Innovative. Interdisciplinary. Internationally renowned.
The Department of Pharmacology and Physiology may be rooted in basic science, but its mission is complex—to be the leader in advancing research of the mechanisms and treatment of human disease; to educate and train the next generation of scientists, clinicians, and scholars; and to cultivate a culture of inclusion and collaboration.
“The department is certainly a vibrant environment where we can pursue our research programs and not be limited by technology that’s available,” says David I. Yule, PhD, who holds the Louis C. Lasagna Professorship in Experimental Therapeutics.
In spite of the disruptions caused by COVID-19, the department realized a number of notable milestones, awards, and achievements in 2020. Among them was receiving New York State approval for a new MS degree in Medical Pharmacology.
Research conducted in the department’s laboratories has an impact on dozens of diseases and health-related conditions. In addition to obsessive-compulsive disorder (OCD)—characterized by obsessions and compulsions despite the awareness that these behaviors are unproductive—and other neuropsychiatric disorders, they include, among others, wound healing; osteoarthritis; muscular dystrophy; and opiate addiction, dependence, and reward.
Much of that research focuses on ion channels and drug receptors—proteins present in the membrane of all cells—and signaling. Ion channels form pores in the membrane, which can open and close, and receptors provide specific signals for cells and tissues; channels and receptors control transmission of nerve impulses, contraction of muscles, and secretion of hormones. Together, receptors and ion channels represent that majority of targets by which most clinically used agents work.
“To me, it’s the most interesting part of biology,” says John Lueck, PhD, assistant professor of Pharmacology and Physiology and of Neurology. Lueck suggests envisioning a house with windows and doors that allow information to pass from the inside to the outside: “Basically, ion channels [and receptors] are the windows and doors of the cell that allow information to be passed inside and out. It’s a very complicated network of events that researchers in this department are looking at in unity—just one ion channel at a time—and how they work together in a symphony of activity.”
Some of the pioneers of receptor and ion channel research, as well as those who have made some of the most significant impacts in the field, received their training, or continue to work, in the department.
Led by Chair Robert T. Dirksen (MS ’88, PhD ’91), the department, which evolved from an expansion of the original Department of Physiology established in 1924, even boasts educating a member of the prestigious National Academy of Sciences. Physiologist Wolfhard Almers (PhD ’71) developed a reputation around the world for his studies of exocytosis and endocytosis, two processes fundamental to almost every cell.
Another metric showcasing the department’s prestige: From 2015 through 2020, its faculty published more than 250 research studies, many in top-tier, peer-reviewed journals such as Cell, Science, Nature Communications, Science Signaling, and PNAS.
Between conducting experiments and writing joint grants and papers, collaborative relationships among researchers are standard within the department—as well as with faculty and students in other departments and centers across campus.
One of the strongest and longest-standing links is with the Department of Biomedical Engineering. In fact, former Department of Pharmacology and Physiology faculty member Richard E. Waugh, PhD, helped establish the Department of Biomedical Engineering, where three Pharmacology and Physiology faculty members hold joint appointments.
Interdisciplinary research also takes place with faculty in the departments of Neurology, Neuroscience, Anesthesiology and Perioperative Medicine, and in the centers for Cardiovascular Research and Musculoskeletal Research. For example, Pharmacology and Physiology faculty have well-honed skills when dealing with drug interactions with biological materials, channels, and receptors. Partnering with neurology/neuroscience faculty who treat patients can help them figure out how their molecular- and cellular-level research can lead to new and effective interventions to combat neurological diseases.
“Not to get too folksy about it, but there’s a Midwestern feel to Rochester that translates into an environment that’s somewhat more easygoing,” says John Foxe, PhD, Kilian J. and Caroline F. Schmitt Chair in the Department of Neuroscience. “Not that people aren’t serious here. But they take a bit of time, and maybe are a bit more invested in their colleagues, and so the pathways to interactions across departments tend to be highly collaborative rather than competitive, [the latter being] something many of us who came from other universities would have experienced.”
In a vacuum, basic science, or discovery science, while critical, can at times be slow and incremental. By bringing together people of different and synergistic strengths, collaborative research can be catalytic and so can propel discovery research in transformative ways.
