Researchers used machine learning techniques, including natural language processing algorithms, to identify clinical concepts in radiologist reports for CT scans, according to a study conducted at the Icahn School of Medicine at Mount Sinai and published in the journal Radiology. The technology is an important first step in the development of artificial intelligence that could interpret scans and diagnose conditions.
From left: Judith Weissman, PhD, JD, MPH; Dolores Malaspina, MD, MSPH, MS; David Kimhy, PhD; Lotje de Witte, MD, PhD; and Cheryl Corcoran, MD
The recent recruitment of five specialists to the Department of Psychiatry at the Icahn School of Medicine at Mount Sinai has revitalized research, treatment, and prevention efforts in the field of psychotic illnesses and has led to the creation of the Critical Connections Program, which will help advance these endeavors.
Critical Connections will incorporate the collaborative efforts of multiple specialties within the Mount Sinai Health System—including neuroimaging, psychophysiology, genetics, neural stem cells, immunology, and epidemiology—with the goal of using the latest technologies and developments to find personalized interventions and treatments for psychosis. Clinical sites across the Health System also will contribute to a shared biorepository of samples collected from people with these illnesses.
Dolores Malaspina, MD, MSPH, MS, a leader in the field of psychosis, and Director of the new Critical Connections Program, says, “The most fundamental human quality is the ability to connect with others. Severe mental illness, particularly psychosis in schizophrenia, bipolar disorder, depression, and other conditions, disrupts this capacity and has an enormous impact on individuals, families, communities, and the general population.” The costs of social services, hospitals, courts, and prisons have an economic impact, as well. “In spite of significant scientific advances, we still know little about how to prevent and treat most psychotic illnesses. Breakthrough discoveries require innovative designs,” she adds.
Resilience, genetic susceptibility, family characteristics, environmental exposures, and other factors that account for the influences of nature and nurture will be studied by the program’s researchers. Pivotal changes occur in the brain throughout young adulthood that can be directed toward recovery and resilience. Plans call for educational training of medical students, residents, and fellows to translate new findings into evidence-based treatments.
Prior to her recruitment to Mount Sinai, Dr. Malaspina established successful clinical research programs in psychosis at the New York State Psychiatric Institute and at Bellevue Hospital Center. One of her currently funded National Institutes of Health studies that uses the Genomic Psychiatry Cohort examines the gut microbiome-brain axis, with respect to brain inflammation.
The following renowned recruits to the Icahn School of Medicine will be working with Dr. Malaspina to create a robust center of psychosis at the Mount Sinai Health System:
Cheryl Corcoran, MD, Senior Faculty, and Program Leader in Psychosis Risk at the Mount Sinai Health System, plans to launch two programs: a clinical risk and resilience research program for teens and young adults who have unusual thoughts, perceptual disturbances, and suspiciousness, and a familial-risk program for young relatives of patients with psychosis. Dr. Corcoran also plans to partner with community clinicians and experts in adolescent medicine to implement early identification and intervention programs for at-risk youth, and collaborate with basic and translational neuroscientists to study the pathophysiology underlying illness risk.
Currently, her main focus is natural language in neuropsychiatric disorders. Working with computational neuroscientists, Dr. Corcoran has identified language features that predict psychosis onset in at-risk youths. This includes subtle decreases in semantic coherence and complexity of speech (such as using shorter sentences and eliminating the words “which” and “that”). Funding from the National Institute of Mental Health has enabled Dr. Corcoran to study the neural correlates of these language abnormalities in a larger international cohort that will determine replicability and develop targets for preventive intervention.
David Kimhy, PhD, Senior Faculty, also serves as Director of the Experimental Psychopathology Laboratory, and Leader in New Interventions in Schizophrenia at the Icahn School of Medicine at Mount Sinai. Dr. Kimhy will focus on the development of novel interventions for schizophrenia and investigate the pathophysiology and phenomenology of cognitive, affective, and social functioning in individuals with schizophrenia.
Over the past decade, Dr. Kimhy has pioneered the use of mobile phone technologies in the study of psychotic symptoms and functioning, and the use of active-play video games as part of aerobic exercise training aimed at improving neurocognition in people with schizophrenia.
Preliminary work from his laboratory indicates that aerobic exercise training is effective in improving cognitive functioning in this population, with improvements linked to exercise-related upregulation of Brain-Derived Neurotrophic Factor (BDNF), a biomarker of neuroplasticity. His current funding includes an award from the National Institute of Mental Health supporting a multisite, single-blind, randomized clinical trial examining the impact of aerobic exercise on neurocognition and biomarkers of neuroplasticity in individuals with schizophrenia.
