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December 10, 2012

 

 

 

Novel Drug Therapy Targets Aggressive Form of Non-Hodgkin's Lymphoma

 

Researchers One-Step Closer to Discovering Combination Drug Therapy for Lymphoma and Avoiding Toxicity of Chemotherapy

 

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma and the seventh most frequently diagnosed cancer. The most chemotherapy resistant form of DLBCL, called activated B-cell – DLBCL (ABC-DLBCL), remains a major therapeutic challenge. An international research team, led by two laboratories from Weill Cornell Medical College, has developed a new experimental drug therapy to target this aggressive form of lymphoma.

 

In the journal Cancer Cell, researchers report the discovery of an experimental small molecule agent, MI-2, that irreversibly inactivates MALT1 — a key protein responsible for driving the growth and survival of ABC-DLBCL cells.

 

"In our study we show the drug MI-2 we developed inactivates any MALT1 protein it touches, and without any apparent toxicity in animal models," says the study's lead investigator, Dr. Ari Melnick, associate professor of medicine and director of the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences at Weill Cornell Medical College.

 

The research team, which includes investigators from Spain, Canada and several other U.S. institutions, are now working to optimize the drug while testing MI-2 with other drug therapies that could be less toxic than current chemotherapy regimens.

 

"No single drug can cure lymphoma. This is why we need to combine agents that can strike-out the different cellular pathways that lymphoma cells use to survive," says Dr. Melnick, who is also a hematologist-oncologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. "We want to eliminate the use of toxic chemotherapy in the treatment of lymphoma patients, and these new study findings take us one-step closer to our goal of creating effective combinational molecular targeted therapy regimens to reduce treatment toxicity and improve lymphoma patient outcomes."

 

"A Bonafide Therapuetic Target"

 

MALT1 is highly active in ABC-DLBCL and plays an important role in lymphoma cancer cell growth and survival. The unique protein is the only paracaspase produced in humans —and is a particular type of protease protein that cuts apart other proteins. But when MALT1 slices proteins in ABC-DLBCLs, it activates growth-promoting molecules and stops the work of other proteins that inhibit that growth.

 

"In essence, MALT1 turns off the brakes and presses the gas pedal to accelerate cell growth and survival in this aggressive cancer," Dr. Melnick says.

 

In this study, the researchers developed an activated form of MALT1 in the test tube that allowed them to study the structure of the molecule, and search for small molecule agents to shut it down. The key insights enabling this technical feat were achieved by co-lead investigator Dr. Hao Wu, an expert in biochemistry and structural biology and a former faculty member at Weill Cornell who is now at Harvard Medical School.

 

The researchers screened libraries of chemicals until they found one that tightly bonded to MALT1, preventing it from cutting other proteins. The agent, MI-2, also inactivated MALT1 in human samples of ABC-DLBCL, according to researchers.

 

When they tested the agent in mice, the research team found it stopped cancer growth without toxicity in normal tissues — a trait Dr. Melnick says is due to the fact that MALT1 is not required for biological processes essential for life.

 

If tested successfully in human clinical trials, MI-2 could have benefits for other diseases, including MALT1 lymphoma, a lower-grade type of lymphoma. It could also possibly play a role in a variety of inflammatory and autoimmune disorders.

 

"MALT1 is a bona fide therapeutic target, and with the discovery of MI-2 we have provided a lead compound that forms the basis of a new class of therapeutic agents," says Dr. Melnick.

 

The Cornell Center for Technology Enterprise and Commercialization, on behalf of Cornell University, has filed a patent application on this research work.

 

This study was funded by the Leukemia & Lymphoma Society, Burroughs Wellcome Foundation, the Chemotherapy Foundation and the Beverly and Raymond Sackler Center for Physical and Biomedical Sciences at Weill Cornell Medical College.

 

Other study co-authors include Dr. Lorena Fontan, Dr. Chenghua Yang, Dr. Venkataraman Kabaleeswaran, Monica Garcia, Dr. Leandro Cerchietti, Dr. Rita Shaknovich, Shao Ning Yan and Dr. Fang Fang from Weill Cornell Medical College; Dr. Elena Beltran and Dr. Jose Angel Martinez-Climent from the University of Navarra, Spain; Dr. Katherine Borden, Dr. Laurent Volpon and Dr. Michael J. Osborne from the University of Montreal, Canada; Dr. Randy D. Gascoyne from the British Columbia Cancer Agency, Canada; and Dr. J. Fraser Glickman from The Rockefeller University.

