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Monarch of Crystallography: Dorothy Crowfoot Hodgkin and the Structure of Large Molecules. (Women in Science 73)

Two scientists.

Two crystallographers.

Both successful, but one died young after her most significant discovery was snatched from her, while the other lived to a ripe old age after a string of ground-breaking discoveries and a Nobel Prize.  The former, Rosalind Franklin, is a household name.  But the latter, in spite of the foundational importance of her work, has always remained on the fringe of our cultural perception: Dorothy Crowfoot Hodgkin (1910-1994).

It’s one of the truly frustrating things about studying women in science – while we are willing to remember multiple men in each scientific field, we seem to be stuck in this One Scientist, One Discipline mentality when it comes to women researchers.  Lise Meitner is the one female physicist.  Marie Curie the one chemist.  Emmy Noether the one mathematician.  And Rosalind Franklin is the one crystallographer we’ve chosen to bother to remember.

In crystallography this tendency is doubly frustrating, because the early years of the field were filled with so many women of genius who deserve a place in our memory.  Polly Porter, the tireless veteran of classical crystallography.  Kathleen Lonsdale, who vastly improved x-ray crystallography by her use of Fourier mathematical analysis.  Eleanor Dodson, who worked on the computer programming that made analyzing large molecules possible.  Kalyani Vijayan, the Indian cephalosporin researcher who went on to become a materials scientist at the National Aerospace Laboratory.  And the reigning titan of them all, Dorothy Crowfoot Hodgkin, who spent decades developing methods that unlocked the structure first of penicillin, then of Vitamin B-12, and THEN of insulin.

Her famous tirelessness and independence were locked in at an early age.  If ever the phrase Salutary Neglect fit a person’s upbringing, it was Crowfoot’s.  From the age of four on, she was left in England with a nurse and her younger sisters while her parents worked in Egypt and explored the world, checking back in with their children for a month here and there before flitting off on another adventure.  Dorothy had to learn early to fend for herself, to care for her siblings when they got sick, to pay the bills from the often insufficient funds sent home by her parents, and to take her education into her own hands.

a This long distance parenting was common practice at the time, particularly for children whose parents had positions in the far flung corners of the British Empire, and as much as it strikes us as rather a sad lot to befall a child, the qualities of informal self-reliance it taught young Crowfoot were exactly those that would make her such a successful survivor in the uncertain early years of crystallography.

Crowfoot was only two years old when Max von Laue proposed an experiment to figure out exactly what X-Rays were.  With visible light, we can show its wave-like properties by using a barrier with two thin slits cut in it.  When the light strikes the slits, it ripples outwards and interferes with itself, creating a distinctive pattern of light and dark spots.  X-Rays weren’t responding to that experiment, because we couldn’t physically make the slits thin enough to produce the effect.  But then von Laue had the notion of using crystals in place of slitted barriers – the tiny spacing between the molecules of a crystal could act like slits to force x-rays to ripple out and interfere with themselves.

 

The experiment, once performed, proved that X-Rays indeed had wave properties like visible light, but more importantly, proved that you could use x-rays as a probe to investigate the physical properties of a crystal.  X-Rays striking a crystal cause the electrons of the crystals atoms to oscillate, producing waves of electromagnetic energy that constructively and destructively interfere with each other.  By meticulously recording the light and dark spots produced by incoming x-ray beams aimed at different angles to the crystal surface, you could build up a picture of the spaces between the atoms in a crystal, and thereby determine its structure.  X-Ray Crystallography was born.

Crowfoot was fascinated with growing crystals from a young age, but it wasn’t until 1929, when she was reading through scientific papers as a student in the library at Oxford, that she came across an issue of the Transactions of the Faraday Society that reviewed how x-rays could be used to determine molecular structures, and was fired with the desire to unlock hidden shapes using the methods of the x-ray crystallographer.

Fortunately, several of the field’s leading lights were working in England precisely then.  Kathleen Lonsdale had just discovered the structure of benzene working in the Royal Institution lab of William Bragg, the grand old man of crystallography.  And at Cambridge, at the Cavendish Laboratory, there was an irresistible polymath named John Desmond Bernal, who was so well versed in all fields of thought that all his friends called him Sage.

Crowfoot’s first significant work was done at the Cavendish, where she had a front row seat as Bernal, in 1934, used x-ray techniques to unveil the basic structure of the biological enzyme pepsin.  It was the first protein that had been successfully probed using x-rays, and opened up the exciting possibility that other, larger biological molecules might some day fall to x-ray methods as well.  What was once a field dedicated to sussing out the structure of minerals and salts was, all at once, science’s best hope at unlocking the dizzying complexity of proteins and enzymes.

Bernal’s pepsin work was a defining inspiration to Crowfoot, who dedicated herself to using x-rays, along with the most cutting edge analytical tools she could find, to illuminate the structures that had defeated traditional chemistry.  She returned to Oxford in 1934 to carry out her own research, and started in on the structure of insulin, which had just been introduced in the treatment of diabetes a decade earlier.  Though it could be produced, nobody knew exactly what it looked like or how it worked.

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Help support this column! Buy the book!

The difficulties one had to surmount in the early years of x-ray crystallography were daunting.  A crystal had to be made of the material you wanted to study, and some molecules simply did not want to crystallize, meaning you had to often make do with undersized or impure samples.  Then, using an x-ray powered by a high voltage power source that was likely to zap you across the room if you weren’t careful, you had to take painstaking x-ray photos at every conceivable angle to slowly build up a log of diffraction pictures which you then had to submit to Lonsdale’s badass Fourier mathematical analysis, guided by some educated guesswork about the constituent atoms, to build up an electron density picture that you might then be able to start interpreting physically, if everything went perfectly.

