05 January 2023

Two Nobel Prizes contradicting each other: Watson and Crick versus Tomas Lindahl

In 1962 Watson, Crick and Wilkins received the Nobel Prize for the discovery of the structure of DNA. In 2015, Tomas Lindahl received the Nobel Prize for the discovery of DNA repair. The first prize symbolizes the beauty of the DNA molecule. The second Nobel Prize symbolizes the weaknesses of the same molecule. So, in a sense, these prizes contradict each other.

Watson-Crick versus Lindahl

How the beauty of DNA (and the Nobel Prize?) blinded scientists for the weaknesses of DNA. Surprise: later those weaknesses were awarded a Nobel Prize!

Why is DNA perfect? Because DNA structure has been proven chemically correct and because the structure gives for the first time a satisfactory explanation of heredity in the biological world. Two problems solved at once. Heredity requires a a stable structure. Since all life forms from bacteria to humans are based on DNA, and life is some 3 billion years old, DNA simply must be a stable structure.

But then came Swedish scientist Tomas Lindahl. He showed that the apparent stability of DNA is not based on its structure, but –totally unexpected – on enzymatic repair and proofreading! So, DNA only seemed stable. But when he started his research, repair-enzymes were unknown. Clearly, his idea contradicted known facts. To see how it could be that all biologists were blinded by the beauty and the logic of DNA, we must first look at some details of DNA structure. Here, I follow the description of Francis Crick in What Mad Pursuit (1988).

In 1950, three years before the discovery of the structure of DNA, chemist Chargaff had found in DNA from many different species the amount of base A equaled the amount of T and the amount of C equaled the amount of G. The relative amounts of AT and CG in species differ. Chargaff did not conclude anything from his data about the structure of DNA. For Watson and Crick it was crucial evidence for AT and CG base pairing. Furthermore, AT and CG base pairs have equal dimensions. So they fit perfectly in a regular double helix. This is important for a very long molecule. Furthermore, to fit in the double helix the four bases have to be in the correct tautomeric form [1]. The beauty of the DNA model is that the specificity of base pairing gives a mechanism for replication (making a copy of DNA). This is a crucial function in biology (cell division, heredity!). Base pairing guaranties an exact copy of a DNA string. So, a crucial biological property is explained with an elegant chemical structure and its properties. "This base pairing is the key feature of the structure [of DNA]" (Crick, 1988, p.166).

One problem remains: a mutation implies that a wrong base is incorporated, but how can mutations occur if base-pairing is always correct? In their second paper in Nature, Watson and Crick wrote: 

"We believe that the bases will be present almost entirely in their most probable tautomeric forms." ... "spontaneous mutation may be due to a base occasionally occurring in one of its less likely tautomeric forms." [2]

So, they explained mutation theoretically and in principle, but had no data about how often the bases were in the 'correct' or 'wrong' tautomeric form [4], [6]. Consequently, they had no idea how often spontaneous mutation occurs. Neither did they seem to care. They simply assumed it occurs in negligible frequencies. They ignored the problem. It apparently did not invalidate the structure as a carrier of hereditary information.

In the years after 1953 scientists were busy with experimental validation of the double helix model. This took some time. Furthermore, solving the genetic code (how the DNA code is translated into proteins) took some hard work too. The solution of these two problems created a solid foundation of molecular biology. It was a tremendous breakthrough. In fact it was a solid foundation for the whole of biological science including evolutionary biology. It seemed no important problems remained. Crick wanted to move on to other fields of research! 

But, than came Lindahl: 

"It was at the time a far-fetched idea that DNA might be unstable in the cellular environment. (Lindahl Nobel lecture )

Tomas Lindahl discovered the intrinsic fragility of DNA. This constituted no less than a paradigm shift. For example: could anyone predict on the basis of the structure of DNA that Uracil could be present in DNA? (it normally occurs only in RNA!). That specific enzymes exist that continuously scan DNA for the presence of Uracil? Also: oxidative damage (see Lindahl Nobel Prize lecture). Water is a damaging agent for DNA! For a complete overview see the Wikipedia article about the endogenous causes of DNA damage.