 

 

November 26, 2012

 

 

 

Argentina Honors Dr. Laurie H. Glimcher for Enriching Scientific Cooperation


Dean of Weill Cornell Medical College Receives Argentina’s Prestigious Dr. Luis Federico Leloir Prize of International Cooperation in Science, Technology and Innovation

 

Dr. Laurie H. Glimcher, the Stephen and Suzanne Weiss Dean of Weill Cornell Medical College and provost for medical affairs of Cornell University, is a winner of the Dr. Luis Federico Leloir Prize of International Cooperation in Science, Technology and Innovation from Argentina's Ministry of Science, Technology and Productive Innovation. One of Argentina's most prestigious awards, it recognizes Dr. Glimcher's contributions to enriching international scientific cooperation with the nation.

 

"It is exciting and deeply humbling to accept this high accolade from Argentina's Ministry of Science, Technology and Productive Innovation," Dr. Glimcher says. "Science and medicine shouldn't have any barriers or borders hindering its advancement to heal patients. The most significant and pivotal biomedical research discoveries are often the result of meaningful collaborations, and it is among my deepest honors to be able to contribute to the successes of fellow investigators in Argentina and science around the globe."

 

The Dr. Luis Federico Leloir Prize is named after the outstanding Argentine biochemist Luis Federico Leloir (1906-1987), who in 1970 became the first Argentine winner of the Nobel Prize in Chemistry and throughout his life advocated for international scientific cooperation with Argentina. The prize was established in 2010 by Minister of Science, Technology and Productive Innovation Dr. Lino Barañao in order to recognize the work of foreign experts who have made meaningful contributions to the promotion and strengthening cooperation in science, technology and innovation with Argentina.

 

Minister Dr. Barañao named Dr. Glimcher a Leloir Prize winner on Nov. 23 at the Ministry of Science, Technology and Productive Innovation's ceremony hosted at the Palacio San Martín in Argentina. This year, other honorees included: Dr. Manuel Cardona and Dr. Arsenio Muñoz de la Peña of Spain; Dr. Ignacio Grossmann of the United States; Mr. Günter Kniess, Argentina's former German Ambassador; Dr. Thomas Maibaum and Dr. Robert Pankhurst of the United Kingdom; Dr. Mogessie Aberra of Austria; Dr. Esther Oliveros of France; Dr. Rafael Radi of Uruguay; and Dr. Paulo Slud Brofman of Brazil. Dr. Glimcher plans to travel to Argentina next year to accept her award.

 

Nominated by Argentina's science and technology advisors and chosen by the Minister, Dr. Glimcher was acknowledged for her generous research contributions and collaborations investigating immune responses in cancer with top Argentinian physician-scientists, including Dr. Gabriel Rabinovich and Dr. Eduardo Arzt. Dr. Rabinovich is the head of the Laboratory of Immunopathology at the Institute of Biology and Experimental Medicine of the Argentinean National Research Council (CONICET) and professor of immunology at the Faculty of Exact and Natural Sciences at the University of Buenos Aires. Dr. Artz is a member of the Research Scientific Career of the National Research Council of Argentina, professor at the University of Buenos Aires and director of the BioMedicine Institute of Buenos Aires – CONICET – Partner Institute Max Planck Society.

 

Dr. Glimcher joins the ranks of some of the most world-renowned scientists who have earned the Leloir Prize honor, including Margaret Ann Shipp, director of Dana-Farber Cancer Institute's Lymphoma Program in Boston, Mass.; Jorge Allende, a professor at the University of Chile; Ugo Montanari, a professor at the University of Pisa, Italy; Robert Boyer, director of research at the Centre National de la Recherche Scientifique in France; Ricardo Ehrlich, Uruguay's minister of education; and Jose Manuel Silva Rodriguez, former director-general for Research of the European Commission.

