Editorial: Neurogenetics gets its Nobel Journal of Neurogenetics

Journal of Neurogenetics

The 2017 Nobel Prize in Physiology or Medicine awarded to Jeffrey C. Hall, Michael Rosbash, and Michael W. Young is not only eminently well-deserved for discoveries both brilliant and beautiful but one that Journal of Neurogenetics readers can celebrate. These investigators and the work they carried out over decades perfectly epitomize the power and promise of neurogenetics. Those of us associated with the Journal of Neurogenetics also take special pride in noting that Jeff Hall advocated for the founding of this Journal, serving first as an Associate Editor and later as Editor-in-Chief for nearly two decades.1

In the broader context, not only does this award recognize the exceptional achievements of Hall, Rosbash, and Young but it is also a recognition—50 years after its founding—that the field of neurogenetics no longer needs to defend itself.  The insight, vision, and boldness of Seymour Benzer (1921-2007), the field’s founding father, is fully culminated with this award. In discussions with young investigators in the field, we have found, much to our surprise, that there are many who have only the slightest familiarity with its origins and the contributions of those who paved the way for the work in which they are now engaged. The name Benzer elicits a faint trace of recognition, akin to their response to the names of Mendel, Darwin, Morgan, Crick and others of some bygone eras.  But it is all shrouded in the misty past and not something they have read about in the latest issues of “high impact” journals, thus hardly meriting their time and attention.  

So even as we celebrate Hall, Rosbash, and Young, it is worth recounting how it all began. In the mid-1960’s, with the end of the golden age of molecular biology imminent, Seymour Benzer, along with other early pioneers, including Sydney Brenner, Julius Adler, George Streisinger and others, became brave expatriates from the fields they knew in search of bigger biological mysteries to tackle.  The complexity of brains and behavior and the question of whether the tools of genetics and molecular biology could be applied to unravel this complexity proved irresistible.  The opening sentences from Seymour Benzer’s first publication (1967) in this new venture, resonate as presciently today as they did 50 years ago:

Complex as it is, much of the vast network of cellular functions has been successfully dissected, on a microscopic scale, by the use of mutants in which one element is altered at a time. A similar approach may be fruitful in tackling the complex structures and events underlying behavior, using behavioral mutations to indicate modifications of the nervous system. Drosophila offers the same advantages to such a study as it did to classical genetics, namely, large numbers and short generation time, to which may now be added an enormous store of accumulated knowledge concerning the organism.

For the thousands of investigators currently pursuing some aspect of this approach in Drosophila, nematodes, and other organisms, the logic in Benzer’s brief outline is so powerful and obvious, it is hard for them to appreciate the resistance—and sometimes, outright derision—confronted by those in the early days who were drawn to Seymour’s vision. At meetings and seminars it was not at all uncommon to hear the refrain, “What can genetics/Drosophila possibly contribute to our understanding of behavior/neurobiology?”. The most ardent and prolific defender of the faith in those early days was none other than Jeff Hall, who used his vast knowledge of everything being done by every investigator working in some area of Drosophila neurogenetics to write books as well as numerous review articles that described and expounded upon the significance of this work to anyone willing to evaluate it with an open mind. All of us working in the field still owe Jeff a huge debt of gratitude for his huge investment of time, energy, and stress in his efforts to gain acceptance and recognition for neurogenetics as a bona fide branch of biology. 

It is particularly fitting that the first Nobel prize to recognize achievements in neurogenetics be for work on the circadian clock. Not only is it the most complete and cogent example of the elucidation of a complex behavior from genes to molecules to rhythmic output—truly marking fulfillment of Benzer’s vision “from gene to behavior”—but it is also one of the first behaviors on which Benzer and his students fixed their sights. Ronald J. Konopka (1947 2015) started it all in a paper he published with Seymour in 1971 (Konopka and Benzer, 1971). Once again, the introductory paragraphs present the problem and the approach in language that readers today will relate to easily:

An approach that has been successful in unravelling mechanisms in some systems is the use of genetic alterations. Since the expression of a rhythm requires an integrated system, mutation of the genes responsible for development and function of the system could lead to abnormal rhythms.

And in what is surely one of the most incredibly successful mutant screens ever recorded, Konopka goes on to describe the isolation of three mutations on the X chromosome that alter circadian rhythm in different ways—short period, long period, and arrhythmic.  Almost miraculously, all three mutations all turned out to be alleles of the same gene, designated per (period). The discovery of three mutant alleles of one gene that altered the clock in every way that could be envisioned left little doubt that Per was a central component of the clock machinery. With the advent of gene cloning, the game was afoot to identify per at the molecular level—a goal reached successfully over a decade later by Hall and Rosbash working together at Brandeis (Reddy et al., 1984) and independently by Young (Bargiello and Young, 1984) working at Rockefeller. The identification of other players in subsequent mutant screens, including timeless (tim), double-time (dbt), clock (clk) and others, their detailed molecular characterization, and the elegant analysis of how all these pieces fit together to produce a clock that maintains an ongoing 24 hour cycle after being entrained by light will forever be a classic story in biology whose overwhelming beauty and elegance rightfully place it alongside the lac operon.

It is noteworthy that this beautiful example of science at its best was not performed under some administrative mandate of NIH; no brain initiative, no large sequencing project, no -omics of any sort. Instead, it was the outcome of creative thinking and willingness to depart from accepted approaches, freedom to dedicate full energy to the pursuit of questions that the investigators were personally passionate about, and the opportunity to engage in the painstaking process of piecing together small bits of the puzzle until the full picture emerged after decades of effort and insight. This is not “big data” science. Quite the opposite; rather than accumulating small bits of information about many genes and proteins, Hall, Rosbash, and Young obtained detailed information on a relatively small set of genes and proteins. It is “focused” science with the emphasis on big understanding. For ambitious young investigators, eager to make seminal contributions, there are lessons to be learned.  The same is true for funding agencies whose goal should be to promote the curiosity-driven pursuits of these investigators to unravel the unknown.

Barry Ganetzky, Associate Editor, Laboratory of Genetics, University of Wisconsin
Chun-Fang Wu, Editor-in-Chief, Department of Biology, University of Iowa

References

Benzer, S. (1967) Behavioral mutants of Drosophila isolated by countercurrent distribution. Proc Natl Acad Sci USA. 58:1112-1119.

Konopka, R. J. and S. Benzer (1971) Clock mutants of Drosophila melanogaster. Proc Natl Acad Sci USA. 68:2112-2116.

Reddy, P., Zehring, W. A., Wheeler, D. A., Pirrotta, V., Hadfield C, Hall, J. C. and M. Rosbash (1984) Molecular analysis of the period locus in Drosophila melanogaster and identification of a transcript involved in biological rhythms.  Cell 3:701-710.

Bargiello, T. A. and M. W. Young (1984) Molecular genetics of a biological clock in Drosophila. Proc Natl Acad Sci USA 81:2142-2146.

Endnotes 

As a founding Editor, he applied rigorous standards and recruited papers of original discoveries from researchers in the nascent field. As a result, the Journal has reached an outstanding citation record for those papers published during his tenure as Editor‐in‐Chief, with an average of over 50 citations per paper and an unusually long mean citation half-­‐life of over 10 years.