249 Years Strong PS&

Columbia 2016 ANNUAL EPO T Medicine Columbia University College of Physicians & Surgeons Features:

4 12 18 Big Data: Map Quest: Microbes The New Math New Techniques Within Us: in Patient Care Reveal How the How the Immune System Microbiome “Big data” is only as good Stays Nimble Infuences as the computational Human Health tactics leveraged by Researchers combine investigators to make genome engineering, After early microbiome the information clinically genomics, biochemistry, research focused on relevant. Columbia emerging computational naming and describing researchers and clinicians techniques, and unique the species common to the are using multiple murine models to human body, investigators strategies to capture data investigate the mechanisms have turned to exploring how to transform both research by which noncoding the whole system functions, and patient care. RNA infuences both in hopes of identifying immunodefciency interventions to promote and cancer. health and prevent disease.

http://ps.columbia.edu/ ColumbiaMedicine | 2016 nnual Report Issue

Departments:

2 Dean’s Message

32 2016 Research, Clinical, and Education Highlights

40 Philanthropy News

42 P&S News

47 About P&S · Trustees Committee on the Health Sciences · CUMC Board of Advisors · Other CUMC Advisory Groups · CUMC Administration · College of Physicians & Surgeons Administration · Executive Committee of the Faculty Council · Department Chairs · University Centers and Institutes and Directors · Hospital Affliations · Facts & Statistics

On the Cover The opening of the Roy and Diana Vagelos Education Center is only one of the “big things” P&S celebrated in 2016. Visionary discoveries 26 that were among the year’s accomplishments also laid the groundwork Medical for promising future developments described in articles throughout (In)Equality this issue. The Next Big Things begin now.

Working in one of the most diverse cities in the world, 2016 Annual Report Offce of the Chief Executive P&S researchers have a Editor: Bonita Eaton Enochs and Dean of the Faculties of Health Sciences and Medicine unique opportunity to Principal Writer: Sharon Tregaskis study health disparities Columbia University Medical Center Contributing Writers: Nancy Averett, 630 W. 168th St. and develop interventions Alla Katsnelson, Kathleen Lees New York, NY 10032 for concerns that include Art Director: Eson Chan neurodegenerative Illustrator: Helen Friel Communications Offce diseases, obesity, College of Physicians & Surgeons cardiovascular disease, Produced by the Communications 701 W. 168th St., Box 153 and diabetes. Offce at Columbia University New York, NY 10032 College of Physicians & Surgeons Phone: 212-305-3900 Catherine Freeland, Associate Vice Dean, Fax: 212-305-4521 Marketing & Strategic Communications Offce of Development Printed in September 2016 Columbia University Medical Center 630 W. 168th St., P&S 2-421 New York, NY 10032 Phone: 212-342-0088 • DEAN’S MESSAGE

Closing the Books on a Great Year, Looking head to an Even Better One

hat can be said about the past year— 11-year-old with cerebral palsy back into the Academic Year 2016—is similar basketball game she loves, and advancement of W to what we have said about many plans to close a portion of one of our streets to recent years at P&S. We are growing and thriv- build a community square that will be shared ing in so many ways: with our medical center neighbors. • Our ColumbiaDoctors faculty practice orga- One annual report cannot tell all the worthy nization grew by more than 8 percent last year, stories that illustrate a year’s successes, but with an ever expanding geographic reach. this report includes a selection of articles that • We continue to grow our faculty at a net rate describe some of our successes. Our ongoing of about 6 percent per year, with outstanding work in precision medicine is exemplifed in faculty recruits from around the country. an article that shows the role and power of big • Our school’s NIH grants portfolio increased data in modern patient care. An article on the by 11 percent during a year when the NIH microbiome shows how our researchers are budget increased only 1.6 percent. going beyond just describing the microbiome • Our faculty’s prolifc research continues to to now demonstrating its infuence on physi- change the face of biomedical science and medi- ological processes. Another article takes you cal practice, as evidenced by 74 papers in Cell, deep within our cells to explore the important Nature, Science, and the New England Journal role of noncoding RNA, previously thought to JÖRG MEYER of Medicine alone. occupy only a minor role in genomic medicine. • We were able to accept less than 4 percent We also profle the work of four researchers of the nearly 8,000 students who applied to involved in understanding and correcting dis- Dhairya Choudhrie, representing the Choudhrie medical school this year, and year after year we parities in disease and treatment among groups Family Foundation, were also on hand to have one of the country’s highest yield rates on of patients whose health is infuenced by social dedicate the building. It is no exaggeration to accepted students. and environmental factors. What these var- say that we could not have built this amazing • We continue to have one of the most diverse stu- ied efforts have in common is refected in the building, which was constructed entirely with dent bodies, which is nearly double the national theme of this report, “The Next Big Things,” private donations, without the generosity of so average of underrepresented minority students. and these articles show how P&S ingenuity many philanthropists. This group of visionary • Our commitment to our local community and perseverance generate new knowledge to supporters committed resources so that today’s includes partnering in community-based partici- advance patient care. medical students can be trained in 21st century patory research, providing high-quality care to One of our most tangible achievements this techniques in a learning environment that is both all of our neighbors, helping neighborhood chil- year fts nicely into the “big things” category. As functional and architecturally stunning. dren pursue their dreams of careers in medicine included in this report, in June we dedicated our The futuristic theme of this report is also ft- and science, and maintaining our campus as an new 14-story medical and graduate education ting for what we predict Academic Year 2017 open environment for our neighbors to share. building—the Roy and Diana Vagelos Education has in store. As 2016 was turning over to 2017 Behind those headlines are individual stories Center—in honor of the building’s lead donors. on July 1, our faculty received major grants of success in all of our missions. Examples Many other donors, including Cheryl and Philip that will support our strategic priorities. One of include grants large and small to study health Milstein; Kathryn and Mary Jaharis, represent- the frst is an NIH grant to Columbia to enroll across the lifespan, a student’s scholarly proj- ing the Michael Jaharis family; Roger Wu and participants in the Cohort Program of President ect to improve a clerkship for future students, David Wu, representing their parents, the late Barack Obama’s Precision Medicine Initiative. a surgeon’s use of a technique that put an Helen and Clyde Wu; and Sudhir, Anita, and The fve-year award, which has the potential to

2 ColumbiaMedicine total $46.5 million, reinforces our leadership in ensure the quality of the data, and convert the dents. As we look forward to another great precision medicine by extending our ongoing data into a format that is usable by researchers year, we will have the privilege of celebrat- successes in taking an individualized approach involved in the program. We also renewed our ing the frst 250 years of Columbia’s medical to treating cancer and rare genetic diseases to NIH Clinical and Translational Science Award, school by combining historical refections with a broader range of human illnesses. Colum- which funds the Irving Institute for Clinical visionary and strategic planning for the begin- bia will partner with NewYork-Presbyterian, and Translational Research at Columbia and ning of the next 250 years. Harlem Hospital, and Weill Cornell Medicine NewYork-Presbyterian. The $58.4 million We enter this next year energized by an to enroll patients as part of the national goal grant will support the Irving Institute’s ongoing enthusiasm I know you—our faculty, students, to enroll 1 million patient volunteers. P&S work in translational research, speed develop- alumni, generous supporters, and other read- also was chosen to partner with a coalition ment of new medical therapies, and align its ers—share. Thank you for all you contribute to of research organizations awarded $13.7 focus on precision medicine with Columbia our success—past, present, and future. million from the NIH to establish the Data University’s own Precision Medicine Initiative. and Research Support Center as part of the The end of Academic Year 2016 marks my With best wishes, national Precision Medicine Initiative. Biomed- 10-year anniversary as dean of this remarkable ical informatics experts at P&S will help curate school. What our faculty, students, and sup- health information being contributed to the porters have accomplished during that decade Precision Medicine Initiative Cohort Program, is truly inspirational, from our phenomenal including electronic health records, medical growth in research funding to our expanded and pharmaceutical databases, and payer data- clinical footprint to our impressive success in Lee Goldman, MD, Dean bases. P&S will standardize the information, recruiting the best medical and graduate stu- [email protected]

2016 Annual Report ColumbiaMedicine 3

BIG DATA THE NEW MATH IN PATIENT CARE

t was an undergrown 7-year-old boy who kindled but the approach worked. Ritalin, they learned, was Precision Medicine Karina Davidson’s epiphany, some 25 years ago, not working. It suppressed his appetite and did noth- about the value of truly personalized medicine. The ing to reduce his violent and suicidal episodes. And Refnes its Calculus Ichild weighed just 37 pounds, within the lowest his aggression seemed to be triggered by the dynamic with Emerging percentile range for boys his age; he was not only fail- with his mom. Based on these hard-won data, so spe- nalytical Tools ing to thrive, but also intensely violent toward himself cifc to this one child, Dr. Davidson and her colleagues and others. Dr. Davidson—then an intern in clinical devised a treatment plan that helped him gain weight and Innovative psychology at the University of Waterloo in Canada— and rein in his emotional turbulence. Study Designs and the rest of the boy’s clinical team struggled with “The lesson that has stayed with me for a lifetime is how to care for him. Might megadoses of Ritalin that excellent clinical care should be informed by sci- temper his behavior? And what drove his rages? The ence, but it’s best informed by the patient in front of By lla Katsnelson team brainstormed hypotheses: Poor sleep? A lack of you,” says Dr. Davidson, director of Columbia’s Cen- structure in his environment? Insuffcient calories? His ter for Behavioral Cardiovascular Health. It is what interactions with his mother? she calls “precision therapeutics”—pinpointing the To fnd out, they designed a randomized, controlled treatment that will help a specifc person, rather than trial—a stretch of Ritalin followed by a stretch of starting with what might beneft the average person placebo—in which the boy was the sole subject and and making guesses from there. his own time-lapsed control. Dr. Davidson asked the Her intern experience cemented Dr. Davidson’s practice’s pharmacist to formulate a Ritalin lookalike vision for excellence in the practice of medicine, but she placebo. She had a statistician from the university cre- has had to wait to see its potential begin to be realized. ate randomization codes to blind the clinical staff, the Only in the past few years have genome sequencing and boy, and his family to which treatment he was receiv- other molecular techniques advanced enough to allow ing. The team hand-recorded endless checklists to researchers to identify precise molecular differences track his acting out against sleep, diet, social interac- between people and to begin to understand how those tions, and other factors, then entered the observations differences can be targeted therapeutically. Meanwhile, into a computer for analysis. It was labor-intensive, personal health tracking devices and mobile phone Photographs by Jörg Meyer Karina Davidson, PhD

apps can now seamlessly capture and digitize blood pressure, he type of approach that Dr. Davidson takes is called an sleep patterns, mood changes, and more in real time—the exact TN of 1 study—a highly systematic and statistically rigorous information Dr. Davidson and her colleagues painstakingly examination of a single subject. Until recently, single-patient took down with pen and paper. By matching this phenotypic studies such as the one she ran for her young Canadian patient data to genomic and other types of molecular data, research- have been considered interesting and informative, perhaps, but ers think they can begin to fgure out the underlying cause for anecdotal and ungeneralizable. Instead, for the past half-century, each individual’s illness—be it acute, like a fast-moving cancer, randomized controlled trials with a large N—the letter that sym- or chronic, like high blood pressure. bolizes the number of patients—have been the gold standard in “We can now measure so much in exquisite detail,” says Mure- determining a treatment’s effcacy. What these studies identify is dach P. Reilly, MBBCh, who this year moved from the University essentially the treatment that works best for the average patient. of Pennsylvania to be director-designate of the Irving Institute for But as researchers increasingly come to understand the Clinical and Translational Research. “We have extent of inter-individual variability among patients, they are these incredible tools that allow us to look at realizing that what helps the average patient—whoever he or “For most chronic health each individual’s genomic and physiological she may be—often does little for their specifc patient. “For problems we don’t have profle and to map them in health and disease.” most chronic health problems—pain, obesity, sleep issues, The ability to capture this vast quantity of asthma, the list goes on and on—we don’t have a single treat- a single treatment that data is transforming both research and medical ment that works for everybody,” Dr. Davidson explains. works for everybody.” care—and Columbia researchers and clinicians Because frst approximations are extremely useful, and work are at the forefront of that transformation. well for many people, randomized controlled trials will prob- “The institutional vision for precision medicine ably remain the bread and butter of clinical research for the at Columbia is very strong,” says Dr. Reilly, who will succeed indefnite future, she says. But alongside them, more personal- Henry N. Ginsberg, MD, as director of the Irving Institute for ized approaches are sorely needed. Clinical and Translational Research next year. “There’s huge, Take blood pressure pills. There are many kinds, and over- top-down support here for developing precision medicine tools all they have similar effcacy. But for any one person some and big-data know-how for personalized care. And there’s also will work while others will not. A doctor might prescribe one a vibrant feeling on the ground of a commitment to collabora- and then, if the desired effect isn’t achieved, add a second and tion among different felds of medicine—from bioinformatics, to even a third, never fguring out which is actually doing the job. genomics, to cancer, to behavioral health—to make ours the lead- “But if we standardly test those medications at the lowest dose ing precision medicine program in the U.S.” in a randomized way, we might control people’s symptoms

6 ColumbiaMedicine Andrea Califano, PhD

with the fewest drugs,” she says. A clinician could identify the of 1 studies come in an array of permutations. Andrea unique protocol that works best for one specifc patient, mar- NCalifano, PhD, uses the approach to fnd better ways to rying the promise of evidence-based approaches with a truly treat rare and otherwise incurable cancers. The FDA has now personalized touch. approved a few dozen drugs that target particular genetic Working with internist Ian Kronish, MD, Dr. Davidson is using mutations in tumors—but it is unclear why many patients fail N of 1 studies to help individuals improve their cardiovascular to respond and, even in the best cases, initial response is fol- health. Recently she and her colleagues completed a study funded lowed invariably by relapse. And although genome sequencing by the National Heart, Lung, and Blood Institute that explored is becoming increasingly routine in cancer care, less than 11 the relationship between exercise and stress. The link, they found, percent of patients who are treated with a drug based on their was highly specifc for every individual: For some, exercise seemed genomic data experience a long-term beneft. to drive down stress levels; for others, stress drove down exercise That is because mutated genes, pinpointed through sequencing, levels; and for others, still, there was no correlation at all. “All of are not always the best therapeutic targets, says Dr. Califano. In those scenarios make sense, don’t they?” Dr. Davidson says. “It’s some patients, genes associated with proteins that are hyperactive just that you have to fnd what’s true for you—not for the average in the cancer cell do not carry mutations and vice versa—some person.” Unfortunately, that kind of individual variation washes mutations do not cause proteins to misbehave because other out in large trials, which tend to fnd no association at all between genes can compensate for the bad code. Instead, the clinically rel- stress and exercise. evant players are “master regulators,” effectively the puppeteers Now Dr. Davidson’s team is surveying physicians, nurses, and of the cell transcriptional state. Dr. Califano and his colleagues patients nationwide to identify conditions for which N of 1 tri- have used massive supercomputers to reconstruct the regulatory als would most beneft patients. Hypertension is a strong candi- networks of more than 30 different cancer types. Using the RNA date because it is a costly disease for which patients often take fngerprint of a patient’s tumor—its gene expression profle— multiple drugs for life. Pain is another possibility; being able to they can use these networks to predict both the master regula- systematically test the effcacy of multiple interventions in one tor proteins and the drugs that are likely to be most effective for person could provide life-altering relief. The team is also survey- that person’s cancer. These drugs are then taken for a test run in ing cancer survivors about their interest in using the approach mouse “avatars”—models created with the patient’s own tumor to manage their depressive and fatigue symptoms. Whichever tissue. In November, Dr. Califano was named a National Can- they tackle will be a vital step toward realizing Dr. Davidson’s cer Institute outstanding investigator and received a seven-year, vision of 25 years. “It’s an exciting time,” she says, “because we $6.7 million grant to pursue the work. He has already piloted the could be the frst in the country to offer such a service.” approach in more than 40 patients and is testing it more widely in

2016 Annual Report ColumbiaMedicine 7 several follow-up clinical trials. “The fact that you can computa- PATIENT- RIENTED tionally predict the most effective drugs and test them in a mouse model of the patient’s tumor to fnd the ones that effectively kill RESEARCH it,” he says, “is unprecedented.” Master regulator networks play a role, too, in alopecia areata, It can take decades for knowledge to go from bench to bedside. a genetically inherited condition in which deranged immune cells To spur the momentum of early-career investigators who have attack hair follicles. Associated with severe hair loss and currently promising research programs, the Irving Scholars program very diffcult to treat, the disease has been the primary topic of annually selects a cohort of P&S assistant professors to receive study by genetics and dermatology researcher Angela M. Chris- stipends of $60,000 annually over three years along with a tiano, PhD, since she was diagnosed with the condition more named professorship. This year’s recipients: than 15 years ago. In November 2015, Cell Systems published work by post- • Ali Jabbari, MD, PhD, Dermatology: Patients suffer devastating psychosocial doc James C. Chen, PhD, with Dr. Christiano and her team to consequences of the hair loss triggered by alopecia areata, an autoimmune untangle how master regulator networks infuence the pathology disease for which the FD has yet to approve a treatment protocol. Clinical of alopecia areata. “We wanted to track the process of immune research by Dr. Jabbari and others suggests that a class of compounds cells infltrating an organ,” says Dr. Christiano, who notes that known as J K inhibitors has the potential to reverse alopecia areata unlike cancer, which typically involves a single cell type, a techni- symptoms. By integrating patient data with insights from mouse models cal challenge associated with autoimmune disease is the interac- of the disease, Dr. Jabbari seeks to identify the mechanisms by which J K tion among tissue types—in this case, hair follicles and T cells. inhibitors spur hair regrowth. Beyond insights into the mechanisms of pathology in autoim- • Fay Kastrinos, MD, Medicine: s a gastroenterologist with Columbia’s munity, Dr. Christiano’s work offers a through-the-looking-glass Pancreas Center, Dr. Kastrinos oversees the clinical practice for the Muzzi perspective on the quest for better ways to fght cancer. In alope- Mirza Pancreatic Cancer Prevention and Genetics Program. By integrating cia areata, overzealous T cells destroy otherwise healthy hair fol- data from the center’s pancreatic cancer family registry with patient imaging licles. In their quest for immunotherapy treatments, oncologists and other clinical information, Dr. Kastrinos and her collaborators are seek a tactic to spur T-cell function to boost patients’ capacity to developing a clinical prediction model to identify people at greatest risk for blast their own tumors. “Our hypothesis was that if we could do hereditary susceptibility to pancreatic cancer, the fourth leading cause of it in autoimmunity, we could fnd the drivers and extend it back death for merican men and women. to cancer,” says Dr. Christiano. “For autoimmunity, we’d like • Krzysztof Kiryluk, MD, Medicine: Dr. Kiryluk investigates Ig nephropathy, to down-regulate or dampen the process of T cells attacking an the most common form of primary glomerulonephritis worldwide. While organ, but for cancer you would try to fnd ways to enhance it.” up to 40 percent of patients with Ig nephropathy develop end-stage kidney Dr. Christiano credits Dr. Chen—a recipient of one of four failure within two decades of the diagnosis, the variable course of the precision medicine fellowships announced by the Irving Institute disease has prevented doctors from offering patients a clear prognosis. for Clinical and Translational Research in January 2016—for Dr. Kiryluk and his team seek to home in on the genetic mechanisms of spurring the new line of inquiry for her group, which has used Ig nephropathy, enable noninvasive diagnosis, improve personalized genome-wide association studies to identify pathways that could prognostication, predict relapse and recurrence, and, ultimately, develop be targeted by a class of compounds known as JAK inhibitors novel targeted therapeutics. to spur complete hair regrowth for 75 percent of clinical trial • Joanna E. Steinglass, MD, Psychiatry: Now an associate professor, Dr. participants with alopecia areata. As a doctoral student with Dr. Steinglass investigates the cognitive neuroscience of anorexia nervosa, Califano, Dr. Chen investigated the role of master regulator net- a debilitating illness for which clinical interventions are only modestly works in a particularly vicious form of brain tumor known as effective. Her analyses combine clinical data with brain imaging to reveal the glioblastoma. Now he works with Dr. Christiano to extend those link between neural mechanisms that drive food choice and the behavioral techniques to autoimmunity and understand what is going on at disturbances manifested by people with the illness. She aims to leverage a molecular level for patients who do or do not respond to treat- those insights to develop treatments to prevent relapse. ment with JAK inhibitors. “When a patient comes in with a new • Nicholas Tatonetti, PhD, Biomedical Informatics: Every day, electronic spot of hair loss from alopecia areata, it’s not clear just by looking health records capture billions of clinical data points around the world. at them whether they’ll get better, get worse, or stay the same,” Dr. Tatonetti and his team use rigorous computational and mathematical says Dr. Christiano. “For us, precision medicine means better methods to advance data science in the realm of “systems pharmacology.” diagnosis and being able to direct them toward or away from a By integrating medical observations with systems and chemical biology JAK inhibitor or other new therapies on the horizon.” models, they intend to pursue understanding of basic biology and human Data scientist Raul Rabadan, PhD, takes an in silico approach disease, explain drug effects, and predict adverse drug reactions. to patient-specifc data. A theoretical physicist by training who turned his attention to biology about a decade ago, Dr. Rabadan