Thirty five years after the discovery of the double helix and twenty six years after the Nobel Prize, Francis Crick published What Mad Pursuit (1988). By that time Lindahl had already published several papers demonstrating DNA-repair enzymes, his first in 1974. Surprisingly, I found only 1 page about DNA error-correction [3] in What Mad Pursuit. Not important enough? It did not fit in his DNA-is-perfect-paradigm? Yes, Crick knew very well mutations exist. He did experimental work with phage mutants. The mutations he studied were created with chemical mutagens (acridine, proflavin). So, the damage came from outside DNA, not from the inside. It wasn't spontaneous damage. Those mutations were not a threat to the DNA-is-perfect-paradigm. But Lindahl showed that DNA is inherently unstable in its normal cellular environment. Certainly a revolutionary idea. The reason must be clear by now: DNA must be reliable to function as a carrier of genetic information. Evolution produced complex beings such as humans. How much evidence do you need?


Life exists - so DNA must be stable

Life exists - so DNA must be repairable

Watson, Crick, and Wilkins received the Nobel Prize for the structure of DNA. Although they did not explicitly claim DNA is stable, it is implicit in the statement that DNA is the carrier of hereditary information and the structure explains why this is the case. The Nobel Prize in Chemistry 2015 was awarded to Tomas Lindahl, Paul Modrich and Aziz Sancar for DNA repair. Repair implies DNA on its own is not a stable molecule. Although the Watson-Crick model is not refuted, its assumed stability certainly has been refuted. I didn't find this contradiction clearly in the literature [5]. I wrote this blog because it is worth pointing out.

In a next blog I will reveal important consequences of the stability/instability of DNA. This blog resulted from shocking remarks in Kondrashov (2017) Crumbling Genome (see previous blog).



  1. Tautomerism is a dynamic equilibrium between two compounds with same molecular formula. Crick did not elaborate on the frequency of right/wrong tautomeric forms of the bases. In his What Mad Pursuit he writes that "Jerry Donohue, who shared an office with us, told us that some of the textbook formulas were erroneous and that each base occurred almost exclusively in one particular form." (p.65). (Which from?). Please note: "almost exclusively"!
  2. Watson, Crick (1953) Genetical Implications of the Structure of Deoxyribonucleic Acid, Nature, May 1953. This is the second publication of Watson and Crick.
  3. and a rough estimate about error-rate. I will return to that in a next blog. 
  4. It seems there are no data and there is no theory to predict the frequency of wrong base tautomeres after 70 years! See:  "calculating the position of tautomeric equilibria in nucleobases is certainly within the grasp of contemporary quantum chemistry, and semi-empirical parameters on which the positions of these equilibria might most sensitively depend could presumably be identified." page 354 in Fitness of the Cosmos for Life. CUP 2008 [added: 9 Jan 2023
  5. Intelligent Design theorist Michael Denton (1998) triumphantly claims that DNA is a remarkably stable structure! I added a paragraph to my review of his Nature's Destiny. How the Laws of Biology reveal Purpose in the Universe on my DWD website. [added: 10 Jan 2023]
  6. Hubert Yockey (1992) is the first author where I found a probability of mispairing of the AT and CG base pairs. In an aside on page 300 he calculates that "the probability that adenine will mispair to cytosine is about 10-4 x 10-4 = 10-8." About the CG pair he writes: "...the base selected has a probability of about 10-4 of being in the imino or enol tautometirc form that leads to mispairing."  (see: keto–enol tautomerism). [added: 11 Jan 2023]



Further Reading


  1. [GK: this comment is copied from a previous blog:]

    Rolie Barth Friday, January 6, 2023 at 1:40:00 PM GMT+1

    Gert, you gave an interesting sketch of DNA-history. Thanks.
    Your conclusion:
    "Although the Watson-Crick model is not refuted, its assumed stability certainly has been refuted. I didn't find this contradiction clearly in the literature."
    seems wrong to me.
    Errors in DNA-script are not due to the (un)stability of the DNA-double helix, but they are the result of the copying processes, whether during transcription or replication. During these processes new RNA- or DNA-strings are build by molecular machines and these strings are not exactly the mirror-copies of the originals due to imperfections of the copying process.
    So I think, Lindahl et al. showed that the number of copying errors can be large and is reduced by all kind of repair proteins. For human cells the error rate is as low as 10^-8 in case of replication. For microbes this rate can be thousand times higher.
    So, I think your conclusion nor the title of this blog is correct.

  2. Dear Rolie Barth, thank you for your comments.
    You wrote: "Errors in DNA-script are not due to the (un)stability of the DNA-double helix, but they are the result of the copying processes".