As Director of Education at The Mental Illness Research, Education and Clinical Center at the James J. Peters VA Medical Center in the Bronx, Dr. Kimhy will continue his longstanding commitment to training future researchers and clinicians.
Lotje de Witte, MD, PhD, Assistant Professor of Psychiatry, combines clinical work and scientific exploration in immunology in pursuit of treatments and interventions for psychiatric diseases. Her laboratory investigates the connection between the immune system and the pathogenesis of psychiatric disorders, such as schizophrenia, mood disorders, and autism.
Recently, Dr. de Witte set up a novel stem-cell derived brain organoid model to study microglia, and established the methodology to isolate microglia from postmortem brain tissue. Microglia cells are part of the immune system and involved in both inflammation and reconstruction in the brain, processes thought to be involved in schizophrenia.
After studying the cell biological mechanisms of HIV-1 transmission, Dr. de Witte used this experience to start a distinctive research line at the Brain Center Rudolf Magnus in Utrecht, the Netherlands. She received her MD and PhD at the VU University Medical Centre, Amsterdam. Her research has been published in Nature Medicine, the Journal of Clinical Investigation, PLOS Pathogens, and Proceedings of the National Academy of Sciences.
Judith Weissman, PhD, JD, MPH, Assistant Professor of Psychiatry, serves as a Research Health Specialist at the James J. Peters VA Medical Center. Her expertise is in using national data sets to examine health care patterns in the mentally ill.
At the VA Medical Center, she will collaborate with other researchers to investigate the incidence and risk factors of suicide, along with the access and utilization of mental health care services among vulnerable populations, particularly military veterans with mental illness. Dr. Weissman will also research possible interventions. Suicide by veterans remains a critical problem, and few empirically based treatment strategies for suicide prevention among post-deployed military personnel currently exist.
Serving as a Senior Service Fellow at the U.S. Centers for Disease Control and Prevention earlier in her career helped hone Dr. Weissman’s skill in analyzing large data sets. She has also investigated topics such as polypharmacy in the nation’s elderly and disparities in antidepressant prescribing practices.
Mone Zaidi, MD, PhD
A single hormone whose levels rise at menopause could be responsible for the weight gain and bone loss that many women experience in middle age, and blocking that hormone could help reverse those effects, according to a study in mice that was led by Mone Zaidi, MD, PhD, Professor of Medicine (Endocrinology, Diabetes and Bone Disease), at the Icahn School of Medicine at Mount Sinai. The strong clinical potential of these results has been noted in The New England Journal of Medicine, and in Nature Medicine, which in December 2017 named the study one of the year’s eight “notable advances.”
The work began about 10 years ago when Dr. Zaidi challenged endocrinology’s long-held notion that the pituitary follicle-stimulating hormone (FSH) controlled only reproductive targets: the production of estrogen in women and sperm in men.
Using animal models, Dr. Zaidi showed that FSH had direct effects in conserving bone. That discovery piqued Dr. Zaidi’s curiosity: Could FSH also play a role in the sharp increase in visceral fat that occurs in women during late perimenopause?
To answer the question, his group conducted a study that included injecting a polyclonal antibody that blocked FSH signaling into several groups of mice: females that had their ovaries removed and were fed a normal diet; male and female mice that were fed a high-fat diet; and female mice on a normal diet.
“What we found was that by targeting FSH and blocking its action, we could not only prevent bone loss but also reduce body fat and improve energy homeostasis,” he observes. “We thought to ourselves, ‘This is really a weird finding.’”
Dr. Zaidi, who is founding director of the Mount Sinai Bone Program, then enlisted the support of Clifford J. Rosen, MD, a bone and fat expert who is Director of the Center for Clinical & Translational Research at the Maine Medical Center Research Institute. For the next two and a half years, the scientists replicated each other’s work, culminating in the publication of a comprehensive study in the June 2017 issue of the journal Nature. Their findings confirmed that blocking access of FSH to its receptor using an epitope-specific polyclonal antibody resulted in increased bone mass and a marked reduction in visceral fat in ovariectomized mice. As for the possible mechanism behind these changes, Dr. Zaidi found that the antibody reduced white adipose tissue—where fat is stored—and converted it to brown (or beige) adipose tissue, the type of fat that is burned to provide energy.
Images from the study in Nature show CT scans of the abdomens of mice that were fed a high-fat diet. The amount of visceral fat (in red) was significantly lower, right, when a mouse was injected with an antibody to the follicle-stimulating hormone, compared with a mouse injected with the control substance IgG.
In humans, a version of the antibody used in his study might be able to simultaneously treat bone loss and fat accumulation in women, offering a new approach to associated medical conditions, such as osteoporosis, cardiovascular disease, cancer, and diabetes. And because the antibody was found to be effective in both male and female mice, the benefits could extend to both genders in humans, particularly in controlling obesity.
