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236 RESONANCE ⎜ March 2009

GENERAL ⎜ ARTICLE

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,

2008.

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 eS 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 0than n iversa ry o ® ers an id ea l op p ortu n ity to re-evalu ateth 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 eF ren ch m o lecu lar b iologist J acq u es M o n o d w as th e ¯ rstto rem in d C rick th a t \ A d og m a is so m eth in g w h ich atru e b eliever can n o t d o u b t" [2]. T h is is p rob a b ly n otw h a t C rick h ad in m in d w h en h e coin ed th e p h rase. O nm 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 tralD 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, letu s ex am in e ¯ rst th e circu m sta n ces u n d er w h ich C rick

237RESONANCE ⎜ March 2009

GENERAL ⎜ ARTICLE

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 ichh 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 asin 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 esitu ation w as in m o lecu la r b io lo gy in th e m id -19 50s. Ith ad p rog ressively b eco m e clea r from th e ex p erim en ts ofA v ery a n d co lleagu es1 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 in19 53, sh ow ed th a t it w a s p erfectly a b le to fu l l th e m ainfu 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 ofD 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 tarityof 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 sp 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 Ad id n ot ex p la in th e co rrelation b etw een th e a b u n d a n ceof 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 ido ccu r. R etrosp ectively, th e D N A {R N A { p rotein relationm 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 eresea 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.


GENERAL ⎜ ARTICLE

T h e situ atio n h ow ev er w a s less clear. C ru cial m ech a -n ism s w ere lack in g , an d a d d ition a l p u zzlin g ob serva tio n sh ad b een m ad e. If rib o som es w ere resp on sab le p er se for

p rotein sy n th esis, th e ch em ica l sta b ility o f th eir R N Aseem ed in com p a tib le w ith th e rap id ch an ges in p ro teinsy n th esis th at m ay o ccu r in cells. N o th in g w as k n ow nof th e en zy m atic m ach in ery th at cou ld cop y D N A in toR N A , a n d to tran sla te R N A in to p rotein s. It w as co n -

ceivab le th a t R N A w as th e p ro d u ct of D N A b y a d irectch em ical m o d i ca tio n . T h e com p lex m o d els elab oratedin th e m id -19 50s b y th e B elg ia n b io ch em ist an d em b ry -olog ist J ea n B ra ch et to a ccou n t fo r th e n u m erou s o b ser-vation s m a d e th u s fa r in clu d ed all th e p o ssib le rela tio n sb etw een m acrom olecu les [3].

In th e con tex t of th ese facts, w e a re b etter a rm ed to u n -d erstan d th e e® o rts of C rick to p rop ose sim p le h y p oth e-ses (m ay b e to o sim p le) to im p ose som e ord er o n th e

ab u n d an ce of p iecem eal an d con ° ictin g resu lts. C rickw ord ed th e C en tral D o gm a in th is w ay : \ T h is statesth at o n ce in fo rm a tio n ' h as p a ssed in to p rotein it can not

get out again . In oth er w o rd s, th e tran sfer of in fo rm a -tio n from n u cleic acid to n u cleic a cid or from n u cleic a cid

to p ro tein m ay b e p ossib le, b u t tran sfer from p rotein top rotein or from p ro tein to n u cleic a cid is im p ossib le.In fo rm a tio n h ere m ean s th e precise d eterm in a tion of se-q u en ce, eith er o f b a ses in th e n u cleic acid or of am in oacid resid u es in th e p rotein " [1].

T o fu lly u n d erstan d th e m o d el p rop o sed b y C rick , th eC en tra l D o gm a h as to b e com p lem en ted b y tw o oth erh y p oth eses fo rm u lated b y C rick in th e sam e lectu re: th eseq u en ce h y p oth esis { \in its sim p lest form it a ssu m es

th at th e sp eci city of a p iece of n u cleic a cid is ex p ressedso lely b y th e seq u en ce o f its b ases, a n d th a t th is se-q u en ce is a (sim p le) co d e for th e a m in o a cid seq u en ceof a p a rticu lar p rotein " ; an d th e h y p o th esis reg ard in gth e m ech an ism of p ro tein fold in g th a t C rick p rop osed

earlier in th e sam e lectu re { \ ::: th e m o re likely h y -

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.


