Watson’s Double Helix, one small clue, and the importance of knowing what you don’t know

This piece contains some longer excerpts from Watson’s writing about the discovery of DNA that tell the story far more beautifully than I ever could. The tale is full of false starts, randomness, and human flaws. I do my best to tie points together where necessary. But, for this piece, I let the story of the discovery of DNA itself be the star of the show.

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It ain’t what you don’t know that gets you into trouble. It’s what you know for sure that just ain’t so. – Mark Twain

This week I began reading Flowers for Algernon. Thus far its status as a classic seems entirely well-deserved. In the early stages of the book, Charlie, the human main character, writes numerous journal entries that introduce the reader both to the particulars of his tragic life and the limitations of his mental capacity.

The descriptions put on full display Charlie’s constant confusion about what is going on. Charlie, with an IQ of 68, was plucked from the ‘beekmin collidge center for retarded adults’ by researchers carrying out testing and screening to find a subject for a brain augmentation study. He is first asked by the researchers to take a ‘raw shock test’, an anxiety-inducing experience given his poor past experiences with all kinds of tests. “Dr Strauss said do anything the testor telld me even if it dont make no sense because thats testing.”

When prompted by the tester to find pictures in the inkblots he first said that he saw ink spilled on a white card. This did not satisfy the tester. When the tester informed him that there are pictures there and he should be able to see them, he figures that maybe he just needs his glasses and then he’ll be able to see them. No matter how hard he tried, all he could see was ink spilled on a page.

“I don’t think I passed the raw shok test.”

The day after that, there is no testing. The researchers are just asking Charlie questions. Some he knows most of the answer to, but is unaware of or forgetful of the rest of the answer. In these cases, he communicates exactly as much as he knows and makes a point of telling the questioner what he does not know.

They said they got to get permissen from my familie but my uncle Herman who use to take care of me is ded and I dont rimember about my familie. I dint see my mother or father or my littel sister Norma for a long long long time. Mabye their ded to. Dr. Strauss askd me where they use to live. I think in brooklin. He sed they will see if mabye they can find them.

Other times, even though a normally functioning adult would either remember or at least be able to piece together some reasonable hypothesis, he has no memory and he does not endeavor any kind of guess.

Dr Strauss askd me how come you went to the Beekman School all by yourself Charlie. How did you find out about it. I said I dont remembir.

The day after this, he was asked to take another test. He was told to make up stories about the people in random photos he was shown. His inability to generalize beyond what he knew for sure got him in trouble again.

I said how can I tell storys about pepul I dont know. She said make beleeve but I tolld her thats lies. I never tell lies any more because when I was a kid I made lies and I always got hit. I got a pictur in my walet of me and Norma with Uncle Herman...I said I coud make storys about them because I livd with Uncle Herman along time but the lady dint want to hear about them.

“I gess I failed that test too.” He blames himself. He’s been stupid, in his own estimation, his whole life. Charlie is forgetful, has trouble picking up new things he hasn’t done repeatedly, and can’t generalize knowledge to new tasks. In these three components of knowledge, he is obviously deficient.

But he, at least as far as I’ve seen, does not seem to misremember anything. That should count for something. And he gets absolutely no credit for this all-important component of knowledge. And this isn’t just overlooked because Charlie is so low-performing at these other components of knowledge. In general, this is a remarkably underrated aspect of human knowledge. It is not something one actively does, but, rather, something one does not do. Things of that sort are harder to notice.

But, in the scientific community, this little skill can make all the difference. In today’s piece, I’ll tell you all about possibly the most famous story of a scientist correcting his view of something that was systematically misremembered, and the massive returns to this simple correction.

Today, we’re going to talk about James Watson, an obscure table in a textbook, and his chance encounter with another researcher that precipitated the discovery of DNA’s true structure, transforming the field of biology in the process.

