Take a deep breath. With luck, that felt good, maybe even a little relaxing. But if you're one of the 25 million Americans living with asthma, or are among the more than 15 million who have chronic obstructive pulmonary disease (COPD), or the 221,000 who will be diagnosed with lung cancer this year alone, perhaps it didn't.
You could even suffer from airway disease but not yet know it. Twenty percent of the so-called "silent zone" of lung function can disappear before it becomes palpable. Researchers at the University have been tracing those airways to their very ends and beyond and in so doing, have raised UVM to a level of national and, indeed, global distinction in lung research.
Much of the reason for that prominence is due to the Vermont Lung Center, led by Professor of Medicine Charles Irvin, Ph.D. Irvin came to Vermont in 1998 from the National Jewish Hospital in Denver, the leading respiratory hospital in the United States, where he was the medical director of the largest lung-function lab in the country, and a professor at the University of Colorado Medical Center. But with his work divided equally between animal models and understanding basic mechanisms, he yearned to get involved in clinical research, which was not possible in Denver. Former Denver colleagues who'd moved on to UVM helped draw Irvin to Burlington, where his charge was to set up an asthma center in the Department of Medicine.
"There was a history of excellence here, and an association with the medical school and the University," says Irvin. "And that was basis enough to establish the Center." Soon after he arrived, a new grant was announced: the American Lung Association- Asthma Clinical Research Center program. The following year, after being awarded a Centers of Biomedical Research Excellence (COBRE) grant from the National Institutes of Health, the Vermont Lung Center fully came to life.
The first-cycle COBRE brought "serious money" some $40 million over a total of 15 years, with successful renewals at five-year intervals, with the VLC often earning the best score in the competition. The funding cycle was successfully completed in July of 2015. Irvin takes pride in the fact that the VLC was among the small number of COBRE grantees that qualified for all 15 years of funding. Faculty members continue to receive grants from a variety of sources, and he points to those as confirmation of the VLC's success. "There's a track record of outstanding excellence based on peer review," he says, "so when I say we have a terrific center, I base it on this consistent high level of peer review."
Those grants fund continually innovative research by an interdisciplinary faculty whose members collaborate across the departments of medicine, microbiology and molecular genetics, physiology, and pathology, and the College of Engineering and Mathematical Sciences. Their collective basic science, translational, and clinical research focuses on a range of lungrelated issues including bacterial genetics and metabolism, cell therapy, cystic fibrosis, pulmonary fibrosis, critical care, obesity, and asthma.
"That was a game-changer when Charlie came on board and recruited all these fantastic people," says Professor of Pathology Yvonne Janssen-Heininger, Ph.D., whose primary research interest is the biochemical processes underlying the chronic remodeling of airways in lung tissue. She is also behind an active research partnership between UVM and the Maastricht University Medical Center in the Netherlands, where she earned her Ph.D.
Asthma and obesity receive significant attention from UVM lung researchers in fact, says Benjamin Suratt, M.D., obese asthma is becoming its own category of asthma. He and several colleagues have conducted several clinical trials and ancillary studies to comprehend the mechanics behind it, exploring the possibility that it is an inflammatory response, and what the best treatment might be. Suratt, professor of medicine and vice chair of medicine for academic affairs, has also looked at the effects of obesity on Acute Respiratory Distress Syndrome (ARDS), which is common to hospital intensive care units and kills roughly 30 percent of patients who have it.
"Most of the work that's been done over the last 30 years has looked at cardiovascular and endocrine disease in obesity, so there's very little that's known about what obesity does to the lung, and how it modifies both the incidence of a disease like asthma, but also how it modifies the actual manifestation of the disease," says Suratt.
Together with Professor of Medicine Anne Dixon, M.D., Suratt coordinates a biannual conference on these issues; "Obesity and Metabolism: An Emerging Frontier in Lung Health and Disease" which was hosted at UVM's Davis Center this past October. He also frequently collaborates with Associate Professor of Medicine Renee Stapleton, M.D., Ph.D., whose own research is largely clinically based and focuses on nutrient and other supportive care interventions in the ICU, as well as communication around treatment preferences in palliative care.
"The great thing about the VLC for investigators is that it really brings together a diverse and multidisciplinary group of scientists that come from all areas of pulmonary investigation. It's a wonderful coalescence of clinical research and basic science and physiology that I think is very difficult to find at other institutions," says Stapleton.
HEALING WITH SEAWEED
Rachael Oldinski, Ph.D., would like to patch punctured lungs with seaweed.
Healing with Seaweed
BY JOSHUA BROWN
RACHAEL OLDINSKI, PH.D., would like to patch punctured lungs with seaweed. One afternoon this spring, behind the doors of her lab in Votey Hall the Engineered Biomaterials Research Laboratory the professor points to three of her graduate students and four undergrads. "Everyone here works with alginate," she says, "which is purified seaweed."
