Issue 23 Edison Liu, M.D., President and Chief Executive Officer, The Jackson Laboratory (JAX)

March 2021

Dr. Liu in a laboratory at the Bar Harbor JAX campus

Dr. Edison Liu, you have been recognized for your contributions to cancer biology, particularly the molecular analysis of breast cancer, and to the global advancement of

human genomics. Can you share with our readers what motivated! you to become a

physician and to specialize in the functional genomics of human cancers?

I have always wanted to be a physician since I was five years old. Both my parents were physicians, as were uncles and aunts, and my only brother is also a physician, so you can say it’s a family vocation. However, the deviation from this family tradition was when I decided to go into research and academics. In medical school, I was considering cardiovascular surgery or cardiology as a specialty until I encountered a remarkable teacher by the name of Dr. Saul Rosenberg, who was then the chief of oncology at Stanford University. He was a world-renowned lymphoma expert who pioneered the curative treatment of Hodgkin’s disease. His knowledge and reputation were superior, but it was his demeanor as a compassionate healer that drew me to the discipline. Despite the grueling nature of the treatments that often were not successful, Saul had more impact on patients’

sense of well-being than the heart surgeon who could technically restore health more definitively. This was because of his ability to connect with his patients and to project caring with competence. He taught me the technical knowledge to optimally treat cancer patients,

but equally importantly, he showed me how my persona as a physician can make a difference to the comfort and security of my patients and their families. When Saul Rosenberg asked me to continue my training in oncology with him at Stanford, I readily agreed.

Throughout my medical training, I always thought I would end up practicing medicine. However, it was also during my oncology training that I found that the knowledge of medicine, about how cancer started and why the drugs work in some and not other malignancies, was surprisingly rudimentary. Everything seemed uncomfortably empirical and without secure theoretical grounding. At the close of my medical training, I decided to take a detour from the practice of medicine to explore the new field of molecular biology as it was being applied to answer fundamental questions about cancer. Another great mentor then entered my life: Dr. J. Michael Bishop at the University of California at San Francisco. Mike is well known because he won the Nobel Prize in 1989 for his discovery of oncogenes. It was in his lab that I investigated the oncogenes that start cancers. From that work, I published a seminal paper showing that a specific mutation in the K-ras gene was present in a premalignant disorder (preleukemia). This work launched my academic career as a faculty member at the University of North Carolina at Chapel Hill Lineberger Cancer Center.

My research was focused on the discovery of oncogenes in human cancers and investigating their function in the treatment and outcomes of cancer patients. I began the

laboratory of Molecular Epidemiology at UNC’s school of public health and moved into the field of population based somatic genetics. In 1996, I was then asked to lead the Division of Clinical Sciences as scientific director at the National Cancer Institute (USA), and it was there that I used genomic technologies to interrogate the clinical meaning of the expression profiles of human cancers which was the basis then of function genomics. Genetics

is the study of individual genes and their function; genomics is the study of how all genes work to generate a biological output or outcome. Functional genomics goes beyond the DNA sequence, focusing on how the genetic workhorse, RNA expression, is configured to explain state changes such as from benign to malignant, from undifferentiated to differentiated cells, from an egg to an embryo. It was at the National Cancer Institute (NCI) that I began my conversion to become a genomicist.

Dr. Liu at the 2019 Healthcare Forum at The Jackson Laboratory for Genomic Medicine in Farmington Connecticut

In 2001, my conversion was complete when the Singaporean government asked me to start the Genome Institute of Singapore (GIS) as the foundation for

genomic sciences for the country. We focused on using genomic tools to explain human disease in the Asian

context. Because the field was young, we contributed to developing new technologies such as ditag (1) approaches to understand distant chromatic interactions. As the founding executive director of the GIS, I was able to

recruit a wonderful group of both Singaporean and overseas scientists to bring genomic technologies to the country and to build the GIS into one of the top powerhouses of genomics in all of Asia.

Dr. Liu spoke at a conference focused on molecular mechanisms of cancer therapy in Cadenabbia, Italy in 2019. His talk was titled: “Genomic Configurations Define a Cancer State: Tandem Duplicator Phenotype”

Finally, at The Jackson Laboratory (JAX), I was able to bring deep genomic and computational platforms to mouse genetics and murine models of human disease. This moved us to yet another level of analysis, a systems genomics approach to bring a greater resolution to complex mechanisms into this system’s logic of breast cancer genomics. I have been extremely fortunate to have had such a rich experience in science and medicine.