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Watson’s Double Helix: A Story of Serendipity

In the years following Watson, Crick, Wilkins, and Franklin’s discovery of DNA, Watson was encouraged to write up his personal story that led to the discovery of DNA’s double-helix structure. This strong encouragement was in no small part to give the world a sense of the randomness, stops and starts, chance meetings, bureaucratic happenstance, and serendipity involved in a discovery like this. This encouragement came primarily from Sir Lawrence Bragg himself, Director of the Cavendish Laboratory at Cambridge, who features prominently throughout the book and even attempts to get Watson and Crick to drop the DNA problem several times. Bragg, a Nobel winner in his own right, saw the nature of this particular discovery as in-line with many great discoveries he’d seen before as both a researcher and head of the world’s most prominent laboratory. Watson did up writing the book. It book was called The Double Helix.¹

(A note: Much has been made of Watson’s apparent sexism that came through in this text. And, while I do not disagree with these prior criticisms, I would encourage readers to seek out those criticisms elsewhere if they’d like to know more. This piece is about the serendipity of the discovery itself and how to use the lessons of the text to build a better system of discovery.)

Knowing all along that the researchers would solve DNA’s structure makes the tale that much more shocking as a reader. Every piece of Watson’s journey felt serendipitous in the most surreal way. Just to name a few:

• As an aspiring researcher, Watson attended a conference in Naples that lead him to the DNA structure problem. He was invited to the conference by Herman Kalckar in spite of the fact that they were not doing any work together at all. Watson was invited because, technically, he was meant to be researching under Kalckar. In practice, Watson was not interested in Kalckar’s research and Kalckar did not mind Watson’s absence day-to-day since he was distracted by the ongoing process of a painful divorce. Nonetheless, Kalckar invited Watson more or less on a whim.

• Morris Wilkins, who gave the talk at this same conference that put Watson onto the problem, was only invited to speak because the professor initially slated to speak, JT Randall, was overcommitted. He arbitrarily selected Wilkins to speak at the conference in his place. His talk showed Watson that X-ray crystallography was the key to genetics and inspired Watson’s move to the Cavendish in Cambridge.

• Watson’s move to Cambridge on his US research fellowship was only allowed due to some help from a few friendly professors and a thinly veiled lie about what he would be working on in Cambridge that the fellowship office in the US acquiesced to.

• This move lead him to meet his partner in crime, Francis Crick, whose in-depth knowledge of chemistry complimented Watson’s own knowledge of the DNA problem marvelously. Watson, who Crick referred to as a ‘former bird-watcher’ did not have anywhere near the level of chemistry knowledge to make an attempt at the DNA problem on his own.

• And, to top it all off, Jerry Donohue, the world’s second-leading expert on hydrogen bonds behind Linus Pauling, happened to share an office with Watson and Crick and gave the pair the final clue that led them to solve the structure of DNA.

Without Donohue’s help, it is very likely the pair would have gone on a wild-goose chase guessing completely impossible helical structures of DNA. The clue was so basic but so important to the problem itself that it is shocking to consider the consequences of such a small occurrence.

In the best case, Linus Pauling would have beaten the pair to the discovery, but taken a little longer to do so. In the worst case, with Pauling and the pair competing for the Nobel Prize-winning discovery, the sides would have not shared information and the discovery could have been prolonged by many years.

What was the clue?

At the time Donohue’s piece of advice was given to Watson and Crick, they were using an approach that came off as a bit odd and less than scientific to some of their colleagues. They were, in essence, guessing at the structural model of DNA and seeing what worked. What made this a not totally unreasonable approach was that there was a smattering of existing evidence that provided some constraints to narrow the search. What shape and angle the sugar-phosphate backbone could and could not look like had been roughly sketched out based on X-ray crystallographic evidence—largely due to Franklin and Wilkin’s work. The rough water content of the backbone was also known based on work by Franklin. Erwin Chargaff’s observation, known as Chargaff’s rule, noted that there should be a 1:1 ratio of purines to pyrimidines (adenine, thymine, guanine, cytosine, etc.). Whatever the final structure was that Watson and Crick determined, would reasonably explain this surely non-random phenomenon. Most importantly, the pair knew that whatever structure they came up with must provide some hints as to how DNA strands were able to replicate.

