The Road to the Double Helix, the Structure of DNA

Fifty years ago, on April 25, 1953, James Watson and Francis Crick published a short letter in the science magazine Nature . It described a remarkable two-chain helical structure for DNA--the genetic material in living organisms. Their double-helix model provided the key to understanding how living cells can produce two exact copies of themselves and how genetic material stores all the information for synthesizing the proteins needed to build a living organism.

A second major advance came a few months later, when Max Perutz discovered a technique to determine the structures of large molecules like myoglobin and hemoglobin. Since then, X-ray structural analysis of protein molecules has helped us to understand the chemistry of biological reactions.

Both discoveries--DNA structure and protein structure--were made at Cambridge University's Cavendish Laboratory. So why were these two foundation stones of the revolution in biology and medicine that dominated science in the second half of the 20th century uncovered in a British physics lab?

The great breakthroughs of 1953 rested on the strength of experimental physics at Cambridge, beginning in the late 19th century. This legacy shaped the intellectual environment in which the father-and-son team of William and Lawrence Bragg were trained, and where Lawrence Bragg--first as an undergraduate and then as a research student--developed in 1912 the ideas that led to X-ray structural analysis.

Although Max von Laue, Walter Friedrich, and Paul Knipping had discovered the diffraction of X-rays by crystals, it was Lawrence Bragg who understood how it could be exploited scientifically. Reflection by "Bragg planes"--sheets of atoms that can diffract X-rays at specific angles that are determined by the separation between sheets--enabled the Braggs to calculate the exact arrangement of sodium and chloride atoms in a crystal of salt.

William Bragg graduated in mathematics in Cambridge in 1884, and became professor of physics in Adelaide, Australia. In 1909 he returned to Britain to take up a chair at Leeds, continuing his work on the nature of X-rays. He became director of the Royal Institution in London in 1923, where he attracted some outstanding young scientists interested in the X-ray field. Among them were two recent Cambridge graduates, William Astbury and John Desmond Bernal, who became interested in the problem of protein structure--Astbury as a result of being asked by Bragg to provide X-ray diagrams of wool and silk.

Secure your copy of PS Quarterly: The Year Ahead 2023
YA-Magazine_Promo_Onsite_1333x1000

Secure your copy of PS Quarterly: The Year Ahead 2023

PS Quarterly: The Year Ahead 2023 is almost here, and available only to Digital Plus or Premium subscribers.

Subscribe now to secure a print copy of the magazine, as well as digital access to all its content, including exclusive insights from German Minister of Foreign Affairs Annalena Baerbock, US Treasury Secretary Janet Yellen, Nobel laureate economist Joseph E. Stiglitz, and more.

Subscribe Now

Bernal moved back to Cambridge as a lecturer in structural crystallography in 1927, and in 1931 was promoted to assistant director of research in crystallography, by then a sub-department of the Cavendish Laboratory. Bernal's main scientific interest was initially the atomic structure of crystals, metals, and minerals, then of hormones and sterols--and of some amino acids, the building blocks of proteins.

Astbury, meanwhile, moved to Leeds in 1928, where he also began working on amino acids and proteins. Describing his unsuccessful attempts to obtain well-ordered X-ray diffraction patterns from crystals of the protein pepsin, he wondered whether Bernal could help obtain crystals of other proteins. A friend of Bernal's named Glenn Millikan had happened to visit a lab in Uppsala, Sweden, where large pepsin crystals had been obtained, and he brought some of the crystals, still in their mother-liquor, back to Cambridge.

Bernal and Dorothy Crowfoot (later Hodgkin) obtained patterns of the dry crystals, as Astbury had, and with similarly disappointing results. But when Bernal observed the crystals in a light microscope, he noticed that as the large amount of water in the crystal lattice evaporated, they became disordered. They repeated the X-ray experiment, but with the crystal surrounded by its mother-liquor and sealed in a glass capillary, obtaining patterns with large numbers of crystalline reflections.

The results of this first defining moment in protein crystallography were published as a letter in Nature in 1934. Having deduced the presence of polypeptide chains, Astbury continued to pursue his pioneering studies of their configurations in fibrous proteins. He also obtained the first X-ray patterns of partially oriented samples of DNA.

Max Perutz, a chemistry graduate from Vienna, arrived in Cambridge in 1935 to work as a graduate student with Bernal. The next year, he was given excellent hemoglobin crystals and soon produced the best X-ray diffraction patterns to date. But the observable diffraction pattern--the intensities and positions of the individual reflections--represents only half of the data needed to deduce the structure of the diffracting object. In mathematical terms, it gives the amplitude, but not the phases--i.e., the stages in an oscillatory motion--without which the atomic positions could not be determined.

With simpler structures made up of small numbers of atoms, chemistry could provide considerable guidance as to the atomic arrangements, and a solution could thus often be found by trial and error. But proteins, which contain thousands of atoms, were far too complicated for this to work. So despite the enormous amount of excellent data that was collected, the solution remained tantalizingly out of reach.

But the faith remained that detailed information about protein structure could be obtained from the X-ray patterns in some way, if only it could be discovered. It was only natural that where chemistry fell short, physics--and its premier laboratory--showed the way forward, a way grasped by Watson and Crick in the epic breakthrough that we celebrate this month.

https://prosyn.org/X5VJjyL