Dodgy dogma and biology

Dogma is a funny word to appear so prominently in a science like biology. Any picture, any model, any theory currently in vogue is resting on the shifting sands of biological weirdness. I love, for instance, the fact that the Nobel Prize in medicine this year was awarded for major form of genetic regulation that nobody knew existed eight years ago.

A few weeks ago after I posted a link to some lovely molecular biology animations, my good friend Mike Onken made a comment that contained an oblique but cutting reference to the so-called Central Dogma of molecular biology. Since Mike is a certified Level 50 Molecular Biology Warlock at Washington University in St. Louis, I knew there was a good story behind that remark. I hounded him until he gave it up. “Everybody loves the Central Dogma,” I intoned. “It’s so dogmatic, and quasi-religious certainty is very sexy these days. What have you got against it?”

I got the response I was looking for, which I happily share below. Please allow me to present the words of Mike Onken:

The Central Dogma of Biology

by Mike Onken

This is the “Central Dogma of molecular biology”: the flow of information originates from, and is maintained in, DNA; it is carried through RNA; and it is realized in proteins. Wonder at life-giving DNA! Marvel at glorious protein! Acknowledge the ‘Dogma’s erotic masculinity! Question the naming of RNA – I mean, why should wondrous DNA be essentially deoxyRNA; if anything RNA should be hydroxyDNA, pitiable cousin that it is? So goes the Grand Unifying Theory of biology of the 1950’s, which was still hotly debated by Linus Pauling, who preferred:

I wish I could find my old copy of Tom Cech’s “The RNA World”, because it had a great preface by Francis Crick, in which he talked about coining the “Central Dogma of molecular biology” and how he felt at the time that it was an oversimplification and would quickly be revised by new discoveries in RNA research. He was half-right. Within a decade of saying this, tRNA and rRNA had been identified as major actors in translating the newly solved genetic code, and reverse transcription (using RNA as a template to make DNA) had been identified in viruses with genomes composed entirely of RNA. But geneticists have always been a powerful and vocal lobby within the biological sciences, and geneticists really liked the “Central Dogma” – it put genes (DNA) at the center of biology and said, “All biologists know this to be the one truth.” It made them the keepers of the faith. So instead of passing into obscurity, Crick’s statement was touted as the key to understanding life, the universe, and everything. It was biology’s “42”. And to this day, every high school biology textbook (as well as many college texts) states not only the pathway but refers to it as the “Central Dogma” cementing our unity of belief in the minds of the laiety.

The first big problem with the “Central Dogma” is that science is supposed to be empirical; that is, away from the media and the politics, scientists are never sure of anything: we question, we test, we examine, we experiment, we are not supposed to have “unquestioned beliefs authoritatively laid down by a particular school of thought.” The second big problem is its simplicity; the “Central Dogma” is unidirectional, linear, and ordered, and it fans the hopes that life can be seen as crystalline and clear: it cannot. Life is dynamic and interconnected. Biology is not the place for reductionism; it is the realm of systems theory and parallel multiprocessors.

Ahem, back to the story. Through the ‘70s and ‘80s, researchers found more and more things that RNA could do: it could store its own genetic information and was required for DNA replication; it could translate its own genetic code; it could even catalyze simple biochemical reactions. It prompted many in the nucleic acids field to wonder if RNA hadn’t started it all in a pre-cellular “RNA World”. For them, the “Central Dogma” looked more like this:

Around this same time, Stanley Prusiner was being ignored for demonstrating that the Scrapie in sheep, Bovine Spongiform Encephalopathy in cattle, and Creutzfeldt-Jakob Disease in humans were all caused by an infectious protein particle that he called a prion. This was particularly annoying to the geneticists, because DNA had earned its place at the center of biology by acting as an infectious agent in bacteria — if protein could act as an infectious agent, it would set molecular biology back to the dark ages before the “Central Dogma”, and that smug Linus Pauling would have been right all along! In reality, it simply said that proteins could transmit and replicate infectious (heritable) information to other proteins:

At last, the model is beginning to look more like biochemistry and less like teleology. It has equilibria and velocities and rate limiting steps and substrates. It has reproduction and propagation within each pool. And it still has RNA as the intermediate between DNA and protein, sort of the catalyst/substrate complex of the reaction, embodied in the active translation complex of ribosomes, tRNAs, and mRNA. Very satisfying indeed, but still missing something. The model is still very genetic in its content — each loop represents a discovery based on infection with simple particles; each arrow represents the conversion of one simple linear code to another. There are no higher order structures; there is no regulation; there is no way to extend the biochemistry much beyond the simplest bacterium. Our DNA is wrapped up in proteins that determine what genes are used where and when, and those proteins are controlled by elaborate networks of interconnected cascades of signals from all corners of each cell. Many mRNAs never make it to the ribosomes because of regulatory proteins and regulatory RNAs that target unwanted messages for destruction. Many proteins sit in their cellular compartments inactive, waiting for signals that may never come in the life of the cell, while others become too active and routinely have to be destroyed. A good model should have some sense of regulatory networks and epigenetics to be considered central to molecular biology.

So, although it is still missing cofactors, second messengers, membrane components, and the whole of intercellular communication, I propose the new Central Phenomenon of Molecular Biology:

Hmmm… Looks sorta like the biohazard sign…