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Consortium Sheds New Light on Brain Disorders

Updated on Jun 30, 2022 | Featured, Neuroscience, Psychiatry, Research

From left: Kristen Brennand, PhD, Associate Professor, Neuroscience, Genetics and Genomic Sciences, and Psychiatry; Prashanth Rajarajan, MD/PhD candidate; and Schahram Akbarian, MD, PhD, Professor, Psychiatry, and Neuroscience.

Reprinted with permission from AAAS.

More than two dozen researchers at the Icahn School of Medicine at Mount Sinai are advancing brain science by mapping the complex molecular underpinnings of autism spectrum disorder, schizophrenia, and bipolar disorder through their work in the National Institute of Mental Health’s (NIMH) PsychENCODE Consortium. Since this work began in 2015, their contributions—and that of their PsychENCODE colleagues from 14 other U.S. institutions—have helped identify several hundred new risk genes for mental disorders. The research has also revealed critical time windows during brain development when these genes can influence the disease process.

In December, the Consortium published its initial findings in 10 studies that appeared in Science, Science Translational Medicine, and Science Advances. The researchers analyzed more than 2,000 postmortem brain samples from people with no psychiatric conditions and those with schizophrenia, autism, and bipolar disorder. They created and then integrated data sets that included information on DNA variations and gene expression for about 32,000 cells from major regions of the brain. Then the investigators employed machine learning to create a predictive model of risk for the psychiatric disorders.

Their seminal findings received an enthusiastic response from the NIMH. “The PsychENCODE project came through,” said Thomas Lehner, PhD, MPH, Director of the Office of Genomic Research Coordination at the NIMH. “We’re at the beginning—I cannot overstate how early we are. But I can confidently say that for the first time we have a beginning of an understanding of the biology—the molecular pathophysiology of mental disorders—of schizophrenia, and bipolar and autism spectrum disorder.”

Unraveling the Complexity of the Human Brain

“Exploring how the human genome is folded and packaged into the nucleus of each of our billions of brain cells was both awe-inspiring and humbling at the same time,” says Prashanth Rajarajan, MD/PhD candidate at the Icahn School of Medicine at Mount Sinai, who was first author on seminal brain research that was published in the December 14, 2018, issue of Science.

The scientific team discovered that early development is associated with major changes in the spatial organization of DNA inside of brain cells. These changes in how the chromosomal material is packed seem to disproportionately affect DNA sequences linked to schizophrenia heritability risk and provide new insights into the genetic causes underlying this disease.

The study, which was conceived and executed at the Icahn School of Medicine, included senior authors Schahram Akbarian, MD, PhD, Professor, Psychiatry, and Neuroscience; and Kristen Brennand, PhD, Associate Professor, Neuroscience, Genetics and Genomic Sciences, and Psychiatry. Colleagues at the New York Genome Center and the University of Massachusetts also contributed to the study.

According to Mr. Rajarajan, “There is so much more to the genome than just the four-letter DNA code (A, T, C, G)—such as its folded architecture, which is a highly organized and regulated process. Eighteen years after fully sequencing the human genome, we still understand very little about how it actually comes to life. Our study, and the others that were published, are beginning to unravel more nuances than previously imagined, making it a really exciting time to be in the field of neuroscience and psychiatry research.”

NIMH Program Director Geetha Senthil, PhD, added that the massive scope of the project required a “concerted effort. Many investigators had to come together and do this collectively.” While the mental disorders in the studies are distinct, Dr. Senthil said, “There are some aspects where the biology is similar. The genes interact with each other in a way to influence the disease process. If we can find biological clues early on, we can intervene early on. While we are building and generating more data, analyzing this data to find basic mechanisms, there’s an opportunity also for drug discovery.”

The 10 papers published by the PsychENCODE Consortium were dedicated to the late Pamela Sklar, MD, PhD, former Chair of the Department of Genetics and Genomic Sciences at the Icahn School of Medicine, and a pioneer in genomic brain research, who was an early leader of the NIMH effort. The Icahn School of Medicine last year renamed the division she created the Pamela Sklar Division of Psychiatric Genomics.

Mount Sinai laboratories within The Friedman Brain Institute, The Seaver Autism Center for Research and Treatment, the Department of Psychiatry, The Mindich Child Health and Development Institute, the Department of Genetics and Genomic Sciences, the Department of Neuroscience, and the Icahn Institute for Data Science and Genomic Technology were involved in the PsychENCODE Consortium.

