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T I B S 2 0 - JANUARY 2 99,5 REFLECTIONS . . . ? :S c h r o d n g e s What / s L f ea 5 0 o y e a r ref lect ion

E r w i n S c h r 6 d i n g e f s What bs Life?(Cam br idge Unive r s i t y Pre ss , 1944 ) i so n e o f t h e m o s t t a l k e d a b o u t b o o k s i n" " ~ " . . . . . . . . T h e.~,.l,.l'~C,.. booktv ,r,.nt~,.~,,o,.,.,,t ,,, ~, "~ """c a m e u n d e r i n t e n s e s c r u t i n y a t th ecen t ena ry o f Schrh d inge r ' s b i r t h i n 1987( rev i ewed in Re f . 1 ) and was r ev i s i t eda t a r e c e n t s y m p o s i u m ( s e e R e f . 2 ).Di scuss ion ha s focused l a rge ly on i t si m p a c t on t h e e a r ly d e v e l o p m e n t ol o u ru n d e r s t a n d i n g o f c h r o m o s o m a l s t r u c -t u r e a n d o f t h e c o n c e p t o f t h e ' g e n e t i ccode ' . Re f l ec t i ng on t he cour se o f t hesc i en t i f i c un i ty o f phys i c s and b io logyove r t he 50 yea r s s i nce i t s pub l i c a t i on ,one m igh t a sk , 'Does t he f i xa t i on on t heh i s to r i c a l ro l e o f What is Life? in theb i r t h of m o l e c u l a r g e n e t i c s r e p r e s e n t am y o p i c v i e w o f t h e a u t h o r ' s p h i lo s o p h i -c a l i n t e n t a n d s h o r t c h a n g e t h e b o o k ' sb iophys i ca l l egacy? Were t he book ' si dea s o r ig ina l ? Was Schr fd inge r m e re lyapp ly ing phys i c s a s a t oo l t o ana lyse abiologica l objec t ; or , ra ther , was he pon-d e r i n g a n e x p a n d e d n a t u r a l p h i l o s o p h ytha t wou ld p rov ide a phys i ca l i s t ba s i sf i ) r b iology? ' The f i f t ie th anniversary o ft he pub l i ca t i on o [ What i s Li fe? s e r v e sa s a f i t t i ng oppor tun i ty t o ( r e )exam inethe s ign i f i c ance o f t he b iophys i ca li ssues ra ised by Schrhdinge~:A b i o g c a p h l c a lp r e l u d e

S c h r 6 d i n g e r w a s c e r t a i n l y n o t t h eo n l y t h e o r e t i c i a n f r o m t h e g o l d e npe r iod o f phys i c s i n t he ea r ly twen t i e thc e n t u r y t o d e l v e i n t o t h e s c i e n c e o fb io logy . Nie l s Bohr , whose f a the r wasa phys io log i s t , i s a no t ab l e exam ple ;b u t o f t h e p i o n e e r s f r o m t h a t g e r -m ina l r e a lm o f r e l a t i v i t y and quan-t u m p h y s i cs , I w o u l d s u g g e s t t h a tS c h r f d i n g e r h a d p e r h a p s t h e d e e p e s ti n t e re s t i n t he phys i ca l i s t r am i f i ca t i onso f t he l i f e sc i ences . Hi s apprec i a t i on o fb io logy can be t r a ced t o f r equen t ch i l d -h o o d d i s c u s s i o n s w i t h h i s f a th e r , w h o s ea v o c a t i o n w a s b o t a n y . (What i s Li fe?i s d e d i c a t e d t o t h e m e m o r y o f h i sp a r e n t s . ) S c h r f d i n g e r r e a d D a r w i n ' sThe Or ig in o f Spec ie s a t a n e a r l y a g e a n db e c a m e e n t h r a l l e d b y t h e m e c h a n i s t i cv i ew o f t he l iv ing wor ld .S c h r f d i n g e r e n t e r e d t h e U n i v e r s i t yo f V i e n n a in 1 9 0 6 , h o p i n g t o p u r s u ep h y s i c s u n d e r t h e g r e a t L u d w i g 1995,ElsevierScienceLtd 0968.--0004/95/$09.50

B o R z m a n n . T h e u n t i m e l y d e a t h o fB o l t z m a n n d i c t a t e d a c o u r s e o f s t u d yf o r S c h r h d i n g e r u n d e r t h e m a s t e r ' scapab le p ro t eges . Hi s c lose s t f r i endf r o m t h o s e d a y s i n V i e n n a w a s F r a n z( 'F r~ inze r ) Fr im m eL a bo t any s tuden twi th whom he had l ong l a t e -n igh t d i s -c u s s i o n s a b o u t t h e m e a n i n g o f l i f e .T oge the r , t hey r ead R icha rd $em on ' s1904 book , Die Mneme a l s e rha l t endesFrinzip ( T h e M n e m e a s C o n s e r v a t i v ePrinc iple) , which le f t a last ing im-p r e s s i o n o n t h e y o u n g S c h r h d i n g e LSem on was a pup i l o f E rns t Haecke l andthe a tom is t i c ' p l a s t i du l a r ' v i ew o f l iv ings y s t e m s . S e m o n ' s D i e M n e m e w a s d e -r i ved f rom a psycho- l am arck i an ana logyb e t w e e n m e m o r y and inher i tance . I t i sp r o b a b l y m o r e t h a n c o i n c i d e n c e t h a ~L a m a r c k ' s Phi losophic Zoologique w aso n e o f t h e f e w b o o k s S c h r h d m g e rre t a ined f rom h i s f a the r ' s l i b ra ry ( t her e m a i n d e r h a v i n g b e e n s o l d o w i n g t of inancia l necessi ty) .From the wr i t i ngs , l e c tu re s and pe r -sona l con t ac t s o f h i s l a t e r l i f e a s awor ld - fam ous phys i c i s t , i t i s ev iden ttha t Schrod inge r m a in t a ined a s i de l i neinterest in biology. Much of his th inkingc o m e s t o a h e a d i n What ~ Li fe?, w h i c hwas ba s ed ~)n a se r i e s o f pub l i c l e c tu re sa t Tr ini ty Col lege in Dubl in . The text i san am a lgam of t he s t a t i s t i c a l phys i c sa n d t h e r m o d y n a m i c s o f t h e a u t h o r ' sturn-of- the-century t ra ining in Vienna ,t h e q u a n t u m p h y s i c s o f h i s l a t t e r - d a ypro fe ss ion , and h i s e a r ly conv ic t i ontowards b io log i ca l o rde r , evo lu t i on andhea ' ed i t y a s de t e rm in i s t i c Da rwin i anp r o c e s s e s .T h e D u b l i n l e c t u r e s w e r e v e r y p o p u -lar . However , the book e l ic i ted con-t rove r sy even be fo re i t s pub l i c a t i on .In p repa r ing t he wr i t t en ve r s ion ,S c h r 6 d i n g e r a d d e d a n e p i l o g u e ' O nDe te rm in i sm and Free Wi l l ' , wh ich con-t a ined a denunc i a t i on o f Wes t e rn ph i l -o s o p h y / r e l i g i o n a n d a n e s p o u s a l o fVedan t i c be l i e f s . Ob jec t i on t o t h i sa t t a ck on t he Church r e su l t ed i n a co l -lapse in the or igina l p lan for Cahi l l &Co. i n Dub l in t o pub l i sh t he book .T h r o u g h a f r i e n d , t h e p h y s i c a l c h e m i s tF r e d e r i c k D o n n a n , S c h r 6 d i n g e r g o t t h et ex t pub l i shed by Cam br idge Unive r s i t yP r e s s ; a n d t h u s d id Wh at i s Li fe? e n t e r

