GENERAL ⎜ ARTICLE

The Central Dogma of Molecular Biology A Retrospective after Fifty Years Michel Morange

Michel Morange was trained in biochemistry and molecular biology at the Pasteur Institute in Paris. His main interests are in the history and philosophy of science and the transformation of biology during the 20th century, in particular the rise of molecular biology. He is also interested in the emergence of new disciplines such as synthetic biology and systems biology, the role of epigenetics and the re-emergence of the question of life.

Based on the article entitled ‘Fifty Years of the Central Dogma’ published in Journal of Biosciences, Vol. 33, pp.171–175, 2008. Keywords The central dogma, chaperone, evolution, prion, reverse transcriptase.

236

T h e C e n tr a l D o g m a o f m o le c u la r b io lo g y w a s e n u n c ia te d m o re th a n 5 0 y e a r s a g o b y F r a n c is C r ic k to d e ¯ n e th e r e la tio n s b e tw e e n th e m a in in fo r m a tio n a l m a c r o m o le c u le s: D N A , R N A a n d p r o te in s. S in c e th a t tim e , m a n y d isc ip lin e s h a v e m im ic k e d b io lo g y , a n d in tr o d u c e d th e ir o w n `C e n tr a l D o g m a '. T h is a rtic le is a n a tte m p t to r e v ie w th e sta tu s o f th e C e n tr a l D o g m a in th e c o n te x t o f th e n e w d isc o v e r ie s th a t w e r e m a d e d u r in g th e p a st ¯ fty y e a r s. In tr o d u c tio n T h e y ea r 2 0 0 8 w a s th e ¯ ftieth a n n iv ersa ry o f th e p u b lica tio n o f a lectu re b y F ra n cis C rick in w h ich h e p u t fo rw a rd tw o m a jo r co n cep ts: th e C en tra l D o g m a a n d th e S eq u en ce H y p o th esis [1 ]. T o g eth er w ith D a rw in 's p rin cip le o f n a tu ra l selectio n , th ese tw o co n cep ts a re b eliev ed to p rov id e th e u n d erp in n in g to a ll o f b io lo g y. T h e 5 0 th a n n iv ersa ry o ® ers a n id ea l o p p o rtu n ity to re-eva lu a te th e va lid ity o f th e C en tra l D o g m a . W h a t a stra n g e n a m e fo r a scien ti¯ c h y p o th esis! T h e F ren ch m o lecu la r b io lo g ist J a cq u es M o n o d w a s th e ¯ rst to rem in d C rick th a t \ A d o g m a is so m eth in g w h ich a tru e b eliev er ca n n o t d o u b t" [2 ]. T h is is p ro b a b ly n o t w h a t C rick h a d in m in d w h en h e co in ed th e p h ra se. O n m a n y o cca sio n s, C rick h a s sta ted th a t, a s a n o n -b eliev er o f relig io n , h e co n sid ered d o g m a s sim p ly a s b o ld h y p o th eses w ith o u t p ro o f. S in ce its in cep tio n , th e C en tra l D o g m a h a s b een rep ea ted ly ch a llen g ed a n d criticized . B efo re ex a m in in g th e serio u sn ess o f th ese ch a llen g es, let u s ex a m in e ¯ rst th e circu m sta n ces u n d er w h ich C rick

RESONANCE ⎜ March 2009

GENERAL ⎜ ARTICLE

p ro p o sed th e C en tra l D o g m a a n d th e ex a ct w a y in w h ich h e fo rm u la ted it. F o r m u la tio n o f th e C e n tr a l D o g m a F o r m a n y stu d en ts, n ow fa m ilia r w ith th e C en tra l D o g m a sin ce th eir ea rly y ea rs o f ex p o su re to m o lecu la r b io lo g y, it is p ro b a b ly im p o ssib le to im a g in e h ow co n fu sin g th e situ a tio n w a s in m o lecu la r b io lo g y in th e m id -1 9 5 0 s. It h a d p ro g ressiv ely b eco m e clea r fro m th e ex p erim en ts o f A v ery a n d co llea g u es1 in 1 9 4 4 th a t D N A w a s a n im p o rta n t co m p o n en t o f th e g en etic m a teria l, m ay b e th e o n ly o n e. Its stru ctu re, esta b lish ed b y C rick a n d W a tso n in 1 9 5 3 , sh ow ed th a t it w a s p erfectly a b le to fu l¯ l th e m a in fu n ctio n a l req u irem en t o f a g en etic m a teria l, n a m ely, self-rep lica tio n . W h en sep a ra ted , th e tw o stra n d s o f D N A w ere a b le to g en era te co m p lem en ta ry co p ies o f th em selv es, essen tia lly b eca u se o f th e co m p lem en ta rity o f th e b a ses, a d en in e p a irin g o n ly w ith th y m in e a n d g u a n in e w ith cy to sin e. T h e p o ssib ility th a t D N A co u ld d irectly d eterm in e th e seq u en ce o f p ro tein s w a s p ro p o sed b y th e p h y sicist G eo rg e G a m ow in 1 9 5 4 2 . B u t th ere w a s a m a jo r p ro b lem : D N A w a s a co m p o n en t o f ch ro m o so m es a n d ch ro m o so m es w ere lo ca lized w ith in th e cell n u cleu s, w h erea s p ro tein sy n th esis w a s k n ow n to o ccu r in th e cy to p la sm o f eu ka ry o tic cells. In a d d itio n , th is d irect ro le o f D N A d id n o t ex p la in th e co rrela tio n b etw een th e a b u n d a n ce o f R N A s in th e cy to p la sm a n d th e ra te o f p ro tein sy n th esis. S tu d ies a t th a t tim e h a d a lso sh ow n th a t m icro so m es, cy to p la sm ic p a rticles fo rm ed o f R N A s a n d p ro tein s, w ere th e p recise p la ce w h ere p ro tein sy n th esis d id o ccu r. R etro sp ectiv ely, th e D N A { R N A { p ro tein rela tio n m ig h t a p p ea r a s th e sim p lest so lu tio n to th e p ro b lem . A ll th e p ieces o f th e p u zzle w ere a lrea d y th ere, a n d so m e resea rch ers lik e A lex a n d er D o u n ce h a d sta rted to a ssem b le th em in th e co rrect w a y.

