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Friday, September 14, 2012

Does the Central Dogma Still Stand?

Lots of people don't understand the Central Dogma of Molecular Biology and that's probably why there are so many articles announcing its death. The article and book by James Shapiro is just one example [Revisiting the Central Dogma in the 21st Century].

The correct version of the Central Dogma of Molecular Biology is .... [see Basic Concepts: The Central Dogma of Molecular Biology]
... once (sequential) information has passed into protein it cannot get out again (F.H.C. Crick, 1958)

The central dogma of molecular biology deals with the detailed residue-by-residue transfer of sequential information. It states that such information cannot be transferred from protein to either protein or nucleic acid. (F.H.C. Crick, 1970)
Eugene Koonin has an article in Biology Direct entitled Does the central dogma still stand (Koonin, 2012).

Koonin is a smart scientist, he pretty much knows what the Central Dogma actually says. Here's part of the introduction to his paper.
There are very few firm principles in biology. It is often said, in one form or another, that the only actual rule is that there are no rules, i.e. exceptions can be found to every "fundamental‟ principle if one looks hard enough. The principle known as the Central Dogma of molecular biology seems to be an exception to this "ubiquitous exception‟ rule. The Central Dogma was conjured by Francis Crick in response to the discovery of reverse transcription, when it became clear that the RNA to DNA information transfer was an integral part of the life cycle of retro-transcribing genetic elements (subsequent developments demonstrated the broad occurrence of reverse transcription in cells). Crick realized that, all its biologically fundamental implications notwithstanding, reverse transcription was essentially business as usual, i.e. interconversion of different forms of nucleic acids on the basis of universal rules of base complementarity. The central dogma places the actual „exclusion principle‟ at another stage of biological information transfer, translation. Thus, "There is no information transfer from protein to nucleic acid‟, postulates the Central Dogma.
Koonin goes on to argue that prions violate the Central Dogma. Prions are an example of proteins that can have multiple conformations and the transition from one conformation to another is often cooperative. Thus, if one protein changes conformation, it can trigger changes in hundreds of others.

Some prion-like proteins affect translation or transcription or even chromatin conformation. In some cases the transformation in conformation is triggered by stress so that under some specific conditions the prion-like protein senses the trigger and modifies nucleic acid. According to Koonin ...
Thus, the Central Dogma of molecular biology is invalid as an "absolute‟ principle: transfer of information from proteins (and specifically from protein sequences) to the genome does exist. This is not to deny that the Central Dogma does capture the principal route of information transfer in biology: the main flow information does follow the path in Figure 1, and elaborate mechanisms ensuring acceptable fidelity operate on each step. And, there is a major discontinuity between the levels of RNA and protein because during translation because the coupling of amino acids with the cognate tRNAs does not involve direct recognition but rather requires dedicated enzymes, aminoacyl-tRNA synthetases, that recognize and connect the partners. The opposite direction of information flow, from proteins to the genome, is asymmetrical (not a simple reversion), much more modest quantitatively and intrinsically stochastic but nevertheless appears to be important in evolution.
This is largely a question of how you define information flow. In Crick's original version of the Central Dogma he was quite obviously talking about the flow of genetic information as specified in the sequence of bases in DNA (sequential information). In that sense the Central Dogma would only be refuted by demonstrating reverse translation.

Proteins that modify DNA or RNA have been known for 35 years. I don't think they count as violations of the Central Dogma even if their activity is influenced by the environment. However, if people like Eugene Koonin are so bothered by the Central Dogma that they want to quibble over issues like this then maybe we should stop talking about it altogether. The Central Dogma may have outlived its usefulness. (At least one textbook—Berg, Tymoczko, and Stryer—has dropped it.)

Koonin, E. (2012) Does the central dogma still stand? Biology Direct 1:27 [doi: 10.1186/1745-6150-7-27] [Biology Direct Abstract]


Claudiu Bandea said...

Larry Moran: if people like Eugene Koonin are so bothered by the Central Dogma that they want to quibble over issues like this then maybe we should stop talking about it altogether

Don’t give up Larry, there is still hope!

Let me start by saying that your Basic Concepts: The Central Dogma of Molecular Biology, as well as Crick’s papers, should be mandatory reading for anyone writing about Central Dogma, including reputable scholars like Koonin.

As pointed out in your Basic Concepts article, the only confusion about Central Dogma was that introduced by James Watson, who proposed his own version, which was repudiated shortly after its introduction; but, in any case, that is not the problem with Koonin’s perspective as he specifically refers to Crick’s central Dogma.

Crick made it clear what Central Dogma is starting with his 1958 article, an article that, surprisingly, Koonin doesn’t use as a reference:

In more detail, 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. Information means here the precise determination of sequence, either of bases in the nucleic acid or of amino acid residues in the protein (emphasis mine)

In light of this definition of the Central Dogma, I don’t understand Koonin’s statements:

the Central Dogma of molecular biology is invalid as an "absolute‟ principle: transfer of information from proteins (and specifically from protein sequences) to the genome does exist, and that:

The prion-mediated heredity that violates the Central Dogma appears to be a specific, most radical manifestation of the widespread assimilation of protein (epigenetic) variation into genetic variation

Do you?

roger shrubber said...

If a prion effecting conversion of another protein to the infections prion fold violates the central dogma, so does a protease cleaving a protein. Nobody argues that proteases chopping up other proteins violates the central dogma. Neither does DNA methylation violate the central dogma or hundreds of other molecular tricks for persisting information for a few generations.

The only good news in these stories is the affirmation that scientists are still trying to upset the apple cart, testing and questioning everything. Science needs that sort of mutagenesis to more forward. We also need to ruthlessly apply selection and eliminate defective ideas. Cheers to THE REAPER.

Anonymous said...

I agree; prions dont count as a violation. The only thing I can think of that might come close is RNA editing. But why does anyone really care about the Central Dogma? Its not some fundamental law such as E=MC2. Its just some bit of history to throw into freshman bio.


Mikkel Rumraket Rasmussen said...

The way I was taught the central dogma was kind of like this: Because of code redundancy (multiple possible codons for the same amino acid) you can never know, from protein sequence alone, what the code it was translated from was). And therefore, you could never get an enzyme that would be able to reverse-translate protein into the original nucleic acid code.

Or perhaps more correct, that's how I understood it's central message.

Tim Tyler said...

Crick explicitly stated that precise determination of sequence of amino acid residues in the resulting protein would be enough to qualify (see the bold quote in an earlier comment). Prions don't violate the central dogma - contrary to what Koonin argues. Genetic engineering can do so though. Engineers can reverse engineer genes from proteins these days.