Further exploration of the possibilities was slow going. Chemists were needed to really explore the possibilities, but there wasn’t a dedicated team, and failures left researchers thinking penicillin might not be of practical use to medicine. Then, in 1940, scientists Howard Florey and Ernst Chain conducted an experiment that showed some promise—mice injected with both bacteria and penicillin lived weeks longer than those injected with just bacteria, which died within a day.
Hodgkin Joins the Effort to Understand Penicillin
War put the pressure on. Clinical trials in 1941 showed penicillin could be miraculous in humans. There were so many soldiers in World War II who needed this medicine, but it was still in its infancy and could not be mass-produced. Scientists needed to know the structure of penicillin to do that. Hodgkin was on the team of British and American scientists from universities and corporate laboratories in the United States and the United Kingdom working together to solve this.
As an X-ray crystallographer, Hodgkin needed penicillin crystals in order to determine penicillin’s structure. The team of scientists developing this medicine did so collaboratively, with a spirit of international partnership. Hodgkin obtained some crystals also through community effort. Many people and organizations from different parts of the world helped her. In 1943, US pharmaceutical company Squibb isolated mold growing on a melon into a sodium salt called benzylpenicillin (later known as penicillin G). British chemist Robert Robinson, who would win the Nobel Prize in 1947, brought the crystals from the United States to Hodgkin. The British Royal Institute and the US military worked together to obtain and transport more needed crystals in 1944.
Hodgkin is known as pioneering the use of X-ray crystallography in complex organic substances like proteins. She was first in another way too: In the 1940s, she used IBM analog computers to help complete calculations. This was one of the first uses of a computer, and definitely the first time one was put to the task of solving a biochemical problem.
PRECIOUS CARGO
In the stories of crystallography, there are always fun little asides about people carrying crystals. The structures that crystallographers study are real, even if they’re incredibly tiny, and so are the crystals they live in. A protein crystal, for example, may be 0.1 millimeters (0.004 inches), the size of the smallest grain of sand you can see. And within that speck are millions of molecules. Like a snow globe with a city built inside it, a crystal can hold a whole world too. When Hodgkin was working with Bernal on pepsin, other scientists were as well. John Philpot, a chemist and biochemist from Oxford, had made some pepsin crystals in Scandinavia. Glenn Millikan, a colleague of Bernal’s and Philpot’s, told Philpot that Bernal would do anything for some of those beautiful crystals. Philpot casually said he could just take a tube full of them, and Millikan carried them home to Oxford in his shirt pocket. In remembering this story later, Hodgkin suggested that the fact that they survived the journey in their mother liquor was “the important part, scientifically, of the story.” To someone who isn’t a scientist, this could be rather humorous. To photograph a complicated structure may seem like the true scientific advancement. Of course, to an advanced scientist such as Hodgkin, the intrigue is in the details. She knew that understanding how to handle crystals better would mean the world to future study.
B12 AND THE NOBEL PRIZE
Figuring out penicillin did not mean that Hodgkin took a vacation. The next challenge was always the goal—Hodgkin liked to work; she liked what she did. Her next puzzle was vitamin B12.
Humans don’t naturally produce enough B12 for healthy living, so we must supplement with B12 from diet. If a person’s diet is deficient or if a body can’t absorb the vitamin, the effects can be fatal. If scientists knew its structure, they could, as with penicillin, understand how it reacts with the body and synthesize it.
After the vitamin was isolated in 1948, Hodgkin started looking at it. By 1961, she had a complete answer. While her mentor, Bernal, thought that she’d get the Nobel Prize for her work on penicillin, it seemed Hodgkin had to prove herself in a big way not once with penicillin but twice, with both penicillin and B12. And then she had to wait—she won the award three years after she calculated B12’s structure.
