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The Central Dogma of Molecular Biology
A Retrospective after Fifty Years
Michel Morange
Keywords The central dogma, chaperone, evolution, prion, reverse tran- scriptase.
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 emer- gence 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 Bio- sciences, Vol. 33, pp.171–175,
T h e C e n tra 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 rs a g o b y F ra n c is C rick to d e ¯ n e th e re la tio n s b e tw e e n th e m a in in fo rm a tio n a l m a c ro m o le c u le s: D N A , R N A a n d p ro 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 tro d u c e d th e ir o w n `C e n - tra l D o g m a '. T h is a rtic le is a n a tte m p t to re v ie w th e sta tu s o f th e C e n tra 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 rie s th a t w e re m a d e d u rin g th e p a st ¯ fty y e a rs.
In tro d u c tio n
T h e yea r 200 8 w a s th e ¯ ftieth a n n iv ersary of th e p u b li- catio n of a lectu re b y F ran cis C rick in w h ich h e p u t fo r- w ard tw o m a jor co n cep ts: th e C en tral D og m a a n d th e S eq u en ce H y p oth esis [1]. T o geth er w ith D a rw in 's p rin ci- p le of n a tu ral selection , th ese tw o co n cep ts a re b elieved to p rov id e th e u n d erp in n in g to a ll o f b iolog y. T h e 5 0th an n iversa ry o ® ers an id ea l op p ortu n ity to re-evalu ate th e valid ity of th e C en tral D o gm a.
W h at a stra n ge n am e fo r a scien ti¯ c h y p o th esis! T h e F ren ch m o lecu lar b iologist J acq u es M o n o d w as th e ¯ rst to rem in d C rick th a t \ A d og m a is so m eth in g w h ich a tru e b eliever can n o t d o u b t" [2]. T h is is p rob a b ly n ot w h a t C rick h ad in m in d w h en h e coin ed th e p h rase. O n m an y o ccasio n s, C rick h as sta ted th a t, a s a n o n -b eliever of religion , h e con sid ered d og m a s sim p ly as b old h y - p o th eses w ith ou t p ro of. S in ce its in cep tion , th e C en tral D o gm a h a s b een rep eated ly ch allen ged a n d criticized. B efore ex am in in g th e seriou sn ess of th ese ch a llen g es, let u s ex am in e ¯ rst th e circu m sta n ces u n d er w h ich C rick
(^1) See article by S Mahadevan, Resonance, Vol.12, No.9, pp.4– 11,September 2007.
(^2) See article by Vidyanand Nan- jundiah, Resonance, Vol.9, No.7, pp.44–49, July 2004.
p rop osed th e C en tra l D o gm a a n d th e ex act w ay in w h ich h e form u la ted it.
F o rm u la tio n o f th e C e n tra l D o g m a
F or m a n y stu d en ts, n ow fam ilia r w ith th e C en tralD ogm a sin ce th eir early years o f ex p o su re to m o lecu la r b iolog y, it is p ro b ab ly im p ossib le to im ag in e h ow co n fu sin g th e situ ation w as in m o lecu la r b io lo gy in th e m id -19 50s. It h ad p rog ressively b eco m e clea r from th e ex p erim en ts of A v ery a n d co lleagu es^1 in 194 4 th a t D N A w as a n im p o r- tan t co m p on en t of th e gen etic m aterial, m ay b e th e o n ly on e. Its stru ctu re, esta b lish ed b y C rick a n d W a tson in 19 53, sh ow ed th a t it w a s p erfectly a b le to fu l¯ l th e m ain fu n ctio n al req u irem en t o f a gen etic m ateria l, n am ely, self-rep lication. W h en sep a rated , th e tw o stran d s of D N A w ere ab le to gen erate com p lem en ta ry cop ies of th em selves, essen tially b ecau se of th e co m p lem en tarity of th e b ases, ad en in e p airin g on ly w ith th y m in e a n d gu a - n in e w ith cy tosin e.