 

As a leading immunologist, Dr. Glimcher's research discoveries have helped improve understanding of the human immune system and how to manipulate it to better fight cancer. Her laboratory uses biochemical and genetic approaches to elucidate the molecular pathways that regulate lymphocyte development and activation in the immune system. Cell-mediated immunity involves T helper lymphocyte responses that are critical for both the development of protective immunity and for the pathophysiologic immune responses underlying autoimmune, infectious, allergic and malignant diseases. Dr. Glimcher's laboratory has studied the regulatory pathways that control these important immune checkpoints by controlling the production of small hormone-like mediators called cytokines. Dr. Glimcher is a fellow of the American Academy of Arts and Sciences, a member of the National Academy of Sciences USA, and the Institute of Medicine of the National Academy of Sciences. She is also a member and past president of the American Association of Immunologists, which awarded her the Huang Meritorious Career Award in 2006 and the Excellence in Mentoring Award in 2008. She was elected to the American Society of Clinical Investigation, from which she received the Outstanding Investigator Award in 2001, the American Association of Physicians and the American Association for the Advancement of Science. Dr. Glimcher previously directed the Division of Biological Sciences program at the Harvard School of Public Health and was a professor of medicine at Harvard Medical School, where she headed one of the top immunology programs in the world. She also served as senior physician and rheumatologist at the Brigham and Woman's Hospital.

 

This is the third award Dr. Glimcher received in 2012. Earlier this year, she was awarded the William B. Coley Award for Distinguished Research in Basic Immunology from the Cancer Research Institute and the Ernst W. Bertner Memorial Award from the University of Texas MD Anderson Cancer Center. Her numerous other awards include the American Association of University Women Senior Scholar Award (2006); American College of Rheumatology Distinguished Investigator Award (2006); Dean's Award for Leadership in the Advancement of Women Faculty at Harvard Medical School (2006); the Klemperer Award from the New York Academy of Medicine (2003); the American Society of Clinical Investigation Outstanding Investigator Award (2001); and the FASEB Excellence in Science Award (2000).

 

 

November 8, 2012

 

 

 

A New Hub of Scientific Discovery Located on Campus: The Glimcher Laboratory


Dr. Laurie H. Glimcher, the Stephen and Suzanne Weiss Dean of Weill Cornell Medical College, has brought her own laboratory to Weill Cornell — a brand new hub of scientific discovery.

 

The Glimcher Laboratory is housed within 2,371 square feet of space and is equipped with a full spectrum of state-of-the-art equipment. The research focus is on immune and--ER stress responses in disease processes, skeletal biology and the study of cancer. Dr. Glimcher currently serves as principal investigator on 3 NIH-funded projects.

 

A world-renowned investigator in the fields of immunology and rheumatology and a professor of medicine in the Department of Medicine, Dr. Glimcher's research is distinguished by its innovative biochemical and genetic approaches. While at Harvard, she and her team had achieved landmark advancements regarding the molecular pathways that regulate CD4 T helper cell development and activation, which opened the door to further elucidating the complex regulatory pathways that govern T helper cell responses: These pathways are critical to the development of protective immunity and the pathophysiologic immune responses underlying autoimmune diseases. Her team identified a transcription factor XBP1 that is critical in the ER stress response in multiple organs and secretory cells. In the area of skeletal biology, she and her team discovered a novel protein called Schnurri-3, which controls adult bone formation.

 

Dr. Glimcher's five post-doctoral trainees are Drs. Juan Cubillos-Ruiz, Stanley Adoro, Xi Chen, Alexander Espinosa and Anju Singh. Dr. Cubillos-Ruiz is focused on understanding the molecular mechanisms whereby transcription factor XBP1 imprints pro-tumoral functions in leukocytes that infiltrate the microenvironment of solid cancers. He is also studying the role of HIV-induced cellular microRNAs as orchestrators of T Cell depletion and progression to AIDS. Dr. Adoro studies the role of the E3 ligase transcription factors (Trim24 and Trim28) on hematopoietic stem cell differentiation and in the molecular pathogenesis of blood cancers. He is also carrying out a study on cytokines implicated in HIV-1 replication and AIDS. Dr. Chen is studying the function of the endoplasmic reticulum (ER) response in the setting of immunity and cancer. These pathways play a role in allowing the survival and growth of tumor cells. Dr. Espinosa studies novel inducers of endoplasmic reticulum (ER) stress; he is investigating the mechanisms involved both in vitro and in vivo using RNAi library screens with Drosophila cells and genetically modified mice. He has generated a novel BAC transgenic mouse model used together with biochemical methods and RNA-sequencing techniques to detect proteins and RNA molecules bound by the important ER stress inducer IRE1. His ultimate goal is to achieve discoveries that will lead to potential new treatments for certain cancers. Anju Singh works on the stem cell biology of the skeletal system. And graduate student, Sarah Bettigole, is investigating the molecular mechanisms by which the transcription factor XBP-1 controls Type 2 immune responses in macrophages and eosinophils in disease models.