GENERAL ⎜ ARTICLE

p o th esis is th at th e folding is sim ply a function of the

order of the am ino acids, p rov id ed it ta kes p lace a s th en 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 israth er an in form ation a l on e. H e follow ed th e tran sfer ofin fo rm a tio n b etw een m acrom olecu les, an d fo r in sta n cen 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 cleicacid s an d p rotein s resp ectively. T h e ela b ora tio n of th eC 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 dex 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 strationb y H ein z F raen kel-C on ra t, sh ow in g th at w h en y ou h avetw 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 eR 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 teinitself. 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 ofan 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 ceof its am in o acid s to an o th er p rotein , a s w ell a s th etota 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 eto sp eci ca lly alter g en o ty p e or for som a to m o d ify th egerm 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 tractfrom th is con fu sed ¯ eld , a lim ited set of ex p erim en tallytestab le h y p oth eses. A s a p h y sicist, h e w a s con v in cedth 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.


GENERAL ⎜ ARTICLE

3 Resonance, Vol.7, No.7, July

2002.

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 dfreq u en tly m o d i ed . O n e of th e ¯ rst to d o th is w a sW 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 ene p u b lish ed in 1 96 5 [5]. In steadof leav in g op en th e d i® eren t p ossib ilities o f in form ationtran sfer, h e ex clu d ed th e tra n sfer o f in fo rm a tio n fromR N A to D N A . O th ers in clu d ed in th e C en tra l D o gm aan 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 ath 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 ofform ation o f p rio n s (th e in fectio u s ag en ts of sp on g iformen cep h a lo p ath ies su ch as th e \ m a d cow " d isea se), th erole o f ch ap ero n es in p rotein fo ld in g, a n d a series of n ewp 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 itw as in itia lly im ag in ed { ep ig en etic m o d i ca tio n s o f D N Aan 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 ichcataly 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 lyin to th e g en o m e o f th eir h ost. B u t it w as m u ch m orefor 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 sh 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 .


GENERAL ⎜ ARTICLE

The discovery of

reverse transcriptase

did not contradict the

Central Dogma as he

had formulated; it

contradicted only the

version popularized by

Watson.

T h e op p ositio n T em in en co u n tered w h en h e p rop o sed , a searly as 19 64, th at th e R N A o f th e R o u s S arcom a V iru sw as cop ied in to D N A an d in tegrated in to th e gen om e,

w as n ot th e co n seq u en ce of a b lin d b elief in th e C en tralD o gm a as m a n y su gg ested . It w a s m ore d u e to th e a b -sen ce of ex p erim en tal ev id en ce in fav ou r of th is h y p o th -esis: th e ex p erim en ts of T em in u sin g d i® eren t in h ib ito rsan d la b els w ere in con clu siv e.

L et u s ad d an oth er p iece to th is co m p lex h istory. C rickh ad not rejected th e p o ssib ility of a con version o f R N Ain to D N A , b u t h e con sid ered th at it w a s p rob ab ly a rarep h en om en on . In con trast, T em in su g gested in h is 1 97 0

p u b lication th a t th is d iscovery m ig h t h av e \ stron g im -p lication s" fo r th eories o f in form ation tran sfer. H e laterd evelo p ed th ese p ersp ectiv es in fu rth er p u b lication s inw h ich h e ex p la in ed h ow actively ex p ressed gen es cou ldb e am p li ed in th e g en om e b y su ch a p ro cess. T h ere-

fore, th ere cou ld b e a retu rn from th e activation stateof th e g en om e to its stru ctu re, a L am a rck ian p ro cess atth e cellu lar level! A lth ou g h th e n u m ero u s sel sh ' D N Aseq u en ces in th e gen om e of eu karyo tes are p rob ab ly th eresu lt of th e actio n o f reverse tran scrip tase, th e h ereti-

cal' p ro p o sition s of T em in h ave n o t b een con ¯ rm ed .