the hi~to~y of sc ience . (Fo~ further bio-g raph ica l de t a i ls , s ee R d s 3-5.)

I do not in te l~d here to rev iew them a n y c o m m e n t a r i es o n What is Lifp?would, howeve{; l ike to address (andhope fu l ly g ive som e red re ss t o ) t hequest ion of the or iginadi ty of his cent ra li dea s - a sub j ec t t ha t ha s a t t r a c t edm u c h a t t e n t i o n a n d t h a t , s o m e w o u ~ da rgue , i s t he ba s i s o f t he bo ok ' s l egacy .The maior i t3 , of the book 's content i s , a tf a c e v a l u e , d e v o t e d t o t h e m o l e c u l a ra spec t s o f gene t i c a c t i on , a s t he au thorr e g a r d e d th e c h r o m o s o m e a s t h e f u nd a -m en ta l d i r ec t i ng e l em en t i n t he gene r -a t ion of l i fe ' s order . Accordingly, mosto f t h e c o m m e n t a r i e s o n t h e b o o k h a v ec o n c e n t r a t e d o n t h e g e n e t i c a s p e c t s o :i t s h is tor ica l s ta tu s. Max P erutz 6 , focexam ple , ha s p ro fe ssed cogen t ly t ha tWhat is Life? c o n t a i n s a c o n s i d e r a b l ea m o u n t o f t e x t b o o k i n f o r m a t i o n o nh e r e d i t a r y m e c h a n i s m s a n d m u t a t i o n s ,t ha t t he book ' s ' backbone ' i s s im plya p a r a p h r a s e o f a 1 9 3 5 a r t ic l eby Timof~eff-Ressovsky, Zimmer andDelbr i ick7 ( .ent it led 'The Natu re ofGene t i c Muta t i ons and t he S t ruc tu re o fthe Gene ' ) , and t ha t Schr6d inge r ' s l a ckof knowledge o f t he r e l evan t l i t e ra tu reinval ida tes the or igina l i ty of his v iews.T he l eg i t im acy o f such c l a im s a s ide ,m a n y c o m m e n t a t o r s ( r e v i e w e d i n R e [ s1 , 3 -5 , 8 ) have a rgued tha t t he book ,wi th i t s e l egan t ly wr i t t en , a l t houghspecula t ive , popular is t s ty le , was inf lu-en t ia l i n a t t r a c t i ng t he ea r ly a t ten t i on o fphys i c i s t s and chem is t s , a s we ll a s b io l -og i s t s , t o t he pa ram oun t b io log i ca lp rob l em of t he m olecu l a r ba s i s o f geneac t i on . Jam es W a t son 9 , fo r exam ple ,r eca l l ed ' . . . I c am e back t o t heUnive r s i t y o f Ch icago and spo t t ed t het i ny book Wh at i s Li fe? by the t heore t i -ca l physic is t Erwin Schr6dinger . In tha tl i t t l e gem , Schr6d inge r sa id t ha t t hee ssence o f l i f e was t he gene . Up un t i lt hen I was i n t e re s t ed i n b irds . Bu t t henthough t , w e ll , if t he gene i s t he e ss enceof l i f e , ! wan t t o know m ore abou t i t .And tha t was f a t e fu l because , o the r -wi se , ! wou ld ha ve sp en t m y l if e s t udy-ing b i rds , and no one wou ld have hea rdof me . '

Moving away f rom the o f t -d i scussedrole of What i s Li fe? i n t he h i s to ry o fgenet ics , I shou ld l i ke t o cons ide r i ns o m e d e p t h S c h r 6 d i n g e f s a p p l i ca t io n o fs t a ti s ti c a l p h y s i c s a n d t h e r m o d y n a m i c sto biology. His posi t ion was tha t ' i t i s inre l a t i on t o t he s t a t i s t i c a l po in t o f v i ewt h a t t h e s t r u c t u r e o f t h e v i t a l p a r t s o f4 5

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Rgure 1A po rtrait of S chr6dinger, take n by Lo tteMeitner-Graf (c. :I.935 ). The P rofesso r isshown sm oking his favorite Petersonpipe from Dublin. Reproduced fromRef. 3 w ith perm ission from CambridgeUniversity P ress.