8 ColumbiaMedicine Angela M. Christiano, PhD Raul Rabadan, PhD

uses genomics and a branch of mathematics called topology to same set of mutations, but a tumor’s evolu- map large genomic datasets. He is the director of an NCI center, tion may well affect the cancer’s response to By following the the Center for Topology of Cancer Evolution and Heterogene- subsequent therapies. Some mutations will trajectories of single ity, that connects mathematicians, physicists, biologists, and cli- affect the tumor’s growth, or its resistance cells, researchers seek nicians to study cancer using large-scale genomic data. to a particular drug protocol, while some Dr. Rabadan is leveraging genomic and mathematical will not have any effect at all. Last year, by to capture the biological approaches to gain greater insight into the mechanisms by using a mathematical approach to probe phenomena that would which tumor cells evolve in response to cancer-killing drugs. the genomes of patients with a particularly otherwise be lost in the Mutations accrue over time, as well as in response to the ther- aggressive form of lymphoma, Dr. Rabadan’s shuffe of complexity. apies that a patient receives. No two patients will develop the team was able to identify a novel pathway that drives the cancer in many cases. Because drugs targeting this pathway have already been approved by the FDA to treat other conditions, the study identifed a new tactic available to oncologists treating patients in whom that target is mutated. Now Dr. Rabadan has focused his efforts on understanding how brain tumors evolve under therapy. A recent analysis reported in Nature Genetics in June was the largest ever study of brain tumors, conducted through an inter- national collaboration led by his group. The group identifed several genetic mechanisms of resistance that drive evolution of these tumors under standard therapy, providing important clues for novel treatments and showing how genomics can be used for precision medicine approaches to cancer. Dr. Rabadan is also working with the group led by Tom Mania- tis, PhD, director of Columbia’s Precision Medicine Initiative, to refne and apply these computational tools to the study of stem cell differentiation at the single cell level. By following the trajectories of single cells—and the 20,000 or so genes they express—through space and time, his group seeks to capture the biological phenom-

Tom Maniatis, PhD 2016 Annual Report ColumbiaMedicine 9 ena that would otherwise be lost in the shuffe of complexity. This Using those records, any network participant can set up quick collaborative study has identifed new genes involved in the differ- observational studies that analyze the patient data to address entiation of embryonic stem cells to produce motor neurons and an important question about health care. “Observational made it possible to identify all of the genes expressed in individual studies don’t prove causality, but randomized clinical trials cells at multiple stages of differentiation, a “systems” approach often can’t be generalized to my patient,” says Dr. Hripcsak. to understand complex cellular differentiation. In addition, this By analyzing subsets of patients matched for shared features— method should make it possible to identify neurodegenerative response to a particular sequence of drugs, for example—cli- disease mechanisms using cells obtained from neurodegenerative nicians may be able to tailor treatment more narrowly within disease patients, such as those with amyotrophic lateral sclerosis, large populations, such as people with diabetes, hypertension, known as Lou Gehrig’s disease. In this case, patient fbroblasts heart disease, and other chronic conditions. are converted to induced pluripotent stem cells—iPS cells—which In the network’s frst major paper, published in June in the Pro- in turn are differentiated to produce motor neurons. Comparison ceedings of the National Academy of Sciences USA, Dr. Hripcsak with motor neurons produced from control cells may provide and his colleagues provided proof of concept of that strategy with important insight into ALS disease mechanisms. an analysis of the treatments received by patients with diabetes, hypertension, and depression around the world. The team set esearch and interventions focused on individual patients narrow parameters for which patients to include, whittling down have an unprecedented ability to pinpoint biological dis- the study sample to fewer than 1.8 million records. Then they ease mechanisms and identify therapies that traditional clini- queried the database for the sequence of treatments these select cal trials will miss. But scientists do not have to work at the patients had received. Generally, patients with diabetes received individual level to contribute to the endeavor of precision the same frst treatment around the world, but the researchers medicine, says George Hripcsak, MD, a clinical informatics found huge variability for the other conditions. pioneer. His research gleans information about widely used Knowing which therapies are actually used is crucial in conduct- treatments by examining select groups of patients with similar ing randomized trials for new therapies, says Dr. Hripcsak, and for characteristics—an approach known as “stratifed medicine.” integrating evidence-based approaches gleaned from randomized Dr. Hripcsak is the co-PI of an international program called trials with a more personal approach. “It’s hard to learn what’s Observational Health Data Sciences and Informatics, or good treatment, or compare a prospective therapy to some stan- OHDSI, a voluntary network of 60 patient databases in 14 dard care, when clinicians worldwide are all doing something dif- countries that so far total about 600 million patient records. ferent. If it turns out nobody uses the recommended therapy, then Network investigators aim to enroll 1 billion patients by 2023. you end up doing very expensive randomized trials to prove that one unused drug should be replaced with another unused drug.” That study was something of a trial run for the network, but Dr. Hripcsak looks forward to addressing other questions using Who’s Who the network. His team’s next study will examine side effects for · Andrea Califano, PhD, the Clyde’56 and · George Hripcsak, MD, the Vivian Beau- all marketed medications. Of course, the massive analysis will Helen Wu Professor of Chemical Biology (in mont llen Professor of Biomedical not show whether any particular drugs cause the side effects, Biomedical Informatics and the Institute for Informatics and chair of the Department but the analysis will be able to fag the high and low fiers, he Cancer Genetics), professor of biochemistry of Biomedical Informatics says. Meanwhile, independent of the OHDSI project, Dr. Hripc- & molecular biophysics, and chair of the · Ian Kronish, MD, Florence Irving ssistant Department of Systems Biology sak and colleagues are beginning to design patient-specifc com- Professor of Medicine putational models for people with type 2 diabetes that predict in · Angela M. Christiano, PhD, the Richard · Tom Maniatis, PhD, the Isidore S. Edelman and Mildred Rhodebeck Professor of real time how their bodies will respond to certain food intake or Professor of Biochemistry & Molecular Dermatology and professor of genetics activity levels. When programmed into a wearable device, these Biophysics, chair of the Department of & development Biochemistry & Molecular Biophysics, programs, tuned to the specifcs of the wearers’ bodies, will help · Karina Davidson, PhD, professor of and director of the Columbia University diabetics know when and what to eat and when and how much behavioral medicine in medicine and Precision Medicine Initiative to exercise to achieve their goals for disease management. “The psychiatry, director of Columbia’s Center · Raul Rabadan, PhD, associate availability of all these data—and also new algorithms and for Behavioral Cardiovascular Health, and professor of systems biology and computing techniques—allows us to calculate things that even a vice dean for organizational effectiveness of biomedical informatics few years ago just weren’t feasible,” he says. · Henry Ginsberg, MD, the Herbert and · Muredach P. Reilly, MBBCh, director- Dr. Reilly, too, studies subsets of human subjects, but his goal Florence Irving Professor of Medicine and designate of the Irving Institute for Clinical is to hand-select subjects with specifc genetic mutations in order director of the Irving Institute for Clinical and Translational Research and the Florence and Translational Research to conduct deep-dive research into how genes function in health and Herbert Irving Professor of Medicine and disease. Genomic analysis has linked a multitude of genes to specifc conditions, but of some 18,000 protein-coding genes in

10 ColumbiaMedicine the human genome, the effect of about 15,000 is unknown. Dr. and which in turn can alter the risk for other deleterious condi- Reilly studies the genomics of cardiovascular disease, and you tions, such as diabetes, stroke, and cancer. He and his colleagues set Muredach P. Reilly, MBBCh, left, joined might call one focus of his studies “natural mutants,” people who up a paradigm to inject tiny levels of infammatory toxin into 300 P&S as director- have been found, through gene sequencing, to have a mutation healthy people, then intensely studied their subjects’ responses, designate of the Irving in a gene that has been implicated but not proved in a condition. following their innate immune responses as well as gene tran- Institute for Clinical and Translational Dr. Reilly riffs that he works not on N of 1 studies, but on N of scription changes in multiple cell types like blood and adipose Research and will 10, or 20, or 30. “These are really intense studies of very selected tissue. That work, published in March, led them to discover a become director next year when he people,” he says, “to understand what a particular gene does.” new part of the genome that regulates whether a person develops succeeds Henry N. In many cases these people appear healthy and “normal,” he a high or a low fever in response to an immune system stressor. Ginsberg, MD, who explains, but subtle changes in factors like response to stressors “The area of the genome associated with the fever was not associ- has been director since 1995. or immune or metabolic changes can be uncovered by probing ated at all with a person’s resting temperature,” says Dr. Reilly. widely into their physiology. “If we think a gene alters the course That fnding points to a separate genetic dial controlling how of heart disease, it may affect multiple things, like exercise capac- a person regulates his or her response to infection and trauma. ity, metabolic rates, or energy consumption.” Maybe it affects a Understanding that is important because both person’s heart rate and blood pressure during exercise, but not at high- and low-temperature response to infec- rest, for example. “We need to study the human very carefully tion and trauma predicts death. “When it comes to to gain these insights into personal health and the role of specifc Ultimately, the next frontier in medicine understanding molecular genes in the human setting.” will involve analyzing multiple layers of data mechanisms of the In genetic studies of people with coronary artery disease, for on sick and healthy people, to tie molecular example, Dr. Reilly’s group explored one gene, ADAMTS7, which differences within and among people to dif- genome of a human, the codes for an enzyme that modulates matrix proteins in the blood ferences in physiology, behavior, and envi- human is the best model.” vessel walls. The group is now looking for loss-of-function muta- ronment, says Dr. Reilly. “We spend a lot of tions of this gene in humans to understand specifcally how that time knocking out genes in mice, zebrafsh, or gene function contributes to cardiovascular effects. Following the Drosophila to create models of disease and those are incredibly trail of genes by characterizing them from the molecular to func- important for understanding molecular, biochemical, and physi- tional level can create possibilities for therapeutic targets, he says. ological mechanisms,” he says. “But when it comes to under- Another focus of Dr. Reilly’s inquiry is immune response to standing molecular mechanisms of the genome of a human, the stress, which can change in response to high-fat food and exercise human is the best model.” v

2016 Annual Report ColumbiaMedicine 11

enis Burkitt, an Irish surgeon with a glass eye and a missionary’s zeal, traveled 10,000 dusty Dmiles in a cantankerous Ford station wagon across equatorial Africa in the 1950s. His aim was to map the boundaries of an aggressive cancer that caused grapefruit-sized facial tumors forcing children’s eyes to protrude, their cheeks to bulge, and their teeth to fall out. Through his travels, Dr. Burkitt discovered that the fatal malady was common in lush, forested regions and rolling savannas where mosquitoes and the malar- ial parasite they spread are endemic. During the next decade, he integrated his observations with those of New Techniques Reveal others to realize that where DDT-spraying programs controlled mosquito populations—as on the island of How the Immune System Zanzibar, off the Tanzanian coast—both malaria and Stays Nimble the cancer were almost nonexistent. Sixty years later, African children are still dying from what’s now known as Burkitt lymphoma—the cause of death for 3,000 children each year and the most common pediatric cancer in sub-Saharan Africa—and investigators are still trying to piece together its relationship to malaria. Scientists are not without clues: Among Burkitt lym- phoma patients, a particular chromosomal mutation— known for its potential to promote unregulated cell growth—is common. And that genetic glitch nestles within the immune system’s B cells—the same cells that produce the antibodies needed to fght off pathogens, the same cells that malaria kicks into overdrive. Many investigators suspect the malaria pathogen reprograms the immune system’s antibody manufactur- ing process to produce the precancerous mutation. The Map details, though, remain a mystery. “The correlation has been reported for many years,” says Columbia malaria expert David Fidock, PhD. “But no one had the faintest idea what connected the two.” This fall, Uttiya Basu, PhD, will embark on an inves- tigation that might fnally reveal the missing link. Like Quest Dr. Burkitt, Dr. Basu boasts a detective’s meticulous y Nancy Averett attention to detail. And like Dr. Burkitt, the microbi- ologist builds maps related to disease. But unlike Dr. Burkitt, whose maps spanned vast geographical regions, Dr. Basu will focus on microscopic areas deep within our cells, inhabited by long-ignored actors in the human genome known as noncoding RNA—the foremen of the manufacturing sites—where he suspects antibody produc- A few years later, Dr. Burkitt sent tumor samples to Michael tion sometimes goes bad. “If we can understand how malaria Anthony Epstein, who thought a virus might be causing the chil- and Burkitt lymphoma are related,” Dr. Basu says, “we could dren’s jaw cancers. Dr. Epstein found virus particles for what is attack them simultaneously.” now known as Epstein-Barr virus (EBV) in some of the tumor cells, providing the frst evidence that endemic Burkitt lymphoma r. Burkitt moved to Africa in 1946. His dream of becom- cells are often infected by EBV. Nevertheless the role of this virus Ding a surgeon had been cut short by the loss of his right in the pathogenesis of Burkitt lymphoma remains controversial. eye during a childhood scuffe, but he harbored another pas- Whether from Epstein-Barr or malaria, pathogens only make sion—missionary work. So he took a post at Uganda’s Mulago us sick if they dupe our immune system. To detect such hazards, Hospital. It was there in 1958 that he encountered a 5-year- the immune system conducts constant surveillance—and it only old boy with a jaw tumor and extensive facial disfgurations. works if we have the right antibodies. While genetic mutation can A few days later, while visiting a hospital in a nearby town, quickly go off the rails, the process serves a vital, adaptive func- Dr. Burkitt saw another child with a similar tumor. When he tion within the immune system. “We encounter more pathogens returned to Mulago, he began digging through records; 29 in our lifetime than the number of stars we can count,” says Dr. other children had been admitted with comparable tumors. Basu. “Each requires a perfect ft with an antibody to neutralize it, but we only have so many genes that can make antibodies.” To surmount that constraint, the immune system leverages a kind of guided mutation to shift DNA sequences within each antibody gene to create a rich diversity of antibodies. Dr. Basu began studying those processes at Harvard in 2004 as a postdoc in the lab of immunologist Frederick Alt, PhD, a former member of the Columbia faculty. In Dr. Alt’s lab, Dr. Basu homed in on activation-induced cytidine deaminase (AID), an enzyme whose presence during transcription seemed central to those guided mutation processes. “When I started working in Fred’s lab, antibody diversity was new to me and it was very exciting,” says Dr. Basu. “But in the last six to eight years, things have changed and how antibodies generate this diversity by genome rearrangement and mutagenesis has taken a new twist.”