Watson and Crick were, naturally, building on top of these findings using a large body of scientific principles that were known to be true, the kind of knowledge one finds in textbooks. This is more or less what you’d expect; new theories should generally be based on new findings such as those in the paragraph above and the ‘standard’ scientific knowledge one finds in textbooks. One of the textbooks that proved helpful to the pair was Linus Pauling’s The Nature of the Chemical Bond. Watson credited this book as vital in helping him work towards the discovery. And, while it might seem odd to some to require the heavy use of your competitor’s textbook but somehow still think you could beat him, it did not strike Watson and Crick that way. They had different backgrounds than Pauling and were using a completely different approach to attack the area. They’d be fools to not trust the world expert in hydrogen bonds and related topics in his own area. This deferral to Pauling in the sub-problems he was best at, but confidence in their own abilities to model the structure, is the kind of mental delegation on which all great scientific discoveries are built. There’s no reason you can’t stand on the shoulders of a previous generation’s giant and not attempt to compete with him at the same time.

The next most important book was what Watson referred to as ‘Jay and Davidson’s little book’, The Biochemistry of Nucleic Acids. “A copy of which I kept in Claire [his dorm] so I could be sure that I had the correct structures when I drew tiny pictures of the bases on Cavendish note paper.” This book contained many formulas and basic, mundane information about the nucleic acids that were pivotal references for Watson and Crick’s work.

Based on the numbers in these books, Watson was toying around with the idea of a double helix backbone with “like-with-like” nucleic acid pairs where pyrimidines paired with pyrimidines and purines with purines. The physical models he was toying with did not exactly fit together cleanly. The angles of the helical backbone required to make the nucleic acid pairs fit did not exactly fit in with Franklin’s crystallographic evidence. In addition, since the different base pairs had different lengths, to make the model work either the backbone would have to continually bow in and out to account for the different shapes, or there would have to be some irregular type of hydrogen bond or trick to pair like-with-like in such a way that the backbone would not need to bow in and out. This was a major problem to work through because the X-ray evidence did not indicate that they should expect bowing. Watson writes:

But each time I tried to come up with the solution, I ran into the obstacle that the four bases each had a quite different shape. Moreover, there were many more reasons to believe that the sequences of the bases of a given polynucleotide chain were very irregular. Thus, unless some very special trick existed, randomly twisting two polynucleotide chains around one another should result in a mess. In some places, the bigger bases must touch each other. While in other regions, where the smaller bases would lie opposite each other, there must exist a gap or else their backbone regions must buckle in.

In spite of the problems, Watson felt that this structure roughly explained a lot of the problems they needed it to solve, fit with the existing facts and evidence, and, as many a hopeful scientist or mathematician has thought before, believed that something this elegant was too beautiful to not exist. He was so excited that he brought the idea to his lab mates one morning after a night of long thinking on the problem. In the office that morning he found Jerry Donohue.

I no sooner got to the office and began explaining my scheme than the American crystallographer Jerry Donohue protested that the idea would not work. The tautomeric forms I had copied out of Davidson's book were, in Jerry's opinion, incorrectly assigned. My immediate retort that several other texts also pictured guanine and thymine in the enol form cut no ice with Jerry. Happily, he let out that for years organic chemists had been arbitrarily favoring particular tautomeric forms over their alternatives on only the flimsiest of grounds. In fact, organic-chemistry text books were littered with pictures of highly improbable tautomeric forms. The guanine picture I was thrusting toward his face was almost certainly bogus. All his chemical intuition told him that it would occur in the keto form. He was just as sure that thymine was also wrongly assigned an enol configuration. Again he strongly favored the keto alternative.

Jerry, however, did not give a foolproof reason for preferring the keto forms. He admitted that only one crystal structure bore on the problem. This was diketopiperazine, whose three-dimensional configuration had been carefully worked out in Pauling's lab several years before. Here there was no doubt that the keto form, not the enol, was present. Moreover, he felt sure that the quantum-mechanical arguments which showed why diketopiperazine has the keto form should also hold for guanine and thymine. I was thus firmly urged not to waste more time with my harebrained scheme.