“The bigger questions—cures for Alzheimer’s disease, schizophrenia—need to be tackled by teams of scientists working across different domains,” says Foxe.
Assistant Professor Whasil Lee, PhD, has dual appointments—in Pharmacology and Physiology and in Biomedical Engineering. She specializes in mechanobiology, an emerging field of science that combines biology, engineering, and biophysics, which she uses to investigate ways to treat cartilage disease.
One of the department’s recent hires, Lee says she needed a device to detect mechanotransduced cellular signals that would help her better understand the underlying molecular mechanisms of cartilage degeneration—so she built one. The device is a combination of three types of existing microscopes and is called a mechano-microscope.
The system is now up and running, and the Lee laboratory has been using this innovative system to capture intracellular Ca2+ signals and monitor cell death in living tissues. While concentrating on activity levels of mechanotransducers in the cells of the knee and rotator cuff, she assembled a multi-disciplinary team that includes Jennifer Jonason, PhD; Sandeep Mannava, MD, PhD; and Devon Anderson, MD, all from Orthopaedics and its Center for Musculoskeletal Research; and Christoph Proschel, PhD, from Biomedical Genetics.
Lee has plans to branch out to research human disease-associated mechanotransduction signals of other mechanosensitive tissues.
“I envision myself constructing a comprehensive Mechanosignaling Table of human tissues during my career at URMC,” Lee says.
Meanwhile, novel investigative approaches in the department were buoyed by a 2019 push to significantly expand advanced imaging capabilities.
Using an NIH grant obtained by Yule and V. Kaye Thomas, PhD, the department purchased the first super-resolution microscope in Western New York. The Abberior Expert Line 3D STED microscope allows images to be taken with a higher spatial resolution than with conventional light microscopy, and is being used by researchers across the institution, as well as by investigators from other universities in the region.
For instance, the STED microscope allows Yule, who studies the role of calcium in salivary gland function, to resolve the intimate localization and interaction of proteins within specific subcellular regions of cells that are needed for normal levels of saliva production.
“So I’m seeing different things than I was before,” Yule says. “The bottom line is that if we can visualize things, we can study them.”
Both the STED microscope and a new fluorescence lifetime imaging system open up for faculty and trainees new research questions that relate to the precise localization of proteins in cells. These studies have great potential to reveal important insight—previously not possible—in to the normal working of cells and alterations of these processes in disease.
‘No Barriers Here’
Lauded by colleagues as a visionary, Dirksen has been witness to an infusion of new faculty, energy, ideas, directions, and approaches since he became chair of the department in July 2015.
“We got to a point where there were a lot of full professors and tenured professors, but no assistant professors and very few associate professors,” he says. “The recruitment of six new faculty members since I’ve been in this role has fundamentally changed our demographics and really helped to elevate the esprit de corps of the department.”
That positive energy feeds an atmosphere of cooperation and camaraderie.
“There are no barriers here,” says Lueck.
When he was doing postdoctoral research at the University of Iowa, Lueck had to walk to different floors—and sometimes different buildings—to share ideas with colleagues within his department. At URMC, those who work in the Department of Pharmacology and Physiology largely share the same floor of the same building. “Your ideas just become better when you’re in that type of environment,” he continues.
“When you have lots of collaborative interactions happening daily, you know you’re eventually going to hit on something that will make a difference in your research.” Lueck has two lines of research that both revolve around RNA.
One involves developing innovative, RNA-based therapies for genetically-inherited diseases resulting from nonsense mutations. In support of this cutting-edge research, he is one of two Medical Center investigators—the other is Denise C. Hocking, PhD—to be awarded an inaugural Empire Discovery Institute Grant. With this support he aims to evaluate the therapeutic promise of suppressor tRNA technologies, a field he has helped rejuvenate, for treatment of so-called nonsense-associated diseases that affect 10 to 20 percent of individuals with genetic diseases.
n addition, Lueck is investigating the mechanisms behind skeletal muscle weakness in myotonic dystrophy type 1, the most common muscular dystrophy in adults. In collaboration with Charles A. Thornton, MD (Flw ’90, Flw ’92), professor of Neurology and Saunders Family Distinguished Professor in Neuromuscular Research, they are working to understand the mechanistic link between the genetic lesion and altered skeletal muscle function that may lead to a viable therapeutic target.