T h e p ossib ility th a t D N A cou ld d irectly d eterm in e th e seq u en ce o f p ro tein s w as p rop osed b y th e p h y sicist G eo r- ge G am ow in 195 4^2. B u t th ere w as a m a jo r p rob lem : D N A w as a co m p on en t o f ch rom oso m es an d ch ro m o - so m es w ere lo calized w ith in th e cell n u cleu s, w h erea s p rotein sy n th esis w a s k n ow n to o ccu r in th e cy top lasm of eu karyo tic cells. In ad d itio n , th is d irect ro le of D N A d id n ot ex p la in th e co rrelation b etw een th e a b u n d a n ce of R N A s in th e cy to p la sm a n d th e rate of p rotein sy n - th esis. S tu d ies a t th at tim e h ad a lso sh ow n th a t m icro - so m es, cy to p la sm ic p articles fo rm ed of R N A s an d p ro - tein s, w ere th e p recise p lace w h ere p ro tein sy n th esis d id o ccu r. R etrosp ectively, th e D N A {R N A { p rotein relation m igh t a p p ear a s th e sim p lest so lu tion to th e p rob lem. A ll th e p ieces of th e p u zzle w ere a lread y th ere, an d so m e resea rch ers like A lex an d er D ou n ce h ad sta rted to assem - b le th em in th e correct w ay.
p o th esis is th at th e foldin g is sim ply a fun ction of the order of the am in o acids, p rov id ed it ta kes p lace a s th e n ew ly fo rm ed ch ain com es o® th e tem p late" [1 ].
W h at C rick p ro p o sed is n ot a ch em ica l con cep t, b u t is rath er an in form ation a l on e. H e follow ed th e tran sfer of in fo rm a tio n b etw een m acrom olecu les, an d fo r in sta n ce n eglected th e p ossib le d irect co n v ersio n o f a D N A to an R N A. B u t h e g ave in form ation a p recise m ean in g: th e seq u en ces o f n u cleotid es an d am in o acid s in n u cleic acid s an d p rotein s resp ectively. T h e ela b ora tio n of th e C en tra l D og m a w a s th e resu lt o f b o ld h y p oth eses a n d ex p erim en tal ob serva tio n s, tw o of w h ich w ere p articu - la rly im p orta n t. T h e ¯ rst o n e w as th e d em on stration b y H ein z F raen kel-C on ra t, sh ow in g th at w h en y ou h ave tw o d i® eren t strain s of to b acco m o saic v iru s d istin g u ish - ab le b y th e stru ctu re o f th eir co at p ro tein s, it is th e R N A w h ich is req u ired for th e p ro d u ction of th e co rrect coat p ro tein d u rin g in fection an d n o t th e co at p ro tein itself. S eco n d , in a tota lly d i® eren t ¯ eld , C h ristian A n - ¯ n sen h a d recen tly sh ow n th e sp on tan eou s refo ld in g of an en zy m e, rib o n u clea se, a fter it h ad b een d en atu red in vitro [4]. T h e fact th at it w as d i± cu lt to im ag in e h ow a com p actly fo ld ed p rotein cou ld tra n sm it th e seq u en ce of its am in o acid s to an o th er p rotein , a s w ell a s th e tota l a b sen ce o f an y k n ow n m a ch in ery a b le to \cop y " p rotein s in to n u cleic a cid s w ere a d d ition a l a rgu m en ts. T h e fa ct th at it w as im p ossib le to tra n sfer in form ation (in th e sen se C rick h a d im p lied ) fro m p ro tein to n u cleic acid tu rn ed o u t to b e th e m o lecu la r eq u iva len t of som e- th in g else th a t w a s im p o ssib le, n am ely fo r p h en o ty p e to sp eci¯ ca lly alter g en o ty p e or for som a to m o d ify th e germ lin e.
W e m u st n o t fo rget th a t C rick 's g oa l w a s to ex tract from th is con fu sed ¯ eld , a lim ited set of ex p erim en tally testab le h y p oth eses. A s a p h y sicist, h e w a s con v in ced th at th is th eoretical w ork w a s u sefu l to gu id e th e w ork of ex p erim en ters, a n d th at it h ad its fu ll p la ce in b iolog y.
“...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.
(^3) Resonance, Vol.7, No.7, July
The Central Dogma has been repeatedly mentioned and frequently modified.
