Researchers Develop Method to Identify Patient-Specific Drugs for Treating Diabetes


This image shows human embryonic stem cell-derived pancreatic beta cell clusters after being transplanted into immunodeficient mice. 

Image credit: Drs. Hui Zeng and Min Guo

An innovative method that uses human embryonic stem cells to model type 2 diabetes caused by genetic mutations may enable researchers to identify drugs that could treat the disease. The research by Weill Cornell Medicine investigators was published Aug. 11 in Cell Stem Cell, and may extend the use of precision medicine to metabolic diseases.

Using precision medicine approaches that target genetic mutations "is becoming commonly used in cancer, and we think it may be an approach we can use for diabetes," said senior study author Dr. Shuibing Chen, an assistant professor of chemical biology in surgery at Weill Cornell Medicine.

Type 2 diabetes is a condition in which the body does not correctly respond to insulin, a hormone that regulates the amount of glucose, or sugar, in the blood. As a result, people with the condition have high blood sugar levels. While obesity is a risk factor for diabetes, people may develop the disease for a variety of reasons. Genomic studies scanning complete sets of DNA have revealed many genetic mutations implicated in diabetes. But the precise role of these mutated genes, including three chosen for this study — CDKAL1, KCNQ1 and KCNJ11I — has been largely unknown.

To determine the functional role of these genetic mutations, Dr. Chen and colleagues, including Dr. Todd Evans, the Peter I. Pressman, M.D. Professor in Surgery at Weill Cornell Medicine, and Dr. Johannes Graumann, an assistant professor of biochemistry at Weill Cornell Medicine-Qatar, used human embryonic stem cells that were directed to function like pancreatic cells. The cells, called beta-like cells, produce, store and release insulin.

The investigators found that mutations in CDKAL1, KCNQ1 and KCNJ11I hinder the function of beta cells, resulting in decreased insulin release and problems with the regulation of blood sugar levels. They found the same to be true when the cells were studied in a Petri dish or when used in mouse studies. CDKAL1 mutations also caused the beta cells to be highly sensitive to high blood sugar and high fat levels, both of which are a common cause of beta cell death in diabetic patients.

The investigators then screened 2,000 drugs and found "one compound in phase II clinical trials that corrects the CDKAL1-related beta cell defect," Dr. Chen said. Dr. Chen and study co-authors Dr. Hui Zeng and Dr. Min Guo have filed a patent on the application of this compound for the treatment of CDKAL-related beta cell defects. Based on these study results, scientists may be able to "develop gene variant-specific therapy for different categories of diabetic patients," she said.

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Overcoming a Roadblock, Scientists Now Envision Future in Which Ailing Hearts Mend Themselves


For the first time, scientists can efficiently generate large numbers of rare cells in the network that pushes the heart's chambers to consistently contract. The technique, published May 28 in Stem Cell Reports, could be a first step toward using a person's own cells to repair an irregular heartbeat known as cardiac arrhythmia.

Investigators discover how to generate rare cells in the network that pushes the heart's chambers to contract

Investigators at Weill Cornell have discovered how to generate large numbers of rare cells in the network that pushes the heart's chambers to consistently contract. For this image, investigators stained these rare cells, generated from embryonic stem cells, to reveal cell-specific genes (green and red, indicated by arrows). The blue color represents stained cell nuclei. Image credit: Tsai et al./Stem Cell Reports 2015

"This study, while done using mouse cells, will now allow us to develop human heart cells and test their function in repairing damaged hearts," says the study's senior author, Dr. Todd Evans, vice chair for research and the Peter I. Pressman Professor in the Department of Surgery at Weill Cornell Medical College.

The human heart beats billions of times during a lifetime, so it's not surprising that development of irregular heartbeats can lead to a variety of cardiac diseases, Dr. Evans says. But treatments for these disorders are costly as well as insufficiently effective, he says.

"The government pays more than $3 billion each year for cardiac arrhythmia-related diseases. Despite this enormous expense, the treatments we have available are inadequate," he says. "For example, artificial pacemakers are often used, but these can fail, and are particularly challenging therapies for children."

One solution is to coax a patient's own cells to generate the specific kinds of cells in the cardiac conduction system (CCS) that maintain a regular heartbeat.

"We can imagine someday using these cells, for example, to create patches that can replace defective conduction fibers. Of course this is still a long way off, as we would need to study how to coax them into integrating properly with the rest of the CCS," Dr. Evans says. "But previously, we did not even have the capacity to generate the cells, and now we can do so in a manner that is 'scalable,' so that such preclinical research is now feasible."

