January 20, 2020

The Double Helix Review

Why the Structure of DNA was Actually Such a Big Deal

The Double Helix

Everyone knows that Watson and Crick earned the Nobel Prize for discovering the structure of DNA. But why was that important? Who cares that it’s a double helix, and what new information did that yield? I recently read The Double Helix by James Watson (as in, the Watson of Watson and Crick), and the answers to the above questions were way more interesting than I thought they would be (I originally picked up the book because I’d heard it was so grossly sexist and cruel toward Rosalind Franklin that I wanted to see it for myself. It was that sexist and cruel, not only toward her but toward many other people in the book, but the actual content of the memoir was so much more interesting that I’ve focused on that instead - see the end for notes about his treatment of Franklin).

Why discovering the structure of DNA was such a big deal

Before reading this book, I knew that Watson and Crick got the Nobel Prize for “discovering” the structure of DNA - as in, it was a double helix. What I didn’t understand was why that was significant, how difficult of a discovery it was, and what that new knowledge enabled. As I read, I was continually struck not only by how much scientists didn’t know at the time, but also by how much they did! A bunch of discrete pieces of information about DNA that are second-nature to anyone who works with it were known before they knew the structure of DNA. I hadn’t realized how piecemeal the whole discovery process was, and it led to a deeper appreciation for how dependent scientific discoveries are on the tools available at the time.

Scientists knew a remarkable amount about the structure of DNA already:

  • They knew that DNA was made up of bases
  • They knew the bases were A (adenine), C (cytosine), T (thymine), and G (guanine), and they knew the chemical structure of each of the bases
  • They knew the bases were attached to a sugar and phosphate backbone in a readable row.
  • They knew the proportions of the bases were not random: “In all their DNA preparations the number of adenine (A) molecules was very similar to the number of thymine (T) molecules, while the number of guanine (G) molecules was very close to the number of cytosine (C) molecules. Moreover, the proportion of adenine and thymine groups varied with their biological origin. The DNA of some organisms had an excess of A and T, while in other forms of life there was an excess of G and C. No explanation for his striking results was offered by Chargaff, though he obviously thought they were significant. When I first reported them to Francis they did not ring a bell, and he went on thinking about other matters.”

With the hindsight we have today, it could seem like it’d be an obvious leap to get to a double helix where the bases are paired together, but it was anything but! The whole book details the various wrong paths they went down to get to the right answer:

  • People didn’t know how many strands were in DNA - one? two? three? four? and there wasn’t much evidence to support any of the theories (that evidence was later gathered by Franklin)
  • People didn’t know how the strands were connected, if there were multiple strands at all. For a while, Watson and Crick explored a theory that magnesium ions held the backbones together.

Mg++ theory

  • Even once Watson and Crick starting thinking that the backbone was facing outward and the bases faced inward in a multiple-strand scenario (an insight they got from Rosalind Franklin, who was the empiricist to their theorists, and was an expert at X-ray crystallography), they still didn’t get it right initially, and thought that bases would bind to themselves - As to As, Gs to Gs, etc.

I hadn’t realized how difficult it was to get empirical data and validate theoretical ideas. On the empirical side, I think I thought we just kinda had good enough microscopes that we could just “see” the structure (something that wouldn’t happen until 2017). Instead, scientists were forced to rely on X-ray crystallography, a technique that required a decent amount of training to both perform and interpret its results. This technique was what Rosalind Franklin was an expert in, and Watson couldn’t be bothered to learn it. It produces results like the image below:


On the theoretical side, if you thought “hmm maybe the molecules fit together like so!”, you couldn’t run your idea through a computer simulation to see if it worked. Instead, you had to go to a machine shop that knew the precise angles at which different atoms could combine, and they would literally make the model custom for you - a process that takes so long that Watson was actually worried their rival at CalTech would get there first while they were waiting for the machinists to finish! Only after the machinists produced a verified model could the theorists feel confident enough to publish.

