Dorothy Hodgkin

by Kristin Thiel

  You may have seen all this represented with marbles connected by sticks. In those drawings or models, the marbles symbolize atoms and the sticks symbolize the bonds between atoms. Together, they form molecules. The marbles and sticks of a diamond look like a box, and the marbles and sticks of graphite are arranged like nets. If you had to guess how each substance would behave based on those two models, you might assume the one with the boxy structure would be stronger than the one that looks rather like something you could nap on. Again, we can see the big picture of a substance—how it will act in the world and how it will react with other things—once we know what it is by itself. How it is made, down to the smallest detail.

  A SUMMARY OF HODGKIN’S SCIENCE

  Hodgkin’s science feels complicated in part because we don’t experience it in our daily lives. It affects our daily lives, though. Because of it, we know what so many things in our world are, which means we can make use of those things and improve our lives. But we can’t see or feel atoms, and we don’t often interact with X-rays. Even if we did, we couldn’t see those either.

  Hodgkin was a pioneer in protein crystallography. Proteins are polymers, long chains of repeating units folded into three-dimensional shapes that are larger and more complicated than other biological molecules. The first video in a two-part Royal Institution video on understanding crystallography explains it well: Picture a long string of beads. That’s the start of a protein molecule. Now let that string pile into your palm. It’s a jumble, isn’t it? That’s what each protein molecule looks like. (Remember, this is just a helpful visual, not an exact representation of a protein molecule. A real protein molecule doesn’t fold up in random ways as a string of beads does. It folds in a now predictable, known manner, but it looks about as complicated as that pile of beads.) If you were just figuring out what a protein molecule looked like, how could you begin to guess that complicated shape? You couldn’t. You’d need to see it. But you couldn’t do that because the molecule is much too small, even with a microscope.

  In comes the use of X-rays. If you shoot a vial of protein with X-rays, you could see the molecules inside the protein, just as you would see the bones of your hand if you shot it with X-rays. Unfortunately, naturally, there are millions of these molecules floating around in one small tube of protein, turning this way and that. If you took an X-ray of a pond of fish, the image the X-ray produced would be confusing because at the time it was taken, the fish would be moving, and some would be facing one way and some the other. You wouldn’t be able to tell from the X-ray image what a fish looked like because the rays would catch different parts of different fish. You would need to get the fish to tread water, all facing one way. That’s what crystallization does to a substance. It forces the molecules to line up in one direction, equal spaces between them. This way, when you shoot X-rays at the molecules, the shadows they cast make an accurate picture of the tiny shapes.

  UNDERSTANDING ATOMIC AND MOLECULAR STRUCTURE

  Atoms and molecules and the way they arrange themselves in an object, which then makes the object, are very important to crystallography. Understanding that is the whole point of that science. So, let’s make sure the definitions of atoms and molecules and the way they work together in a structure are clear.

  Consider this sentence: I am listening to music.

  What are the pieces of the sentence? Words. Words put together make a sentence. Are words the smallest parts in a sentence, or can you cut the words into pieces? Yes, you can divide words into smaller parts: letters. Letters put together make words. Can you cut letters into anything smaller? Sure, you could write just a dot from an i, or you could cut the tail off a g, but that dot and that tail are not meaningful things on their own. So, no, letters are the smallest complete pieces of a word. And can you arrange the letters and words in any old way to form the same sentence? Is “I am listening to music” the same as “Ili amtostmusic icening”? Listening is always l-i-s-t-e-n-i-n-g, and music is always m-u-s-i-c, just like atoms always arrange a certain way for one molecule and another way for a different molecule. And the words, or molecules, must then also arrange themselves in a certain order.

  Let’s bring this back to crystallography. In this example, we could imagine each letter as an atom and each word as a molecule. Put together, they form a sentence. There can be no words without letters and no sentences without words.