Her friends seemed to mind the delay in international recognition of her work more than Hodgkin did. Max Perutz, who received the Nobel Prize for Chemistry two years before Hodgkin, said he was “embarrassed” to be recognized in such a way before she was, because she’d started having scientific success before he had. But Hodgkin did not think she deserved major international recognition by any particular time. Her acceptance speech for the Nobel Prize emphasized gratitude for the scientists who came before her and those who worked as her colleagues, “on whose hands and on whose brains I have relied.” Her speech also expressed generosity, wishing for all her peers congratulating her to one day be standing at the place of honor. She told a story of attending a party in England the night before her trip to the Nobel ceremony in Sweden:
DOROTHY AND THE PUGWASH MOVEMENT
As invested as Dorothy Crowfoot Hodgkin was in science, she was passionate about social justice. Her work for peace took a great leap forward after the publication of the Russell-Einstein Manifesto in 1955.
Mathematician Albert Einstein also believed there was work to be done outside the classroom. He, philosopher Bertrand Russell, and many other leading intellectuals gathered in London in 1955 to express great concern about war and science’s role in war. They feared that impressive advancements in technology, such as the creation of the atomic bomb, would also be humankind’s downfall. They warned that people didn’t even know the level of destruction possible because of the new technology. They called on scientists from all fields to join together to figure out what to do about this, working toward a peaceful end.
The Pugwash movement grew out of this manifesto. The group still brings together scientists and policy makers “to seek the elimination of all weapons of mass destruction, to reduce the risk of war especially in areas where weapons of mass destruction are present and may be used, and to discuss new scientific and technological developments that may bring more instability and heighten the risk of conflicts.” Hodgkin was president of the group for more than a decade, until 1988.
During World War II, the British military asked her to join the war effort, but she was skeptical about that, and her boss agreed—she was, after all, working on penicillin at the time, and that seemed much more important!
Hodgkin, pictured here meeting fans of hers from the Swedish royal family, received the Nobel Prize in Chemistry in 1964.
“My hosts advised me then, telling me how one should reply in Arabic to congratulations that one receives, congratulations on some very happy event: the birth of a son, perhaps or the marriage of a daughter. And one should reply: ‘May this happen also to you.’ And now even my imagination will hardly stretch so far that I can say this to every one in this great hall. But at least, I think, I might say to the members of the Swedish Academy of Science: ‘In so far as it has not happened to you already, may this happen also to you!’”
ELSEWHERE IN X-RAY DIFFERENTIATION
This book celebrates Dorothy Crowfoot Hodgkin’s life and work, but it would be wrong to ignore DNA as the most major discovery connected to X-ray differentiation. It was not one of Hodgkin’s projects; though, because she was such an important scientist, she was invited to view the results privately before they were released to the public in 1953. Also, the story involves a scientist who was relatively excluded from history because she was a woman, as well as a scientist who worked as much for peace as he did for pure science, sometimes to the detriment of his science. Both shared commonalities with Hodgkin. This story also showcases X-ray differentiation as the multidisciplinary tool it is.
DNA, deoxyribonucleic acid, is the body’s instruction manual. It’s what makes us who we are. It’s our structure. Everyone has unique DNA. We didn’t know what DNA looked like, and therefore how it r
eally worked, until 1953. Thanks to that discovery, we have made rapid advances in everything from gene therapy to forensics. We now know more about who we are and how genetic information is passed from parent to child.
Four scientists are linked directly to DNA’s discovery: Rosalind Franklin, Maurice Wilkins, James Watson, and Francis Crick. Franklin studied chemistry at Cambridge in England and then X-ray crystallography in Paris. Her first job after her studies was to update the crystallography lab at King’s College London in order to work on this strange thing called DNA. Wilkins was a Cambridge-trained physicist also working on DNA at King’s College. He inadvertently got Watson, an American, interested in DNA when Watson heard Wilkins’s speech at a zoology conference in 1951. Watson had studied zoology as well as genetics and viruses. He found work at the Cavendish Laboratory, where physicist Crick was working with Max Perutz, who was working with William Bragg (one of Hodgkin’s teachers and mentors). Crick was supposed to be working on X-ray crystallography of hemoglobin, but Watson persuaded him to look to DNA instead.
