As clinician-scientists, both investigators realized early on that they shared an interest in discovering how fatness translated into disease.
You’d be hard-pressed to find an odder coupling than a pediatric endocrinologist and an adult bariatric surgeon, two medical professions without a naturally overlapping Venn diagram. One physician sees the early development of diabetes in a child, the other treats adult patients already suffering from advanced disease.
One such partnership exists at the School of Medicine: the investigative team of Daniel Marks, MD, PhD, Associate Professor, Department of Pediatrics, and Robert O’Rourke, MD, Associate Professor, Department of Surgery.
“It’s an unusual and mutually beneficial collaboration,” said Dr. Marks. “My expertise is in cachexia , in addition to obesity and its attendant complications such as diabetes, while Bob, aside from being a bariatric surgeon, is an immunologist.” The two have very little scientific and clinical overlap, except for the conceptual idea that they both understand obesity, and share a belief that obesity is not bad because of cosmetic reasons, but rather because of the pathology that it generates.
So how is it that these two OHSU investigators came together?
It began when Dr. O’Rourke arrived on campus nine years ago. “I was interested in investigating how inflammation translated to metabolic disease in obesity,” he said. “Dan was among the many scientists I met as I made my initial rounds through the scientific community at OHSU. Many people helped me in one way or another get my research started, but the relationship with Dan has blossomed.”
It initially seemed like an odd fit. Dr. Marks’ interests lie in how the hypothalamus, a part of the brain that controls appetite, regulates body weight in the context of cachexia, a state which is characterized by a lack of adipose tissue and is associated with chronic diseases like cancer. Dr. O’Rourke’s interests, in contrast, focus not on the brain, but rather on adipose tissue, and how dysfunctional adipose tissue leads to metabolic disease in the context of obesity.
“We were coming at this from different tissues and different disease states,” said Dr. O’Rourke. “But we both had an interest in how inflammation regulates these processes, and that common interest kept us working together. Over the years, we have both learned how similar cachexia and obesity are, despite being at opposite ends of the body weight spectrum.”
An important driving force behind their collaboration was the need for mentorship. To support the development of his research, Dr. O’Rourke, at the time considered a “young scientist” in the field, applied for a Mentored Clinical Scientist Development Award (K08) with the NIH. Securing a K08 required that a senior-scientist with experience in metabolic disease research serve as his mentor. He turned to Dr. Marks to fill this role.
“Dan is a talented educator with a strong sense of responsibility about scientific mentorship,” said Dr. O’Rourke. “Scientific mentorship is critical for the success of young scientists, especially clinician-scientists like myself, and I could not have achieved NIH funding without Dan’s help.”
As it turned out, the NIH liked the idea of collaboration between two investigators coming at it from opposite ends of the disease spectrum, and funded the research.
Eight years later, their “unusual” scientific partnership is as strong as ever, having produced multiple papers, including a recent F1000 paper titled, “Hypoxia-induced inflammatory cytokine secretion in human adipose tissue stromovascular cells,” which is a study of the response of human adipose tissue to hypoxia in human obesity.
“As clinician-scientists, we realized early on that we shared an interest in discovering how fatness translated into disease,” said Dr. Marks. “Bob’s access to a variety of subcutaneous and visceral human fat, taken from the operating room, has laid the foundation for our investigation.”
Dr. Marks, in contrast, has significant experience in murine models of obesity, and has helped Dr. O’Rourke translate findings from his human cell culture system into in vivo murine models of obesity. This work has guided them down the path of studying the effect of adipose tissue oxygen deprivation on inflammation in adipose tissue, and identifying the molecules that regulate oxygen stress responses in adipose tissue and lead to inflammation and metabolic disease.
While one scientist investigates from the perspective of cachexia and neuroscience, and studies primarily mouse models, and the other from the perspective of obesity and adipose tissue and studies human tissue models of disease, each has zeroed in on a common mechanism that appears to effect how weight contributes to metabolic diseases: inflammation.
“Surprisingly the molecules that regulate inflammation in the brain and in adipose tissue in both cachexia and obesity are similar,” said Dr. O’Rourke. “The hope is someday we will find the molecule that we can manipulate in our human in vitro or murine in vivo model systems and dramatically regulate metabolism. Once we achieve that goal, then we have made the first steps towards developing therapy for use in primates and humans.”
As NIH funding becomes increasingly sparse, OHSU faculty members are growing more creative, often reaching across the spectrum in the way Drs. Marks and O’Rourke have, in order to organize for success and create partnerships that haven’t existed in the past.
Pictured above: (L to R) Drs. O'Rourke and Marks