"Central dogma of molecular biology"

Date:: 1970

Reference:: PP/CRI/I/1/25

Credit: "Central dogma of molecular biology". Source: Wellcome Collection.

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$The latter was the transfer postulated by Gamow,.from (double stranded) DNA to protein, though by that time his particular theory had been disproved. The third class consisted of the three transfers the arrows of which have been omitted from Fig. 2, These were the transfers : III (a) Protein—>-Protein III (&) Protein—»-RNA III ,(c) Protein—»-DNA The general opinion at the time was that class I almost certainly existed, class II was probably rare or absent, and that class III was very unlikely to occur. The decision had to be made, therefore, whether to assume that only class I transfers occurred. There were, however, no overwhelming structural reasons why the transfer in class II should not be impossible. In fact, for all we knew, the replication of all RNA viruses could have gone by way of a DNA intermediate. On the other hand, there were good general reasons against all the three possible transfers in class III. In brief, it was most unlikely, for stereochemical reasons, that protein—s-protein transfer could be done in the simple way that DNA—*-DNA transfer was envisaged. The transfer protein—>RNA (and the analogous protein—s-DNA) would have required (back) translation, that is, the transfer from one alphabet to a structurally quite different one. It was realized that forward translation involved very complex machinery. Moreover, it seemed unlikely on general grounds that this machinery could easily work backwards. The only reason able alternative was that the cell had evolved an entirely separate set of complicated machinery for back translation, and of this there was no trace, and no reason to believe that it might be needed. I decided, therefore, to play safe, and to state as the basic assumption of the new molecular biology the non existence of transfers of class III. Because these were all the possible transfers from protein, the central dogma could be stated in the form once (sequential) information has passed into protein it cannot get out again 4 . About class II, I decided to remain discreetly silent. At this stage I must make four points about the formula tion of the central dogma which have occasionally pro duced misunderstandings. (See, for example, Commoner 5 : his error has been pointed out by Fleischman 6 and on more general grounds by Hershey 7 .) (1) It says nothing about what the machinery of transfer is made of, and in particular nothing about errors. (It was assumed that, in general, the accuracy of transfer was high.) (2) It says nothing about control mechanisms—that is, about the rate at which the processes work. (3) It was intended to apply only to present-day organisms, and not to events in the remote past, such as the origin of life or the origin of the code. (4) It is not the same, as is commonly assumed, as the sequence hypothesis, which was clearly distinguished . from it in the same article 4 . In particular the sequence hypothesis was a positive statement, saying that the (overall) transfer nucleic acid—>protein did exist, whereas the central dogma was a negative statement, saying that transfers from protein did not exist. In looking back I am struck not only by the brashness which allowed us to venture powerful statements of a very general nature, but also by the rather delicate discrimination used in selecting what statements to make. Time has shown that not everybody appreciated our O DNA // \ RNA- ►PROTEIN Fig. 3. A tentative classification for the present day. Solid a general transfers; dotted arrows show special transfers, absent arrows are the undetected transfers specified by dogma. General and Special Transfers A general transfer is one which can occur in all cells. The obvious cases are DNA—s-DNA DNA—»RNA RNA—5-Protein Minor exceptions, such as the mammalian reticulocyte, which probably lacks the first two of these, should not exclude. A special transfer is one which does not occur in most cells, but may occur in special circumstances. Possible So much for the history of the subject. What of the present ? I think it is clear that the old classification, though useful at the time, could be improved, and I suggest that the nine possible transfers be regrouped tentatively into three classes. I propose that these be RNA—>RNA RNA—>DNA DNA—>Protoin At the present time the first two of these have only been shown in certain virus-infected cells. As far as I know there is no evidence for the third except in a special cell- free system containing neomycin 8 , though by a trick it could probably be made to happen, using neomycin, in an intact bacterial cell. Unknown Transfers These a,re the three transfers which the central dogma postulates never occur: Protein—»Protein Protein—»DNA Protein—»RNA Stated in this way it is clear that the special transfers are those about which there is the most uncertainty. It might indeed have profound implications for molecular biology 1 if any of these special transfers could be shown to be general, or—if not in all cells—at least to be widely distributed. So far, however, there is no evidence for the first two of these except in a cell infected with an RNA virus. In such a cell the central dogma demands that at least one of the first two special transfers should occur—- this statement, incidentally, shows the power of the central dogma in making theoretical predictions. Nor, as I have indicated, is there any good theoretical reason why the transfer RNA—»DNA should not sometimes be used. I have never suggested that it cannot occur, nor, as far as I know, have any of my colleagues. Although the details of the classification proposed here are plausible, our knowledge of molecular biology, even in one cell-—let alone for all the organisms in nature is still far too incomplete to allow us to assert dogmatically that it is correct. (There is, for example, the problem of the chemical nature of the agent of the disease scrapie:$

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"Central dogma of molecular biology"

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