The Power of Applied Physiology

Gary Sieck, Ph.D., has devoted much of his career to the study of how muscles function. Specifically, he studies the neurological mechanisms that control respiratory muscles, which include pulmonary muscles responsible for moving air in and out of the lungs. Named a Mayo Distinguished Investigator in 2007, Dr. Sieck is credited with discoveries that have improved treatments associated with recovery after spinal cord injury, muscle weakness after mechanical ventilation in the intensive care unit, asthma, chronic obstructive pulmonary disease, hypertension, aneurysms, stroke and heart failure.

Dr. Sieck is a basic scientist building upon the scientific foundation established by some of Mayo Clinic’s giants in physiology, such as Frank Mann, M.D., a physiologist who early in the 20th century worked under Mayo’s legendary champion of medical research, Henry Plummer, M.D. Dr. Mann served as president of the American Physiological Society (APS) one of the oldest professional organizations of basic and applied biomedical research in the United States. The post is filled by scientists who have made noteworthy contributions to medicine. And like his predecessor, Dr. Sieck too was elected by his peers APS president. In 2007, he became the fifth APS president from Mayo Clinic.

Dr. Sieck completed his undergraduate and doctoral studies in physiology and biophysics at the University of Nebraska. That was followed by an NIH fellowship in neurophysiology at UCLA where he eventually joined the faculty in the Department of Anatomy and Cell Biology. His route to Rochester, Minnesota took him to the University of Southern California where he was on the faculty in Biomedical Engineering. He joined Mayo Clinic in 1990.

Dr. Sieck is a Mayo Clinic professor of physiology and chair of the Department of Physiology and Biomedical Engineering. He is Mayo Clinic’s deputy director and associate dean for research. He holds numerous institutional committee appointments and is director of the Biomedical Engineering Graduate Program.

Being named a Mayo Distinguished Investigator is one of his most prized achievements he said during an interview in his laboratory last fall.

"It is recognition by your peers. It’s recognition that other people see value in the research I do and the contributions I make. It’s always important to recognize people for the work they do. I try to do that on a regular basis. It’s always well received and appreciated,' he said.

Q. What is applied physiology?

A. Here at Mayo Clinic some of the most important discoveries in medicine were made by physiologists. The first ever catheterization procedure was conducted at Mayo Clinic and achieved as a result of research in physiology. The heart-lung machine that was developed to enable open-heart surgery is all based on physiological science.

Every morning at Mayo Clinic we start 90 to 100 surgeries and almost everyone of those patients will go on a ventilator during the surgery. Of course most patients have no problems while ventilated, which is why we can do surgeries without too many difficulties, but in the intensive care unit where patients have more complex problems, it’s different. Patients in intensive care are on a mechanical ventilator for longer periods of time, which we know is associated with weakness or dysfunction of the diaphragm muscle. The longer you are on a ventilator, the higher the risk of muscle weakness. In my lab, we are trying to understand what happens in those situations. We think it is the removal of a neurotrophic influence meaning that the normal chemical signals released by nerves may be altered during mechanical ventilation.

Another good example of applied physiology is my work is in spinal cord injuries. When the upper cervical spinal cord is damaged in spinal cord injury cases such as that of Christopher Reeve’s, the damage to the cervical spinal cord impacts your ability to breathe because the neural signals that drive rhythmic breathing are removed and the pump muscle (the diaphragm) is paralyzed. We are trying to understand how we might restore normal rhythmic activity of the diaphragm muscle following spinal cord injury. Doing so would mean that these spinal cord injury patients could be taken off mechanical ventilators, which would dramatically improve their quality of life.

Q. What do you study?

A. Most of my research over the last 25 years has focused on the diaphragm muscle (the muscle below the lung that supports breathing) and how it’s controlled by the nervous system. More recently, in the last 10 to 12 years, we’ve also focused on airway smooth muscles, which line the trachea and bronchi and are responsible for conditions such as asthma, which affects more than 20 million people in the U.S.

