To Be Precise
By Andrea Crawford
Columbia’s precision medicine initiative was announced by President Lee C. Bollinger in February 2014, but the seeds for the effort were planted years earlier with key recruits, including Tom Maniatis, who now directs the university-wide endeavor. President Bollinger and P&S Dean Lee Goldman co-chair the task force for the initiative aimed at creating new knowledge across the university, from basic research and teaching to more focused diagnostic tools and improved patient care. That vision is now being implemented by legal scholars and human geneticists, by public health experts and data scientists, and by cancer doctors and neuroscientists. The following pages show just a few examples of how precision medicine has moved from concept to clinical relevance over the past year.
Late last year, Wendy Chung, MD, PhD, received a phone call from the White House. “To be honest,” says Dr. Chung, who serves on the advisory board for the National Human Genome Research Institute, “I thought it was one of those phishing things where someone was just trying to get my Social Security number.” But in January, Dr. Chung, associate professor of pediatrics (in medicine), and Tom Maniatis, PhD, director of the Columbia University precision medicine initiative, were guests of President Obama as he presented details of his $215 million initiative in precision medicine, which he had announced during the State of the Union address days before. Precision medicine, President Obama told those assembled, “gives us one of the greatest opportunities for new medical breakthroughs that we have ever seen.”
https://www.youtube.com/watch?v=QHi10faBP4w
To bring that great promise to fruition, Columbia University and NewYork-Presbyterian Hospital have made several investments this past year to advance work on precision medicine, following up on the launch in early 2014 of Columbia’s university-wide initiative in precision medicine. The initiative supports efforts across schools and disciplines, brings significant new investments in personnel and infrastructure, and creates a number of 10 ColumbiaMedicine administrative structures, including the establishment of the Columbia Institute for Genomic Medicine to integrate genetics and genomics into research, patient care, and education. No other major university in the world is doing what Columbia is doing, says Donald Landry, MD, PhD, chair of the Department of Medicine and physician-in-chief of NYP/Columbia. “As articulated best in a recent address by President Bollinger, perhaps once in a generation, an opportunity presents itself for the growth and development of a new academic area that allows the university to achieve its highest ambitions: to understand ever more profoundly what it means to be human,” Dr. Landry says. “Precision medicine is such an area.”
With a major commitment that includes infrastructure, appointments within the Institute for Genomic Medicine, and joint appointments between the institute and clinical departments, the precision medicine initiative supports knowledge and innovation across the intellectual spectrum by enhancing efforts in science, medicine, technology, privacy, and more. “It’s impacting, across the board, all of the attendant technologies and activities necessary to understand genetic information in a way that it becomes actionable medically,” says Dr. Maniatis, who chairs the Department of Biochemistry & Molecular Biophysics at P&S.
Precision medicine will require expertise from every aspect of medical delivery if the field is to create the advances in human health that it portends, he adds. That encompasses disciplines centered at Morningside Heights—basic research, engineering, law, ethics, computer science, journalism, business, and economics—and those across the medical center, from foundational basic science to clinical departments. With CUMC faculty’s commitment to innovative care, coupled with the hospital’s mission to provide the best possible service to patients, says Dr. Landry, “Precision medicine brings the university and the hospital together at the cutting edge of a new scientific and clinical venture.”
It has always been important for other sectors to work in concert with medicine, says Paul Appelbaum, MD, the Elizabeth K. Dollard Professor of Psychiatry, Medicine, and Law. And precision medicine—with its use of highly sensitive personal data, information that is predictive as well as diagnostic and could be used for discriminatory purposes—raises the stakes. “When we make these findings in medicine, they don’t stay in medicine. They affect societal views of illness and people who have illnesses,” says Dr. Appelbaum, who directs a center funded by the National Human Genome Research Institute that looks at the ethical, legal, and social implications of genetics. When an individual’s genome is sequenced and analyzed, for example, an almost limitless amount of data could be generated. “If you ask most people, they will say they want to know everything about their genomes. But much of what could be told to them today would be of uncertain significance, leaving them without much to do and without much clarity about the implications of the findings,” he says. “We need to be sure that the information we generate offers benefits to patients that outweigh the potential harms.”
During the past year, Columbia’s precision medicine initiative task force set to work to identify all of the disciplines and departments across the university and medical center whose participation would contribute to the effort. They then began to plan the necessary enhancements in infrastructure and faculty recruitment. “Recruitment of highly talented individuals is our most important response to the opportunities that present themselves through Manhattanville,” says Dr. Landry, for as those new facilities open and many neuroscience faculty move there, vacancies arise at the medical center, allowing for recruitment of scientists with a predominant focus in precision medicine.
