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If one of the giants of quantum All of Benzer’s papers from the phage Obituary mechanics could speculate seriously era end with an acknowledgement that the problem of heredity might to Delbrück “for his invaluable reveal new laws of nature, then it must moderating influence” (when is Seymour Benzer be challenging enough for the last time you heard of a to tackle. The romantic notion of prominent scientist exerting a (1921–2007) exploring totally uncharted waters moderating influence?). appealed to Benzer then and for the With the dissemination of Watson Ralph J. Greenspan rest of his life. He was undaunted and Crick’s model for DNA structure by the fact that many traditional in 1953, and its implications for A man of genius makes no mistakes. geneticists took a dim view of phage, linear coding, Benzer hatched a His errors are volitional and are the telling Benzer that if he wanted to plan to use classical genetic portals of discovery — James Joyce study genetics, he should work on a mapping to define the functional ‘real organism’. structure of the . The discovery Biology lost one of its greats with Schrödinger’s book highlighted of mRNA was still eight years off in the death on November 30th last year the genetic speculations of Max the future, and there was no way to of Seymour Benzer. In the century Delbrück, a young quantum define the gene biochemically. So that began with the rediscovery of who had been bitten by the genetic Benzer used a traditional genetic Mendelian units of heredity and ended bug and taken up investigations of approach to move genetics down to with the sequencing of the human as an ‘elemental’ the molecular level. In a 1952 review genome, Benzer’s studies of gene fine genetic entity. In 1948, while an article, entitled “Genetic Formulation structure defined the pivotal moment assistant professor of at of Gene Structure and Gene in the transition from classical to Purdue, Benzer took Delbrück’s Action”, the fungal geneticist Guido molecular genetics. This quiet summer phage course at Cold Spring Pontecorvo had framed the problem devoté of science, with an impish Harbor and parted ways with physics as follows: sense of humor and a taste for the research for good. He joined the small phylogenetically exotic in food, then international community of scientists “[There are] various ways in went on to found what has become known as the ‘’ (led by which a gene can be defined; the bustling field of the genetic Max Delbrück and Salvadore Luria they are consistent with one analysis of behavioral mechanisms. It and including Alfred Hershey, Leo another at certain levels of is rare enough in the history of science Szilard, and Gunther genetic analysis, but not at for someone to make a discovery Stent, among others) and spent as others…(1) as a part of a as momentous and synthetic as much time away from Purdue in which is the Benzer’s phage findings, let alone various phage labs as he did being ultimate unit of ; (2) as to go on afterwards to inaugurate a a faculty member. Delbrück served the ultimate factor of inheritable new approach that grows into a major this group as founder, organizer, differences, i.e., as unit of scientific field. cheerleader, critic and even as physiological action; and (3) as Born in Brooklyn in 1921 to Jewish scout- master for its regular camping the ultimate unit of hereditary Polish immigrant parents, he was the trips in the deserts east of Caltech. recombination.” [2] first member of the family to go beyond high school. Science was his first love, and it lasted his whole life. He was interested in biology from an early age, but ended up majoring in physics and chemistry at , because they were more challenging than the taxonomic approach typical of the biology teaching of the day. As a graduate student at in the mid-1940s doing research related to the war effort (Figure 1), he discovered the key properties of germanium crystals that eventually made it the element of choice for . He joined the Physics faculty at Purdue in 1947, but soon gravitated back towards biology. While a graduate student, he had read Erwin Schrödinger’s What Is Life? [1], a seminal book which framed the question of what was the physical basis of the gene, and which was so effective in attracting physicists into Figure 1. Benzer and Karl Lark-Horowitz at the Purdue Physics Department in 1944. (Courtesy the nascent field of phage genetics. of Seymour Benzer and the Purdue Department of Physics.) Magazine R107

Pontecorvo pointed out that resolution of these issues would require the ability to detect extremely rare recombination events in order to map within the same gene, as well as to construct strains with two closely linked mutations on the same chromosome. The latter strategy was a prerequisite for Benzer’s variation on the ‘cis- trans’ test — this was Ed Lewis’ complementation test [3] for assaying whether two mutations produce similar or different phenotypes when they are on the same chromosome (in ‘cis’) as compared to being on opposite (in ‘trans’). The selectability of the phenotype and the sheer number of progeny that could be generated in phage made the analysis possible down to a level of resolution and degree of saturation unthinkable in Drosophila. By taking Figure 2. Benzer and Matthew Meselson at the Cold Spring Harbor Symposium in 1961. advantage of the observation that (Courtesy of the Cold Spring Harbor Laboratory Archives.) with a high enough titre, it was possible to infect single bacterium with more than one phage, Benzer