Cobb on Crick: The “Central Dogma”

December 2, 2024 • 9:45 am

As I’ve mentioned several times, Matthew Cobb has written what will likely prove the definitive biography of Francis Crick (1916-2004), co-discoverer of the structure of DNA and a general polymath. While writing it, Matthew came across some Crick material showing that biologists and historians have misunderstood Crick’s “Central Dogma” of molecular biology.

Matthew has corrected the record in the piece below from the Asimov Press. Click the headline, as it’s free to read:

You may have learned this dogma as “DNA makes RNA makes protein,” along with the caveat that it’s a one-way path. But Matthew shows that this was not Crick’s contention. I’ve indented Mathew’s words below:

The Central Dogma is a linchpin for understanding how cells work, and yet it is one of the most widely misunderstood concepts in molecular biology.

Many students are taught that the Central Dogma is simply “DNA → RNA → protein.” This version was first put forward in Jim Watson’s pioneering 1965 textbook, The Molecular Biology of the Gene, as a way of summarizing how protein synthesis takes place. However, Watson’s explanation, which he adapted from his colleague, Francis Crick, is profoundly misleading.

In 1956, Crick was working on a lecture that would bring together what was then known about the “flow of information” between DNA, RNA, and protein in cells. Crick formalized his ideas in what he called the Central Dogma, and his original conception of information flow within cells was both richer and more complex than Watson’s reductive and erroneous presentation.

Crick was aware of at least four kinds of information transfers, all of which had been observed in biochemical studies by researchers at that time. These were: DNA → DNA (DNA replication), DNA → RNA (called transcription), RNA → protein (called translation) and RNA → RNA (a mechanism by which some viruses copy themselves). To summarize his thinking, Crick sketched out these information flows in a little figure that was never published.

Crick’s figure is below. Note that the dogma is simply the first sentence typed in the diagram, implying that information from either DNA or RNA, translated into a protein, cannot get back into the DNA or RNA code again. Thus changes in protein structure cannot go back and change the genetic code (see the bottom part of the diagram).

As you see, the DNA—>RNA—>protein “dogma” is an extreme oversimplification of Crick’s views. And he meant the word “dogma” to mean not an inviolable rule of nature, but a hypothesis. Nevertheless, Crick was widely criticized for using the word “dogma”.

But getting back to the diagram:

The direct synthesis of proteins using only DNA might be possible, Crick thought, because the sequence of bases in DNA ultimately determines the order of amino acids in a protein chain. If this were true, however, it would mean that RNA was not always involved in protein synthesis, even though every study at that time suggested it was. Crick therefore concluded that this kind of information flow was highly unlikely, though not impossible.

Crick also theorized that RNA → DNA was chemically possible, simply because it was the reverse of transcription and both types of molecules were chemically similar to each other. Still, Crick could not imagine any biological function for this so-called “reverse transcription,” so he portrayed this information flow as a dotted line in his diagram.

We now know, though that the enzyme “reverse transcriptase” is used by some RNA viruses to make DNA to insert into their hosts’ genomes.

Here’s what Crick said he meant by the “Central Dogma,” and, in fact, this schema has not yet been violated in nature:

In other words, in Crick’s schema, information within the cell only flows from nucleic acids to proteins, and never the other way around. Crick’s “Central Dogma” could therefore be described in a single line: “Once information has got into a protein it can’t get out again.” This negative statement — that some transfers of information seem to be impossible — was the essential part of Crick’s idea.

Crick’s hypothesis also carried an unstated evolutionary implication; namely, that whatever might happen to an organism’s proteins during its lifetime, those changes cannot alter its DNA sequence. In other words, organisms cannot use proteins to transmit characteristics they have acquired during their lifetime to their offspring.

In other words, there can be no Lamarckian inheritance, in which environmental change affecting an organism’s proteins cannot become ingrained into the organism’s genome and thus become permanently heritable.