    I wonder, did you read the literature, especially Tomas Lindahl? If so, are you saying that Tomas Lindahl got it all wrong? See for example his review article in Nature (which I listed in Further Reading):

    Tomas Lindahl (1993) Instability and decay of the primary structure of DNA, Nature.

    Finally, you wrote: "So, I think your conclusion nor the title of this blog is correct". That is rather strong and overconfident claim! It seems you are very certain in a scientific discipline outside your own... You seem not to know any doubts...

  3. Gert, may be my statements are too solid, that was not my intention.
    What I wrote is not based on the paper of Lindahl, but on your blog.
    But other literature about the process of replication makes clear (as far as I understand) that errors arise after opening the original DNA-helix and copying both strings to a mirror one.
    So my conclusion is a matter of logic: before starting replication no mutants arise (except for external influences) and after replication we find them. Isn't that a strong indication the errors are due to the process of replication?

    I hope this clears the sky.

  4. Thanks Rolie for the clarification! To clear the sky further: by unstable DNA Lindahl means DNA is unstable under enzym-free physiological conditions without harmful external influences present. There is no point in citing mutation frequencies, because those are measured AFTER repair processes have taken place. You need to know the damage BEFORE enzymes do their repair. You can only measure the real stability/instability without those repair enzymes. That's the whole point.
    Secondly, indeed there is a difference between 'DNA in rest' and 'DNA after replication'. Damage occurs in both. But the whole point is that the DNA in nonreplicating cells is damaged just by water and oxygen!
    Lindahl (2004):
    "Living organisms dependent on water and oxygen for their existence face the major challenge of faithfully maintaining their genetic material under a constant attack from spontaneous hydrolysis and active oxygen species and from other intracellular metabolites that can modify DNA bases. Repair of endogenous DNA base damage by the ubiquitous base-excision repair pathway largely accounts for the significant turnover of DNA even in nonreplicating cells, "

  5. Ok I want to withdraw my statements, because I dindn't realize what you write in the last citation. I need to study more on this subject.
    To be continued.

  6. For me, it teaches me that readers can misunderstand what I write. So, I need to write in such a clear way (preferably with not too many words) that readers can understand everything without first consulting the literature! :-)

  7. Excellent observations
    looking forward to the next blog
    to repair or no to repair - that seems the clinching question!

  8. Ps
    "There is no point in citing mutation frequencies......." etc
    There's another paradigm shift in the making?

  9. Hello mr Anonymous,
    Yes, I think certainly that Lindahl introduced a new paradigm opposed to the Watson-Crick paradigm. This is not clearly recognized in the literature, and he himself did not emphasize this. But he received a Nobel prize: and that means he did original and innovative research. Nobel prize winners do always new things. Go against the flow.
    Students always learn DNA with the names of Watson & Crick attached to it and think DNA is a perfect (even holy) molecule without flaws or weaknesses. I think when introducing DNA in the textbooks, Watson & Crick & Lindahl should be mentioned together.

  10. Rolie Barth: I discovered that Tomas Lindahl is present in your book 'De cosmos en het leven een Meesterwerk' on page 285 !!! Even more amazing, on the same page you even mention that Uracil can be present in DNA! and you even mention that it is removed by a special enzym!!! Congratulations.

  11. You might be interested in
    https://doi.org/10.1038/s41559-022-01925-6 as an example of a first attempt at paradigm shift sensu Lindahl

  12. Thanks. I have seen this remarkable publication... I wonder how RNA's that have never been translated in to a protein can immediately have a useful function in the cell without a long period of natural selection adapting such a protein to a useful function...

  13. "I wonder how... .."etc
    two more things to wonder about- I'd say:
    where did these key U1 mutations come from (random combination?)
    why weren't these mutations *not* repaired?

  14. Anonymous, You might be interested in the fact that Intelligent Design theorist Michael Denton (1998) triumphantly claims that DNA is a remarkably stable structure!!! I added a paragraph to my review of his Nature's Destiny. How the Laws of Biology reveal Purpose in the Universe on my DWD website. With my new insights in the 'stability' of DNA, I am now checking older books which I reviewed in the past to see what they say about the 'stability' of DNA. It is really great fun!

  15. Great fun indeed, to hear that stable DNA even proves the existence of God etc !

    looking forward to your next blog about the important consequences of the stability/instability of DNA.
    must be a long list!

  16. Mr. Anonymous, about those U1 mutated RNAs that get translated, a News story also appeared in
    Science by Elizabeth Pennisi. U1 is mentioned but not explained. Fascinating stuff for sure!


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