Crystalline

Shayla Love

It’s the winter of 1987, and my mother is sitting in her office at the University of Pittsburgh with a Big Mac and an electron density map. It looks like topography, where curvy, concentric lines show the height of mountains and depth of valleys. My mother’s map is a different kind of landscape; it shows the electron clouds surrounding atoms in a crystallized protein that she X-rayed earlier that day.

The map is of the Bowman-Birk protease inhibitor, a small protein found in grains and cereals, and a potential anticancer agent. She wants to know what it looks like. X-ray protein crystallography is like having a high-resolution image of someone’s shadow and trying to see the crook in the nose. From the shape and size of the electron clouds, she tries to guess the atoms. Once she settles on the kinds of atoms, she tries to visualize how they’re connected. It’s a process called chain tracing, and it’s like chasing the atoms around on a looping roller coaster.

It’s getting late. She blinks and looks at the map again. She feels something, as though she’s getting closer.

“It’s almost like you’re staring at a picture, then finally you see,” she says. “It’s just like art. You look at art, and it’s like you’re looking at nothing. But you stare long enough and you finally get it. There’s the sky, there’s the water, there’s the flower, there’s the building. So once I stared long enough, I could see the alpha helix, I could see the beta sheet, and then just suddenly I figured out where everything connects. I could see the whole thing from beginning to end. And I just traced it.”

When my mother tells me this story, I think she is a genius. She tells me that some people are good at puzzles, and she happens to be good at chain tracing. Both of my parents have made careers of determining protein structures. Their ability to chart the contours of our proteins feels less to me like solving a difficult Sudoku square, and more like having a third eye.

Proteins do everything, are everything. They can be made of any combination of twenty amino acids joined together in an order determined by the genetic code. Multiple chains can link to make extremely complicated, tangled proteins, but even from a chain with just ten amino acids, ten trillion different proteins can be formed.

They perform all of our functions and make up all of our vital organs. Our heart and brain are made of proteins. They are our enzymes, hormones, antibodies, cells, and tissues. They can transport other proteins, signal to each other, store and receive other proteins. The structure of a protein defines what it does, which is why it’s so important to know how each one folds up.

My mother and father met in Pittsburgh around the time she traced the Bowman-Birk. She was finishing her PhD, and he was doing postdoctoral work. They both began studying protein structure, not only because it was challenging, but because proteins were the next frontier in pharmaceutical drug design.

Academics traced unknown proteins beginning in the late 1950s and then began to deposit their findings in the Protein Data Bank, which was founded in 1971. It now holds over one hundred thousand protein structures. This wealth is dwarfed by all the proteins we still do not know and might never know. My mother and father didn’t want a life of discovering protein structures just to deposit them in the bank. So in 1989 they moved to San Diego to work at a small pharmaceutical company called Agouron. The name comes from the Greek word agora, for a gathering place or assembly, which was very important in early Greek cities. The CEO imagined Agouron as the meeting of scientific minds. At Agouron, my parents would not just trace protein structures but use them to help chemists make medicine. A well-worn metaphor describes an X-ray crystallographer’s job as figuring out what the inside of a lock looks like so that a chemist can build the key.

The Agouron team sometimes gathered in a meeting room as the CEO told them stories of people struck with disease. These people had hope because of the scientists in the room, he said. His eyes filled with tears, and the scientists would erupt into applause, going back to their labs with fresh determination to understand human weakness.

In 1996, my father published the structure of the protease from Hepatitis C Virus (HCV) in Cell, the same year my mother published the protease from Cytomegalovirus (CMV) in the same journal. The HCV protease structure was used to develop drugs still used today to treat and cure patients. In 1997, Agouron’s drug Viracept, one of the first protease inhibitors for HIV, went on the market. A single blue pill was encased in glass and given to all employees, like a trophy.

A simplified version of my parents’ resume from the 1990s reads like a list of terrifying fates: HCV, CMV, diabetes, HIV, rhinovirus, RAS, cancer. They had a sense of purpose, of pride in their work. They were shining light on the deadliest illnesses humans faced. I think there must have been also a feeling of immense power over nature.