 

Plans are underway to expand the number of trainees, and there are two technicians (Chen Tan and Christina Lee) and an assistant professor in pathology, Dr. Jae Hyuck-Shim, working in the lab. Dr. Hyuck-Shim works closely with a consultant, Dr. Matthew Greenblattfrom Brigham and Women's Hospital. Their work focuses on the cell lineages of osteoblasts and osteoclasts. Dysregulation of these two cell lineages underlies the pathogenesis of many human skeletal disorders, such as osteoporosis, rheumatoid arthritis and Paget's disease. By utilizing knowledge of certain pathways that are important mediators in the immune system — Schnurri-3, MAPK I (mitogen activated protein kinase), and PI3K (phosphoinositide 3-Kinase) — in collaboration with Dr. Glimcher, they seek to uncover the next generation of targeted therapeutics for the treatment of skeletal disorders.

 

The Glimcher Laboratory, taking a creative, eclectic approach to research, is one of many labs pioneering a new era in breakthrough research at Weill Cornell. While trainees benefit from Dr. Glimcher's mentorship in the laboratory setting, there is great promise on the horizon for better treatments at an opportune time for improving patient care. NewYork-Presbyterian Hospital/Weill Cornell Medical Center has seen increasing numbers of cancer patients in recent years, and conditions such as osteoporosis or rheumatoid arthritis are sure to grow as the U.S. population ages. The spark of scientific discovery in Dr. Glimcher’s lab serves as a model for the type of first-rate biomedical research enterprise that is set to find new solutions.

 

 

October 18, 2012

 

 

 

Cancer Research Institute Honors Dr. Laurie H. Glimcher

Dr. Laurie H. Glimcher, the Stephen and Suzanne Weiss Dean of Weill Cornell Medical College and provost for medical affairs of Cornell University, is a winner of the 2012 William B. Coley Award for Distinguished Research in Basic Immunology from the Cancer Research Institute for her outstanding achievements in immunology and cancer research.

 

The William B. Coley Award for Distinguished Research in Basic Immunology was established by the Cancer Research Institute in 1975 in honor of Dr. William B. Coley, the father of the Institute's late founder, Helen Coley Nauts. This award is presented to scientists who have made significant achievements in the field of basic immunology that deepened the understanding of the immune system's response to disease — including cancer — promising further progress in the development of novel and effective future immunotherapies.

 

As a leading immunologist, Dr. Glimcher's research discoveries have helped improve understanding of the human immune system and how to manipulate it to better fight cancer. The Coley Award was presented to Dr. Glimcher at the Cancer Research Institute's 26th annual Awards Dinner hosted Oct. 17 at the Waldorf Astoria in New York City. She shares this year's award with Dr. Ken Murphy, from Washington University School of Medicine in St. Louis, and Dr. Richard Flavell, from Yale University. The honorees are recognized for their pioneering work to define the transcription factors that regulate CD4+ T cell differentiation.
"I am honored and humbled to receive this prestigious immunology research award from the Cancer Research Institute," says Dr. Glimcher, the Stephen and Suzanne Weiss Dean of Weill Cornell Medical College, who is also a member of the Cancer Research Institute's Scientific Advisory Council. "Research discoveries identified about T cells hold tremendous promise for enhancing our knowledge of the fundamental immune responses involved in malignant diseases. Together, our steadfast progress can catapult cancer care to the next level of discovery to develop innovative therapies that improve the lives of cancer patients."

 

Dr. Glimcher has made significant contributions to cytokine research, particularly as it relates to inflammatory diseases of the immune system and cancer immunology. Cytokines are protein molecules secreted by the nervous system and immune system that are used for intercellular communication.
Her primary research specialty is cytokine-specific lymphocyte subtypes. Dr. Glimcher's research has investigated the genetic bases of cytokine expression in T helper lymphocytes. Her research interests are the biochemical and genetic approaches that elucidate the molecular pathways that regulate cell development and activation of lymphocyte subtypes such as CD4 T helper. The complex regulatory pathways governing T helper cell responses are critical for both the development of protective immunity and for the pathophysiologic immune responses underlying cancers. In 1996, she discovered that development of T cells, which are important in allergy and asthma, is regulated by the transcription factor c-maf, a proto-oncogene.