SENSE VS. ANTISENSE For decades, biology’s central dogma has been that DNA makes coding or messenger RNA (mRNA), mRNA makes proteins, and proteins drive our cellular functions. Since nonprotein coding RNA (ncRNA) does not appear in that litany, it has received relatively short shrift in the genomic medicine revolution. The disregard was once so pervasive, it even informs the molecule’s alternative eponym—“antisense” RNA (sense RNA being, of course, mRNA). With limited computational and analytical tools and a dom- inant paradigm intent on DNA and mRNA, scientists ignored ncRNA. Instead, they focused on transcription, the produc- tion line on which our genes make proteins. The manufactur- ing process begins when an enzyme attaches to a gene and uncouples the gene’s DNA from its double helix shape—imag- ine opening a zipper. Next, the enzyme slides along one strand of the zipper, adding complementary nucleotides to create a strand of mRNA (a process termed “transcription”). Finally, when the enzyme reaches the gene’s end, transcription stops and the freshly manufactured mRNA detaches and foats away Uttiya Basu, PhD to be translated on the ribosome and form a protein. Think of AID, the enzyme Dr. Basu was investigating at

JÖRG MEYER Harvard, as a special foreman who only intermittently visits

14 ColumbiaMedicine the transcription factory foor. In its absence, DNA and RNA P&S researchers use an array of options— nucleotides match cytosine to guanine and adenine to thymine. biomolecular assays, whole exome sequencing, But in its presence, the pairing process “deaminates,” linking cytosine to uracil and creating a U:G mismatch. whole transcriptome sequencing, and genetically At Harvard, Dr. Basu discovered the “switch” that activates engineered mouse models—to disclose the cellular AID in the immune system. Nature published the fnding in pathways disrupted by the genetic mutations October 2005. Little did Dr. Basu realize, when that highly acclaimed paper was released, just how much more there was common to lymphoma. to learn. AID creates the good mutations needed for antibody diversifcation but also introduces genomic alterations that how does the process go wrong to create mutations and trans- can lead to chromosomal translocations including those found locations like those seen in c-MYC? As would be expected, Dr. in people with Burkitt lymphoma. Basu was motivated and infuenced by Dr. Dalla-Favera’s ear- The key genetic lesion detectable in 100 percent of Burkitt lier studies. In a 2011 Cell paper, Dr. Basu and his lab showed lymphoma cells, the chromosomal translocation involving that a large cellular complex called the RNA exosome recruits the c-MYC oncogene, was identifed in 1982 by Riccardo AID to modify DNA during transcription. Dalla-Favera, MD, then an investigator at the National Can- Until Dr. Basu’s discovery of the RNA exosome’s role in cer Institute. Now director of Columbia’s Institute for Cancer guided mutation, scientists thought of the exosome’s primary Genetics, Dr. Dalla-Favera has published dozens of papers on job as degrading ncRNA. Combined with his new insight into the oncogene and its role in Burkitt and other forms of non- the role of the RNA exosome in antibody diversifcation, Dr. Hodgkin’s lymphoma. His work has yielded new insights into Basu and his team turned their attention to a new question: the pathogenesis of human B-cell lymphomas and, in particu- What is the relationship between noncoding RNA and AID? lar, the genetic lesions and biological mechanisms responsible The RNA exosome works so fast to degrade ncRNA that for the development of these diseases. scientists cannot even see it happen. To investigate its role, Since joining the Columbia faculty in 2009, Dr. Basu has Dr. Basu and his students engineered a knockout mouse with focused on how the immune system’s B cells regulate AID— a nonfunctioning exosome. The knockout lets noncoding what is the quality control mechanism that allows most of us RNA pile up in the murine B cells, giving Dr. Basu and his to beneft from AID-activated antibody diversifcation, and team enough time to collect data on them. Data in hand, they

2016 Annual Report ColumbiaMedicine 15 turned to quantitative computational scientist Raul Rabadan, were large quantities of ncRNA on the parts of antibody genes PhD, and his postdoc, Jiguang Wang, PhD, to build a tool that where DNA double-strand breaks happen to create the “good” would analyze those accumulated ncRNA. mutations that diversify our antibody inventory. But there were To help the investigators visualize their data, Dr. Wang wrote also large quantities of ncRNA near fve precancerous genes known algorithms to sort the various ncRNA and create a Google to be erroneous targets of AID, including c-MYC, the proto-onco- Maps-like browser. Users type in a gene name and the program gene common among people with Burkitt lymphoma. The results, spits back any ncRNA in that region. Color coding highlights which were published in Nature in October 2014, were strong evi- ncRNA expression in both exosome-defcient mice and normal dence: Antisense RNA plays a leading role in guiding mutations. mice; by zooming in and out, scientists can get a local or global The implications of the results were further discussed in a review view of the genome. “Because we can actually map the ncRNA article in Advances in Immunology published in May 2015. and study it globally, we can learn much more about it,” says “When you make a discovery like that,” says Dr. Basu, “it’s Dr. Basu. “There are long ncRNA, micro ncRNA, enhancer a bit like being the frst to go to the moon, or Mars, or some ncRNA, and promoter ncRNA—they come in many favors.” other crazy planet.” Perhaps even more important than revealing the existence of LIKE SPACE EXPLORATION that crazy planet, his team had assembled the tools to explore The favors Dr. Basu’s lab was most interested in were those con- it. Now that they could poke around within the immune sys- trolled by the exosome. But frst they had to build their exosome- tem’s ncRNA, Dr. Basu’s team created additional exosome- defcient knockout mouse, sequence its ncRNA, and hand off that defcient mouse models to extend their reach. information to Dr. Wang, a process that took nearly 12 months. In the new knockout mice, they found additional types of In 2012, the data were fnally ready. Now a research scientist at antisense RNA, including genetic sequences that activate gene Regeneron Pharmaceuticals, Evangelos Pefanis’14 PhD, was a transcription (called enhancers). These antisense RNA also graduate student at the time. On one fateful February morning, Dr. tended to be adjacent to genes susceptible to both good and bad Pefanis got to the lab early, opened his laptop, and began typing AID-induced mutations. They also found that without a func- gene names into Dr. Wang’s browser. Right away, he says, “I could tioning exosome quickly degrading the ncRNA as soon as its job see something interesting was going on.” Moments later, when Dr. was done, the presence of ncRNA set the stage for yet another Basu walked in, Dr. Pefanis waved him over. “Hey, take a look at type of mutation. When functioning optimally, Dr. Basu and his this gene,” he said. “And take a look at this one and this one.” team concluded, the antisense RNA works like a matchmaker: Dr. Basu stared at the screen as the graduate student clicked It steps in to attract AID to various genes but then it better get through the data. There they were, plain as day: strands of ncRNA lost; its mere presence can lead to inappropriate attraction of spread across the genome, clustering around genes known to AID to genes, which will cause unwanted mutations. undergo bidirectional transcription, a unique regulatory mecha- Finally, because DNA exists in tertiary structures called nism that may play a role in switching genes on and off. There also chromosomes that are bunched and looped, Dr. Basu and his

New Celiac Risk Factor Identifed

FOR PEOPLE WITH CELIAC DISEASE, ingesting gluten—proteins found in wheat, rye, and barley—triggers an autoimmune reaction characterized by severe gastrointestinal symp- toms. An estimated 40 percent of the population has the gene variants associated with celiac disease, but only 1 percent of people with these genes will develop intestinal infam- mation and damage after ingesting gluten. Researchers from Columbia’s Celiac Disease Center and the Department of Microbiology & Immunology—including Peter Green, MD, director of the Celiac Disease Center, and Sankar Ghosh, PhD, chair of microbiology & immunology—have identifed a segment of RNA that, when suppressed, may contribute to celiac-associated intestinal infammation. The fndings point to a possible new risk factor for the disease. In a series of experiments reported in Science, the team demonstrated that a long non- coding chain of RNA dampens the expression of celiac-associated genes. They then discov- ered that people with celiac disease had unusually low levels of this RNA in their intestines, suggesting that the reduced levels may contribute to the infammation seen in celiac disease by turning of the normal regulatory pathway.

16 ColumbiaMedicine students wondered if some antisense RNA might infuence that three-dimensional topography. The investigators knew that sometimes DNA loops shift and when they touch one another, Who’s Who the adjacency can alter gene expression. Might antisense RNA · Uttiya Basu, PhD, associate professor · Evangelos Pefanis, PhD, scientist, serve not only as a matchmaker among enzymes and genes, of microbiology & immunology Regeneron Pharmaceuticals but also as a facilitator to the unique bunching and looping of · Riccardo Dalla-Favera, MD, the Percy · Raul Rabadan, PhD, associate DNA strands within a chromosome? & Joanne Uris Professor of Clinical professor of systems biology and of Indeed, when Dr. Basu’s team started removing strands of Medicine, professor of microbiology biomedical informatics and director & immunology, pathology & cell of the Center for Topology of Cancer antisense RNA depending on their location within the genome, biology, and genetics & development, Evolution and Heterogeneity they found that they could impede the capacity of a regulatory and director of the Institute for · Adam Sonabend, MD, assistant component of antibody genes to initiate guided mutation some Cancer Genetics professor of neurological surgery 2.6 million nucleotides away from the material they had removed. · David Fidock, PhD, professor of · Jianbo Sun, PhD, former associate As they pondered these discoveries, which Cell published in May microbiology & immunology and research scientist in microbiology of medical sciences (in medicine/ 2015, Dr. Basu and his students began to wonder: Could some- & immunology thing other than a scientist—a pathogen or a virus, perhaps—also division of infectious diseases) · Jiguang Wang, PhD, associate research · Laura Pasqualucci, MD, associate disrupt all of that carefully calibrated ncRNA machinery? scientist in biomedical informatics professor of pathology & cell biology (in the Institute for Cancer Genetics) STUDYING MICE WITH MALARIA TO HELP at CUMC BURKITT LYMPHOMA PATIENTS This fall, Dr. Basu and his students will begin infecting mice with the malaria parasite—the frst step in generating a new map to show how the mosquito-borne pathogen affects the ncRNA land- the journal PLOS Pathogens published their analysis. “When scape. Based on earlier work from their team and other groups, studying the mutational profle of endemic Burkitt tumors,” the researchers have a hunch about the location within the genetic wrote Dr. Rabadan and his co-authors, “we fnd recurrent altera- code where the mutation common to Burkitt lymphoma patients tions in genes rarely mutated in sporadic Burkitt lymphomas.” originates. To test their hypothesis, they are zeroing in on differ- As technology has advanced, P&S investigators, including Dr. ences in that region between normal mice and infected mice. They Dalla-Favera, Dr. Rabadan, and Laura Pasqualucci, MD, have lev- expect that the pathogen will cause increases in ncRNA—as well eraged an array of options including biomolecular assays, whole as the increased potential for structural mutations—near a genetic exome sequencing, whole transcriptome sequencing, and geneti- component common among people with Burkitt lymphoma. cally engineered mouse models to disclose the cellular pathways Finally, they will experiment with methods to prevent the muta- disrupted by the genetic mutations common to lymphoma and tion by injecting mice with antibodies that inhibit AID expression. Burkitt lymphoma in particular. That work promises to reveal new Eventually, they hope to develop drugs to cause that suppression. therapeutic targets to boost treatment options for the condition, Even as they dig deeper into the mechanisms at play in which remains incurable in approximately 30 percent of patients. Burkitt lymphoma, Dr. Basu and his collaborators continue to Such endeavors would have been hard for Dr. Burkitt to refne their understanding of the various mechanisms by which imagine. When the missionary doctor encountered the disfg- lymphocytes operate within the immune system to monitor pro- uring lymphoma that now bears his name, cancer treatments gression of cancer and onset of many other diseases. In Novem- were in their infancy and nothing could be done for his young ber 2015, Cell Reports published Dr. Basu’s paper, co-authored patients. “This is the gloomy part of medicine,” he told a col- with Jianbo Sun, PhD, Dr. Rabadan, Dr. Pefanis, Dr. Wang, and league. Little did he know that his own persistence in describ- other scientists, on the use of transcription analyses to identify ing the disease—one that took him around the edges of his a biomarker for B cells with immune suppression functions. adopted land—might culminate decades later in another epic Unpublished studies from Dr. Basu’s laboratory done in col- journey, only this time in the tiniest of landscapes. laboration with Columbia neurosurgeon Adam Sonabend, MD, Dr. Basu believes the work has implications far beyond have yielded identifcation of a novel mechanism of immune Burkitt lymphoma, with the potential to help clinicians fght system-mediated clearance of cancer of the human brain. a wide variety of diseases at the molecular level. He looks for- Meanwhile, Dr. Rabadan and his systems biology colleagues ward to growth in the feld as fellow investigators map ncRNA have delved deeper into the association of Epstein-Barr virus in cell types throughout the body, including neuronal cells and with some cases of Burkitt lymphoma. By using next-generation cardiac muscle cells, and continue to innovate and refne tech- sequencing, they were able to classify the RNA mutations associ- niques for investigating how ncRNA operates. Says Dr. Basu: ated with each of the three clinical forms of Burkitt lymphoma— “There’s all kinds of different noncoding RNA species just endemic, sporadic, and immunodefciency-related. In October, waiting to be discovered.” v

2016 Annual Report ColumbiaMedicine 17 nyone who has ever announced a preg- Mailman School of Public Health. “We interact nancy knows how freely others offer with them continuously and they mold who we Aadvice on sleeping habits, feeding, and are and what we will become. They’ve played other challenges that follow birth. But P&S bacte- important roles in evolution and they play ria researcher Yiping Han, PhD, offers a tip rarely important roles in everyday life—from how the included in the free-fowing advice: See a dentist immune system is tuned to how we respond to and get serious about brushing, fossing, and rins- our environment and how we digest food.” ing with an alcohol-free mouthwash. Early research in the feld—including the NIH’s Her advice goes further: Optimize dental health Human Microbiome Project, which launched in in the months before you start trying to conceive 2007—focused on naming and describing the spe- Microbes to boost the baby’s prospects for a healthy birth cies common to the human body. Dr. Lipkin, fea- weight and full gestational age. Should an infec- tured in a video as part of the American Museum tion and swollen, bleeding gums simultaneously of Natural History exhibition “The Secret World Within strike during pregnancy, says Dr. Han, see a doctor. Inside of You,” has been a leader in such efforts The advice emerges from more than 15 years for more than three decades. “We have a symbi- in which Dr. Han’s research has investigated the otic, or at least mutually respectful, relationship Us role of the oral microbiome in adverse pregnancy with our microbiome,” he says. “It’s when things outcomes—miscarriage, preterm labor, low birth get out of balance that we have diffculties—the weight, and neonatal sepsis. Much of that work dis-ease we perceive as disease.” has focused on Fusobacterium nucleatum, a tubu- Dr. Lipkin and Dr. Han are among a growing Scientists lar bacterium implicated in periodontal disease cadre of P&S investigators exploring what consti- and also associated with appendicitis, rheumatoid tutes balance within the microbiome and how the Investigate arthritis, Alzheimer’s disease, and other maladies. many species involved maintain homeostasis with How the “There’s a saying in the dental feld that the us, their human hosts. By getting a better handle Microbiome mouth is the gateway to your health,” says Dr. on how the whole system functions, they hope to Han, also a faculty member in Columbia’s College identify interventions that can promote health and Infuences of Dental Medicine. “I think there’s some justif- prevent disease. “What I have been pushing for Human Health cation to that.” the last few years is for us to create an effort that Trillions of bacteria, fungi, and viruses popu- moves beyond description,” says Microbiology & late our skin, sinuses, lungs, guts, and urinary and Immunology Chair Sankar Ghosh, PhD, “to start reproductive tracts. The oral cavity alone is home exploring the mechanisms by which the microbi- By Sharon Tregaskis to between 700 and 1,000 species of microorgan- ome infuences physiological processes.” isms, which occupy such distinct habitats as the That effort extends from basic science to clini- teeth, tongue, hard palate, soft palate, tonsils, and cal applications, from new methods for microbial the “gingival sulcus,” where teeth meet gum tissue. analysis to classic culturing. In Dr. Ghosh’s lab, So many billions of beings comprise the human a team seeks to reveal how receptors within the microbiome that scientists now estimate that their immune system monitor the microbiome and the genes outnumber our own by a factor of 100 to 1. mechanisms by which our bodies respond briskly “If you add up all of the microbes in the gut, they and aggressively to potentially dangerous species weigh more than the brain in terms of physical while giving benefcial species a pass. This year, mass,” says biologist Harris Wang, PhD, assistant Harris Wang received more than $4 million in professor of systems biology. “They outnumber awards from the NIH, the Defense Advanced human cells 10 to 1. They constitute a very impor- Research Projects Agency, and the Offce of Naval tant area of the normal human physiology.” Research to develop computational techniques to Don’t make the mistake of imagining those speed microbial discovery and genomic engineer- microbes as mere bit players, says internation- ing strategies to unlock the secrets of microbes ally renowned virus hunter W. Ian Lipkin, MD, that scientists have not yet been able to culture in Photographs by Jrg Meyer who has joint appointments in P&S and the the lab. The projects include collaboration with

Ivaylo Ivanov, PhD, assistant professor of micro- about bacteria, fungi, viruses, and human cells as Framework of Microbial Trade,” appeared in biology & immunology, on engineering commen- existing in equilibrium,” says Dr. Lipkin. “If equi- PLOS One in July 2015. “A large fraction of micro- sals involved in infammation. librium is maintained, we have health.” bial life on Earth exists in complex communities In a project funded by the NIH with a fve- Like the keystone at the crown of a Roman arch, where metabolic exchange is vital,” he and his co- year, $2 million award, Dr. Han has partnered commensal species serve as vital placeholders. authors wrote. “Microbes trade essential resources with Timothy Wang, MD, chief of digestive and Take, for example, the commensal oral microbe F. to promote their own growth in an analogous liver diseases, to explore the role of F. nucleatum nucleatum, the subject of Dr. Han’s research and way to countries that exchange goods in modern in colorectal cancer. Dr. Lipkin combines novel a building block of dental plaque. “Oral plaque economic markets.” Extending the metaphor, the molecular diagnostic innovations with epidemi- consists of many, many bacteria—hundreds of spe- collaborators developed a model of microbial pop- ology and conventional clinical data to investi- cies,” she says. “They don’t all just pile up ran- ulation dynamics based on the economic theory gate the microbial hit-and-run events that seem domly; they’re very organized.” Early colonizers of general equilibrium. “Our model suggests that to trigger such conditions as autism and chronic bind to the protein layer that coats the tooth sur- microbial communities can grow faster when spe- fatigue. Hepatologist Elizabeth C. Verna, MD, face, creating crags and crevices for the secondary cies are unable to produce essential resources that has begun monitoring the gut microbiome of colonizers—F. nucleatum and its ilk. Late coloniz- are obtained through trade,” they wrote, “thereby people with liver disease, looking for clues to ers bind to the Fusobacterium. Without the bacte- promoting metabolic specialization and increased optimize post-transplant recovery. ria, we would be spared tooth decay triggered by intercellular exchange. Furthermore, we fnd that the acidic byproduct of bacterial metabolism but species engaged in trade exhibit a fundamental An Ecological Mindset would be at risk of attack from more dangerous trade-off between growth rate and relative popula- When it comes to interactions between microbes microbes. “The commensal bacteria occupy the tion abundance, and that different environments and their human hosts, researchers sound rather sites in the host so that foreign pathogens—the that put greater pressure on group selection versus like park rangers discussing how fre, drought, and exogenous pathogens—cannot colonize,” says Dr. individual selection will promote varying strategies myriad other environmental conditions can weight Han. “They build colonization resistance.” along this growth-abundance spectrum.” the scales in favor of one species or another. It’s all Imagine the give and take among microbes as Imagine, then, how easily a commensal within about the web that holds the species together, their something akin to international commerce, sug- the human habitat can become a pathogen. Take, fates inextricably linked. “It’s important to think gests Harris Wang, whose paper, “An Economic for example, the fungus Candida, a standard fea-