Linus Pauling, an American chemist, was almost the fifth scientist in the race to discovery. He created the model-building method Watson and Crick ultimately used. Pauling’s work had started people thinking of helixes, the form DNA has, but he ultimately proposed a threestranded helix, and DNA is a double helix. Some people think he could have figured DNA out first, but he too would have needed Franklin’s amazing, one-of-a-kind photographs, and he didn’t stand a chance of getting them. He was outspoken in politics, as were some of his colleagues, including Hodgkin. Because of that, he was denied a passport by the US government for years. Ultimately, he was allowed to leave the country to accept the first of his two Nobel Prizes, in chemistry, in 1954, the year after DNA’s discovery was announced. (He also won a Nobel for Peace in 1962.)
Rosalind Elsie Franklin was, like Hodgkin, a British chemist and crystallographer. Her role in the discovery of the structure of DNA changed the world forever.
Franklin had used X-ray diffraction and photographed DNA. Without Franklin’s knowledge, Wilkins, along with Perutz, showed her work to Watson and Crick, and that was the key to the puzzle. Because of her photographs of two distinct forms of fibrous DNA, they knew that DNA was a double helix, and they knew its dimensions.
INSULIN, FINALLY
Hodgkin turned fifty-nine years old in 1969, and the world was in flux. There were wars, like the one in Vietnam, and fights for civil rights, growth in feminism, and the Stonewall riots. Hodgkin was about to take new steps, both in her career and in social justice. She had finally wrapped up what she had started more than thirty years ago. She’d finally calculated insulin’s structure. In many ways, insulin was a defining substance for Hodgkin. Its role in her life started well before her first photographing it when she was in her twenties.
More Family Inspiration
When Hodgkin was fourteen, her mother connected her with their distant cousin Bobby, a biochemist. Later, he would be known widely as Sir Charles Robert Harington and would go on to hold such illustrious positions as director of the National Institute for Medical Research in Great Britain. His first news-making success was to isolate thyroxine, T4, a thyroid hormone used to treat hypothyroidism. It’s also the thyroid hormone that, if it’s being produced at low levels, causes hypothyroidism. Hypothyroidism is a condition in which the thyroid gland, which is located in the neck and helps to regulate growth and development, is underproducing. This can lead to feelings of fatigue and depression and, if untreated, serious concerns such as heart disease and pregnancy complications. His synthesizing of this thyroid hormone would have important medical implications. By understanding how thyroxine is structured, he could understand what it does and how, and he could replicate it in the lab. People naturally low in thyroxine could take his synthesized versions.
Hodgkin’s mother asked her if she was inspired by their cousin’s work discovery. Hodgkin said yes, and Molly wrote to Bobby for advice. He suggested D. S. Parsons’s book Fundamentals of Biochemistry. In it, Hodgkin found a description of the isolation of insulin. She was fascinated by the hormone.
With the understanding of insulin’s structure, scientists could understand how it helped lessen diabetic symptoms and modified it to increase its benefits. With Hodgkin’s deciphering of insulin’s structure, she again made a huge contribution to the medical community. She also made another professional leap forward. Vitamin B12 had been the largest molecule Hodgkin had been able to figure out. Now she’d had success on the other end of the spectrum. Insulin is one of the smallest protein molecules.
When you send X-rays through a crystal, a photograph of the inside of the crystal is created. Using math to “connect the dots,” X-ray crystallographers can draw and then create 3-D models of molecules.
CHAPTER
THREE
WHERE THERE’S A CRYSTAL, THERE’S A STRUCTURE; WHERE THERE’S A STRUCTURE, THERE’S UNDERSTANDING
It can be so easy to skip wondering why an object is what it is and jump to immediately thinking about what it does. This is especially true today because we live at a time when we understand so much.
