Picture This: The Central Dogma
When Francis Crick and James Watson were sure they had adduced the correct molecular structure of the DNA molecule in 1953, Crick barrelled into the Eagle, their favorite pub in Cambridge, “to tell everyone within hearing distance that we had found the secret of life.” Or so Watson recounts in The Double Helix—his 1968 account of their remarkable discovery.
Watson has now admitted he made the story up. It’s just one among the many distortions and fabrications in the book, but you can perhaps understand his reasons. That elegant double helix didn’t just describe the shape of the molecule believed to be the gene carrier in our cells. It also suggested how genes—the hitherto mysterious entities responsible for inherited traits—actually work. DNA, Watson and Crick deduced, is like a string of letters: the twin strands are chains of interlinked molecules that each contain one of four so-called nucleotide bases: A, T, C and G. Genes were then distinct segments of these chains with particular base sequences.
Watson and Crick described the implications of DNA’s structure in a May 1953 paper in Nature. It “seems likely,” they wrote, “that the precise sequence of the bases is the code which carries the genetic information.” Here was the key to the modern theory of genetics: it was all about information encoded in molecules, an idea that melded perfectly with the emerging technology of digital computers, which was all about information encoded in data strands of magnetic tape.
In a 1957 lecture in London, Crick spelled out “the main function of the genetic material,” which, he said, “is to control . . . the synthesis of proteins.” Proteins—folded-up chains of amino acids—were, in the form of enzymes, already known to facilitate particular biochemical processes. Somehow, the base sequence on DNA was “decoded” and converted into the amino-acid sequence of a protein. Neither Crick nor anyone else understood the details yet, but the process was known to involve the intermediary molecule RNA, which was also a string of nucleotide bases. In his lecture, which became the basis of an article in Scientific American the same year, Crick presented this picture in terms of the information flow between the molecules.
He had sketched the concept the previous year in a note titled “Ideas on protein synthesis,” where he declared, “Once information has got into a protein it can’t get out again.” In other words, information was passed from DNA to RNA (a process called transcription) and then to protein (translation). It might flow back from RNA to DNA, Crick said, but it could not go back from protein to the nucleic acids.
He gave the scheme a striking name: the Central Dogma. It was a curious choice, given that science is meant to be always open to correction rather than dogmatically stuck to any preconceived idea. Crick later explained that he simply didn’t know, until Nobel laureate biologist Jacques Monod pointed it out to him, what “dogma” meant:
I used the word in the way I myself thought about it, not as most of the rest of the world does, and simply applied it to a grand hypothesis that, however plausible, had little direct experimental support.
That was Crick for you: an error became simply his personal choice. “I have never seen Francis Crick in a modest mood,” was how Watson began The Double Helix, to his professional partner’s irritation. But it was perhaps an unfortunate confusion, because there is nothing like calling an idea a “dogma” to motivate some to defend it trenchantly, and others to challenge it.
The status of Crick’s Central Dogma today, now that we have learnt so much more about how genetics and molecular biology work, still excites passionate debate. Some think that the Dogma is obsolete; others assert that it remains intact, despite originally being a guess way beyond what the knowledge then available could support. One might even be tempted to suppose from the intensity of the arguments that the integrity of modern biology rests upon it.
But it really doesn’t. The Central Dogma, however poorly named, states something that is important and true. If one can adduce possible exceptions to it, that’s not such a big deal in itself, for there are very few statements one can make about biology for which exceptions can’t be found: the living world is a messy place with little respect for general rules. What perhaps matters more is what these arguments represent. The Central Dogma itself encodes a hidden message about how life works—and it is this implicit message that needs updating. For not only is the Central Dogma not a dogma, but it is not really very central.
It doesn’t help matters that the Dogma was garbled by Watson in his influential 1965 textbook, Molecular Biology of the Gene. Presaging the sloppy relationship to rigor that he displayed in The Double Helix, he presented it as a simple linear sequence: DNA → RNA → protein. This is unambiguously wrong—not just because it ignores the ability of DNA to copy itself but also because it was found in 1970 that viruses that encode their genomes in RNA use an enzyme called reverse transcriptase to write their genes into the DNA of the host cell: the kind of possibility Crick had tentatively but sagely included in 1956.
Responding to the discovery of reverse transcriptase (which prompted Nature to call the Central Dogma “a considerable over-simplification”), Crick clarified his views in 1970. He now presented the Dogma in its more iconic form as a triangular series of information transfers. He explained that the only way information could flow back from proteins to nucleic acids was if “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.” The discovery of one of these forbidden information transfers, he said, “would shake the whole intellectual basis of molecular biology.” All the same, he was sensibly cautious about what surprises biological research might yet have in store, saying of the Dogma that “our knowledge of molecular biology . . . is still far too incomplete to allow us to assert dogmatically [!] that it is correct.”