Further analysis of chromosomal Award of the University of Chicago, was able to perform cis-trans deletions of various sizes inside, election to the National Academy of tests on these otherwise haploid outside and across the rII region, Sciences USA, the Canadian Gairdner genomes [4]. Practically speaking, including one that resulted in a fusion Award, the Lasker Award, the T. the work involved doing the same of the two adjacent cistrons of rII Duckett Jones Award of the Helen experiment over and over — isolate into what he inferred to be a chimeric Hay Whitney Foundation, the mutations, map them with respect to gene product, allowed Benzer to Prix Charles Leopold Mayer of each other, perform cis-trans tests. perform a topological analysis of the French Academy of Sciences, Working mostly by himself, Benzer the arrangement of all of these the Louisa Gross Horwitz Prize of described it as “Hershey Heaven”, factors [5]. The result supported the , and election in reference to another of the early conclusion that a functional gene was to the Royal Society. By the end of phage geneticists, Alfred Hershey, a linear stretch of DNA with definable his life, the list of awards for all of who described biological heaven as boundaries, and that these stretches his work covered almost every prize an experiment that works and goes of DNA are all linked to each other in existence, including the National on and on. as adjacent pieces of chromosome. Medal of Science, the Thomas The result was a physical map of (See [6] for a full account of Benzer’s Hunt Morgan Medal of the Genetics the rII region of phage T4 almost phage experiments.) Society of America, the Wolf Prize for to the level, from which These mid-century findings Medicine, the of the Pontecorvo’s three units of genetic reverberated forty years back to the Royal Swedish Academy of Sciences, function could be discerned. The units early days of genetics when Alfred the Gruber Award and the Albany of mutation and of recombination were Sturtevant first discovered that the Medical Center Prize. His impish at the limit of resolution, suggesting stable Mendelian units of heredity humor would leak out occasionally that they were at the single nucleotide were arranged linearly along the during his many speaking level. The unit of physiological function, chromosome in Drosophila [7]. engagements. In one such incident, on the other hand, was a long stretch Benzer had forged the link between he described the discovery of a new of hundreds of with distinct the macro level of Sturtevant’s map drug, bubbamycin, that reversed boundaries. These units were defined and the micro level of the linear the flow of genetic information: in the cis-trans test by the fact that structure of DNA. The road to relating from protein to RNA to DNA. ‘Bubba two mutations in the same functional the biochemical properties of meises’ is a phrase in Yiddish that unit would fail to complement in trans to their physiological functions was literally means grandmother’s stories, configuration, whereas two mutations now open, all accomplished by the and is figuratively used to refer to ‘old in adjacent functional units would be simple act of performing genetic wives’ tales’. (This joke preceded by able to complement in trans. In the crosses — beautifully conceived and ten years the discovery of reverse cis configuration, both types could analyzed genetic crosses. transcriptase, thus proving the law be complemented by a wild-type The work was received as that parody is conserved.) chromosome. Thus was coined earth- shaking from the outset and As the magical decade of early the term ‘cistron’ for the unit of the awards began to roll in. These (1953–1963) genetic function. would eventually include the Ricketts unfolded (Figure 2), Benzer’s Current Biology Vol 18 No 3 R108

research became more biochemical all of which confirmed McConnell’s neglected field and shown that fly and resulted in additional seminal basic findings, until the bubble burst behavior could be dramatically altered contributions. One of these was the when it was shown that all of the after selective breeding for divergent demonstration that it is the aminoacyl results had been unduly influenced phototactic or geotactic behavior tRNA synthetases, the enzymes by wishful thinking [11]. The [15,16]. Hirsch’s work was directed which attach the correct amino excitement at the time, however, is at showing that behavior has a basis acid to each tRNA molecule, that readily understandable as a possible in genetics, but his flies could not be actually ‘translate’ the molecular mechanism for learning further analyzed for which genes were [8]. This was shown by chemically and memory and there was much responsible, let alone the mechanisms modifying cysteine to alanine, after speculation as to whether there might responsible. Benzer’s approach was it was already linked to its tRNA, and be a ‘neuro-genetic code’. Benzer to take the power of genetic analysis observing in an in vitro translation even tried his hand at conditioning as practiced in phage and bacteria system that alanine was now Planaria, but gave up when he found and bring it to bear on the problem of incorrectly inserted into a hemoglobin that an electric shock split the worms behavior in Drosophila. He published polypeptide where cysteine should in two. A second influence was his first paper on fly behavior in have been. Another of his studies reading The Machinery of the Brain 1967, the same year he joined the from this period demonstrated the by Dean Wooldridge [12]. Wooldridge