Brendan Harley: More than the sum of its parts

Robert W. Schaefer Professor Brendan Harley grew up playing with Legos and watching his dad develop clean water systems as a civil engineer. These formative experiences inspired Harley to pursue engineering as an altruistic path for someone with an aptitude for science and math.

Harley’s interest in a discipline of engineering that hardly existed — bioengineering — was piqued in high school when he heard about the group at the Massachusetts Institute of Technology (MIT) that demonstrated the promise of tissue engineering by growing an ear on the back of a mouse. “I thought it was wild; I decided to try to figure out this biology and engineering thing,” he said.

Harley fit his academic interests together like Lego blocks at Harvard University, where he studied engineering sciences and worked as an undergraduate researcher in a leukemia research laboratory. 

Next, he applied to medical schools and engineering graduate programs, describing a desire to regenerate the liver in his essay. Harley’s future graduate advisor, professor Ioannis V. Yannas, emailed him to ask if he’d like to work on regenerating skin and nerves instead at MIT. 

For his master’s degree, Harley worked on developing materials to induce the regeneration of peripheral nerves after injury. 

Working with animal models showed him the limitations of in situ — limited access to check the status of his materials and tissue growth that would get in the way, literally. “It was incredibly difficult to measure degradation in a living model, but if we put a biomaterial in a bath with a defined concentration of an enzyme, we can tightly measure degradation in the laboratory,”  he said.

Inspired, Harley studied the fundamentals of how cells interact with porous materials in vitro for his doctoral thesis, co-advised by Yannas and Lorna Gibson, Matoula S. Salapatas Professor of Materials Science and Engineering at MIT. 

“All the tissues and organs of our body are complex — they're not a uniform sack of cells; they change in space, change in time, have multiple different cells, and have structure,” he said. “Most tissue engineering projects are trying to fill this space, but if you put a dense block of material into a defect — cells don't grow in, vasculature doesn't grow in, nutrients don't diffuse in — nothing comes in.”

The goal was to engineer porous structures with a specific size, shape, and orientation and add biological cues to elicit stem cell responses. But before Harley could construct a material to drive these complex interactions — he first needed to figure out how to design a uniform material. 

“You had to make a material so uniform that you got the same response everywhere, so when you change a property, you get a change in response,” Harley said. “Then you could think about creating two and three materials integrated in a defined way to get a graded response that you could control.”

Toward the end of his doctorate, Harley combined his porous collagen materials with mineral materials developed by University of Cambridge graduate student Andrew Lynn, now the chief executive officer at Fluidic Analytics, to create implants that activate bone repair. Their collaboration yielded a start-up company called Orthomimetics, which TiGenix acquired to continue a Phase I clinical trial to repair osteochondral defects in the knee. 

“It was exciting to see that you could be an academic and do basic research that can extend into other applications,” Harley said. “That's when I decided that I wanted to become a professor.”

Harley deferred his offer to come to the University of Illinois Urbana-Champaign to pursue a postdoctoral research position within the Joint Program in Transfusion Medicine at the Children's Hospital Boston. The unique program combined fundamental research in immunology in a multidisciplinary training environment that importantly included a direct clinical connection. 

In 2008, he came to UIUC equipped with a porous biomaterial, knowledge of cell biology, and a familiarity with the needs of medical practitioners, ready to put it all together. 

Engineering bone marrow

“The area that I'm most excited about right now is the opportunity for us to use tissue engineering applications as model systems,” Harley said.  During his fellowship at the children’s hospital, Harley studied hematopoietic stem cells in the bone marrow. While they may be few, they can turn out huge numbers of blood immune cells, red blood cells in platelets, white blood cells, macrophages, etc.

“All these different cells have different lifespans, so it's not like you make the same number in the same frequency of every cell every day — it's a complicated process,” Harley said. “I’m interested in how the tissue environment around the stem cells in the bone marrow provides signals that influence the behavior of hematopoietic stem cells.”

Harley wants to understand the external stimuli that trigger stem cells to respond to illness and injury, or how to repopulate cells lost over time. His team has engineered artificial bone marrow to understand how stem cells use these signals to make decisions about proliferating or differentiating. 

