Book review: "Unraveling the Double Helix: The Lost Heroes of DNA", by Gareth Williams.

Newton rightly decried that science progresses by standing on the shoulders of giants. But his often-quoted statement applies even more broadly than he thought. A case in point: when it comes to the discovery of DNA, how many have heard of Friedrich Miescher, Fred Griffith or Lionel Alloway? Miescher was the first person to isolate DNA, from pus bandages of patients. Fred Griffith performed the crucial experiment that proved that a ‘transforming principle’ was somehow passing from a virulent dead bacterium to a non-virulent live bacterium, magically rendering the non-virulent strain virulent. Lionel Alloway came up with the first expedient method to isolate DNA by adding alcohol to a concentrated solution.

In this thoroughly engaging book, Gareth Williams brings these and other lost heroes of DNA. The book spans the first 85 years of DNA and ends with Watson and Crick's discovery of the structure. There are figures both well-known and obscure here. Along with those mentioned above, there are excellent capsule histories of Gregor Mendel, Thomas Hunt Morgan, Oswald Avery, Rosalind Franklin, Maurice Wilkins and, of course, James Watson and Francis Crick. The book traces a journey through a variety of disciplines, most notably the fields of biochemistry and genetics, that were key in deciphering the structure of DNA and its role in transmitting hereditary characteristics.

Williams’s account begins with Miescher’s isolation of DNA from pus bandages in 1869. At that point in time, proteins were well-recognized, and all proteins contained a handful of elements like carbon, nitrogen, oxygen and sulfur. The one element they did not contain was phosphorus. It was Miescher’s discovery of phosphorus in his extracts that led him and others to propose the existence of a substance they called ‘nuclein’ that seemed ubiquitous in living organisms. The two other towering figures in the biochemical history of DNA are the German chemist Albrecht Kossel and the Russian-born American chemist Phoebus Levene. They figured out the exact composition of DNA and identified its three key components: the sugar, the phosphate and most importantly, the four bases (adenine, cytosine, thymine and guanine). Kossel was such a revered figure that his students led a torchlight procession through the streets from the train station to his lab when he came back to Heidelberg with the Nobel Prize.

Levene’s case is especially interesting since his identification of the four bases set DNA research back by years, perhaps decades. Because there were only four bases, he became convinced that DNA could never be the hereditary material because it was too simple. His ‘tetra-nucleotide hypothesis’ which said that DNA could only have a repeating structure of four bases doomed its candidacy as a viable genetic material for a long time. Most scientists kept on believing that only proteins could be complex enough to be the stuff of heredity.

Meanwhile, while the biochemists were unraveling the nature of DNA in their own way, the geneticists paved the way. Williams has a brisk but vivid description of the lone monk Gregor Mendel toiling away with thousands of meticulous experiments on pea plants in his monastery in the Moravian town of Brünn. As we now know, Mendel was fortunate in picking the pea plant since it’s a purebred species. Mendel’s faith in his own work was shaken toward the end of his life when he tried to duplicate his experiments using the hawkweed plant whose genetics are more complex. Tragically, Mendel’s notebooks and letters were burnt after his death and his work was forgotten for thirty years before it was resurrected independently by three scientists, all of whom tried to claim credit for the discovery. The other major figure in genetics during the first half of the 20th century was Thomas Hunt Morgan whose famous ‘fly room’ at Columbia University carried our experiments showing the presence of hundreds of genes are precise locations on chromosomes. In his lab, there was a large pillar on which Morgan and his students drew the locations of new genes.

From the work of Mendel, Morgan, Levene and Kossel we move on to New York City where Oswald Avery, Colin MacLeod and Maclyn McCarty at the Rockefeller University and the sharp-tongued, erudite Erwin Chargaff at Columbia made two seminal discoveries about DNA. Avery and his colleagues showed that DNA is in fact the ‘transforming principle’ that Fred Griffith had identified. Chargaff showed that the proportions of A and T and G and C in DNA were similar. Williams says in the epilogue that of all the people who were potentially robbed of Nobel Prizes for DNA, the two most consequential were Avery and Griffith.

By this time, along with biochemistry and genetics, x-ray crystallography had started to become very prominent in the study of molecules: by shining x-rays on a crystal and interpreting the resulting diffraction pattern, scientists could potentially figure out the structure of the molecule on an atomic level. Williams provides an excellent history of this development, starting with the Nobel Prize-winning father-son duo of William Henry and William Lawrence Bragg (who remains the youngest Nobel Laureate at age 25) and continuing with other pioneering figures like J. D. Bernal, William Astbury, Dorothy Hodgkin and Linus Pauling.