faculty at Caltech, and the field of degeneracy of the genetic code by had been director of electronics fly was launched [17]. correlating the different insertion research at Hughes Aircraft and then It had the requisite romantic appeal sites of leucine into hemoglobin one of the founders of the aerospace for Benzer: a problem for which the (again in vitro) with specific leucine company TRW. In his 1963 book, contours of a solution could not yet codons [9]. During this period, Wooldridge laid out a Schrödinger- like be seen. And in a further echo of his Benzer’s publication rate rocketed challenge to explain the workings earlier romantic quest, traditional from less than one paper per year of the brain in terms of physics and neurobiologists told him he was to nearly four per year. chemistry. The third influence was crazy to think that genetics would The proliferation of these papers, Benzer’s observation that his second have anything to contribute to the and their distinctly non-romantic daughter, Martha, totally differed study of the brain. nature, prompted a rebuke from his in personality from his first, Barb, For the next forty years, until erstwhile mentor, Max Delbrück. despite the apparent lack of change in his death, Benzer would attract In a letter from his wife Manny to his and Dotty’s behavior as parents. bright young scientists to his lab to Seymour’s wife Dotty, Delbrück added The catalytic event in Benzer’s explore new areas of fly behavior, a note saying, “[P]lease tell Seymour change of research was a sabbatical neurobiology, and (later on) aging to stop writing so many papers. If I year in Roger Sperry’s lab at Caltech (Figure 3). Among them were most of gave them the attention his papers in 1965. His initial project was to test the founders of what now constitutes used to deserve, they would take the effect of his phage mutagens on the field (reviewed in [18–20]. No all my time. If he must continue, tell the wiring projection of the frog’s behavior was too far out to be tried, him to do what asked his retinal ganglion cells onto its optic no idea too crazy to entertain. Is mother to do in her long daily letters, tectum. The specificity of neuronal there a neurogenetic code? Is there namely underline what is important” wiring was Sperry’s signature system one gene per synapse? Are there (quoted in Benzer, 1966 [10]). The at the time, based on the evident such things as ‘behavioral’ genes? comment hit home and reinforced a fidelity with which a rotated eye would (Recall that this was the pre-cloning, nascent interest that Benzer had been reconnect with the brain. The prospect pre- sequencing era, and the identities cultivating on the side in his Purdue of using mutagens in this system of most genes were still a mystery.) lab — the brain. For the previous few appeared to Benzer to be an avenue Some of these questions still provoke years, he and his technician, Mary into molecular mechanisms underlying argument. If Benzer’s phage work Lou Pardue, had been dissecting brain function. Unfortunately, the was laser-like in its penetrating focus, and sectioning brains from various dose required to see an effect was his fly work had the character of a animals, from fruit flies to cows. (As also that at which death ensued. fountain with streamlets flying off in part of Seymour’s phylogenetically But Benzer was undaunted (see all directions. In 1973, he wrote an promiscuous taste for food, some of quote at beginning). With some article for Scientific American entitled these were taken home and cooked encouragement from Ed Lewis, he “Genetic Dissection of Behavior” [21], for dinner afterwards.) began experimenting with fruit flies which helped lure many (including this Benzer’s interest in genetic and their phototactic behavior. author) into the nascent field. influences on the brain was prompted Fruit fly phototaxis had a long The lab itself was like a carnival by several events. He had been research history, going back to the with a sideshow in every room. intrigued with the findings of one original pre-Morgan fly lab Unsuspecting visitors entered the James McConnell in 1962, a former of William Castle at Harvard, where assembled lunch room at their own advertising executive who claimed F. Carpenter [13] had documented the peril, as likely to encounter peals of that RNA isolated from trained fly’s responses to light and gravity. laughter from the constant joking Planaria could be administered A decade later in Morgan’s lab, (much of it sophomoric), as probing to untrained Planaria and transfer R.S. McEwen [14] had shown that fly questions. Many mutants and the behavior to them. This finding mutants such as tan were defective genetic approaches that anticipated spawned a bubble of experiments in phototactic behavior. In the 1950s, or started new fields came out of in rats and reports in top journals, had taken up this this first decade at Caltech: the Magazine R109

there was no other reason to go into it), but also pursued questions whose answers were not at all visible, and for which there was no guarantee of obtaining any results at all. And finally, he was surely the last of an era in which a scientist did not have to be fast-talking, slick, or self-promoting. Benzer’s accomplishments are emblematic of the half-century during which he worked, an era that saw the problem of the physical basis of the gene solved and the tangled relationship between gene and behavior seriously addressed. He approached science with rare fearlessness, imagination, and insight, and his legacy will survive all of us.

