GENERAL ⎜ ARTICLE
The Central Dogma of Molecular Biology
A Retrospective after Fifty Years
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.
Keywords
The central dogma, chaperone,
evolution, prion, reverse tran-
scriptase.
236
Michel Morange
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 li-
ca 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 r-
w 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 ci-
p 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 r- 1
See article by S Mahadevan,
ta 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 Resonance, Vol.12, No.9, pp.4–
o n e. Its stru ctu re, esta b lish ed b y C rick a n d W a tso n in 11,September 2007.

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 r-
g 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 : 2
See article by Vidyanand Nan-
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 - jundiah, Resonance, Vol.9,
No.7, pp.44–49, July 2004.
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 237

 GENERAL ⎜ ARTICLE

The transfer of T h e situ a tio n h ow ev er w a s less clea r. C ru cia l m ech a -

information from
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
nucleic acid to nucleic
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
acid or from nucleic
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
acid to protein may be
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
possible, but transfer
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
from protein to protein
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 -
or from protein to
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
nucleic acid is
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
impossible.
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 ser-
va 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 e-
ses (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 se-
q 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 se-
q 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 “...folding is simply a

order of the am in o acids, p rov id ed it ta k es p la ce a s th e function of the order
n ew ly fo rm ed ch a in co m es o ® th e tem p la te" [1 ].
of the amino acids,
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 provided it takes
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 place as the newly
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 formed chain comes
n eg lected th e p o ssib le d irect co n v ersio n o f a D N A to off the template’’.
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 e-
th 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.
What Crick
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
proposed is not a
fro m th is co n fu sed ¯ eld , a lim ited set o f ex p erim en ta lly
chemical concept,
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
but is rather an
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
informational one.
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.

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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

The Central
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
Dogma has been
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 -
repeatedly
lar B iology of the G en e p u b lish ed in 1 9 6 5 [5 ]. In stea d
mentioned and
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
frequently
tra n sfer, h e ex clu d ed th e tra n sfer o f in fo rm a tio n fro m
modified.
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 c-
cu 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 .
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 , si-
m 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 is-
cov ered a n en zy m e n a m ed rev erse tra n scrip ta se, w h ich
3
Resonance, Vol.7, No.7, July 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 .
2002.
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 r-
g 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 .

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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 The discovery of

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 reverse transcriptase
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, did not contradict the
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
Central Dogma as he
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 -
had formulated; it
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 -
contradicted only the
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
version popularized by
a n d la b els w ere in co n clu siv e.
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 ere-
fo 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 ereti-
ca 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 The discovery of
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 - protein-only
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 pathogenic agents
retu rn to C rick 's lectu re, th e o n ly fo rm o f in fo rm a tio n has also been
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 - considered as a
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 blow to the Central
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 Dogma.
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

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The feeling that the 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

discovery of prions
th e d iscov erers o f th e p rio n p h en o m en o n w ere fu lly re-
contradicted the
sp 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
Central Dogma did
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
not disappear when
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
the present model,
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-
fully compatible with
¯ th is in fa ct v ery clo se to th e p resen tly a ccep ted o n e),
Crick’s version of the
S ta n ley P ru sin er in terp reted th e resu lts o f h is ex p eri-
Central Dogma, finally
m 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 i-
emerged. fo 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
The discovery in 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
the mid-1980s of 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
proteins facilitating 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
the folding of other 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
proteins was a 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 er-
complete surprise. m 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

242 RESONANCE ⎜ March 2009

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fo ld in g ; th e m o st sta b le sta te rea ch ed is \ sim p ly a fu n c- Thermodynamics

tio 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 remains the only rule
b rin g steric in fo rm a tio n to th e p ro tein w ith w h ich th ey
that guides protein
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
folding; the most
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
stable state reached
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
is “simply a function
o n e.
of the order of amino
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 , acids”. Chaperones
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 do not bring steric
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 information to the
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 protein with which
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 - they interact
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 ° ict-
in g o n ly if o n e (fa lsely ) co n sid ers th a t reg u la to ry in fo r-
m 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 ere-
fo 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 z-
zlin 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

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 GENERAL ⎜ ARTICLE

The Central
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.
Dogma has
survived in spite of 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
the accumulation O r ig in a te ?
of many new
observations since
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
its inception.
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 re-
m 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 r-
lier, 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 -
The Central
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 ,
Dogma is simply its \ resilien ce" , co m e fro m ? O n e a n sw er, w h ich h a s n o t
the result of 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
evolution. sim p ly th e resu lt o f ev o lu tio n .

244 RESONANCE ⎜ March 2009

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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 - Only two types of

tiv e
macromolecules,
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 RNAs and proteins,
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 existed initially, and
¯ 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 le- DNA was invented
cu 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 re- later to stabilize the
p 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 - genetic information.
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 r-
m 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 ce-
m 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 e-
sized 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 er-
fo rm 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 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 r-
m 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 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 le-
cu 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 is-
ten 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.
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
The raison d’être of co n v ersio n ?
the Central Dogma
C o n c lu sio n
originates in the
complex 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
evolutionary history 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 e-
of macromolecules. h ow , it is a \ fro zen a ccid en t" o f th is ev o lu tio n a ry h isto ry.
“The failure to 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
embrace evolution is 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 le-
the Achilles’ heel of cu la r b io lo g y " [8 ]. In th is a rticle, I h av e tried to sh ow
molecular biology. “ 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

246 RESONANCE ⎜ March 2009

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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] 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
Address for Correspondence
and the central dogma of molecular biology, Hist. Phil. Life Sci., Vol.28,
Michel Morange
pp.491–512, 2006.
Centre Cavaillès and IHPST,
[5] J D Watson, Molecular biology of the gene, New York: W A Benjamin.
Ecole normale supérieure,
[6] S B Prusiner, Novel proteinaceous infectious particles cause scrapie,
29 rue d’Ulm, 75230
Science, Vol.216, pp.136–143, 1982.
Paris Cedex 05, France
[7] P Forterre, The origin of viruses and their possible roles in major
Email,
evolutionary transitions, Virus Res., Vol.117, pp.5–16, 2006.
morange@biologie.ens.fr
[8] C R Woese, Translation: In retrospect and prospect, RNA, Vol.7,
p.1055–1067, 2001.

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