Breaking rules to learn more about cancer cells
Matt Paszek was 17 years old. He was standing in his socks on the partially-completed roof of a house, trying desperately to avoid damaging the new shingles as sweat poured down his head and into his eyes. It was 90 degrees in the shade and, looking back, Paszek is pretty sure he was on the verge of heat exhaustion. His boss—who was also his uncle—looked at him and said “Matt, THIS is why you want to go to college.”
Paszek, who is now an assistant professor in the Robert Frederick Smith School of Chemical and Biomolecular Engineering (CBE) at Cornell, had his own reasons for wanting to go to college—in addition to avoiding heat strokes. “I grew up in Lackawanna (NY), which was a steel town,” says Paszek during a conversation in his office in Olin Hall. “My father was a groundskeeper at a cemetery and my mom was a nurse. I learned carpentry before I was even in my teens. But even then I had a drive to go to college. I had a strong internal motivation to go learn more.”
So Paszek worked hard in high school and applied to Cornell, where he was sure he was going to study economics and get a job in finance. But then Paszek discovered the potent one-two punch of chemical engineering and biology.
“I took Intro to Bio, taught by Carol Hardy McFadden, in the spring semester of my sophomore year,” says Paszek. “I started the course out of sequence and then went off for a Co-op job junior year working with Merck Pharmaceutical in Pennsylvania. Carol and I bent the rules a bit and I took the other half of her class by mail—I would just drive up to Ithaca for the practicals and then head back to Merck. I shouldn’t say this out loud, but she even mailed me my rat. When I was done with my Co-op and back on campus for senior year, I TA’ed the Intro class.”
Back on campus as a senior CBE major, Paszek found himself in a tough position. He knew for certain he wanted to go into bioengineering and he knew just as certainly that the required Senior Design and Unit Operations classes might feel like a waste of his final year at Cornell. He met with his advisor, Professor Paulette Clancy, and pleaded his case. “She was totally supportive,” says Paszek, and as he does you can still hear the relief in his voice, a full fifteen years after the actual events. “Paulette Clancy was breaking the rules before that was even a thing around here.”
“So, I used my senior year to explore several different academic areas and it set me up well for graduate school,” says Paszek.
Paszek knew by then that he wanted to bring engineering to the study of cancer. He was accepted into a Bioengineering Ph.D. program at the University of Pennsylvania, working with pioneers Daniel Hammer and Valerie Weaver. “Dan Hammer is a brilliant chemical and biomolecular engineer who is really well known for his theoretical work,” says Paszek. “And Valerie Weaver is a visionary. She was not well known at the time, but she was about to be. She published a huge paper that demonstrated for the first time the mechanical component of cancer and its progression.”
Weaver and Paszek’s work showed that cancer cells generate large amounts of force on their surroundings and their surroundings become stiffer. Knowing these things opens the doors to possible therapeutic approaches to fighting cancer and cancer metastasis.
From Penn, Paszek moved into a postdoctoral associate position at the University of California, San Francisco, still under the mentorship of Valerie Weaver. “In California I began to focus on glycobiology,” says Paszek. Glycobiology is the study of the structure, biosynthesis, and biology of sugar chains called saccharides. All living cells have polysaccharide chains—sugars—embedded in their surface membranes. Paszek and others have found that on cancer cells, this sugary membrane is especially thick. Paszek has taken the research one step further and found that this extra-thick sugary coating causes physical changes in the cellular membrane that allow the cell to thrive and the cancer to be more deadly.
At Cornell, Paszek is now homing in on the study of these carbohydrates and protein-carbohydrate compounds that reside on cell surfaces. Together, these molecules are called the glycocalyx. “If you could shrink yourself down to ‘Honey I Shrunk the Kids’ size and go touch one of these cancer cells, the surface would feel slimy like a banana slug,” says Paszek. One gets the feeling, listening to Paszek describe the feel of the glycocalyx, that the ‘Honey I Shrunk the Kids’ idea is more than just an intellectual exercise to him—if he was given the opportunity to do it, he would jump at the chance.
“This slime is a very complicated biomaterial that we know next to nothing about,” continues Paszek. So Paszek and his lab are using polymer physics to study the glycocalyx. “We want to know what contributes to its structure and how cancer changes the material in a functional way,” says Paszek. “We know that cancer rewires cellular metabolism and that this coating is a result of cellular metabolism. We want to learn the mechanisms behind these changes.”
One way to learn more about the glycocalyx is to look at it, yet traditional light microscopy simply does not have fine enough resolution to see the details researchers must see. Cornell has a long history of being at the forefront of microscopy, and this is part of the reason Paszek came back to Cornell as a professor twelve years after receiving his Bachelor’s degree. “We needed a tool that would allow us to see into the glycocalyx under ‘normal’ conditions of temperature and environment,” says Paszek, “and that tool did not exist. So we are making one that will allow us to measure the thickness and characterize the protein organization of the glycocalyx to a resolution never seen before.”
“Being here at Cornell has allowed us to go crazy,” continues Paszek. “We are working with Warren Zipfel in biomedical engineering to create a completely customized and fully optimized microscope that is better and faster than anything that exists for this work. It is really good at making clear the architecture of cellular machinery.”
While standing and sweating on that roof almost twenty years ago Matt Paszek had no idea where college would take him. Now, when Paszek looks around his lab and thinks about the possible clinical trials and treatment applications his work could bring about, perhaps he thinks to himself “THIS is why I went to college.”