RESONANCE ⎜ March 2009

1

See article by S Mahadevan, Resonance, Vol.12, No.9, pp.4– 11,September 2007.

2

See article by Vidyanand Nanjundiah, Resonance, Vol.9, No.7, pp.44–49, July 2004.

237

GENERAL ⎜ ARTICLE

The transfer of information from nucleic acid to nucleic acid or from nucleic acid to protein may be possible, but transfer from protein to protein or from protein to nucleic acid is impossible.

T h e situ a tio n h ow ev er w a s less clea r. C ru cia l m ech a n ism s w ere la ck in g , a n d a d d itio n a l p u zzlin g o b serva tio n s h a d b een m a d e. If rib o so m es w ere resp o n sa b le p er se fo r p ro tein sy n th esis, th e ch em ica l sta b ility o f th eir R N A seem ed in co m p a tib le w ith th e ra p id ch a n g es in p ro tein sy n th esis th a t m ay o ccu r in cells. N o th in g w a s k n ow n o f th e en zy m a tic m a ch in ery th a t co u ld co p y D N A in to R N A , a n d to tra n sla te R N A in to p ro tein s. It w a s co n ceiva b le th a t R N A w a s th e p ro d u ct o f D N A b y a d irect ch em ica l m o d i¯ ca tio n . T h e co m p lex m o d els ela b o ra ted in th e m id -1 9 5 0 s b y th e B elg ia n b io ch em ist a n d em b ry o lo g ist J ea n B ra ch et to a cco u n t fo r th e n u m ero u s o b serva tio n s m a d e th u s fa r in clu d ed a ll th e p o ssib le rela tio n s b etw een m a cro m o lecu les [3 ]. In th e co n tex t o f th ese fa cts, w e a re b etter a rm ed to u n d ersta n d th e e® o rts o f C rick to p ro p o se sim p le h y p o th eses (m ay b e to o sim p le) to im p o se so m e o rd er o n th e a b u n d a n ce o f p iecem ea l a n d co n ° ictin g resu lts. C rick w o rd ed th e C en tra l D o g m a in th is w ay : \ T h is sta tes th a t o n ce `in fo rm a tio n ' h a s p a ssed in to p ro tein it can n ot get ou t again . In o th er w o rd s, th e tra n sfer o f in fo rm a tio n fro m n u cleic a cid to n u cleic a cid o r fro m n u cleic a cid to p ro tein m ay b e p o ssib le, b u t tra n sfer fro m p ro tein to p ro tein o r fro m p ro tein to n u cleic a cid is im p o ssib le. In fo rm a tio n h ere m ea n s th e precise d eterm in a tio n o f seq u en ce, eith er o f b a ses in th e n u cleic a cid o r o f a m in o a cid resid u es in th e p ro tein " [1 ]. T o fu lly u n d ersta n d th e m o d el p ro p o sed b y C rick , th e C en tra l D o g m a h a s to b e co m p lem en ted b y tw o o th er h y p o th eses fo rm u la ted b y C rick in th e sa m e lectu re: th e seq u en ce h y p o th esis { \ in its sim p lest fo rm it a ssu m es th a t th e sp eci¯ city o f a p iece o f n u cleic a cid is ex p ressed so lely b y th e seq u en ce o f its b a ses, a n d th a t th is seq u en ce is a (sim p le) co d e fo r th e a m in o a cid seq u en ce o f a p a rticu la r p ro tein " ; a n d th e h y p o th esis reg a rd in g th e m ech a n ism o f p ro tein fo ld in g th a t C rick p ro p o sed ea rlier in th e sa m e lectu re { \ ::: th e m o re lik ely h y -

