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,
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
thus 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• tbst tuitly 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 Iy o 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
in RNA considemd to be divided rouÖly into three pupa. ß*igmp

DN
A
PROTEI
N them was neither any experimeatd evidence any
Q.)
Flg. 1. The •rmws •bow •Il •eh' poadbie •imple bet—en
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
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
8tmng theontical
11 RNA—DNA (see the reference to Temin'a woüt)
11 (b) {DNA—Protein
NATURE VOL. 227 AUGUST B 1970
dogma could be stated in the fom "Gnce
(sequential) infonnation ped into protein it
get 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 Protein—RNA
regrouped tnta€ively into three olusæ. I
propose that these be Stated in this wsy, it is cleu thBt the transfers those
about which thew is the most uncertüty, It might indeed
DNA 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 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 at least one of the ßNt two
RNA ...-1....-........-......-..........> PROTEIN
special •bould ooour— this statement,
incidentally, shom the power of the central doen» in
Pig. g, tentative cluidcatlon tor the present day. Solid arrows show general
uauters; dotted show oveclal transfer. Again, the making theoretinl aoredictions. Nor, u I have indaoated, is
•been' arron are undetected transfen •pecißed by the central there any good theomtical reason why the troufer RNA—
DNA should not •sometimes be uæd.
I have nover suggested that it cannot oocur, nor, far
called general transfors, special transfers and unkiown
transfen. I how, have of my
Although the details of the olU8ifioation pro are
plausible, our knowledF of molecular bio og, even in one
General and Special Transfers cell—lot alone for ell the organims_in ntum-— is still far
A genenl transfor ig one which can occur in 811 cells.
too incomplete to allov us to a—ert that it is oomot.
The obvious cues are
(Theo is, for emmple, the pmbln of the chemical natun of
DNA—DNA the agent of the disease
DNA—RNA
RNA—Protein NATURE VOL 227 AUGUST e 1970
Minor exceptions, such 88 the mammalian Nticulocyte, see the articlos by Gibbons and Hunter' and by Griffth 10.
which probably lacks the first two of these, should not Nevertheless, wo know enough to say thBt 8 non-trivial)
exclude. showing that the clusißcation wrong could be an
A special trsnsfer is one which does not occur in most cells, but may occur in important discovery. It would certainly be of greot interest to
special circumstances. Possible candidates find o cell (68 opp«ed to virus) which had RNA its genetic
material and no DNA, or o cell which used single.stronded
RNA—RNA DNA messenger rather than RNA. Perhsps the so-called
RNA—DNA repetitive DNA is produced by an RNA-+DNA transfer. Any
DNA—Prot-ein of these would be of the intend, but they could be
At the pm—nt time first two of these have only been aecon:modated into our thinking without undue strain. On
oertain virus.infected oells. As far as I know thew is no the other hand,
evidence for the exoept in a special cell. free system 363
neomycin', though by a trick it and it is for this reason that the central dogrna is
could probably be made to happen, using important today as when it was first proposed.
in an intact bacterial cell. Received S, 1970.
1198 (1970).
' Tania, E. Z, S.. 1211 (1970). con. u.iM tbe to Dr Temln" earlier
Unknown Transfers work dating back to 1968.
These are the three truÜferg which the central dogma D., Ndee, DC, 1209 (1970). See also the brief
wooant of Spleebaa s reeent work on page 1202. r H. C In 8
postulates never occur: e. E". Biol.,

Protein-+Protein u.Zib, (1968).

Protein—DNA Be, N, 834 (1968).
' 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).