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.

Dr. Todd Evans, the Peter I. Pressman, M.D. Professor in Surgery and a professor of cell and developmental biology in surgery, gave the keynote lecture "Building a Translational Research Program" at the Endocrine Society's Translational Research Workshop on March 4 in San Diego. The society works to foster a greater understanding of endocrinology among the general public and practitioners of complementary medical disciplines, and to promote the interests of all endocrinologists at the international and national scientific research and health policy levels of government.

Dr. Lisa G. Roth, the Charles, Lillian and Betty Neuwirth Clinical Scholar in Pediatric Hematology/Oncology and an assistant professor of pediatrics, pathology and laboratory medicine, and pediatrics in medicine, joined the Lymphoma Research Foundation's Adolescent and Young Adult Initiative Advisory Committee in December. The foundation is the nation's largest voluntary health organization devoted exclusively to funding lymphoma research and providing patients and healthcare professionals with critical information on the disease. The young adult initiative aims to assist young lymphoma patients in addressing the unique medical challenges, psychosocial needs and access issues they may encounter by providing expert materials and programs.

Dr. Manikkam Suthanthiran, the Stanton Griffis Distinguished Professor of Medicine and a professor of biochemistry, medicine in surgery and medicine, received the International Society of Nephrology Jean Hamburger Award on March 14 at the World Congress of Nephrology in Cape Town, South Africa. The Jean Hamburger Award recognizes outstanding research in nephrology with a clinical emphasis. The award was established in memory of Jean Hamburger, the "Professeuer de Paris," pioneer of clinical nephrology and founding president of the International Society of Nephrology. The society has more than 9,000 professional members from at least 126 countries working toward the goals of reducing the incidence and impact of kidney disease worldwide and making the society the leading international organization for all issues related to the science and practice of nephrology.

The Weill Cornell Department of Medicine's Quality and Patient Safety Committee won the Association of American Medical Colleges' Learning Health System Champion and Pioneer Research Award on Feb. 12. The award recognizes innovations in medical education, care delivery, research, and diversity and inclusion. The Quality and Patient Safety Committee won for its project "A bridge to multidisciplinary and inter-institutional collaboration to build a culture of high value high quality care," which provides funding support to physicians and allied healthcare professionals who are researching innovative ways to improve the quality and safety of patient care in the hospital and in community practice.

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 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.

A consortium of scientists and transplant clinicians from the Ansary Stem Cell Institute at Weill Cornell Medical College and the Center for Cell Engineering at Memorial Sloan Kettering Cancer Center has been awarded a $15.7 million, four-year research grant from the New York State Stem Cell Science Program (NYSTEM) to translate their innovative approach to expand and manipulate hematopoietic stem cells to cure acquired and inherited blood disorders.

For many patients with such blood diseases, including sickle cell disease, the only hope for curing them requires transplanting normal blood stem cells. However, in many instances, suitable normal blood stem cells cannot be found or there are insufficient numbers of cells for transplantation. The consortium seeks to address this critical need with an innovative system to expand stem cells outside the body using specialized blood vessel cells — known as a vascular niche — to support and nurture the stem cells as they do inside the body.

The consortium will conduct two clinical trials using this platform to expand hematopoietic stem cells. The first trial uses the vascular niche to expand umbilical cord blood stem cells for transplantation in patients with blood cancers that cannot be cured by chemotherapy or available donors. The second trial aims to correct the genetic abnormality in blood stem cells from patients with sickle cell anemia and then return these cells to the patients to supply healthy, functioning stem cells. If successful, the techniques may provide safer, more broadly available stem cell transplants to many thousands of patients affected by blood disorders.

"This innovative approach marries Weill Cornell Medical College's stem cell expansion capabilities with Memorial Sloan Kettering's robust cell engineering and gene-transfer techniques," said Principal Investigator Dr. Shahin Rafii, director of Ansary Stem Cell Institute and a professor of medicine, genetic medicine and reproductive medicine at Weill Cornell.

"We are indebted to our NYSTEM partners for their support, because this award offers the opportunity for new curative therapies for patients with blood malignancies and sickle cell disease," said co-Principal Investigator Dr. Joseph Scandura, who is a hematopoietic stem cell physician-scientist and scientific director of the Richard T. Silver, M.D. Myeloproliferative Neoplasm Center at Weill Cornell. Dr. Scandura is also an assistant professor of clinical medicine at Weill Cornell.

Sickle cell disease is caused by a mutation in the oxygen-carrying protein hemoglobin that distorts the size and shape of red blood cells, causing them to clump together and stick to blood vessel walls, cutting off blood and oxygen supply to vital organs. Despite the need, there are no FDA-approved techniques to expand blood-forming stem cells to cure this disease, and any patients who do not receive transplants of normal blood stem cells, either because genetically matched stem cells are not available or because transplanting the cells from another person, risks life-threatening complications.

"The expansion of blood-forming stem cells is a critical advance for the successful implementation of a number of genetic therapies based on gene addition or gene correction," said Principal Investigator Dr. Michel Sadelain at MSK, a leader in T cell and stem cell engineering. "Our combined expertise in stem cell expansion and globin gene therapy for thalassemia is a strong foundation for developing a potentially curative therapy for sickle cell disease," he said, referring to a blood disorder in which the body makes an abnormal hemoglobin.

Consortium scientists expect that the vascular niche platform will generate large numbers of patients' own blood-forming stem cells, enabling a genetic modification of their stem cells and avoiding the risks of transplanting cells from another person. These two trials will require manufacturing of clinical grade human blood vessel, or endothelial cells, for intravenous infusion for "first in man" clinical trials.

The NYSTEM consortium grant supports a collaborative effort led by Principal Investigators Drs. Rafii and Scandura at the Ansary Stem Cell Institute at Weill Cornell and Drs. Sadelain and Isabelle Rivière at MSK. The group, led by Drs. Rafii and Scandura, is joined by co-investigators Drs. Jason Butler, Todd Evans and Koji Shido at the Ansary Stem Cell Institute to complete comprehensive pre-clinical studies in accordance with U.S. Food and Drug Administration guidelines. The team led by Drs. Sadelain and Rivière brings significant expertise with stem-cell engineering and clinical translation of innovative cell therapies. Drs. Juliet Barker, Sergio Giralt and Farid Boulad will lead the phase I clinical trials at MSK that are expected to start within the next two to three years.