2 4 7 T HE BIT H OR AX C O MPLEX: T HE FI RST FIFTY YE A RS Nobel Lect ure, Dece mber 8, 1995 b y E D WA R D B. L E W I S Divisio n of Biology, T he Califor nia I nstit ute of Tec h nology, Pasa de na, C A 9 1 1 2 5, U S A. “ T he po wer of usi ng abstractio ns is t he esse nce of i ntellect, a n d wit h every i ncre ase i n abstractio n t he i ntellect ual tri u mp hs of scie nce are e n ha nce d. ” Bertra n d R ussell I NTRODUCTIO N Ge netics is a disci pli ne t hat has s uccessf ull y use d a bstractio ns to attac k ma n y of t he most i m porta nt proble ms of biology, i ncl u di ng t he st u dy of evol utio n a n d ho w a ni mals a n d pla nts develo p. T he po wer of ge netics to be nefit ma n- ki n d was first recog nize d by t he a war d of t he Nobel Prize i n p hysiology or me dici ne i n 1933 to T. H. Morga n. I n t he 23 years t hat ha d i nter ve ne d be- t ween the ti me Morgan intro d uce d Droso p hil a as a ne w orga nis m for t he st u d y of ge netics a n d t he a war d of t he Prize, he a n d his st u de nts, es peciall y, A. H. St urt e v a nt, C. B. Bri d g es a n d H. J. M ull er, h a d v astl y e xt e n d e d t h e l a ws of Me n del as t he res ult of a h ost of disc o veries, t o me nti o n o nl y a fe w: t hat t he ge nes ( Me n del’s factors) are arra nge d i n a li near or der a n d ca n be place d o n ge netic ma ps, t hat t hey m utate i n for war d a n d reverse directio ns, t hat t he y ca n exist i n ma n y for ms, or alleles, a n d t hat t heir f u nctio ni n g ca n de pe n d u po n t heir positio n. P urely o n t he basis of bree di ng ex peri- me nts, t hese early workers were able to de d uce t he existe nce of i nversio ns an d d u plications, for exa m ple, before it beca me possible to de monstrate t he m cytologically. T he list of t heir ac hie ve me nts is a lo ng o ne a n d o ne t hat has bee n p ut i nto historical pers pective by St urteva nt i n A History of Ge netics (1). All of t hese disc o veries were ma de wit h Droso p hil a by taki ng a d va ntage of its s mall size, ease of c ult uri n g, hi g h fec u n dit y, s h ort life c ycle, s mall c hr o- moso me nu mber, wealth of spontaneous and induced mutations, and, after their discovery in 1935, its giant salivary glan d chro moso mes. Of i m mense i m porta nce also was t he existe nce of sta n dar d or “ wil d-ty pe” strai ns. T hat Morga n’s co ntrib utio ns satisfie d t he criterio n of bei ng of be nefit to ma nki n d was evi de nt by t he re markable exte nt to w hic h t he ne w discoveries wit h Droso p hil a ha d direct a p plicatio n to t he u n dersta n di ng of t he i n heri- 2 4 8 P hysiology or Me dici ne 1995 ta nce of many h u man traits. For exa m ple, the inheritance of colorblin dness a n d he mo p hilia i n h u ma n bei ngs co ul d be u n derstoo d for t he first ti me. T h e s e c o n d N o b el Pri z e f or w or k i n t h e g e n eti cs of Droso p hil a was a war de d i n 1946 to H. J. M uller for his disco very i n 1928 t hat X-rays pro d uce ge ne m utati o ns a n d d o s o i n direct pr o p orti o n t o t he d ose (2) . M uller calle d atte ntio n to t he ge netic risks to t he h u ma n race pose d by i n discri mi nate use of ionizing ra diations, an d, pro phetically, he arg ue d that s uch uses wo ul d als o i ncrease t he ris k of ca ncers, if ca ncer is t he res ult of s o matic m utati o ns. T he i m plicatio ns of M uller’s work were not o verlooke d wit h t he a d ve nt of t he ato mic a ge. As a res ult, exte nsi ve ge netic st u dies were carrie d o ut i n Droso p hil a a n d mi c e t o ass ess t h e r el ati v e r at es of m ut ati o n i n t h es e or g a nis ms as a mea ns of assessi ng t he ge netic risks to h u ma n bei ngs fro m t he use of ato mic energy. The a war d of the Prize in 1995 for work with Droso p hil a recog nizes t he gro w- i ng i m porta nce of a fiel d t hat has co me to be calle d de velo p me ntal ge netics. The work of my co- winners, Eric Wiescha us an d Christiane N usslein- Volhar d, has i de ntifie d cr ucial ste ps i n t he earl y de velo p me nt of t he or ga nis m. S pecificall y, t he y ha ve i de ntifie d maj or ge nes i n v ol ve d i n setti n g u p t he i niti- al axes of t he e mbr yo a n d its ger m la yers (3) t hereb y setti n g t he sta ge for gro u ps of master co ntrol ge nes t hat t he n progra m t he fi nal bo dy pla n of t he or ga nis m. It is t his latter gr o u p of ge nes wit h which we will be concerne d h er e: w h at t h e y d o a n d h o w t h e y c a m e t o b e dis c o v er e d. M y p art i n t his st or y b e g a n i n t h e l at e 1 9 3 0s a n d it will b e first e x a mi n e d i n r el ati o n t o t h e c o n- c e pt of t h e g e n e at t h at ti m e. T HE GE NE C O NCEPT Jo ha n nse n coi ne d t he ter m, “ge ne,” in 1909 an d it q uickly re place d Me n del’s “factor” (4). T he co nce pt of t he ge ne is o ne of t he most po werf ul a bstractio ns i n biolo g y a n d o ne of great utilit y. For ma n y years t he ge ne co ul d be satisfactorily defi ne d as a u nit wit hi n w hic h ge netic reco mbi natio n, or crossi n g o ver, does not occ ur. T he u nit defi ne d i n t his wa y te n de d to cor- res po n d to a u nit of f u nctio n, as defi ne d b y t he sta n dar d p he not y pic test for all elis m, or t h e “co mple mentation” test, t o be disc usse d bel o w.