T h e C en tra l D o gm a h as b een rep eated ly m en tio n ed a n d freq u en tly m o d i¯ ed. O n e of th e ¯ rst to d o th is w a s W atson h im self in h is h igh ly in ° u en tial b o ok M olecu - lar B iology of the G en e p u b lish ed in 1 96 5 [5]. In stead of leav in g op en th e d i® eren t p ossib ilities o f in form ation tran sfer, h e ex clu d ed th e tra n sfer o f in fo rm a tio n from R N A to D N A. O th ers in clu d ed in th e C en tra l D o gm a an d in its co n cep t of in form ation , th e th ree-d im en sion al stru ctu re of p ro tein s, an d th e regu lato ry p ro cesses o c- cu rrin g in orga n ism s. T h e ex p ression \C en tra l D og m a " b ecam e eq u iva len t to th e n ew v ision o f o rgan ism s ela b - ora ted b y m olecu lar b io lo gists.
C h a lle n g e s to th e C e n tra l D o g m a
I w ill su ccessively ex a m in e fo u r sets of ob serva tio n s th at h ave b een co n sid ered as ch allen g es to th e C en tralD ogm a: th e d iscovery o f reverse tra n scrip ta se, th e m ech a n ism of form ation o f p rio n s (th e in fectio u s ag en ts of sp on g iform en cep h a lo p ath ies su ch as th e \ m a d cow " d isea se), th e role o f ch ap ero n es in p rotein fo ld in g, a n d a series of n ew p ro cesses m ak in g th e tran sfer of in form ation from D N A to p rotein s th rou gh R N A m u ch m ore co m p lex th a n it w as in itia lly im ag in ed { ep ig en etic m o d i¯ ca tio n s o f D N A an d ch ro m a tin w h ich m o d ify gen e ex p ression , R N A in - terferen ce, R N A sp licin g an d ed itin g.
In 197 0, H ow ard T em in an d S a tosh i M izu tan i an d , si- m u ltan eou sly an d in d ep en d en tly, D av id B a ltim o re, d is- covered a n en zy m e n a m ed reverse tra n scrip ta se, w h ich cataly zes th e sy n th esis of D N A fro m a tem p la te of R N A 3. T h is d iscov ery ex p la in ed h ow certain R N A v iru ses, su ch as th e R o u s S arcom a V iru s, a re ab le to in tegra te sta b ly in to th e g en o m e o f th eir h ost. B u t it w as m u ch m ore for T em in a n d an a n on y m o u s com m en tato r of N ature { it w a s a b low to th e C en tra l D ogm a. C rick rap id ly a r- gu ed th at th is w a s n o t th e case. T h e d iscovery of reverse tran scrip tase d id n ot con trad ict th e C en tral D ogm a a s h e h a d fo rm u lated ; it co n tra d icted o n ly th e version p o p - u larized b y W atson.
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.
d og m a. In a sim ilar w ay to th e p rev io u s ca se, so m e of th e d iscoverers of th e p rion p h en om en on w ere fu lly re- sp on sib le fo r th is u n n ecessa ry d eb a te a b o u t th e C en tral D o gm a. W h erea s J S G ri± th h ad sh ow n a s early a s 1 96 7 th at th e con version of th e p rio n in to a p a th og en ic form cou ld b e ex p la in ed b y m o d els fu lly com p atib le w ith th e C en tra l D o gm a (o n e of 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 accep ted o n e), S tan ley P ru sin er in terp reted th e resu lts of h is ex p eri- m en ts sh ow in g th a t th e p a th ogen ic form of th e sp o n gi- form en cep h a lo p ath ies w as a p u re p rotein w ith th e h elp of h eretical m o d els in vo lv in g th e d irect self-rep lication of p rotein 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 at th e d iscovery of p rio n s co n trad icted th e C en tra l D ogm a d id n o t d isap 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 ersion of th e C en - tral D o gm a, ¯ n ally em erg ed. O n ce ag ain , on ly a fu zzy ex ten d ed version o f th e C en tral D og m a w as ch allen ged b y th e ch aracterization of th e stru ctu re o f th is n ew cla ss of p ath og en ic ag en ts.