l iving orga nism s differs so en t i re ly fromt h a t o f a n y p i e c e o f m a t t e r t h a t w ep h y s i c i s t s a n d c h e m i s t s h a v e e v e rhandled . . . ' . Schr6dlnger i l l us t ra t ed h i sb io log ica l conce rn by re fe rence to theso-called '~ /n rule ' , wh ereb y ph ys lco-chemica l l aws mani fes t an inaccuracywi th a re la t i ve e r ro r o f the o rder o fl / ~ l n , where n Is the n um ber o f mo l .ecules res l~aslb le for the process. Asmost physical laws deal w i th systemsenta il ing very la rge numb ers o f par -t ic les, the error in predic tabi l i ty isusual ly ins igni f icant . Whence, he won.dered how the gene (or chromosom e) - as i n g l e macromolecule - could deter-mine dynamica ll y ' the ve ry o rd er l y andlawful events w i th in a l iv ing organism' .Sehr6d i nger 's reso l u t ion to the para -d o x l e d h i m t o p r o p o s e t h a t l i f e 'ss p a t io t e m p o r a l o r d e r m u s t b e d u e , u l ti -m ate l y , to the Inheren t s t ruc tu ra lp roper t ies o f the chromosome, wh ichh e conceptual ized as a heat-s table'aper iodic crysta l ' , involv ing a 'min ia-tu re code ' fo r a one- to -one correspon.dence w i th the o rgan ismic p lan . Thus ,he sa id , 'we are here obv ious ly facedw i th events whose regu la r and law fu lunfo ld ing is guided by a "mechanism"ent i re ly d i f ferent f rom the =probabi l i tymechanism" of physics ' . Schr6dinger 'slongs tand ing romance w i th b io logyseems to reach a crescendo here, as hemused over such a ' fantast ic descr ip-t ion, p e r h a p s l ess becoming a sc ien t is tthan a p o e t ' .

S c h r S d l n g e r ' s c o n c e n t r a t i o n o n t h era t iona l i ty of o rde red ce l lu l a r p roces s -es f rom the s t andpoin t o f s t a t i s t i ca lphy s ics was inc i s ive , bu t (a t t h e r i sk ofi m p a r t i n g a w h i g g i s h h i s t o r i o g r a p h y * )w e n o w s e e h i s a n a l y si s a s m o r e a p p r o -p r i a t e t o t h e m o l e c u l a r c h a r a c t e r i z -a t i o n o f t h e p h e n o t y p e r a t h e r t h a n t ot h a t o f t h e g en o t yp e . In Schr6dinger ' sday , l i t t l e was known empi r i ca l ly aboutt h e s t r u c t u r a l o r g a n i z a t i o n o f c e l l u l a rmetabol i sm. Also , we should bereminded tha t b io log i s t s (e spec ia l ly int h e e a r l y t w e n t i e t h c e n t u r y a n d , t os o m e e x t e n t , e t ,e n t o d a y ) t e n d t or e g a r d s u b c e l l u | a r p r o c e s s e s a c c o r d i n gto s impl i s t i c n ine teen th-cen tury phys i -c o c h e m i c a l n o t i o n s b a s e d o n d i l u t e ,w e a k - e l e ct r o ly t e a q u e o u s s o l u t io n s a n don gas -ph ase k ine t ic s . Even so , ea r ly int h e t w e n t i e th c e n t u r y a n u m b e r o f th e o r -e t i c i a n s f r o m s u c h a r e a s a s b i o c h e m -i s t ry , ce l l b io logy and deve lopmenta lb i o l o g y w e r e a l r e a d y c o n t e m p l a t i n gs e r i o u s l y t h e i d e a s o f s p a t ia l o r d e r a n dm i c r o e n v i r o n m e n t a i d e v i a t i o n i n t h ece l lu l a r machine ry ( rev iewed in Refs11-13) . In pa r t i cu la r , t he c rys ta lm e t a p h o r w a s b e i n g u s e d a t t h i s t i m eas a ' f i e ld ' concept by deve lopmenta lbiolo gis ts (se e Ref. 11) .

An in te res t ing pa ra l l e l toS c h r S d i n g e r ' s q u e s t f o r u n d e r s t a n d i n gof the phys ica l bas i s o f ce l lu l a r o rde r ,b u t o n t h e p h e n o t y p l c r a t h e r t h a n t h egenotyplc s ide , may be s een in an ea r lypaper ent i t l ed 'Sur face S t ruc ture tn theIn tegra t ion of C e l l Ac t iv i ty ' , pu bl i shedin 1 93 0 by the Oxford b iochem is t ,Rud olph Pe te rs =4. Akin to Sch r fd ln ger ' smot iva t ion , Pe te rs fe l t t ha t ' t he prob-l em of grea tes t s ign i f i cance I s tha t p re -s e n t e d b y t h e o r d e r l y , c o n t i n u o u s a n dc o o r d i n a t e d d i r e c t i o n o f c h e m i c a l p r o -ces ses ' i n the l iv ing ce i l . Wi th on lyl imi ted cy to log ica l ev id ence ava i l ab le a tthe t ime , he a rgued for a =nechani smo f ' d i r e c t e d c h e m i c a l c h a n g e ' e x e c u t e db y e n z y m e p o p u l a t i o n s a s s o c i a t e d w i t ha re f l ex ive pro te inaceous ne twork ex-t e n d i n g t h r o u g h o u t t h e c e l l . B a s e d o ns i m p l e n u m e r i c a l c a l c u l a t i o n s f o r t h ep u t a t i v e m i c r o c o m p a r t m e n t s p o s e d b ys u c h u l t r a s t r u c t u r e , P e t e r s p i c t u r e dh o w f l u c t u a t i o n s a b o u t s o m e m e a s u r e da v e r a g e v a l u e o f c e l l u la r c o n c e n t r a t i o nc a n b e o f g r e a t k i n e ti c c o n s e q u e n c e f o rthe loca l i zed b iochemica l event s , i n as imi la r ve in to Schr6dinger , he a s se r t ed*As phrased by Ernst Mayrt, 'whiggish' is the termapp l ied to tha t k ind o f b iased, h indsighted h is toryo f sc ience, ' in wh ich every sc ien t is t is judged by theextent of his [s/c] contribut ion towa rd the establish-ment o f our current in te rpre ta t ion o f sc ience. '