Crick’s Central Dogma articulates the central principles of protein synthesis and of enzyme function. The reason your body contains the same enzymes as your parents’ did is that the instruction for making them was passed along in the parental genes to the sperm and egg cells that combined at the start of your being. These enzymes all do the same things because they have the same shapes—and those shapes are themselves specified by the amino-acid sequences.
However, the simple formula that informed the Central Dogma—the notion that a gene encodes a particular protein and that protein plays some well-defined role in building and maintaining the organism—is now known to be inadequate. For one thing, genes often encode more than one protein. On average, each human gene encodes around six, and our 20,000 or so protein-coding genes can give rise to around 80,000-400,000 proteins. This is because the base sequence of the RNA that encodes a protein is typically reshuffled before it is translated. Which variant of a protein is produced in a given instance depends on many things, such as the type of cell in which the gene is transcribed—the result might be different, say, in a heart cell to a kidney cell. What’s more, proteins interact with one another in complex networks, and for some proteins—especially ones that feature as key connecting hubs of the networks—it is impossible to associate the molecule with any specific trait or feature of the organism. And RNA molecules do much more than just encode proteins. For example, some of them instead regulate which genes get transcribed, helping to turn that process on or off, or influence the reshuffling that determines how RNAs are translated to proteins. The organism is not, then, a transparent and linear “readout” of the genome sequence.
Does any of this threaten the Central Dogma itself? Not obviously—for Crick wisely left space for RNA to have more roles, and the reshuffling of protein sequences doesn’t alter the fact that the information ultimately encoded in a given protein cannot make its way back into an RNA or DNA sequence. One component of the Central Dogma that has been challenged is the assertion that proteins can’t inform other proteins. In particular, proteins called prions can misfold into aberrant forms that stick together in tangles and cause disease—they can trigger the death of neurons, leading to neurodegenerative conditions such as bovine spongiform encephalopathy (BSE) in cattle, scrapie in sheep, or the human equivalent, Creutzfeldt-Jakob disease (CJD). Crucially, a misfolded prion can induce another to misfold too, making the disease transmissible. (Some people have contracted CJD by eating beef afflicted with BSE.) This is arguably a kind of information transfer from protein to protein. But it doesn’t happen in the way Crick specified in the Central Dogma, by a letter-by-letter transfer of sequence information. All the same, Crick presciently alluded to scrapie in his 1970 paper as a possible fly in the ointment.
There is no reason to suppose that the Dogma is inviolable in principle. It’s possible to imagine designing enzymes that can selectively edit another protein’s sequence. Though nothing like this is known to happen in nature, it could probably be done synthetically in the lab. Even so, it would merely be an exception that proves the rule.
Rather than seeking doggedly to disprove the Central Dogma, it’s probably more helpful to put it in its rightful place. The Central Dogma seems to impute a hierarchy of importance that gives primacy to the gene. Perhaps that is the subtext to Watson’s misconceived one-way information flow: it makes the gene the origin of all biological information. This is surely the wrong way to see things. A DNA sequence has no intrinsic meaning—it only becomes informative in the context of a living cell. It’s not just that the cell is needed to enable a gene to be “read”; the very notion that there is anything to be read and decoded is only meaningful when genes and their products are part of the information economy of living organisms. Further, many developmental biologists now believe that theories of how organisms evolve must take better account of how they grow.
Even then, genes don’t (contrary to common belief) control the cell. To some extent, it’s the other way round: genes are regulated in response to the overall state of the cell, which in turn depends on its surroundings: on signals received from the outside, perhaps from other cells or from the environment. And even when a gene is activated, what actually gets made from it (and what role the product performs) is also often determined by top-down control of RNA reshuffling. Sure, this top-down information flow doesn’t alter a genetic sequence, but it may control what effect a gene has on, say, metabolism or development. Some microbiologists even argue that cells in effect have some say in their DNA sequences. Whether or not that’s so, biological information flow is not purely bottom-up, but omnidirectional.
Increasingly, genes look ever less like the elements of a blueprint for life, and more like source material that a cell consults for growth and metabolism. Crick’s Central Dogma summarized, well before the data were in, the story of how cells mobilize those resources. Keep it in perspective and it remains a startling intuition. ♦
Subscribe to Broadcast