The process of clonal evolution underpins the maintenance of a normal healthy colon, and the “unwanted evolution” of mutant cells leads to the development of colon cancer.  However, despite the central importance, a quantification of the parameters that define the clonal evolutionary process in human colon (and indeed all human tissues) has remained lacking.  Our current understanding is derived from studies performed in model organisms, and it is uncertain if and how these insights apply to humans.  I will describe how we coupled a novel “lineage tracing” strategy in human colon, that allows the fate of different clonal lineages to be visualised, with a reductionist mathematical analysis that allows us to infer the parameters governing clonal evolution in the human gut.

Our analysis has shown that human intestinal stem cells evolve through a process of neutral drift, and that the neutrality of this process is disrupted by mutation to the APC gene that functions as a key tumour-suppressor in the colon.  In the colon, cells are organized into millions of “crypts” – small tubular structures each housing a few thousand cells. Through our quantitative analysis of lineage-tracing data, we have been able to infer the number of functional stem cells per human crypt, and also how they behave over time.  Further, our mathematical analysis reveals how often colon crypts divide, both in normal colon and in colon tumours.  This parameterisation allows the age of colon tumours to be determined.

Our work demonstrates how quantitative analysis of a “static picture” from a single sample of human tissue can resolve the temporal dynamics of the clonal evolution occurring within that tissue.