Acknowledgments Sources for this article, unless otherwise cited, are personal conversations with S. Benzer and with various former members Figure 3. Benzer and friend at Caltech in 1974. (Courtesy of the Archives, Caltech.) of his lab. I thank Jeff Hall, Chun-Fang Wu and Jim Haber for additional comments. mutant period founding of a ‘Journal of …’ and an R.J.G. is the Dorothy and Lewis B. Cullman [22]; the neurodegeneration mutant ‘International Congress of …’. This Fellow in Experimental Neurobiology at drop-dead [23,24]; the learning decade, however, also saw the loss The Neurosciences Institute, which is mutant dunce [25]; the cell fate of Benzer’s wife to cancer, but then supported by the Neurosciences Research Foundation. mutant sevenless [26]; the mapping subsequent meeting and remarriage of behavioral effects to specific sites to Carol Miller, a neuropathologist and cells in the nervous system from USC with whom he collaborated References [27–29], and the neurophysiological on several papers and a son. 1. Schrödinger, E. (1944). What Is Life? The analysis of mutants [30–32]. During As the new millennium dawned, Physical Aspect of the Living Cell (Cambridge: this extraordinarily fertile period, the lab transmogrified again into Cambridge University Press). 2. Pontecorvo, G. (1952). Genetic formulation of Benzer’s publication rate hovered the study of neurodegeneration and gene structure and gene action. Adv. Enzymol. around one paper per year, but aging, where it continued to explore 13, 121–149. 3. Lewis, E.B. (1951). Pseudoallelism and gene not because of lack of attention to new territory. But behavior and fly evolution. Cold Spring Harb. Symp. Quant. the science. Benzer was notorious psychology were never abandoned. Biol. 16, 159–174. for his inclination to finesse other Mutants affecting thermo- and 4. Benzer, S. (1955). Fine structure of a genetic region in bacteriophage. Proc. Natl. Acad. Sci. professorial duties, nor was he a hygro-sensation were isolated [34], USA 41, 344–354. political operator in the larger world as was a nociceptive mutant dubbed 5. Benzer, S. (1959). On the topology of the genetic fine structure. Proc. Natl. Acad. Sci. of science. He founded this field painless [35], and studies were USA 45, 1607–1620. but never warmed to the role of an initiated on feeding behavior [36]. 6. Holmes, F.L. (2006). Reconceiving the Gene: institutional leader of it. Benzer was an active and insatiably Seymour Benzer’s Adventures in Phage Genetics. (New Haven: Yale University Press). In the lab’s second decade, eye curious scientist to the end. His 7. Sturtevant, A.H. (1913). The linear arrangement development became the principal example reminds us of the philosophy of six sex-linked factors in Drosophila, as shown by their mode of association. J. Exp. topic of research, following a seminal that we should die young — as late as Zool. 14, 43–59. study of the dynamics of retinal possible. 8. von Ehrenstein, G., Weisblum, B., and Benzer, development in the fly [33]. Benzer’s The foregoing recounts the many S. (1963). The function of sRNA as amino acid adaptor in the synthesis of hemoglobin. Proc. publication rate crept back up after scientific ‘firsts’ for which Benzer Natl. Acad. Sci. USA 49, 669–675. 1976, peaking at eight papers in 1993 was responsible. By the same token, 9. Weisblum, B., Gonano, F., von Ehrenstein, G., and Benzer, S. (1965). A demonstration of and then plateauing at roughly four there are several scientific ‘lasts’ that coding degeneracy for leucine in the synthesis papers per year for the duration. accompany his passing. He is the of protein. Proc. Natl. Acad. Sci. USA 53, Delbrück died in 1981, so there was last (or nearly so) of the generation of 328–334. 10. Benzer, S. (1966). Adventures in the rII region. no one to repeat the earlier rebuke children of eastern European Jewish In: Phage and the Origins of Molecular Biology. about publishing too many papers. immigrants to Brooklyn and New J. Cairns, G.S. Stent, and J.D. Watson eds., (Cold Spring Harbor, NY: Cold Spring Harbor But no reminder was necessary York’s Lower East Side who helped Laboratory). at this point. Benzer made fun of propel U.S. science to the forefront of 11. Morange, M. (2006). What history tells us VI. himself for publishing so much and the world, and one of the last of the The transfer of behaviours by macromolecules. J. Biosci. 