W. Ian Lipkin, MD

Sankar Ghosh, PhD

20 ColumbiaMedicine of the stomach’s acid-secreting cells, with a con- comitant rise in pH, which ultimately makes the stomach inhospitable to H. pylori. At the same time, other species thrive in the less acidic environ- ment. “There are two microbiomes of the stom- ach, one with H. pylori and one without,” says Timothy Wang. Perhaps, he says, H. pylori should be recon- ceived as a commensal—basically neutral, provid- ing that it stays where it belongs and remains in balance with the other species in its web of life, host included. For evidence, he turns to ancient his- tory. Stomach ulcers are a 20th century affiction, but DNA evidence suggests that H. pylori has been present in the human gut for more than 200,000 years—long before our population outgrew the Ivaylo Ivanov, PhD, cradle of civilization. “In the vast majority of peo- and Harris Wang, PhD ple—85 to 90 percent of people—they experience no harm from the bacteria and there may be some protective effects,” he says. “Maybe in the past, we never survived long enough to get ulcers.” ture of the human microbiome. Typically, our cell induction, one of the frst direct examples of a The same might be said of gastric cancer, another immune system keeps its population in check. But specifc commensal modulating intestinal immune hazard of long-term exposure to H. pylori. Among when the system gets disrupted—as with AIDS function. “It was a huge advance,” says Dr. Ghosh. people whose gut hosts the bacterium, between or in the aftermath of intensive antibiotic treat- “It took the microbiome down from trillions of 1 percent and 2 percent develop malignancies in ment—oral thrush or a yeast infection emerges. bacteria and thousands of different species to one Likewise, F. nucleatum is ubiquitous within the bacteria and from many physiological processes to oral cavity but typically held in check by a robust the production of one cell.” “We have a symbiotic, immune system abetted by regular brushing and In 2012, Dr. Ivanov was named a Pew Scholar fossing. “Everybody has Fusobacterium, but not in the Biomedical Sciences and in 2013 he received or at least mutually everybody has periodontal disease,” says Dr. Han. a senior research award from the Crohn’s and respectful, relationship “Under normal, healthy conditions, this bacte- Colitis Foundation of America to investigate how with our microbiome. rium can exist in our oral cavity without causing commensal microbes battle infammatory bowel much harm. What kind of role the bacterium plays diseases. In March his project, “Keeping a Healthy It’s when things get depends on the host ecological environment.” Gut: Commensal Bacteria Know-Hows,” earned out of balance that we The human immune system factors heavily Dr. Ivanov a 2016 Schaefer Research Scholar have diffculties.” among the environmental infuences on the micro- award—$50,000 in discretionary funds and biome, and vice versa. Over the past fve years, Dr. $200,000 in direct costs. Such investigations of the Ivanov has investigated how relationships between mechanisms by which key commensal species reg- the lining of their stomachs. Early in his career, commensal microbes and their host regulate and ulate host immunity are sure to reveal new ways of Timothy Wang leveraged that statistic to develop modulate the immune system. Using a combination treating immune diseases, says the scientist. the frst rodent model of gastric cancer, by expos- of genomic techniques and studies conducted in a ing mice to Helicobacter felis, a close relative of germ-free facility with specially engineered mice, Good Bug, Bad Bug H. pylori. Since then, he has devoted much of his his team has elucidated the molecular communion Healthy and unhealthy guts alike feature Heli- research portfolio to uncovering the mechanisms between segmented flamentous bacteria, an intesti- cobacter pylori, a common stomach bacterium by which the bacterium induces malignancy. “It nal commensal, and the leukocytes known as Th17 whose population takes its cues from conditions turned out, in our animal models—and we found cells. Known to contribute to host defense against within each individual’s digestive tract. Once vili- this was also true in human patients—that when extracellular pathogens, Th17 cells also have been fed as a pathogen for its role in stomach ulcers, the the cancer actually develops it’s in the setting of implicated in the pathogenesis of multiple infam- helical microbe gets more complicated with each severe infammation,” he says. “It was our hypoth- matory and autoimmune disorders. In 2009, Cell clue investigators eke from their studies. Timothy esis that the bacteria were modulating the host published Dr. Ivanov’s discovery that colonization Wang’s research, for example, has revealed that immune response leading to the cancer. This is the with segmented flamentous bacteria spurs Th17 long-term exposure to H. pylori triggers atrophy view of many people in the microbiome feld—that

2016 Annual Report ColumbiaMedicine 21 it’s through the modulation of infammation that a development of esophageal adenocarcinoma,” he hepatitis C, the focus of Dr. Verna’s prior research, lot of the effects occur.” says. “At least, that’s the hypothesis.” turns the gut barrier into a leaky sieve. It also trig- In particular, Timothy Wang and his collabora- Another possible explanation for the negative gers shifts in gut ecology to favor more pathogenic tors have homed in on a curious detail: While the association of H. pylori with esophageal cancer is organisms, which can throw blood chemistry for presence of H. pylori is predictive of future can- that H. pylori is our microbial canary in the coal a loop. The combination puts a dual strain on the cer risk, the bacterium seems to disappear around mine—just one among many gut microbes whose liver, tasked with cleaning every ounce of blood the same time malignancies actually take root. In populations are failing under the onslaught of that flters from the digestive tract before it moves a series of experiments with knockout mice in a antibiotics and the rise of modern living. “There on through the rest of the body. Says Dr. Verna: germ-free facility, Timothy Wang and collabora- are thousands of species and there’s a dynamic “Bacterial particles that leak across the gut and tors have shown a role for the additional bacte- balance,” says Dr. Lipkin. “We know that bacte- changes in metabolism both have a very strong riophages control levels of bacterial populations, impact on infammation and scarring in the liver.” but we don’t yet know the details.” The hazard As a clinician with Columbia’s Center for Liver “Right now a lot of is a slow, steady constriction of the microbial Disease and Transplantation, Dr. Verna sees the microbiome research populations that hold our immune system in bal- aftermath of infammation and scarring, the hall- ance—and potentially the rise of far more vicious marks of chronic liver disease. Each year, she and is correlative. Actually pathogens. As Dr. Lipkin notes, “Nature abhors a her colleagues manage postoperative care for 140 showing causality vacuum.” Perhaps, says Timothy Wang, H. pylori patients recuperating from a liver transplant, a is diffcult.” actually has nothing to do with esophageal can- major abdominal surgery followed by a lifelong cer and some other microbe—not yet detected or protocol of immune-suppressing medications. named—is the real protector of esophageal health. In December, the National Institute of Diabe- ria whose populations thrive as H. pylori pushes “It’s like frogs disappearing in the swamps,” he tes and Digestive and Kidney Diseases awarded the stomach pH ever higher. “We demonstrated says. “We’re not really that concerned about the her a $607,941 grant for a four-year project to unequivocally that late-stage progression of gastric frogs; it’s what the frogs represent, which is the investigate the role of the intestinal microbiome cancer is inhibited in a germ-free facility,” says Dr. disappearance of a lot of other species.” in recurrent disease following liver transplanta- Wang: “It’s really the bacterial overgrowth that is tion. “I’m interested in mechanisms of liver injury responsible for the progression of gastric cancer.” Exploring Mechanisms of Infammation and scarring in general and in particular among Stomach acidity is not the only host environmen- A growing body of research—including work by liver transplant patients,” she says, “because they tal condition that constrains H. pylori. It turns out Timothy Wang—delves into the mechanisms by that modern living itself—our penchant for antibi- which infammation mediates the microbial ecol- otics and a class of antacids known as proton pump ogy and its association with malignancy. “When inhibitors—has precipitated a dramatic decrease in you get infammation, even if that infammation the number of people whose gut microbiome even is not due to the bacteria, it changes the bacteria contains H. pylori. Meanwhile, esophageal cancer around that tissue,” says Dr. Wang. “It’s dysbio- seems to have reached epidemic proportions in sis—abnormal bacterial colonization.” While the developed countries. The divergent trends have led association is robust, scientists have struggled to some scientists to speculate that perhaps H. pylori demonstrate how A leads to B leads to C—or actually protects against esophageal cancer. whether, perhaps, C initiates A. “The chicken To test the association, Timothy Wang has or the egg is complicated. Does the infammation partnered with Julian Abrams, MD, an expert in come frst or the change in the bacteria? Do they esophageal cancer. “We think that the upper GI occur simultaneously? It’s hard to say. Right now tract microbiome plays a big role in the develop- a lot of microbiome research is correlative. Actu- ment of gastric cancer,” says Dr. Wang. “We’re ally showing causality is diffcult.” starting to see that at the junction of the esoph- Hepatologist Elizabeth C. Verna, MD, has agus and stomach, the microbiome probably turned her attention to the mechanisms by which changes based on whether or not H. pylori is pres- the ecology of the digestive tract affects infamma- ent in the stomach.” To reveal the mechanisms tion of the liver, that rubbery, three-pound organ by which the bacterium exerts its infuence, Dr. tucked under the rib cage to flter and detoxify Wang is running a new series of experiments in a our blood. “The gut in a normal person is flled germ-free facility, this time with mice susceptible with millions of microbes, but for the most part to esophageal cancer. “Perhaps H. pylori alters the the intestine creates a barrier to contain those Anne-Catrin Uhlemann, MD, PhD stomach microbiome, thereby altering the esoph- microbes,” she explains. “And that barrier is ageal microbiome, and that somehow affects the tightly regulated.” Chronic liver disease, including

22 ColumbiaMedicine have an abnormal intestinal microbiome at the time of transplant, which puts them at high risk of having this mechanism of liver injury. Trans- plant recipients can have very severe outcomes, including mortality.” Over the past three years, Dr. Verna has enrolled individuals willing to provide serial blood and stool samples as they prepare to undergo a liver transplant and in the months and years follow- ing the procedure. To track participants’ diges- tive microbes, Dr. Verna and her collaborators, including bacteriologist and infectious diseases specialist Anne-Catrin Uhlemann, MD, PhD, per- form 16S rRNA sequencing of the stool samples. To approximate the burden of digestive microbes within the blood, the scientists have homed in on endotoxins, bacterial cell wall components the liver has failed to flter, and immune mark- Elizabeth C. Verna, MD ers associated with intestinal permeability. Over time, they plan to collect additional samples from the digestive tract to expand their data set. It is a particularly exciting project, says Dr. Verna. recalibrate. “Those who seem to develop disease factors as diet, immune status, smoking, and “This work is at the interface between big data— are those who still have the biomarkers of trans- hydration all infuence just how much weight the large bodies of information about large numbers location three months after surgery.” microbe can throw around the ecological play- of people, each of whom has a large population of Of particular importance to the scientifc ground. Blood chemistry, too—in the form of hor- digestive microbes—and the specifcity of person- community, says Dr. Verna, are the implications mones and blood sugar levels—infuences which alized medicine to assess an individual patient’s of that preliminary analysis for study design: At microbes live or die. Pregnancy, it turns out, is a risk and how we might modulate that risk.” least in the case of recovery from a liver trans- double whammy for the oral cavity. Such efforts got a technical boost this year when plant, it’s not enough to take a single snapshot Women and their physicians have long known the Department of Medicine committed funds to of the digestive microbiome. “The key to study- that intense hormonal shifts—puberty, pregnancy, launch a Microbiome Core Facility for research- ing this, which is really missing in the literature, menopause—seem to increase susceptibility to ers across campus. Services include guidance on is that you have to study patients over time. If the swollen, bleeding gums and other symptoms various elements of study design; protocols for you just have a cross-section of one patient at of periodontal disease caused by rampant micro- collecting, storing, and shipping sensitive samples one moment in time, you’re not really going to bial growth in the oral cavity. During pregnancy, for genetic sequencing; and analyses. In addition, understand what’s happening.” the immune suppression that prevents a woman’s the facility provides assistance with DNA extrac- The next phase of analysis will focus on predic- body from rejecting her fetus seems to exacerbate tion and batch samples from multiple labs to make tive features of the microbial census, as well as the situation. Pregnancy-related gingivitis afficts sequencing more cost-effective across the institu- correlations with such clinical details as the rate of approximately 50 percent to 75 percent of preg- tion. Dr. Uhlemann leads the facility. “Our idea,” metabolism of various drugs within the anti-sup- nant women. “It’s an often overlooked condition says Dr. Uhlemann, “is to enable researchers with- pression protocol and the incidence of metabolic because it’s self-limiting,” says Dr. Han. “After out a large experimental lab or computational disruption among transplant survivors. “The idea childbirth, hormonal levels are restored, and the expertise to do large-scale, data-intensive studies.” is that eventually we will know enough to target condition subsides.” Preliminary analyses of Dr. Verna’s liver trans- specifc microbes or specifc metabolic pathways,” Among healthy individuals with regular access plant data have revealed a critical insight: Timing says Dr. Verna, “so we can fne-tune things to max- to dental care, F. nucleatum is no big deal and it is matters. “Most patients, to some degree, experi- imize each patient’s post-transplant outcomes.” rarely found beyond the oral cavity. Among those ence this process of bacterial translocation early with compromised immune function—some- after the transplant,” she says. The observation Understanding Why Microbes Go Bad one fghting off a respiratory infection or some comes as no surprise, given the dysbiosis asso- While Dr. Verna investigates a single clinical out- other illness—doctors often detect the nonmotile ciated with major abdominal surgery and the come—triggers for scarring and infammation anaerobe far from where it belongs, including drugs used to suppress organ rejection. The data within the liver—Dr. Han has homed in on how within the joints, lungs, and reproductive tract. point most relevant for long-term prognosis, a single bacterium can toggle from commensal to In an August 2015 review for Current Opinion then, is how long it takes for a patient’s gut to pathogen. In the case of F. nucleatum, such host in Microbiology, Dr. Han recorded the microbe’s

2016 Annual Report ColumbiaMedicine 23 association with appendicitis, atherosclerosis, and ria in the Shigella genus, for example, are highly says Dr. Han. “For some people, once you have cerebral aneurysm, among others. “This bacte- acid-tolerant; exposure to just 20 of the rod-shaped the bleeding, once the bacteria enter circulation, rium has been implicated in a wide array of dis- anaerobes can cause a severe case of dysentery. they survive only a few minutes; for others, the eases,” says Dr. Han. “It’s been associated with The comma-shaped Vibrio cholerae, on the other bacteria persist for hours.” cardiovascular disease and isolated from abscesses hand, is extremely acid-sensitive and a very high In 2004, the Journal of Infection and Immunity in every organ, even the brain.” dose of the shellfsh-borne bacterium is required to published a paper describing the frst animal model Just how, exactly, does a nonmotile, oral microbe cause symptoms. “That passage doesn’t need a lot elucidating the role of F. nucleatum in adverse make its way into the joints, across the blood-brain of convincing,” says Dr. Han. “People understand pregnancy outcomes. By injecting the bacterium barrier, and throughout the reproductive tract? So that you swallow these microbes all the time, but into the tail vein of pregnant mice, Dr. Han and far, scientists have identifed two modes by which F. your exposure depends on how heavy your oral colleagues mimicked dental bacteremia, demon- nucleatum makes its journey: through our digestive inoculum is.” strating how F. nucleatum invades placental tissue To explain the presence of F. nucleatum in and, ultimately, the amniotic fuid, causing preterm meningitis and the joints of people with rheu- birth and miscarriage without causing systemic “New molecular matoid arthritis, as well as amniotic fuid, pla- maternal infections. In 2007, Dr. Han’s paper in cental tissue, and chorioamniotic membranes of the Journal of Immunology revealed the biochemi- techniques have made women who experienced premature labor, Dr. cal mechanism at play: F. nucleatum stimulates it possible to identify Han has focused her investigations on blood- placental infammation by hijacking receptors in organisms that could borne pathways. “For the bacteria to spread to the immune system; treatment with an anti-infam- not be grown in so many parts, the only logical explanation is matory agent reduced the risk of fetal death. the circulation,” she says. “It’s the only passage Two years later, a woman who had been afficted culture. That’s been that can reach every part of the body.” by excessive gum bleeding during an otherwise an enormous boon.” Like a mosquito inadvertently introducing Zika uncomplicated pregnancy approached Dr. Han or West Nile virus as it sucks down its dinner, a after having a miscarriage just two weeks before nick or cut in the mouth—whether from vigorous her due date. Dr. Han’s team dug into the case, tract and in our blood. “We have tons of bacteria fossing or chomping on a piece of toast—allows confrming that identical strains of F. nucleatum in our saliva,” says Dr. Han. “It’s like a washing bacteria within the oral cavity to pass into the isolated during autopsy from the fetus’s lungs and solution.” And ultimately, the bacteria that mix bloodstream. As with the symptoms of H. pylori stomach were also present in the woman’s mouth, with our food as we chew and swallow make their infection, host susceptibility factors into the gin- but not in any of the other samples they collected way to the stomach. “Whether they proceed to the givitis equation, along with the unique census of from her. Almost certainly, they concluded, the intestine depends on how resistant or sensitive they an individual’s oral microbiome. “Each person’s woman had suffered pregnancy-related gingivitis; are to stomach acid. It’s a numbers game.” Bacte- susceptibility to dental bacteremia is different,” it was only when a brief respiratory illness further weakened her immune system that the oral com- mensal persisted long enough in her bloodstream to invade the placenta, infuse the amniotic fuid, Who’s Who and infect the fetus. The Journal of Obstetrics and Gynecology published the full report in 2010. · Julian Abrams, MD, assistant professor of · W. Ian Lipkin, MD, the John Snow Professor of While vaginal microbes have frequently been medicine and epidemiology Epidemiology, director of Columbia’s Center implicated in miscarriage, preterm labor, and other for Infection and Immunity, and professor of · Sankar Ghosh, PhD, the Silverstein and Hutt neurology and pathology adverse pregnancy outcomes, microbial com- Family Professor of Microbiology & Immunology mensals associated with other parts of the human and chair, Department of Microbiology & · Anne-Catrin Uhlemann, MD, PhD, Florence Immunology Irving ssistant Professor of Medicine habitat—like F. nucleatum—may be implicated in many of the adverse outcomes doctors previously · Yiping W. Han, PhD, professor of microbial · Elizabeth C. Verna, MD, assistant professor of sciences (in dental medicine, microbiology medicine and director of clinical research for dismissed as “idiopathic.” Perhaps, Dr. Han and & immunology, obstetrics & gynecology, the Transplant Initiative co-authors speculated, the failure to identify F. and medical sciences in medicine) and a · Harris Wang, PhD, assistant professor of nucleatum as the cause owes to the technical diff- member of the Herbert Irving Comprehensive systems biology (in pathology & cell biology) culty of microbial detection using conventional cul- Cancer Center turing techniques, especially for anaerobic species. · Timothy C. Wang, MD, the Dorothy L. and Daniel · Ivaylo Ivanov, PhD, assistant professor of H. Silberberg Professor of Medicine, chief of the In the Obstetrics and Gynecology case study, Dr. microbiology & immunology Division of Digestive and Liver Diseases in the Han and colleagues deployed a genomic approach, Department of Medicine, and a member of the using polymerase chain reactions to amplify genes Herbert Irving Comprehensive Cancer Center within the samples they had collected, then checked them against the Human Microbiome database.