238

RESONANCE ⎜ March 2009

GENERAL ⎜ ARTICLE

p o th esis is th a t th e foldin g is sim ply a fu n ction of the order of the am in o acids, p rov id ed it ta k es p la ce a s th e n ew ly fo rm ed ch a in co m es o ® th e tem p la te" [1 ]. W h a t C rick p ro p o sed is n o t a ch em ica l co n cep t, b u t is ra th er a n in fo rm a tio n a l o n e. H e fo llow ed th e tra n sfer o f in fo rm a tio n b etw een m a cro m o lecu les, a n d fo r in sta n ce n eg lected th e p o ssib le d irect co n v ersio n o f a D N A to a n R N A . B u t h e g av e in fo rm a tio n a p recise m ea n in g : th e seq u en ces o f n u cleo tid es a n d a m in o a cid s in n u cleic a cid s a n d p ro tein s resp ectiv ely. T h e ela b o ra tio n o f th e C en tra l D o g m a w a s th e resu lt o f b o ld h y p o th eses a n d ex p erim en ta l o b serva tio n s, tw o o f w h ich w ere p a rticu la rly im p o rta n t. T h e ¯ rst o n e w a s th e d em o n stra tio n b y H ein z F ra en k el-C o n ra t, sh ow in g th a t w h en y o u h av e tw o d i® eren t stra in s o f to b a cco m o sa ic v iru s d istin g u ish a b le b y th e stru ctu re o f th eir co a t p ro tein s, it is th e R N A w h ich is req u ired fo r th e p ro d u ctio n o f th e co rrect co a t p ro tein d u rin g in fectio n a n d n o t th e co a t p ro tein itself. S eco n d , in a to ta lly d i® eren t ¯ eld , C h ristia n A n ¯ n sen h a d recen tly sh ow n th e sp o n ta n eo u s refo ld in g o f a n en zy m e, rib o n u clea se, a fter it h a d b een d en a tu red in vitro [4 ]. T h e fa ct th a t it w a s d i± cu lt to im a g in e h ow a co m p a ctly fo ld ed p ro tein co u ld tra n sm it th e seq u en ce o f its a m in o a cid s to a n o th er p ro tein , a s w ell a s th e to ta l a b sen ce o f a n y k n ow n m a ch in ery a b le to \ co p y " p ro tein s in to n u cleic a cid s w ere a d d itio n a l a rg u m en ts. T h e fa ct th a t it w a s im p o ssib le to tra n sfer in fo rm a tio n (in th e sen se C rick h a d im p lied ) fro m p ro tein to n u cleic a cid tu rn ed o u t to b e th e m o lecu la r eq u iva len t o f so m eth in g else th a t w a s im p o ssib le, n a m ely fo r p h en o ty p e to sp eci¯ ca lly a lter g en o ty p e o r fo r so m a to m o d ify th e g erm lin e. W e m u st n o t fo rg et th a t C rick 's g o a l w a s to ex tra ct fro m th is co n fu sed ¯ eld , a lim ited set o f ex p erim en ta lly testa b le h y p o th eses. A s a p h y sicist, h e w a s co n v in ced th a t th is th eo retica l w o rk w a s u sefu l to g u id e th e w o rk o f ex p erim en ters, a n d th a t it h a d its fu ll p la ce in b io lo g y.

RESONANCE ⎜ March 2009

“...folding is simply a function of the order of the amino acids, provided it takes place as the newly formed chain comes off the template’’.

What Crick proposed is not a chemical concept, but is rather an informational one.

239

GENERAL ⎜ ARTICLE

The Central Dogma has been repeatedly mentioned and frequently modified.