Matthew discusses several suggested modifications of Crick’s version of the Central Dogma. Prions, misfolded proteins that cause several known diseases, were thought by some to have replicated themselves by somehow changing the DNA that codes for them, but it’s now known that prions are either produced by mutations in the DNA, or can transmit their pathological shape by directly interacting with other proteins. Prion proteins do not change the DNA sequence.

Some readers here might also be thinking that “epigenetic inheritance”, in which DNA is modified by chemical tags affixed to its bases, might refute the central dogma, as those modifications are mediated by enzymes, which of course are proteins. But as Matthew notes, those modifications are temporary, while the DNA sequence of nucleotides (sans modifications) is forever:

In other cases, researchers have pointed to epigenetics as a possible exception to Crick’s Central Dogma, arguing that changes in gene expression are transmitted across the generations and thus provide an additional, non-nucleic source of information. But still, epigenetics does not violate Crick’s Central Dogma.

During an organism’s life, environmental conditions cause certain genes to get switched on or off. This often occurs through a process known as methylation, in which the cell adds a methyl group to a cytosine base in a DNA sequence. As a result, the cell no longer transcribes the gene.

These effects occur most frequently in somatic cells — the cells that make up the body of the organism. If epigenetic marks occur in sex cells, they are wiped clean prior to egg and sperm formation. Then, once the sperm and eggs have fully formed, methylation patterns are re-established in each type of cell, meaning that the acquired genetic regulation is reset to baseline in the offspring.

Sometimes, these regulatory effects are transmitted to the next generation through the activity of small RNA molecules, which can interact with messenger RNAs or proteins to control gene expression. This occurs frequently in plants but is much rarer in animals, which have separate lineages for their somatic and reproductive cells. A widely-studied exception to this is the nematode C. elegans, where RNAs and other molecules can alter inheritance patterns.

No matter how striking, though, none of these examples violate Crick’s Central Dogma; the genetic information remains intact and the epigenetic tags are always temporary, disappearing after at most a few generations.

That should squelch the brouhaha over epigenetics as a form of Lamarckian evolutionary change, as some have suggested that epigenetic (environmental) modifications of the DNA could be permanent, ergo the environment itself can cause permanent heritable change. (That is Lamarckian inheriance.) But we know of no epigenetic modifications that last more than a couple of generations, so don’t believe the hype about “permanently inherited trauma” or other such nonsense.

And there’s this, which again is not a violation of Crick’s “Dogma”:

. . . enzymes can modify proteins in the cell after they have been synthesized, so not every amino acid in a protein is specified in the genome. DNA does not contain all the information in a cell, but Crick’s original hypothesis remains true: “Once information has got into a protein it can’t get out again.”

Now Matthew does suggest a rather complicated way that the Dogma could be violated, but it’s not known to occur, though perhaps humans might use genetic engineering to effect it. But you can read about it in his piece.

It’s remarkable that Crick’s supposition that information in a protein can’t get back to the DNA or RNA code—made only three years after the structure of DNA was published—has stood up without exception for nearly seventy years. This is a testament to Crick’s smarts and prescience.

And if you remember anything about the Central Dogma, just remember this:

“Once information has got into a protein it can’t get out again.”

28 thoughts on “Cobb on Crick: The “Central Dogma””

  1. A welcome corrective. Larry Moran, the biochemist who blogs at The Sandwalk, has been harping on this very point for many years.

  2. That Crick cast this as “information” shows how high a level he was thinking about the biological rules here.

    Consider, Claude Shannon’s work in e.g. the late 40s on information transfer. Perhaps this was part of Crick’s wide-ranging interest.

    Richard Dawkins makes this point about information in a quote… lemmee find it…

    “If you want to understand life, don’t think about vibrant, throbbing gels and oozes, think about information technology.”

    Apparently from The Blind Watchmaker (1986)

    I think “dogma” is a category of word usurped by witty scientists – as in, it’s humorous – not literal. It aids understanding of an abstract idea – especially in conversation/lecture/informal setting. I think we’ve seen other examples.

    Excellent article, very exciting, looking forward to this Crick biography!