Even if we ourselves don’t understand something, we just expect that thing to do what it does because it has behaved that way a thousand times before. There was a time in the not-too-distant past when homes didn’t have electricity; now, we flip a switch on the wall in even the most basic of structures, and the room is illuminated with light. We don’t usually think about what is special about electricity that allows it to cast artificial light. We just think about how we need electricity in order to be able to see at night. But the only reason we can so casually incorporate something like electricity into our lives is because people before us figured out its properties. That’s the role of X-ray crystallographers: to figure out what something is made of in order for us to understand it better. Specifically, they study anything that can be crystallized, and that includes many things, from biological building blocks to medicines and viruses and, yes, rocks and minerals.
WHY UNDERSTANDING WHY IS SO IMPORTANT
Because we know the structure of water, we can cook with it. The structure tells us at what temperature water boils (100 degrees Celsius and 212 degrees Fahrenheit). We know to press the graphite of pencil and not a diamond to paper because even though they’re technically the same thing—carbon—they’re completely different in structure. We know that muscles contract because they’re made of two proteins, actin and myosin, and we know the structure of those proteins. So we know how they slide over each other repeatedly, and how two other proteins, tropomyosin and troponin, control actin and myosin. Again: because we know what makes tropomyosin and troponin tick, we know when they’ll tick. Max Perutz talked about all of those whats and whys when he was trying to define why structural analysis is so important.
Why teeth are sometimes pink is another question that can be answered by studying a substance’s composition. Hodgkin came across this interesting, and rare, phenomenon via the work of a family friend, Sir Archibald Garrod. He was retiring from Oxford not long before she entered the university, but before he left, she was able to secure a tour with him of the new biochemistry lab. In his research, Garrod had discovered a family with pink-tinted teeth. This was caused by the metabolism of porphyrins having gone astray. Porphyrins are chemicals that occur naturally in the body, but too many of them, and the body can start to look a little strange. For example, people suffering from some kinds of porphyria can have purplish urine (the word for these diseases comes from the Greek porphyrus, meaning “purple”). Understanding the structure of hematoporphyrin, a type of porphyrin, allowed Garrod to understand the reason for the strangely colored teeth. The story stuck with Hodgkin for the rest of her life. It was one of her early inspirations to learn the composition of something in order to understand what it does.
The father-and-son team of William and Lawrence Bragg figured out the structure of diamonds in 1913 and then, eleven years later, the
structure of graphite. William Bragg came to be considered the father of X-ray crystallography, so his and his son’s work really set the stage for Hodgkin’s research and advancement of crystallography.
Diamonds are known to be incredibly hard. This can be seen when looking at a diamond’s structure: carbon atoms are arranged in a three-dimensional tetrahedron, sturdy in all directions. It’s no wonder a diamond isn’t strong with a composition like that. Graphite is also made of carbon, but its atoms are arranged in two-dimensional hexagonal nets that can slide past one another. This makes graphite very soft, so soft that it leaves a mark when it’s dragged across a surface. If we were going to make a pencil in a laboratory, we’d have to know how the atoms of graphite are arranged, or we could wind up making a diamond and leaving no mark at all. If we know the order of atoms in a substance, we know its material properties. Then we know what it does and what we can do with it.
We can thank crystallography and its practitioners, crystallographers, for allowing us to understand so much about the world around us.
WHAT IS CRYSTALLOGRAPHY?
Crystallography is a long word for the study of tiny things—some of the tiniest things known to us, atoms—and how they group together to form objects or substances. An atom is the smallest complete component of a substance, and everything is made up of atoms. Crystallographers, or scientists who study crystallography, also study molecules. Atoms that are joined together form molecules. So, everything is also made up of molecules. Atoms always arrange themselves the same way for each type of molecule. That’s called a structure.
Dorothy Hodgkin Page 3