Though my immediate reaction was to hope that Jerry was blowing hot air, I did not dismiss his criticism. Next to Linus himself, Jerry knew more about hydrogen bonds than anyone else in the world. Since for many years he had worked at Cal Tech on the crystal structures of small organic molecules, I couldn't kid myself that he did not grasp our problem. During the six months that he occupied a desk in our office, I had never heard him shooting off his mouth on subjects about which he knew nothing.

Thoroughly worried, I went back to my desk hoping that some gimmick might emerge to salvage the like-with-like idea. But it was obvious that the new assignments were its death blow. Shifting the hydrogen atoms to their keto locations made the size differences between the purines and pyrimidines even more important than would be the case if the enol forms existed. Only by the most special pleading could I imagine the polynucleotide backbone bending enough to accommodate irregular base sequences. Even this possibility vanished when Francis came in. He immediately realized that a like-with-like structure would give a 34 Å (Angstrom) crystallographic repeat only if each chain had a complete rotation every 68 Å. But this would mean that the rotation angle between successive bases would be only 18 degrees, a value Francis believed was absolutely ru1ed out by his recent fiddling with the models. Also, Francis did not like the fact that the structure gave no explanation for the Chargaff rules ( adenine equals thymine, guanine equals cytosine).

The model was dead. It could not be. All of Watson’s fiddling had come to naught. Something he thought to be a fact written in stone (the textbooks), purines and pyrimidines being enols, all of a sudden gave way and left him with a model in shambles. Watson found an excuse to stay away from the lab for the rest of the day because he could not face the reality of having to fiddle with his now-defunct models.

When he returned to model-building, this new, unfortunate fact left him with the need to start over on his models. The next day, he restarted.

When I got to our still empty office the following morning, I quickly cleared away the papers from my desk top so that I would have a large, flat surface on which to form pairs of bases held together by hydrogen bonds. Though I initially went back to my like-with-like prejudices, I saw all too well that they led nowhere. When Jerry came in I looked up, saw that it was not Francis, and began shifting the bases in and out of various other pairing possibilities. Suddenly I became aware that an adenine-thymine pair held together by two hydrogen bonds was identical in shape to a guanine-cytosine pair held together by at least two hydrogen bonds. All the hydrogen bonds seemed to form naturally; no fudging was required to make the two types of base pairs identical in shape. Quickly I called Jerry over to ask him whether this time he had any objection to my new base pairs.

When he said no, my morale skyrocketed, for I suspected that we now had the answer to the riddle of why the number of purine residues exactly equaled the number of pyrimidine residues. Two irregular sequences of bases could be regularly packed in the center of a helix if a purine always hydrogen-bonded to a pyrimidine. Furthermore, the hydrogen-bonding requirement meant that adenine would always pair with thymine, while guanine could pair only with cytosine. Chargaff's rules then suddenly stood out as a consequence of a double-helical structure for DNA.

Even more exciting, this type of double helix suggested a replication scheme much more satisfactory than my briefly considered like-with-like pairing. Always pairing adenine with thymine and guanine with cytosine meant that the base sequences of the two intertwined chains were complementary to each other. Given the base sequence of one chain, that of its partner was automatically determined. Conceptually, it was thus very easy to visualize how a single chain could be the template for the synthesis of a chain with the complementary sequence.

Upon his arrival, Francis did not get more than halfway through the door before I let loose that the answer to everything was in our hands. Though as a matter of principle he maintained skepticism for a few moments, the similarly shaped A-T and G-C pairs had their expected impact. His quickly pushing the bases together in a number of different ways did not reveal any other way to satisfy Chargaff's rules. A few minutes later he spotted the fact that the two glycosidic bonds (joining base and sugar) of each base pair were systematically related by a diad axis perpendicular to the helical axis. Thus, both pairs could be flip-flopped over and still have their glycosidic bonds facing in the same direction. This had the important consequence that a given chain could contain both purines and pyrimidines. At the same time, it strongly suggested that the backbones of the two chains must run in opposite directions. The question then became whether the A-T and G-C base pairs would easily fit the backbone configuration devised during the previous two weeks.