T h e C en tra l D o g m a h a s b een rep ea ted ly m en tio n ed a n d freq u en tly m o d i¯ ed . O n e o f th e ¯ rst to d o th is w a s W a tso n h im self in h is h ig h ly in ° u en tia l b o o k M olecu lar B iology of the G en e p u b lish ed in 1 9 6 5 [5 ]. In stea d o f leav in g o p en th e d i® eren t p o ssib ilities o f in fo rm a tio n tra n sfer, h e ex clu d ed th e tra n sfer o f in fo rm a tio n fro m R N A to D N A . O th ers in clu d ed in th e C en tra l D o g m a a n d in its co n cep t o f in fo rm a tio n , th e th ree-d im en sio n a l stru ctu re o f p ro tein s, a n d th e reg u la to ry p ro cesses o ccu rrin g in o rg a n ism s. T h e ex p ressio n \ C en tra l D o g m a " b eca m e eq u iva len t to th e n ew v isio n o f o rg a n ism s ela b o ra ted b y m o lecu la r b io lo g ists. C h a lle n g e s to th e C e n tr a l D o g m a I w ill su ccessiv ely ex a m in e fo u r sets o f o b serva tio n s th a t h av e b een co n sid ered a s ch a llen g es to th e C en tra l D o g m a : th e d iscov ery o f rev erse tra n scrip ta se, th e m ech a n ism o f fo rm a tio n o f p rio n s (th e in fectio u s a g en ts o f sp o n g ifo rm en cep h a lo p a th ies su ch a s th e \ m a d cow " d isea se), th e ro le o f ch a p ero n es in p ro tein fo ld in g , a n d a series o f n ew p ro cesses m a k in g th e tra n sfer o f in fo rm a tio n fro m D N A to p ro tein s th ro u g h R N A m u ch m o re co m p lex th a n it w a s in itia lly im a g in ed { ep ig en etic m o d i¯ ca tio n s o f D N A a n d ch ro m a tin w h ich m o d ify g en e ex p ressio n , R N A in terferen ce, R N A sp licin g a n d ed itin g .

3

Resonance, Vol.7, No.7, July 2002.

240

In 1 9 7 0 , H ow a rd T em in a n d S a to sh i M izu ta n i a n d , sim u lta n eo u sly a n d in d ep en d en tly, D av id B a ltim o re, d iscov ered a n en zy m e n a m ed rev erse tra n scrip ta se, w h ich ca ta ly zes th e sy n th esis o f D N A fro m a tem p la te o f R N A 3 . T h is d iscov ery ex p la in ed h ow certa in R N A v iru ses, su ch a s th e R o u s S a rco m a V iru s, a re a b le to in teg ra te sta b ly in to th e g en o m e o f th eir h o st. B u t it w a s m u ch m o re fo r T em in a n d a n a n o n y m o u s co m m en ta to r o f N atu re { it w a s a b low to th e C en tra l D o g m a . C rick ra p id ly a rg u ed th a t th is w a s n o t th e ca se. T h e d iscov ery o f rev erse tra n scrip ta se d id n o t co n tra d ict th e C en tra l D o g m a a s h e h a d fo rm u la ted ; it co n tra d icted o n ly th e v ersio n p o p u la rized b y W a tso n . RESONANCE ⎜ March 2009

GENERAL ⎜ ARTICLE

T h e o p p o sitio n T em in en co u n tered w h en h e p ro p o sed , a s ea rly a s 1 9 6 4 , th a t th e R N A o f th e R o u s S a rco m a V iru s w a s co p ied in to D N A a n d in teg ra ted in to th e g en o m e, w a s n o t th e co n seq u en ce o f a b lin d b elief in th e C en tra l D o g m a a s m a n y su g g ested . It w a s m o re d u e to th e a b sen ce o f ex p erim en ta l ev id en ce in fav o u r o f th is h y p o th esis: th e ex p erim en ts o f T em in u sin g d i® eren t in h ib ito rs a n d la b els w ere in co n clu siv e.

The discovery of reverse transcriptase did not contradict the Central Dogma as he had formulated; it contradicted only the version popularized by Watson.

L et u s a d d a n o th er p iece to th is co m p lex h isto ry. C rick h a d n ot rejected th e p o ssib ility o f a co n v ersio n o f R N A in to D N A , b u t h e co n sid ered th a t it w a s p ro b a b ly a ra re p h en o m en o n . In co n tra st, T em in su g g ested in h is 1 9 7 0 p u b lica tio n th a t th is d iscov ery m ig h t h av e \ stro n g im p lica tio n s" fo r th eo ries o f in fo rm a tio n tra n sfer. H e la ter d ev elo p ed th ese p ersp ectiv es in fu rth er p u b lica tio n s in w h ich h e ex p la in ed h ow a ctiv ely ex p ressed g en es co u ld b e a m p li¯ ed in th e g en o m e b y su ch a p ro cess. T h erefo re, th ere co u ld b e a retu rn fro m th e a ctiva tio n sta te o f th e g en o m e to its stru ctu re, a L a m a rck ia n p ro cess a t th e cellu la r lev el! A lth o u g h th e n u m ero u s `sel¯ sh ' D N A seq u en ces in th e g en o m e o f eu ka ry o tes a re p ro b a b ly th e resu lt o f th e a ctio n o f rev erse tra n scrip ta se, th e `h eretica l' p ro p o sitio n s o f T em in h av e n o t b een co n ¯ rm ed . T h e d iscov ery o f p ro tein -o n ly p a th o g en ic a g en ts h a s a lso b een co n sid ered a s a b low to th e C en tra l D o g m a . P rio n s a re cellu la r p ro tein s th a t a re a b le to ch a n g e th eir co n fo rm a tio n to a d o p t a p a th o g en ic, p ro n e-to -a g g reg a tio n fo rm . T h is co n v ersio n is sp o n ta n eo u s, o r a ctiva ted b y th e p a th o g en ic fo rm . It ex p la in s th e o ccu rren ce o f b o th sp o n ta n eo u s a n d in fectio u s ca ses o f th ese d isea ses. T h ere is a tra n sfer o f 3 -d im en sio n a l in fo rm a tio n fro m th e p a th o g en ic fo rm o f th e p ro tein to th e n o rm a l o n e. B u t if w e retu rn to C rick 's lectu re, th e o n ly fo rm o f in fo rm a tio n h e co n sid ered w a s seq u en ce in fo rm a tio n . T h e h y p o th esis th a t a ll th e in fo rm a tio n w ith in a cell o rig in a tes in th e lin ea r seq u en ce o f D N A { a p o p u la r v ersio n o f th e C en tra l D o g m a { d o es n o t ¯ t th e in itia l w o rd in g o f th is