24 ColumbiaMedicine Among the vital insights F. nucleatum has yielded to Dr. Han’s manipulations is its reliance on a unique adhesin protein the scientist dubbed FadA. “It’s one small molecule of only 129 amino acids,” she says, “but it can do a lot of things.” Key to F. nucleatum’s ability to colonize so many parts of the body is FadA’s connectivity with a type of recep- tor known as a cadherin, which serves as a cellular gatekeeper. “Cadherins are ubiquitous in our cells. You have vascular-endothelial, VE-cadherins, and epithelial, E-cadherins; neuron cells have N-cad- herins, and in the placenta are P-cadherins.” Like Spider-Man clinging to a wall, FadA can lock on to a wide array of sites by binding to the specialized cadherins it encounters throughout our bodies. “As a microbiologist, I’m amazed by how smart and effcient these bugs are,” says Dr. Han. “They have such a tiny genome—only 2 million base pairs. However, they can manipulate us, their hosts, so effciently, making us work for them.” FadA goes far beyond merely clinging to the cadherins; it leverages something of a Trojan horse effect. “Once FadA binds to cadherin, it loosens the tight junction, like a key,” Dr. Han explains. “Not only can Fusobacterium get into the circulation by itself, but whatever bacteria are in the vicinity can Timothy C. Wang, MD, and Yiping W. Han, PhD come along. It’s like a facilitator, an enabler.” In their investigation of the role of Fusobac- terium nucleatum in colorectal cancer, Timothy Wang and Dr. Han are drawing on her investiga- PCR and other molecular assays have been vital (each of us hosts only a few hundred of those spe- tions of the particularly diabolical synergy of FadA to growth in the feld, says Dr. Lipkin, whose team cies). “Only half have been cultivated. The other with E-cadherin, a well-known cancer suppressor, developed VirCapSeq-VERT, a technique that half, we know they are there, but we don’t know as well as his expertise in H. pylori, particularly allows simultaneous testing for hundreds of differ- what kind of growth conditions they require to its knack for altering its environment. Already, ent viruses and provides near complete sequences grow in the laboratory setting.” they have demonstrated that in knockout mice of their genomes. “New molecular techniques Scientists have their work cut out for them engineered with a predisposition for colon polyps, have made it possible to identify organisms that and Dr. Han has made the development of F. nucleatum can accelerate activation of the can- could not be grown in culture,” he says. “That’s new microbial techniques a top priority for her cer. “It’s proof of principle that the bacteria alone been an enormous boon to identify organisms research team. In April 2015, the Journal of Clini- are not suffcient to cause colon cancer,” says Dr. more rapidly, which has allowed us to think in cal Microbiology published Dr. Han’s description Wang, “but can wake up dormant cancer stem cells terms of how we might more rapidly respond to of a specialized mass spectrometry technique for to go on to become tumors in the large intestine.” acute infectious disease and implicate chronic and identifying subspecies of F. nucleatum. In Novem- The prospect of showing that a single bacte- viral pathogens in cancer, even in those instances ber 2015, Dr. Han and her collaborators received rium can induce cancer is an exciting one, says where we can’t grow them.” a patent for the polymerase chain reaction tech- Dr. Wang, but the work will not be that simple. Ever more affordable prices for PCR analysis nique they used to detect bacterial pathogens in “In most cases, it’s not going to be a single bacte- are especially critical for boosting diagnostic accu- the Obstetrics and Gynecology case study. “One rium,” says Dr. Wang, noting that he and Dr. Han racy in clinical settings, says Dr. Han. “Currently of the frontiers in microbiology is to cultivate the have a lot of genomic sequencing and bioinfor- in the hospital laboratory, the gold standard is still uncultivated,” she says. “In order to study patho- matics work in their future. “These things live in the culturing method but we know that many bac- genic mechanisms, we need to know the condi- student dorms with a lot of their friends. They’re teria that live in or on us are uncultivated or dif- tions under which they thrive or die and we have like fraternities, in a way. Just looking at one at fcult to cultivate.” In the oral cavity, for example, to be able to cultivate them so we can manipulate a time makes it really diffcult to fgure out the scientists have identifed as many as 700 species and study them in the laboratory setting.” source of the noise late at night.” v

2016 Annual Report ColumbiaMedicine 25 Medical Scientists Work to Level the Field for Equality Medical Care From Shanghai to Kinshasa, humans have most of the same DNA. sure, anthropometric measures, and cardiovascular status. On Aug. 1, the But in the matter of longevity and well-being, nurture—including such National Institute on Aging awarded another $8.8 million to Dr. Mayeux personal choices as the foods we eat and the amount of exercise we get— and his collaborators to continue their work in the community. often trumps nature. Disparities researchers seek to untangle the relative Designed to investigate dementias related to stroke, Parkinson’s disease, power of social and environmental factors, including race, education, and and Alzheimer’s disease, WHICAP quantifes the rates of late onset Alzheim- income, from the infuence of shared genetic predispositions, such as the er’s disease, mild cognitive impairment, and age-related cognitive decline APOE Alzheimer’s gene more common among African-Americans or the among the three major ethnic groups in the community. WHICAP investiga- tendency toward Tay-Sachs disease among Ashkenazi Jews, to identify tors have authored scores of papers that untangle the relationships among interventions that can boost longevity for all Americans. age, sex, race and ethnicity, and clinical risk factors to guide prevention, From their vantage in Northern Man- clinical care, and future research. Their fndings include the discovery—after hattan, P&S investigators have a unique controlling for an array of correlated factors—that African-American and opportunity to identify and explain Caribbean-American elders are at greater risk for Alzheimer’s and identifca- health disparities and develop interven- tion of a new gene associated with late-onset Alzheimer’s. tions to boost the well-being of the people “Disparities research is intended to generate new knowledge that will help who call the medical center area home— us improve health through prevention and treatment. Investigations of ethnic especially the working-class Hispanic populations that have migrated across several cultures offer the opportunity immigrants of Washington Heights, the to study groups for which genetic factors essentially remain the same but denizens of Harlem’s vibrant African- environmental and cultural forces undergo dramatic change,” says Dr. May- American community, and the Cauca- eux. “At the same time, comparing groups residing in the same environment sian residents of Northern Manhattan. with similar socio-economic status and equal exposure to risk factors helps Perhaps the most ambitious of those us uncover genetic factors responsible for all kinds of health conditions.” projects, the multiethnic Washington Being located in Washington Heights, Dr. Mayeux says, has given research- Heights, Hamilton Heights, Inwood, ers an extraordinary opportunity to contribute to new knowledge about the Columbia Aging Project—WHICAP— health of Hispanics of Caribbean descent. “Our local community is the most Richard Mayeux, MD is led by Richard Mayeux, MD, the ethnically diverse in New York, home to the largest population of individuals Sergievsky Professor of Neurology, from the Dominican Republic outside of the Dominican Republic, and we Psychiatry, and Epidemiology. Con- have long been dedicated to not only treating this population, but also partner- tinuously funded by the NIH since 1989, WHICAP has enrolled more ing with them to understand how to improve the health of the community.” than 5,900 participants and collected some 40,000 biological samples, The following pages profle four researchers who are studying dis- 1,300 MRI and 200 PET scans, and longitudinal data on cognitive per- parities in diabetes, obesity, cardiovascular disease, and Alzheimer’s and formance, emotional health, independence in daily activities, blood pres- other neurodegenerative diseases.

By Sharon Tregaskis | Photographs by Jrg Meyer

Implementation Science Nathalie Moise

n African-American woman theories to boost breast cancer Ain her 60s who was hospital- screening among African-American ized frequently for heart failure women. More than a decade later, struggled to follow what doc- Dr. Moise is assistant professor of tors had prescribed to control medicine in Columbia’s Center for her cardiovascular disease and Behavioral Cardiovascular Health. depressive symptoms—aspirin, She acknowledges that health prescription medication, exercise, care professionals still struggle to and diet changes—and she had provide optimal care for minority limited social support. For her patients. “While there were clear, doctor, Nathalie Moise, MD, then evidence-based strategies for treat- a research fellow in Columbia’s ing my patient’s disease,” she says, Division of General Medicine “it was diffcult to implement them while earning a master’s degree in real-world settings.” in public health at Columbia, the African-American and Hispanic patient’s case crystallized a plan individuals, who are at greater risk she had been thinking about for for both depression and cardiovas- more than a decade: Identify bar- cular disease, need clarity about the riers and scale implementation of relationships among gender, socio- economic status, race, depression, Dr. Moise has conducted com- for a multicenter grant from the A model for and cardiovascular disease. “The puter simulation analyses to assess National Heart, Lung, and Blood depression barriers to implementing cardio- how medication costs, adherence, Institute, Dr. Moise is investigating treatment vascular disease guidelines in my and race infuence the cost-effec- the American Heart Association would have a own clinic revolve around my tiveness of hypertension guidelines, guideline that recommends depres- patients’ mental illnesses, inad- published recently in Hyperten- sion screening in patients follow- care manager equate psychosocial resources, sion and the American Journal ing stroke and heart attack. As a collaborate with and uncertainty about their adher- of Hypertension. Last fall, Dr. policy scholar with the New York the patient’s ence,” says Dr. Moise, who sees Moise was awarded funds from State Offce of Mental Health physician and patients at Columbia’s Associates the Columbia Provost’s Grants she is investigating a model for a psychiatrist. in Internal Medicine Clinic and Program for Junior Faculty Who depression treatment in which a CoSMO, the free, student-run Contribute to the Diversity Goals care manager collaborates with the evidence-based guidelines in minor- clinic for uninsured residents of of the University to conduct inter- patient’s physician and a psychia- ity patient groups. Washington Heights. For someone views of predominantly minority trist; the model has been especially “In college, I was struck by struggling with depression and and Spanish-speaking patients effective among minority popula- how evidence-based guidelines are other chronic diseases, implement- with depression to better under- tions but diffcult to implement poorly disseminated in minority ing a regimen of diet change and stand the barriers to care that they with patients and doctors. “To communities,” says Dr. Moise, exercise—plus the daily handful of encounter. The insights Dr. Moise truly impact health disparities,” whose frst foray into research was pills to control both conditions— gains will inform a subsequent she says, “systems-level interven- as an undergraduate at Princeton can be especially challenging. From study to assess the effectiveness tions in real-world settings will be University, where she designed and the vantage point of the treating of an electronic, shared decision- just as integral as tailored, patient- implemented a randomized, con- physician, uneven adherence com- making tool to engage minority level approaches. Involving minor- trolled trial to compare the effec- plicates the process of tailoring patients in their own treatment. ity patients as stakeholders in tiveness of four behavioral change treatment over time. As the site primary investigator creating interventions is also key.”

28 ColumbiaMedicine A Clear Picture José Luchsinger

ast fall, the National Insti- are recruited from the Washington clinical care. “There are a lot of In addition to brain imaging, the L tute on Aging awarded José Heights neighborhood, because they studies showing that the presence team, which includes Adam Brick- Luchsinger, MD, associate pro- are at higher risk for type 2 diabetes of diabetes is related to various man, PhD, associate professor of fessor of medicine, two fve-year and dementia. His hypothesis is that forms of cognitive impairment, neuropsychology in neurology, and grants: $3,238,671 to investigate diabetes can cause both Alzheimer’s particularly Alzheimer’s,” says Dr. Herman Moreno, MD, of SUNY diabetes status and brain amyloid in disease and stroke and that the Luchsinger, who also has investi- Downstate Medical Center, also middle-aged Hispanics from North- memory impairment common gated the benefts of exercise and a will use mouse models and clinical ern Manhattan and $5,294,619 to among people with type 2 diabetes Mediterranean diet to slow cogni- data from 200 Hispanic study par- pursue interdisciplinary research to is actually the earliest symptom of tive decline among different racial ticipants to explore the hypothesis. understand the relationship among that pathogenic process. Dr. Luchs- “Traditionally, studies looking at diabetes, cerebrovascular disease, inger and his collaborators hope “I’m looking at a this question have looked at older and Alzheimer’s disease. to reveal the biochemical process group in their early people, 70 or 75,” says Dr. Luchs- He focuses on study participants underway and identify therapeutic 60s. That’s the inger. “I’m looking at a group in of Hispanic origins, most of whom targets or biomarkers to enhance best time to see their early 60s. This is important because we hope we’re collecting what’s happening our frst observations before they in the brain, actually manifest the dementia, or instead of waiting when they’re just beginning to have until they already a defcit. That’s the best time to have dementia.” see what’s happening in the brain, instead of waiting until they already and ethnic groups. “Diabetes is have dementia.” also a very well known cause of By examining a broad range of vascular disease, which in the brain data, the team hopes to elucidate translates to strokes. some of the mechanisms explain- “In the clinic, doctors see memory ing the contributions of diabetes, impairment that worsens over time cerebrovascular disease, and and diagnose Alzheimer’s without Alzheimer’s disease to dementia, really knowing for sure if the symp- which disproportionately affects toms are caused by the presence of minorities in Northern Manhattan. amyloid plaques and neurofbrillary “Societies are getting older,” says tangles containing abnormal tau,” Dr. Luchsinger, “and there’s some he adds. The only defnitive diagno- controversy as to whether AD rates sis of the disease, however, depends are stable, getting worse, or getting on autopsy. Emerging imaging better. Regardless, because we’re techniques could allow the team to living much longer and the older defnitively reveal how diabetes cor- population is getting larger, we’re responds to amyloid deposition and absolutely going to have more num- tau formation. “I’m very excited, bers of people with dementia, which because our imaging is going to be affects spouses, families, and chil- unique. Even if we fnd that diabetes dren, and this problem is worse for has nothing to do with the amyloid, minorities, who tend to have fewer that will be very informative.” resources to cope.”

2016 Annual Report ColumbiaMedicine 29 Giving Kids a Chance Jennifer Woo Baidal

ennifer Woo Baidal, MD, was minorities show no signs of fall- program, the New York Obesity enough understood for scientists Ja college freshman working ing. In Washington Heights and Nutrition Research Center, and to explain why some who are as a teacher’s assistant on the Inwood, where Dr. Woo Baidal the National Institute on Minor- merely overweight develop the affuent West Side of Los Angeles investigates strategies to promote ity Health and Health Disparities, disease while some obese individu- when she came across a youngster healthy weight, 47 percent of Dr. Woo Baidal currently serves as als do not, says Dr. Woo Baidal. distressed that his mother had children are overweight or obese. principal investigator on a suite of “If we can reduce the burden of forgotten his snack. Just then, a “At the root of obesity disparities studies intent on developing non- obesity and fatty liver early in woman came dashing across the are a lot of social determinants of invasive techniques to diagnose life, we can have a positive effect playground. “Here you are,” she health like socio-economic status nonalcoholic fatty liver disease, on everything that comes later called, “I packed your favorite— and other inequities,” she says. which afficts 40 percent to 70 by having a healthier workforce, bell peppers.” “I’m looking at the outcome and percent of overweight and obese reducing health care costs, and For Dr. Woo Baidal, raised in thinking about how we best lever- children and can lead to cirrhosis giving children from all back- the lower-income, predominantly age our health care system, insti- and even liver failure. The disease, grounds the chance to start out on tute better practices to really help which disproportionately affects the same foot,” she says. “It’s a “I’m thinking patients who need it the most.” Hispanic children, is not well social justice issue.” about how we In a series of papers published best institute earlier this year—co-authored with her mentor at Harvard, where she better practices earned her MD and a master’s of to really help public health—Dr. Woo Baidal patients who and her colleagues explore “the need it the most.” frst 1,000 days,” from concep- tion through 24 months, a period minority neighborhoods of LA’s that seems critical to modifying East Side, the difference from childhood obesity risk. The team her own childhood was stark. recruited 49 low-income Hispanic “These kids knew the names of women at a federal community fruits and vegetables and they ate health clinic and engaged them so much more healthfully,” says in a series of focus group conver- Dr. Woo Baidal, assistant profes- sations—in Spanish—between sor of pediatrics and director of pregnancies through their chil- pediatric weight management for dren’s second birthdays. To boost the Division of Pediatric Gastroen- retention rates, the team provided terology, Hepatology, and Nutri- stipends for travel and child care tion. “On the East Side, kids were associated with the meetings and eating highly processed foods for hired a bilingual facilitator. “It’s lunch—chicken nuggets, French always a consideration who’s on fries—and ketchup was considered the research staff,” says Dr. Woo a vegetable.” Baidal, “fnding people from National rates of obesity seem diverse backgrounds to connect to have plateaued but remain with research participants.” historically high, and rates of With funding from Colum- overweight and obesity among bia’s KL2 Career Development

30 ColumbiaMedicine School Daze Jennifer Manly

o quantify memory loss over about cognitive function most Ttime, investigators must relevant to the study hypothesis. be able to measure and com- The majority of older Hispanics pare individual function. Yet in recruited by P&S investigators in a study with a diverse sample, Washington Heights, for example, participants’ vocabulary, analyti- grew up in rural communities in cal skills, and spatial skills vary the Dominican Republic. Many broadly—often directly refecting African-American elders living in their life experiences. And those the Northeast attended segregated experiences often refect a per- schools in the South. “The things son’s race, culture, gender, and we think about are, ‘Has this per- socio-economic status. So how is son held a pencil before? Have they a disparities researcher intent on drawn or copied something before? untangling the infuence of nature Does this person know the rules of and nurture to make sense of the scanning a multiple-choice array? data? “If cultural differences get in Do they value—as the people do the way of a person’s performance who developed this test—speed so much that we’re not measur- over accuracy? Have they ever seen ing anything to do with memory,” this visual representation? How says neuropsychologist Jennifer familiar are they with two-dimen- Manly, PhD, “the study’s results will be misleading.” “More time in Dr. Manly has made it her mis- the classroom as sion to impose scientifc rigor on a kid and a lower data collection and analysis asso- student-teacher ciated with cognitive assessments published her work with a team and because kids were expected of African-American and Hispanic ratio translates of investigators from across the to work in the felds. “In general, elders in studies of aging-related into better United States that concluded that the amount of money spent on disparities in multiethnic popula- cognitive function quality of education appears to the school system relates to better tions. “Most of us who see diverse 70 years later.” be more important than cerebro- cognitive function for people who older adults are seeing a lot of vascular risk factors in explaining attended those schools.” different educational experiences sional line drawings to represent differences in memory and execu- A series of studies underway and language competencies,” says three-dimensional visual stimuli?’” tive function between white and collects data on middle-aged study the associate professor of neuro- In the past year, Dr. Manly has African-American older adults. participants to reveal factors that psychology. “There’s always a role co-authored papers that explore “More time in the classroom as a may provide protection against of background and experience in the effect of the Mediterranean kid and a lower student-teacher disparities early in life. “This is terms of what you bring to cogni- diet on brain structure and func- ratio translates into better cogni- a life-course process,” says Dr. tive testing.” tion, the relationship between type tive function 70 years later,” says Manly. “We fnd links between In addition to collecting quan- 2 diabetes and cognitive change, Dr. Manly, noting that Southern cognitive impairment late in life titative data on years of schooling and the association of late-life schools attended by African- and early childhood experiences, and other demographic details depression with cognitive func- American children a generation but a lot of things happen between from study participants, Dr. Manly tion and brain volume. In August ago were open for fewer days each those two points that could confer chooses tests likely to reveal details 2015, Journals of Gerontology year because of lack of funding resilience or vulnerability.” v