Mechanical models

Additionally, separately from the nitty-gritty of the structure of DNA, I hadn’t realized how fuzzy the state of the world was around its purpose, either; many scientists at the time thought that genes were proteins and that the mystery of how genetic material was transmitted would come from the study of proteins. Watson and Crick thought differently:

Given the fact that DNA was known to occur in the chromosomes of all cells, Avery’s experiments strongly suggested that future experiments would show that all genes were composed of DNA. If true, this meant to Francis that proteins would not be the Rosetta Stone for unraveling the true secret of life. Instead, DNA would have to provide the key to enable us to find out how the genes determined, among other characteristics, the color of our hair, our eyes, most likely our comparative intelligence, and maybe even our portential to amuse others. Of course there were scientists who thought the evidence favoring DNA was inconclusive and preferred to believe that genes were protein molecules. Francis, however, did not worry about these skeptics. Many were cantankerous fools who unfailingly backed the wrong horses. One could not be a successful scientist without realizing that, in contrast to the popular conception supported by newspapers and mothers of scientists, a goodly number of scientists are not only narrow-minded and dull, but also just stupid.

Eventually, after much trial and error (and validation from Rosalind Franklin’s stolen data), they realized the GC content was the key, and that if As bound to ts, and Cs bound to Gs, that would account for the parallel proportions and would allow for the helical structure they had been suspecting for a long time (there was a whole bunch of confusion about how to get bases to pack regularly, which the A-A, G-G type of pairing wouldn’t have allowed).

Moreover, putting the high-up view (what is genetic material made of and how does it get passed on?) together with the low-down view (given all these discrete bits we know about DNA, how is it put together?), a double-helix with complementary bases suggested a mechanism for copying DNA, and therefore for transmitting genetic information. This was the key insight, and the reason their discovery was so important! (The following quote is from when he thought As bound to As, but the general insight is the same)

If this was DNA, I should create a bombshell by announcing its discovery. The existence of two intertwined chains with identical base sequences could not be a chance matter. Instead it would strongly suggest that one chain in each molecule had at some earlier stage served as the template for the synthesis of the other chain. Under this scheme, gene replication starts with the separation of its two identical chains. Then two new daughter strands are made on the two parental templates, thereby forming two DNA molecules identical to the original molecule.

When they wrote up the paper that eventually won them the award, they commented (briefly, and, for once, humbly) on its implications:

It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.

Replication mechanism

It it remarkable how accurate their predictions were.

Other topics of note from The Double Helix

Misogyny and Cruelty

Yep, the people didn’t lie about this one. The sexism was rampant and frequent, but was more of a special flavor of cruelty for Watson, as he was unkind and unnecessarily gossipy about many of the people in the book, including men. However, his main vitriol was saved for Rosalind. He calls her ‘Rosy’ throughout the book, a nickname she didn’t go by. She was an X-ray crystallographer working in a lab with Maurice Wilkins, studying DNA. Here is how she is introduced:

…it was increasingly difficult to take Maurice’s mind off his assistant, Rosalind Franklin.

Not that he was at all in love with Rosy, as we called her from a distance. Just the opposite - almost from the moment she arrived in Maurice’s lab, they began to upset each other. Maurice, a beginner in X-ray diffraction work, wanted some professional help and hoped that Rosy, a trained crystallographer, could speed up his research. Rosy, however, did not see the situation this way. She claimed that she had been given DNA for her own problem and would not think of herself as Maurice’s assistant.

I suspect that in the beginning Maurice hoped that Rosy would calm down. Yet mere inspection suggested that she would not easily bend. By choice she did not emphasize her feminine qualities. Though her features were strong, she was not unattractive and might have been quite stunning had she taken even a mild interest in clothes. This she did not. There was never lipstick to constrast with her straight black hair, while at the age of thirty-one her dresses showed all the imagination of English blue-stocking adolescents. So it was quite easy to imagine her the product of an unsatisfied mother who unduly stressed the desirability of professional careers that could save bright girls from marriages to dull men. But this was not the case. Her dedicated, austere life could not be thus explained - she was the daughter of a solidy comfortable, erudite banking family.