RESONANCE ⎜ March 2009

The discovery of protein-only pathogenic agents has also been considered as a blow to the Central Dogma.

241

GENERAL ⎜ ARTICLE

The feeling that the discovery of prions contradicted the Central Dogma did not disappear when the present model, fully compatible with Crick’s version of the Central Dogma, finally emerged.

The discovery in the mid-1980s of proteins facilitating the folding of other proteins was a complete surprise.

242

d o g m a . In a sim ila r w ay to th e p rev io u s ca se, so m e o f th e d iscov erers o f th e p rio n p h en o m en o n w ere fu lly resp o n sib le fo r th is u n n ecessa ry d eb a te a b o u t th e C en tra l D o g m a . W h erea s J S G ri± th h a d sh ow n a s ea rly a s 1 9 6 7 th a t th e co n v ersio n o f th e p rio n in to a p a th o g en ic fo rm co u ld b e ex p la in ed b y m o d els fu lly co m p a tib le w ith th e C en tra l D o g m a (o n e o f th e m o d els p ro p o sed b y G rif¯ th is in fa ct v ery clo se to th e p resen tly a ccep ted o n e), S ta n ley P ru sin er in terp reted th e resu lts o f h is ex p erim en ts sh ow in g th a t th e p a th o g en ic fo rm o f th e sp o n g ifo rm en cep h a lo p a th ies w a s a p u re p ro tein w ith th e h elp o f h eretica l m o d els in v o lv in g th e d irect self-rep lica tio n o f p ro tein s [6 ]. T h ese m o d els w ere n ev er co n ¯ rm ed , b u t th e feelin g th a t th e d isco v ery o f p rio n s co n tra d icted th e C en tra l D o g m a d id n o t d isa p p ea r w h en th e p resen t m o d el, fu lly co m p a tib le w ith C rick 's v ersio n o f th e C en tra l D o g m a , ¯ n a lly em erg ed . O n ce a g a in , o n ly a fu zzy ex ten d ed v ersio n o f th e C en tra l D o g m a w a s ch a llen g ed b y th e ch a ra cteriza tio n o f th e stru ctu re o f th is n ew cla ss o f p a th o g en ic a g en ts. T h e d iscov ery in th e m id -1 9 8 0 s o f p ro tein s fa cilita tin g th e fo ld in g o f o th er p ro tein s w a s a co m p lete su rp rise. A s w e saw in th e in tro d u ctio n , C rick h y p o th esized th a t \ p ro tein fo ld in g is sim p ly a fu n ctio n o f th e o rd er o f a m in o a cid s" a n d th a t n o sp ecia l m a ch in ery o f th e cell w a s req u ired fo r th is p ro cess. A co m p lex m a ch in ery w a s d iscov ered , fo rm ed o f d i® eren t ch a p ero n es p resen t in th e d i® eren t cell co m p a rtm en ts, a n d m a n y a rg u ed th a t it d em o n stra ted th a t C rick w a s w ro n g . F o ld in g w a s n o t \ sim p ly a fu n ctio n o f th e o rd er o f a m in o a cid s" , b u t th e resu lt o f th e a ctio n o f ch a p ero n es. B u t th e h o p e o f ov erth row in g th e C en tra l D o g m a u sin g th e ch a p ero n e a rg u m en t ra p id ly va n ish ed . T h e fu n ctio n o f ch a p ero n es is o n ly to p rev en t \ a ccid en ts" in fo ld in g , a n d in th e ca se o f th e m o st co m p lex ch a p ero n es (th e ch a p ero n in s), to p rov id e co n d itio n s fa v o u ra b le to p ro p er fo ld in g . T h erm o d y n a m ics rem a in s th e o n ly ru le th a t g u id es p ro tein

