When you look at the world, what do you see? Nobel prize winner Dorothy Hodgkin (1910–1994) saw puzzles waiting to be solved. Using x-ray crystallography, Dorothy solved some of the most challenging puzzles of her time: the complex atomic structures of penicillin, vitamin B12 and insulin.
So, what is x-ray crystallography? Put simply, it’s a method for discovering the atomic structure of a molecule by studying how x-rays bounce off a crystal of the molecule. The main requirement of the crystal is order. Like wallpaper which has a repeating two-dimensional pattern, a crystal has a repeating three-dimensional pattern. Once you have a good-quality crystal, you shoot a beam of x-rays at the crystal, they bounce off the atoms in the crystal and you record the resulting pattern made by the diffracted x-rays. From these patterns, you can work out the structure of the molecule (with the help of a lot of mathematics and a little imagination).
From a young age Dorothy was fascinated by crystals and as a teenager she was inspired to become a scientist by the 1923 and 1925 Royal Institution Christmas Lectures by Sir William Bragg, a pioneer in using x-rays to study the atomic structure of materials.
Dorothy went to Somerville College, Oxford to study chemistry. Luckily for her, the university set up its first x-ray crystallography lab just as she was due to start her undergraduate project. As I’m writing about Dorothy, I’m sure you can guess that her project was a great success. In fact, her thesis on the structure of thallium dialkyl halides was published as a short note in Nature. *Keep jealously under control*
Dorothy did her PhD at Cambridge, under J. D. Bernal. Working in Cambridge opened her eyes to the potential of x-ray crystallography to solve the structure of complex biological proteins. She carried out initial measurements on sterols and pepsin crystals (and published a lot!), but she returned to Oxford to focus on cholesterol. Soon Dorothy published the first structure of a steroid, cholesteryl iodide, with Harry Carlisle, but this was just the first of many biologically important molecules that Dorothy would solve.
In 1940, Dorothy wasn’t the only future Nobel laureate working in Oxford. Howard Florey and Ernst Chain were culturing penicillium mould to extract the new and powerful antibiotic, penicillin. The day after their first historic experiment showing that penicillin could protect mice against streptococcal infections, Chain ran into Dorothy “in a very excited state” and promised her some crystals. Easier said than done. Penicillin proved to be extremely difficult to crystallise. At first, Dorothy and her research assistant, Barbara Low, could only work on smaller, breakdown products of penicillin such as penicilliamine and penicillic acid. In 1943, they started working with penicillin crystals, and in 1945, with the help of an early computer, they finally had the structure which contained (for the chemists out there) a thiazolidine ring and a β-lactam ring, much to everyone’s surprise. If you think you’re having a slow month, take heed! It took almost five years to discover this one structure. As Dorothy herself noted,
“I seem to have spent much more of my life not solving structures than solving them.”
But the effort paid off, and the discovery of penicillin’s unusual structure led to the development of a whole new class of β-lactam antibiotics. Dorothy’s model of penicillin was featured as Google’s Doodle on 12th May 2014, her 104th birthday.
Dorothy was an encouraging mentor to many enthusiastic young researchers. The most notable, perhaps, was Margaret Thatcher (then Roberts), the first female prime minister of the UK and the first with a degree in science (interestingly, she was said to be more proud of the latter)! Thatcher spent a year in Dorothy’s lab trying to determine the structure of the antibiotic gramicidin B (which wouldn’t be solved for another 30 years). It turned out that x-ray crystallography was not for her, but the pair maintained a warm relationship, and later Thatcher installed a portrait of the scientist in 10 Downing Street.
Dorothy herself was very politically engaged, but far to the left of her famous student. Dorothy’s husband and many of her close friends were Communists and, although Dorothy was never a card-carrying member, she was denied a visa to the US for her left-wing views. She later became President of Pugwash, a group which campaigns for nuclear disarmament (and itself won a Nobel Peace Prize in 1995).
After the war, Dorothy’s lab continued to churn out papers on a huge variety of molecules. In 1948, the new problem was vitamin B12. This vitamin is essential for the normal functioning of the brain, and had recently been discovered to treat pernicious anaemia rather effectively. Two rival pharmaceutical companies, Merck and Glaxo, were very interested to discover its structure. Dorothy was working with Glaxo, but she discovered that John White, a British scientist working at Princeton, was also working on vitamin B12 with Merck. There was an understanding in the x-ray crystallography community that different groups did not compete over the same structure, and so Dorothy suggested that they keep each other informed over their progress. She noted later that Glaxo must have thought her wholly unreliable, but she thought it was the honourable thing to do.
Dorothy’s group was making progress, but the complex structure was proving extremely difficult to untangle, as the mathematics involved was so computationally intensive. A group in California stepped in to lend a helping hand with their new, speedy computer, and together they solved it!
This discovery was huge and in 1964 Dorothy Hodgkin won the Nobel Prize for Chemistry, but she still wasn’t finished in the lab. Dorothy had decided to solve the crystal structure of insulin in 1934, but it was 35 years (and a Nobel prize) before she actually published the structure. The technology was just not advanced enough back then, but with continued effort (just a bit of an understatement) Dorothy and her lab discovered the structure. Dorothy’s own words make it clear how important this final major discovery was:
“I used to say that the evening I developed the first x-ray photograph of insulin in 1935 was the most exciting moment of my life. But the Saturday afternoon in late July 1969, when we realised that the insulin electron density map was interpretable, runs that moment very close.”
Dorothy Hodgkin’s story is not one of a triumphant but lonely, female figure who had to sacrifice everything to be a scientist in a world built for men. On the contrary, she was married with three children. Somerville, her forward-thinking women’s college at Oxford, even gave her paid maternity leave (a first for the college and the university). Her colleagues (including many women) admired her and sought her advice. She was an extremely successful scientist and that is how they saw her, irrespective of her sex. It is certainly how she saw herself.
Thank you to Vicki Hughes from the Nuffield Foundation for suggesting Dorothy Hodgkin. Who would you like me to write about next? Please leave your suggestions in the comments below, or tweet me @labcoatlucy!
Dorothy Hodgkin: A Life by Georgina Ferry (1998)
The University of Oxford’s Bodelian Library has an incredible collection of Hodgkin’s notes and data.