University of Vermont

Office of the Vice President for Research (OVPR)

INQUIRY 2016 Research, Scholarship and the Arts at UVM

Innovate and Incubate

THE INSPIRATION AND RESEARCH OF UVM FACULTY MEMBERS LEAD TO THE DEVELOPMENT OF COMMERCIALLY VIABLE PRODUCTS THAT IMPROVE DAILY LIFE.

It hardly looks like the setting for a Eureka moment: a small room with barely enough space for a computer screen, microscope and chair. But what Professor of Medicine Jeff Spees, Ph.D., saw on a microscope slide in that monkish cubbyhole off his main lab at UVM's Colchester Research Facility — an army of healthy cells successfully grafted to heart muscle — was a watershed moment in regenerative medicine.

Jeff Spees, Ph.D.The grafted cells adhered and thrived in great number — breaking the record for graft success by a huge margin — thanks to a biochemical cocktail derived from bone marrow Spees had bathed them in.

"When I looked on the scope, and there was a beautiful graft on the heart, I was so amazed I actually shed a tear," says Spees.

This trailblazing achievement is one of several Spees discoveries that are clearing a plausible, and promising, path to the holy grail of cardiac medicine; regenerating healthy new heart muscle in the necrotic area of a heart attack. The work clearly has great clinical significance. Because of patents Spees and the University hold or have applied for on key elements of the work, it has potentially sizable commercial import as well.

Pursuing the commercial application of research discoveries as Spees is doing, in addition to pushing the boundaries of science in the lab, is emblematic of a new culture that has swept UVM over the last decade, one that places great value on applied, as well as purely theoretical, research.

"It has become OK at UVM to think that financial value is also important; that having your research grow into being a commercial product or service is a good thing," says Corine Farewell, director of UVM's Office of Technology Commercialization (OTC). A sign of the new environment, Farewell says, is the record 56 invention disclosures the University saw last year, a 40 percent increase over the prior year, a signal not only of robust intellectual activity, but of a new faculty willingness to reach out to Farewell's office and share the innovations.

In keeping with this new spirit, UVM Provost David Rosowsky, Ph.D., notes that the University is putting systems in place that energize and promote faculty entrepreneurship and is attracting talented new faculty who "want to play in this space."

"All of these things are driving us forward," he says.

DESTINATION PATIENT

Faculty motivations for commercializing research vary but are rarely purely financial, says Professor of Medicine Mercedes Rincon, Ph.D. She explains,

My main motivation is that I want what we do in the lab to get to the patient. The only way you can do that is through commercialization. It's not because you want to make a lot of money, it's because you want your research to have an impact on people.

Rincon's research has the potential to significantly impact patient care in two areas that have eluded modern medical treatment: resistance to chemotherapy among some breast cancer patients and treating fatty liver disease, which affects a quarter of the world's population. The therapies Rincon is in the process of developing and commercializing, via a start-up company called Mitotherapeutix rely on her discovery of the special talents of a single protein called MCJ.

MCJ, Rincon has found, regulates the metabolic activity of cells by acting as a kind of brake on the mitochondria, the peanut-shaped protein tangles in a cell's nucleus that control its energy output.

Mercedes Rincon, Ph.D.She draws on an analogy to explain. "If you're going 80 miles an hour in a car, you're using a lot of energy," she says. "You slow down and use less energy when you put the brake on. That's what MCJ does. It decreases the activity of the mitochondria, which is the engine that produces the cell's energy."

For breast cancer chemo-resistance, Rincon has shown that giving mice a therapy that mimics MCJ greatly reduces their chemo-resistance, perhaps slowing down the mechanism, she speculates, that some cells use to eject foreign substances like the chemotherapeutic agent. She has published some of her results, patented the therapy and applied for federal grants to take the research and the commercialization effort further.

By contrast, Rincon has shown that treating fatty liver disease requires the opposite approach: speeding up cell metabolism. When mice given a special therapy that reduces their MCJ activity were fed a fatty diet that leads to the condition, they burned off the fat in the liver and were protected, while a control group with normal MCJ activity levels developed the disease. What's more, the livers of mice with an advanced state of the disease given the same therapy miraculously healed — a signal result, since no medications exist for treating fatty liver disease, which eventually leads to potentially fatal cirrhosis. Rincon has applied for patent for her therapy.

Given the magnitude of the problems Rincon is addressing and the clear promise of both MCJ therapies, she would seem poised for major commercial success. But the path to commercialization is an arduous one. "We have mouse data, but that's just the beginning," she says. To advance further, she'll need to win more competitive grants and raise venture capital, the prospect of which leaves her cautiously optimistic.

Rosowsky sees faculty entrepreneurship as a way for research universities like UVM to fulfill a 21st century version of their land grant mission, providing value of a new kind to their home states.

"It's part and parcel of the land-grant mission," he says.

HELP FROM THE HIGGS

It's hard to imagine a skill set more perfectly matched to contemporary community needs than the one possessed by mechanical engineering Professor Dryver Huston, Ph.D., a serial inventor who's thriving in UVM's new entrepreneurial culture. Where Huston was once on his own with his legion of ideas, he's now supported by an entire system that encourages faculty innovation and entrepreneurship.

Huston and his collaborator, Associate Professor Tian Xia, Ph.D., a colleague in electrical engineering, were winners in the University's 2015 SPARK-VT program, a new Shark Tank-like competition among faculty with innovative ideas that awards $50,000 to each of four winning proposals a year. Their project was a ground penetrating radar, or GPR, system that can be hauled over bridges at highway speeds to detect structural defects.