T h e d iscovery of p rotein -on ly p ath o gen ic agen ts h a s a lsob een co n sid ered as a b low to th e C en tral D ogm a . P rio n sare cellu lar p rotein s th at are ab le to ch an g e th eir co n -

form ation to ad o p t a p a th ogen ic, p ro n e-to-a gg reg ationform . T h is co n v ersio n is sp on tan eo u s, or a ctivated b yth e p a th ogen ic form . It ex p lain s th e o ccu rren ce o f b othsp on tan eou s a n d in fectio u s ca ses of th ese d iseases. T h ereis a tran sfer of 3-d im en sio n al in fo rm a tio n fro m th e p ath o -

gen ic form of th e p ro tein to th e n o rm a l on e. B u t if w eretu rn to C rick 's lectu re, th e on ly form o f in form ationh e con sid ered w a s seq u en ce in form ation . T h e h y p o th -esis th at all th e in form ation w ith in a cell origin ates inth e lin ea r seq u en ce of D N A { a p o p u la r version of th e

C en tra l D o gm a { d o es n o t ¯ t th e in itia l w ord in g o f th is

The discovery of

protein-only

pathogenic agents

has also been

considered as a

blow to the Central

Dogma.


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.

d og m a . In a sim ilar w ay to th e p rev io u s ca se, so m e ofth 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 7th at th e con version of th e p rio n in to a p a th og en ic formcou ld b e ex p la in ed b y m o d els fu lly com p atib le w ith th eC 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 elpof h eretical m o d els in vo lv in g th e d irect self-rep licationof 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 tm 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 zzyex ten d ed version o f th e C en tral D og m a w as ch allen gedb 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 gth 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 ofam in o acid s" a n d th at n o sp ecia l m ach in ery of th e cellw as req u ired fo r th is p ro cess. A com p lex m ach in ery w a sd iscov ered , fo rm ed of d i® eren t ch ap ero n es p resen t in th ed 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 tth e resu lt of th e actio n of ch a p eron es. B u t th e h op e ofoverth row in g th e C en tra l D og m a u sin g th e ch a p eron earg 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 caseof th e m o st com p lex ch a p eron es (th e ch a p eron in s), top 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


GENERAL ⎜ ARTICLE

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 otb 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 eencalled th e \ A n ¯ n sen 's cage" to em p h asize th e fact th atth e p ro cess of fold in g w ith in th is cav ity is a sp on tan eo u son 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 aketh e tran sfer of in form ation from D N A to p rotein m orecom p lex an d fu zzy. T h e tra n scrib ed R N A can b e sp licedin 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 Am o d i cation (m eth y latio n ), ch rom atin altera tio n s, a n dth 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 tralD 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 ativesp 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 inb 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 toth e sp licin g an d ed itin g m ach in es to th e R N A s th at arem o d i ed ? Is it tru e th at th e \p recise d eterm in ation ofseq 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 ean 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 ap 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 daltern ativ e sp licin g lea d s to th e p ro d u ction of p rotein s


GENERAL ⎜ ARTICLE

h av in g , in m o st cases, rela ted , a lb eit sligh tly d i® eren t,fu n ctio n s.

W h e re d o e s th e S tre n g th o f th e C e n tra l D o g m a

O rig in a te ?

I h ave sh ow n th a t th e C en tral D o gm a h as su rv iv ed in

sp ite o f th e accu m u lation of m an y n ew o b servation s sin ceits in cep tion . W h ere d o es its stren g th com e fro m ? T h e¯ rst an sw er w ou ld b e to say th at it is p recisely th e resu ltof th is a ccu m u lation of d ata a n d th e ab sen ce o f resu ltsop p osin g it. In p articu lar, n o m a ch in ery th at is a b le to

con vert a p rotein seq u en ce in to a n u cleic acid seq u en ceh as ever b een fo u n d . B u t is th is su ± cien t to reg ard th atth e C en tral D og m a h a s n ow b een p roven ? O n e m u st re-m em b er th a t th e d iscovery o f ch ap ero n es w as an u ttersu rp rise a n d it is im p o ssib le to ex clu d e th e p o ssib ility

th at co m p lex m ech an ism s resp on sib le fo r fu n ctio n s th atare so far u n k n ow n rem a in to b e d iscovered , d esp ite th eseq u en cin g o f several gen o m es.