31, 323–327. acknowledged that the world had original molecular biologists. He is one 12. Wooldridge, D.E. (1963). The Machinery Of The changed. He mused that the greatest of the last of the scientific romantics Brain. (McGraw-Hill: New York.) 13. Carpenter , F. (1905). Reactions of the pomace danger to a field was its successful who not only pursued science for its fly to light, gravity, and mechanical stimulation. establishment, as measured by the own sake (when it paid so poorly that Amer. Nat. 39, 157–171. Current Biology Vol 18 No 3 R110

14. McEwen, R.S. (1918). The reactions to light synonymous with those behaviours and to gravity in Drosophila and its mutants. J. Primer Exp. Zool. 25, 49–106. and abilities. 15. Hirsch, J., and Boudreau, J.C. (1958). Studies At an abstract level of processing, in experimental behavior genetics. I. The least tied to routine behaviour, are heritability of phototaxis in a population of . J. Comp. Physiol. Executive function flexible representations of goals Psychol. 51, 647–651. and intentions. Such ‘higher-level’ 16. Hirsch, J. (1959). Studies in experimental Sam J. Gilbert* and Paul W. Burgess representations are often contrasted behavior genetics. II. Individual differences in geotaxis as a function of chromosome variations with ‘lower-level’ cognitive processes in synthesized Drosophila populations. J. Comp. Executive functions are the high-level involved in analysing specific Physiol. Psychol. 52, 304–308. 17. Benzer, S. (1967). Behavioral mutants of cognitive processes that facilitate new perceptual inputs (such as visual Drosophila isolated by countercurrent ways of behaving, and optimise one’s processing of stimuli such as ‘BLUE’) distribution. Proc. Natl. Acad. Sci. USA 58, approach to unfamiliar circumstances. and generating specific motor outputs 1112–1119. 18. Greenspan, R.J. (1990). The emergence of As many situations in everyday life are (such as vocal responses). According neurogenetics. Semin. Neurosci. 2, 145–157. not exactly the same as ones that we to most theories, executive function 19. Weiner, J. (1999). Time, Love, Memory. (Knopf: have encountered before, it follows that entails the modulation of lower-level New York.) 20. Vosshall, L.B. (2007). Into the mind of a fly. the operation of executive processes processes by those at a higher level. Nature 450, 193–197. accompanies a very wide range of Depending on our current goal, we 21. Benzer, S. (1973). Genetic dissection of behaviours. But we particularly engage are able to modulate lower-level behavior. Sci. Am. 229, 24–37. 22. Konopka, R.J., and Benzer, S. (1971). Clock such processes when, for instance, we perceptual-analysis and mutants of Drosophila melanogaster. Proc. make a plan for the future, or voluntarily speech-output processes in order Natl. Acad. Sci. USA 68, 2112–2116. 23. Hotta, Y., and Benzer, S. (1972). Mapping of switch from one activity to another, to produce appropriate behaviour. In behavior in Drosophila mosaics. Nature 240, or resist temptation; in other words, different contexts we might ignore the 527–535. whenever we do many of the things word, read it out, or name its colour, 24. Buchanan, R.L., and Benzer, S. (1993). Defective glia in the Drosophila brain degeneration mutant that allow us to lead independent, even though we are presented with the drop-dead. Neuron 10, 839–850. purposeful lives. These processes are same perceptual input in each case. 25. Dudai, Y., Jan, Y.-N., Byers, D., Quinn, W.G., thought to be supported, at least in part, Thus, executive functions allow us and Benzer, S. (1976). dunce, a mutant of Drosophila deficient in learning. Proc. Natl. by structures within the frontal lobes to behave flexibly, rather than being Acad. Sci. USA 73, 1684–1688. of the brain. But they are understood slaves to our environment and always 26. Harris, W.A., Stark, W.S., and Walker, J.A., far less comprehensively than some of behaving in a stereotyped manner (1976). Genetic dissection of the photoreceptor system in the compound eye of Drosophila the functions supported by other brain when particular events occur. This melanogaster. J. Physiol. 