" r IBS 20 - J A N U A R Y . ~ 9 9 5t h a t ' i t i s d a n g e r o u s t o a p p l y t h e r m o -d y n a m i c a r g u m e n t s d i r e c tl y ' to c e l l u la rp r o c e s s e s . I n s t e a d , P e t e r s s u g g e s t e dt h a t ' o w i n g t o t h e m i c r o - h e t e r o g e n e o u sn a t u r e o f t h e s y s t e m , s u r f a c e e f f e c t st a k e p r e c e d e n c e o v e r o r d i n a r y s t a t i s t i -ca l , mass ac t ion re l a t ionsh ips , andb e c o m e i n t h e u l t i m a t e li m R r e s p o n -s ib le for the in t egra t ion of the wholeand the re fore the d i rec t ion of ac t iv i -t i e s . ' Cros s ing pa ths wi th Schr6dinger ,P e t e r s , t a k i n g ' t h e " g e n e " t h e o r y a s aguide , ' s pecula t ed tha t , ' i f we i so la t e int h o u g h t t h e i n s t a n t . . . a t w h i c h t h e" g e n e " f i r s t c o m m e n c e s t o e x e r t i t sd i rec t ive e f fec t . . .. ' we shou ld f ind th a tt h e p r o t e i n - b a s e d c e l l u l a r o r d e r b e g i n swi th the ' p ro tamine ' por t ion ( ) f t hec h r o m a t i n .W e n o w k n o w t h a t l a r g e r e u k a r y o t i cce i l s a re , i ndeed , l aced wi th a densea r ray of f ib rous pro te inaceous e l ement s ,a s we l l a s w i th spac ious l ipopro te inm e m b r a n e s u r f a c e s ; a n d a m u l t i t u d e o fm e t a b o l i c p a t h w a y s h a s b e e n f o u n d t ob e a s s o c i a t e d w i t h t h i s c y t o m a t d x ~3.The theore t i ca l i s sue of m~croenvi ron-menta l s t a t i s t i ca l va r i a t ion in me tabol i cp h e n o m e n a h a s c o n t i n u e d t o d r a win te res t even in l a t e r yea rs ( s ee , fo rexamp le , R ef . 15) . Pe rh~ ,ps the mo s ts u c c i n c t w a y o f c h a r a c t e r i z i n g l o c a lb iochemica l f low proces ses in l iv ingce l l s i s t o re fe r to them in a modi f i ed'p robabl l i s t i c ' manner , a s a d i f fus ionu n d e r a b i a s , w h e r e t h e b i a s is r e n d e r e db y t h e a m b i e n t s t r u c t u r a l s e t t i n g ( s e eRef . 13) . Such a spec i f i c des ign a t ionwas , In fac t, sugg es ted in 1925 by th ema them at i ca l b io log i s t A lf red Lo tka ~ .Schr~dinger a l so examined the g l ,~ba lprob lem of accou nt ing for the or~ ,. "z -a t ion of the l iv ing s t a t e w i th in the con-t e x t o f t h e s e c o n d l a w o f t h e r m o d y n a m -i c s . H e m a i n t a i n e d t h a t s u c h i n t e r n a lo r d e r m u s t b e ' p a i d f o r ' a t t h e e x p e n s eo f d e g r a d a t i o n o f s u b s t r a t e s - ' n e g a t i v ee n t r o p y ' ( o r ' n e g e n t r o p y ' ) - f r om t h es u r r o u n d i n g s . I n t h e i m m e d i a t e a f t e r -m a t h o f t h e p u b l i c a t io n o f W h a t i s L i f e?,S e h r 6 d i n g e r w a s c r i t ic i z e d f o r n o t b e i n gexpl i c i t w i th th e t echn ica l de ta i l s o f then a t u r e o f o p e n s y s t e m s a n d w i t h t h es ign i f i cance of G ibbs f ree ene rgy in re -l a t i o n t o n e g e n t r o p y . H e r e t o r t e d t h a tt h e b o o k w a s d i r e c t e d t o a l a y a u d i e n c ea n d t h a t h e w a s d e l i b e r a t e l y s h o r t o nde ta i l , a l though in a l a t e r ed i t ion hep r o v i d e d a n a d d e n d u m o n t h i s p o i n t .W h i l e S c h r 6 d i n g e r l a c k e d k n o w l e d g e o fsome of the re l evant b io logy , we canr e s t a s s u r e d t h a t , f r o m h i s a c a d e m i cu p b r i n g i n g u n d e r t h e s h a d o w o fBol t zm ann in Vienna , he was we l l aw are