Repairing musculoskeletal injuries

Harley has not lost sight of the original goal of tissue engineering: trying to engineer materials to implant in the body to regrow tissues after injury.

Their porous sponges are made out of collagen to aid musculoskeletal reconstruction, acting as a temporary “space filler” to encourage cell growth (as opposed to a permanent implant).

“We've spent a lot of time engineering the chemistry and the mechanical/structural properties to support cells to generate different muscle-skeletal tissues, like bones and tendons, and the transitions between them,” he said. “We have many projects now thinking about adapting these materials to regenerate craniofacial bone, repair rotator cuffs, and adapt them for spinal fusion volumetric muscle injuries.” 

Currently, his team is wrapping up a large study testing the efficacy of a biomaterial used for craniofacial bone repair — the last hurdle before moving on to clinical trials through the Food and Drug Administration. 

Now the team is turning to the bigger question of how to create a translational product that surgeons can use. “They want something they can use easily without changing their surgical protocols — something that works the same way, every time,” he said. “They don't want anything hard or complicated or tricky or fidgety; they just want it to work, the same way, 100 out of 100 times.”

Mimicking the tumor microenvironment

About a decade ago, the National Institutes of Health became interested in using tissue engineering methods to study cancer and asked Harley to visit to discuss how to develop alternative cancer models. 

Back then, cancer studies depended on animal models or flasks with cancer cells placed on a flat piece of plastic — neither of which perfectly captures the human body, Harley said. 

Today his team creates models of glioblastoma, the most common and deadly form of brain cancer. They aim to address questions like: When a tumor mass is removed, how many stem-like tumor cells remain and are likely to spread? How do brain tumors respond to drug combinations? How does radiation affect areas adjacent to the tumor?

“We've shown that you can create a multi-cellular model of a tumor with cancer cells, stromal cells, vascular cells, and immune cells that we can put together to gain actionable insight,” Harley said. 

Past, present, and future work

Going forward, Harley is excited about how to build increasingly complex and useful models to study disease progression, therapeutic advocacy, and advance basic research.

“When engineers, like my dad, build a structure made out of steel and concrete, it has a defined shape. Ten years later, it should have the same mechanical properties as it did in the initial spec,” Harley said. “Biology is soft and squishy; it's evolving, which is fascinating. Over time, cells divide, die, produce new tissue, and degrade — these dynamics shape stem cell responses, healing immune responses, drug responses, and more.” 

His lab is expanding its modeling portfolio to study osteosarcoma, a type of bone cancer, and endometriosis where the lining of the uterus grows outside the organ.

Harley credits his research group for championing all of these models. “I have prioritized people over projects — we recruit a diverse group of trainees whose different backgrounds and perspectives drive better science,” he said. “My job is to provide a supportive, inclusive, and equitable climate where they can do their best work.”  Harley’s model of running a research lab has evolved from his own graduate experience working with Yannas, Gibson, and his postdoctoral mentor Dr. Les Silberstein, a professor of pathology at Harvard Medical School and director of the Joint Program.

“I had the luxury of working for great advisors who were kind and flexible,” he said. “They showed me how to model and sustain an environment of support, and we've been trying to create an environment of inclusion and support in my group.”

Over Harley’s academic career, the outcomes for cancer patients have changed dramatically — which is meaningful for him professionally and personally. 

Harley was diagnosed with a deadly form of leukemia in high school and said he was “incredibly lucky” to survive. “If I had gotten that leukemia in 1980, I would have been dead — there's nothing that would have brought me back,” he said. “In 1995, I had a very small chance of surviving. If my kids had it today, their survival rate would be even better.”

Continued progress toward these generational shifts will take a collective effort and investing more in the diverse perspectives — like those that Harley cultivates within his research group and collaborations. 

“The process to improve health and care for diseases, cancer in particular, is measured on the order of decades,” he said. “But it's a worthwhile investment because we have a lot of perspectives here that will change the way we treat, diagnose, and understand cancer.”

Perhaps his greatest accomplishment as an engineer: Harley has built a community that is truly more than the sum of its parts.