Dr. Zaidi points out that two classes of obesity drugs are currently on the market: those that suppress appetite and those that reduce the absorption of fat from the gut. Both classes, however, come with significant side effects.
“The FSH-blocking antibody works on neither of these sites, but instead acts directly on fat cells by converting white to brown fat tissue,” Dr. Zaidi says. “This is truly a new game.”
In collaboration with Mount Sinai Innovation Partners, Dr. Zaidi is exploring opportunities to realize the vast potential of this research through commercial partnerships.
Samuel Gandy, MD, PhD, Professor, Neurology, Psychiatry, Icahn School of Medicine at Mount Sinai, was featured in a 60 Minutes report on CTE, or chronic traumatic encephalopathy. The report explains how the brain disorder that has been diagnosed in many football players is now being found in a growing number of combat veterans exposed to explosions.
From left: Ramon E. Parsons, MD, PhD; Neil S. Calman, MD; and Yasmin L. Hurd, PhD
Three Icahn School of Medicine at Mount Sinai faculty members recently received the professional honor of being elected to the prestigious National Academy of Medicine (NAM): Neil S. Calman, MD, Chair of the Department of Family Medicine and Community Health; Yasmin L. Hurd, PhD, Director of the Addiction Institute and Ward-Coleman Chair in Translational Neuroscience; and Ramon E. Parsons, MD, PhD, Director of The Tisch Cancer Institute and Ward-Coleman Chair in Cancer Research.
The esteemed group joins 21 Mount Sinai colleagues who also have received the professional distinction of being members of the NAM, formerly the Institute of Medicine, an independent organization that serves as a national and international advisor on health and related policy formation. Academy membership demonstrates outstanding commitment to issues related to health care, prevention of disease, education in the health professions, or biomedical research.
Neil S. Calman, MD: Providing low-income patients with affordable, accessible, and comprehensive health care
Dr. Calman joins fewer than 50 family physicians in an Academy populated mainly by the world’s leading medical specialists. His election rewards his work over three decades to reduce health disparities in the broad context of social and medical issues. “It’s the hallmark of what I have done,” he says.
Dr. Calman launched the Institute for Family Health in 1983 with a staff of four and became affiliated with Mount Sinai in 2012. Today, the Institute employs more than 1,400 staff and receives more than 650,000 patient visits annually to its 31 locations in Brooklyn, Lower Manhattan, Harlem, the Bronx, and the Hudson Valley. It provides more than 102,000 low-income patients with services that include primary care, mental health, dental care, and social work that satisfy national standards for affordable, accessible, and comprehensive health care.
The Institute also trains health professionals, and operates three distinct family medicine residency programs and fellowships in women’s health and for family nurse practitioners. Dr. Calman has led the Institute’s research efforts that focus on improving health equities and making high-quality health care available to anyone in need.
Dr. Calman’s focus on population health and public health has earned him a long list of accolades, including the Robert Wood Johnson Foundation’s Community Health Leadership Award, the American Academy of Family Physicians’s Public Health Award, The Pew Charitable Trusts’s Primary Care Achievement Award, and the Physician Advocacy Award from the Institute on Medicine as a Profession. Accreditation by The Joint Commission and recognition by the National Committee for Quality Assurance certify the highest levels of patient care.
Yasmin L. Hurd, PhD: Developing new treatments for addiction that really change lives
Having so many faculty members at the NAM is a testament to the quality of the work being done at Mount Sinai, says Dr. Hurd, a neuroscientist and founding Director of the Addiction Institute at the Icahn School of Medicine. “It proves the degree to which Mount Sinai is influencing the course of science, medicine, health care, and more. And that is pretty impressive.”
Discovering effective therapies for addiction has become a national call to action and is Dr. Hurd’s specialty. According to the 2016 U.S. Surgeon General’s Report, more than 20 million Americans have substance abuse disorders.
In studying the neurology behind addiction, Dr. Hurd’s laboratory at Mount Sinai examines the environmental and genetic causes of addiction visible in animal behavior, molecular biology, cell biology, pharmacology, psychology, neuroimaging, bioinformatics, and biotechnology. Her lab has analyzed human and animal tissues at the single-cell level and pioneered the technique of DREAMM (DREADD-assisted metabolic mapping), a source of high-resolution quantitative mapping of functional brain circuits associated with the disturbance of genes expressed in specific cell populations.
Dr. Hurd’s lab has made major inroads in addiction research by showing that marijuana use has different effects on developing brains and adult brains. Individuals who are exposed to the active ingredient in marijuana—tetrahydrocannabinol (THC)—early in life, for example, show greater sensitivity to opiates, which could make them more vulnerable to addiction and other problems.