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T~BS 20 - J A NU A R Y 1 9 9 5 REFLECT I ON Sof t h e o v e r a l l t h e r m o d y n a m i c n a t u r e o it h e m a t t e r.S c h r 6 d i n g e r 's t h e r m o d y n a m i c r e a so n -i n g h e r e w a s p e r s p i c a c i o u s . A l t h o u g ht h e b a s i c p r i n c i p l e s h a d b e g u n t oa p p e a r i n p h y s i c s / c h e m i s t r y t e x t b o o k s(see , fo r example , Ref . 17) a t t h e t ime ,t h e s u b i e c t o l n o n e q u i l i b r i u m t h e r m o -dyna mics wa s no t we ll known, e spec ia l lyi n t h e s c i e n c e of biology. Today, thet h e r m o d y n a m i c s o f n o n e q u i li b r iu m p r o -c e s s e s h a s g e n e r a t e d a w e l l - d e f i n e dsc ien t i f i c ed i f i ce tha t dea l s impl i c i t lyw i t h t h e i d e a of n e g e n t r o p y a s f r e e -e n e r g y e x c h a n g e a c r o s s t h e b o u n d a r yof o p e n s y s t e m s a n d i n t e r n a l d i s s i -pat ion (see, for example, Reis 18, 19) .P e r h a p s S c h r 6 d i n g e r ' s v i e w c a m e f r o mB o l t z m a n n w h o , i n t h e l a t e n i n e t e e n t hcentury , had l ec tured and wr i t t en of l i v -i n g o r g a n i s m s a s e v a d i n g t h e s e c o n dl a w o f t h e r m o d y n a m i c s b y f e e d i n g o nn e g a t iv e e n t r o p y ( s e e R e f . 2 0 ) . T h ebioenerge t i c s ign i f i cance of BoR zmann ' sd e p i c t i o n h a d b e e n i d e n t i fi e d ( a n d d u l yc i t ed) , l ong be fore W hat i s L i f e? , b yLotka ( s ee Ref . 13). In 1940 , Ludwig yonBer ta lanf fy ( re spec ted by many as thefa the r of 'gene ra l sys tems theory ' ) ,i n d e p e n d e n t l y h a d c h a r a c t e r i z e d l i v i n gs y s t e m s i n v i r tu a l ly th e s a m e t e r m s a sSchr6 dinge r ( s ee Ref . 21) .T h e c e n t r a l i d e a s i n W hat i s L i f e? ,when cons ide red ind iv idua l ly , wouldnot s e em a ll tha t o r ig ina l . Nev er the les s ,S c h r 6 d i n g e r ' s u n i q u e s y n t h e s i s a n dphys ica l i s t i ns igh t gave no t i ce , t o awide and d ive rse s c i en t i f i c audience , o fa number of impor tan t , bu t re l a t ive lyobscure , b iophys ica l (a s we l l a s g ene t i c )issue s . Th is role , in i tse lf , i s suff ic ient toe n s u r e a v e n e r a b l e p o s i t i o n f o r t h eb o o k i n th e h i s t o r y o f sc i e n c e .Fr0m ideas i0 ih0ughtsT h e t r u e l e g a cy o f W h a t i s L i f e ? is tob e r e a li z e d b y r e fl e ct in g n o t s o m u c h o nt h e a u t h o r ' s ' i d e a s ' b u t o n t h e b a c k -g r o u n d ' t h o u g h t s ' t h a t m a y h a v e d r i v e nh i m t o a s s o c i a t e t h e i d e a s . A t p r e s e n t ,the re i s a communa l fee l ing of un i ty( p e r h a p s a f i n - d e . s t a l e e u p h o r i a ? )a m o n g s t m a n y s c i e n t i s t s , e s p e c i a l l ytho se of a theore t i ca l ben t . As the tw en-t i e t h c e n t u r y ( a n d a n o l d m i l l e n n i u m )c o m e s t o a c lo s e , b o o k s h o p s a r e r e p l e t ewi th t i t le s beg inning wi th T h e E n d o f . . . ,f rom a l l f ie lds of human endeav or . M anyp r o m i n e n t p h y s i c i s t s a r e n o w b o l d l ya s s e r t i n g t h a t a ' t h e o r y o f e v e r y t h i n g '( the so-ca l l ed 'TOE' ) is a t hand . O ne haso n l y t o o p e n t h e p a g e s , f o r e x a m p l e , o fPaul Davies ' book T h e N e w P h y s i c s(Cam br idge Unive rs i ty P res s , 1989) , t o

i ee ] the exc i t ing ho t i sm i~ presen todayphys ics and the urgency in i t s un i f i -ca t ion wi th b iology.T h e s e h o i i s t i c t i m e s s t i m u l a t e m a n yt h i n k e r s t o c r o s s t h e b a r r i e r s s e p a r a t -ing the ind iv idua l in t e l l ec tua l d i s c i -p l ines and to engage in l ibe ra i ana logi -c a l th i n k i n g b e t w e e n t h e m . 5 c h r S d i n g e rw a s a p e r c e p t i v e a n d i n q u i s i t i v e s t u -d e n t o f s c i e n c e d u r i n g a s i m i l ar p e r i o dsom e 100 yea rs ago . ! agree wi th theb i o g r a p h i c a l s p e c u l a t i o n of W~lterM o o r ea, that W h a t i s L i f e ? h a d i t so r i g i n s i n t h e a u t h o r ' s s t u d e n t d a y s i nVienna , in those l a t e -n igh t b io log ica ld i s cus s ions wi th F r l inze l F r immeL Ast h e n i n e t e e n t h c e n t u r y t u r n e d i n to t h et w e n t i e t h c e n t u r y , t h e r e w a s a n a b u n -dance of books ha i l ing the un i ty of s c i -ence ( rev iew ed in Ref . 13) , am ong thems o m e b y b i o l o g i s t s s u c h a s E r n s tH a e c k el , o f w h o m w e k n o w S c h r O d i n g erwas a wa re ( s ee Ref . 3 ) . Moreover , t hephys ic i s t Bol t zmann, Schr6dinger ' s s c i -en t i f i c ido l f rom h i s un ive rs i ty pe r iod ,w a s a D a r w i n e n t h u s i a s t a n d h a d g i v e ncons ide rab le no t i ce to b io log ica l i s suesi n t h e l a t e n i n e t e e n t h c e n t u r y ( s e eRef. 20).M o o r e a s u g g e s t s t h a t S c h r 6 d i n g e r ' sincent ive for in t e rd i s c ip l ina ry t ranscen-d e n c e c a m e f r o m t h e N a t u r p h i l o s o p h i esp i r i t o f Goe the , i n whom he was we l lv e r s e d . T h e p o l y m a t h i c c r e d o i nG o e t h e ' s O n G enerq l Thc :ory tells all: ' Ifyou d es i re to reach ou t in to the in fin it e,move in a l l d i rec t ions in the f in i t e . 'G o e t h e a n d L a m a r c k ( w h o m , a s n o t e da b o v e , S c h r 6 d i n g e r a l s o r e a d ) w e r e t w oo f t h e g r e a t e s t u n i v e r s a l is t s in t h e m o d -e rn h i s tory of s c i ence ( s ee Ref . 22) .