T h e d iscov ery in th e m id -19 80 s of p ro tein s facilitatin g th e fold in g of oth er p rotein s w as a com p lete su rp rise. A s w e saw in th e in tro d u ction , C rick h y p oth esized th at \p ro tein fold in g is sim p ly a fu n ction of th e ord er of am in o acid s" a n d th at n o sp ecia l m ach in ery of th e cell w as req u ired fo r th is p ro cess. A com p lex m ach in ery w a s d iscov ered , fo rm ed of d i® eren t ch ap ero n es p resen t in th e d i® eren t cell com p artm en ts, an d m an y arg u ed th at it d em o n strated th at C rick w as w ron g. F o ld in g w as n ot \sim p ly a fu n ction of th e ord er o f am in o acid s", b u t th e resu lt of th e actio n of ch a p eron es. B u t th e h op e of overth row in g th e C en tra l D og m a u sin g th e ch a p eron e arg u m en t rap id ly van ish ed. T h e fu n ctio n of ch ap eron es is on ly to p rev en t \a ccid en ts" in fo ld in g, a n d in th e case of th e m o st com p lex ch a p eron es (th e ch a p eron in s), to p rov id e con d ition s favou ra b le to p rop er fold in g. T h er- m o d y n a m ics rem a in s th e o n ly ru le th at gu id es p ro tein
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
fold in g ; th e m ost stab le sta te reach ed is \sim p ly a fu n c- tio n o f th e ord er of am in o acid s". C h ap ero n es d o n ot b rin g steric in form ation to th e p rotein w ith w h ich th ey in teract: th e in tern al cav ity of th e ch a p eron in s h as b een called th e \ A n ¯ n sen 's cage" to em p h asize th e fact th at th e p ro cess of fold in g w ith in th is cav ity is a sp on tan eo u s on e.
S in ce th e tim e C rick ¯ rst en u n cia ted th e C en tra lD ogm a, m an y cellu lar p ro cesses h ave b een d iscovered th at m ake th e tran sfer of in form ation from D N A to p rotein m ore com p lex an d fu zzy. T h e tra n scrib ed R N A can b e sp liced in to d i® eren t fo rm s o f m R N A s, g en eratin g d i® eren t p ro - tein s. R N A can a lso b e ed ited ; n u cleotid es ca n b e ad d ed , so th a t th e ¯ n a l m R N A is n ot a cop y o f th e D N A tem - p late. T h e ex p ression of gen es can b e reg u la ted b y D N A m o d i¯ cation (m eth y latio n ), ch rom atin altera tio n s, a n d th e action o f sm all in terferin g m icro R N A s. D o th ese resu lts m a ke th e C en tral D og m a ob solete? T h e n ew ly - d iscov ered ep ig en etic m ech a n ism s con trollin g gen e ex - p ression d o n ot ch allen ge th e version of th e C en tral D o gm a p rop osed b y C rick. T h ese resu lts a re con ° ict- in g on ly if on e (falsely ) con sid ers th at reg u la tory in fo r- m atio n w a s in clu d ed in th e C en tral D o gm a a n d th ere- fore m u st o rigin ate in th e D N A. T h e cases of a ltern ative sp licin g an d ed itin g are m o re in terestin g, an d m ore p u z- zlin g. C o m p lex p rotein (an d R N A ) m ach in eries are in b o th ca ses alterin g th e in form ation en co d ed in D N A. D o th ese m o d i¯ cation s o f R N A s th erefore rep resen t a tran sfer of in form a tion from th e p rotein s b elo n gin g to th e sp licin g an d ed itin g m ach in es to th e R N A s th at are m o d i¯ ed? Is it tru e th at th e \p recise d eterm in ation of 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 an sw er is \yes" , b u t th is d o es n ot m ean th at th is m o d i- ¯ cation corresp on d s to a tran sfer of in form ation fro m a p rotein seq u en ce to a seq u en ce o f n u cleic a cid. In a d - d ition , th o u gh th ese p ro cesses ex ist, ed itin g is ra re a n d altern ativ e sp licin g lea d s to th e p ro d u ction of p rotein s
Only two types of macromolecules, RNAs and proteins, existed initially, and DNA was invented later to stabilize the genetic information.