Science is done by scientists, but it’s made possible by science administrators. Two major characters star in the DNA drama as science administrators par excellence. Both had their flaws, but without the institutions they set up to fund and encourage biological work, it is doubtful whether the men and women who discovered DNA and its structure would have made the discoveries when and where they did. William Lawrence Bragg repurposed the famed Cavendish Laboratories at Cambridge University – where Ernest Rutherford had reigned supreme - for crystallographic work on biological molecules. A parallel effort was started by John Randall, a physicist who had played a critical role in Britain’s efforts to develop radar during World War 2, at King’s College in London. While Bragg recruited Max Perutz, Francis Crick and James Watson for his group, Randall recruited Maurice Wilkins, Ray Gosling and Rosalind Franklin.

One of the strengths of Williams’s book is that it resurrects the role of Maurice Wilkins who is often regarded as the least important of the Nobel Prize-winning triplet of Watson, Crick and Wilkins. In fact, it was Wilkins and Gosling who took the first x-ray photographs of DNA that seemed to indicate a helical structure. Wilkins was also convinced that DNA and not protein was the genetic material when that view was still unfashionable; he passed on his infectious enthusiasm to Crick and Watson. But even before his work, the Norwegian crystallographer Sven Furberg had been the first to propose a helix – although a single one – as the structure of DNA based on his density and other important features. A key feature of Furberg’s model was that the sugar and the base were perpendicular, which is in fact the case with DNA.

The last third of the book deals with the race to discover the precise structure of DNA. This story has been told many times, but Williams tells it exceptionally well and especially drives home how Watson and Crick were able to stand on the shoulders of many others. Rosalind Franklin comes across as a fascinating, complex, brilliant and flawed character. There was no doubt that she was an exceptional scientist who was struggling to make herself heard in a male-dominated establishment, but it’s also true that her prickly and defensive personality made her hard to work with. Unlike Watson, she was especially reluctant to build models, perhaps because she had identified a fatal flaw in one of the pair’s earlier models. It’s not clear how close Franklin came to identifying DNA as a helix; experimentally she came close, but psychologically she seemed reluctant and bounced back and forth between helical and non-helical structures.

So what did Watson and Crick have that the others did not? As I have described in a post written a few years ago on the 70th anniversary of the DNA structure, many others were in possession of key parts of the evidence, but only Watson and Crick put it all together and compulsively built models. In this sense it was very much like the blind men and the elephant; only Watson and Crick bounced around the entire animal and saw how it was put together. Watson’s key achievement was recognizing the precise base pairing: adenine with thymine and guanine with cytosine. Even here he was helped by the chemist Jerry Donohue who corrected a key chemical feature of the bases (organic chemists will recognize it as what’s called keto-enol tautomerism). Also instrumental were Alec Stokes and John Griffith. Stokes was a first-rate mathematician who, using the theory of Bessel functions, figured out the diffraction pattern that would correspond to a helix; Crick who was a physicist well-versed with the mathematics of diffraction, instantly understood Stokes’s work. Griffith was a first-rate quantum chemist who figured out, independently of Donohue, that A would pair with T and G with C. Before the advent of computers and what are called ab initio quantum chemical techniques, this seems like a remarkable achievement.

With Chargaff’s knowledge of the constancy of base ratios, Donohue’s precise base structures, Franklin and Gosling’s x-ray measurements and Stokes’s mathematics of helix diffraction patterns, Watson and Crick had all the information they needed to try out different models and cross the finish line. No one else had this entire map of information at their disposal. The rest, as they say, is history.

I greatly enjoyed reading Williams’s book. It is, perhaps, the best book on the DNA story that I have read since Horace Freeland Judson’s “The Eighth Day of Creation”. Even characters I was familiar with newly come to life as flawed, brilliant human beings with colorful lives. The account shows that many major and minor figures made important discoveries about DNA. Some came close to figuring out the structure but never made the leap, either because they lacked data or because of personal prejudices. Taken as a whole, the book showcases well the intrinsically human story and the group effort, playing out over 85 years, at the heart of the one of the greatest discoveries that humanity has made. I highly recommend it.