Hocking, professor of Pharmacology and Physiology, and of Biomedical Engineering, has shown that topical application of small engineered proteins that mimic the extracellular matrix protein, fibronectin, to skin wounds in diabetic mice increases the rate of healing. The Discovery award will advance one of those proteins, known as Chimectin, first in animal models of diabetes and then, potentially, in the clinic, for the healing of diabetic wounds.
Grants like these are important because significant funding is required to do this type of work. The department manages more than $10 million in outside research funds annually—earning $8.4 million from the National Institutes of Health alone in FY19—and has an additional $9.7 million in pending proposals.
Suzanne N. Haber, PhD, who heads the Silvio O. Conte Center for Research in Obsessive Compulsive Disorder, secured a highly coveted five-year, $10 million grant from the National Institute of Mental Health—twice—to study how neural pathways in the brain can be stimulated to help understand and treat OCD. With joint appointments in the departments of Pharmacology and Physiology, Neuroscience, Psychiatry, and Brain and Cognitive Science, Haber would like more attention given to this chronic, understudied psychiatric illness.
Through the Conte Center, Haber’s lab has employed deep brain stimulation and transcranial magnetic stimulation—currently used as therapeutic approaches—to probe particular dysfunctional circuits in the brain.
Specifically, these studies start with experiments that improve our understanding of the complex connections of association cortex and how functional networks are organized in the normal brain. The networks studied are those that modulate behavioral flexibility—brain regions that work together to evaluate previous experience coupled with a changing environment. The inability to change behavioral responses despite a potential negative outcome is one hallmark of OCD. However, this behavioral inflexibility is not unique to OCD and can be observed in other disorders.
“As these networks are identified, the next step is to develop therapeutic approaches that specifically target the circuits connecting them,” says Haber.
Importantly, these connections are also linked to a wide range of other psychiatric disorders, including depression, post-traumatic stress disorder, and addiction, so the work is expected to have broad implications that reach well beyond OCD.
Haber’s grants extend beyond Rochester. As the parent institution for the Conte Center, URMC subcontracts with Harvard University, the University of Pittsburgh, the University of Puerto Rico, and Brown University.
Diversity in Leadership
Gender diversity is one aspect of the department’s culture that has helped cement its reputation as a leader among the top research universities in the world.
The department has a long history of outstanding and successful female faculty members. Currently, half of the full professors and 40 percent of all faculty in the department are women. In addition, three key leadership positions in the department—associate chair, director of graduate studies, and faculty/staff diversity officer—are headed by female faculty members.
Hocking recently was appointed the Department of Pharmacology and Physiology Faculty and Staff Diversity Officer. She chairs a new Diversity and Inclusion Committee—made up of faculty, staff, and students—charged with making the department a more diverse, inclusive, and equitable environment for teaching, learning, and working. The committee has developed diversity inclusion and anti-racism statements for the department and has formed an internal educational forum for discussing timely topics on diversity and inclusion.
Associate Chair Jean M. Bidlack (MS ’77, PhD ’79), currently working on developing new therapeutic targets and compounds for treating opioid dependence and tolerance, has been in the department since 1987: “We have been able to get our own labs going and fund our own research, where we are assisting younger faculty in developing their own careers. It becomes a pipeline within the department.”
As director of the Cellular and Molecular Pharmacology and Physiology Graduate Program, Associate Professor Angela Glading, PhD, emphasizes that the department’s dedication to training graduate students is something else that brings them together.
In her own work, she has been collaborating with Professor James McGrath, PhD, in the Department of Biomedical Engineering, where Glading holds a joint appointment as an associate professor. Together, they are simulating inflammatory responses that compromise the blood-brain barrier—special vessels in the brain that tightly regulate what enters the brain from the bloodstream.
As for the graduate students themselves, they are ambitious and open to all sorts of possibilities.
“As a small department with relatively small labs, our students are really critical to our research mission,” says Glading. “And so we make a concerted effort to make sure they are really well-trained and well-positioned to launch into any career in science when they leave our hallways.”
According to Lueck, they are in the constant company of people incredibly devoted to their craft.
“What we find out isn’t always translated to a therapy,” he says. “But everything we find out in the cell is important and will give us new information about how something works, which can become very important for translation later, regardless.”