They fit like a charm. No fiddling necessary. Donohue’s revelation had broken open the problem, and Watson and Crick quickly worked through the last details of their model, triumphantly wrote up their findings, and sent the paper to Nature that they knew would win them their Nobel Prize.

The bigger problem

If he [Jerry Donohue] had not been with us in Cambridge, I might still have been pumping for a like-with-like structure. Morris, in a lab devoid of structural chemists, did not have anyone about to tell him that all the textbook pictures were wrong. But for Jerry, only Pauling would have been likely to make the right choice and stick by its consequences.

Mistakes happen and science, in principle, is the process of trial and error. Findings tend to be argued about and re-argued about, experimented and (ideally) replicated, until something is established as true. That is what makes the process beautiful and quintessentially human. Scientific fields, however, are doing an absolutely horrendous job of keeping track of how confident they are about different claims in their field.

Fields of science need to do a much better job of keeping track of how confident they are in different claims! Many hot, controversial topics in a field are kept track of extremely efficiently. But small, unsexy things like, “How sure are we of the tautomeric forms of some nucleic acids?” are prone to fall through the cracks.

It should be unsurprising that many major scientific discoveries are made by people who are outsiders to a field, weird, or just learning the ropes. These are the individuals that are most likely to come across the claims of a field and are more likely to question them. But this questioning will always be the exception rather than the rule. In general, those who are just learning the ropes of a particular area largely trust the prior claims of the experts. Few people learn anything from true first principles. We stand on the shoulders of those before us and largely trust what the field considers as proven evidence to be just that, proven.

For every ‘fact’ that is much closer to a coin flip, or, in the case of the tautomeric forms of nucleic acids, just plain wrong, there is a pivotal discovery such as the structure of DNA that eludes our best minds because it seems impossible given what they believe to be the facts of the matter.

Everyone wants to talk about the newest and most complex methods. Flashy ideas whose findings seem to be proof of just how fantastically high-powered the human mind can be draw the most attention. And that makes sense. When I watch a basketball game, I am drawn to the most athletic players who can soar high and dunk over anyone who tries to contest them. But, as fantastic as that is, that feat is only worth two points. In science, similarly, we are likely overlooking executing the fundamentals in favor of these flashy findings. Keeping track of what is a natural law, what is almost certainly true, what is likely true, what we’re unsure of, and former ‘facts’ that have been overturned should be seen as the fundamentals of the field. And, while nobody would disagree with this in principle, it is time that fields begin putting efforts towards proper auditing and tracking of ‘certainty levels’ for most claims in a field, not just the hotly contested points.

A boring point guard with great court vision and basic passing may never be as exciting to watch as players who are destined to win the dunk contest, but basketball leaves plenty of room for both to thrive. Without this ‘fundamentals’-type work, plenty of ‘freak athlete’ researchers may be rising up to dunk on baskets that prove not to be there after all. And, furthermore, many unbelievably useful discoveries may be a simple layup away if only we kept track of our certainty levels of a few innocuous points more effectively.

Unlike most areas of science, this auditing might seem quite straightforward. Many might even view it as glorified housekeeping for Ph.D. researchers who understand the literature moderately well. If that proves to be the case, fantastic. This housekeeping might even prove to be so effective that it helps create multiple Nobel-level discoveries per year that would not have happened otherwise. It would also be a public good to each and every researcher who is in no way able to look into the certainty level of every single fact they use in every research paper.

It is a testament to the scientific community that this small, all-important fact found its way to Watson. But this just as easily could have not happened, and the odds of fortunate events like this are likely going down rather than up. Most fields are no longer the extremely small boys club where all the ‘first-rate men’ know each other and are friends. The fields have seen extreme growth in the number of researchers, diversity, number of papers, and topics being researched.

And while that is fantastic, it drives the probability of a happenstance encounter between someone like Watson and Donohue down substantially. The researchers of the mid-20th century, to be sure, could have used audits like the ones I am describing. But, in the modern era of research, these audits are vital. Without them, many courses of research are dead. The scary part is that many are likely dead already. We just have no clue which ones they are.

It ain’t what you don’t know that gets you into trouble. It’s what you know for sure that just ain’t so. – Mark Twain

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