A n oth er ju sti cation of th e C en tra l D o gm a th at w a s

p o in ted o u t so o n a fter its in cep tion , as d iscu ssed ea r-lier, w a s its close relatio n to th e sep a ration o f th e som aan d th e germ lin e in tro d u ced b y A u gu st W eism a n n atth e en d of th e 1 9th cen tu ry, an d th e asso cia ted p rin cip leth at th e p h en o ty p e ca n n ot sp eci cally m o d ify th e g en o -

ty p e. P rotein s can b e id en ti ed w ith th e p h en oty p e,an d th e gen o ty p e w ith D N A . B u t correla tin g th e va lu eof th e C en tral D og m a w ith a n u n d em o n strated p rin cip leis p rob a b ly n o t a go o d so lu tion . T h e sep a ratio n b etw eenth e som a an d th e g erm lin e d o es n o t ex ist in a ll orga n -

ism s. S o , w h ere d o es th e stren g th of th e C en tra l D ogm a,its \resilien ce", co m e from ? O n e an sw er, w h ich h as n otyet b een fu lly ex p lored , is th at th e C en tral D og m a issim p ly th e resu lt of evo lu tion .

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.


GENERAL ⎜ ARTICLE

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 tionof 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 Aw 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 reasonof 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 tof 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 atth 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 Ain itially o ccu rred in v iru ses [7]. T h is m ig h t h av e b eenth e w ay fo r th ese v iru ses to escap e d efen ce m ech an ism sag ain st foreign R N A ex istin g in cells con tain in g o n lyR 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 ofb acteria . In a p rev io u s liv in g w orld w h ere th e gen eticin fo rm a tio n w as R N A , it is h igh ly p rob a b le th at sim ilarm 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 toselect D N A in stea d of R N A as a g en etic m a terial. T h ead 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


GENERAL ⎜ ARTICLE

step , m ay b e w h en th ese v iru ses con verted R N A cells' inw h ich th ey h a d p en etrated in to D N A cells', i.e., ch an g edth 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 Aw as req u ired to sh ift from a g en etic m a terial m a d e ofR N A to a n ew on e m a d e of D N A . A tra n sfer from D N Ato R N A h ad a lso to b e in ven ted to read th e n ew formof 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 ticrole 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 ortin 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 ofth 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 atw ou ld h ave b een th e selective ad va n ta ge of in v en tin gth e rev erse m ech a n ism , from p ro tein seq u en ces tow a rd sR N A seq u en ces? W h ereas th e p assage fro m p o o r R N Acataly zers to m ore e± cien t p rotein on es m a d e b io log icalsen 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 ecom 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 owth 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. “


GENERAL ⎜ ARTICLE

Suggested Reading

[1] F H C Crick, On Protein Synthesis, Symp. Soc. Exptl. Biol., Vol.12,

pp.138–163, 1958.

[2] H F Judson, The Eighth Day of Creation, The makers of the revolution

in biology, New York: Cold Spring Harbor Laboratory Press, 1996.

[3] D Thieffry and R M Burian, Jean Brachet’s alternative scheme for

protein synthesis, Trends Biochem. Sci., Vol.21, pp.114–117,1996.

[4] 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.

[5] J D Watson, Molecular biology of the gene, New York: W A Benjamin.

[6] S B Prusiner, Novel proteinaceous infectious particles cause scrapie,

Science, Vol.216, pp.136–143, 1982.

[7] P Forterre, The origin of viruses and their possible roles in major

evolutionary transitions, Virus Res., Vol.117, pp.5–16, 2006.

[8] C R Woese, Translation: In retrospect and prospect, RNA, Vol.7,

p.1055–1067, 2001.

Address for Correspondence

Michel Morange

Centre Cavaillès and IHPST,

Ecole normale supérieure,

29 rue d’Ulm, 75230

Paris Cedex 05, France

Email,

[email protected]

C en tra l D og m a : th e on ly w ay to ju stify its ex isten ce is

th rou g h th e d escrip tion o f th e evolu tio n ary h istory th at

sh a p ed th e rela tio n s b etw een D N A , R N A s a n d p rotein s.

A c k n o w le d g e m e n t

T h e a u th or is in d eb ted to D av id M arsh for critica l rea d -

in g o f th e m a n u scrip t.

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