Dr. Evans worked with Dr. Shuibing Chen, an expert in stem cell and chemical biology, and Dr. Su-Yi Tsai, a postdoctoral fellow and the study's lead investigator. Other key contributors were from the laboratory of Dr. Glenn Fishman, who specializes in cardiac physiology at New York University.

Their first goal was to increase the efficiency of coaxing mouse embryonic stem cells to become CCS cells. They created mouse stem cells that can express a CCS marker gene that researchers can quantify. This allows them to measure how many embryonic cells morph into CCS cells.

By screening about 5,000 small molecules, the investigators found one that increased expression of this marker gene. That molecule pushed over 30 percent of differentiating cells to become rare cells, known as Purkinje cells, which are the terminal part of the conduction system and integrate with working muscle cells. Before, fewer than 1 percent of cells differentiated into these Purkinje cells.

The small molecule worked by activating the cAMP signaling pathway, which then helps push embryonic cells to differentiate, "and which is very druggable — meaning we can find a way to turn it on when we need to produce CCS cells," says Dr. Evans.

"This finding suggests we now have the beginnings of the technology needed to produce specialized cells that may be able to repair the precise areas where contraction is faulty in human hearts," he says.

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Weill Cornell Researcher Receives $1.5 Million NIH New Innovator Award


Weill Cornell Medical College researcher Dr. Shuibing Chen's pursuit of a treatment or cure for type 2 diabetes received a boost a few weeks ago after receiving one of 51 New Innovator awards from the National Institutes of Health.

The award carries $1.5 million in funding over five years supporting Dr. Chen's research into type 2 diabetes — which affects more than 25 million Americans and consumes more than $210 billion in United States health care costs every year — and how to prevent or treat it.

"This new award is extremely important for my laboratory," said Dr. Chen, assistant professor of chemical biology in surgery and assistant professor of chemical biology in biochemistry at Weill Cornell. "Finding the cure for type 2 diabetes mellitus is the core mission of my laboratory. This innovator award recognizes the significance of this mission."

Established in 2007, the New Innovator award initiative supports investigators who are within 10 years of their terminal degree or clinical residency, but who have not yet received a research project grant or equivalent grant from the National Institutes of Health to conduct exceptionally innovative research.

Type 2 diabetes is a metabolic disorder, often caused by obesity, that's characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. While those involved in health care, as well as policymakers, are working on ways to curb the obesity epidemic, Dr. Chen is working behind the scenes to see if type 2 diabetes, once it's developed in a patient, can be reversed.

To determine that, Dr. Chen will study the role of the environment and genetic factors in the progression and regression of cellular dysfunction characteristic of type 2 diabetes in mouse models humanized through stem cells. Using these models, Dr. Chen and her team hope to identify the "tipping point," of type 2 diabetes' progression, thereby learning how to prevent or treat the chronic disease.

"The classic pathogenesis of type 2 diabetes mellitus involves insulin resistance and pancreatic β cell dysfunction," Dr. Chen said. "Pancreatic β cell dysfunction is a key step determining the progression from metabolic impairments to a disease state. We will create two novel models to monitor the progression and regression of pancreatic β cell dysfunction in real-time. By studying the mechanism controlling the progression, we will learn how to prevent type 2 diabetes mellitus. Understanding the mechanism controlling the regression of pancreatic β cell dysfunction will help us to identify novel drug target to reverse the disease state."

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Awards and Honors Across Weill Cornell Medical College - May 4, 2012


Assistant Professor in Emergency Medicine Elected President-elect of Wilderness Medical Society

Dr. Jay Lemery

Dr. Jay Lemery, assistant professor in emergency medicine and director of Wilderness and Environmental Medicine in the Department of Emergency Medicine at Weill Cornell

Assistant Professor in Emergency Medicine Elected President-elect of Wilderness Medical Society Dr. Jay Lemery, assistant professor in emergency medicine and director of Wilderness and Environmental Medicine in the Department of Emergency Medicine at Weill Cornell, was elected president-elect of the Wilderness Medical Society. His term will begin in July.

Founded in 1983, the Wilderness Medical Society is the world's leading organization dedicated to wilderness medical challenges. Dr. Lemery, who is also an assistant attending physician at NewYork-Presbyterian Hospital/Weill Cornell, was previously the society's secretary.