1 Also known as paired-end tags (PET) sequencing; it refers to a short DNA sequence that is unique enough to identify a particular segment of the

genome (Dawson et al., 2019)

The Jackson Laboratory (JAX) is an independent, nonprofit biomedical research

institution, which has now become a major international research center for complex

genetics and genomics. As the President and CEO of the JAX, please share with our

readers the JAX’s mission and operations. What do you envision for the future of the

JAX and how do you hope to contribute?

JAX is a unique organization that started in 1929 as a small research institution focused on the new discipline of genetics, using the mouse as a model system for cancer genetics; JAX pioneered the use of mice in disease research, and our research have led to key medical breakthroughs ever since. We were the place that generated many of the commonly used mouse strains; we discovered the first sign that a pluripotent

stem cell existed; we identified the viral transmission of an oncogenic virus that causes breast cancers in mice; we uncovered the genetic roots of tissue rejection for which one of our senior scientists, George Snell, received the Nobel Prize in 1980; and we found the

biochemical cause for obesity. Over the years, as a not for-profit, not only did we uncover important genetic discoveries, but we also progressively became a key provider of research mice for all of North America, and now the world. Therefore, our mission is a bipartite

one: To discover precise genomic solutions for disease and empower the global biomedical community in the shared quest to improve human health. We are unique because of the focus and scale of our work. Our focus is on complex genetics and functional genomics to explain human disease using two model systems, the human and the mouse. The scale is found in the 2,500 staff at JAX who share this focus.

"At The Jackson Laboratory (JAX), I was able to bring deep genomic and computational platforms to mouse genetics and murine models of human disease"

With these capabilities, we integrate computational, genomic, and experimental approaches and iterate towards predictive biology. This means we wish to predict clinical outcomes more precisely using individual genomic, and epigenetic profiles. Because the majority of human diseases are disorders of entire systems rather than single cells, this systems approach will be the only way to resolve biological complexity.

Dr. Liu at the 2016 JAX Board of Trustees farewell dinner with trustees Richard S. Gurin and Charles E. Hewett, Ph.D. Gurin is now a Trustee Emeritus and Hewett, former EVP and COO of JAX, currently serves on the Board of Trustees

As an internationally esteemed physician and scientist with decades of experience,

you have served on many notable committees and advisory boards. You have been a member of the American Association for Cancer Research (AACR) Board of Directors since 2018 and you were recently designated as a member of the board of directors for the American Cancer Society (ACS). What are the major challenges that current cancer research faces and what advancements do you foresee to conquer these challenges in

the next 10 years?

When oncogenes were discovered, we thought that the cure for cancer was in sight now that we knew the genetic causes of cancer. Though we found new therapies, the cure remained elusive. This is because of the major challenge in cancer research—its genetic

complexity. Even though a few genetic mutations may initiate a malignancy, each cancer ultimately has a multitude of genomic mutations by the time it emerges clinically. Though there are genetic similarities among some tumors, there is not one tumor that is identical to

another. Moreover, these mutations change overtime and like the changes in the SARS-CoV2 virus that cause the COVID-19 pandemic, these mutations alter the virulence

and the resistance to therapy of any cancer.

The big question is how to fight something so complex and ever-changing. The first step is to be able to detect all the components of the complex system. In this step, genomic sequencing and accompanying analytical capabilities are essential in identifying each and

every important oncogenic element. The second step is acquiring knowledge of the biological meaning of each mutation. This requires knowledge of each gene’s function, which comes from basic research and will be an ever-continuing effort. The third step is gaining the ability to use this information about gene mutations and gene functions to create a virtual model of tumor behavior, including projecting evolutionary changes when the cancer is subjected to therapeutic interventions. This kind of systems genomics has not yet been achieved and is what The Jackson Laboratory seeks to do.

You led the scientific response for the country of Singapore for the SARS crisis in 2003, introducing several key measures to strengthen Singapore’s pandemic management capabilities. How have the lessons learned from and the measures taken during the SARS outbreak informed our response to COVID-19? With COVID-19 presenting a greater challenge globally, how are you seeking answers to the many unknowns of the pandemic?