 

Also, Dr. Glimcher's research laboratory has studied the transcriptional pathways that control important immune system checkpoints, leading to many discoveries, including the T-bet transcription factor, which helps regulate a variety of adaptive and innate immune functions. In a landmark paper published in the journal Cell, her laboratory identified T-bet as the master regulator of T lymphocyte helper cells that are vital for fighting off pathogens and cancer. This paper has gone on to be cited over 1,100 times in the literature and has revolutionized the understanding of immunological lineage commitment.
In addition, in a groundbreaking paper published in Nature, her laboratory identified XBP-1 as the first transcription factor known to be required for the generation of antibody-secreting plasma cells from B lymphocytes. She has shown that endoplasmic reticulum stress controlled by XBP-1 is important in inflammatory diseases and in the immune system. Most recently, her laboratory has identified new proteins that control osteoblast (bone formation) and osteoclast (bone loss) commitment and activation in skeletal biology with significant implications for diseases of bone, including cancer metastasis to bone.
Dr. Glimcher is a fellow of the American Academy of Arts and Sciences, a member of the National Academy of Sciences USA, and the Institute of Medicine of the National Academy of Sciences. She is also a member and past president of the American Association of Immunologists, which awarded her the Huang Meritorious Career Award in 2006 and the Excellence in Mentoring Award in 2008. She was elected to the American Society of Clinical Investigation, from which she received the Outstanding Investigator Award in 2001, the American Association of Physicians and the American Association for the Advancement of Science. Dr. Glimcher previously directed the Division of Biological Sciences program at the Harvard School of Public Health and was a professor of medicine at Harvard Medical School, where she headed one of the top immunology programs in the world. She also served as senior physician and rheumatologist at the Brigham and Woman's Hospital.

 

In addition to the Coley Award, her numerous awards include the Ernst W. Bertner Memorial Award from the University of Texas MD Anderson Cancer Center (2012); the American Association of University Women Senior Scholar Award (2006); American College of Rheumatology Distinguished Investigator Award (2006); Dean's Award for Leadership in the Advancement of Women Faculty at Harvard Medical School (2006); the Klemperer Award from the New York Academy of Medicine (2003); the American Society of Clinical Investigation Outstanding Investigator Award (2001); and the FASEB Excellence in Science Award (2000).

 

 

October 12, 2012

 

 

 

Graduate Student Wins Young Investigator Award

PBSB student Jonathan Bourne was recognized with a Young Investigator Award at the 1st Annual Arnold and Madaleine Penner Musculoskeletal Repair and Regeneration Symposium for his work entitled "Covalent Cross-Linking Accelerates Collagen Enzyme Mechano-Kinetic Cleavage: Nanomechanics Predicts Microscale Behavior".  The category included both PhD students and postdoctoral fellows from a number of institutions in the New York City area. The mission of the symposium is to promote and enhance collaboration for researchers in the NYC area and beyond.  The symposium focused on osteoarthritis biology and biomechanics, metabolism regulation in bone and joint tissues, bone remodeling and mechanotransduction, tendon injury and repair, imaging techniques, and stem cell and skeletal tissue repair and regeneration.  The symposium was sponsored by Albert Einstein College of Medicine and Montefiore Medical Center (Bronx, NY) and drew over 225 attendees. 

 

 

September 21, 2012

 

 

MD Anderson Cancer Center Honors Dr. Laurie H. Glimcher
The Ernst W. Bertner Memorial Award Recognizes Dean of Weill Cornell Medical College for her Distinguished Contributions to Cancer Research

Dr. Laurie H. Glimcher, dean of Weill Cornell Medical College and provost for medical affairs of Cornell University, is the winner of the 2012 Ernst W. Bertner Memorial Award from The University of Texas MD Anderson Cancer Center for her distinguished contributions to cancer research.
The Ernst W. Bertner Memorial Award is the oldest award conferred by The University of Texas MD Anderson Cancer Center, and was established in 1950 in honor of Ernst William Bertner, MD, who was the first acting director of MD Anderson Cancer Center and the first president of the Texas Medical Center. The award is made possible by funds from the former Bertner Foundation and MD Anderson Cancer Center.
The award was presented to Dr. Glimcher at the annual MD Anderson Cancer Center's Symposia on Cancer Research 2012 on September 21. The focus of this year's meeting is immunology and inflammation in cancer. As a leading immunologist, Dr. Glimcher's research discoveries have helped improve understanding of the human immune system and how to manipulate it to better fight cancer. Dr. Glimcher presented the Ernst W. Bertner Memorial Award Lecture and Presentation entitled "The Stress Sensor XBP1 in Cancer" at the Symposia on Cancer Research.