256, 415–439. regions. Indeed, a review published as equips us with the ability to adapt to 27. Hotta, Y., and Benzer, S. (1976). Courtship in Drosophila mosaics: sex-specific foci for recently as 1996 described this domain novel, or changing, situations. sequential action patterns. Proc. Natl. Acad. as a “somewhat embarrassing zone The modulation of various cognitive, Sci. USA 73, 4154–4158. of almost total ignorance” (Monsell, perceptual, and motor processes 28. Kankel, D.R., and Hall, J.C. (1976). Fate mapping of nervous system and other internal 1996). But cognitive neuroscience according to abstract goals and tissues in genetic mosaics of Drosophila has recently made significant strides intentions is commonly referred to melanogaster. Dev. Biol. 48, 1–24. in characterising the nature of these as ‘top-down control’. However, this 29. Hall, J.C. (1977). Portions of the central nervous system controlling reproductive processes, and their underlying brain should not imply a strict unidirectional behavior in Drosophila melanogaster. Behav. mechanisms. This Primer surveys some influence from higher-level to Genet. 7, 291–312. of the theoretical frameworks commonly lower- level processes. Instead, the role 30. Siddiqi, O., and Benzer, S. (1976). Neurophysiological defects in used for understanding executive of executive function in cognition is temperature-sensitive paralytic mutants of functions, and their relationship with the probably more accurately considered Drosophila melanogaster. Proc. Natl. Acad. Sci. USA 73, 3253–3257. frontal lobes. in terms of continual interaction 31. Jan, Y.N., Jan, L.Y., and Dennis, M.J. (1977). between higher- and lower-level Two mutations of synaptic transmission in Role of executive processes processes. Higher-level processes are Drosophila. Proc. R. Soc. Lond. B Biol. Sci. 198, 87–108. in the organisation of cognition commonly triggered in everyday life 32. Wu, C.F., Ganetzky, B., Jan, L.Y., Jan, Y.N., and At the heart of most (but not all) by conflicts between representations Benzer, S. (1978). A Drosophila mutant with a theories of executive function is a or inputs at lower levels, for instance temperature-sensitive block in nerve conduction. Proc. Natl. Acad. Sci. USA 75, 4047–4051. distinction, or gradation, between when something unexpected occurs 33. Ready, D.F., Hanson, T.F., and Benzer, S. routine (or ‘automatic’) and non- routine or when behaviour does not have the (1976). Development of the Drosophila retina, a (or ‘controlled’) processing. Routine usual consequences. neurocrystalline lattice. Dev. Biol. 53, 217–240. 34. Sayeed, O., and Benzer, S. (1996). processing refers to mental operations Behavioral genetics of thermosensation and that are well rehearsed or overlearned, Paradigms in executive hygrosensation in Drosophila. Proc. Natl. Acad. Sci. USA 93, 6079–6084. for example reading out a word. By function research 35. Tracey, W.D., Jr., Wilson, R.I., Laurent, G., and contrast, non- routine processing most Historically, a major obstacle to Benzer, S. (2003). painless, a Drosophila gene commonly refers to mental operations progress in research into executive essential for nociception. Cell 113, 261–273. 36. Carvalho, G.B., Kapahi, P., Anderson, D.J., and that are used in situations when function has been the difficulty of Benzer, S. (2006). Allocrine modulation of feeding there is not a well-established quantifying the processes supported behavior by the Sex Peptide of Drosophila. Curr. stimulus-response association, or by the human frontal lobes, a Biol. 16, 692–696. where a behavioural impasse has problem compounded by the variety occurred (for example one notices an of cognitive, social, and emotional The Neurosciences Institute, 10640 John Jay Hopkins Drive, San Diego, California 92121, error, or realises that one is behaving changes that have been reported to USA. in a sub-optimal fashion). The term occur as a consequence of damage E-mail: [email protected] ‘executive functions’ has become to this region. Methodological and