Waterston attended Princeton as an undergraduate where he majored in engineering; he wrote his senior dissertation on the plays of Eugene O'Neill.

While on a visit to Germany he took courses in biology – in German – and returned to take up a place at the school of medicine of the University of Chicago.

However, the only space available was in the room where John Sulston and Alan Coulson were beginning to map the genome of the nematode worm C. elegans.

Waterston joined them, and after his return to St. Louis, the worm map became a collaborative project between the two labs.

They were so successful that at the same time that the Wellcome Trust established the Sanger Centre (now the Wellcome Sanger Institute) with Sulston at its head, Waterston received funding from the National Human Genome Research Institute to undertake large-scale human sequencing at his Washington University lab.