 

"I am honored to receive this prestigious cancer research award from the MD Anderson Cancer Center," says Dr. Glimcher, who is also a professor of medicine at Weill Cornell. "My field of cytokine and inflammation research holds much promise for better understanding immune responses underlying malignant diseases. I am so proud to be a part of the discoveries in cancer immunology over the last few decades that have played a pivotal role in our progress against devastating cancers, and toward discovery of innovative cancer therapies to halt this disease in its tracks."

 

Dr. Glimcher has made significant contributions to cytokine research, particularly as it relates to inflammatory diseases of the immune system and cancer immunology. Cytokines are protein molecules secreted by the nervous system and immune system that are used for intercellular communication.
Her primary research specialty is cytokine-specific lymphocyte subtypes. Dr. Glimcher's research has investigated the genetic bases of cytokine expression in T helper lymphocytes. Her research interests are the biochemical and genetic approaches that elucidate the molecular pathways that regulate cell development and activation of lymphocyte subtypes such as CD4 T helper. The complex regulatory pathways governing T helper cell responses are critical for both the development of protective immunity and for the pathophysiologic immune responses underlying cancers. In 1996, she discovered that development of T cells, which are important in allergy and asthma, is regulated by the transcription factor c-maf, a proto-oncogene.

 

Dr. Glimcher's research laboratory has studied the transcriptional pathways that control important immune system checkpoints, leading to many discoveries, including the T-bet and XBP-1 transcription factors, which regulate a variety of adaptive and innate immune functions, as well as the endoplasmic reticulum stress response. In a landmark paper published in the journal Cell, her laboratory identified T-bet as the master regulator of T lymphocyte helper cells that are vital for fighting off pathogens and cancer. This paper has gone on to be cited over 1,100 times in the literature and has revolutionized the understanding of immunological lineage commitment. Also, in a groundbreaking paper published in Nature, her laboratory identified XBP-1 as the first transcription factor known to be required for the generation of antibody-secreting plasma cells from B lymphocytes. She has shown that endoplasmic reticulum stress controlled by XBP-1 is important in inflammatory diseases and in the immune system. Most recently, her laboratory has identified new proteins that control osteoblast (bone formation) and osteoclast (bone loss) commitment and activation in skeletal biology with significant implications for diseases of bone, including cancer metastasis to bone.
Dr. Glimcher is a fellow of the American Academy of Arts and Sciences, a member of the National Academy of Sciences USA, and the Institute of Medicine of the National Academy of Sciences. She is also a member and past president of the American Association of Immunologists, which awarded her the Huang Meritorious Career Award in 2006 and the Excellence in Mentoring Award in 2008. She was elected to the American Society of Clinical Investigation, from which she received the Outstanding Investigator Award in 2001, the American Association of Physicians and the American Association for the Advancement of Science. Dr. Glimcher previously directed the Division of Biological Sciences program at the Harvard School of Public Health and was a professor of medicine at Harvard Medical School, where she headed one of the top immunology programs in the world. She also served as senior physician and rheumatologist at the Brigham and Woman's Hospital.

 

In addition to The Ernst W. Bertner Memorial Award, her numerous awards include the American Association of University Women Senior Scholar Award (2006); American College of Rheumatology Distinguished Investigator Award (2006); Dean's Award for Leadership in the Advancement of Women Faculty at Harvard Medical School (2006); the Klemperer Award from the New York Academy of Medicine (2003); the American Society of Clinical Investigation Outstanding Investigator Award (2001); and the FASEB Excellence in Science Award (2000).

 

 

September 10, 2012

 

 

 

Pain Drug Can Kill Resistant Tuberculosis

Researchers Find Low Cost Drug Wipes Out Drug Resistant TB, But Worry It

May Not Reach Patients In Need

An off-patent anti-inflammatory drug that costs around two cents for a daily dose in developing countries has been found by researchers at Weill Cornell Medical College to kill both replicating and non-replicating drug resistant tuberculosis in the laboratory — a feat few currently approved TB drugs can do, and resistance to those is spreading.

