By Matthew Cobb
One of the closest things to a purely biological law is a hypothesis Francis Crick outlined in 1957, which he called ‘the central dogma’ of genetics. This refers to potential transfer of genetic information in our cells, and states, among other things, that
. . . once information (meaning here the determination of a sequence of units) has been passed into a protein molecule it cannot get out again, either to form a copy of the molecule or to affect the blueprint of a nucleic acid.
In its full form, Crick’s hypothesis was that information can get out of DNA into RNA to determine the structure of a protein, but proteins cannot specify the sequence of new proteins, and the information in proteins cannot make the reverse journey back into your genes – your DNA cannot be rewritten by a protein. (This idea – often called ‘epigenetics’ – has been dealt with many times here.)
The central dogma has been the focus of repeated criticism over the past sixty years, partly because of the discovery of new facts, and partly because the unfortunate term ‘dogma’ tends to be a lightning rod for debate (Crick later said ‘the use of the word dogma caused almost more trouble than it was worth’ – he coined the term without realising its full implications).
In a paper that appeared in this week’s issue of Science, researchers from a variety of US laboratories, led by Jonathan Weissman and Adam Frost of UCSF and Onn Brandman from Stanford, have chipped away at one part of the central dogma, which states that a protein cannot determine the amino acid sequence of another protein. They have discovered that in very unusual circumstances, a protein can indeed determine the sequence of amino acids, by adding two particular amino acids, Alanine and Threonine to one end (the ‘C’ terminal) of a protein that is being synthesised, but which for some reason has ‘stalled’.
These happily-named CAT tails (you can work out why they are called this from the previous sentence) may mark defective proteins (they are only partially complete, because biosynthesis has stalled) so they can be disposed, or they may enable cells to identify the cellular structures – ribosomes – that have caused the stalling, and which may themselves be defective. So they form part of the cell’s housekeeping functions, and are not part of most examples of protein synthesis.
The exact detail of the paper is pretty heavy biochemistry – I don’t claim to understand it all – so I’ll focus on the most striking issue, which the authors surprisingly don’t mention at all.
This research shows that, strictly speaking, Crick was wrong. In these extremely unusual conditions (they emphasise this repeatedly in the paper), a set of molecules called the ribosome quality control complex (RQC), intervene to add the CAT tails. This involves a protein called Rqc2p recruiting transfer RNA (tRNA) molecules that gather Alanine and Threonine respectively. Up until now, it was thought that only messenger RNA could recruit tRNA molecules to add ‘information’ to a protein, that is, adding amino acids (this is happening right now in every cell of your body).
On the one hand this discovery is fascinating, and it adds to our knowledge. On the other, it does not shake the foundations of biology, which is presumably why the authors did not cite Crick’s 1957 lecture or even mention the central dogma (maybe they tried to put their finding into the bigger picture and the reviewers complained – sadly Science is closed in more than one respect – unlike some open access journals like eLife, it does not publish the reviewers’ comments; we can discuss the advantages of this another time).
That having been said, normally the practice is to sex-up and exaggerate the significance of results, so we should be grateful to the authors for not trumpeting ‘central dogma reversed’ or some such. The truth, as always, is more interesting than hype.
In 1970, following the discovery of reverse transcriptase, an enzyme that enables RNA viruses to copy themselves into DNA (so carrying out the allegedly impossible information transfer RNA→ DNA), Crick felt obliged to explain exactly what he had originally meant by the central dogma. As he had made clear in 1957, this was not actually a dogma – something that could not be questioned – it was a hypothesis based on current knowledge. Crick had in fact said that the pathway RNA→ DNA was possible, but he had no evidence for it and could see no biological function for it.
In his 1970 clarification, Crick highlighted three information transfers that he postulated would never occur: protein → protein, protein → DNA and protein → RNA. However, even as he made such a clear prediction, Crick was cautious, underlining our ignorance and the fragility of the evidence upon which he based his slightly revised ‘dogma’:
our knowledge of molecular biology, even in one cell – let alone for all organisms in nature – is still far too incomplete to allow us to assert dogmatically that it is correct.
And he went on to highlight one potential exception, the disease “scrapie”, which we now know involves pathological prion proteins altering the shape of normal prion proteins, with devastating results (this is also the basis of ‘mad cow disease’ and its human equivalent, variant Creuzfeld-Jacob Disease).
In both the benign and the pathogenic forms of the prion, the amino acid sequence remains the same, so there is no transfer of information as defined by the central dogma. Although three-dimensional conformation is a form of information – indeed, Crick accepted as much – the change induced by the prion protein is probably more similar to the action of a crystal growing by assembling identical copies of itself. There are similar effects whereby chaperone proteins allow proteins to correctly fold themselves in our cells, thereby facilitating the expression of the sequence information into three dimensions.
The new results on the behaviour of Rqc2p allow no such wiggle-room, however. These findings show that under very particular circumstances, a protein can change the amino acid sequence of another protein by adding information, something that Crick was confident could not happen.
However, in the grand scheme of things, this doesn’t really matter as it is clear that this is an extremely unusual case. The vast majority of protein synthesis events involve the classic information flow DNA → RNA → protein. Despite this striking and odd example, the central dogma remains intact as a description of how our cells function. This is just one more of those pesky things that biology revels in, but which physics abhors – an exception.
This relaxed attitude, which I share with the vast majority of biologists, underlines a difference between general statements or hypotheses in biology and axioms or laws in mathematics or physics. Exceptions to the central dogma – even a solid example of information flowing directly from protein → DNA, which has still not been found – would only radically revise how genetics and evolution work if they took place systematically and on a wide scale.
The example of CAT tails encoded by proteins does not challenge our key understanding. It is fascinating, and it may open the road to new biotechnological tools. But virtually all of our existing results and experimental protocols emerge unscathed, because they function perfectly well in the absence of this additional mode of information transfer.
The reason that scientists accept the central dogma is not because it is a dogma but because the evidence supports it. When new evidence arises, then, as the French phrase puts it: Il n’y a que les imbéciles qui ne changent pas d’avis – only fools do not change their mind.
You can read more about the central dogma, its place in our understanding of how biology works, and recent challenges to it, in my forthcoming book Life’s Greatest Secret: The Race to Crack the Genetic Code, to be published this summer by Profile (UK) and Basic Books (USA).
Reference ($$$): Shen PS, Park J, Qin Y, Li X, Parsawar K, Larson MH, Cox J, Cheng Y, Lambowitz AM, Weissman JS, Brandman O, Frost A. (2015) Protein synthesis. Rqc2p and 60S ribosomal subunits mediate mRNA-independent elongation of nascent chains. Science 347:75-8.