Happy 60th birthday, central dogma!

JAC Intro: Today is precisely 60 years after Francis Crick, more of a genius than you realize, gave a famous lecture in London laying out what’s been called the “Central Dogma” of biology—about how information gets from genes to proteins via RNA intermediates. I asked Matthew, who wrote a very nice book  about the history of molecular genetics (Life’s Greatest Secret: The Race to Crack the Genetic Code), to give us a piece about Crick’s great contribution. It’s below. He also wrote a PLOS Biology article about Crick’s lecture and its sequelae, a reference given at the bottom of this post. There Matthew tells us that the Central Dogma has often been mischaracterized as “DNA makes RNA makes protein.”

Finally, Matthew appeared on the BBC Radio 4 today to talk about Crick and the Central Dogma. Click on the screenshot below to get to the program, and then start listening at 1:23:00.  As usual, Matthew does an excellent job, though they gave him but three minutes.

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by Matthew Cobb

[This article about Francis Crick’s lecture 60 years ago is slightly adapted from one written for the BBC website, so it is in a style that is a bit simpler than that we sometimes use on this site.]

Sixty years ago this week, one of the greatest British scientists, Francis Crick, gave a lecture in London in which he accurately predicted how genes work, setting the course for the genetic revolution we are now living through. According to the American author Horace Freeland Judson, in this talk Crick ‘permanently altered the logic of biology’.

Only four years earlier, Crick and the young American Jim Watson had solved the double-helix structure of DNA, using data from Rosalind Franklin. Aged 41, Crick was still five years away from winning the Nobel Prize for this work, but he had a reputation as a powerful and profound thinker.

His lecture, entitled ‘On protein synthesis’, was given at University College London for the Society for Experimental Biology. In it, Crick spoke about how genes do what they do. At the time, this subject was still very murky – some scientists were not even convinced that genes were made of DNA.

Fig 2a

Crick speaking about the central dogma in 1963. (C) Cold Spring Harbor Laboratory Library.

Crick came up with four key predictions about genes and their link to proteins. In each of these ideas, he was right.

Crick started with the main thing that genes do: they control the production of proteins.

The problem Crick explored was that the DNA in a gene is simply a string of chemical bases – A, C, T, G. Crick had to explain how the cell could get from the one-dimensional sequence of bases in DNA to the complex three-dimensional structures of proteins, which can take nearly any shape.

Crick’s answer was simple: the order of bases in the gene – what he called ‘genetic information’ – corresponded to the order of the amino acids that make up each protein, and nothing more. There was no 3-D structural information about the protein encoded in the gene, he claimed. He called this the sequence hypothesis.

Somehow, the cell read off the information in the gene and assembled the amino acids together like beads on a string. Then the protein molecule spontaneously folded itself into its final 3-D structure. We still cannot easily predict the 3-D structure of a protein from the order of its amino acids, but Crick’s sequence hypothesis remains good.

To explain how the cell assembles the protein, Crick predicted there must be small molecules  – he called them ‘adaptors’ – that could recognise each of the 20 different amino acids in the body, and would bring them to where they could be turned into a protein in the right order. As Crick gave his talk in London, this molecule was being identified in an American laboratory. It is now called “transfer RNA”.

The French geneticist François Jacob was in the audience. He recalled Crick’s lecture in his memoirs:

“Tall, florid, with long sideburns, Crick looked like the Englishman seen in illustrations to 19th century books about Phileas Fogg or the English opium eater. He talked incessantly. With evident pleasure and volubly, as if he was afraid he would not have enough time to get everything out. Going over his demonstration again to be sure it was understood. Breaking up his sentences with loud laughter. Setting off again with renewed vigour at a speed I often had trouble keeping up with. . . Crick was dazzling.”

The most controversial and influential part of the lecture was what was called the central dogma. Crick explained that as proteins are synthesised, information is taken from the DNA molecule, first into an RNA molecule, and is then used to make a protein.