Their findings, published online by the journal PNAS, point to a potential new therapy for the more than 500,000 people worldwide whose TB has become resistant to standard drug treatments. But the researchers worry that the effective drug, oxyphenbutazone, may never be tested in TB clinical trials.

Weill Cornell's Dr. Carl Nathan and his research team found what they call the "completely surprising" ability of oxyphenbutazone to kill drug resistant TB after testing thousands of approved drugs against the bacteria. This repurposing of agents already on the market can lead to quicker testing for new uses.

"This agent might help save lives if there was a way to test it in TB patients," says Dr. Nathan. Oxyphenbutazone went on the market as a patented drug for arthritis-like pain in the early 1950s, and lost its patent and market dominance by the 1970s.

"It is difficult today to launch clinical studies on a medication that is so outdated in the United States, that it is mainly used here in veterinary medicine to ease pain," says the study's senior author, Dr. Nathan, chairman of the Department of Microbiology and Immunology, the R.A. Rees Pritchett Professor of Microbiology, and the director of The Abby and Howard Milstein Program in the Chemical Biology of Infectious Disease at Weill Cornell. "No drug firm will pay for clinical trials if they don't expect to make a profit on the agent. And that would be the case for an off-patent drug that people can buy over the counter for pain in most of the world."

He adds that oxyphenbutazone, best known under the trademark name of Tandearil, does have some established toxicities, "and is not a drug you should take for aches and pains if a safer alternative is available." But the drug's major toxicities appear to be less frequent than the major side-effects of the drug regimens that are currently used to treat TB, he says.

 

TREATING THE TB THAT HIDES

Mycobacterium tuberculosis is unusual among disease-causing bacteria in that it naturally infects just humans. One-third of the world's population is infected with TB, but the bacteria typically remain dormant in a person with a healthy immune system.

Nonetheless, TB becomes active in enough people that it is the leading cause of death in humans from a bacterial infection. It is difficult to treat, and the bacteria can become resistant to therapy. TB treatment in a drug-sensitive patient takes six months, using a combination of agents. If the TB is sensitive to these first-line agents and the therapy is completed with full-strength, non-counterfeit drugs, up to 95 percent of patients can be cured.

However, if a patient's TB becomes resistant to these drugs, second-line agents are administered every day for two years or more. "These second-line drugs are often toxic and expensive, and are not readily available in developing countries, where most of the infections occur," Dr. Nathan says. Mortality in drug resistant TB patients can be as high as 80 percent.

A major issue in treating TB is that the bacteria can "hide out" in the body in a non-replicating form, even when a TB patient is undergoing treatment.

To find agents that could attack non-replicating TB, Dr. Nathan's research team first identified four conditions that keep bacteria in that state within the human body: low oxygen, mild acidity, a fat instead of sugar to eat and a small amount of the natural defense molecule nitric oxide.

The research team replicated those conditions in the test tube and then methodically tested the effectiveness of thousands of agents against the bacteria. After testing 5,600 drugs, researchers found oxyphenbutazone.

Researchers then delved into the mechanism by which oxyphenbutazone kills TB and found that the conditions that allow the bacterium to remain dormant modify the drug to the point that it starts reacting against both non-replicating and replicating TB. "When this happens, TB can't defend itself and dies," Dr. Nathan says.

But the researchers were unable to test oxyphenbutazone in mice, because the animals metabolize the drug to an inactive form far faster than humans.

"This makes testing the drug for TB use in humans problematic since the FDA requires preclinical animal testing studies for safety and efficacy," Dr. Nathan says. "Yet there is a long track record of oxyphenbutazone's relatively safe use in hundreds of thousands of people over decades."

Dr. Nathan and his team are continuing their research, testing hundreds of thousands of compounds for their action against TB. His team has already found another approved drug, nitazoxanide, to be effective against the bacteria, publishing his findings in 2009.

Nitazoxanide, a drug with an excellent safety record, is still on patent for use against some infections caused by other microbes. Discussions have been held about testing it in TB, Dr. Nathan says, but have stalled because of the same problem as oxyphenbutazone. The drug is metabolized so quickly in mice that it cannot be tested against experimental TB in that species.