RESONANCE ⎜ March 2009

GENERAL ⎜ ARTICLE

fo ld in g ; th e m o st sta b le sta te rea ch ed is \ sim p ly a fu n ctio n o f th e o rd er o f a m in o a cid s" . C h a p ero n es d o n o t b rin g steric in fo rm a tio n to th e p ro tein w ith w h ich th ey in tera ct: th e in tern a l cav ity o f th e ch a p ero n in s h a s b een ca lled th e \ A n ¯ n sen 's ca g e" to em p h a size th e fa ct th a t th e p ro cess o f fo ld in g w ith in th is cav ity is a sp o n ta n eo u s o n e. S in ce th e tim e C rick ¯ rst en u n cia ted th e C en tra l D o g m a , m a n y cellu la r p ro cesses h av e b een d iscov ered th a t m a k e th e tra n sfer o f in fo rm a tio n fro m D N A to p ro tein m o re co m p lex a n d fu zzy. T h e tra n scrib ed R N A ca n b e sp liced in to d i® eren t fo rm s o f m R N A s, g en era tin g d i® eren t p ro tein s. R N A ca n a lso b e ed ited ; n u cleo tid es ca n b e a d d ed , so th a t th e ¯ n a l m R N A is n o t a co p y o f th e D N A tem p la te. T h e ex p ressio n o f g en es ca n b e reg u la ted b y D N A m o d i¯ ca tio n (m eth y la tio n ), ch ro m a tin a ltera tio n s, a n d th e a ctio n o f sm a ll in terferin g m icro R N A s. D o th ese resu lts m a k e th e C en tra l D o g m a o b so lete? T h e n ew ly d iscov ered ep ig en etic m ech a n ism s co n tro llin g g en e ex p ressio n d o n o t ch a llen g e th e v ersio n o f th e C en tra l D o g m a p ro p o sed b y C rick . T h ese resu lts a re co n ° ictin g o n ly if o n e (fa lsely ) co n sid ers th a t reg u la to ry in fo rm a tio n w a s in clu d ed in th e C en tra l D o g m a a n d th erefo re m u st o rig in a te in th e D N A . T h e ca ses o f a ltern a tiv e sp licin g a n d ed itin g a re m o re in terestin g , a n d m o re p u zzlin g . C o m p lex p ro tein (a n d R N A ) m a ch in eries a re in b o th ca ses a lterin g th e in fo rm a tio n en co d ed in D N A . D o th ese m o d i¯ ca tio n s o f R N A s th erefo re rep resen t a tra n sfer o f in fo rm a tio n fro m th e p ro tein s b elo n g in g to th e sp licin g a n d ed itin g m a ch in es to th e R N A s th a t a re m o d i¯ ed ? Is it tru e th a t th e \ p recise d eterm in a tio n o f seq u en ce" o f n u cleic a cid s is m o d i¯ ed b y p ro tein s? T h e a n sw er is \ y es" , b u t th is d o es n o t m ea n th a t th is m o d i¯ ca tio n co rresp o n d s to a tra n sfer o f in fo rm a tio n fro m a p ro tein seq u en ce to a seq u en ce o f n u cleic a cid . In a d d itio n , th o u g h th ese p ro cesses ex ist, ed itin g is ra re a n d a ltern a tiv e sp licin g lea d s to th e p ro d u ctio n o f p ro tein s

RESONANCE ⎜ March 2009

Thermodynamics remains the only rule that guides protein folding; the most stable state reached is “simply a function of the order of amino acids”. Chaperones do not bring steric information to the protein with which they interact

243

GENERAL ⎜ ARTICLE

The Central Dogma has survived in spite of the accumulation of many new observations since its inception.

The Central Dogma is simply the result of evolution.

244

h av in g , in m o st ca ses, rela ted , a lb eit slig h tly d i® eren t, fu n ctio n s. W h e r e d o e s th e S tr e n g th o f th e C e n tr a l D o g m a O r ig in a te ? I h av e sh ow n th a t th e C en tra l D o g m a h a s su rv iv ed in sp ite o f th e a ccu m u la tio n o f m a n y n ew o b serva tio n s sin ce its in cep tio n . W h ere d o es its stren g th co m e fro m ? T h e ¯ rst a n sw er w o u ld b e to say th a t it is p recisely th e resu lt o f th is a ccu m u la tio n o f d a ta a n d th e a b sen ce o f resu lts o p p o sin g it. In p a rticu la r, n o m a ch in ery th a t is a b le to co n v ert a p ro tein seq u en ce in to a n u cleic a cid seq u en ce h a s ev er b een fo u n d . B u t is th is su ± cien t to reg a rd th a t th e C en tra l D o g m a h a s n ow b een p rov en ? O n e m u st rem em b er th a t th e d iscov ery o f ch a p ero n es w a s a n u tter su rp rise a n d it is im p o ssib le to ex clu d e th e p o ssib ility th a t co m p lex m ech a n ism s resp o n sib le fo r fu n ctio n s th a t a re so fa r u n k n ow n rem a in to b e d iscov ered , d esp ite th e seq u en cin g o f sev era l g en o m es. A n o th er ju sti¯ ca tio n o f th e C en tra l D o g m a th a t w a s p o in ted o u t so o n a fter its in cep tio n , a s d iscu ssed ea rlier, w a s its clo se rela tio n to th e sep a ra tio n o f th e so m a a n d th e g erm lin e in tro d u ced b y A u g u st W eism a n n a t th e en d o f th e 1 9 th cen tu ry, a n d th e a sso cia ted p rin cip le th a t th e p h en o ty p e ca n n o t sp eci¯ ca lly m o d ify th e g en o ty p e. P ro tein s ca n b e id en ti¯ ed w ith th e p h en o ty p e, a n d th e g en o ty p e w ith D N A . B u t co rrela tin g th e va lu e o f th e C en tra l D o g m a w ith a n u n d em o n stra ted p rin cip le is p ro b a b ly n o t a g o o d so lu tio n . T h e sep a ra tio n b etw een th e so m a a n d th e g erm lin e d o es n o t ex ist in a ll o rg a n ism s. S o , w h ere d o es th e stren g th o f th e C en tra l D o g m a , its \ resilien ce" , co m e fro m ? O n e a n sw er, w h ich h a s n o t y et b een fu lly ex p lo red , is th a t th e C en tra l D o g m a is sim p ly th e resu lt o f ev o lu tio n .