W h a t i s L i f e ? i s no t rea l ly aboutgenes , nor i s i t about en t ropy .Schr6dinger , i n [ac t , dec la res h i s pur -p o s e i n t h e o p e n i n g p a g e s . A ft e r e m p h a -s i z ing ' t he keen longing for un i f i ed , a l l -e m b r a c i n g k n o w l e d g e ' a n d a p o l o g i z i n gt o t h e r e a d e r f o r h i s ' s e c o n d - h a n d a n di n c o m p l e t e k n o w l e d g e ' o f b io l o g y i n t h ePre face , he s t a t e s on the f i r s t page ofthe f i r s t chap te r h i s focus , ' a t t he r i sk ofmaking foo l s o f ourse lves , ' on the fun-d a m e n t a l q u e s t i o n : 'H o w c a n t h e e v e n t si n s p a c e a n d t i m e w h i c h t a k e p l a c ewi th in the spa t i a l boundary of a l i v ingo r g a n i s m b e a c c o u n t e d f o r b y p h y s i c sand chemis t ry? ' (Schr6dinger ' s i t a l i c s ) .T h e t r u e s i g n if i ca n c e o f W h a t i s L i f e ? ist o b e u n d e r s t o o d w i t h i n t h e r e a l m o fphys ica l i sm, a ph i losoph ica l p rogram, ofuni f i ca t ion tha t accords a spec ia l re l a -t iona l p r iv i l ege to phy s ics ( s ee Ref . 23) .W i t h i n t h i s p a r a d i g m , t h e n a t u r a l w o r l di s n o t a n a l y s e d b y m e r e l y r e d u c i n g

ma ieria l su bs tan ce to ,+~imp~e phy sicalobjec ts ; ra the L t i~: t~eoe+et icai characot e r o f s p a c e - t i m e ~ s o c i a t i o n s f o r p r o -ces se s to a phys ica l foemat i s reduced .Schr6d inger was , o f course , cau ght inthe begin ning of the ~mo!ecc~!arb io logy 'e ra , whic t t ' - ' ,comme~:.e(~ ih earnestshor t ly a f t e r the tu~r~ ,~ -&e-centuryred i s cov ery of M endeFa wm-k. Ye t h i sconcern was no t w i t~ the nah~re ofg e n e s p e r s e ; r a t h e r , h e w ~ i : e d t o L ~ owt h e c a u s a l , d y n a m i c a l b a s i s o f ' e v e n t s '( s u c h a s s t r u c t u r e s , o r g a n i z a t i o n a r mhered i t a ry t rans i t ions ) in the i i~ ' ings ta t e . SchrSdinger ' s famous ' ape r , :oa icc r y s t a l ' m e t a p h o r f o r c h r o m o s o m a ls t r u c t u r e s h o u l d b e i n t e r p r e t e O i n t h i sdynam ica l s ense . To a theore t i ca l phys i -c i s t , t he idea of a ' c rys t a l ' immedia te lyc o n j u r e s u p m a t h e m a t i c a l s y m m e t r ygroups . A ha l lmark of re l a t iv i ty andq u a n t u m p h y s i c s i n t h i s c e n t u r y h a sb e e n t h e e l u c i d a t i o n o f s y m m e t r y /a s y m m e t r y a s t h e d y n a m i c a l p r i n c i p l eunder ly ing a l l t he forces of Na ture ( s eeRef. 24) . Pierre Curie 25, in the la te 1800s ,u s e d t h e c o n c e p t s o f c r y s t a l s y m m e t r yg r o u p s i n a d y n a m i c a l m a n n e r ( p r o b -a b l y u n k n o w n t o S c h r 6 d i n g e O t h a t ,today , p rovides the theore t i ca l bas i s fo ro u r u n d e r s t a n d i n g o f m a n y k i n d s o fc o u p le d t h e r m o d y n a m i c f l o w p r o c e s sin living cells (s ee Refs 13, 18). W hile wec a n n o t t h a n k S c h r 6 d i n g e r s o l e ly f o r t h eappearance of th i s pa rad igm in b io logy ,the p resc ien ce of h i s ana logica l th ink ingi s h i s tor i ca l ly no tewo r thy . In looking a t t he p le thora of works onthe theore t i ca l founda t ion of the un i f i -ca t ion of b io logy and phys ics be ingwr i t t en today , SchrSdinger would sure lysmi le conten ted ly . Not on ly should hebe reve red for h i s fundamenta l ro l e inthe phys ics revolu t ion of the twent i e thc e n t u r y , b u t h e s h o u l d b e r e m e m b e r e di n t h e h i s t o r y o f s c i e n c e a s o n e o f t h ef i r s t p ionee rs f rom the ea r ly s t age oftha t revolu t ion to ex tend the phys ica l -i s t impl i ca t ions ( ' a lbe i t , ' a s he s a id , ' w i th s e c o n d L a n d a n d i n c o m p l e t ek n o w l e d g e ' ) to o t h e r a r e a s.D e s p i t e t h e p h e n o m e n a l s u c c e s s e sof t h e o r e t i c a l p h y s i c s a n d o f m o l e c u la rbiology, we are , a las , no closer toa n s w e r i n g t h e u l t im a t e q u e s t i o n W h a t i sL i f e? t han in Schr6dinger ' s day . Wi tht i m e , t h e e x p l a n a t i o n b e c o m e s m o r ee lus ive and me taphys ica l . Dare we infe rt h a t t h e a u t h o r s e n s e d t h e u n c e r t ai n t yh imse lf , i n adding the cont rove rs i a l ep i-logue? As vo iced by Lotka16, a contem-pora ry of Schr6dinger , ' ( i n ) s ea rch ingfor the e s sen t i a l cha rac te r i s t i c s o f l i fe ,t hose tha t should f ina lly and conc lus ive ly

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: i _ ~ _

BOOKREVIEW T I B S 2 0 - J A N U A R Y 1 9 9 5d i s t i n g u i s h ~ h e l i v i n g f r o m t h e n o n -l i vi n g , a r e w e n o t j u s t s e a r c h i n g f o r t h et h i n g i n n a t u r e t h a t s h o u l d c o r r e s p o n dt o a w o r d i n o u r v o c a b u l a r y ? A r e w e n o th u n t i n g t h e J a b b e r w o c k ? '

Aknow~lgemntI a m g r a t e f u l t o D . B . K e l l a n d J . A .W i t k o w s ~ J f o r h e l p f u l c o m m e n t s .R e f e r e n c e si We lch. G. R. (1989 ) BioEssays 1L 1 8 7 - 1 9 02 Gnaiger, E. et aL (1994) Wh at is Controll ingLife?, ;nnsbruck Univers i ty Press3 Moore, W, (1989) SchrSdinger:L i fe andThought, Cambr idge U nivers ity Press4 Yoxen, E. J. (1979 ) Hist. Sci. 17 , 17 -525 Wi tkowski , J . A. (1986) Trends 8 iochem. Sci .1 1 , 2 6 6 - 2 6 86 Perutz, M. F. (1987) Nature 3 2 6 , 5 5 5 - 5 5 87 TimoE.=eff-Ressovsky,N. W., Zimm er, K. G. andDelbn3ck, M. {1935 ) Nachrichten aus t ier