Clearly Rosy had to go or be put in her place. The former was obviously preferable because, given her belligerent moods, it would be very difficult for Maurice to maintain a dominant position that would allow him to think unhindered about DNA. Not that at time he didn’t see some reason for her complaints … Unfortunately, Maurice could not see any decent way to give Rosy the boot. To start with, she had been given to think that she had a position for several years. Also, there was no denying she had a good brain. If she could only keep her emotions under control, there would be a good chance that she could really help him … The real problem, then, was Rosy. The thought could not be avoided that the best home for a feminist was in another person’s lab.

This was just one of many jabs at her, both personal and scientific. He takes issue with her clothes, her appearance, and her personality. He derides her for her empiricism while taking her data to confirm his theories, sometimes without her consent:

Moreover, there was no longer any fear that it [his and Crick’s current theory for the structure of the backbone] would be incompatible with the experimental data. By then it had been checked out with Rosy’s precise measurements. Rosy, of course, did not directly give us her data. For that matter, no one at King’s realized they were in our hands. We came upon them beacuse of Max’s [a colleague] membership on a committee appointed by the Medical Research Council to look into the research activities of Randall’s lab. Since Randall wished to convince the outside committee that he had a productive research group, he had instructed his people to draw up a comprehensive summary of their accomplishments. In due time this was prepared in mimeograph form and sent routinely to all the committee members. As soon as Max saw the sections by Rosy and Maurice, he brought the report in to Francis and me.

This makes it all the more ironic that his epilogue tries to undo the image he draws of her in the book:

All of these people, should they desire, can indicate events and details they remember differently. But there is one unfortunate exception. In 1958, Rosalind Franklin died at the early age of thirty-seven. Since my initial impressions of her, both scientific and personal (as recorded inthe early pages of this book) were often wrong, I want to say something here about her achievements. The X-ray work she did at King’s is increasingly regarded as superb. … By then all traces of our early bickering were forgotten, and we both came to appreiate greatly her personal honesty and generosity, realizing years too late the struggles that the intelligent woman faces to be accepted by a scientific world which often regards women as mere diversions from serious thinking.

It’s sad that she died so young, as the Nobel is not allowed to be given posthumously, and no one will ever know if she would have been jointly awarded the prize with Watson and Crick.

English Science vs American Science

Watson comments on the difficulty of deciding to study the structure of DNA given that someone else was already working on it:

…and even in the best of financial circumstances it would take two or three years to set up a new research group primarily devoted to using X rays to look at DNA structure.

Moreover, such a decision would create an awkward personal situation. At this time molecular work on DNA in England was, for all practical purposes, the personal property of Maurice Wilkins, a bachelor who worked in London at King’s College. Like Francis, Maurice had been a physicist and also used X-ray diffraction as his principal tool of research. It would have looked very bad if Francis had jumped in on a problem that Maurice had worked on for several years. The matter was even worse because the two, almost equal in age, knew each other and, before Francis remarried, had frequently met for lunch or dinner to talk about science.

It would have been much easier if they had been living in different countries. The combination of England’s coziness - all the important people, if not related by marriage, seemed to know one another - plus the English sense of fair play would not allow Francis to move in on Maurice’s problem. In France, where fair play obviously did not exist, these problems would not have arisen. The States also would not have permitted such a situation to develop. One would not expect someone at Berkeley to ignore a first-rate problem merely because someone at Cal Tech had started first. In England, however, it simply would not look right.

This kind of candidness is common throughout The Double Helix, and it makes me sad that you don’t see this kind of assessment directly from scientists these days. The culture of science - what is allowed/forbidden, easy/difficult, is a fascinating topic that has real implications for the pace of scientific discoveries. What other insights have we missed out on because of customs like this?