NATURE VOL 227 AUGUST e 1970

Central Dogma of Molecular Biology

by The central dogma of molecular biology deals with the detailed FRANCIS CRICK residue-by-residue transfer of
sequential information. It states NRC Laboratory of Molecular Biology, that such information cannot be transferred
from protein to either
-Hills Road, protein or nucleic acid.
Cambridge CB2 2QH

"Tho centml dogma, enunciated by Crick in 1958 and the analogous to thymine in DNA, thus
considerable over-slmpnnalon." The principal problem could then be stated u the
THIS quotation is taken the beginning of on unsigned fomnulotion of the general rules for information trusfer
giving of molecular bld«y ever since, is likely eo prove a symbols for the
oomponenta of nucleic

article* "Central dogna nverscd", recounting the one polymer with a alphabet very importut work of Dr
Howard Tomin' and others' This could be mpresented by tbe d*sm of s}wwing tkut an RNA tumour virus con use
vinl RNA Fig. 1 (which was drawn st •th8t I a template for DNA synthesis. This ig not the first un not sum that it
n
ever published) in • which, all

time that the idea of the oentnl dogma hu boon mis- possible simple •em mpmented by, undentood, in one way
or another. In thig article I The do not, of course, mpnsent the Row of matter explain why the torrn wu originally
introduced, its true bat the directional flow of detailed, residue.by-N8idue,• meming, and state why I think that,
properly under. sequence inforrnation from one polymer to stood, it is still on idea of fundamental importance.
another.
The central dogma wu put forward' at a period when Now if all transfers commonly occurnd it much of That we
now know in moleoulE genetics not would have been impossible emstruct unfil established. A.ll to work on wom
certain theoriea Nevertholeæ, such our mentary experimental ræulte, themselves often rather di"üziong.
This because it being uncertain md confused, md a boundless optiminn• tbsttuitly umed that certain troufew
could not Occur.

the ' basic oonoepta involved wen rathor Bimple and It oocumd to me that it would be wise to state thes pmbably
much tho game in all living thing. In auch a preconceptions explicitly. situation woll constructed theories can play
a really useful part in stating problems clearly and thug guiding oxperi. ment.
The two central concept' which had boon producod, originally without explicit statement of tkw
simplifico• DNA tion being introduced, wen those of sequential and of defined alphabet'. ' Neither of
thæe steps wu trivial. Because it oleu by time that protein b &ßnod thne dimensional struo. ture, md
that ita activity depended crucially on thig struatun, it neo—ary to put the foldirw•up pmoe•s peptide
on one side, chain and folded postul•t.e itcelf up. that, Thisby and l•rF, the Iyo PROTEIN
the central problem from a throe one to a one dimenNonal one. It also to that in spite of the misoellMeous list
of amino-uids re 2.- u it seemed in 1958.' found in proteins (as then given in biochemical text. •bunt rtpmeat arm.
probable (compee . dotted 1) æpræent arron impoeibJe books) some of them, such u phæphosorine, wen æcond.
patuted by the d •m tbe th.ree poible arm— ry modifications ; and that there wu probably a tmiversal mm protein,
eet of twenty uÆd thmughout In the game way minor modifications to the nucleic acid buz Wred ; A little showed
that the could "be
considemd to be
in RNA