I wrote an op-ed for The Straits Times of Singapore on November 23, 2020, that touched on Singapore’s excellent current response to COVID-19 and its relationship to what we learned in 2003. We encountered a major epidemic challenge in 2003 that our generation had not experienced before, so the public health infrastructures of most countries, including Singapore, were not prepared. However, Singapore mobilized its resources and efficiently organized them around scientific principles. With each successive epidemic, such as the H5N1 and H1N1 influenzas, Singapore exercised the infrastructure and improved as a learning system, so that when COVID-19 hit, Singapore was ready and so was China. The first and most important step was to understand the pathogenic cause. Sequencing (genomics) showed that the epidemic was caused by a coronavirus akin to SARS. The sequence was then relayed to all health agencies throughout the world by our Chinese scientific colleagues. Everything, from the diagnostics to the formulation of the vaccines was based on the dissemination of the SARS-CoV2 viral sequence.

How do we “predict” future pandemics? The answer is the same as predicting tumor behavior; it is the challenge of predicting the behavior of a complex system. We need

a great amount of data and the ability to use this data to create a model behavior—no different from modeling global weather systems to predict local weather


Actor Patrick Dempsey, founder of the Dempsey Center - an organization that provides free quality of life care to people impacted by cancer - and members of the Center’s team, visited with Dr. Liu in 2016

Dr. Liu, you have extensive publications and authorship in over 300 scientific

papers, reviews, and books. As an opinion leader whose scientific investigations span molecular epidemiology to molecular biochemistry of humans, what do you think are current necessities and urgencies in these fields? How does your projection

affect your research?

In the past, the works of a few individual brilliant scientists were sufficient to drive innovation in medicine. Individual brilliance still is important but cannot be the only force to advance the field. The urgency today is how to collate all these efforts into a cogent information system so that we can mine the collective wisdom. This means standard data formats and mandatory data submissions. The scale of the data is such that no single lab can handle

the onslaught. There need to be national and global efforts.

This new reality is what JAX is preparing for, and it is in this new reality that JAX will further strengthen its role as a global leader.

Many of our readers will find your path to be an inspiration. Could you please share a message for future physicians and healthcare professionals that aspire to exceptional careers and accomplishments?

As I mature in my profession, I have found this question a difficult one to answer. There isn’t a definite path to success but there are traits that I have found in successful people—individuals who are deemed successful over their lifetime rather than a flash-in-the-pan success. They love what they do. They seek excellence even in the small tasks

and can weave a wonderful narrative of this work. They are resilient in that failure does not alter that passion; they are realists and will change course when facts tell them their plans are futile, and they are unbelievably adaptable. It is the convergence of contradictory traits, the balancing of opposing proclivities that seems to be the core to success in scientific (or any other) endeavors—detailed but comprehensive, steadfast but flexible, always able

to tell a compelling story.

Finally, the one unifying force that has guided me is my determination to always “do good.” No matter what I am doing, regardless of how big the task is, whether I’m helping my kids or building an institute, I always seek to do good. This has been my North Star that has guided me to whatever success I have achieved and has given me personal contentment

Edison Liu, M.D.

President and Chief Executive Officer, The Jackson Laboratory (JAX)

Edison Liu, M.D., is the president and CEO of The Jackson Laboratory, an independent research institute focused on complex genetics and functional genomics with campuses in Maine, Connecticut, and California. Previously, he was the founding executive director of the Genome Institute of Singapore and the president of the Human Genome Organization (HUGO). He was also the scientific director of the National Cancer Institute’s Division of Clinical Sciences in Bethesda, MD, where he was in charge of the intramural clinical translational science programs. In his earlier career, Dr. Liu was a faculty member at the University of North Carolina at Chapel Hill, where he was the director of the UNC Lineberger Comprehensive Cancer Center ’s Specialized Program of Research Excellence in Breast Cancer; the director of the Laboratory of Molecular Epidemiology at UNC’s School of Public Health; and the Chief of Medical Genetics. Dr. Liu is an international expert in cancer biology, systems genomics, human genetics, molecular epidemiology, and translational medicine. Dr. Liu’s own scientific research has focused on the functional genomics of human cancers, particularly breast cancer, uncovering new oncogenes, and deciphering on a genomic scale the dynamics of gene regulation that modulate cancer biology. He has authored over 320 scientific papers and reviews and co-authored two books. He obtained his B.S. in chemistry and psychology, as well as his M.D., at Stanford University. He then received his residency and fellowship training at Washington University, St, Louis, and Stanford, and post-doctoral training in molecular oncology at the University of California at San Francisco.

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