B,ologie der G ese#schafl der WissenschaftenG6ttingen1 , 1 8 9 - 2 4 5. . . . L

The teenage w eakling andother storiesB i o c h e m i s tr y f o r t h e M e d i c a lS c i e n c e s : A n I n t e g r a t e d C a s eApproache d i t e d b y S . J . H i g g i n s , A . J . T ~ t m e r a n dE . J . W o o d , Lo n g m a n , i 9 9 4 . 1 4 , 9 9( x ii i + 2 0 : t p a g e s ) IS B N 0 5 8 2 1 0 1 2 9 8T h is i s a s e l f- s tu d y b o o k th a t s h o u lda t t r a c t t h e in t e re s t o f s tu d e n t s i n t h eh e a l th s c i e n c e s , i t m ig h t h e lp th e md e v e lo p p ro b le m -s o lv in g s k il l s a n dc u r io s i ty , a n d a l lo w th e m to a v o id th et r a d i t i o n a l b a r r i e r s b e tw e e n b a s i c s c i e n c ed i s c ip l in e s a n d b e tw e e n b a s i c v e r s u sc l in ic a l d e p a r tm e n t s .i t i s n o w q u i t e c l e a r t h a t t h e e m p h a s i si n m e d i ca l e d u c a ti o n h a s c h a r g e d . G o n ea x e th e ' d a y - lo n g ' l e c tu re s a n d th e p a s s iv es ty l e o f e d u c a t io n . T h e r e s p o n s ib i l i t y fo re d u c a t io n i s n o w t r a n s l e r r e d , t o a l a rg ed e g re e , f ro m th e f a c u l ty to th e s tu d e n t ,F u r th e r , t h e re i s a g re a t n e e d fo rin t ro d u c in g c l in i c a l r e l e v a n c e a n dm o t i v a t i o n fo r s t u d e n t s t o s e e kin fo rm a t io n , i n t h i s l i g h t, t h i s t e x t s e e m sv e r y t im e ly . T h e m e d ic a l s c h o o l f a c u l tym u s t s e a r c h f o r o r c r e a t e n e w w a y s t op r e s e n t t h e b a s i c s c i en c e s , w a y s t h a tc a p t u r e t h e p o t e n t i a l e n t h u s i a s m o f th es tu d e n t w h i l e a v o id in g o v e r -b u rd e n in gth e s t u d e n t i n i ti a l ly . C o n c e p t s a n dt h i n k i ng p a t t er n s , r a t h e r t h a n f a c to v e r lo a d , a re o n e v e ry o n e ' s m in d s .N e v e r th e l e s s , t h e re a re f e w t e x t s a v a i l a b leto a c h ie v e th e s e a im s .Biochem istry for the M edical Sciences i sa la rge s tep in the r igh t d i rec t ion . I t i s we l lw r i t t e n , c l e a r ly p re s e n te d , c o n c i s e a n d48

8 Symon ds, N. (1986) O. Rev. Biol. 61 ,2 2 1 - 2 2 69 W atson, J. (1993) Science2 6 1 ,1 8 1 2 - 1 8 1 31 0 Mayr , E. (1982) The Grow th of BS.ologicalThought, Harvard Univers ity Press11 Haraway, D. J. (1976) Crystals, Fabrics, andReM s: Metapho rs of Organicism in Twentieth-Century Developm entalBiology,Yale UniversityPress1 2 Witkowski , J . A. (1987) Medical History 31.2 4 7 - 2 6 81 3 Welch, G. R. (1992) Prog. Biophys. Mot. B iol.5 7 , 7 1 - 1 2 814 Peters, R. A. (1930) Trans. Faraday Soc. 26 ,797--822,t5 Smeach, S. C. and Gold , H. J. (1975) J. Theor.Biol. 5 1 , 5 9 - 9 61 6 Lotka , A. J. (1925) Elem ents of Ph ysical Biology,Wil l iams & Wi lk ins1 7 De Donder , T. and Van Rysse lberghe, R (1936)ThermodynamicTheoryof A ff inity, StanfordUniversity Press1 8 Caplan, S. R. and E ssig , A. (1983)Bioenergetics and Line ar Nonequilibr iumThermodynamics,Harvard Univers i tyPress