I was born in 1990, and they worked seven days a week throughout most of my childhood. When I was old enough, I went with them to work. I sat in my mother’s office, reading in an oversized office chair beside her desk. Sometimes I drew pictures on her whiteboard, asking first if I could erase the molecular structures, whose octagonal shapes looked to me like exploded soccer balls.

I roamed the halls unbothered, which were black marble and maze-like. I learned my way around and felt like an ant in my hill, maneuvering the corridors with expertise to the kitchen, where there was always hot chocolate, or the supply room, where I would sneak away pencils and highlighters.

The doors to the labs were often open, though marked with foreboding signs of toxic chemicals and eye-flushing stations. In the labs, the air changed. It smelled sterile and cool. People were hushed, focused, and wearing white jackets. From my child’s eye view, the tables and stools loomed high above me, like the tops of buildings. I knew that disease was fought in these rooms. It had the feeling of passing through a holy place.

I loved that my parents’ jobs involved growing crystals. My father collected geodes, ugly, cement-looking rocks with dazzling diamond insides. I would close them and open them, playing peek-a-boo with the hidden beauty.

In 1611, Johannes Kepler theorized that the secret to a snowflake crystal was well-organized water molecules. In 1912, seventeen years after X-rays were discovered, a group of scientists shot them through a crystal. Max von Laue won the Nobel Prize in 1914 for what they found: that crystals contain a neat, periodic array of atoms and that X-rays bounce off each atom to create a diffraction pattern that can be captured on light-sensitive paper.

A father and son team, W. L. and W. H. Bragg, wrote Bragg’s Law, a way to calculate an atom’s position in a crystal, using the angle from the point of diffraction. They won the 1915 Nobel Prize. Proteins, though first crystallized in the nineteenth century, eluded structure determination for another forty-five years. It wasn’t until 1960 that John Kendrew and his team published the atomic structure of myoglobin, a protein that delivers oxygen throughout the body. To grow their crystals, they extracted pure myoglobin from an abundant source: a sperm whale.  Soon afterward, Max Perutz solved the more complicated human hemoglobin, and the two men shared the 1962 Nobel Prize.

To grow a protein crystal involves “black magic,” my father says, because even he cannot predict when crystallization will occur. I wonder why something unexplainable must be “black” and not just simply “magic.”

You must start with a pure protein sample, and lots of it. It’s an easy task now with cloning, but when my parents were starting out, the protein often had to be taken directly from a source. My mother once extracted endless proteins from soybeans, while her lab partner brought buckets of horse blood to work each day. My father extracted a specific neurotoxin from whole snake venom, along with a neuromuscular receptor from the specialized organs of electric rays caught off California shores; he wanted to study how the neurotoxin bound to the receptor and caused paralysis.

To make a protein crystallize, they add a precipitant to the solution, either salt or another organic molecule. Then, they force the mixture to evaporate and the precipitant starts to greedily hog the remaining water. Most of the time, the proteins will squish together and make an amorphous glob my father calls “protein mud.” But sometimes, the proteins will form delicate intermolecular contacts that repeat perfectly through space and build a three-dimensional lattice.

My father explains it like this: imagine a small pond with a school of minnow swimming about. You pour some salt into it and then shine sunlight on it, forcing evaporation. As the pond grows smaller, the fish are crowded together, and the fresh water is running out. What will the fish do? You would expect to look in the pond and see them clumped together at random until, eventually, they die. But what if you saw them lining up and stacking themselves, like an M .C. Escher tessellation? The formation of a crystal is as miraculous as seeing a group of fish self-organizing into perfect symmetry.

Even more delightful to a child like me was the protein itself. I loved to put on 3-D goggles and play with the computer-simulated protein models, which were always in bright, primary colors. They looked like a photo of a party popper, if the shutter closed at just the moment when the thin slivers of paper were furling out of it. It took me a long time to understand that those curls and ribbons were inside of me. That they were me.

I learned that lots of things lived within me. When I was sick, my father would draw me a cartoon of the war between viruses and my antibodies. He was kind enough to give my antibody army more men. They were gallant, Y-shaped figures with muscles and smiling faces. The viruses were angry with down-pointed eyebrows. I looked at this image then at my body in the mirror. I peered at my arms and my face. I lifted my shirt up to examine my stomach. Where was this battle taking place? I knew about them but could not feel them: the cells, the blood, the viruses, the proteins. I walked around in the world with my skin tingling, as if I had just passed through a spider web and still felt the invisible strands sticking to my skin.