  We don’t normally think of sentences in terms of atoms and molecules, but now that we understand the basic way those things work together, we can see how they work in things that scientists do study. Let’s keep it simple by looking at something we use every day, usually more than once a day. Even if you haven’t brushed your teeth, taken a shower, or held a glass under the kitchen faucet yet today, you’ve probably flushed the toilet—so, yes, you’ve probably used water today.

  What is water? It’s ... just water. Right? Even something that seems so basic is made up of atoms and molecules. You may have heard water called H2O. H stands for the atom hydrogen and O for the atom oxygen. Two hydrogen atoms bonded, or stuck together, with one oxygen atom makes one molecule of water. The molecules bond together at certain points: The oxygen atom of one molecule does not stick to the oxygen molecule of another. Instead, the oxygen of one always connects to the hydrogen of another. Now, go pour yourself 8 x 1024 molecules of water (that’s about a glass full), and we’ll get back to this book’s hero: Dorothy Crowfoot Hodgkin.

  You can’t feel or see the atoms or molecules in your glass of water, so they must be extremely small. How does a scientist see which atoms and molecules make up a thing, and how those atoms and molecules stick together? How can you understand something whose parts you cannot see or feel? That was the challenge Hodgkin faced. Though she was far from the first chemist to look at the atomic and molecular structures of things, she helped make it easier to do so. Because she used a revolutionary technique, X-ray crystallography, she was able to make discoveries a lot sooner than scientists would have without the use of X-rays.

  Chemists before her had to conduct lengthy experiments that took a lot of effort and probably were at least a little bit messy. Remember that penicillin was discovered basically because of a sink of dirty dishes. Even before those dishes found their way to the sink, they were dirty— Alexander Fleming had purposefully filled them with staph bacteria.

  Emil Fischer was one such chemist who came before Hodgkin. He died only nine years after she was born, so when he was working, the world was a very different place from when Hodgkin was working. He might put a substance through reaction and degradation. This would help him hypothesize a molecular structure. Then, in order to check his work, he’d try to synthesize the substance. Fischer also used oxidation and epimerization. Picture a lab of bubbling liquids and sparking reactions. Hodgkin’s work required no less brainpower or effort, but it required a vastly different kind of laboratory. Fischer had to physically manipulate substances. Because of their complicated and small structures, this was a lengthy process, and he could only expect to progress so far. There are limitations to all forms of experimentation. Scientists needed X-ray crystallography to take their research to the next level and learn about substances they could not have learned about before, at least not easily, such as proteins.

  A water molecule’s structure is two hydrogen atoms (shown here in blue) attached to one oxygen atom (red).

  THE EARLIEST DAYS OF CRYSTALLOGRAPHY

  Crystallography can be traced back to the late 1700s. While it has changed a lot in 250 years, one thing seems to have stayed the same: its ability to surprise even the most curious and open-minded of scientists. Hodgkin said her work often showed her a structure that completely surprised her. Crystallography itself started in 1781 with an unintentional fumble.

  Crystallographers now study anything that can crystallize into an ordered set of molecules, which even includes things that don’t seem very solid, like viruses, fibers, and gases. But the science started with a crystal more of the sor
t you might think of when you hear that word: a beautiful, jagged chunk of calcite. In 1781, Rene-Just Haüy, who would come to be considered the creator of crystallography, was looking at a friend’s beautiful new piece of calcite when he dropped it. Picking through the pieces, he noticed that the mineral had shattered in a very unique way. The shards did not look like pieces of a broken cookie, each one ragged and different from the other. Instead, each piece had smooth sides that met at constant angles. He later broke the pieces further and found the pattern continued. No matter how small the piece, it always broke the same way—he couldn’t make it break along different lines or crumble it. This was the start of a theory of crystal structure.

  Through the 1800s, scientists like Ludwig Seeber, Gabriel Delafosse, August Bravais, Leonhard Sohncke, Arthur Schoenflies, and Evgraf Fedorov continued the experimentation. Then, in April 1912, Max von Laue did something for which he’d win the Nobel Prize: he created X-ray crystallography, which Dorothy Hodgkin would use to change the world.