This is but one of Dr. Lemery's recent accomplishments. He has also joined the Centers for Disease Control and Prevention as a consultant for its Climate and Health Program, established in 2009 to lead efforts to prevent and adapt to the anticipated health impacts associated with climate change.

He has also become an official contributing editor to Health and Human Rights: An International Journal, the flagship publication of the François-Xavier Bagnoud Center for Health and Human Rights at the Harvard School of Public Health. The journal provides intellectual leadership in the global effort to realize the right to health, especially for children and other vulnerable groups. Founded in 1993, the academic center is the first of its kind to focus exclusively on the practical dynamic between the issues of health and human rights.

In addition, Dr. Lemery was invited to join the Institute of Medicine's Roundtable on Environmental Health Sciences, Research and Medicine, which addresses current and emerging issues in environmental health through discussions related to the state of the science, research gaps, and policy implications.

Lastly, Dr. Lemery was elected into the Council of Foreign Relations' Stephen M. Kellen Term Member Program, which encourages promising young leaders in government, media, nongovernmental organizations, law, business, finance, and academia to engage in a sustained conversation on international affairs and U.S. foreign policy. The Council, an independent, nonpartisan membership organization, think tank and publisher, is comprised of more than 4,500 people — including Brian Williams, Fareed Zakaria, Angelina Jolie, Chuck Hagel and Erin Burnett.

In recent months, Dr. Lemery has been working with Dr. Neal Flomenbaum, professor of clinical medicine at Weill Cornell and emergency physician-in-chief at NewYork-Presbyterian Hospital/Weill Cornell Medical Center, on a new model for a two-year Wilderness Medicine and Rural Health fellowship designed in part to address the severe shortage of physicians in rural areas surrounding the Adirondack wilderness in New York state.

Dr. Masri Awarded Fellow Status from National Lipid Association

Dr. Bassem Masri

Dr. Bassem Masri, the Daisy and Paul Soros/Racanati Kaplan Professor of Cardiac Prevention and Helen and Stephen Appel Lipid Scholar Award Chair at Weill Cornell Medical College.

Dr. Bassem Masri, the Daisy and Paul Soros/Racanati Kaplan Professor of Cardiac Prevention and Helen and Stephen Appel Lipid Scholar Award Chair at Weill Cornell Medical College, was recently awarded Fellow status with the National Lipid Association. He will receive the award during the association's Annual Sessions May 31-June 1 in Scottsdale, Arizona. Dr. Masri joins more than 200 physicians and allied health care professionals from across the nation to achieve this prestigious credential.

The association awards Fellow status to those who have distinguished themselves amongst their colleagues and who have satisfied the requirements established by the association for recognition: good standing with the organization, possess a professional degree, be nominated by at least two other Fellows of the National Lipid Association, be recognized by peers for contributions to the field of clinical lipidology and have demonstrated a significant commitment to the association at the national or regional level.

Dr. Masri established the lipid clinic and Cardiac Prevention Center at Weill Cornell in 1999, when he joined the Medical College, taking referrals for difficult to treat patients with lipid disorders as well as diagnosing and managing care of patients with cardiovascular disease, diabetes, carbohydrate and lipid metabolic disorders. He also conducts clinical research and clinical trials on lipids, hypertension and diabetes and metabolism.

The National Lipid Association is a nonprofit, multidisciplinary medical society with nearly 3,000 members dedicated to reducing the morbidity and mortality from dyslipidemia and strengthening cardiovascular disease prevention.

Additional Awards and Honors

Dr. George S. Alexopoulos, the Stephen P. Tobin and Dr. Arnold M. Cooper Professor in Consultation Liaison Psychiatry, professor of psychiatry, professor of psychiatry in integrative medicine and director of the Weill Cornell Institute of Geriatric Psychiatry, was recognized by the American Psychiatric Association this year as a Distinguished Fellow.

Dr. Holly S. Andersen, clinical associate professor of medicine in the Division of Cardiology, became a member of the Dartmouth Medical School Board of Overseers this year.

Dr. Shuibing Chen, assistant professor of chemical biology in surgery and assistant professor of chemical biology in biochemistry, was awarded the American Diabetes Association's Junior Faculty Award in January. This award provides $342,000 over three years to support Dr. Chen's research on the disease modeling of maturity onset diabetes of the young 1 (MODY1) using human induced pluripotent stem cells. The models established in this study can also be used to examine the role of genetic factors in the progression of type-2 diabetes.

