Credit: Charlyn Paradis/Will Ludwig/C&EN | Stacy Malaker
he tattoo on Stacy Malaker’s ankle bears inky testament to her fascination with glycobiology. It depicts the core of a sugar molecule—a six-membered oxane ring, arranged in the classic chair configuration. “I figured I’ve devoted my entire career/life to glycobiology, so it made a little bit of sense,” she says.
Despite the simple elegance of the tattoo, Malaker’s research involves more complex sugar chains called glycans. These unite with proteins to form glycoproteins such as mucins, which are major components of mucus and provide a protective barrier for tissues and organs.
Malaker, an assistant professor of chemistry at Yale University, is developing mass spectrometry methods to analyze and understand mucins, which also play various roles in cancer and lung diseases. She hopes the research could eventually provide better ways to diagnose and monitor such conditions. “The area that she’s specializing in—mucin biology—is so important,” says Benjamin Garcia, a mass spectrometrist at Washington University in St. Louis.
Malaker was drawn to science by television series such as CSI: Crime Scene Investigation. As an undergraduate at the University of Michigan, she even considered pursuing a master’s degree in forensics, until one of her professors encouraged her toward a PhD instead.
Two experiences as an undergraduate steered her graduate research choices. Her job in a mass spec core facility sparked her interest in the technique, and a class assignment that involved writing a research proposal got her interested in epigenetics. As a graduate student at the University of Virginia, she joined the lab of Donald Hunt, one of the early leaders of biological mass spectrometry. “Not realizing how prominent this man was, I ended up joining his lab,” Malaker says. “That was one of the best decisions I ever made.”
—Stacy Malaker, professor, Yale University
Although she originally wanted to work on an epigenetics- related project in Hunt’s lab, she ultimately studied immune system peptides instead. She discovered heavily glycosylated peptides that could stimulate immune responses in healthy individuals. The finding piqued her interest in glycobiology and led her to postdoctoral work in Carolyn Bertozzi’s lab at Stanford University, which is where she first encountered mucins.
Malaker joined a project that had identified an enzyme that cleaves mucin domains—densely glycosylated regions of the proteins—from cell surfaces. She realized that the enzyme, called StcE (pronounced “sticky”), could also cleave the protein backbones of mucins and was useful for digesting mucins for mass spectrometry.
The enzyme neatly solved a tricky problem for glycobiologists. Mucins are O-linked glycoproteins, meaning the glycans are attached to oxygen atoms on either serine or threonine residues in the protein. All O-linked glycoproteins are difficult to analyze by mass spectrometry because there isn’t a single enzyme that can release all the glycans from the protein. Mucins are particularly challenging because they have a very dense covering of glycans that makes them resistant to all the enzymes commonly used to break down proteins in the lab. StcE helped overcome that obstacle, making mucins much more tractable.
Malaker “can really innovate all along the workflow of biological mass spectrometry to biological discovery,” Bertozzi says. “She’s got the instrument prowess that she can open up the mass spec, customize it, enable it to do new things, and write code to run it, as well as do all the biology.”
Building on her success with StcE, Malaker looks for complementary enzymes that could expand the mucin tool kit. For example, some enzymes might be present in different biological settings or cut different sites within the mucins than StcE does. “I’d estimate there’s millions and millions of these enzymes in the gut, and we’ve only characterized, let’s say, 10 of them,” Malaker says.
Malaker’s team is also using mass spectrometry to learn more about MUC-16, a mucin that is used as a biomarker to detect ovarian cancer. But MUC-16 isn’t a particularly good biomarker, because it’s also found at various levels in people without ovarian cancer. “If we can see what it looks like and how it changes with disease, we might be able to get a better biomarker for ovarian cancer, which is sorely needed,” Malaker says.
“Stacy has never shied away from difficult challenges,” says Garcia, who also did his PhD in Hunt’s lab, though not at the same time as Malaker. “She’s on the verge of breaking open this field with the combination of advanced mass spectrometry and computational approaches to analyze this type of data.”
PhD alma mater:
University of Virginia
How I’ve faced adversity in my career:
“I am a first-generation college student. I had to navigate the complex world of academia with a combination of intuition, mentorship, and just plain luck! I had to work various jobs to keep myself afloat: in undergrad I worked at a mass spec core facility and as a stocker in a bulk grocery food store, in grad school I drove for Uber, and as a postdoc I picked up catering gigs.”
My athletic skills are::
“I’m most proud of my 5 kickball championships. I was on a couple of teams in grad school, and we absolutely dominated the Charlottesville kickball league.”
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