Forty years ago, 16-year-old Ron DePinho, the son of Portuguese immigrants born “under the shadow of Yankee Stadium” in The Bronx, set upon a path that would prove instrumental in instilling certain fundamental principles that would help guide him throughout his life.
The principles were respect, discipline, courtesy, and courage, and combined with the lesson of giving back learned from his family, he would spend the next four decades as a serious student, focused physician-scientist, and pragmatic entrepreneur forging a career that would lead him to his most recent accomplishment and challenge—his appointment as President and CEO of the University of Texas MD Anderson Cancer Center.
I spoke via telephone with Ronald A. DePinho, MD, last month, a few weeks before the official transition date of September 1 when he succeeded John Mendelsohn, MD, (OT, 7/25/11) as the Houston cancer center's fourth president in 70 years.
Dr. DePinho discussed some of his presidential plans as well as a few of the formative factors that influenced him philosophically, socially, and scientifically.
He was raised in an altruistic household that always gave back, and that spirit melded with the four principles he had learned as a teenage martial arts student, he explained.
“When I started training in martial arts I was fortunate to be part of a school that dominated world competition in the 1970s. It was Kang Tae Kwon Do and Hapkido, and we represented the United States in the 1976 world championships.”
An All-American, he was captain of the team that won the world championship that year, which had five of the top 10 US fighters at the time.
“We had a very gifted teacher who taught us a lot more than just kicking and punching, and I credit a lot of my academic success to many of the guiding principles he established at that point.
“It helped hone my academic skills and gave me discipline to take on big challenges, and I was very fortunate to be exposed during my formative years,” he said. He competed for six years, training five hours a day, before starting Albert Einstein College of Medicine, where he established his own martial arts academy, now in its 33rd year.
6th-Degree Black Belt
And as he takes on the task of running one of the biggest and best cancer centers in the world, the sixth-degree black belt vowed to find the time to work out, and said he intends to stay active in the laboratory, a goal that many scientists turned academic administrators have found elusive.
As founding director of the Belfer Institute for Applied Cancer Science at Dana-Farber Cancer Institute and Professor in the Department of Medicine (Genetics) at Harvard, he is internationally renowned for his basic and translational research in cancer, aging, and age-associated degenerative diseases.
His laboratory guided major basic and translational research programs focused on brain, colorectal, pancreatic, and prostate cancers, and Belfer is known for adhering to industry-like principles when translating basic research findings into clinical endpoints, a philosophy and practice he intends to integrate on a grander scale into MD Anderson's research modus operandi.
Dr. DePinho acknowledged that he has “very big shoes to fill, “referring to John Mendelsohn's tremendous legacy, and calling him “the greatest leader in modern cancer medicine.”
When Dr. DePinho was selected as the sole finalist from a field of 70 candidates (OT, 6/10/11), some speculated that his lack of recent clinical experience and untested ability leading a large organization with a staff of 18,000 might be limiting factors.
He confessed that he wasn't even interested in the job at first until the urgings of colleagues got him to submit a letter of intent at the last moment, and he realized, after spending 48 hours interviewing on the Houston campus he had visited many times before in other capacities, that he wanted to be president of MD Anderson.
“I was raised to help others, and that it was never about position or accomplishment,” he said.
“But I was blown away by the magnitude of talent across all levels of the institution on a clinical level, the amount of resources and the capabilities of the institution, and after two days there I really wanted this job. It was an amazing place, with an esprit de corps and collaborative spirit that offered a unique opportunity. I knew then that I had to convince the Board of Regents.”
Started with Biology in High School
He said he was first bitten by the research bug when he took biology in high school, and since he also wanted to work with people, he thought the best way to combine the two would be to become a physician.
He loved clinical medicine in medical school as well as the challenges of trying to understand disease, and became increasingly interested in understanding the molecular underpinnings of disease pathogenesis.
“It was just that we didn't know what causes certain diseases, and since I was fascinated about why diseases started in the first place, I thought if I was going to make an impact on these diseases, I had to understand the why and harness that information in ways that could direct therapies that could actually cure these diseases.”
Joined Lab of Frederick Alt, Also Worked with Matthew Scharff
By his fourth year at Einstein he was dedicating every free moment he had to laboratory-based experiments and when he went to Columbia for his internship and residency he joined the lab of Frederick Alt, PhD, who had just arrived from David Baltimore's laboratory, and who became one of the dominant figures in the then newly evolving field of molecular immunology.
For a short time he also simultaneously worked as a post doc in cellular immunology back at Einstein with Matthew D. Scharff, MD.
“Both experiences taught me to be a scientist, because I essentially had no rigorous scientific training at that point, and I was also one of the first recipients of the K8 physician-scientist awards that trained physicians to become scientists and bridge the divide between the bench and the clinic, which allowed me to hone my basic science skills and apply them to specific areas.”