Before the lecture, he drew a little diagram to explain what he meant. The arrows show what Crick called the flow of information going from DNA to RNA to protein. DNA and RNA could also copy themselves, so there are also arrows going from DNA to DNA and from RNA to RNA.

Fig 1

Crick’s first description of the central dogma, from 1956. (C) Wellcome Library.

Because the experimental data were not clear, Crick accepted it might just be possible that DNA could directly lead to the production of proteins, so he drew an arrow there, too (this is not in fact the case).

The most important point was that, as Crick put it, once the information had gone from DNA into a protein, it could not get back into your DNA. There was no biochemical route for a protein to change your DNA sequence.

Crick thought it might be possible for information to go from RNA to DNA, and this later turned out to be the case, when it was discovered that some RNA viruses can get into our DNA. But the route from protein to DNA is impossible.

This central dogma emphasises that our DNA sequence cannot be changed by our proteins, or by how they are changed by experience. Over the last 60 years this has proved to be correct. Darwin thought that an individual’s experience changed the characters they transmit to their offspring – for example, he thought it self-evident that blacksmiths have children with big arms.

In the case of humans, and most other animals, this is not possible because the cells that produce our offspring (eggs and sperm) are completely separate from the cells that make up our bodies. This was shown by August Weismann at the end of the 19th century.

But in some animals, and in plants, fungi and all single-celled organisms, this separation does not exist. Nevertheless, Crick’s central dogma shows that there is no biochemical route from protein to DNA. Your experience cannot ‘rewire’ your DNA.

Despite the excitement about what is called epigenetics, which explains how genes can be turned on and off by the environment, this never leads to a change in our DNA sequence. Crick’s dogma was absolutely right.

Crick later cheerfully admitted that when he coined the phrase, he didn’t know what a dogma was. What he really meant was that it was a basic assumption about how genes worked. Whatever its name, it still guides scientists today.

Crick’s final brilliant prediction was to suggest that in the future biologists would use sequence data to understand evolution, by comparing the sequences of different species.

In 1957, when Crick was speaking, protein sequences were known from only five species, while DNA sequencing was science fiction and 20 years in the future. But this is exactly what happened, and we can now understand how organisms evolved in unprecedented detail, by comparing their sequences, just as Crick suggested.

Crick’s lecture, which was published the following year, continues to be read and cited by scientists all over the world. It is a monument of clear and penetrating thinking by one of the 20th century’s greatest minds. In all his key predictions, Francis Crick was right, and he did indeed change the logic of biology.

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JAC: Matthew has a nice paper in PLOS Biology giving a lot more details as well as references. The piece, free online, is referenced below along with a link. Besides Crick’s incredibly prescient hypothesis about the way DNA carries and translates the “code of life,” he also proposed in that lecture that one could use the sequence of DNA (and, by extension, of proteins), to work out evolutionary relationships between species. Here’s Crick’s quote form the lecture:

“Biologists should realise that before long we shall have a subject which might be called ‘protein taxonomy’—the study of the amino acid sequences of the proteins of an organism and the comparison of them between species. It can be argued that these sequences are the most delicate expression possible of the phenotype of an organism and that vast amounts of evolutionary information may be hidden away within them.”

What a smart guy he was! And here’s the reference to Matthew’s paper:

Cobb, M. 2017. 60 years ago, Francis Crick changed the logic of biology. PLOS Biology, online, published: September 18, 2017. https://doi.org/10.1371/journal.pbio.2003243

 

 

35 Comments

  1. KD33
    Posted September 19, 2017 at 10:41 am | Permalink

    Great stuff, thank you. That’s the first I’ve heard that Crick anticipated the use of sequences to study evolution. The ribosome is to me one of the most amazing pieces of machinery, physically assembling proteins from RNA “player piano” scripts. If I recall correctly, it’s been a puzzle to pose a plausible evolutionary sequence that would produce ribosomes. Any insight on that would be appreciated!

