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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.
238 RESONANCE ⎜ March 2009
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.
239RESONANCE ⎜ March 2009
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.
240 RESONANCE ⎜ March 2009
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 .
241RESONANCE ⎜ March 2009
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.
242 RESONANCE ⎜ March 2009
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
243RESONANCE ⎜ March 2009
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
244 RESONANCE ⎜ March 2009
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.
245RESONANCE ⎜ March 2009
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
246 RESONANCE ⎜ March 2009
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. “
247RESONANCE ⎜ March 2009
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,
morange@biologie.ens.fr
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.