      1. Although it would seem that given a protein any nucleic acid sequence that used synonymous codons would be equivalent, that is not necessarily so. The 3D structure of the DNA/RNA can be affected.
        I believe the latest NOPV polio vax uses synonym codons to weaken the virus.

  3. That one-sentence description is an excellent restatement of the Central Dogma. I’m still going to capitalize the Central Dogma, as it is so important and central to how cells work. When I was taking undergraduate biology in the mid 1970’s the Central Dogma was dogma. It factored highly in the courses I took and biology was rightly proud of the accomplishment. The phrase itself may be a bit over the top in that my biology professors—and the students—seemed to take it quite literally as a law of nature.

  4. Thanks for this post! As others above have indicated — I have read that Crick’s use of the word: dogma — has been misinterpreted and that the central argument was that information encoded in amino acid sequence was unidirectional, if I can use that term. This is a refreshing and enlightening discussion of a widely shared misleading concept of Crick’s original thinking and — dogma.

    If my memory serves, this issue was also discussed in the book: The Eighth Day of Creation (H.F. Judson, 1979) [I haven’t learned to do italics in this mode]

      1. It’s interesting to speculate about what the recognition system would have to look like to “read” a complex folded tetrameric protein that’s had disulphide bonds formed and bits excised from it after translation…and then impute the RNA sequence that created it (taking into account the degeneracy of the code) and then assemble an RNA chain faithful to that read. The termini of the protein chain(s) may be hidden deep inside a globular protein where the reader couldn’t even find it to get to work on it.

        (The closest we have to protein recognition for nuclei acid purposes are the twenty enzymes that recognize each amino acid for what it is and attach it to the tRNA with the proper anticodon. But unincorporated amino acids are small monomeric molecules that are recognized as such by many other processes, such as gluconeogenesis.)

        I think it is quite reasonable to suggest that the process of translation is both thermodynamically and informationally irreversible.

  5. PEPTIDE-MHC COMPLEXES?

    “Once information has got into a protein it can’t get out again.” This remark may have later blinded immunologists to the extent that none had anticipated that peptides from proteins deemed as “foreign” within a cytoplasm can be displayed at the cell surface as peptide-MHC complexes. The serendipitous discovery surprised them all. The complexes could be detected by those policing T-cells that had survived thymic auditioning (for non-reactivity to self-peptides). Thus, in different contexts to that which Crick envisaged, information can indeed get out of a protein (both within a thymus and outside it).

      1. Right. As with “epitope spreading”, which occurs with auto-antigens, it is a process akin to selection; it works on existing mutants.

        But the olde student in me wonders why information cannot flow backwards from a protein. I am not looking for a simple; “because the biochemical mechanisms aren’t there” answer. Rather it’s more of a question about fundamentals. Is there a reason vis energy transfer? Is there an evolutionary reason information can’t go that way? If so, it must be very strong.

        I suppose I should just pick up a basic biology text. But it seems easiest to ask here.

        Best, EdM

        1. Due to post-translational changes, there is a loss of information as you go from RNA to a completed in vivo protein such that you can’t unambiguously reconstruct the RNA sequence that coded for it. Even if you can read the amino-acid sequence unambiguously as it exists in its active state, as you can in the lab and has been done for many proteins, you can’t reverse-impute the now invisible post-ribosomal changes, especially large excisions, that you would need to reconstruct the mRNA template. It’s a bit like modolo arithmetic in cryptography.

      2. Of course. This point is made in Mathew Cobb’s fourth footnote (below) regarding the diversification of potential antibody genes, which resembles the diversification of potential T cell receptor genes. In both cases the nucleic acid sequence arises first, before there can be information-dependent activity at the protein level.

        “Genes encoding antibodies, a part of the adaptive immune system, are changed at the DNA level through several processes, including VDJ recombination, class switch recombination, and somatic hypermutation. Somatic hypermutation occurs …. , triggering cells to mutate variable regions of immunoglobulin genes. However, these altered genes are not passed on to the organism’s offspring; Crick’s Central Dogma remains intact”

    1. Thanks for this link. It’s quite good. I first encountered the term: epigenetics — in an advanced genetics course in 1973. At the time it seemed to be a collection of phenomena that fit well with what was then called developmental biology.