“Mount Sinai serves as one of the lead sites in this national consortium. The discoveries that are being made by our scientists and their colleagues at other major institutions are moving us closer to understanding and finding treatments for these devastating brain disorders,” says Eric J. Nestler, MD, PhD, Nash Family Professor of Neuroscience, Director of The Friedman Brain Institute, and Dean for Academic and Scientific Affairs, Icahn School of Medicine at Mount Sinai.

First He Donated His Bone Marrow, Then He Gave Her a Kidney: How Two Strangers Became ‘Family Forever’

Updated on Jun 30, 2022 | Featured, Transplant

When Jeramy Davies was a senior at Texas Tech University in 2010, he helped organize a charity drive for Be the Match®, the national program that matches potential donors to those needing a bone marrow transplant. Little did he know that five years later he would donate his own bone marrow to a stranger in New Jersey— Kelly Ribeiro, who was being treated for lymphoma. And in 2018, he would give Ms. Ribeiro one of his kidneys, effectively saving her life twice.

Since hospital protocol forbids the exchange of any information between donor and recipient for one year, and then only if both parties agree, Mr. Davies and Ms. Ribeiro remained unknown to each other immediately following her successful bone marrow transplant. In 2016, Mr. Davies reached out to her and they began exchanging emails and text messages and speaking frequently by phone.

But over time, they both faced significant challenges. Ms. Ribeiro was dealing with kidney failure due to her previous condition. During a bout with pneumonia she fell into a coma. When she emerged, she began dialysis three times a week. “I never felt so sick and depleted as I did with kidney failure,” she says. “Every day, I could feel the life draining out of me.”

At the same time, Mr. Davies was helping his wife batt le a brain tumor that would take her life in July 2017. “Kelly was great moral support for me,” Mr. Davies recalls. “She understood everything we were going through, and she was a huge source of strength.”

But Ms. Ribeiro did not want to burden him with her own struggle, and even as her kidney function dwindled to 19 percent, she did not ask for his help. Only after her mother told Mr. Davies how sick she was did he understand the full extent of Ms. Ribeiro’s situation. Immediately, he offered Ms. Ribeiro his kidney. Immediately, she turned him down.

“It didn’t feel right,” she says. But he persisted, and in late December 2018, she underwent a successful kidney transplant at The Mount Sinai Hospital. Since Ms. Ribeiro now had Mr. Davies’ immune cells and even his blood type from the earlier bone marrow transplant, they were a 100 percent match. This also meant she would require fewer antirejection medications.

“It’s the most satisfying thing I’ve ever done,” says Mr. Davies, 38. For her part, Ms. Ribeiro says, “I never met anyone so selfless. He really acted like it was no big deal. But he saved my life twice. He is my guardian angel, and he is now family forever.”

Ms. Ribeiro’s surgeon, Vikram Wadhera, MBBS, Assistant Professor, Surgery, says, “The surgery for both patients went extremely well but, for most of us involved, it was the human and emotional aspects of this case that touched us deeply.”

Says donor surgeon Edward Chin, MD, Professor of Surgery, and Director of the Living Kidney Donor Program at the Mount Sinai Health System: “This is such a compelling story. It was such an altruistic thing for Jeramy to do. It reminds us that there’s so much good in the world.”

This winter, Ms. Ribeiro has been regaining her strength and looking forward to jump-starting her life, which had been on hold for the past six years. She expects to complete her master’s degree in Library and Information Science from Rutgers University later this year. Mr. Davies, who now lives in Denver, says he is close to getting back to his routine. He is looking forward to snowboarding and training for a triathlon later this year.

Living donation is the shortest route to organ transplantation and often results in a closer match and better outcome for the recipient. The Zweig Family Center for Living Donation at Mount Sinai is one of the largest living donor programs in the United States.

For information about The Zweig Family Center for Living Donation, click here.

Carnegie Hall Fundraiser Supports Mount Sinai West Program

Updated on Jun 30, 2022 | Community, Featured

The Mount Sinai Health System, along with the UN Chamber Music Society at the United Nations and members of the New York Philharmonic Orchestra, partnered to host a benefit concert at Carnegie Hall on Tuesday, January 15, in support of the Helen Sawaya Fund at Mount Sinai West, a philanthropy program whose mission is to enhance the experience of cancer patients through art, music, reflexology, and more.

The fund was established in 2005 by Gabriel A. Sara, MD, Assistant Professor of Medicine (Hematology and Medical Oncology), Icahn School of Medicine at Mount Sinai, and his friend from high school, Fuad Sawaya, in memory of Mr. Sawaya’s wife, Helen, who had been a cancer patient at Mount Sinai West.

Says Dr. Sara, “Our program addresses the emotional component of the disease and helps alleviate the stress of treatment. It has had an unbelievable impact on patients’ lives and on staff experience. Art and music, especially, reach us where words cannot.”