2016 Annual Report ColumbiaMedicine 31 Counting Neurons in the Spinal Cord Researchers at Columbia’s Mortimer B. Zuckerman Mind Brain Behavior Institute have Contagious Cancers described new approaches to Seen in Shellfsh identify individual classes of Direct transmission of cancer neurons in the spinal cord. Two among some marine animals papers published in Cell highlight may be more common than how statistical approaches could once thought, suggests a study provide neuroscientists with a published in Nature. A study led critical tool to quantify cellular by Stephen Goff, PhD, the Hig- diversity of any brain region. The gins Professor of Biochemistry research focused on a group of & Molecular Biophysics and neurons in the spinal cord called professor of microbiology & V1 interneurons that orchestrate immunology, in collaboration Highlights the activity and output of motor with researchers from Canada neurons, the class of neurons that and Spain, revealed that in sev- give muscles the power to move. eral species of bivalves, includ- Turning Taste On and Off Researchers looked at these neu- ing mussels, cockles, and clams, In research published in Nature, rons in laboratory mice and were cancer cells spread from animal scientists demonstrated in mice able to distinguish 50 distinct to animal through sea water. The the ability to change the way types of V1 interneurons. cancer, known as disseminated neoplasia, is a leukemia-like dis- something tastes by manipulat- ease that affects bivalves in many ing cells in the brain. In one parts of the world. Until recently, experiment, researchers used direct transmission of cancer optogenetics to activate neurons cells had been observed in only to trick mice into thinking they were tasting bitter or sweet even

two species of mammals. Research when drinking water. “These

experiments formally prove that the sense of taste is completely hardwired, independent of learn- ing or experience,” says Charles S. Zuker, PhD, professor of bio- chemistry & molecular biophys- ics and of neuroscience. 2016

32 ColumbiaMedicine Brain Tumor Differences Cellular ‘Switch’ and the Foundation Research Institute to Pathologists currently determine Perception of Danger create a new type of embryonic if a glioma, the most common In a study published in Science, stem cell that carries a single copy malignant brain tumor, is low- Jayeeta Basu, PhD, then a post- of the human genome. It is the frst grade or high-grade based on doctoral fellow in the laboratory time human cells have been known the tissue’s appearance under of neuroscience chair Steven to be capable of cell division with the microscope. Research pub- Siegelbaum, PhD, examined how just one copy of the parent cell’s lished in Cell explains why some a cellular circuit in a mouse helps genome. The researchers were able patients diagnosed with slow- the brain remember which envi- to show that these haploid cells growing or low-grade tumors ronments are safe or harmful. were pluripotent or able to differ- succumb to the disease faster The fndings suggest that disrup- entiate into many other cell types, than those with more aggressive Drug Activates Brain’s tions in neural pathways may including heart, nerve, and pancre- tumors. Researchers analyzed ‘Garbage Disposal’ contribute to an inappropriate atic cells, while retaining a single samples to look for epigenetic To remain healthy, brain cells fear response, a key characteristic set of chromosomes. The fndings, changes in the tumors’ DNA. must continually clear out old, of conditions such as anxiety or published in Nature, show the They found that DNA methyla- worn, or damaged proteins, a task post-traumatic stress disorder. potential for the cells to be used to tion levels might infuence tumor performed by a small molecular develop cell-based therapies for dis- progression. Co-senior author cylinder called the proteasome. Protein ‘ aptor’ Prevents eases in which genetically identical Antonio Iavarone, MD, professor The proteasome acts as a kind Fatty Liver Disease cells offer a therapeutic advantage. of neurology and of pathology & of garbage disposal, but in neu- Researchers at Columbia’s Naomi cell biology, says the results may rodegenerative diseases such as Berrie Diabetes Center have identi- Fighting ‘Superbugs’ help identify patients who require Alzheimer’s, Parkinson’s, and fed a pathway that prevents insulin Bugs like E. coli, Salmonella, more aggressive treatment. Huntington’s, proteins tagged or insulin-sensitizing therapy from and Klebsiella pneumoniae—all for destruction accumulate in causing fatty liver without getting gram-negative bacteria—alter the brain’s neurons, suggesting rid of the favorable effects of insulin their electrostatic charge to evade that the cell’s proteasomes are to reduce blood sugar. They found detection by polymyxin antibiot- impaired. Researchers identifed a protein called Raptor that exists ics, our last line of defense against a new way to activate the brain’s within a protein complex known some “superbug” infections. garbage disposal system, success- as mTORC1 that is involved in cell Researchers using high-resolution fully using a drug to activate the growth and cell differentiation. “As imaging techniques to peer inside system and slow down disease it turns out, young healthy mice— the bacteria have found places in a mouse model. Even though and, we assume, young, healthy where drugs could disrupt the the drug used in the research, people—have a lot of this free Rap- bugs’ defense and restore their rolipram, is not a good drug for tor,” says Utpal Pajvani, MD, PhD, susceptibility to powerful antibi- humans because it causes nausea, assistant professor of medicine. otics. Bacteria become resistant similar drugs without that side “As mice age or get fat, free Raptor to polymyxins by placing a cap, effect could be tested, says study disappears. When free Raptor dis- made from a sugar molecule, over leader Karen E. Duff, PhD, pro- appears, mice get fatty liver. If you the negative charge, altering the fessor of pathology & cell biology give them back free Raptor, fatty electrostatic forces between bac- (in psychiatry and in the Taub liver goes away but leaves insulin’s teria and antibiotics. An enzyme Institute for Research on Alzheim- ability to lower blood sugar intact.” called ArnT in the membrane of er’s Disease and the Aging Brain). bacteria is responsible for the cap- “This has the potential to open New Embryonic Stem Cell ping. The researchers were able to up new avenues of treatment for P&S partnered with researchers at visualize the precise details of the Alzheimer’s and many other neu- the Hebrew University of Jerusa- process by using X-ray crystal- rodegenerative diseases.” lem and the New York Stem Cell lography to reveal the location of

2016 Annual Report ColumbiaMedicine 33 2016 Research Highlights

each individual atom in the ArnT researchers found that defcits in as a hormone. Their newest studies formed the Observational Health enzyme before and after it grabs social memory, the inability to show that osteocalcin has a pro- Data Sciences and Informatics the sugar. Because the images recognize familiar faces, may be found effect on muscle and exer- program, which allows research- reveal places where the enzyme due to a decrease in the number cise capacity. When the hormone is ers to combine and analyze patient could be disabled, the researchers of inhibitory neurons in a little- injected into old mice, the animals data from widely different sources are using computerized techniques explored region within the brain’s are able to run as far and as fast as in the United States and abroad. to screen millions of potential memory center. “We can now young mice. The researchers found Columbia University serves as the drug candidates that might work examine the effects of schizophre- that osteocalcin is able to improve program’s coordinating center. with polymyxins to eliminate nia at the cellular level and at the exercise capacity by increasing the antibiotic-resistant bacteria. behavioral level,” says Steven amount of glucose and fatty acids New Mouse Model Siegelbaum, PhD, chair of neuro- that skeletal muscle can take in of Anorexia Understanding Schizophrenia science, who led this study along and consume during exercise. Columbia researchers have P&S and Mortimer B. Zuckerman with Dr. Gogos. “This essentially described a new mouse model that Mind Brain Behavior Institute opens up a whole new avenue for Clinical Practice features a combination of genetic investigators made signifcant research that could lead to earlier by the Numbers and environmental risk factors fndings in schizophrenia this year. diagnosis and more effective treat- An international observational that can trigger the compulsive Zuckerman Institute research- ments for schizophrenia.” A study study has uncovered widespread restriction of food intake seen in ers Joseph Gogos, MD, PhD, by P&S and New York State differences in the treatment of patients with anorexia nervosa. and Joshua Gordon, MD, PhD, Psychiatric Institute researchers, patients with common chronic Previous models of anorexia successfully disrupted a genetic this one published in Biological diseases, including type 2 diabetes, included some of the variables Psychiatry, identifed a pattern of hypertension, and depression. thought to raise the risk of brain activity that may be a sign Using data from 250 million anorexia (genetic, biological, psy- of memory problems in people records of patients from four coun- chological, and sociocultural), but with schizophrenia. The research tries, researchers demonstrated the no model captured the elements for the frst time linked a brain feasibility of performing large-scale of social stress and genetic suscep- signal in the dorsolateral prefron- observational research to obtain tibility to anxiety and anorexia tal cortex directly to working information about clinical practice that appear to contribute to the memory performance in patients among diverse groups of patients. onset of the disorder in humans, with schizophrenia. “We found that while the world particularly in adolescents. “This is moving toward more consistent model not only shows us the most Turning Back Time therapy over time for the three dis- important factors that contribute As people reach their 30s and eases, there remain signifcant dif- to the onset of anorexia, it’s also 40s, muscle strength and endur- ferences in how they are treated,” helping us to identify signaling ance decline. New research now says George Hripcsak, MD, the pathways in the brain that ulti- suggests that changes in a protein chair and Vivian Beaumont Allen mately drive this potentially fatal from bones may be partly respon- Professor of Biomedical Informat- eating disorder,” says study leader chain of events in a mouse model sible. Researchers in the lab of ics. Observational research, in Lori Zeltser, PhD, associate profes- of schizophrenia and reversed Gerard Karsenty, MD, PhD, chair which patterns of care are gleaned sor of pathology & cell biology. memory defcits, one of the dis- and the Paul A. Marks Professor from large data sets—such as elec- For the new mouse model, the order’s most diffcult-to-treat of Genetics & Development and tronic health records, insurance researchers exposed adolescent symptoms. In a paper published in professor of medicine, years ago claims, and pharmacy records—has mice with at least one copy of a Neuron, scientists used a chemical discovered that osteocalcin, a pro- the potential to offer insight into variant of the BDNF gene, which compound to regrow connections tein that is produced by bone cells real-world treatment scenarios that has been associated with anorexia between neurons, which in turn in both mice and humans, is pres- may inform clinical trial design and anxiety in mice and humans, restored memory. In another study ent in the bloodstream and deliv- and, ultimately, clinical practice. and also exposed the mice to social published in Neuron, Zuckerman ered to other organs where it acts An international group of scientists stress and caloric restriction.

34 ColumbiaMedicine Killing Drug- esistant Bacteria Alternative to Heart Disease isk Scientists from Columbia’s Center Open Heart Surgery and Sleep Apnea for Radiological Research have A study conducted by the Colum- For millions of adults, obstruc- shown that a narrow wavelength bia Heart Valve Center found that tive sleep apnea results in sleep

Highlights of ultraviolet light killed drug- women undergoing transcath- disruption and then daytime resistant MRSA bacteria in mice, eter aortic valve replacement— sleepiness and diffculty concen- demonstrating a potentially safe TAVR—have better survival rates trating. Sleep apnea also triples and cost-effective way to reduce than men one year after the pro- the risk for developing heart surgical site infections. A par- cedure. The results, published in disease, including hypertension ticular wavelength of UV light the Annals of Internal Medicine, and ischemic stroke. A study has known as “far-UVC” is as effec- are opposite of results seen in revealed some of the underlying tive as conventional germicidal surgical aortic valve replacement, mechanisms that may increase the UV light in killing MRSA, as for which women had poorer out- risk and also found that statins Clinical shown in a previous study, but comes. Another Columbia study, may reverse the process. “We

the new study shows for the frst published in the New England were surprised to discover that time that, unlike conventional Journal of Medicine, showed that these commonly prescribed drugs germicidal UV, far-UVC does TAVR is a viable alternative to appeared to reverse the process not cause biological damage to traditional open heart surgery for that leads to vascular injury, and exposed skin, reports David J. patients with severe aortic stenosis ultimately heart disease, in people Brenner, PhD, the Higgins Profes- at intermediate risk for surgery. with sleep apnea,” says Sanja sor of Radiation Biophysics and Jelic, MD, associate professor of director of the Center for Radio- medicine at CUMC. logical Research. 2016

2016 Annual Reportt ColumbiaColumbiaMedicineMedicine 3535 2016 Clinical Highlights

Steroids Beneft Late also have other health problems, kines than adults. The results sug- of animal studies have suggested Preterm Babies including neurodevelopmental gest that health offcials may be that exposure to commonly used Babies born to women at risk for disorders and other congenital able to enhance the effectiveness anesthetic agents in early devel- late preterm delivery may beneft problems. Researchers looked of vaccines given in early infancy, opment could lead to defcits in from corticosteroids, reports new at genetic information from says author Donna Farber, PhD, learning, memory, attention, and research published in the New 1,213 children with congenital professor of surgical sciences other cognitive functions,” says England Journal of Medicine. heart disease and their parents to (in surgery and microbiology Lena S. Sun, MD, the Emanuel Cynthia Gyamf-Bannerman, analyze more than 4,000 genes. & immunology). M. Papper Professor of Pediatric MD, the Ellen Jacobson Levine After comparing the fndings Anesthesiology and professor and Eugene Jacobson Associate with data on families not affected Model Cancer Care of pediatrics at CUMC. “How- Professor of Women’s Health by congenital heart disease, the The Centers for Medicare & ever, few clinical studies have (in Obstetrics & Gynecology), researchers showed that many Medicaid Services selected adequately addressed whether found that babies whose moth- children with congenital heart Columbia, NewYork-Presbyte- this is also true in humans. Based ers received the corticosteroid disease had spontaneous muta- rian Hospital, and Weill Cornell on our fndings, we can reas- betamethasone had signifcantly tions in heart development genes. Medical College to participate sure parents that one exposure lower rates of severe respiratory A single genetic mutation was in a care delivery model that to anesthesia is safe for healthy complications shortly after birth responsible for about 20 percent supports and encourages higher young children.” compared with those whose moth- of cases of severe congenital heart quality, more coordinated cancer ers received a placebo. Babies in disease accompanied by neuro- care. Nearly 200 physician group Pioneering Public-Private the study’s treatment group also developmental disorders and/ practices and 17 health insurance Cancer Initiative were signifcantly less likely to or other congenital problems. companies are participating in the Columbia’s Herbert Irving Com- require long-term stays in the Mutations in children born with Medicare arm of the Oncology prehensive Cancer Center is one hospital’s NICU or require respi- a combination of heart, brain, Care Model, which includes more of four cancer centers that have ratory treatment. Since the early and other congenital disorders than 3,200 oncologists and will formed a research consortium 1990s, corticosteroids have been occurred in a subset of genes that cover approximately 155,000 to accelerate the discovery and used in mothers at risk of deliver- act like conductors, orchestrat- Medicare benefciaries nation- development of novel cancer ing before 34 weeks of gestation ing the formation and function wide. Participants in the fve-year therapeutics and diagnostics. The to accelerate the development of of organs. Knowing these links Oncology Care Model will pro- four cancer centers also entered the baby’s lungs, but research- could help doctors predict risk vide treatment following nation- into public-private collaboration ers believed that corticosteroids and may allow interventions to ally recognized clinical guidelines agreements with Celgene Corpo- were unnecessary for later pre- be put in place while the brain is for benefciaries undergoing che- ration in which Celgene will pay term births because 99 percent of still developing. motherapy, with an emphasis on each institution $12.5 million for babies born after 34 to 35 weeks person-centered care. the option to enter into future survive. Research shows that even Infants, Immune System, agreements to develop and com- infants born during the “late” and Vaccines Safety of Anesthesia mercialize novel cancer therapeu- preterm period (between 34 and A study published in Nature for the Young tics arising from the consortium’s 36 weeks) have increased neonatal Medicine provides new insights Columbia participated in a mul- efforts. Over the next 10 years and childhood respiratory compli- into how the infant immune sys- ticenter study that found that a the institutions plan to present cations compared with newborns tem functions and suggests strate- single exposure to general anes- research programs to Celgene born at 37 weeks or later. gies for enhancing vaccination thesia poses no cognitive risk with the goal of developing new programs. Researchers took tissue to healthy children under age life-saving therapeutics. Precision Medicine Tools from 64 organ donors to measure 3. Findings from the Pediatric Link Congenital Disorders T cells and found that children Anesthesia Neurodevelopment Surgical Treatment A study published in Science under age 2 had more regulatory Assessment study were published for Spasticity explains why many children T cells in their tissues and lower in the Journal of the American Spasticity, an involuntary with congenital heart disease levels of infection-fghting cyto- Medical Association. “A number stretching refex that stiffens

3636 ColumbiaColumbiaMedicineMedicine 467-Gene Cancer Panel The New York State Department of Health approved the Columbia Combined Cancer Panel, which queries 467 cancer-related genes. The panel was designed by the Lab- oratory of Personalized Genomic Medicine at CUMC in collabora- tion with Columbia oncologists.

muscles, is a common problem as part of the Electronic Medical Columbia study published in the those who received counsel- for people with cerebral palsy. Records and Genomics Network American Journal of Geriatric ing and referrals to community One way to reduce spasticity is administered by the National Psychiatry found that adults who treatment centers without the with a procedure called selec- Human Genome Research Insti- used a hearing aid performed injections. “Medications like tive dorsal rhizotomy, in which tute. The goal is to combine signifcantly better on cognitive methadone and buprenorphine a surgeon disconnects overactive genetic data with electronic medi- tests. The study showed that have proved essential to the sensory nerves that tell muscles cal record systems to improve adults with hearing loss who treatment of opioid dependence,” to contract. CUMC is one of diagnosis, disease risk assessment, used a hearing aid performed notes study co-author Edward only a few medical centers in prevention strategies, and treat- signifcantly better on the Mini- V. Nunes, MD, professor of psy- the United States to offer a less- ment options. Researchers will Mental State Examination, in chiatry at CUMC. “But people invasive procedure that reaches look for new disease-causing which participants give vocal with opioid dependence are bet- the crucial sensory nerve roots by variations in about 100 genes responses to verbal commands. ter served by having a range of removing a much smaller piece that have been linked to cancer, The research suggests that using options to prevent relapse and of bone from the spine than is cardiovascular disease, stroke, a hearing aid could prevent or reduce the risk of death from standard. Once the nerve roots kidney disease, and other health slow the development of demen- overdose. Naltrexone injections are accessible, the surgeon uses problems. The research is led by tia, says Anil K. Lalwani, MD, offer another effective therapeu- electrical signals to differentiate principal investigators Chunhua professor of otolaryngology/head tic option for people struggling motor nerve roots from sensory Weng, PhD, associate profes- & neck surgery. with opioid addiction in a variety nerve roots and determine which sor of biomedical informatics; of settings.” sensory nerves are causing the George Hripcsak, MD, the Viv- Treating Opioid Addiction most spasticity. Physical and ian Beaumont Allen Professor of Opioid addiction is a growing New Option for Some occupational therapists in the OR Biomedical Informatics and chair problem in the general popula- Forms of Lung Cancer confrm the results before the sur- of biomedical informatics; and Ali tion, but it is disproportionately The FDA approval of pembroli- geon disconnects any nerve roots. Gharavi, MD, professor of medi- high in prison populations. A zumab (brand name Keytruda) cine and chief of nephrology. study published in the New Eng- provides a new immunotherapy Combining Genomic land Journal of Medicine found option to treat some patients Information and Slowing Cognitive Decline that ex-prisoners who received with metastatic non-small cell Electronic ecords with Hearing Aids six monthly injections of naltrex- lung cancer. “The durability of A group of researchers will Though more than half of adults one, a long-acting medication response with immune check- incorporate genomic information over the age of 75 have hearing that blocks opioid receptors in point inhibitors is exciting and into electronic health records for loss, less than 15 percent of this the brain, were signifcantly less has given new options for our thousands of Columbia patients population uses a hearing aid. A likely to resume opioid use than patients,” says Naiyer Rizvi, MD,