RESONANCE ⎜ March 2009

GENERAL ⎜ ARTICLE

T h e C e n tra l D o g m a in a n E v o lu tio n a r y P e r sp e c tiv e W h a t is p resen tly k n ow n a b o u t th e o rig in a n d ev o lu tio n o f th e m a jo r m a cro m o lecu les p resen t in o rg a n ism s? T h e ¯ rst h y p o th esis w a s th a t th e th ree cla sses o f m a cro m o lecu les a p p ea red sim u lta n eo u sly, b u t th is w a s ra p id ly rep la ced b y th e p ro p o sitio n th a t o n ly tw o ty p es o f m a cro m o lecu les, R N A s a n d p ro tein s, ex isted in itia lly, a n d D N A w a s in v en ted la ter to sta b ilize th e g en etic in fo rm a tio n . D N A is ch em ica lly m o re sta b le, b u t th e m a in rea so n o f its sta b ility resid es in its d o u b le h elica l stru ctu re, w h ich a llow s co rrectio n o f erro rs { w h en o n e stra n d is a ltered , th is a ltera tio n ca n b e rep a ired fro m th e in fo rm a tio n co n ta in ed in th e co m p lem en ta ry stra n d . B io ch em ists a lrea d y h a d a rg u m en ts in fav o u r o f th e rep la cem en t o f R N A b y D N A : d eox y rib o n u cleo tid es a re sy n th esized fro m rib o n u cleo tid es { th e rev erse is n o t tru e. In a d d itio n , th e m ech a n ism o f th is co n v ersio n seem s o u t o f rea ch o f th e m o st so p h istica ted rib o zy m es (R N A en zy m es), a n a rg u m en t in fav o u r o f th e h y p o th esis th a t th is su b stitu tio n to o k p la ce a fter th e in v en tio n o f p ro tein s, a n d th eir ta k eov er o f th e fu n ctio n s p rev io u sly p erfo rm ed b y R N A s (see b elow ). P a trick F o rterre h a s recen tly p ro p o sed th a t th e co n v ersio n o f R N A in to D N A in itia lly o ccu rred in v iru ses [7 ]. T h is m ig h t h av e b een th e w ay fo r th ese v iru ses to esca p e d efen ce m ech a n ism s a g a in st fo reig n R N A ex istin g in cells co n ta in in g o n ly R N A s a n d p ro tein s. W e k n ow th a t m a n y o rg a n ism s h av e m ech a n ism s to co n tro l th e en try o f fo reig n D N A in fo rm a tio n , su ch a s th e restrictio n / m o d i¯ ca tio n sy stem s o f b a cteria . In a p rev io u s liv in g w o rld w h ere th e g en etic in fo rm a tio n w a s R N A , it is h ig h ly p ro b a b le th a t sim ila r m ech a n ism s, ta rg eted a g a in st R N A , ex isted . W ith su ch a scen a rio , th e sta b ility o f D N A w a s n o t th e rea so n to select D N A in stea d o f R N A a s a g en etic m a teria l. T h e a d va n ta g e p rov id ed b y th is sta b ility w a s a n ex a p ta tio n , a ch a ra cteristic w h ich b eca m e a d va n ta g eo u s in a seco n d

RESONANCE ⎜ March 2009

Only two types of macromolecules, RNAs and proteins, existed initially, and DNA was invented later to stabilize the genetic information.

