For our final post of 2005, I’d like to highlight an important anniversary that seems to have been overlooked. Twenty-five years ago (on October 30, 1980, to be exact), Nature published a report by Christiane Nusslein-Volhard and Eric Weischaus, entitled “Mutations Affecting Segment Number and Polarity in Drosophila. The abstract:

In systematic searches for embryonic lethal mutants of Drosophila melanogaster we have identified 15 loci which when mutated alter the segmental pattern of the larva. These loci probably represent the majority of such genes in Drosophila. The phenotypes of the mutant embryos indicate that the process of segmentation involves at least three levels of spatial organization: the entire egg as developmental unit, a repeat unit with the length of two segments, and the individual segment.

Thus was a revolution in developmental genetics born.

And what a moment it must have been—if it was a single moment—when this massive and risky screen started to yield mutant phenotypes that, remarkably, could be neatly placed into only three categories.

The loci identified were cubitus interruptus, wingless, gooseberry, hedgehog, fused, patch, paired, even-skipped, odd-skipped, barrel, runt, engrailed, Kruppel, knirps, and hunchback. Think of the avalanche of work that was set off by the identification of every one of these genes, in fields such as developmental biology, molecular biology, cell biology, cancer, and others.

Perhaps the more interesting thing to think about, however, is the philosophical shift in science, and why it is that such a seminal experiment wasn’t done until the late 1970s, when the technical advances made by Nusslein-Volhard and Weischaus were really rather modest. Some of this is discussed in various sources, including a reprint of the paper published in the July 1994 issue of the Journal of NIH Research, accompanied by revealing interviews of both authors and Matthew Scott (I’m looking at a print copy ripped from the original journal, but the online version of this journal—now defunct—is sadly nowhere to be found on the web). Perhaps the best discussion of this work is an overview written by David States and Fotis Kafatos, and posted on the EMBL website (EMBL being justifiably proud of having provided the setting for the work, and thoughtfully providing a view of the ‘Bierhelderhoff’ restaurant—shown below—which, in this story, is apparently Heidelberg’s version of ‘The Eagle,’ Watson and Crick’s Cambridge haunt).

States and Kafatos insightfully outline the state of the field in the mid-1970s, Nusslein-Volhard and Wieschaus’s meeting in the Basel laboratory of Walter Gehring, their shared lab at EMBL-Heidelberg, the concept of the saturation screen for zygotically active mutants in Drosophila, the essential new method to make the embryos transparent, the equally essentially dual microscope, and the ultimate realization in the mid-1980s that these segmentation genes are conserved across 600 million years of evolution. The Nobel lectures of each author (Nusslein-Volhard and Wieschaus) also reward reading.

The concept of the genetic screen that their work exemplifies is an interesting subject in its own right. A few years ago, our colleagues at Nature Reviews Genetics had the clever idea to commission a series of reviews under the heading, “The Art and Design of Genetic Screens”. Links to these reviews can be found for each of the major model organisms, including D. melanogaster, C. elegans, A. thaliana, mammalian cells, filamentous fungi, E. coli, mouse, D. rerio, and yeast.

To close in the present day, Peter Robin Hiesinger and Bassem Hassan recently wrote the following in Cell:

It seems that, by mistaking the “omics” wave for the systems approach itself, we are forgetting some of the most influential systems approaches of the past: when Christiane Nusslein-Volhard and Eric Wieschaus targeted the whole Drosophila genome using random mutagenesis to unravel the riddle of embryonic pattern formation, they were doing systems biology.

And so they were.