Dr. Gregory DiFelice, assistant professor of orthopaedic surgery, received the 2011 CORR Multimedia Award for his article "Surgical Technique: When to Arthroscopically Repair the Torn Posterior Cruciate Ligament." The CORR Multimedia Award, an annual prize of $5,000 for the best multimedia award, is bestowed by the journal Clinical Orthopaedics and Related Research, in conjunction with the Association of Bone and Joint Surgeons and Springer. The award is given to articles showing unique and/or distinct observations and illustrations with video clips that complement and reinforce information published in print.

Dr. Joshua S. Dines, clinical assistant professor of orthopaedic surgery, received a Scientific Exhibit Award of Excellence for the exhibit "Managing Bone Loss in Anterior Instability" from the American Academy of Orthopaedic Surgeons and American Association of Orthopaedic Surgeons in February. That same month, he was also named social media editor for the Journal of Shoulder and Elbow Surgery.

Jan Dlabal, a summer student from the Lycée Français de New York, was selected Jan. 11 as a semi-finalist in the 2012 Intel Science Talent Search for work on the determination of large-scale genomic structure performed in the lab of Dr. Olivier Elemento, assistant professor of physiology and biophysics and assistant professor of computational genomics and computational biomedicine.

Dr. Dmitriy N. Feldman, assistant professor of medicine in the Division of Cardiology, was elected a member of the Peripheral Vascular Disease Committee in the Society for Cardiac Angiography and Interventions last year.

Dr. Daniel Gardner, professor of physiology and biophysics and professor of physiology and biophysics in neuroscience, will receive an Excellence in Teaching Award from Weill Cornell.  The award will be presented at the annual Celebration of Teaching dinner June 19.

Dr. Mehmet R. Genc, associate professor of obstetrics and gynecology, was named chairman of the American Society for Reproductive Medicine's Reproductive Immunology Special Interest Group. In addition, he was appointed associate editor of the Journal of Perinatal Medicine.

Jeanette Gerould, a member of the Weill Cornell Master of Science in Health Sciences for Physician Assistant Program Class of 2012, became in January the first recipient of the Bettye Epstein Beaton Memorial Scholarship. The scholarship is the first that Weill Cornell's physician assistant program has offered to recognize an outstanding student who demonstrates financial need and an interest in pursuing a surgical specialty. The scholarship honors Bettye Epstein Beaton, who graduated from the second class of the surgical assistant program at the former New York Hospital. She worked in plastic surgery and became clinical director of the surgical assistant program. Her husband, Dr. Howard Beaton, family and friends established the scholarship in her memory after she lost her battle with acute myeloid leukemia last year.

Dr. Daniel W. Green, associate clinical professor of orthopaedic surgery, became president of the New York County Medical Society for a one-year term beginning in 2011. He is also a new at large member of American Academy of Orthopaedic Surgeons' Communications Cabinet for a two-year term commencing in 2012. In addition, he last year was named a medical officer for the National Disaster Medical System in the U.S. Department of Health and Human Services' Office of Assistant Secretary for Preparedness and Response.

Dr. Xavier Keutgen, a resident in the Department of Surgery, won the New York Surgical Society 2011-2012 Henry Sands Award for best paper presentation, titled, "A Panel of Four MicroRNA's accurately differentiates malignant from benign indeterminate thyroid lesions on fine needle aspiration."

Dr. Mario Lacouture, associate professor of dermatology, received the 2012 Boyer Award in Clinical Research from Memorial Sloan-Kettering Cancer Center, which honors the Center's physicians and scientists under the age of 40 who have demonstrated great promise and accomplishment in clinical and laboratory investigations.

Dr. Fabrizio Michelassi, The Lewis Atterbury Stimson Professor of Surgery at Weill Cornell and surgeon-in-chief at NewYork-Presbyterian Hospital/Weill Cornell, was appointed president of the New York Surgical Society this year. He was the invited lecturer for the first annual Keith A. Kelly MD Lectureship and Visiting Professorship at the Mayo Clinic, hosted Feb. 10 in Phoenix, Ariz. The grand rounds lecture was titled, "Management of Complex Small Bowel Crohn's Disease." In addition, he gave the annual Jameson Chassin Visiting Professor Lecture at NewYork Queens Hospital April 18 about "Management of Complex Small Bowel Crohn's Disease."

