Systems biology ahead of its time

In this genomic age, we take for granted the availability of complete genome sequences, proteome sets or even interactomes — exhaustive descriptions of protein–protein interactions. Instead of focusing on an individual gene or an individual problem, the challenge is to take a 'holistic approach' to biology, in what has been dubbed 'systems biology'.

Those who think that systems biology was only born with the advent of whole-genome sequencing, however, should consider the tour-de-force efforts of John Sulston and colleagues, who in the late 1970s and early 1980s set out to determine the entire cell lineage of C. elegans.

Image courtesy of S. Reichett, MRC Laboratory of Molecular Biology, Cambridge, UK.

The work on the worm had something 'systematic' about it from the beginning, as exemplified by its conscious choice as a model — for neurobiology, in particular — by Sydney Brenner. Following the classical observations that nematode early development was invariant, Sulston and Horvitz set out to map out all of these cell divisions. They, aided by Judith Kimble, achieved this bold undertaking by directly watching cell divisions, migrations and death in living nematodes, under Nomarski optics.

Detailed lineage information had a huge impact on subsequent research — for example, Sulston and Horvitz saw that in a number of lineages some cells always died in an invariant way. Focusing on the fate of these cells in subsequent mutant screens allowed researchers (mainly the Horvitz group) to dissect the genetic pathway for programmed cell death (see Milestone 15). Defined neuronal cell lineages had a similar impact on neurobiology studies in the worm.

Six years after the post-embryonic lineage was defined, Sulston and colleagues turned to the embryo to show the divisions involved in transforming a zygote into the 671-celled embryo at hatching. Importantly, the authors described in detail the early asymmetric cell divisions and the developmental potential of what they called the founder cells. Subsequent work from many labs showed how these asymmetric cell divisions are achieved and that this asymmetry is important for the lineage specification and normal development.

So, should we push back the birth date of systems biology by some 20 years? It might seem fitting to think of John Sulston as a pioneer of this approach. After all, he was to go on to be one of the early champions of the Human Genome Project and subsequently one of the leaders of the publicly-funded international consortium.