Crowfoot made her methods available to anybody who had an interesting crystal available, and so divided her time between insulin and other structures until the Second World War came, and with it the need to devote all research to wartime ends.  Crowfoot (who had since become Hodgkin after marrying in 1937, but who kept her maiden name for scientific publication for some time) put her insulin work on pause and set about cracking penicillin, the Wonder Cure that stood to make all the difference in wartime casualty rates.

She was an expert in the technique of Patterson maps whereby you introduce different large atoms into a crystal structure and build up from the subsequent x-ray pictures a map of vectors that point towards those large atoms, giving a sense of structure without all of the mind-numbing guess-and-check work that had plagued early crystallography.  She had had great success using these methods in breaking the structure of cholesteryl iodide earlier, and by analyzing potassium and rubidium salts of penicillin was able to crack penicillin by 1945, though for war secrecy reasons the result was not announced officially until 1949.

Penicillin was a warm up for the work Crowfoot ultimately won the Nobel Prize for, the unmasking of Vitamin B12.  Penicillin has 27 atoms to place, with a molecular mass of 243 g/mol.  Vitamin B12 has 181 atoms to place, at a mass of 1355 g/mol.  The leap in complexity was intimidating – trying to piece together a three dimensional structure from the interactions of hundreds of rippling electrons combining to produce two dimensional interference cross sections that must be interpreted one by one was a task of years when there were just 27 atoms contributing, but 181?

Fortunately, Crowfoot was not only pushing the Patterson methods of heavy atom replacement that served her well with penicillin, but was also eager to make use of the first wave of computers she could get her hands on to handle the laborious process of crunching through the mathematical analysis of the x-ray images.  Using punch card programs run at night when computers weren’t in demand by the departments they actually belonged to, Crowfoot created a guerilla computing squad within her research department to break the impossible into the merely superhuman.

A modern rendering of Vitamin B12 (from Diamond Light Source)
A modern rendering of Vitamin B12 (from Diamond Light Source)

From 1948 to 1955 she and her team slogged away at B12.  Their end model was not only admired for its elegance, and as a testament to what could be accomplished by pushing crystallography to its bleeding technological edge, but was a declaration that crystallography would shirk no task, a statement of daring that Crowfoot underlined with her next project, the return to insulin.

Insulin has 788 atoms wrapped up in two main chains of amino acids connected by disulfide bridges.  It’s a bit of a thing.  At the time, no full map of a protein had been completed.  Bernal’s pepsin structure was a rough sketch to prove the principle, but as was typical of his style, he never followed it through to completion.  However, Max Perutz, who was, like Crowfoot, an early student of Bernal, had been steadily working on hemoglobin since the late 1930s, and stood a good chance of cracking it before she could ramp her original efforts with insulin back up to speed again.  As it happened, he solved hemoglobin in 1959 after two decades of research on that single molecule, while it took Crowfoot until 1969 to break insulin.  She was devastated at not being the first to completely describe a protein’s three dimensional structure, but between her work in the lab and her role as a passionate advocate for world peace, nuclear disarmament, and international scientific cooperation, she didn’t allow herself much time to mourn the loss.

Frustrated crystallographers don’t get sad.

Frustrated crystallographers strap on their x-ray cannons and solve 788-atom structural maps.

#CrystallographyRealness

It took a few rounds of voting, but Dorothy Crowfoot Hodgkin eventually won the  Nobel Prize in 1964 for her work on solving vitamin B12’s structure, and was also the Royal Society’s Wolfson Research Professor since 1960, two achievements that gave her international fame which she used to argue for open scientific exchange with communist China and Russia, and a stable income which she used to keep her lab together and independent of Oxford’s on-again, off-again support of her work.  That independence shaped Crowfoot’s famously informal lab management style – rooms cluttered with papers while researchers played cricket in the hallways with bats and balls formed from folded and wadded sheets of calculations, scientists calling each other by their first names, and everything funded by outside sources as needed.

Meanwhile, Crowfoot continued the tradition of political engagement she had learned from Bernal’s example.  An idealistic communist himself, he exuded confidence in the potential of a future freed from the oppressive structures of international capitalism.  While she didn’t follow him to that extent, Crowfoot did head organizations that brought Cold War nations together to discuss the future of nuclear disarmament, and vocally criticized America’s intervention in Vietnam.  She fostered strong connections with Chinese and Indian crystallography laboratories, publishing their findings to Western audiences and working to include them in the international community.

What she ultimately left behind, besides her immortal scientific work, were pockets of people who considered Dorothy Crowfoot Hodgkin to be uniquely “theirs.”  She was so welcoming to people of every walk of life, and so eager to let science thrive without borders, so fostering of new talent and open to new methods of solving old problems, that there is hardly a sour word to be found against her.  While other researchers ossified and bitterly faced irrelevance, Crowfoot never ceased to be at the center of things, even when her body, which had suffered severe arthritic pains as early as her twenties, slowly betrayed her.  She died in 1994 while in a state of unconsciousness, at home, surrounded by family, a quiet end to a life of curiosity, work, and deep attachment to humanity.

 

FURTHER READING:  Georgina Ferry’s Dorothy Hodgkin: A Life (1998) is one of the best biographies of women in science out there.  It is a masterful mix of the history of crystallography, the travails of international science during the Cold War, and the curious quirks of Hodgkin’s particular approach to research and life.  Emotionally poignant without being overwrought, and scientifically detailed without requiring specialist knowledge, it just gets better with each re-reading.

 

A NOTE ON NAMES: We know her as Dorothy Hodgkin, but professionally she used the name Dorothy Crowfoot Hodgkin, and her original papers, that established her reputation, were under the name of Crowfoot.  As such (and because her husband was a serial adulterer who originally wanted her to abandon her research after marriage) I’ve gone with Crowfoot throughout this article.

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