      I’ve been frustrated but the use of that term by the pseudoscience crowd to the point of being a pest in, for example, a public forum on (get this) psychedelic dugs, where a credentialed crank was assuring people that disease would be cured by mental processes via epigenetics. I rose to point out that when I heard the term in that context, it was an indication of bullshit. They love me everywhere I go.

      1. HAHAH. I bet!
        Oh psychedelic drugs are great, I’ve written articles on them and I’m a huge “psychonaut” myself.

        But you’re totally right, they have nothing to do with epigenetics. There’s a lot of fuzzy and stupid pop-sci around psychedelics unfortunately.
        The upside is they’re used and understood more, or at least the positive side. They’re not – and shouldn’t be – feared when used properly.

        I remember in the 80s the “LSD damages your DNA” panics. (sigh)
        best,

        D.A.
        NYC

        1. David Anderson (howdy, friend) Yes, well, typo, that was as you properly read, drugs, not “dugs” as I wrote. Having already dated myself, I recall when the LSD – DNA damage panic was new, late ’60’s, the arguments around it (planar molecule), the debunking, and the increasing demonization & draconian legal consequences. Maybe related to my use of a ‘nym.

          Ironically, Timothy Leary had some purple prose around “learn the DNA/RNA code”, not related to damage argument but, rather, directed to his own fancies. And, in ~ 1987, in a public forum, in response to my question “What about Francis Crick?”, Leary’s response: “Much hipper than Watson.” But, in reading further I would not add to any rumors of Crick’s involvement in psychedelics. He was just curious about the brain & minds and I await the definitive biography.

  7. “Once information has got into a protein it can’t get out again” is the most deterministic statement I’ve groked in a long time.

    Woke peeps are wrong to freak out about genetic determinism when their attention would more aptly be placed on proteins.

    (Giggles evilly.)

  8. Fascinating post. As I get older I’ve migrated most of my reading to the humanities, but I am looking forward to Matthew’s book release.

  9. I suspect that some molecular biologists are trying to get their 5 minutes of fame by claiming that “Crick was wrong” (a variation of our pet peeve “Darwin was wrong”).

  10. I’m very much looking forward to the Crick biography. I was thinking it would make the perfect Christmas present for me this year, but when I asked Professor Cobb on Twitter about the publication date he had this to say:

    “The bizarre vagaries of the book trade mean that it will be completed in October 2024 and be published a year later. I think it is being produced using a John Bull Printing Set.”

    Older readers may remember the John Bull Printing Sets, which required a huge expenditure of labour to produce a single page of poor quality type. https://easyontheeye2.wordpress.com/packaging/john-bull-printing-sets/

    1. I just do not understand a one-year lag between completing a book and its publication in today’s world…my guess is that completion is more formal than Matthew scribbling long hand on yellow legal pads.

      In 2007, I led some teams of subject matter experts and high school teachers in reviewing Virginia’s curriculum standards in physics, chemistry, and engineering. Among our recommendations were the removal of some outdated content and the inclusion of some contemporary ideas both in physics and chemistry. For example, addition of a fourth state of matter, plasmas, to solids, liquids, and gasses and the inclusion of quarks in the physics course. Of course, most teachers were not familiar with these concepts, so, upon learning that the time to get updated textbooks to the classroom was on the order of seven years, we embarked to write a reasonably vetted book of our own and make it freely available on the web under a creative commons license. The Governor’s Office issued a call for volunteer authors drawn mostly from high school teachers with a few professors. This all volunteer effort strongly supported by the CK-12 Foundation produced a ten chapter book, peer reviewed by authors and vetted by a college physics dept chair in five months. It wasn’t the best written in educationalese sense, but with the reviewby other teachers, two high senior students, and the final hechsher from the university physicist chair, we felt confident in our freely and timely available product.

  11. “In other words, there can be no Lamarckian inheritance, in which environmental change affecting an organism’s proteins becomes ingrained into the organism’s genome and thus become permanently heritable.”
    — FTFY

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