My fears have always been focused on the small. When I was eight, I could not eat with my hands until they had been washed. At school, I hunched over to eat with my face, like I was bobbing for apples, or like an animal. On the weekends, when my family and I would go to lunch, I would scrub my hands at home and clench my fists tight in the car, protecting their clean surface. When we got to the restaurant and my food sat in front of me, I could open them. Then, I was safe. As I ate, I could feel where my nails had dug deep into my palms.

The code for our home security system is 8064. At Agouron, all chemical compounds that could be used for drugs were labeled with a number. The number for my father’s crystal structure of the protease enzyme from human rhinovirus—the common cold—is 8064. If you type that number into the keypad, the house becomes protected. Any window or door that opens will set off an alarm, warning us of intruders. My parents’ work does not cast as easy a protective shield. Of the diseases they have been fighting for twenty-five years, few have seen cures; AG8064 never made the market.

My mother rarely uses our alarm system. She tells me that research is not a straight line. “Sometimes you create a perfect drug design, but it comes back inactive,” she says. “We try to rationalize, but nature always comes up with a smarter way. You solve one thing. You say, ‘Oh, this is how it works.’ Even if we think we’re so smart, nature always comes and amazes you every time.”

I don’t wash my hands more than anyone else these days, but I still seek protection from science. During low periods, I find myself sitting in doctors’ offices and asking, “What’s wrong?” A few years ago, I got three MRIs in rapid succession because I desperately needed to see inside of me. When I looked at the scan of my brain, I did not see what I know to be “me.” But I felt better. I could see in.

My father says he was first drawn to science because he likes to know the mechanisms behind life. He and my mother both started out in physics, the rule book to the natural world. My family is made of scientists: geologists, astronomers, and microbiologists. They are people who are not comfortable with what we know about our existence. They all want to see in, too.

My father’s father died two years ago. I found out through a voicemail while I was bartending in Brooklyn near my apartment. My grandfather was not my first encounter with death. When I was twenty, I found a girl stabbed to death in the apartment below me. The owner of the bar I worked at died from cirrhosis. My friend’s boyfriend overdosed. All these people’s cells and proteins were still there when they died. I called my father on my walk home from work, not really to comfort him, but to ask him why it had to happen, to explain it to me.

My father took enough philosophy courses in college to qualify for the minor. A whole bookshelf in our study is devoted to different religions and philosophy. I used to eye these books curiously, especially as I grew to understand that my family didn’t believe in God, that we were atheists. But my father likes to know how things work. He has dissected everything to the smallest level and found nothing. No miracle, no prophecy, no spark of intelligent design. Science has been unable to tell him the meaning of life, or why we are self-aware, only that things continue to work the same, before and after our existence.

“Nature is structured a certain way, and there are parts of it we are always coming to understand anew,” he says. “But science says there’s nothing else beyond that. No supernatural events or entities are necessary. You don’t need anything more than nature running by itself. But in the end, that’s not enough for some people. Sometimes I wonder, maybe it’s not enough for me.”

I used to tell my Christian friends that science was my family’s religion when they asked why we didn’t go to church. I ask my father about this, and in his thoughtful way, he says that science is not a religion but that the scientific method is already part of our everyday lives.

“There’s not some big encyclopedia of knowledge that we worship,” he reminds me. “To me, there is only the scientific method as a way of understanding the world. But that’s not some dogma; human beings naturally seek experimental verification and repeatable things. That’s how most people define their reality—without even realizing it.”

I am not satisfied with this. I want him to give me a structure, a cartoon or a diagram, like the ones he drew me in childhood. I want my mother and my father to grow a crystal that will give me all the answers. My father will not give me this crystal. He tries to tell me that I do not want it.

“There will always be some level of complexity to the world around us that we just can’t move beyond, like death,” he says. “But do we really want to explain everything in extreme detail? Do we want to reach the point where every psychological state, every feeling can be correlated with some neurotransmitter and set of neurons firing? Would that make us feel better or worse?”