T h e C e n tra l D o g m a in a n E v o lu tio n a ry P e rsp e c - tiv e
W h at is p resen tly k n ow n a b ou t th e origin an d evolu tion of th e m a jor m acrom olecu les p resen t in o rgan ism s? T h e ¯ rst h y p o th esis w a s th a t th e th ree cla sses of m acrom o le- cu les ap p ea red sim u ltan eou sly, b u t th is w as ra p id ly re- p laced b y th e p rop o sitio n th a t o n ly tw o ty p es of m a cro - m olecu les, R N A s an d p ro tein s, ex isted in itia lly, an d D N A w as in ven ted la ter to stab ilize th e gen etic in form ation. D N A is ch em ically m o re stab le, b u t th e m ain reason of its sta b ility resid es in its d ou b le h elical stru ctu re, w h ich allow s correction o f errors { w h en on e stran d is altered , th is altera tio n can b e rep aired from th e in fo r- m atio n co n tain ed in th e com p lem en ta ry stran d. B io - ch em ists alread y h a d a rgu m en ts in favou r of th e rep lace- m en t o f R N A b y D N A : d eox y rib o n u cleo tid es are sy n th e- sized from rib o n u cleo tid es { th e rev erse is n o t tru e. In ad d ition , th e m ech an ism of th is co n v ersio n seem s ou t of reach o f th e m ost so p h isticated rib ozy m es (R N A en - zy m es), an arg u m en t in favo u r o f th e h y p oth esis th at th is su b stitu tion to ok p lace a fter th e in v en tion o f p ro - tein s, an d th eir ta keover o f th e fu n ctio n s p rev io u sly p er- form ed b y R N A s (see b elow ). P a trick F o rterre h a s re- cen tly p ro p osed th a t th e con version of R N A in to D N A in itially 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 escap e d efen ce m ech an ism s ag ain st foreign R N A ex istin g in cells con tain in g o n ly R N A s a n d p rotein s. W e k n ow th at m an y org an ism s h ave m ech an ism s to con trol th e en try of foreign D N A in fo r- m atio n , su ch as th e restrictio n /m o d i¯ cation sy stem s of b acteria. In a p rev io u s liv in g w orld w h ere th e gen etic in fo rm a tio n w as R N A , it is h igh ly p rob a b le th at sim ilar m ech an ism s, targ eted a gain st R N A , ex isted. W ith su ch a scen ario , th e stab ility of D N A w as n ot th e reason to select D N A in stea d of R N A as a g en etic m a terial. T h e ad va n tage p rov id ed b y th is stab ility w as an ex ap tation , a ch ara cteristic w h ich b ecam e ad va n tageou s in a seco n d
step , m ay b e w h en th ese v iru ses con verted R N A cells' in w h ich th ey h a d p en etrated in toD N A cells', i.e., ch an g ed th e n a tu re of th e gen etic m ateria l. If D N A w as a late in v en tion o f evolu tion , a co n versio n fro m R N A to D N A w as req u ired to sh ift from a g en etic m a terial m a d e of R N A to a n ew on e m a d e of D N A. A tra n sfer from D N A to R N A h ad a lso to b e in ven ted to read th e n ew form of 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 oth er m acrom o le- cu les, R N A s an d p ro tein s, an d th eir earlier \in v en tion ". T h e d iscov ery, at th e en d of th e 1 970 s, of th e cata ly tic role o f R N A led N o rm a n P ace a n d T erry M arsh , a n d slig h tly la ter W alter G ilb ert' to h y p oth esize th e ex is- ten ce o f an R N A w o rld th at p reced ed th e R N A a n d p ro - tein w orld , a w o rld in w h ich R N A w as th e o n ly in fo rm a - tio n al m o lecu le. T h is h y p o th esis fo u n d stron g su p p ort in th e d iscovery tw en ty years later th at, in th e 50S rib o - so m a l su b u n it, it is th e R N A m o iety th at is in ch arge of th e form ation of p ep tid e b o n d s in all ex istin g orga n ism s.
If su ch a scen a rio is valid , p ro tein s w ere d erived from R N A s th ro u gh th e in ven tio n of th e gen etic co d e. W h at w ou ld h ave b een th e selective ad va n ta ge of in v en tin g th e rev erse m ech a n ism , from p ro tein seq u en ces tow a rd s R N A seq u en ces? W h ereas th e p assage fro m p o o r R N A cataly zers to m ore e± cien t p rotein on es m a d e b io log ical 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 con version?
C o n c lu sio n
T h e raison d '^etre o f th e C en tral D og m a orig in a tes in th e com p lex evolu tio n ary h istory o f m a crom olecu les. S om e- h ow , it is a \frozen accid en t" of th is evo lu tion a ry h isto ry. T h e em in en t m icro b io lo gist C arl W o ese sa id th at \th e failu re to em b race evo lu tion is th e A ch illes' h eel o f m o le- cu la r b io log y " [8]. In th is a rticle, I h ave tried to sh ow th at C a rl W o ese is com p letely righ t in th e case of th e
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. (^) “
