Fellow's research: A simple sugar enables division of labour within groups of cells in a cell community
19 Jul 2019
Institute for Stem Cell Biology and Regenerative Medicine
Our recently published work identifies simple metabolic rules that enable genetically identical cells to self-organize into spatially structured groups of cells, which carry out different metabolic function (‘division of labour’).
Single-celled organisms often come together as communities of cells, and this coming together allows these cells to survive and persist in sometimes unfavourable conditions. Within these communities, groups of cells seem to have different functions, appear to be specialized in their ability to perform different roles, and show clearly different phenotypes i.e. observable characteristics. This resembles what multicellular organisms achieve, through differentiated tissues. Also, in most microbes, these transitions into such organized communities are reversible. This ‘complexity’ usually appears when conditions are difficult for growth, and when conditions become favourable for growth, the cells become uniform and homogeneous.
We know a lot about gene expression networks that control how cells transition to complex communities. Surprisingly though, we don't know how the different phenotypic states emerge and organize within such communities. To address this, we used a simple model microbe, budding/baker’s yeast, where we first identified the organization of cells into specialized groups, and then, by integrating biochemical and analytical approaches with mathematical modelling, figured out how such specialized groups can form and persist.
First, we observed the development of yeast colonies in low glucose conditions. Here, we serendipitously observed that over time, two very distinct groups of cells appeared within the colony. Using mass spectrometry-based analytical approaches, coupled to some biochemical assays, we found some groups of cells showing metabolic properties that could not be sustained in low glucose conditions. We then built a mathematical model to try to simulate this cell patterning. This model suggested that for cells to form such patterned, specialized states, the system needed to produce an unknown, controlling resource. We then biochemically went on to identify this resource as trehalose, a simple sugar much like sucrose or common sugar. All cells initially make this sugar, as an outcome of the metabolic processes required in low glucose. Remarkably, as more and more of this sugar accumulates, some cells switch to the consumption of this sugar, and by doing so, stop producing it, and change their entire metabolic state. When this happens, the sugar depletes, and so the other cells (still producing the sugar) can no longer switch their states, and a stable, self-organized system develops.
Our study is perhaps the first to suggest how simple biochemical constraints can permit groups of cells to organize and persist in different metabolic (phenotypic) states. This type of phenomenon is widely seen in nature—in microbial biofilms and even in tumour development in cancer. Our findings therefore conceptualize rules that explain the origins of such different phenotypic states in a group of genetically identical cells and shed some light on how multicellular systems might have evolved. This study also has relevance to human disease and infection, since it helps us understand how microbial biofilms might form or how tumours persist.
Metabolic constraints drive self-organization of specialized cell groups. Sriram Varahan, Adhish Walvekar, Vaibhhav Sinha, Sandeep Krishna, Sunil Laxman. eLife. June 2019
Banner Image: Spatial distribution of Pentose Phosphate Pathway (PPP) activity across a yeast colony