Fred Alt had just cloned the first N-Myc oncogene, which was the first oncogene shown to be amplified in cancer, and at that point DePinho's own scientific interests shifted from immunology to oncology and cloning new oncogenes because, as he explained, he had noticed that oncogenes were normal tissues that were developmentally expressed in different ways at different times in different tissues.
That got him thinking that the oncogenes might not just be important in cancer but might also govern normal processes and particular developmental processes, and that cancer was perhaps not just cell cycle deregulation but also involved in abnormalities in developmental processes.
‘Contrary to Every Bit of Advice I Had Received’
“As a physician who understood the organism and not just the gene, I decided to go in a direction that was contrary to every bit of advice I had received from each of my mentors, which was to pursue transgenic mouse technology, which was not robust at that point.
“But I felt if you really had to understand the gene you had to understand it not only on the molecular and cellular levels but also on the organism level, and so I then made an effort to learn transgenic and gene-targeting technology and establish it as a very important foundation for my science that enabled me to develop a lot of genetically engineered mouse models and understand gene function on a very comprehensive level.”
His laboratory has always worked on degenerative diseases as well as cancer since their pathways are linked, and understanding the two processes are two sides of the same coin, he explained.
“Operating at the interface of different diseases related to age-related disorders and cancer has provided a unique perspective allowing us to work across different disciplines and to understand basic principles of disease.”
Dr. DePinho said that advancing age is the most important risk factor for developing cancer and that understanding why advancing age causes cancer has been central to his science.
Most human cancers of aging are epithelial cancers, he explained, and since mice don't develop epithelial cancers as they age, an understanding of the cross species difference may help illuminate this mystery.
Father Died of Colorectal Cancer
His evolution from clinical medicine to basic science took more of a translational turn in 1998 when his father died of colorectal cancer.
Scientific accolades and papers are nice, he said, but when one looks at waterfall plots and realizes that they are not just statistics but that some bars are dramatic responses representing “the families who did not have to put a person in a box, this is what it's all about for me. And one activity we've been very successful with is the translation of science through a series of conduits, one of which is the private sector.”
Dr. DePinho described a research ecosystem comprised of academia and industry, and said that the 95% failure in clinical trials could be caused by lack of due diligence at the preclinical level.
He said what was needed was a community ecosystem well-positioned to have a clear clinical path—a translational engine construct of embedded activities led by seasoned individuals—such as the one he had developed at Belfer.
Plans for Teams at MD Anderson
To that end, Dr. DePinho plans to create teams of staff scientists at MD Anderson charged with the responsibility of taking genomic discoveries though a validation process leading to clinical treatments, a situation that would not have been possible until just a few years ago when science had reached a certain stage.
“Pharma is a business that needs to return [financial] investment to its shareholders. But our shareholders are the patients, and we need to bring knowledge to the level of clinical pathways to enable industry,” he said, noting MD Anderson's newly established Institute for Applied Cancer Science, which will be directed by Giulio Draetta, MD, PhD, who was DePinho's deputy director at Belfer.
In all some 24 members of Belfer's scientific staff will be moving to Houston, including Lynda Chin, MD, Belfer's current scientific director, who will serve as scientific director of MD Anderson's new Institute, as well as head of the soon-to-be launched Department for Genome Medicine, which will be the first ever, according to Dr. DePinho.
Dr. Chin (featured in the conclusion of OT's three-part series last year on cancer-genome sequencing; 10/25/10 issue), is also Dr. DePinho's wife and the mother of their children.
“Lynda was in fact the main reason I was recruited,” he said, adding that he was known as Mr. Chin back in Boston, and that she had helped him co-found some of the cancer biotechnology companies he had created, including Aveo Pharmaceuticals.
He spoke with great pride about his wife's history as a 15-year-old emigrant from mainland China who graduated as valedictorian from a New York City public school before studying neuroscience and computers at Brown, earning her medical degree from Einstein, and training in dermatology, prior to turning to basic and translational research leading to her work at Belfer, as a national leader in the Cancer Genome Atlas (TCGA) project, and principal investigator for a TCGA Genome Data Analysis Center at MIT and Harvard's Broad Institute.
He said they met at his martial arts academy when she was a medical student and he was a post-doc at Columbia before returning to join the faculty at Einstein, and that the only way she got to spend time with him was by helping him in the laboratory so he could leave earlier, an experience that turned her interests from the clinic to the bench.
When we talked, Dr. DePinho was very excited about leading his army of “18,000 troops with a singular focus to understand cancer at a level that will inform optimal clinical care and render some of the most effective and safe clinical care that's available.”
He said that he also thinks that genomics should be considered in the context of prevention, and that fuller views of the architecture of the germ line will help the understanding of survivorship.
“We can harness our knowledge of the genome not only to shepherd patients to the right drug but to really use the appropriate drug against the target that will help spare them specific toxicities and help us understand why some patients respond and other don't, and to understand the risk of cancer better and how to modulate those pathways.
“We're at a very special point in cancer medicine, where science is being brought to bear fully on the practice of medicine.”