Researchers at UChicago ‘speed up evolution’ to treat cancer

Natural evolution, left to its own devices, operates on the scale of centuries. Even our immune system, when faced with an especially pervasive threat like malaria, can sometimes take hundreds or even thousands of years to mount an effective defense. Juan L. Mendoza, assistant professor at the University of Chicago’s Pritzker School of Molecular Engineering (PME), wants to speed up the timeline.

Mendoza is a protein engineer and computational biologist specializing in immune system research. He combines bioengineering with computational analysis to explore and better understand cytokines—a group of proteins that act as the body’s early warning system against infection.

“I am passionate about this work because our research can impact people’s lives positively,” said Mendoza. “Yes, my excitement about the science itself is motivating, but the idea that we can change the prospects for some cancer patients is a big part of my drive.”

Key among Mendoza’s tools is a technique called “directed evolution.” It’s a process in which researchers synthesize an extensive library of mutated proteins that then undergo a series of tests. By studying how the mutated proteins interact with other proteins of interest, researchers like Mendoza can infer how our normal “unevolved” proteins work.

In 2019, Mendoza won the Milstein Young Investigator Award for mapping the structure of the interferon gamma (IFNγ) and interferon lambda (IFNλ) receptors and engineering drug candidates aimed at a broad range of cancers, such as lung, colorectal, liver, cervical, and pancreatic. Now Mendoza is expanding his efforts to map other interferon classes and cytokines more broadly.

Small proteins with a big role

Mendoza established his lab at Pritzker Molecular Engineering in 2018, drawn, he explains, by the school’s work at the forefront of bioengineering. PME is home to the Chicago Immunoengineering Innovation Center, one of the first centers in the nation dedicated to the convergence of bioengineering and immunology.

Much of Mendoza’s focus has been on interferons, a subgroup of cytokines. For forty years, interferons have been used as potent immunotherapies to treat a range of diseases like hepatitis, multiple sclerosis, and certain types of leukemia. However, the protein’s latent toxicity limits its effectiveness in other situations.

“Interferons have so much potential that people refer to them as the ‘holy grail’ of immune modulation, but they’re unfortunately very hard on the body,” Mendoza said.

To unlock interferons’ therapeutic potential, Mendoza is investigating a key mechanism in cytokine signaling—the JAK/STAT signaling pathway.

Janus tyrosine kinase (JAK) and signal transducer and activator of transcription proteins (STATs) are two distinct protein families that, together, act as the cellular equivalent of a 911 dispatcher. They accept distress signals (cytokines) sent from other cells and translate them into instructions for the cell’s defenses. Mendoza believes studying the JAK/STAT pathway could inform interferon therapies and a host of other immunotherapies involving engineered cytokines.

“The past several years have opened up many opportunities in the field of bio- and immunoengineering, but there are still a lot of discoveries left to be made,” said Mendoza. “That’s a challenge that I’m excited about, because I’m able to apply my interest in structure and molecular interactions to lead towards a greater understanding and opportunities for treatment.”

Extending opportunity to new generations

Mendoza has made considerable leaps in bioengineering, but his path to success has come with challenges that he believes are essential to the telling.

As a first-generation college student, Mendoza struggled in school, often feeling out of place and unsure how to approach his education. Money was tight, meaning that Mendoza had to work full-time while he attended classes, forcing him to complete assignments late at night.

That struggle continued until Mendoza made two critical discoveries. The first was an NIH-funded “Bridge to Doctorate” program at San Francisco State University, and the second was Professor Raymond M. Esquerra.

NIH Bridge programs provide funding and research training for PhD-bound students from underrepresented groups, allowing them to earn a living while working in a lab rather than outside of school. For Mendoza, it was a game changer. Shortly after joining the program, he met Prof. Esquerra, his first mentor. Both, Mendoza said, completely transformed his relationship with academia and science.

“Everything I’ve done—my career and my research—has largely been made possible because of the bridge program and my mentors,” said Mendoza. “Raymond and later Phil Thomas at UTSW both afforded me opportunities when I wasn’t always the most obvious candidate. As a scientist, my role is to extend that same opportunity to people who would otherwise be overlooked.”

Mendoza is now an active driver of scientific outreach in Chicago’s local Hispanic and Latinx communities, helping with events like Noche de Ciencias that introduce area kids to science while providing parents with information on financial aid and scholarships.

Mendoza also connects local college students to research experiences at UChicago whenever possible, taking time to amplify job opportunities on local Facebook groups and elsewhere. In his mind, that work is as essential to scientific progress as the science itself.

“You need to support younger people,” Mendoza said. “If you wait for the few that make it to graduate school, you’ll never know how much potential and raw talent—how much good we’ve left behind. As a scientist, you have to start reaching people early, and I mean to do that.”