In his book, The Regulatory Genome: Gene Regulatory Networks (GRN) in Development and Evolution (Academic Press 2006), Eric Davidson, the foremost experimentalist of regulatory genomics, forcefully reminds us that in the scientific method, causality is everything; all other approaches are just distractions. In contrast, Davidson — a notoriously elegant writer — offers devastating criticism of the “posterior Biology" approaches all too impatiently employed today — the “measure first" expression of thousands of genes and then “computationally infer Biology." The last century's luminaries of mathematical statistics taught us in no uncertain terms that causality cannot be inferred from statistical tables. Davidson aligns with them, adding to their argument a practical dose of reality. The exquisite regulatory mechanisms, locked down by evolution, can only be revealed through systematic experimental perturbations. Like his mentor Max Delbruck, and with the sea urchin genome in hand, Eric Davidson become the leading liberator of quantitative principles of cell regulation, trapped in the qualitative, descriptive world of biology without genomic sequence.
In this talk we will discuss several computer science problems, inspired by our 15-year-long collaboration with Professor Davidson, who died in 2015, and rooted in his seminal research on causality, completeness, genomic Boolean logic, and genomically encoded regulatory information. Our collaboration produced the CYRENE cisGRN-Lexicon database containing the regulatory architecture of 600+ transcription-factor-encoding genes and other regulatory genes in eight species: human, mouse, fruit fly, sea urchin, nematode, rat, chicken, and zebrafish; and the CYRENE cisGRN-Browser, a full genome browser dedicated to cis-regulatory genomics.
Professor Davidson's legacy consisted of 400+ papers and six books; he mentored about 300 Ph.D.s, postdocs and faculty in his laboratory in the Division of Biology at the California Institute of Technology. He was also a beacon of critical discourse. In this spirit, my presentation will include some critical comments about "computational systems biology considered harmful" avenues. As our beloved teacher and mentor, and like in his Caltech Laboratory, Davidson united us —biologists, physicists, biochemists, engineers, mathematicians and computer scientists, — in a research renaissance movement towards the quest for the functional meaning of DNA. From such research will ultimately come, by experimental demonstration, the revelation of the much sought-after laws of regulatory biology.