Oldinski has a deadly serious set of goals. One is to do basic work on the mechanics and chemistry of a family of materials called hydrogels. "Can we create products that are smart that are responsive to changing pH or temperature or biological conditions? Can we create products like skin, that stretch and reorganize themselves over and over without failing?" Oldinski asks. On the other side of the bench from her, doctoral student Spencer Fenn squirts a purple blob of alginate onto a glass slide and spins the slide inside a small centrifuge.
He then places the goo-covered slide inside a box filled with green LED lights. Because of complex manipulations he's done to the goo's chemistry, under the light the long strands of polymers within the liquid will link with other strands. After a few minutes, he takes out the slide. "See, it's become a hydrogel film. It's no longer a liquid; it's a solid."
Fenn has been spearheading a research effort to use alginate gels to create a kind of Band-Aid for the lung. Whether from a car crash or disease or battlefield injury, once a lung is punctured it is difficult to seal and heal, since it is constantly inflating and deflating. He and Oldinski and others in both UVM's College of Engineering and Mathematical Sciences and College of Medicine have developed a patch that looks promising for clinical use. Once it is freeze-dried, a surgeon will be able to cut a piece of the hydrogel, apply it to the wound and let it rehydrate from the body's own water. Then, using a scope with a green light, transform the goopy patch into an adhesive lung sealant. This innovation promises to be non-toxic and a recent study by the lab team shows that the patch can withstand lung-like pressures.
At its foundation, Oldinski's aim is to imitate nature "to replace nature," she says but then to use the replacement materials to restore regular biological function.
"Another thing VLC does incredibly well," she notes, "is manage both a very active, productive, successful basic science side as well as a very similarly active and productive clinical research side, two totally different skill sets."
"We're interested in projects that are going to have high impact, and high impact means affecting patient care," Irvin says of the group's broad research targets.
Those also include work by Matthew Wargo, Ph.D., assistant professor of microbiology and molecular genetics, on bacterial lung infections and how various gram-negative opportunistic pathogens respond to surfactant when they get to the lung, as well as how they respond to damage to the host lung surfactant and cells and tissues and cause diseases including cystic fibrosis. Together with Suratt, Wargo is using a mouse model to determine changes in respiratory physiology during infections. The mouse model is a classic approach in studying the lung, and as at centers worldwide, they're using the flexiVent, a device that accurately measures lung function in small animals, which was created by the VLC's Jason Bates, Ph.D., professor of medicine. Bates calls the flexiVent a "plug and play," but in fact it's now the industry-standard tool for measuring lung stiffness and airway resistance.
Bates, who has one foot in UVM's College of Engineering and Mathematical Sciences as well, serving as graduate coordinator for the new bioengineering Ph.D. program, wants to understand the physics of the lung: how big are the airways, how much pressure does it take to force the flow of air through, and how can the lungs be expanded? That applies to asthma, as well as to ARDS: "You have this delicate lung; how do you ventilate it in a way that minimizes the physical damage you do to it?" says Bates. He's also currently collaborating with Matt Poynter, Ph.D., associate professor of medicine, to test hypotheses about allergic inflammation.
"My computational inclinations match up with his immunological knowledge, and we end up doing a lot of interesting work," says Bates. "It's always at the interface between different disciplines or different skill sets that the good stuff comes. The buzzword in research is translational, but here in the VLC it's a natural thing."
Daniel Weiss, M.D., Ph.D., is leading work that focuses on the actual growing of lung tissue: Lung tissue bioengineering, which involves the use of a scaffold or framework of lungs from human cadavers to engineer new lungs for patients with end-stage disease. In end-stage lung disease, transplantation is sometimes the only viable therapeutic option, but organ availability is limited and rejection presents an additional challenge.
The innovative research efforts of Weiss and his colleagues hold promise for this population, which includes an estimated 12.7 million people with chronic obstructive pulmonary disorder, the third leading cause of death in the U.S. In the last few years, Weiss's group has published a number of articles on the topic of stem cell-related lung regeneration, including several articles in Biomaterials, the leading bioengineering journal. And, Weiss himself has been the driving force behind the "Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Lung Diseases" conferences that have drawn hundreds of researchers from across the world to the UVM campus. The tenth anniversary conference was held at UVM's Davis Center in July 2015.
Irvin is justifiably proud of the way lung researchers at UVM work together. "The group is incredibly collaborative," he says. "We've achieved what we set out to do, and that was to develop a world-class center of lung biology and understand disease pathogenesis of the lung. I think we have a lot to be proud of, and we've got a very bright future, because we've got the one thing that matters, and that is fantastic people who get along and collaborate with each other."