Cancer is the leading cause of death worldwide. My grandfather ultimately succumbed to cancer. This year, the Food and Drug Administration approved a breast cancer compound that targets a particular protein responsible for cell growth. My mother says it’s one of the first cancer drugs that can help people without causing severe side effects. She is working to develop even better drugs against this protein. She does mainly cancer research now, designing inhibitors that are potential drugs. Unlike my father, science gives her a profound sense of control over the parts of life she does not understand. I ask her if she is frightened of cancer or of dying.

My mother, the puzzle solver, says that we should only focus on what’s new this year compared to the last. This year, a group of breast cancer patients have a better chance of survival. She hasn’t solved the puzzle of disease yet, but she feels that if she stares at it long enough, the solution might appear to her.

I bathe in her optimism when I feel scared. I dive deep into it and stay underwater. She tells me that one day, people will be able to live to two hundred years old because she will fix any part of you that’s broken.

From beneath the surface I think, “I will not live to two hundred. Am I broken?”

Agouron was bought by Warner Lambert in 1998 and merged with Pfizer in 2000. The holy battleground became corporatized. My parents moved offices, and keycards were required to enter the building. There were no more authentic pep talks, only lectures full of corporate babble. Children were not allowed in the labs. I was no longer a child.

There hasn’t been a distinctive crystallography department at Pfizer since 2009, mostly because X-ray crystallography has gotten much easier. Now, crystallography is a tool, not a trade. For simpler structures, computers can do the chain tracing. Scientists rarely collect their own data anymore, which was time consuming. Large-scale facilities with synchrotron radiation (powerful X-rays) can do the work faster and with more detail. They send back the completed electron density maps. Some of these facilities have X-ray lasers that can be used for tiny microcrystals; there’s no need to grow huge crystals anymore.

A new machine has been exciting structural biologists: the cryo-electron microscope. It uses electron beams to capture images of frozen molecules without a need to grow crystals at all. For now, the cryo-EM is a complement to crystallography because it can only look at bigger proteins that were hard to grow crystals of in the first place. But in twenty years, it’s easy to imagine the cryo-EM determining protein structures just like taking a photograph. Pose the protein and shoot.

This is all good news. My mother reminds me that when she began, protein crystallography was the new exciting field, and now another has emerged to replace it. Knowing structures is getting easier, allowing my parents to imagine more medicines and potential cures. But I don’t know if future scientists will think that proteins are as beautiful as my parents did when they started. It’s another loss of a trade, like blacksmithing or sewing. Scientists will not manipulate crystals by hand, or grow them from solution, following them from birth to death. They will not have the moment my mother had, when the protein appeared to her as a kind of revelation. My father says that whenever he displayed a new protein structure, he knew that he was the first to gaze upon it.

“No one had ever seen this,” he says. “Proteins are probably the most amazing things that nature has ever developed, or evolved. They’re like these little machines that can do so many different things. It’s just incredible.”

Will the future scientists feel the true weight of these tiny atomic structures? They will never really see them, touch them, or feel them, but I know that my parents respect them and know their worth. Perhaps it doesn’t matter for our scientists to revere the subjects in their petri dish. But wouldn’t they like to? Don’t we all need an idol to worship, even it’s made of amino acids?

“Every protein, they’re almost like art, every structure is just so beautiful,” my mother says. “Every protein structure you solve is like a story. Basically we’re just trying to solve the architecture of life.”

I have a false memory from the early Agouron days that is so clear. I do not know if it originated from a dream or a fragment of my childhood imagination.

I am five or six, walking the black hallways at Agouron, and I approach a door. I try the handle and it clicks open. I enter a deserted lab. It is dusk outside and the room is a fading blue. I am surrounded by crystals. They rest quietly at each lab station, large crystalline towers of pink, blue, and green. Through the window, the setting sun drops to a position that lines up with the crystals; its beams hit each one directly through its center. The room explodes with refracting color, spinning in circles like a merry-go-round made of light. It’s a dizzying effect, and my eyes dart around, trying to catch each glimmer as it passes me. The sun continues to set. After a few minutes of this heavenly swirling of light, the sun falls below the horizon and the room grows dark.

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