Dr. Teresa Milner, professor of neuroscience, was the guest editor of a special issue of Brain Research titled, "Window of Opportunity: Menopause, Estrogen and the Brain," published on March 16, 2011 in vol. 1379 of the journal.  This issue was a collection of 23 multidisciplinary articles presenting the proceedings and discussions that ensued from a "Window of Opportunity" workshop hosted in January 2010. The theme of the issue is translational — from human observation, to the laboratory bench and finally, to clinical trials. In addition to soliciting articles and handling the reviews for each article, her lab contributed four studies to this special issue.

Sayan Mondal, a graduate student in the Physiology, Biophysics and Systems Biology program working in Dr. Harel Weinstein's lab, won the Student Research Achievement Award at the Biophysical Society's 2012 annual meeting Feb. 28 for his poster on the interaction of G protein coupled receptors with the membrane.

Dr. Monn Myat, associate professor in cell and developmental biology, won the Charles Frueauff Foundation Award, which carries a cash prize of $30,000 in January. The Charles A. Frueauff Foundation strives to improve the lives of those in need by awarding grants to non-profit organizations in the areas of education, human services and health and hospitals.

The NewYork-Presbyterian/Weill Cornell Kidney Transplant Program is one of just eight national kidney transplant programs to receive a 2012 HealthGrades Kidney Transplant Excellence Award. This award is given to transplant programs with statistically significantly higher three-year survival rates as well as waitlist mortality that was either not significantly different than expected or was significantly lower than expected based on SRTR calculations. HealthGrades is the leading provider of information to help consumers make an informed decision about a physician or hospital.

Dr. Michelle Sahai, a postdoctoral associate in Dr. Harel Weinstein's lab, was awarded March 30 a three-year Canadian Institutes of Health Research Fellowship for her research on "Molecular Mechanisms of the Dopamine Transporter Function: The Effects of Drugs of Abuse."  Dr. Sahai will receive a stipend of $45,000 and a research allowance of $5,000 per annum.

Dr. Arash Salemi, assistant professor of cardiothoracic surgery, received the American Heart Association/American Stroke Association 2011 Young Heart Award for Achievement in Cardiovascular Science and Medicine as well as the American Heart Association Cardiology Fellows Society of Greater New York Award for Outstanding Support of Cardiovascular Education and Research.

Dr. Jane E. Salmon, professor of medicine and professor of medicine in obstetrics and gynecology, received the Virginia Kneeland Frantz '22 Award for Distinguished Women in Medicine May 4.  This award represents the highest honor the Columbia University College of Physicians and Surgeons Alumni Association can bestow in recognition of outstanding accomplishments.

Dr. Eduardo A. Salvati, professor of clinical orthopaedic surgery, was named honorary member of the Spanish Society of Orthopedics and Traumatology. He will be recognized during the Society's annual meeting Oct. 3 in Malaga, Spain, during which he will also give an honorary lecture.

Dr. Dikoma C. Shungu, professor of physics in radiology, was appointed chair of the Research Scientists Committee in the American Society of Neuroradiology for a two-year term beginning in 2013. Dr. Shungu is also a new chartered member of the Center for Scientific Review's Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section at the National Institutes of Health for a three-year term beginning this year.

The Weill Cornell Physician Organization primary care practices received certification as a Level 3 Patient-Centered Medical Home effective March 2012 to July 2013, from the National Committee for Quality Assurance, a private, 501(c)(3) not-for-profit organization dedicated to improving health care quality. The committee's patient-centered medical home certification is an innovative program for improving primary care.

Dr. Daniel Wellner, professor emeritus of the Department of Biochemistry, received a certificate of recognition from the American Chemical Society congratulating him for 50 years of service to and membership in the society.

Dr. Peter G. Wilson, professor of clinical psychiatry, gave a special invited talk for the Heberden Society lecture series March 20 titled "220 Years of Psychiatry at the NYPH-WCMC." The Heberden Society was established at the former New York Hospital, now known as NewYork-Presbyterian Hospital/Weill Cornell Medical Center, in 1975 by a group of medical interns and residents who were interested in promoting the history of medicine.

Dr. Jonathan Zippin, the Clinique Clinical Scholar in Dermatology and an assistant professor of dermatology, received a special invite to attend the 2012 American Academy of Dermatology's Leadership Forum in Arizona April 13-15. The forum is attended by 30 young dermatologists and designed to train the next generation of leaders in the field of dermatology.

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