Monday, April 21, 2008

Overthrowing the Central Dogma

I believe that the Central Dogma of Molecular Biology is widely misunderstood [Basic Concepts: The Central Dogma of Molecular Biology]. It is usually interpreted to mean that information must flow exclusively from DNA to RNA to protein. But he original definition by Francis Crick was ...
... once (sequential) information has passed into protein it cannot get out again (F.H.C. Crick, 1958)
Fig. 1. Information flow and the sequence hypothesis. These diagrams of potential information flow were used by Crick (1958) to illustrate all possible transfers of information (left) and those that are permitted (right). The sequence hypothesis refers to the idea that information encoded in the sequence of nucleotides specifies the sequence of amino acids in the protein.
I think we should retain the original definition.

A biology teacher has been discussing this issue with me and he points out that the term "Central Dogma" is defined by consensus. If the vast majority of scientists define it incorrectly, then that becomes the new definition. I agree, but I'm not yet prepared to concede defeat.

My correspondent made an interesting observation. He noted that the Nobel Prize committee has awarded three Nobel Prizes for, in part, overthrowing the Central Dogma of Molecular Biology. This is very interesting. What's the value of continuing to refer the the "Central Dogma" if it has, indeed, been refuted?

Here are the three examples. The first is from a 1975 press release announcing the Nobel Prizes to Howard Temin, David Baltimore, and Renato Dulbecco [The Nobel Prize in Physiology or Medicine 1975].
Howard Temin was since the end of the 1950ies concerned with studies of tumour viruses which contain the alternative type of genetic material, i.e. RNA. He noticed that certain characteristics of tumour cells arising after infection with this type of virus suggested a possible persistence of virus genetic material in them. It was very difficult however to understand how the genetic information of viruses containing RNA could form a part of the hereditary material of the tumour cells. In order to explain this Temin postulated that the genetic information of an RNA virus capable of giving transformation could be copied into DNA, and that this DNA in a manner similar to that described for a DNA tumour virus could become integrated into the genetic material of cells. This proposal by the overall majority of scientists was considered as heresy since it was in conflict with the central dogma accepted in the field of molecular biology in those days. This dogma implied that information transfer in nature occurred only from DNA to RNA and not in the other direction.
Note that Crick's original paper (see above) allowed for information flow from RNA back to DNA so Temin's work did not overthrow the original concept of theoretical information flow. It did conflict with the incorrect version of the Central Dogma that had been promoted by Jim Watson. It was Temin's work, and the subsequent hype about the Central Dogma, that prompted Crick to publish his 1970 paper.

The second example comes from the press release for 1989 Nobel Prizes to Sydney Altman and Thomas Cech in 1989 [Ribonucleic acid (RNA) - a biomolecule of many functions].
The genetic information in the DNA strand is arranged as a long sentence of three-letter words (e.g. CAG ACT GCC), each corresponding to one of the twenty amino acids which build the proteins. This means that there is a flow of genetic information from the DNA to the proteins, which in turn provide the structural framework of living cells and give them their different functions in the organism. However, this flow of genetic information cannot occur unless the DNA code is transcribed to another code in another type of nucleic acid - RNA (ribonucleic acid). This connection between the nucleic acids (the molecules of heredity) and the proteins (the molecules of structure and function) is what has been called the central dogma of the biosciences.
The genetic information in the DNA molecules determines the composition and function of the proteins. Altman and Cech have now modified this by showing that the RNA molecules not only transmit the genetic information but can also function as biocatalyst.
The third example comes from the press release of the 2006 Nobel Prize to Andrew Fire and Craig Mello for thier work on intrefering RNA [The Nobel Prize in Physiology or Medicine 2006]. In this case, the press release does not claim that Fire and Mello overthrew the Central Dogma but it does give an incorrect version of the Central Dogma of Molecular Biology. This is ironic since, according to the Noble Prize committee, the Central Dogma had been called into question in 1975 and 1989.
The genetic code in DNA determines how proteins are built. The instructions contained in the DNA are copied to mRNA and subsequently used to synthesize proteins (Fig 1). This flow of genetic information from DNA via mRNA to protein has been termed the central dogma of molecular biology by the British Nobel Laureate Francis Crick. Proteins are involved in all processes of life, for instance as enzymes digesting our food, receptors receiving signals in the brain, and as antibodies defending us against bacteria.
It is not true that Francis Crick referred to this process of information flow as the Central Dogma.

Is any of this important? Yes, I think it is. I think there is too much sloppiness in science these days. There are too many instances where sloppy thinking is acceptable. On this particular issue you can't have it both ways. Either the Watson definition of the Central Dogma of Molecular Biology was correct, in which case it has been discredited to such an extent that it's no longer useful. Or, the original Crick version is correct, in which case the work of Temin, Altman, Cech, Fire, and Mello have nothing to do with the Central Dogma.

If a scientist is going to write about the Central Dogma of Molecular Biology then they better be damned sure that they understand it. If they are going to quote the original papers (Crick 1958, 1970) then it might be a very good idea to read them.


