Santos lab
Quantitative Stem Cell Biology Laboratory
: Areas of interest

Multidisciplinary approaches have revolutionised the way we ask biological questions and have been crucial to understanding spatio-temporal control principles in cell decision-making.

During cell decision-making, gene and protein networks dynamically change in response to cues in order to trigger different cellular states. How information is decoded and transmitted in order to commit to specific cell fates has been a fundamental question in cell and developmental biology. In this context, the quantitative cell biology lab aims to understand how signalling molecules are organized into circuits, how these circuits are spatio-temporally regulated and remodel in two important cellular decisions: cell division and cellular differentiation.

The decision to divide is a fundamental decision and the conserved networks that trigger cell division adapt and remodel in a variety of biological contexts including developmental transitions and malignancy. We have been exploring spatio-temporal control of cell division in mammalian cells and remodelling of cell cycle networks during developmental transitions, using embryonic stem cells as a model system.

Embryonic stem cells have the propensity to differentiate into the three germ layers. The switch between pluripotency and differentiation in these cells has been our paradigm of choice to understand how protein and gene networks decode cellular signals and thereby encode irreversible commitment to different cell fates.

Both lines of investigation will have a profound impact in the understanding of normal human development and the transition from healthy to disease states. We use quantitative approaches combining experimental methods (based on single cell live cell imaging, genomics, proteomics and chemical biology) with mathematical modelling. Multidisciplinary approaches have revolutionised the way we ask biological questions and have been crucial to uncover regulatory principles in cell decision-making.

Cell cycle remodelling during developmental transitions

The decision to divide is a fundamental cellular decision and the correct partitioning of chromosomes between two daughter cells requires a tight coordination of the cell cycle machinery in time and in space. Indeed, the evolutionarily conserved networks that control cell division adapt and remodel in a variety of biological contexts including developmental transitions and when cells undergo malignancy. A striking example of this adaptability occurs in normal development during the transition from early embryonic to somatic divisions in the embryo.

Divisions in the embryo are fast, short, with little or no checkpoints nor gap phases. On the contrary, somatic cell divisions are much slower, with long G1- and G2-phases and dependent on checkpoint control. While we have a reasonably good idea on how the embryonic and somatic cell cycles operate, very little is known on how a hyper-proliferative cell cycle such as that of an embryonic cell adapts to become a slow, checkpoint-controlled cell division cycle. We are addressing this classic question using novel tools: using hES cell differentiation as a model system and monitoring single cells as they transit from an embryonic division to a longer, more regulated division cycle during hESC differentiation.

Figure 1: Probing cell cycle dynamics in single cells using biosensors.

Encoding cell fate decisions by decoding cellular signals

During human embryonic stem cell differentiation cells undergo dramatic changes: cells change their morphology, they become flat and elongated; pluripotent markers go down and lineage specific markers come up, epigenetic modifications occur, whereby global methylation of key histones is up-regulated and global acetylation is down-regulated and the cell cycle remodels. We study how cells integrate and decode signals in order to trigger these changes and ultimately commit to a specific fate.