245

GENERAL ⎜ ARTICLE

step , m ay b e w h en th ese v iru ses co n v erted `R N A cells' in w h ich th ey h a d p en etra ted in to `D N A cells', i.e., ch a n g ed th e n a tu re o f th e g en etic m a teria l. If D N A w a s a la te in v en tio n o f ev o lu tio n , a co n v ersio n fro m R N A to D N A w a s req u ired to sh ift fro m a g en etic m a teria l m a d e o f R N A to a n ew o n e m a d e o f D N A . A tra n sfer fro m D N A to R N A h a d a lso to b e in v en ted to rea d th e n ew fo rm o f g en etic in fo rm a tio n . L et u s n ow fo cu s o u r a tten tio n o n th e o th er m a cro m o lecu les, R N A s a n d p ro tein s, a n d th eir ea rlier \ in v en tio n " . T h e d iscov ery, a t th e en d o f th e 1 9 7 0 s, o f th e ca ta ly tic ro le o f R N A led N o rm a n P a ce a n d T erry M a rsh , a n d slig h tly la ter W a lter G ilb ert' to h y p o th esize th e ex isten ce o f a n R N A w o rld th a t p reced ed th e R N A a n d p ro tein w o rld , a w o rld in w h ich R N A w a s th e o n ly in fo rm a tio n a l m o lecu le. T h is h y p o th esis fo u n d stro n g su p p o rt in th e d iscov ery tw en ty y ea rs la ter th a t, in th e 5 0 S rib o so m a l su b u n it, it is th e R N A m o iety th a t is in ch a rg e o f th e fo rm a tio n o f p ep tid e b o n d s in a ll ex istin g o rg a n ism s.

The raison d’être of the Central Dogma originates in the complex evolutionary history of macromolecules. “The failure to embrace evolution is the Achilles’ heel of molecular biology. “

246

If su ch a scen a rio is va lid , p ro tein s w ere d eriv ed fro m R N A s th ro u g h th e in v en tio n o f th e g en etic co d e. W h a t w o u ld h av e b een th e selectiv e a d va n ta g e o f in v en tin g th e rev erse m ech a n ism , fro m p ro tein seq u en ces tow a rd s R N A seq u en ces? W h erea s th e p a ssa g e fro m p o o r R N A ca ta ly zers to m o re e± cien t p ro tein o n es m a d e b io lo g ica l sen se, w h a t w o u ld h av e b een th e sen se o f th e o p p o site co n v ersio n ? C o n c lu sio n T h e ra iso n d '^e tre o f th e C en tra l D o g m a o rig in a tes in th e co m p lex ev o lu tio n a ry h isto ry o f m a cro m o lecu les. S o m eh ow , it is a \ fro zen a ccid en t" o f th is ev o lu tio n a ry h isto ry. T h e em in en t m icro b io lo g ist C a rl W o ese sa id th a t \ th e fa ilu re to em b ra ce ev o lu tio n is th e A ch illes' h eel o f m o lecu la r b io lo g y " [8 ]. In th is a rticle, I h av e tried to sh ow th a t C a rl W o ese is co m p letely rig h t in th e ca se o f th e

RESONANCE ⎜ March 2009

GENERAL ⎜ ARTICLE

C en tra l D o g m a : th e o n ly w ay to ju stify its ex isten ce is th ro u g h th e d escrip tio n o f th e ev o lu tio n a ry h isto ry th a t sh a p ed th e rela tio n s b etw een D N A , R N A s a n d p ro tein s. A c k n o w le d g e m e n t T h e a u th o r is in d eb ted to D av id M a rsh fo r critica l rea d in g o f th e m a n u scrip t. Suggested Reading [1] [2] [3] [4]

[5] [6] [7] [8]

F H C Crick, On Protein Synthesis, Symp. Soc. Exptl. Biol., Vol.12, pp.138–163, 1958. H F Judson, The Eighth Day of Creation, The makers of the revolution in biology, New York: Cold Spring Harbor Laboratory Press, 1996. D Thieffry and R M Burian, Jean Brachet’s alternative scheme for protein synthesis, Trends Biochem. Sci., Vol.21, pp.114–117,1996. B J Strasser, A world in one dimension: Linus Pauling, Francis Crick and the central dogma of molecular biology, Hist. Phil. Life Sci., Vol.28, pp.491–512, 2006. J D Watson, Molecular biology of the gene, New York: W A Benjamin. S B Prusiner, Novel proteinaceous infectious particles cause scrapie, Science, Vol.216, pp.136–143, 1982. P Forterre, The origin of viruses and their possible roles in major evolutionary transitions, Virus Res., Vol.117, pp.5–16, 2006. C R Woese, Translation: In retrospect and prospect, RNA, Vol.7, p.1055–1067, 2001.

RESONANCE ⎜ March 2009

Address for Correspondence Michel Morange Centre Cavaillès and IHPST, Ecole normale supérieure, 29 rue d’Ulm, 75230 Paris Cedex 05, France Email, [email protected]

247