Crick, F.H.C. (1958) On protein synthesis. Symp. Soc. Exp. Biol. XII:138-163
Crick, F. (1970) Central Dogma of Molecular Biology. Nature 227, 561-563. [PDF file]

16 comments :

  1. Reverse Translatase
    "Reverse Translatase ist ein fiktives Enzym..."

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  2. So, I'm not a biochemist or a molecular biologist, just a physical chemist in a biophysics lab. But it would seem to me that if the Central Dogma has been overthrown for over 25 years now, shouldn't there be a new one? It would be pretty easy to replace Crick's dashed line from RNA to DNA with a solid one. Maybe the Central Dogma still has some sentimental value to people? I'm not sure I understand what the fuss is all about.

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  3. I think that concepts are defined by the consensus, but the consensus is often less smart than the original formulation. Not often enough to make a rule, but it does happen.

    Terminology and loose definitions spread either because they are easier to teach students and so forth, or because the original contrasts have been forgotten.

    I think I'll add this to the Basic Concepts list, if you do not mind.

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  4. Either Alex Hansen hasn't understood your point, or I haven't. Of course the central dogma would have been replaced by something else if it hadn't been overthrown 25 years ago, but it wasn't and so it hasn't.

    Anyway, I was very pleased to see your post. If I had a dollar for every argument I've had with people who claim that reverse transcriptases violates the central dogma (and who claim Crick as their authority)...

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  5. This incorrect understanding of the central dogma is clearly widespread; a textbook featured on this blog very recently, Molecular Biology of the Cell (5th Ed. 2008) also gets it wrong (p.331).

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  6. I seem to remember that Crick wrote that he regretted using the word "dogma". I think he said something along the lines of using it because it was a useful buzzword that expressed the idea that this hypothesis was a more powerful or encompassing explanation than previous explanations. Personally, I wish he had found a better term as I think there is little room in the science lexicon for the word.

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  7. ian b gibson says,

    This incorrect understanding of the central dogma is clearly widespread; a textbook featured on this blog very recently, Molecular Biology of the Cell (5th Ed. 2008) also gets it wrong (p.331).

    Here's a challenge to all Sandwalk readers. See if you can find a single textbook that gets it right!

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  8. Here's a challenge to all Sandwalk readers. See if you can find a single textbook that gets it right!

    Lewin, Genes IX, 2008 pp.10-11. Also, the glossary gives the following definition:

    "central dogma -- Describes the basic nature of genetic information: sequences of nucleic acid can be perpetuated and interconverted by replication, transcription, and reverse transcription, but translation from nucleic acid to protein is unidirectional, because nucleic acid sequences cannot be retrieved from protein sequences."

    Where's my prize?!

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  9. Crick rules! I think "On Protein Synthesis," where Crick introduces the Sequence Hypothesis and the Central Dogma, is one of the deepest, richest scientific papers of the twentieth century. The Central Dogma might one day be overturned; I'd bet on it. But the fact that it's still standing attests to Crick's genius.

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  10. Of four university-level textbooks I have that refer to the Central Dogma, three of them get it wrong. One of the uses the DNA -> RNA -> Protein diagram but correctly explains that the Central Dogma does not exclude information flow from RNA to DNA. (Principles of Biochemisty, 4th ed. Horton et al. pg. 3)

    Wikipedia, on the other hand, appears to get it right, although it doesn't mention anything about how it's usually misunderstood.

    I find this situation somewhat peculiar.

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  11. jason says,

    One of the uses the DNA -> RNA -> Protein diagram but correctly explains that the Central Dogma does not exclude information flow from RNA to DNA. (Principles of Biochemisty, 4th ed. Horton et al. pg. 3)

    Wait a minute. I wrote that. Here's what I say on page 3 ...

    As crick predicted in 1958, the normal flow of information form nucleic acid to protein is not reversible. He referred to this unidirectional information flow as the Central Dogma of molecular biology. The term "Central Dogma" is often misunderstood. Strictly speaking, it does not refer to the overall flow of information shown above. Instead, it refers to the fact that once information in nucleic acids is transferred to proteins it cannot flow backwards from protein to nucleic acids.

    That's pretty clear, no? You can't use my textbook as one of your examples. That's cheating.

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  12. (See above two comments)

    100% crystal clear. On the other hand, perhaps my first comment wasn't. Prof. Moran's textbook is the only correct one. The other three were completely wrong. (either no explanation, or even worse, mentioning that the Central Dogma had been revised by the discovery of reverse transciptase etc.)

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  13. Life: the science of Biology (7th ed) by Purves et al. gets it half right. They quote Crick's words "once 'information' has passed into protein it cannot get out again" (p.236) but on the next page, they say that retroviruses are an exception to the central dogma.

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  14. What's the example of DNA passing sequence information directly to protein, or is this linkage hypothetical? (I tried and apparently failed to ask this question earlier.)

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  15. anonymous asks,

    What's the example of DNA passing sequence information directly to protein, or is this linkage hypothetical? (I tried and apparently failed to ask this question earlier.)

    It's purely hypothetical. It is not forbidden according to the Central Dogma.

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  16. Dr. Moran would like to thank Douglas Allchin, author of the "Sacred Bovines" column in American Biology Teacher, for bringing the Nobel Prize citations to his attention.

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