h a s an a p p r o p r i a t e n u m b e r o f c le a ri l lu s t r a t i o n s t o m a k e t h e p o i n t s t h a t t h ea u t h o r s h a v e i n m i n d . O t h e r s t r e n g t h si n c l u d e i t s b r e a d t h , c l i n i c a l r e l e v a n c e ,a n d t h e m o s t l y u p - t o - d a te , c l e a re x p l a n a t i o n s . S t u d e n t s i n t h e h e a l t hs c i e n c e s s h o u l d c e r t a i n l y l i n d i t h i g h l yi n s t r u c t i v e a n d i n t e r e s ti n g . I d o n o t t h i n ks t u d e n t s o r f a c u l t ie s s h o u l d b e , o r w i l l b e ,' p u t o f f ' b y t h e s e l e c t i o n o f c a s e s , s o m e o fw h i c h d e s c r i b e r a r e d i s e a s e s.B e fo re d i s c u s s in g m y in t e rp re t a t io n o ft h e w e a k n e s s e s , a b r i ef c o m m e n t a b o u tt h e l a y o u t . T h e c a s e s a r e p r e s e n t e ds u c c in c t ly . A n in t ro d u c t io n to th ep i :)b l em i s p ro v id e d in u s u a l ly l e s s t h a no n e p a g e . T h i s i s fo l lo w e d b y a c o n c i s eo u t l in e o f t h e p ro b le m , in c lu d in g a ll t h ere l e v a n t d a t a . Q u e s t io n s a re th e n a s k e d ,s o m e b e i n g m o r e u s e fu ! t h a n o t h e r s , b u tm o s t a r e p e r t i n e n t . T h e a u t h o r s c h o o s e(w is e ly in m y o p in io n ) n o t t o p =o v ides p e c i f i c a n s w e rs , b u t p ro v id e ac o m m e n t a r y t h a t a d d r e s s e s a ll t h e k e ye l e m e n t s w i t h r e s p e c t t o t h e q u e s t i o n s .T o s t im u la t e t h e s tu d e n t , fu r th e r( u n a n s w e r e d ) q u e s t i o n s a r e p r o v i d ed .Ma n y o f t h e s e r e q u i re d e t a i l e din fo rm a t io n , b u t a re , n e v e r th e l e s s ,im p o r t a n t q u e s t io n s , i n t h e f in a l s e c t io n ,t h e a u t h o r s a t t e m p t t o e n c o u r a g ei n t e gr a t io n , b o t h h o r i z o n t a l l y b e t w e e nt h e b a s i c s c i e n c e s a n d v e r t i c a l l y t o m o r ec l in i ca l a re a s ; t h i s i s t h e o n ly a re a th a t i sn o t s u f f i c i e n t ly d e v e lo p e d to th e h ig hle v e l of t h e r e m a in d e r o f t h e b o o k . F in al ly ,e x c e l l e n t i n t ro d u c to ry r e fe re n c e s a rep ro v id e d .T h e s t r e n g t h s o f t h i s b o o k a r e a l s o i t sw e a k n e s s e s . I t c o v e r s s o w id e a n a re at h a t e a c h c a s e i s v e r y ' t h i n '; i t d o e s n o tc o v e r a n y s u b j e c t i n d e p t h , a n d r e a d sl ike a co l lec t i on o f in te res t ing , bu tr e l a t iv e ly u n re l a t e d , c a s e s y n o p s e s . I d on o t f i n d th i s t o b e a m a jo r d e t r a c t io n

1 9 W esterhoff , H. V. and Van Dam , K. (1987)Thermodynamicsand Control of Biological Free-Energy Transduction,Elsevier20 Broda, E. (1983) Ludwig Bol tzmann:Man-Physicist-Philosopher,Ox BOW Press2 1 Davidson, M. (1983) UncommonSense:The Life and Thought of Ludwig yon Bertalanffy,] 'archer2 2 Welch, G. R. 'Goethe 's Ge stalt, Bi/dung, an dUrph&nomenin B iology: A Twentieth-CenturyPhys ical ist View ,' in Goethe Scienziato(Grieco,A., ed.), Einaud i ( in press )2 3 Poland, J. (1994 ) Physicalism:The Philosophical Foundations,Oxford U nivers ity Press24 Pageis, H. R. (1985) Perfect Symm etry,S imon & Schus ter25 Cur ie , P. (1908) Oeuvres de Pierre Curie,Gauthier-Villars

G . R I C K E Y W E L C HD e p a r t m e n t o f B i o l og i c a l S c i e n c e s , U n i v e r s i t yo f N e w O r le a n s , N e w O r le a n s , L A 7 0 1 4 8 ,U S A .

b e c a u s e , i f t h e b o o k w e r e m u c h , m u c hlonger , i t wo_,dd look l ike a t ra d i t io na l tex ta n d lo s e i t s a p p e a l . I t i s a d i s t i n c ta d v a n t a g e t o b e a b l e t o p u t t h e b o o kd o w n fo r a p e r io d o f t im e a n d p i c k i t u pl a t e r to r e a d a n y o f t h e c a s e s t h a t o n em a y f in d in t e re s t in g a t t h a t t im e .

T h e re a re , h o w e v e r , s o m e p o in t s Iw o u l d h a v e w a n t e d s t r e s s e d i n a b o o kt h a t s h o u l d ' m a k e s t u d e n t s t h i n k '. F o re x a m p l e , q u a n t i t a t i o n i s u n d e r d e v e l o p e d .in c a s e o n e , t h e t e e n a g e w e a k l in g , i t i sn e c e s s a r y t o k n o w t h a t t lu x th r o u g hp h o ~ v h o l ru c to k in a s e -1 h a s to b e 1 8- fo ldh i g h e r t o r e g e n e r a t e t h e s a m e a m o u n t o fA T P a n a e ro b ic a l ly v e r s u s a e ro b ic a l ly . I ft h e s t u d e n t a p p r e c i a t e d t h i s , i t w o u l dh e l p e x p l a i n w h y t h e p a t i e n t d o e s n ' t h a v es y m p t o m s a t r e s t o r d u r i n g a e r o b i ce x e rc i s e . Mo re o v e r , i n a re a s w h e re I h a v em o re d e t a i l e d k n o w le d g e , i w a s l e s sh a p p y a b o u t s o m e o f t h e d i s c u s s i o n ( f o re x a m p le , c a s e t e n , a c id e x c re to r s ) , b u tth i s a g a in i s n o t a m a jo r c r i t i c i s m .

A s o n e w h o h a s a g re a t i n t e re s t i nt e a c h i n g b a s i c s c i e n c e s t o m e d i c a ls t u d e n t s , a n d o n e w h o h a s a t t e m p t e d t oa c h ie v e a s o m e w h a t s im i l a r a im l , o v e ra l l 1a m v e r y e n t h u s i a s t i c a b o u t t h i s b o o k . !w o u l d r e c o m m e n d i t h i g h l y t o t e a c h i n gfa c u l t i e s t o h e lp ~ e le c t a n d d e v e lo p c a s em a te r i a l , i v, o u ld m a k e s tu d e n t s a w a re o ft h i s b o o k a n d e n c o u r a g e t h e m t o r e a d i t.R e f e r e n c e1 Halper in , M. L . and Rol leston, F. S. (1993)Clinical Detective Stor ies: A Problem.BasedApproach to Clinical Cases in Energyan dAcid-Base Metabol ism,Por t land PressMITCHEL L L. HALPE RINi s the co-author o f Clinical Detective Stor ies and isat St M ichael 's Hospi ta l , 38 5huter S treet , Toronto,Ontar io , Canada M5B 1A6.