Left to right: Dryver Huston, Ph.D., and Tian Xia, Ph.D., test their mobile ground penetrating radar system on the UVM campus with graduate students Yu Zhang and Dan Orfeo.

This innovation addressed the Achilles' heel of GPR when used to diagnose bridge integrity, a key application on any of America's 600,000 aging bridges. Unless driven at a crawl, which requires bridges to be closed, traditional GPR systems had to emit so many radio waves to get accurate readings of bridge integrity that they interfered with the navigation systems of aircraft, and the Federal Communications Commission banned their use at high speeds. The challenge Huston and Xia set themselves was how to obtain the same below-the-surface information with many fewer waves.

Huston found his answer in an unlikely source: particle physics, which used the advanced technology in supercolliders hunting for elusive molecular particles like the Higgs boson. Physicists at the University of Chicago generously shared the hardware they had developed, which Huston and his colleague adapted for GPR. They obtained just the results they had hoped for.

As useful as the technology is for bridge diagnostics, its real promise and commercial value may lie elsewhere — in plumbing the depths of the nation's municipalities, where it can render 3-D images of below-ground infrastructure that are easily read by non-specialists.

That's a capability cities around the country are in need of says Beth Anderson, chief innovation officer for the city of Burlington, which has teamed with the UVM researchers, the city of Winooski and an internet-of-things company called Kardinal Microsystems to field an entry using GPR, sensors and other tools for a competition called the Global City Teams Challenge, co-sponsored by the national Smart Cities Initiative and U.S. Ignite, a National Science Foundation-backed partnership that promotes the development of next generation apps.

"When you hear how cities are struggling because their infrastructure is old and hasn't been maintained, people think of things like roads and bridges," she says. "But it also completely applies to underground infrastructure. The first step is to know what's down there, and what condition it's in. That's exactly what this system does."

The team will pilot the new technology this coming year in the two cities and has hopes of winning grant funding in the Smart Cites competition to expand the work.

RANDOM ACTS OF INSPIRATION

One reason Jeff Spees was so moved by the grafting success he observed in his lab was that he had failed miserably in his attempts to graft cells over the previous eight years.

"I'd given up," he says. "We were trying to figure out, is this the best way to inject (the cells) in the muscle? Or inject them in the vasculature? How should we use these cells? And it didn't matter, because no matter what you did, they were gone in a few days."

The idea of conditioning the cells in a bath of factors derived from bone marrow occurred to Spees randomly. After the initial success, "the real work began," Spees says — isolating which of the more than 1,000 factors were doing the work.

Jeff SpeesA tedious three-month screening process yielded the two instrumental ones: human growth factor and insulin.

Spees is patenting the potent duo as Cell-Kro. The product will have an immediate market among researchers around the world trying graft adult and embryonic stem cells, who had hit the same wall Spees had.

Spees has already solved a problem other researchers, unable to graft cells at all, haven't begun to grapple with: getting grafted cells to travel to the area where they're needed: in Spees' case, the dying tissue of a heart attack. To do that Spees relied on the built-in traits of the heart's epicardial progenitor cells, stem cells found at the surface of the heart that function as the organ's repair kit, traveling to an area of need and transforming themselves into whatever kinds of tissue are needed.

Spees developed and patented a process for isolating, purifying and replicating the peripatetic cardiac progenitors. Along with the progenitor cells and Cell-Kro, Spees has developed a third complementary product: a biologic called VasaPlex that the cardiac progenitors, once grafted and mobile, deliver to the dying area of the heart after a blocked artery is opened, whose toxic contents spill downstream and cause further muscle death. By protecting the heart tissue awash in the toxic arterial flow, VasaPlex can cut the size of the dead tissue — the "infarction" — nearly in half.

"People typically die after a 35 percent infarction of the left ventricle," Spees says. "If we cut that to 10 percent or less, then it's pretty mild. You can have a full, normal life."

Says Kerry Swift, technology licensing officer at the OTC,

What I like about Jeff's portfolio of IP right now is that it's almost a one-stop shop for cardiac repair. That's the basis of a company." A company with bright prospects, considering that over 735,000 heart attacks occur each year in the United States alone.

Spees, also a SPARK-VT winner, has attracted wide interest from venture capitalists and recently won a $1.6 million grant from NIH to continue his work.

David Schneider, M.D., director of the Cardiovascular Research Institute of Vermont, sees the greatest promise in the work that's just ahead for Spees: his plans to collaborate with other researchers involved in cell "reprogramming" to find the recipe for transforming Spees's mobile cardiac progenitors into heart muscle — one tissue they can't make on their own — once they reach the destination of the infarc.

Spees doesn't think all the dead tissue would need to be replaced; only enough to create a lattice of new muscle the heart's natural reparative system could build on.

"If we can get that matrix to form, I'm pretty hopeful we'll get a lot of repair done," he says.

"That would be a game-changer," says Schneider.

In the work of faculty like Spees, Rincon and Huston and in the evolving culture driving innovation, UVM's vice president for research, Richard Galbraith, M.D., Ph.D., sees a synergy developing that will be of broad benefit to the University.

"As we have more people interested, we will be having more disclosures, we will be filing patents for better inventions, we will be developing them faster because of things like SPARKVT," he says. "But more importantly there will be an increase in the intellectual component of entrepreneurial activity at the University and among our students and faculty, and that will benefit everyone."