In addition, the changes it makes in the brain can last through adulthood and even into the next generation. In addition to THC, Dr. Hurd is testing cannabidiol, another active ingredient in marijuana, for its palliative effects. Evidence so far suggests its potential role in preventing relapses in heroin and cocaine addiction, reducing anxiety, and improving overall cognitive function. “I would say that my passion is developing treatments that really change lives,” Dr. Hurd says.
Ramon E. Parsons, MD, PhD: Enhancing translational research and collaborating on the complex puzzle of cancer
Dr. Parsons’s election to the NAM follows his 2017 appointment as Director of The Tisch Cancer Institute and the receipt of a $6.7 million award from the National Cancer Institute that will fund research into the tumor-suppressing functions of the PTEN gene—which encodes a phosphatase enzyme relevant to many types of cancer—that he discovered 20 years ago. Upon analyzing the gene’s sequences that exhibited mutations in cancers, he recalls “the ‘aha moment’ when we saw that the phosphatase—a tumor suppressor—was mutated.”
One of Dr. Parsons’s goals as Director of The Tisch Cancer Institute is to detect hypermutating cancers as early as possible in a patient’s diagnosis so that he or she can receive immune checkpoint therapy at the most advantageous point during treatment. This effort is based, in part, on research that Dr. Parsons began more than two decades ago as a fellow at Johns Hopkins School of Medicine while investigating defective DNA repair that causes hypermutation in colon cancer.
His other goals for The Tisch Cancer Institute include enhancing the infrastructure for translational research, and expanding, recruiting, and training basic and clinical scientists to perform more patient-oriented research, as well as promoting research to address disparities in patient outcomes.
Multiple disciplines working in concert on cancer is pivotal, Dr. Parsons says. When experts with different perspectives collaborate on a complex puzzle, “the further into it you get, the more quickly you can try to finish it.” An optimist, he says, “You can’t be in the cancer field without seeing the glass half full. We must analyze in exquisite detail our success and why it is working, then compare that with failures to be able to develop better care for everyone.”
Andrew F. Stewart, MD
A rare benign tumor may hold the key to regenerating insulin-producing beta cells and lead to novel drugs for patients with diabetes, according to a study led by Andrew F. Stewart, MD, Director of the Diabetes, Obesity and Metabolism Institute and the Irene and Dr. Arthur M. Fishberg Professor of Medicine at the Icahn School of Medicine at Mount Sinai.
Dr. Stewart’s team conducted the largest genomic study of insulinomas—benign pancreatic tumors that secrete insulin—and uncovered multiple pathways to human beta cell proliferation, long seen as a holy grail in treating, and possibly curing, diabetes.
“We’ve sequenced 38 human insulinomas with 30,000 genes each, and now know all the genes that are mutated and misregulated,” says Dr. Stewart. “For the first time, we have a genomic recipe—an actual wiring diagram in molecular terms—that demonstrates how beta cells replicate.” The results of that research were reported in the journal Nature Communications in October 2017.
Dr. Stewart says that one of the reasons he joined Mount Sinai five years ago was that its strong Genomics and Bioinformatics programs offered him the potential to assess the insulinomas he had been collecting. “I wanted to do genome sequencing and RNA expression as part of comprehensive studies to figure out which genes were turned on and which weren’t in insulinomas,” he says.
Eric Schadt, PhD, Dean for Precision Medicine, and the Jean C. and James W. Crystal Professor of Genomics, Icahn School of Medicine at Mount Sinai, assigned a team of bioinformatics specialists to work closely with Dr. Stewart, led by Carmen Argmann, PhD, Associate Professor of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai. “We are now further expanding our sequencing to 100 insulinomas. We already have found many pathways that lend themselves to new drugs,” Dr. Stewart observes.
Dr. Stewart has repeatedly undercut the argument that human beta cells were impossible to reproduce. In the March 2015 issue of Nature Medicine, his team reported the discovery of the first drug that can trigger human beta cell regeneration: harmine. In that study, Dr. Stewart’s team robotically screened 100,000 chemical compounds in search of a drug to make beta cells grow. They identified 86 potential candidates, and eventually winnowed the field to harmine, which is derived from the flowering plant harmal, or ayahuasca.
Harmine, however, has psychoactive properties that act not only on beta cells but on the brain and other tissues throughout the body. That complication has touched off a search within the research community to find other small molecules that target only beta cells. “We’re making considerable progress in making the next-generation versions of harmine in combination with other drugs that will afford us much higher proliferation of human beta cells,” Dr. Stewart says. “With the insulinoma project, we have acquired a road map to even more effective beta cell regenerative drugs.”