2016 Annual Reportt ColumbiaColumbiaMedicineMedicine 3737 2016 Clinical Highlights

professor of medicine at CUMC atrics and of pathology & cell neurotransmission. Drs. Margo- and director of thoracic oncology, biology, found that acalabru- lis and Gershon discovered that who was a principal investigator tinib has less effect on platelet these mice have fewer neurons for Keytruda clinical research. function than ibrutinib because than normally found in the gut, the drug hits its target with a poorly maintained gut lining, Fecal Transplants greater precision. Both drugs are and slower movement of gut con- Treat Severe C. Diff designed to inhibit the cancer- tents. Dr. Margolis says families Cases of Clostridium diffcile infec- promoting molecule Bruton’s and physicians should recognize tions are hard to treat, but several tyrosine kinase, but ibrutinib that gastrointestinal problems are children with recurrent C. diff have also blocks molecules essential common in children with autism, been treated at Columbia with to platelet function, which can who may present in a different transplants involving an infusion of cause hemorrhaging. way. “Often, they’re not verbal a fecal preparation from a healthy or they have sensory issues so donor into the patient’s gastroin- Autism and GI Problems they can’t pinpoint where the testinal tract. The goal is to replace Children with autism spectrum pain is coming from. It’s impor- harmful microbiota with bacteria disorder are four times more tant that when these patients that support a healthy gastrointes- likely to suffer from gastrointesti- present with distress or behav- tinal milieu. “The families we have nal problems than other children. ioral problems, a gastrointestinal worked with describe the therapy A study published in the Journal source is considered.” Highlights as life-changing,” says Norelle of Clinical Investigation found Reilly, MD, director of the pedi- evidence in mice that in some Treatment- esistant atric celiac disease program and types of autism, gastrointestinal Schizophrenia assistant professor of pediatrics. diffculties may originate from the A study published in the Ameri- “Many of the children we have same genetic changes attributed to can Journal of Psychiatry looked treated have experienced years of behavioral and social characteris- at the use of clozapine for patients refractory C. diff infection. It is tics of the disorder. “Because sero- with treatment-resistant schizo- gratifying to be able to intervene in tonin plays an important role in phrenia, which accounts for 30 such a novel and meaningful way.” the gastrointestinal system as well percent of schizophrenia cases. as the brain, we wanted to see Even though clozapine is the Leukemia Drug with if there was a direct relationship only medication approved by Fewer Side Effects between these genes and GI devel- the FDA for treatment-resistant While the cancer drug ibrutinib opment and function,” says Kara schizophrenia, the drug is seen as has signifcantly improved treat- Margolis, MD, associate profes- a last resort and its use in clinical ment for patients with chronic sor of pediatrics, who conducted practice has not been studied in lymphocytic leukemia, it may the study with Michael Gershon, depth. The results of a study led Education increase the risk of bleeding, MD, professor of pathology by T. Scott Stroup, MD, professor particularly in older patients who & cell biology. The researchers of psychiatry, found that patients are taking blood thinners for investigated gastrointestinal devel- with schizophrenia who do not heart disease. A study published opment in a mouse model that respond to standard antipsychotic in the New England Journal of carries a mutation found in some medications have better outcomes Medicine suggests that a similar patients with autism. The muta- if they switch to clozapine instead class of drug, acalabrutinib, has tion decreases serotonin activity of another standard antipsychotic. the same cancer-fghting ability by increasing the activity of the They have fewer hospitaliza- as ibrutinib but reduces the risk serotonin reuptake transporter, tions, stay on the new medication of bleeding. Thomas Diacovo, which pulls serotonin back into longer, and are less likely to need

MD, associate professor of pedi- the neuron after it is released for additional antipsychotics. 2016

3838 ColumbiaColumbiaMedicineMedicine A New Medical School The frst graduates are Siyan dents also gain valuable practice in Lesotho “Stewart” Cao, who matched to applying deep sequencing tech- P&S student Dylan O’Connor’17 an internal medicine residency nologies. “We ask students to contributed to the develop- at UCSF, and Matthew Fleming, fnd a question that has never ment of a new medical school in who matched to an internal medi- been systematically investigated the southern African nation of cine residency at Vanderbilt. before,” says one of the course Lesotho with a hands-on inter- designers, assistant professor national project that satisfed his Student-Led Events Highlight Scholarly Project Yufeng Shen, PhD. “We believe passion for global health and Health Care Issues Impacts Clerkship the best training is to solve a real Medical students hosted and Emily Woodbury’16 not only world problem using the arsenal participated in several national satisfed her scholarly project of experimental and computa- health care events this year. The requirement, she also made an tional knowledge that they take events they organized helped impact on the obstetrics & gyne- away from the lectures.” broaden their understanding of cology clerkship. The scholarly topics such as health care reform, project requirement gives stu- Asylum Clinic human rights, and new technolo- dents a chance to delve into top- The Asylum Clinic, part of the gies, including mobile diagnostic ics that most interest them. For P&S Human Rights Initiative, technologies. Universal health Dr. Woodbury it was a chance to is one of several learning and care was a focus for students engage and mentor medical stu- community service opportunities across the nation at the #TenOne dents in ob/gyn. She worked with for medical students. The clinic development. “When I came to National Medicare-for-All Stu- the clerkship’s director to pilot is among a group of student- Columbia, I knew that global dent Day of Action on Oct. 1. a new ob/gyn rotation, which health was going to be part of my Human rights work was the focus included a new set of interactive package,” says Mr. O’Connor. at the 2015 Physicians for Human lectures. To maximize opportuni- “My experience in Lesotho was Rights National Student Con- ties for students to observe how truly transformative. It showed ference, hosted by P&S, where ob/gyn care is practiced, the new me why it’s important for institu- students discussed medicine, clerkship consolidates the num- tions like Columbia to guide the economics, law, sociology, and ber of days a student performs development of new schools.” each activity and increases the Mr. O’Connor worked with the amount of time spent with each dean of the new Lesotho School clinical team. of Medicine to develop a cur- riculum that would help address Teaching Next-Generation the shortage of doctors in sub- Tools to the Next Generation run clinics that offer students Saharan Africa. A new multidisciplinary, gradu- the opportunity to work with ate-level course organized by the underserved populations to help The Newest MD/PhDs Department of Systems Biology alleviate health care disparities The frst two enrollees in a is helping young investigators afficting minority, immigrant, PhD-to-MD program graduated incorporate new genomics tools and low-income populations. in May 2016. The three-year into their research. The course The Asylum Clinic helps asylum program was launched to give humanitarianism. The P&S Inno- covers both the experimental seekers in the New York City PhD-trained research scientists an vative Medicine Interest Group principles of next-generation metropolitan area gain access to opportunity to move through an hosted the second annual Inno- sequencing and key statisti- pro bono medical evaluations; accelerated medical school cur- vateMED conference with student cal methods for analyzing the medical affdavits are thought to riculum that would prepare them leaders in health and medicine enormous datasets that such considerably increase the chance for careers as physician-scientists. presenting a TED-style event. technologies produce. The stu- of receiving asylum.

2016 Annual Report ColumbiaMedicine 39  PHILANTHR PY NEWS

HELP FROM OUR FRIENDS Numerous individuals and foundations have advanced the P&S missions over this past fscal year, with philanthropic donations exceeding $200 million. Below are just a few of the projects that have benefted from the generosity of donors.

Junior Faculty in Endocrinology Psychiatric Care for At- isk Children The Thomas L. Kempner Jr. Founda- tion has pledged $1.2 million to support The Viola W. Bernard Foundation has junior investigators in the Department of given $1.1 million to support programs Medicine’s Division of Endocrinology. The in the Department of Psychiatry’s gift honors Elizabeth Shane, MD, profes- Division of Child and Adolescent sor of medicine, vice chair for clinical and Psychiatry. The gift will advance efforts epidemiological research, and associate in research, training for child psychia- dean for student research. The gift will try fellows and faculty, and clinical provide salary and administrative support services with an emphasis on the for junior faculty to conduct research in needs of children osteoporosis, helping young physician-sci- in underserved The Kempner Foundation has supported several Department of Medicine junior investigators through current and previous entists establish a career path in research communities. It gifts. Some of those recipients, from left: Emily M. Stein, Serge while strengthening the division’s ability represents a sig- Cremers, Thuy-Tien Dam, Kyle K. Nishiyama, Mishaela R. to retain and recruit the most promising nifcant expansion Rubin, Thomas Nickolas, and Natalie E. Cusano. young endocrinologists. of an endowed fund established at Columbia in Allen I. Hyman Establishes Professorship 1982 to provide permanent support Viola W. Bernard Allen I. Hyman, MD, professor emeritus for the Division of of anesthesiology at P&S, has established Child and Adolescent Psychiatry. The the Allen I. Hyman, MD, Professorship fund honors and extends the legacy of Critical Care Anesthesiology. Through of Viola W. Bernard, MD, a longtime his clinical, investigative, and advisory P&S psychiatry faculty member who work, Dr. Hyman played a lead role in died in 1998. Dr. Bernard, who was shaping critical care anesthesiology at associated with Columbia for more Columbia, and this gift represents his than fve decades, dedicated her career additional investment in the future of the in psychiatry to understanding and feld. The current holder of the Hyman helping adopted and foster children. Professorship is Vivek K. Moitra, MD, An authority on community and social chief of the Division of Critical Care in psychiatry, child psychiatry, and adop- the Department of Anesthesiology and tion, she played an important role in medical director of the cardiothoracic Allen Hyman, center, with his wife, Valerie, the evolution of Columbia’s Division of and P&S Dean Lee Goldman and surgical intensive care units. Child and Adolescent Psychiatry.

40 ColumbiaMedicine Advancing Nurture Science

The Einhorn Family Charitable Trust opment. Previous research conducted has made a commitment to support by program researchers showed that the CUMC Nurture Science Program, mother-child communication begins which plans to roll out a major initia- before birth, conditioning the bodies tive to develop, test, and disseminate of both mother and child to respond nurture-based therapies for U.S. to each other throughout develop- health care providers. The goal of the ment. Mother and child continue to initiative is to provide families across draw on these responses after birth the country with easy-to-follow tech- to achieve a state of emotional and niques that prevent emotional, behav- physiological co-regulation. The ioral, and developmental problems in program has developed a parenting children. The program has received strategy to establish and maintain longstanding support from the Ein- this state of co-regulation and is horn Family Charitable Trust, which working to introduce therapies based supported the program’s launch. on this concept in a variety of health Under the leadership of director Mar- care settings. The Einhorn Trust’s tha G. Welch, MD, and co-director latest gift includes $6 million desig- Michael M. Myers, PhD, the Nurture nated as matching funds. Columbia Science Program has established a sci- and the Nurture Science Program Tyler and Kate Ilie, with their baby, Caroline, entifc link between family emotional have until 2020 to raise $6 million benefted from the Nurture Science Program. connection and healthy child devel- from other sources.

Support for Cardiology Pediatric Precision Medicine

The Mallah Family Foundation has committed $2.5 million to The Sohn Conference Foundation is giving CUMC a $1.5 million grant establish the Mallah Family Professorship of Cardiology in the over three years to establish a pediatric oncology precision medicine pro- Department of Medicine’s Division of Cardiology. The gift hon- gram that provides immediate access to next-generation genomic technolo- ors Allan Schwartz, MD, chief of the Division of Cardiology, and gies for pediatric cancer patients throughout New York City. The goal of the will enhance the division’s ability to recruit and retain outstand- program is to demonstrate the value of the platform to insurers and regula- ing cardiologists whose goal is to provide a holistic approach to tory bodies and to advocate for policy changes to cover these approaches the care of cardiac patients, specifcally geriatric patients. for future patients. At a January 2016 press event to announce the program, Evan Sohn, vice president and co-founder of the foundation, joined CUMC leadership in discussing the importance of translational research to develop- Substance Abuse esearch and Awareness ing a new generation of targeted treatments for pediatric cancer.

The Eric D. Hadar Family Foundation has committed $2 million to support the Division on Substance Abuse within the Depart- Translational Neuroscience ment of Psychiatry. The gift will establish an endowed fund of $750,000 for the Eric D. Hadar Distinguished Lecture, an The Belle and Murray Nathan Philanthropic Fund gave $2.5 million through annual lecture series focused on substance abuse, and $1.25 mil- the Jewish Communal Fund to establish the Belle and Murray Nathan Profes- lion for the Eric D. Hadar Research Fund, which will advance sorship of Neurology. This professorship, named in memory of Columbia research by providing resources for fellowship and faculty College alumni Belle and Murray Nathan, will support a faculty member support, research projects, and laboratory infrastructure. The specializing in translational neuroscience, including the genetics of neurode- inaugural Eric D. Hadar Distinguished Lecture is scheduled for generative diseases. This gift is just one example of the Nathans’ longtime Nov. 2, 2016. This gift represents the foundation’s frst signif- commitment to Columbia and to medical research. Belle and Murray Nathan cant gift since its formation late last year. The foundation plans also established a scholarship at Columbia College and a lecture series at to announce additional support targeted toward substance abuse Columbia’s law school and have funded scientifc research at other institu- research and treatment, with an emphasis on inner city children. tions, including Ben Gurion University.

2016 Annual Report ColumbiaMedicine 41 News from around the College of PhysiciansPS& news & Surgeons PS& news

New Building pens to Fanfare (and a Few Healthy Babies)

PHOTOGR PHS BY NIC LEHOUX, COURTESY OF DILLER SCOFIDIO + RENFRO

42 ColumbiaMedicine ost building dedications follow a traditional and receive immediate feedback through the use of one- agenda: a ceremonial ribbon-cutting, tours way mirrors and video monitors that will allow teachers M of the facilities, photo opportunities, and to observe and comment on student performance. Video cocktail conversations. The June 9 dedication of the new recording is available from multiple angles. medical and graduate education building—the Roy and It was in the simulation center on the night of the Diana Vagelos Education Center—had an added fea- dedication that invitees veered from the traditional ture when participants were invited to test their clinical ribbon-cutting agenda. In the labor and delivery suite, expertise in the building’s simulation center. dedication attendees practiced delivering babies. “I The centerpiece of the building is the simulation cen- would estimate that we had about 15 deliveries in the ter, four foors covering 18,000 square feet and includ- span of three hours,” says Leslie Moroz, MD, a clini- ing standardized patient exam rooms, mock emergency cal fellow in maternal-fetal medicine and critical care. rooms, and surgical suites. Students will use the center’s “Our obstetricians-in-training ranged in age from 7 to advanced equipment and software to hone clinical skills 70 years old. Sim Mom looked tired but happy at the

Built for Success

IN DDITION TO THE SIMUL TION CENTER, N MED FOR M RY J H RIS ND HER L TE HUSB ND, MICH EL J H RIS, THE BUILDING INCLUDES: · multipurpose auditorium, a 270-seat fexible space for lectures, screenings, and concerts · “ cademic Neighborhoods,” groups of classrooms that can be confgured according to need by partitions, drop-down screens, large-scale multi-user touch screens, and suspended ceilings · “ natomy Quad,” a fexible learning space with integrated screens and task lighting · Ground foor lobby and café, which adjoin a “study bar” with views of the Palisades · Student Commons, which features a café, computer work area, and computer labs · South and West Courts, outdoor spaces featuring local plant species

2016 Annual Report ColumbiaMedicine 43 PS& news

patient’s life by assisting the team in adjusting the settings of cardiac bypass and learning how to initiate ECMO.” Left: Pictured at the dedication of the Vagelos The new building, which offcially opened in August Education Center—in when the Class of 2020 matriculated, is named for the cou- front of a wall that spells ple who provided the lead gift for the building’s construc- out the Hippocratic Oath—are, from left, tion, Diana and P. Roy Vagelos, a 1954 graduate of P&S. Roy Vagelos, Columbia Other major donors on hand at the June dedication were University President Lee Bollinger, building Cheryl and Philip Milstein; Kathryn and Mary Jaharis, designer Elizabeth Diller, representing the Jaharis family; Roger Wu and David Wu, Philip Milstein, and P&S representing their parents, the late Helen and Clyde Wu; Dean Lee Goldman. and Sudhir, Anita, and Dhairya Choudhrie, representing the Choudhrie Family Foundation.

BRI N HTTON PHOTOGR PHY The 14-story glass tower, designed by Diller Scofdio + Renfro in col- end of the evening, and all of the babies went to the laboration with Gensler as executive Vagelos Education Center well-baby nursery.” architect, features a distinctive cas- Visionary Leaders In the simulation center’s operating room, dedication cade design that creates fexible social TOP DONORS TO THE V GELOS CENTER: participants were introduced to a scenario of a 56-year- spaces to facilitate team-based learn- old male undergoing heart-lung bypass for coronary ing. The building’s 100,000 square · The Russell Berrie Foundation artery bypass grafting surgery. The patient was under the feet of technologically advanced · Margo and John . Catsimatidis care of a surgeon, an anesthesiologist, and a perfusionist classrooms and collaborative spaces · The Choudhrie Family Foundation during the procedure. After the patient came off bypass, integrates a range of environmentally · Mary and Michael Jaharis his oxygenation deteriorated and he required emergency sustainable features, including locally · Merck & Co. Inc. initiation of extracorporeal membrane oxygenation— sourced materials, green roof tech- · Cheryl and Philip Milstein Family ECMO—to save his life. “It was exciting to showcase nologies, and an innovative mechani- · P. Roy Vagelos, MD P&S ‘54, and Diana T. Vagelos · Clyde Wu, MD P&S ‘56, and Helen Wu the simulator’s capabilities throughout the evening,” says cal system to minimize energy and · George D. Yancopoulos, MD, PhD P&S ‘87 Cara Agerstrand, MD, assistant director of the medical water use. Construction on the build- ECMO program. “Attendees participated in saving the ing began in 2013.

New Chair, Initiative Director Named

Two leadership appointments were made this year. Ansgar Brambrink, MD, PhD, was named chair of the Department of Anesthesiology, and Emmanuelle Passegué, PhD, was appointed director of the Columbia Stem Cell Initiative, which was launched in 2008 to bring together researchers to explore the potential of using stem cells to improve human health. Dr. Brambrink, who also will serve as anesthesiologist-in-chief at NewYork-Presbyterian/Columbia, succeeds Margaret Wood, MD, who retired after more than 20 years as chair. An internationally renowned expert in brain injury, Dr. Brambrink Ansgar Brambrink, MD, PhD Emmanuelle Passegué, PhD joined P&S after serving as professor and vice chair of faculty develop- ment and advancement in the Department of Anesthesiology and Periop- fornia San Francisco, where she was a tenured professor in the Depart- erative Medicine at Oregon Health & Science University. Dr. Brambrink ment of Medicine’s Division of Hematology/Oncology. received his doctorate and medical degrees from Westfälische Wilhelms- An expert in hematopoietic stem cells, Dr. Passegué was an active mem- University School of Medicine in Germany. ber of the UCSF stem cell program and helped shape its programmatic Dr. Passegué spent 11 years in the Eli and Edythe Broad Center of activities for the past decade. Before joining UCSF, she earned a PhD in Regeneration Medicine and Stem Cell Research at the University of Cali- endocrinology summa cum laude from Paris-XI University.