    • Reginald Selkirk
      Posted September 19, 2017 at 10:53 am | Permalink

      If I recall correctly, it’s been a puzzle to pose a plausible evolutionary sequence that would produce ribosomes. Any insight on that would be appreciated!

      The ribosome is a large complex of RNA and protein. Around the most recent turn of a century, tremendous insight into the operation and origin of the ribosome was brought to light by the revelation of the crystallographic structure of the ribosome:

      The catalytic core of the complex is RNA. The ribosome is an RNA enzyme. This was a tremendous validation of the RNA World concept.

    • Reginald Selkirk
      Posted September 19, 2017 at 11:07 am | Permalink

      A simple Google search on evolution of the ribosome brings up several papers.

      Origin and Evolution of the Ribosome, George E. Fox (2010) doi: 10.1101/cshperspect.a003483

      The Origin and Evolution of the Ribosome, Smith, Lee, Gutell & Hartman (2008) doi: 10.1186/1745-6150-3-16

      History of the ribosome and the origin of translation, Petrov, et al. (2015) doi: 10.1073/pnas.1509761112

      And many others. These papers are generally dependent on insights from the crystal structure of the ribosome and comparisons between ribosomes from different branches of the ‘tree of life’.

      • Posted September 19, 2017 at 11:25 am | Permalink

        Thanks! What a co-inkydink. Oddly, weirdly, this very morning I was on the hunt for some papers on ribosomal evolution (a minor question that I don’t understand arose in recent work) and before girding myself to do the literature search, I thought I’d take a break and read WEIT. You never know what you’ll find here.

        In payment for these refs, here’s a ribosome joke.

        Did you hear about the recently discovered ribosome that can only translate CGX codons?

        It’s a pirate ribosome.

        • lkr
          Posted September 19, 2017 at 11:48 am | Permalink

          arg! that is so bad.

          • Posted September 19, 2017 at 1:08 pm | Permalink

            That comment helped me to understand the joke! Thank you.

            • Diane G.
              Posted September 25, 2017 at 1:33 am | Permalink

              And your comment helped me to!

              It takes a village…

      • KD33
        Posted September 19, 2017 at 11:32 am | Permalink

        Reginald – thanks. I’ve looked through a number of papers over the years (though maybe not these specifically). My takeaway is that, in the early stages, the evolutionary pathway to such a complex structure was still perplexing. I was hoping that someone with Matthew’s background could shed some light on this (specifically, is my takeaway still true? Any new insights these days?)

      • Reginald Selkirk
        Posted September 19, 2017 at 11:32 am | Permalink

        You can even find a few Youtube videos:
        The Origins and Evolution of the Ribosome

        I haven’t finished watching that one yet, so I can’t comment on whether it delivers for a general audience.

        • KD33
          Posted September 19, 2017 at 11:33 am | Permalink

          Great, will check this out. Thanks …

          • Reginald Selkirk
            Posted September 19, 2017 at 3:29 pm | Permalink

            I watched the entire video. It didn’t do much for me. They mention a paper to which it is a companion. The only thing I got out of it is that based on current evidence (structure and comparative sequence of ribosomes) they think it evolved in 6 stages. Probably these stages are explained in the paper, but perhaps not for a general audience.

  2. Eli Siegel
    Posted September 19, 2017 at 10:44 am | Permalink

    Horace Freeman Judson ‘The Eighth Day of Creation’, a great book.

    • Reginald Selkirk
      Posted September 19, 2017 at 10:54 am | Permalink

      A great book indeed, but the author’s middle name is Freeland.

      • nwalsh
        Posted September 19, 2017 at 11:18 am | Permalink

        I have the book Francis crick,discoverer of The Genetic Code from the Eminent Lives series. I’ll have to reread.

        • Posted September 19, 2017 at 11:59 am | Permalink

          Also excellent. Written by Matt Ridley.

