Having trained at the National Human Genome Research Institute (NHGRI) in the early 2000s, Konstantinos N. Lazaridis, M.D., is no stranger to sifting through sequences of human genomes to uncover genetic variants and mutations associated with diseases such as Primary Sclerosing Cholangitis (PSC).
“But to sift for the needle in the hay stack, which is required for making impactful discoveries about disease, you need hundreds, thousands of samples; gathering them is no easy task with a disease as rare as PSC,” Dr. Lazaridis said. Despite the fact that PSC affects only 1 in 10,000 people in the United States, Dr. Lazaridis and his team have collected samples from about 1,500 PSC patients during the past 10 years. The result: about 30,000 tubes of biospecimens with more than a half a million clinical data points collected into a single database representing to our knowledge the largest and most comprehensive PSC biorepository anywhere in the world. And as this effort continues and grows the challenges are changing, including how to maintain and enhance this important resource.
“It has been a humbling experience and a privilege,” Dr. Lazaridis said. “I still remember my emotions when holding in my hands a box containing invaluable individual DNA specimens from the first 100 PSC patients who enrolled in our study from all over the United States, entrusting their genetic blueprint to us. I felt I had in my hands the cause of PSC, and I was wondering how long it would take us and others to crack the mysteries of this disease.”
By examining those blueprints, Dr. Lazaridis and several collaborating groups have now discovered 20 genetic variations associated with development of PSC. Recently in collaboration with industry, the team was able to generate exome sequences of nearly all 20,000 genes comprising each PSC genome in the biorepository. “Each patient and data point have something to tell us about the big picture of this disease,” Dr. Lazaridis said. “So, we have many pieces of a really enormous puzzle to put together.”
Destiny it seems brought Dr. Lazaridis from Greece to Mayo Clinic to figure out that puzzle.
“As a medical student in Greece, I was exposed to many patients with autoimmune hepatitis, and autoimmunity as a disease process was a very intriguing to me,” Dr. Lazaridis explained. “Also, the liver is a resilient organ in charge of several body functions including metabolism and detoxification of substances as well as bile production for digestion.”
Thus, after medical school, his transition to studying the molecular biology of systemic lupus erythematous, an autoimmune disorder that affects many organs including the liver, seemed a natural fit. He secured a two year post-doc position at the University of Texas and the Veterans Administration (VA) Hospital in San Antonio. During that time, Dr. Lazaridis realized he needed specialty training in gastroenterology and hepatology, which the immunologists he was working with couldn’t provide.
In the pre-internet era, to learn which medical center offered the best gastroenterology and hepatology training program, he headed to the VA hospital library. He located a copy of Gastroenterology, the top peer-reviewed journal of the specialty, to find out which institutions the Editor and editorial board hailed from. “At that time, the Editor (Dr. Nicholas LaRusso) and the entire editorial team of Gastroenterology were from Mayo Clinic,” Dr. Lazaridis said. "In the spark of a moment, Mayo Clinic became the goal for my training in gastroenterology and hepatology.”
He applied for a spot in the Internal Medicine training program, but received no word as to whether he was invited for an interview. During the last week of the interviews, he decided to call the office of the program director, three times actually.
“I was busy with experiments that day at the VA and almost forgot to call the program; it was late in the afternoon when I got a free moment,” Dr. Lazaridis said. “After getting no answer the first two calls, I could have stopped, but I persisted and the third time I got Dr. Schultz, the program director himself, on the phone. I explained the situation, and was surprised that he reviewed my application as we were talking and told me that I was an excellent candidate for the program. He offered me an interview a week after the official period.”
The first week of February 1993, Dr. Lazaridis visited Rochester for an interview, and shortly thereafter became an Internal Medicine resident with the good fortune of having Dr. Greg Gores as his advisor. Dr. Gores encouraged him to pursue the Clinician Investigator Training Program and to work with Dr. LaRusso in his laboratory on the molecular mechanisms of cholestasis.
Three years later, Dr. Lazaridis sought to bring his research experience to the patient level, pursuing translational research using human biospecimens. At the suggestion of Drs. Gores and LaRusso, Dr. Lazaridis was given an opportunity for additional research training as a Mayo Clinic Scholar. His mentors suggested he make a choice between studying human genomics or virology of hepatitis C with the goal of establishing an innovative, research program on liver disease in the Division of Gastroenterology and Hepatology.
“I chose the former in a heartbeat,” Dr. Lazaridis said. “This was an easy decision. At that time, the Human Genome Project was well underway and the promise of genomics in medicine was overwhelming.” He interviewed with luminary scientists in the field, Eric Lander, Ph.D., at the Massachusetts Institute of Technology and Francis Collins, M.D., Ph.D., at the NHGRI for the opportunity to join one of the laboratories as a Mayo Clinic Scholar. He was offered a position at both places, and made another key decision.
“I decided to join Dr. Collins’ laboratory because the project that Francis proposed to work on for my training in genomics – dissecting the genetics of type 2 diabetes – could serve as a prototype for what I envisioned developing for cholestatic liver disease,” said Dr. Lazaridis. “I saw the potential of genomics to reveal answers where there were none and opportunities to better understand disease pathogenesis tailored to an individual patient’s genetic blueprint. My two year training at NHGRI was an outstanding experience. Working with Francis changed forever the way I was perceiving mechanisms of disease and taught me the fundamental importance of human disease registries and bio-repositories.”
in 2003, Dr. Lazaridis brought that vision and training back to Mayo Clinic and started his own research program dedicated to dissecting the genetic contributions of rare, progressive, cholestatic liver diseases, such as PSC. “I have immensely benefited from the unparalleled mentoring of Drs. Gores and LaRusso over the past two decades.” Lazaridis said. “They always pointed me in the right direction, yet trusted my decisions and efforts as I was developing a novel program within our Division.”
Today, the primary goal of his research program is to find a cure for and improve the care of patients with PSC. But to find a cure, Dr. Lazaridis emphasizes that the causes of the disease need to be understood. “We believe the development of PSC results from the interaction of environmental exposures and the genetic profile of an individual,” Dr. Lazaridis said.
During the past decade, his team has made significant progress to understand the genetic underpinnings that predispose patients to develop PSC. Through such studies they have determined that genomics alone can’t explain why some people develop PSC and others do not. Although Dr. Lazaridis began work to elucidate the role of the genome first because scientific tools were available, he’s now turning his attention to studying the role of environmental exposures (“the exposome”) in developing PSC. With the availability of new scientific tools, his team will examine how the interactions of genetic risks and environmental exposures (i.e., toxins and chemicals, etc.) lead to PSC and its complications.
“We are making great progress to unravel the causes of PSC because of patients trust and contribution to our studies, synergy between PSC-focused scientific groups, strong benefactor commitment and funding support from NIH,” Dr. Lazaridis said. “All these forces are coming together to bring an end to this disease…and we will.”
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