-talk
- To measure cell cycle dynamics during cellular transitions by state-of-the-art live cell imaging
- To integrate sequencing (OMICS) and imaging data sets
More information about the lab, please visit https://www.crick.ac.uk/research/labs/silvia-santos
and check out our Twitter: @SantosLaB8
These studies will have profound implications for understanding both normal development, reprograming and the transition to disease states, such as cancer, where cell cycle regulation takes a central stage.
Lab techniques include
Live cell imaging and advanced microscopy, 2D and 3D (organoid) models, hESCs, CRISPR, biosensors, single cell approaches, multi-OMICs, image analysis and bioinformatics
Students will be exposed to excellent training and mentoring, in both experimental approaches and computational analyses. Students will be encouraged to attend conferences and present their work and well as take advantage of the excellent out-of-the-lab skills training provided at the Crick. Students will have the opportunity to be part of a vibrant scientific community, organise conferences and participate in outreach and science and society activities.
This project will suit any candidate who is intrigued by stem cell biology, fate decisions and cell division and who is keen to learn more about Signalling and Developmental and Cell Biology. Any degree in the Life Sciences or a background in relevant areas to Quantitative Biology is suitable for applying for this studentship. A strong motivation to be exposed to different state of the art techniques including single cell technologies, 2D and 3D organoid models, OMICS and imaging is expected. Motivation to be in an interdisciplinary, highly collegial and collaborative environment is an essential.
1. Gunne-Braden, A., Sullivan, A., Gharibi, B., Sheriff, R.S.M., Maity, A., Wang, Y.F., . . . Santos, S.D.M. (2020)
GATA3 mediates a fast, irreversible commitment to BMP4-driven differentiation in human embryonic stem cells.
Cell Stem Cell 26: 693-706.e699. PubMed abstract
2. Padgett, J. and Santos, S.D.M. (2020)
From clocks to dominoes: lessons on cell cycle remodelling from embryonic stem cells.
FEBS Letters 594: 2031-2045. PubMed abstract
3. Araujo, A.R., Gelens, L., Sheriff, R.S.M. and Santos, S.D.M. (2016)
Positive feedback keeps duration of mitosis temporally insulated from upstream cell-cycle events.
Molecular Cell 64: 362-375. PubMed abstract
4. Santos, S.D.M., Wollman, R., Meyer, T. and Ferrell, J.E., Jr. (2012)
Spatial positive feedback at the onset of mitosis.
Cell 149: 1500-1513. PubMed abstract
5. White, J. and Dalton, S. (2005)
Cell cycle control of embryonic stem cells.
Stem Cell Reviews 1: 131-138. PubMed abstract