David Goldstein, PhD, who joined Columbia in January as founding director of the Institute for Genomic Medicine and who already had a long record of collaboration with Columbia investigators, was the first hire, and his recruitment included provisions to hire others in clinical and basic science departments. “We recognized that human genetics and modern applications of high throughput sequencing in this field were not strengths at Columbia,” says Dr. Maniatis. “David Goldstein was identified as being the best, and we were extremely fortunate to recruit him. This strategy must be taken in discipline after discipline that impacts precision medicine.”
The power of genomic research is based on the magnitude of data; to gather large cohorts of patients and their genomic data, scientists from around the world often collaborate. Dr. Maniatis and Dr. Goldstein have worked together as part of a consortium of some 60 institutions investigating the genetic basis of ALS. One result of their collaboration was the discovery of a gene newly implicated in ALS; Dr. Goldstein’s resulting paper, which Dr. Maniatis and Dr. Chung co-authored, was fast-tracked for February publication in Science. By sequencing the exome, or protein-coding portion of the genome, the consortium collected nearly 3,000 DNA samples from patients with ALS and more than 6,000 unaffected patients whose data served as a reference. In addition to finding the newly associated gene, the researchers confirmed many of the genes previously implicated in the disease and discovered that one gene, known as OPTN, which had been thought to play a minor role in ALS, may play a major role.
The gene newly believed to be associated with ALS, TBK1, had been the focus of investigation within the Maniatis lab in the context of the immune system since 2003 but was not known to be associated with ALS. In ALS, several mutations lead to the generation of aggregates in proteins, similar to what occurs in Parkinson’s and Alzheimer’s diseases. Once these aggregates form, the cell has two pathways to remove them: through the proteasome, a large protein complex that acts like the garbage disposal of the cell, grinding up aggregated proteins, and through a process called autophagy. Autophagy is an intracellular recycling system in which damaged proteins or organelles are surrounded by a membrane to form an “autophagosome” that fuses with lysosomes (bags of chemicals and enzymes that degrade proteins). The breakdown products are recycled to build new proteins and membranes. TBK1 plays a key role at the intersection of two essential pathways—inflammation and autophagy—interacting with and modifying other proteins previously shown to play a role in ALS. Says Dr. Goldstein: “Remarkably, the TBK1 protein and optineurin, which is encoded by the OPTN gene, interact physically and functionally. Both proteins are required for the normal function of inflammatory and autophagy pathways, and now we have shown that mutations in the genes encoding either protein are associated with ALS.”
Large-scale genetic studies like this illuminate pathways that can then become targets for drug delivery. “ALS is an incredibly diverse disease, influenced by mutations that can occur at any of several hundred different genes, which we’re only beginning to discover,” says Dr. Goldstein. “The more of these mutations we identify, the better we can decipher—and influence—the pathways that lead to disease.” The TBK1 gene is also thought to play a role in tumor-cell survival, as well, and compounds targeting it have already been developed for use in cancer patients. “The more we learn about the function of the normal TBK1 gene, and the dysfunction of TBK1 genes bearing the ALS-associated sequence variants, the more likely we will be able to find a treatment for ALS,” says Dr. Maniatis. “The key here, and to precision medicine more widely, is to connect the genetics of disease with the underlying biology and use that knowledge to develop new therapies.”
Medicine is in a moment of profound transition following decades of what Dr. Landry calls “an explosion of knowledge,” as a precise, detailed, molecular understanding of disease emerges coupled with advances in computer science. “We are merely at the threshold of a new age,” he says, “and yet we have a glimpse of the future.”
At the forefront, says Dr. Chung, is the work of identifying how genes act in regulatory networks, a fresh approach that holds promise for both treatment and prevention. “What’s truly beautiful and elegant is that when you start to define a large number of the genes, you can step back and see the organization,” says Dr. Chung. In the case of autism, for example, scientists now estimate that some 500 genes are involved. “It’s not 500 random genes that you picked throughout the genome. It’s actually genes that have to do with very specific cellular processes.” In autism, those include genes that function in synaptic transmission and when defective can affect neurological conditions; in other cases, as with epilepsy, those include genes that encode ion channels, proteins that regulate the passage of ions through cellular membranes, which form the basis of electrical conduction in neurons.
As a physician treating patients with different types of diseases, Dr. Chung says it is easy to see the connections between heart disease and brain disease, for example. Underlying these connections are the genetic regulatory networks that determine when, where, and how proteins are produced.
The mapping of these networks is an important step forward for understanding disease mechanisms. Precision medicine offers the possibility for physicians to not only treat diseases, but also focus on wellness and prevention by making genome-informed predictions about the conditions that individuals or families are at risk for, then designing tailored wellness programs that, for example, feature enhanced screening for those conditions. “Precision medicine affects every aspect of health care from the time of conception to the time of death,” says Dr. Chung, “and it truly permeates everything that we do.”