There are very good treatments for asthma but patients are still suffering. We are constantly trying to explore how we might improve treatment but we have to understand the underlying cause first.

We know that there is excessive airway smooth muscle contraction (hyperactivity) associated with asthma that may be triggered by an inflammatory response and the release of inflammatory cytokines. And, we know that this inflammatory response affects how airway smooth muscles respond to the nervous system. Underlying the contractile response of airway smooth muscles is an increase in intracellular calcium. Our studies are exploring how inflammatory cytokines affect the control of intracellular calcium in airway smooth muscle and how contractile proteins respond to intracellular calcium.

Q. Why is the diaphragm muscle such an important part of your research?

A. The diaphragm is probably the most important muscle in the body in terms of sustaining breathing. It has to work from the time you’re born – even in embryo the diaphragm contracts to cause fetal respiratory movements. The spinal cord controls contraction of the diaphragm and how these muscle contractions are regulated is critical. Our developmental studies focus on the perinatal period because the diaphragm has to be functional at that point. During the very early stages of post natal development, things can go wrong and the most common cause of death is probably respiratory failure.

In the diaphragm muscle, we’re exploring the underlying basis for muscle weakness associated with a variety of conditions, such as mechanical ventilation in the intensive care unit, spinal cord injury, neuromuscular disease and chronic obstructive pulmonary disease. If diaphragm muscle weakness is severe, patients may no longer be able sustain ventilation. As a result, they may require oxygen or need to be placed on a ventilator. We’re exploring the basis for diaphragm muscle weakness. If we can identify the cause, we could try to design effective therapies to reverse the weakness and strengthen the diaphragm.

Q. Your laboratory focuses on Cellular of Imaging and Physiology – what does that mean?

A. We study the nervous system’s control of muscles at the single cell level. We accomplish this by taking advantage of microscopic imaging and biomechanical techniques. We use imaging techniques to learn where proteins are located within cells and how they interact. We also are using imaging techniques for physiological measurements of intracellular calcium. We use laser capture microdissection to capture single cells and measure changes in gene regulation in response to experimental stimuli and other signals. In isolated single muscle fibers, we measure mechanical and energetic responses to calcium and thereby characterize their basic physiological properties. Using these techniques we can determine whether muscle fibers weaken as a result of changes in contractile protein content or their response to calcium.

We collaborate with people from throughout the world who get muscle biopsies from humans: leg muscles and diaphragm muscles. We also conduct studies using genetic animal models and cultured cells.

Q. In his nominating letter, Dr. Bradly Narr, the chair of the Department of Anesthesiology, described you as an "enthusiastic teacher and mentor." You obviously have a passion for teaching. Why is that important to you?

A. I love teaching and mentoring. That’s one of the exciting things about being in science. For years, I have had high school students and undergraduate students work in my lab to explore their interest in biomedical research. I’ve watched as some students who started in my lab in high school have gone on to college and then to medical or graduate school. I am constantly writing letters of recommendation for such students and I’m thrilled and extremely rewarded by their success.

As director of Mayo’s graduate program in biomedical engineering, I am closely involved with a group of extremely bright young people who are pursuing their Ph.D.'s in biomedical engineering over a 5-year period. I get to influence them in terms of discovering what they’re interested in and matching them up with the best advisor. I enjoy this tremendously and occasionally some decide to work with me. I also get to mentor postdoctoral fellows as they develop their careers in biomedical science. Finally, as department chair, I mentor junior faculty members as they develop their careers here at Mayo. Their success is my success.

Q. How do you bring out the best in your students?

A. With a little bit of tough love. The currencies of modern science are publications and grants. Students have to learn how to write and become competitive. Unfortunately, a lot of graduate programs don’t teach how to become successful scientists by these measures. These are valuable skills – professional skills that are often ignored. Students working in my lab for 2-3 years typically leave with no fewer than 3-4 publications and often more. They also participate in writing multiple grants. This may seem extreme, but it sets them up well later in life.