44 ColumbiaMedicine Grants Support Faculty Diversity Efforts

Six P&S faculty members received support through the Columbia University Provost’s Grants Program for Junior Faculty Who Contribute to the Diversity Goals of the University. The pro- gram is part of a $33 million commitment announced last year to reinforce and expand the University’s faculty diversity efforts. The six faculty members received support during two rounds of funding in 2015-16. Since the program began in 2013, 75 projects throughout the university have been funded. MELI P NICO

The 2015-16 P&S recipients and their project titles: AB UT THE

Targeting Systemic Mediators in Cancer CLASS F 2016

Swarnali Acharyya, PhD 166 MD graduates, 50 percent of them women assistant professor of pathology & cell biology 12 also received PhD degrees (in the Institute for Cancer Genetics) 2 also have MPH degrees

2 were inaugural graduates of the Modulation of Circuit Elements for Motion Detection three-year PhD-to-MD program by Locomotion 2 also received MB degrees from Columbia udy Behnia, PhD assistant professor of neuroscience 2 also have DDS degrees

1 also received an MS degree in biomedical engineering Innovative Models for Delivery of Depression Care 28 took an extra year for research and educing Cardiovascular Disease 29 percent took extra time for either Nathalie Moise, MD research or to complete a dual degree assistant professor of medicine 27 percent went abroad for senior electives or scholarly projects, mostly to developing countries Sex Differences and the ole of Novel Calcium Kinase Signaling 30 students got married during medical school Lale Ozcan, MD assistant professor of medical sciences 20 babies were born to students in the class (in medicine) during medical school, and three students had two children during medical school

Graduates completed 55 triathlons or full or half marathons Immune Editing of Glioblastoma Genome During Tumor Progression 47 percent matched to residencies in New York City Adam Sonabend, MD assistant professor of neurological surgery 26.7 percent matched at Columbia for all or part of their training

11 couples participated in the match, including Understanding the Molecular Pathobiology of ight Ventricular 4 in which both were P&S students Dysfunction as a Determinant of Gender Differences in Heart Failure One-third of the class volunteered as senior Emily Tsai, MD student advisers for the class below assistant professor of medicine Many members of the class volunteered for one of the fve student-run free clinics

2016 Annual Reportt ColumbiaColumbiaMedicineMedicine 4545 PS& news

New Academy Recognizes Clinical Excellence

P&S has launched the Academy of Clinical Men- toring and Excellence to measure, recognize, and reward achievements of clinical faculty members who contribute to the school predominantly through patient care. “P&S is ranked consistently among the best U.S. medical schools and is one of the most research intensive, but we also are home to excellence in clinical care in more than 230 medical special- ties and subspecialties,” says Dean Lee Goldman, MD. “The creation of the academy is a way of honoring our faculty who have achieved the very best in patient care. Excellence in clinical care combines compassion with knowledge informed by research, evidence-based practices, and experi- ence to beneft patients and their families.” Adds James McKiernan, MD, the John K. Lat- timer Professor of Urology, chair of the Depart- ment of Urology, and chair of the P&S faculty

committee that developed the academy: “Mem- JÖRG MEYER bership in the academy will honor our expert Columbia clinicians and provide opportunities for and have been at CUMC for at least the past fve “The creation of the academy enables P&S to inductees to also serve the academy as teachers, years. Inductees will have devoted more than 50 honor and foster what makes these faculty mem- mentors, and champions of clinical excellence.” percent of their time to patient care and training bers so special. They have qualities as clinicians Induction into the academy will take place the next generation of clinicians. In 2017, after the that make you want them treating yourself, your annually with an awards ceremony and lecture. inaugural class, nominations for membership will family member, or close friends,” says Robert In its inaugural year, the academy will induct its be made by full-time active clinical faculty mem- Whittington, MD, professor of anesthesiology frst class of members who are P&S full professors bers and will be open to all ranks at P&S. and academy committee member.

Global Innovation

Two projects led by P&S faculty were among 12 projects that received The two projects led by P&S faculty: funding during the fourth round of grants from the Columbia Presi- dent’s Global Innovation Fund. Grants are awarded to faculty mem- Adolescents Living with HIV: Engaging and Empowering bers to leverage and engage Columbia Global Centers in developing through Photography new projects and research collaborations that will increase global opportunities for research, teaching, and service. Elaine Abrams, MD The projects make use of the network of eight Columbia Global professor of pediatrics at CUMC Centers to provide opportunities for faculty and students to address important global issues. In the three previous rounds of funding, 49 projects were supported. “Collectively, these projects play an essen- Laboratory-based PhD Training in Nutritional and Agricultural tial role in realizing the potential of the Columbia Global Centers to Sciences in East Africa create new opportunities for faculty and students and in defning in Debra Wolgemuth, PhD tangible ways what it means for Columbia to explore new frontiers of professor of genetics & development knowledge in the 21st century,” said Provost John H. Coatsworth in (in obstetrics & gynecology and in the Institute of Human Nutrition) announcing the 2016 funded projects.

46 ColumbiaMedicine aboutPS& MEMBERSHIPS ND D T CURRENT S OF JULY 1, 2016, EXCEPT WHERE NOTED

Columbia University Trustees Andrew Solomon, PhD Taub Institute Advisory Board Operations Committee on the Health Sciences Sarah Billinghurst Solomon Richard Mayeux, MD, and Mark McDougle, MPH Ellen Stein Michael Shelanski, MD, PhD, Kenneth A. Forde, MD, Chair Senior Vice President/ Peter Tombros Co-Chairs Rolando Acosta Chief Operating Offcer Leonard Tow, PhD Andrew Barth Savio Tung Transplant Forum Noam Gottesman Amador Centeno, MS Andy Unanue Monica Segal, Chair Mark Kingdon Vice President, Facilities Joseph A. Walker Michael Rothfeld Management and Campus Services Deborah Weinberg Weinberg Family Cerebral Palsy Peter A. Weinberg Center Advisory Board Ross Frommer, JD CUMC Board of Advisors Torsten Wiesel, MD Debby Weinberg, Chair Vice President, Government Richard E. Witten P. Roy Vagelos, MD, Chair and Community Affairs Philip L. Milstein, Vice Chair Roger Wu, MD Women’s Health Care Council Sarah Billinghurst Solomon, Chair George D. Yancopoulos, MD, PhD, William Innes, MS Vice Chair ther CUMC Advisory Groups Chief Human Resources Offcer Keith T. Banks Senior Administration, 250th Anniversary Michael Barry Columbia University Steering Committee Robert V. Sideli, MD Stanley M. Bergman Medical Center P. Roy Vagelos, MD, Chair Chief Information Offcer Gary B. Bettman Lee C. Bollinger, JD E. Garrett Bewkes III Babies Heart Fund President of the University General Counsel Eugene Braunwald, MD Scott Roskind and John Minio, Dana Buchman Patricia Sachs Catapano, JD Co-Chairs Lee Goldman, MD John A. Catsimatidis Associate General Counsel Executive Vice President and Anna Chapman, MD Cancer Advisory Council Dean of the Faculties of Health Neil L. Cohen Senior Administration, Richard Witten and Dina Dublon, Sciences and Medicine and F. Jonathan Dracos College of Physicians & Surgeons Co-Chairs Chief Executive of Columbia John L. Eastman University Medical Center Lee Goldman, MD Loren Eng Center for Radiological Dean Daniel D. Federman, MD, Research Advisory Council Bobbie Berkowitz, PhD, RN Emeritus Member Paul Locke, DrPH, Chair Senior Vice President, CUMC Anne Taylor, MD Marjorie Harrison Fleming Dean, School of Nursing Vice Dean, Academic Affairs Kenneth A. Forde, MD Children’s Board at Columbia Carl Frischling Karen A. Kennedy, MD, Chair Linda P. Fried, MD, MPH Martha Hooven, MPA Lee Goldman, MD Senior Vice President, CUMC Vice Dean, Administration Marc D. Grodman, MD Columbia’s Cardiac Council Dean, Mailman School Gerald L. Hassell Peter J. Sacripanti, Chair of Public Health Steven Shea, MD Ara K. Hovnanian Senior Vice Dean, Affliations Ilan Kaufthal Diabetes Advisory Board Christian S. Stohler, DMD, Thomas L. Kempner Jr. John, Jodie, Jay, and DrMedDent George A. Cioff, MD Karen A. Kennedy, MD Katama Eastman, Chairs Senior Vice President, CUMC Vice Dean, Clinical Affairs, and Jonathan S. Leff Dean, College of Dental Medicine President, ColumbiaDoctors Ellen Levine Health Sciences Advisory Council A. Michael Lipper Stuart Rabin, Chair Development Karina W. Davidson, PhD Paul J. Maddon, MD, PhD Vice Dean for Organizational Robert F. Mancuso Lynne Roth, BA Neurology Advisory Council Effectiveness Paul A. Marks, MD, Senior Vice President Richard Mayeux, MD, Chair Emeritus Member Education Joseph M. Murphy Finance Ophthalmology Board Lawrence Neubauer Ronald E. Drusin, MD of Advisors Joanne M.J. Quan, MA Mark H. Rachesky, MD Vice Dean Sir Howard Stringer, Chair Senior Vice President/ John W. Rowe, MD Chief Financial Offcer Kathe A. Sackler, MD Lisa Mellman, MD Psychiatry Board of Advisors Peter Sacripanti Senior Associate Dean Patricia and William Ramonas, Wil McKoy, MBA Thomas P. Sculco, MD for Student Affairs Co-Chairs Vice President, Budget and Planning G. Lynn Shostack Frank V. Sica Hilda Y. Hutcherson, MD Precision Medicine Council Francine Caracappa, MBA, CPA Richard Silverman Senior Associate Dean for Diversity P. Roy Vagelos, MD, Chair Controller Dinakar Singh and Multicultural Affairs

2016 Annual Report ColumbiaMedicine 47 aboutPS& MEMBERSHIPS ND D T CURRENT S OF JULY 1, 2016, EXCEPT WHERE NOTED

Maurice Wright, MD Ivaylo Ivanov, PhD Dermatology Rehabilitation & Senior Associate Dean, Assistant Professor of David R. Bickers, MD Regenerative Medicine Harlem Hospital Microbiology & Immunology Joel Stein, MD Genetics & Development – Programs in Occupational Therapy Jonathan Amiel, MD Robert Kass, PhD Gerard Karsenty, MD, PhD Janet Falk-Kessler, EdD Associate Dean for Curricular Affairs Hosack Professor of Pharmacology, Director Alumni Professor of Pharmacology Medicine Stephen Nicholas, MD (in Neuroscience), and Chair, Donald W. Landry, MD, PhD – Program in Physical Therapy Associate Dean for Admissions Pharmacology Debra Clayton-Krasinski, PhD Microbiology & Immunology Director Arthur G. Palmer III, PhD Donald Landry, MD, PhD Sankar Ghosh, PhD Associate Dean for Graduate Affairs Samuel Bard Professor of Medicine Surgery and Chair, Medicine Neurological Surgery Craig R. Smith, MD Tony Pillari, MBA Robert A. Solomon, MD Associate Dean for Education Jennifer Levine, MD Systems Biology Administration Assistant Professor of Pediatrics Neurology Andrea Califano, PhD at CUMC Richard Mayeux, MD Elizabeth Shane, MD Urology Associate Dean of Student Research Charles Marboe, MD Neuroscience James M. McKiernan, MD Professor of Pathology & Cell Biology Steven A. Siegelbaum, PhD Noel Robin, MD at CUMC University Centers and Associate Dean, Obstetrics & Gynecology Institutes and Directors Stamford Health System Richard Mayeux, MD Mary E. D’Alton, MD Gertrude H. Sergievsky Professor Naomi Berrie Diabetes Center Henry Weil, MD of Neurology, Psychiatry, and Ophthalmology Robin S. Goland, MD Associate Dean, Epidemiology (in the Gertrude H. George A. Cioff, MD Rudolph L. Leibel, MD Bassett Healthcare Sergievsky Center and in the Taub Institute for Research on Alzheimer’s Orthopedic Surgery Center for Computational Biology Research Disease and the Aging Brain) and William N. Levine, MD and Bioinformatics (C2B2) Chair, Neurology Andrea Califano, PhD Michael L. Shelanski, MD, PhD Otolaryngology/Head Barry Honig, PhD Senior Vice Dean for Research Arthur Palmer, PhD & Neck Surgery Robert Wood Johnson Jr. Professor of Lawrence Lustig, MD Center for Family and Jennifer Williamson Catania, MS, MPH Biochemistry & Molecular Biophysics Community Medicine Associate Vice Dean for Research and associate dean for graduate affairs Pathology & Cell Biology Richard Younge, MD Policy & Scientifc Strategy Kevin Roth, MD, PhD David Seres, MD Center for Motor Neuron Biology lumni Relations and Development Associate Professor of Medicine Pediatrics and Disease Anke Nolting, PhD (in the Institute of Human Nutrition) Lawrence R. Stanberry, MD, PhD Darryl De Vivo, MD Associate Dean and at CUMC Serge Przedborski, MD, PhD Executive Director Pharmacology Hynek Wichterle, PhD Karen Soren, MD Robert S. Kass, PhD Center for Psychoanalytic Executive Committee of the Associate Professor of Pediatrics and Training and Research Faculty Council, 2015-2016 Population and Family Health Physiology & at CUMC Cellular Biophysics Eric R. Marcus, MD Andrew Eisenberger, MD Andrew R. Marks, MD Assistant Professor of Medicine Center for Radiological Research Department Chairs at CUMC Psychiatry David Brenner, PhD, DSc Anesthesiology Jeffrey A. Lieberman, MD Mary Flood, MD, PhD Ansgar Brambrink, MD, PhD Center for the Study of Society Associate Professor of Medicine Radiation Oncology and Medicine and Center on at CUMC Biochemistry & Molecular Biophysics Lawrence H. Schwartz, MD Medicine as a Profession Tom Maniatis, PhD Interim Chair David J. Rothman, PhD Sankar Ghosh, PhD Silverstein and Hutt Family Professor Biomedical Informatics Radiology Center for Translational Immunology of Microbiology & Immunology and George Hripcsak, MD Lawrence H. Schwartz, MD Megan Sykes, MD Chair, Microbiology & Immunology Columbia Stem Cell Initiative Emmanuelle Passegué, PhD

48 ColumbiaMedicine Columbia Translational Herbert Irving Comprehensive Taub Institute for Research Harlem Hospital, Neuroscience Initiative Cancer Center on Alzheimer’s Disease and New York, NY Serge E. Przedborski, MD, PhD Stephen G. Emerson, MD, PhD the Aging Brain Richard Mayeux, MD James A. Peters Veterans Institute for Cancer Genetics Irving Institute for Clinical and Michael L. Shelanski, MD, PhD Administration Hospital, Riccardo Dalla-Favera, MD Translational Research Bronx, NY Henry N. Ginsberg, MD, Clyde and Helen Wu Center for Institute of Comparative Medicine Director Molecular Cardiology Mary Imogene Bassett Hospital, Brian Karolewski, VMD, PhD Muredach P. Reilly, MBBCh, Andrew Marks, MD Cooperstown, NY Director-Designate Institute for Genomic Medicine P&S Hospital Affliations Stamford Hospital, David B. Goldstein, PhD Kavli Institute for Brain Science Stamford, CT Eric Kandel, MD NewYork-Presbyterian Hospital, Institute of Human Nutrition New York, NY Helen Hayes Hospital, Richard J. Deckelbaum, MD Gertrude H. Sergievsky Center West Haverstraw, NY Richard Mayeux, MD New York State Psychiatric Institute, New York, NY Lawrence Hospital, Bronxville, NY F CTS & ST TISTICS, FY16

MEDICAL SCHOOL EN OLLMENT, FALL 2015 DEG EES G ANTED, FY16 Total medical school enrollment ...... 670 MD ...... 168 Enrollment of underrepresented minorities ...... 166 PhD ...... 55 Enrollment of minorities ...... 271 Doctor of physical therapy ...... 54 Enrollment of international/nonresident students ...... 21 MS in nutrition ...... 78 Enrollment of in-state residents ...... 209 MS in occupational therapy ...... 51 Enrollment of men ...... 334 Certificate in psychoanalysis ...... 1 Enrollment of women ...... 336 APPLICATIONS (ENTE ING CLASS 2015) EN OLLMENT BY YEA Number of applicants ...... 7,878 M LE FEM LE Number of applications considered ...... 7,366 First-Year Class 81 79 Number of applicants interviewed ...... 1,090 Second-Year Class 80 77 Number of acceptance letters issued ...... 313 Third-Year Class 89 97 Number of new entrants ...... 161 Fourth-Year Class 84 83 Bassett Program applications ...... 637 Total Enrollment 334 336 Number of new Bassett Program entrants ...... 10

MEDICAL SCHOOL ETHNICITIES FACULTY, 2015-2016 ACADEMIC YEA Nonresident aliens ...... 21 FULL TIME P RT TIME Hispanic/Latino ...... 79 Number of clinical faculty 1,675 2,009 Black or frican- merican, non-Hispanic/Latino ...... 68 Number of basic sciences faculty 238 68 White, non-Hispanic/Latino ...... 318 merican Indian or laskan Native, non-Hispanic/Latino ...... 1 FACULTY HONO S sian, non-Hispanic/Latino ...... 105 Nobel Prize in Medicine ...... 2 Native Hawaiian or other Pacific Islander, non-Hispanic/Latino ... 1 National cademy of Sciences ...... 19 Two or more races, non-Hispanic/Latino ...... 17 National cademy of Medicine ...... 47 Race and/or ethnicity unknown ...... 60 merican cademy of rts and Sciences ...... 25 Howard Hughes Medical Institute ...... 9 OTHE STUDENTS MD/PhD students ...... 120 FINANCIALS, FY16 (except where noted) PhD students ...... 317 Budget ...... $1.7 billion Other students (PT, OT, Nutrition, Informatics) ...... 506 Philanthropic support ...... $204 million Endowment ...... $1.7 billion Endowed chairs/professorships ...... 254 NIH research support (FY 2015) ...... $356.5 million Non-Proft Org. 630 West 168th Street U.S. Postage Paid New York, NY 10032 New York, NY PERMIT NO. 3593

Space MATTERS ‘‘ Our new education building will ensure that Columbia continues to train superior doctors and researchers, educated in the latest techniques, as medicine continues to evolve rapidly throughout the 21st century. The building also will allow us to centralize key activities in a state ---of the art facility that refects our commitment to providing world- class instruction and a superb learning environment for students.”

— Lee Goldman, MD, Dean

More about the new

NIC LEHOUX, COURTESY OF DILLER SCOFIDIO + RENFRO building: Page 42