  3. ThyroidPlanet
    Posted September 19, 2017 at 11:31 am | Permalink

    I think I love this sort of historical science writing because it almost seems like I could have done it – it’s so clear, so simple, so evident, like a musical performance… the little voice in the head that says “oh yeah, you just put your fingers there and it’ll make that note! I can do that!”

    But ah, it’s not how it goes, is it….

    • Posted September 19, 2017 at 11:57 am | Permalink

      As I always say (as a guitarist): Yeah, it’s simple, you just put your fingers in the right places at the right times. But it’s not easy!

      Or, one of my favorite light bulb jokes:

      Q: How many guitarists dos it take change a light bulb?

      A: 200. ! to change the light bulb and 199 to sit in the audience and say to themselves, “I could do that!”

  4. Posted September 19, 2017 at 11:55 am | Permalink

    Thanks for this posting and: Very nice article Matthew, thank you!

    That’s for reproducing Crick’s diagram too: I love that!

  5. lkr
    Posted September 19, 2017 at 12:00 pm | Permalink

    As an undergraduate at the University of Washington, I attended a talk by Francis Crick. This would have been somewhere around 1963, so after he’d received the Nobel Prize. Up to that point I’d taken some basic biology courses, incuding vertebrate embryology and genetics [very fruit fly oriented!], all seeming very concrete. And still very hard to imagine how an organism was built.

    Crick’s talk was on the latest DNA discoveries — the Dogma was rapidly being filled out, punctuation and all. My recollection of the talk is contaminated by the fact that it’s simply high school textbook stuff now, but I easily bring to mind the lecture room, graphics, and most of all Crick’s ease and enthusiasm.

  6. Mark R.
    Posted September 19, 2017 at 12:04 pm | Permalink

    I always like these refresher courses on Crick’s genius. Thanks. In light of these findings that were predicted, proven and still valid after decades, why is epigenetics still a thing? I understand why creationism is still with us, but there is no religious component to epigenetics (that I know of), so why is the term still being thrown around?

    • Reginald Selkirk
      Posted September 19, 2017 at 3:38 pm | Permalink

      Epigenetics is a real thing. Environmental conditions can cause modifications to genetic material that is passed on to further generations.

      Ignorant or unscrupulous people, some of whom wish to attack “Darwinism” tout this a challenge to Darwinian evolution through natural selection. Occasionally it has even been portrayed as a rebirth of Lamarckism (inheritance of acquired traits).

      They are wrong. The way epigenetics works is that you have a receptor molecule sensitive to some environmental condition. When activated, this molecule transmits its signal to a DNA recognition pathway (the DNA recognition may be the same molecule or another) and this binds to a particular sequence of DNA. This activates enzymes that modify the DNA, perhaps through methylation.

      To make this work, you need:
      A gene for the receptor molecule
      A gene for the sequence recognition molecule
      A sequence in the chromosome that gets recognized
      Enzymes to modify the DNA in a reproducible way that affects gene activity

      How do you get all this stuff? In ways that are completely compatible with known biology; i.e. Darwinian evolution through means of natural selection, and Mendelian genetics.

      • Mark R.
        Posted September 19, 2017 at 4:29 pm | Permalink

        Thanks for this clarification, it’s much appreciated.

  7. Posted September 19, 2017 at 12:16 pm | Permalink

    Crick was a genius, but his choice of the term “dogma” was unfortunate. He should have looked it up. The use of the term feeds the lie that science, like religion, is based on articles of faith.

  8. Posted September 19, 2017 at 1:24 pm | Permalink

    Nice to see a discussion of what was right, what was wrong, etc.

    What is *different* biochemically about the organisms for which the central dogma is false?

    As for epigenetics, I think some people tend to play fast-and-loose on the notion of the sequence. I take it methylation doesn’t count. Why *is* that?