  MODERN CRYSTALLOGRAPHY

  The Definition and Function of X-Rays

  Let’s begin by understanding what X-rays are. X-rays were not known until 1895, when Wilhelm Röntgen discovered them. (He too would win a Nobel Prize, for his work with X-rays.) Röntgen was studying a different kind of ray of light, called a cathode. He noticed that a screen coated in a special substance glowed when he aimed the cathode rays through the X-ray tube, but he knew that the rays could not be striking the screen and causing the glow; they couldn’t travel that far. That meant there had to be other rays of light, which he hadn’t known existed, also present and traveling farther than the cathode rays. Röntgen held his hand up between the X-ray tube and the screen and saw his bones projected on the screen!

  X-rays are rays of light. X-rays have a short wavelength, which allows them to pass through objects. This is important because this allows us to see inside objects. Think about the use of X-rays that most of us know: photos taken of the human body for medical reasons. Think about how you cast a shadow when visible light, from the sun or a flashlight, hits you. Bones, which are denser than other parts of the body, cast shadows when X-rays hit them. In a medical X-ray, doctors pay attention to that. Crystallographers pay attention to what else happens: that some of the light scatters.

  The electromagnetic spectrum shows different kinds of light waves and where X-rays fit in that series.

  The Unique Way X-Rays Travel

  When an X-ray strikes an atom, something interesting happens. Most of the light—more than 99 percent of it—passes through the atom. The small bit of remaining light scatters, shooting out from the atom in different directions. A very small particle of matter that has a negative electric charge, called an electron, travels around an atom. The X-ray’s interaction with the electron causes a small amount—less than 1 percent—of its light to diffract, shoot out from, or scatter.

  THE X-RAY ANALYSIS OF COMPLICATED MOLECULES, NOBEL LECTURE, DECEMBER II, I964

  Each Nobel Laureate, or recipient of a Nobel Prize, gives a Nobel Lecture prior to the Nobel Prize Award Ceremony. This excerpt is from Hodgkin’s presentation:

  “Our early attempts at structure analysis now seem to be very primitive. The crystal structures of cholesteryl chloride and bromide proved not sufficiently isomorphous to solve by direct-phase determination. We moved over to cholesteryl iodide, where the heavier atom was both easier to place in the crystal from the Patterson synthesis and contributed more to the scattering. Harry Carlisle showed it was possible to place the atoms in three dimensions by calculating sections and lines in the three-dimensional electron-density distribution with phases derived at first from the iodine contributions alone; it took him months to make calculations on Beevers-Lipson strips which now would take fewer hours. The atomic arrangement found completely confirmed the sterol formula as revised by Rosenheim and King and Wieland and Dane, following Bernal’s first X-ray measurements. We sought for a compound of more unknown structure.

  We were encouraged to try our operations on penicillin by Chain and Abraham before ever the antibiotic itself was crystallized; I grew crystals for X-ray analysis from 3 mg of the sodium salt flown over during the war from the Squibb Research Institute to Sir Henry Dale; the crystals were grown under the watchful eyes of Kathleen Lonsdale, who brought them to me from London. Later, we also grew crystals of potassium and rubidium benzylpenicillin, hoping again for an isomorphous series. But first the sodium salt was not isomorphous with the other two, then the potassium and rubidium ions were in such positions in the structure that they did not contribute to many of the reflections.”

  • Think of an atom as a marble.

  • Think of an X-ray as an arrow.

  • The arrow shoots toward the marble.

  • Most of the arrow continues on through the marble; pieces of it break off and scatter in different directions from the marble.

  Laue’s Groundbreaking Experiments

  Even after Röntgen’s discovery, X-rays were mysterious for many years. Beyond not knowing what use they could have, scientists weren’t even sure what they were. Laue’s experimentation proved that X-rays are a form of electromagnetic radiation. Radio waves, visible light, and infrared light are other forms of electromagnetic radiation.

  Once he knew what X-rays were, Laue could start to imagine what they could do. That sounds like Hodgkin’s work too. She knew that we need to know the structure of things like penicillin and B12—in other words, what those things are—before we can know what they do and how we can use them.