DNA
PROTEIN
Q.)
Flg. 1. The •rmws •bow •Il •eh' poadbie •imple
three familie of polymers. They repræent the directional dov of
detalJed information.
se2
The latter tho transfer postulated by Gamow,
from (double stranded) DNA to protein, though by
that time his particular theory hBd been disproved.
The third class consisted of the threo
transfers thf arrows of which have been omitted
from Fig. 2. Thos were tho transfers :
111 (a)
111 (b) Protein—RNA
111 (c) Protein—DNA
The genenl opinion at the time WB8 that
clb88 1 almost certainly existed, 11 probably rare
or abeent, and that class 111 was unlikely to
occur. The decision to be mode, thenfore, 'whethor
to usume that only clæ I occurmd. There were,
however, no structuml masons why the in clus
should not be impoæible. In fcct, for all we hew,
the replication of all RNA viruses could have gone
by way of a DNA intermediate. On the other hahä,
were sood geneml N•ns 611 the thre
poesible trusfen in claæ In brief, it was most
unlikely, for stemochemical æaeons,
transfer could be done in
the simple vsy thst DNA-*DNA tnnsfer
envisaged. The protein-»RNA (md the •nzlogous
protein—DNA) would havg requind (back)
translation, that is, the tnnsfer from pone alphabet
to 8 structuml]y quite different one. It w88
realized that forwud involved very
complex M0Nover, it seemed unlikely
on general grounds that this muh.i1Er•y could
æsiiywork The only moon. oble the cell had
evolved an entimly sepuat.e Jet of machinery for
translation , and of this there no true, and no Nason
to believe tiwt it m.fÖt be needed.
I decided, themfoæ, to play safe, and to state
the buio usumption of the nev molecular bi010U
the non• eütence of of 01688 m. Beæuse these
were all poæible trenden&from omtein, the
central dogma could be stated in the fom "Gnce
(sequential) infonnation ped into protein it get
divided rouÖly into three pupa. ß*igmp thæe
for which some evidence; dinct or 'indimct, seOd to
exist. mwse •aro by the solid in Fig. 2. They
:
1 (a) DNA—DNA
1 (b) DNA—RNA
1 (c) RNA—Protein
1 (d) RNA—RNA,
The lut of these presumed to occur beOQioe of the
existenæ of RNA +iruoæ.
Next there tm tnnsfen in Fig, 2 u arrows) for which
them was neither any experimeatd evidence any 8tmng
theontical
bet—en 11 RNA—DNA (see the reference to Temin'a woüt)
11 (b) {DNA—Protein
NATURE VOL. 227 AUGUST B 1970
out About clus I decided to remain discreetly
silent.
At this I must make four pointe about the
formu18• tion of the dogma which have
occuionaüy pm. duwd (See, for exee,
Commoners : his error been out by Fleischman'
and on mon Fnemlcountby Hershey'.)
(l) It says nothing about what ± the muhinew
of is of, md in puticular nothing about ermw. (It
that, in general, the of
(2) It nothing about mechanisms—
that is,
about the rate 8t which the pmce—
æ work.
(3) It to only to present-day not to event' in
t1E Emote past, such the oiän of life or the
origin of the code.
ß) It ig not the same, u ig commonly assumed,
88 the wquenw hypothesis, which clearly
distinguished from it in —me In particular the
sequence positive statement, saying that the
transfer nucleic "id•protein did exist, whereu the
dogms b negative statement, saying that
tr•M8fem from protein did not exist.
In looking I am struck not only by the
brashneæ *ich allovd us to ventum pov•erful
statement' of a general nsture, but also by
the rather delicate discrimination used in
selecting what statement. to make. Time bu
shown that not appæciated our
rætmint.
go much for the history of the subject. What
of the pn•ent t I think it is oleu that the old
olaasißoation, thou@ useful at the time, could
be improved, and I that the nine pouible
 transfers bo regrouped tnta€ively into three Protein—DNA
olusæ. I propose that these be Protein—RNA
DNA
Stated in this wsy, it is cleu thBt the transfers those about
which thew is the most uncertüty, It might indeed have
"profound implications for molecule biolog"l if any of these
special transfem could be ahown to be genenl, or—if not in 611
oells-•4t leut to bewidely 'distributed, 80 far, however, there is
RNA ...-1....-........-......-..........> PROTEIN no evidence for the fiNt two of thæe except in a cell infected,
with RNA virus. In such a 0011 the central dogna demands that
Pig. g, tentative cluidcatlon tor the present day. Solid arrows show general uauters; at least one of the ßNt two special •bould ooour— this
dotted show oveclal transfer. Again, the statement, incidentally, shom the power of the central doen» in
•been' arron are undetected transfen •pecißed by the central making theoretinl aoredictions. Nor, u I have indaoated, is there
any good theomtical reason why the troufer RNA—DNA
called general transfors, special transfers and unkiown should not •sometimes be uæd.
transfen. I have nover suggested that it cannot oocur, nor, far
I how, have of my
Although the details of the olU8ifioation pro are plausible,
General and Special Transfers our knowledF of molecular bio og, even in one cell—lot alone
A genenl transfor ig one which can occur in 811 cells.
The obvious cues are for ell the organims_in ntum-— is still far too incomplete to
allov us to a—ert that it is oomot. (Theo is, for emmple, the
DNA—DNA pmbln of the chemical natun of the agent of the disease
DNA—RNA NATURE VOL 227 AUGUST e 1970
RNA—Protein see the articlos by Gibbons and Hunter' and by Griffth 10.
Minor exceptions, such 88 the mammalian Nticulocyte, which Nevertheless, wo know enough to say thBt 8 non-trivial)
probably lacks the first two of these, should not exclude. showing that the clusißcation wrong could be an important
A special trsnsfer is one which does not occur in most cells, but may occur in special discovery. It would certainly be of greot interest to find o cell (68
circumstances. Possible candidates opp«ed to virus) which had RNA its genetic material and no DNA,
or o cell which used single.stronded DNA messenger rather than
RNA—RNA RNA. Perhsps the so-called repetitive DNA is produced by an
RNA—DNA RNA-+DNA transfer. Any of these would be of the
DNA—Prot-ein
intend, but they could be aecon:modated into our thinking without
undue strain. On the other hand,
At the pm—nt time first two of these have only been oertain 363
virus.infected oells. As far as I know thew is no evidence for the
exoept in a special cell. free system neomycin', and it is for this reason that the central dogrna is important
though by a trick it could probably be made to today as when it was first proposed.
Received S, 1970.
happen, using in an intact bacterial cell.
1198 (1970).
' Tania, E. Z, S.. 1211 (1970). con. u.iM tbe to Dr Temln" earlier work
dating back to 1968.
Unknown Transfers D., Ndee, DC, 1209 (1970). See also the brief wooant of
These are the three truÜferg which the central dogma Spleebaa s reeent work on page 1202. r H. C In 8 e. E". Biol.,
postulates never occur:
u.Zib, (1968).
Be, N, 834 (1968).
Protein-+Protein ' mebehman, P., Nü",—, SO (1070).
the discovery of just one type ofpmcont doy cell which ' A. 697 (1970).

could carry out any of the thm unknown trans&rs would ' ' McCarthy, Gibbou, B. m, A.,
and J. G. 1., De, reoe, shake the whole intellectual basis of molecular biology, artmux, J.
S.. ratm,ns, (1967).
sci., 54, 880 (1966). ms,
1041 (1067).