    • Posted September 19, 2017 at 2:08 pm | Permalink

      I don’t know of any organisms for which the central dogma is false. There are viruses that carry RNA and these arrange to get host cells to reverse transcribe their RNA into DNA. But that does not violate the CD.
      There are plenty of cases where proteins modify DNA (proteins that methylate DNA, for example), and where proteins change the DNA sequence (protein products of transposons). But these proteins are products of DNA in their own right, and evolved by changes in the DNA that encode them.

      • Reginald Selkirk
        Posted September 19, 2017 at 3:49 pm | Permalink

        And those proteins have no way to replicate themselves, except through the gene -> ribosome pathway.

        A violation of the Central Dogma would be “reverse translation.” There are very few papers on any reverse translation pathway, because it doesn’t exist. Here is one paper:

        The RNA/Protein Symmetry Hypothesis: Experimental Support for Reverse
        Translation of Primitive Proteins
        Masayuki Nahimoto, J. Theor. Biol. (2001) 209, pp 181-187.
        doi:10.1006/jtbi.2000.2253

        Despite the title, no experimental support is offered. There would be numerous difficulties in making such a system work.

        Conclusion: the author is a whackjob.

      • Posted September 20, 2017 at 11:18 am | Permalink

        The methylation thing: it seems then one has a feedback cycle of a sort.

        I guess one of the things I also don’t understand is what (if anything) the methylation *does* in the life cycle of a cell, or what not.

        • Torbjörn Larsson
          Posted September 21, 2017 at 2:45 pm | Permalink

          Diverse RNA snippets (mRNA, various small RNAs), methylation, histone modifications et cetera builds the “transcriptome” ecology of DNA expression, which can be tagged and/or sequenced in various clever ways (such as reverse transcribing RNA to DNA) and illuminate the DNA sequence information.

          Methylation functions like a versatile tag, conversely the exact changes it confer varies a great deal. On DNA it often blocks transcription factors, but it is also (IIRC) used to promote the origin of replication function in prokaryotes. Et cetera.

  9. Posted September 19, 2017 at 2:09 pm | Permalink

    When I teach translation, I refer to tRNA as an ‘adapter molecule’ because I read that somewhere and liked it. I had no idea the term came from the prescience of F. Crick!
    Every day I learn something around here.

  10. Nilou Ataie
    Posted September 19, 2017 at 3:28 pm | Permalink

    Information does ultimately flow back to the DNA as a consequence of protein function, for example if the DNA were to change in such a way to make a lethal protein, the lineage ends and the DNA is not replicated. Compared to a counter example where the protein functions correctly and ultimately is able to transfer the information of the environment to the next generation in replicating DNA code. What cannot happen is change in information. For example, if an injection of wt protein can save the lethal phenotype, the organism may be successful at replicating the DNA (cells alive and dividing), but only the original unchanged sequence, therefore no change in information, but still transfer of information to next generation cells and back to DNA.

    • Torbjörn Larsson
      Posted September 21, 2017 at 2:50 pm | Permalink

      That strikes me as exactly the kind of result Matthew describes in his interview and article, it does not change the sequence information and its effect disappears quickly in evolutionary terms. In other words, perfectly testing and accepting this:

      “… this never leads to a change in our DNA sequence. Crick’s dogma was absolutely right.”

  11. Posted September 20, 2017 at 3:45 pm | Permalink

    According to Amazon, the Matthew’s book in paperback edition was released in 1796 and the hardcover in 1896!

  12. Torbjörn Larsson
    Posted September 21, 2017 at 2:49 pm | Permalink

    That strikes me as exactly the kind of result Matthew describes in his interview and article, it does not change the sequence information and its effect disappears quickly in evolutionary terms. In other words, perfectly testing and accepting this:

    “… this never leads to a change in our DNA sequence. Crick’s dogma was absolutely right.”

    • Torbjörn Larsson
      Posted September 21, 2017 at 2:51 pm | Permalink

      Oops. Page update problems, this was a response to Bob Barber (reposted) above.

      Fell free to delete!


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