Alumni Spotlight: Melanie Matheu’s Passion for Immunology Sparks Biotech Innovation

Melanie Matheu, a self-described “research scientist turned inventor and entrepreneur,” has launched two biotech startups in the last decade. In 2016, she founded Prellis Biologics Inc., based on her novel system for printing human tissue. In 2024, she created a spinoff company, Lyric Bio Inc., leveraging the Prellis bioprinting system to manufacture complex therapeutics.

What’s behind her biotech innovations?

“Academic research is where it all starts,” says Matheu, who earned her PhD in physiology and biophysics from the UC Irvine School of Medicine.

A Passion for Immunology

“Understanding how the natural world works was a driving force for me from a very young age,” says Matheu. By age 19, she was studying biochemistry and molecular biology at UC Santa Barbara and conducting her first patent work in the field of synthetic organic chemistry.

After earning her degree, Matheu was at a “crossroads,” unsure if she wanted to get an MD or PhD, so she took a year off school to decide. While working in a laboratory at Stanford University, she attended an immunology seminar featuring Ulrich von Andrian from Harvard University. “At the end of his presentation he showed a short video of a dendritic cell crawling along a blood vessel,” she says. “My jaw dropped, because every textbook out there said immune cells don’t move.”

Immediately following the seminar, Matheu looked up the source of the video: Michael Cahalan, PhD, and Ian Parker, PhD, of UC Irvine. “They put together the first video-rate two-photon microscope and looked at a mouse lymph node,” she says, “and they saw immune cells moving rapidly.”

Matheu wrote to Cahalan the same day she saw Dr. von Andrian’s seminar. “I’m applying to graduate school, and I’d like to work with you. Do you have room for a rotation student this fall?” She still remembers her excitement when he responded. “He wrote back immediately and said, ‘I might have room in my lab; let’s see if you get in.’” Matheu was soon on the road to earning her PhD.

Working in Cahalan's lab, her passion for immunology only grew. “He was studying immunology through a biophysical lens, which satisfied so many different curiosities I had,” she says. “It was all about why and how the immune system self organizes to respond to any challenge. It was fascinating.”

After earning her PhD, Matheu spent three years doing post-doctoral research at UC Irvine. “I had a phenomenal working relationship with Mike, and there were so many interesting questions to answer,” she says. She looks forward to catching up with him when she returns to campus in November for the UC Irvine Immunology Fair.

But it was a podcast on tissue engineering that planted the seed for Prellis. Matheu was working as a postdoc at UC San Francisco, tracking immune cells through a highly vascularized tissue, when she listened to a podcast highlighting the unsolved problem of producing human tissues for transplant and large-scale organoids. “I sat there thinking, ‘with a high-resolution microscope that’s non-tissue toxic like a two-photon imaging system, there must be a way to use that system to print the blood vessels needed to support large tissues,’” she says. “That was the nucleus of inspiration for me.”

She tucked away the idea and continued with her research in the laboratory of Jeff Bluestone at UCSF, eventually receiving a large grant from the Juvenile Diabetes Foundation (now Breakthrough T1D). Around that time, she was also invited to join a startup. “It was a tough decision, but I figured I could always come back to academia. I was ready to try something new.”

An Inventor at Heart

The startup Matheu joined shut down after six months, but that experience gave her the knowledge and courage to try it on her own, revisiting the idea of tissue engineering.

“It took about three and a half months to figure out the math and physics behind changing a two-photon imaging system into something that could print,” she says. “People had used two-photon excitation to print before, but the process took years to build larger sized high-resolution systems.” By mid-2018, Matheu’s solution could print high-resolution tissue structures up to 1,000 times faster, distributing the light as a hologram and creating numerous pinpoints simultaneously by laying down microvasculature structures, the critical building blocks of human tissue. “It’s like laying down Legos,” she says.

Then, when the COVID-19 pandemic hit, Prellis pivoted from large human tissue development to focus on rebuilding the human immune system, an area Matheu understood well. “There was a global need for antibodies, and we demonstrated we could leverage the same properties of the immune system I had studied for years to create human antibodies from white blood cells in a dish within six weeks,” says Matheu. This significantly cut down drug development processes, and “functional human tissue in a dish” offered countless opportunities to advance therapies for autoimmune diseases and cancer.

That’s when Matheu realized she was ill-equipped to take the company to the next level. “I’m not a high-powered pharma executive, and that is a steep learning curve,” she says. “At heart, I’m an inventor and a technology builder.”

Launching a Second Startup

With Mike Nohaile taking over as Prellis CEO, Matheu stepped back to be CTO of the rapidly growing biotech and later pitched the idea of launching Lyric Bio to build high-density bioreactors for biomanufacturing. “We’re using the ultra-fine microvasculature that can be printed with Prellis technology, now licensed to Lyric Bio, and we’re filling it with immune cells,” she says, “specifically, B cells that can produce antibodies.”

B cells in humans produce a mixture of different antibodies that bind to all different things. These “polyclonal antibodies” can be purified from plasma donations to produce a powerful therapeutic drug: intravenous and subcutaneous immunoglobulin (IVIG/SCIG). Immunoglobulins have FDA approval and more than 100 off-label uses. “I was exploring where we could apply our technology next, and I saw this high-cost drug with global shortages, because making it requires people to donate plasma,” says Matheu. “This was clearly an important place to start.”

Lyric Bio is short-circuiting the process of IVIG production, which typically relies on up to hundreds of thousands of plasma donations, acquired by taking white blood cells and expanding the B cell population from up to a thousand people. “We’re retaining everything that you would want to fight off pathogens or treat an autoimmune disease, and then we’re scaling down the B cell culture to produce these antibodies into a human tissue-like bioreactor,” she says. This could cut the dependence on human donations by at least a thousand-fold.

They’re also looking at stem cell expansion and red blood cell production. “There are a lot of cool things we can do with this 3D architecture,” says Matheu, “which supplies the same nutrients and oxygen as a microvasculature system would in the human body.” Back in start-up mode, Matheu is right where she wants to be. “When you’re in the lab at midnight, taking out the trash or putting the final touches on a presentation, that’s the rush of it!” she says. “Working in a startup challenges you like no other career.”

She urges anyone “itching to build a startup” to go for it. “It’s incredibly rewarding, and it’s less risky than you think, but you have to fall in love with the idea, kind of like falling in love with your PhD thesis work — you’re in it for the long haul.”

Yet she also encourages continued support for academic research. “Investment in tomorrow’s science and scientists is where these advances come from, and now more than ever, we need to speak up about where good science and research advances come from,” she says. “I look forward to the day I eventually return to academia.”