Mount Sinai and Sema4 Launch Groundbreaking Asthma Study With Global Pharmaceutical Company

Updated on Jun 30, 2022 | Featured, Patient Stories, Research

Andrew Kasarskis, PhD, left, and Linda Rogers, MD, are part of the asthma study team.

Asthma, a chronic disease of the airways of the lungs, is a growing public health problem that now affects 350 million people and results in about 400,000 deaths worldwide each year. Its diagnosis and treatment remain challenging, however, and debilitating symptoms, such as coughing and shortness of breath, are a major cause behind rising health care costs, missed school for children, and loss of productivity and early disability in adults.

Recently, the Mount Sinai Health System and Sema4—a patient-centered predictive health company and a venture of Mount Sinai—joined with Sanofi, one of the world’s largest pharmaceutical companies, to follow 1,200 Mount Sinai patients to gain unprecedented insights into the biological mechanisms and environmental factors implicated in this condition.

The five-year study—the first of its kind—will collect traditional clinical data, such as electronic medical records and clinical samples, including blood samples and nasal brushings, from patients during their doctor appointments. The data will be analyzed for genomic and transcriptomic information and combined with other data collected using the patient’s mobile phone—environmental data, like air quality and pollen counts, data from the patient’s asthma inhaler, and data from home monitoring of activity and sleep. One of the unique elements of this study is that the research will be incorporated into actual clinical practice, and real-world data using remote devices will be integrated with molecular data.

“Despite advances in recent years, we still see many patients struggling with asthma, so there is a tremendous need for innovation to reduce the burden of this disease,” says Linda Rogers, MD, Associate Professor of Medicine (Pulmonary, Critical Care and Sleep Medicine) and Clinical Director of the Adult Asthma Program at the Mount Sinai – National Jewish Health Respiratory Institute. Dr. Rogers is the clinical principal investigator of the study, which is a collaboration among the Respiratory Institute, the Icahn Institute of Genomics and Multiscale Biology, Sema4, and Sanofi.

The Respiratory Institute is uniquely positioned to undertake this research. In addition to the large number of asthma patients that the program treats, the Mount Sinai and Sema4 study team have unparalleled capabilities in specimen analysis, data science, and multiscale biological modeling, allowing researchers to gather large amounts of data more rapidly than using more traditional research methods.

Clinical research teams will deploy advanced analytics on this information to better understand how the disease functions, including what triggers asthma attacks and which patient segments are most likely to respond to certain therapies. “This collection of large amounts of multiple types of data is needed to fully understand asthma—a condition researchers now believe is far more complex than was previously understood—and how best to treat patients,” says Tom Neyarapally, Sema4’s Chief Commercial Officer.

Significantly, gathering and analyzing these kinds of data from patients will demonstrate at the molecular level how their bodies are responding to asthma, says Andrew Kasarskis, PhD, Executive Vice President and Chief Data Officer for the Mount Sinai Health System and a co-principal investigator of the study. For example, analysis of a blood sample will show changes in the cellular activity, such as which proteins are being produced, and a nasal swab may reveal important clues about one’s immune response and what is happening in the lungs.

“We will define asthma subtypes clinically, then understand the molecular basis of disease in each subtype in order to discover new therapies and better manage asthma in all our patients,” says Dr. Kasarskis.

Ultimately, adds Erik Lium, PhD, Executive Vice President of Mount Sinai Innovation Partners, “this collaboration may lead to the identification of novel drug targets and the development of groundbreaking therapies to benefit all patients with asthma.”

Symposium Showcases Neurosurgery Technology

Updated on Jun 30, 2022 | Featured

Fedor E. Panov, MD, center, Assistant Professor of Neurosurgery, Icahn School of Medicine at Mount Sinai, explained the use of a robotic guidance device in epilepsy surgery to Cameron McIntyre, PhD, Tilles-Weidenthal Professor, Biomedical Engineering, Case Western Reserve School of Medicine, left, and Kelly Nicol, MS, medical student at the Philadelphia College of Osteopathic Medicine.

More than 100 physicians, medical and graduate students, residents, advanced practice providers, and other medical professionals attended the Icahn School of Medicine at Mount Sinai Department of Neurosurgery’s Digital Neuro Symposium held at the Hess Center for Science and Medicine on Friday, December 7, and Saturday, December 8. The symposium leaders included Mount Sinai physicians and researchers, joined by 20 academic and clinical experts from across the country, who advanced discussion of the technology revolution taking place in the neurosurgery arena. Topic areas included artificial intelligence, preoperative simulation and navigation tools, the expanding number of digital technologies used in the operating room, next-generation brain circuit therapeutics, and medical device development and entrepreneurship.