  Knowing that X-rays are electromagnetic, Laue wanted to see how they would react when they came in contact with an object, specifically with each of the object’s atoms. Remember that Haüy’s fortunate accident showed how smoothly crystals break. So it was assumed that the atoms within them were lined up in even, regular intervals. Laue further guessed that X-rays could fit through the spaces between atoms in crystals. He felt he could learn something by seeing how X-rays moved through crystals. He shot an X-ray through a crystal, with a photographic plate on the other side, to capture an image of what happened. Even after looking at the images, he wasn’t sure what he was learning.

  William Bragg’s ionization spectrometer was the prototype of all modern X-ray diffractometers, such as this one.

  That was all right. Just trying—not necessarily understanding or succeeding—is an important part of science. The scientists who continued Laue’s work agreed. William Bragg, the father in the fatherson team who took X-ray crystallography to the next level, admired Laue for creating a new science.

  Fourier Transform

  Just as Röntgen lived before his X-ray discovery could be used to its full extent with crystallography, so Jean-Baptiste Joseph Fourier (1768–1830) lived before his mathematical discovery could become the mathematical underpinning of crystallography. So he did not figure out this equation with structural biology in mind, but it’s turned out to be quite useful for that. If you use the Inverse Fourier Transform to measure the scattering, you can work out mathematically the shape of the molecule. It’s basically a description in numbers of what a substance’s structure looks like. Lord Kelvin, an Irish mathematical physicist, thought it was a stunning analysis for the modern world, and he’d be quite right that it would continue to hold up with each passing day.

  Bragg’s Law

  When he got word of Laue’s work, William Bragg was already a physicist working on X-rays. He also had written the book for children on X-rays, Concerning the Nature of Things, that first inspired Hodgkin. His son Lawrence was a university student. Together, they figured out how to make sense of the images Laue first created, and they expanded on his work.

  This is a diffraction pattern made on paper by X-rays shot through a crystallized substance.

  Remember—we’re picturing atoms as marbles. In crystals, these marbles appear in evenly spaced rows, layered upon each other in planes. Picture a box packed with marbles, the marbles sitting on top
of, underneath, and next to each other in an orderly fashion. It’s not a jumbled mess; it’s a nicely packed cube of marbles. Atoms are teeny, so in a crystal, there are millions of planes of atoms.

  Young Lawrence, a student, realized the X-rays were passing not in the spaces between the atoms but reflecting off the planes of atoms. Using trigonometry, he determined what has become known as Bragg’s law. In math and science, a law describes an observed phenomenon; it is a statement based on repeated experimentation. Bragg’s law states in which direction there will be scattering, depending on the angle an X-ray is sent into a crystal, and the spacing is an indication of the structure of atoms within a crystal.

  We have been thinking of rays of light as arrows. For just a moment, so you get the idea of the movement of light, think of it as a ball, as one of those really bouncy little rubber superballs. If light were a superball and you threw it at the ground, it would bounce back up. Remember that if you could throw an X-ray like a superball, most of it would continue on that path and pass through the floor. But little bits of it would break off and fly in different directions. Now we have to start thinking three-dimensionally. Think about that box of marbles again. In your imagination, remove the box, but keep the marbles together in that nicely packed cube. That’s your crystal with its neat atomic structure. If you look at it from one direction, it appears like a sheet, not a box, and you can picture an X-ray (arrow) hitting it from one side, most of the light traveling through the marbles from left to right but some of it scattering off to the same angle in a different direction. But this cube is not a sheet; it is a cube. There are other planes, or layers, of atoms in it. Slowly move around the cube. You can see rows of marbles along the horizontal, the vertical, and the diagonals.

  The spots in a diffraction pattern are all the various reflections that are allowed by Bragg’s law. Some dots are darker than other dots, and that indicates that the X-ray that left that dot on the paper hit a spot with a lot of electrons. All of this tells a scientist where the atoms inside the crystal are.