The event was co-directed by Joshua B. Bederson, MD, Professor and Chair of Neurosurgery, Mount Sinai Health System, and Clinical Director of the Neurosurgery Simulation Core; and Anthony B. Costa, PhD, Assistant Professor of Neurosurgery, Director of Sinai BioDesign, and Scientific Director of the Neurosurgery Simulation Core. The symposium also included world leaders in the medical technology industry who provided hands-on demonstrations that focused on patient-specific, 3D-printed brain models integrated directly into mock operating rooms.

The Department of Neurosurgery has long been a leader in the use of advanced digital technologies. In 2018, Mount Sinai became one of the first health systems to debut a next-generation microscope, which when integrated with other novel simulation and navigation tools, gives neurosurgeons an unprecedented real-time look into the brain’s vasculature. “Our Department of Neurosurgery is committed to advancing neurosurgical care and helping to educate other medical professionals about the tools and insights they need to improve outcomes for their patients,” says Dr. Costa.

Fedor E. Panov, MD, receives compensation as a consultant and lecturer from Zimmer, manufacturer of the ROSA Robot.

New Pathway to Treating Rheumatoid Arthritis Identified

Updated on Jun 30, 2022 | Featured, Research, Your Health

Pércio S. Gulko, MD, center, with team members Teresina Laragione, PhD, Assistant Professor of Medicine (Rheumatology), left, and Carolyn Harris, Senior Associate Researcher.

A new gene associated with disease severity in rheumatoid arthritis (RA) has been identified by researchers at the Icahn School of Medicine at Mount Sinai. This finding could provide a new pathway for treatment and a way to measure the prognosis of patients diagnosed with this autoimmune condition.

Through a series of experiments, Pércio S. Gulko, MD, Chief of the Division of Rheumatology, and the Lillian and Henry M. Stratton Professor of Medicine (Rheumatology), and his colleagues showed that Huntingtin-interacting protein 1 (HIP1) is a driver in inflammatory arthritis severity. The findings were published in July 2018 in the Annals of the Rheumatic Diseases. “It is known that this gene is expressed in some cancers, but precisely how it contributed to cancer was not known, and it has never been implicated in inflammation or arthritis. So this new discovery, that it regulates cell invasion, is completely novel,” says Dr. Gulko, senior author of the paper.

Rheumatoid arthritis is a chronic disease affecting more than 1.3 million Americans. The disease causes pain, swelling, and sometimes deformation of joints and affects about 1 percent of the world’s population. In the last 20 years, there have been major advances in the treatment of RA, but the existing treatments immunosuppress patients, increasing the risk for infections.

Dr. Gulko with images of synovial fibroblasts, cells in the joints that are central to his team’s study of rheumatoid arthritis.

“At my laboratory, we have been looking for alternative strategies,” Dr. Gulko says. “We have focused on understanding the regulation of disease severity and joint damage, and this led us to the synovial tissue and the fibroblasts.” These cells are present in all joints and produce the fluid that lubricates and nourishes the cartilage, but in patients with RA, they grow out of control, invading and destroying cartilage and bone.

Dr. Gulko’s team started with rodent models of arthritis, studying animals that were highly susceptible to RA and those that were resistant. Using a technique called positional cloning, the researchers identified gene variants that control arthritis severity and the behavior of the synovial fibroblasts, finding that HIP1 made the cells highly invasive. Next, the team studied synovial fibroblasts from patients with RA and found that HIP1 was strongly expressed in those cells. To test the finding further, the team used a molecular biology technique to “knock down,” or remove, HIP1 from the cells of RA patients, and found that this significantly reduced the cells’ ability to invade.

The team unexpectedly found further evidence implicating HIP1 while collaborating in a study of RA and epigenetics, the environmental influence on genetics. The study, which was published in May 2018 in Nature Communications, compared the synovial fibroblasts of patients with RA with those from patients with osteoarthritis, which is not considered an inflammatory disease. The researchers were looking for dysregulated genes and pathways that differentiated the two groups of patients.

“One key pathway found to be epigenomically dysregulated was the Huntington protein pathway, including HIP1,” Dr. Gulko says.

Going forward, Dr. Gulko has several goals: improving the understanding of how HIP1 regulates disease; finding a way to quantify HIP1 levels in the blood or synovial fluid cells with the aim of creating a predictor of disease prognosis; and developing a drug that would target the HIP1 gene. The ultimate goal is to achieve remission for RA patients.

“I treat many patients with rheumatoid arthritis,” Dr. Gulko says, “and all the work that we have done throughout my career has been centered on trying to bring a benefit to these patients.”

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