For both oxyphenbutazone and nitazoxanide, Dr. Nathan argues that the requirement for testing in animals with experimental TB should be waived, because these agents work against TB in the test tube, have already been used with relative safety in people and might address an urgent need for treatment of a contagious disease with high mortality and few other treatment options.

This research was supported by the Tuberculosis Drug Accelerator Program of the Bill and Melinda Gates Foundation and the Abby and Howard P. Milstein Program in Chemical Biology of Infectious Disease.

Co-authors of the study include: Dr. Ben Gold, Dr. Maneesh Pingle, Julia Roberts, Dr. Mark Rundell, Dr. Thulasi Warrier, Dr. Aditya Venugopal, Dr. Crystal Darby, Xiuju Jiang, Dr. J. David Warren, Amy Cunningham-Bussel, Poonam Rath, Tamutenda Chidawanyika, Dr. Selin Somersan and Dr. W. Clay Bracken from Weill Cornell; Dr. Steven J. Brickner of S. J. Brickner Consulting; Dr. Ouathek Ouerfelli and Dr. Nilesh Shah from Memorial Sloan–Kettering Cancer Center; Dr. Eric L. Nuermberger from Johns Hopkins Hospital; and Dr. Joseph Fernandez, Ronald Realubit, Dr. J. Fraser Glickman, and Dr. Haiteng Deng from The Rockefeller University.

 

 

July 6, 2012

 

 

Antibiotic Discovery Vital to Counteract Drug Resistance

If discovery of new antibiotics continue to falter while resistance to those currently in clinical use spread, society will soon lack effective remedies to cure infections.

But it doesn't have to be that way. Collaboration between academia, drug companies and the U.S. federal government can stop that trajectory right in its tracks.

That's the assessment from Dr. Carl Nathan, chairman of the Department of Microbiology and Immunology, professor of Microbiology and Immunology, the R.A. Rees Pritchett Professor of Microbiology and professor of Medicine at Weill Cornell.

In a new State of the Art article, "Fresh Approaches to Anti-Infective Therapies," published in the June 27 issue of Science Translational Medicine, Dr. Nathan explained the linked challenges of antibiotic resistance and discovery and recommended new federal policies and collaborative efforts that can rejuvenate antibiotic discovery — the likes of which are vital to the health and safety of people around the world.

"Our shrinking ability to cure bacterial infections threatens to impair much of our modern medical practice, undermines global economic growth, compromises national security and drives up mortality rates for individuals in all stages and stations of life," Dr. Nathan wrote.

Infectious diseases have been a leading cause of human death for much of history, but one that was greatly diminished in the latter part of the 20th century in America due to improvements to sanitation, nutrition, immunization and antibiotics. But as pharmaceutical companies withdrew from antibiotic discovery — in large part due to revenue — and the food industry began to use antibiotics to enhance animal and plant growth —thereby hastening the spread of resistance — the protection antibiotics afforded diminished.

But it's not enough to go back to the "golden age" when antibiotics were believed to be the most effective line of defense against infections, as that perception, Dr. Nathan said, was just a mirage.

"To regain, maintain and extend substantial control over bacterial infections will require continuous development and application of fresh approaches based on new knowledge, practices and policies," he said. "We need to learn more about how antibiotics work, how bacteria resist them and how to discover, test, approve and conserve them."

To that end, Dr. Nathan recommends that researchers from academic institutions, pharmaceutical companies and government team up in collaborative laboratories to investigate innovative approaches, share best practices and share the rights in resulting intellectual property. Such a model is in practice with the Bill & Melinda Gates Foundation's TB Drug Accelerator, an innovative partnership with seven pharmaceutical companies and four research institutions — including Weill Cornell — recently launched to speed the discovery of new treatments for tuberculosis.

Dr. Nathan also suggests that the government create a national interagency Infectious Disease Policy Board that reports to the president of the United States. This board would establish guidelines on antibiotics — including priorities for antibiotic research, recommended legislation on reducing the administration of antibiotics to healthy food animals and plants, directives for new U.S. Food and Drug Administration regulations for clinical trials and education of the public and physicians on appropriate antibiotic use — and create an efficient monitoring system for antibiotic resistance and infectious disease outbreaks.

"We need efforts that are organized, multidisciplinary, multiple and parallel," he said, "and that bring the private and public sectors together in precompetitive space to address them in accord with a new set of national policies."

 

 

May 31, 2012

 

 

Graduate Students Celebrate Commencement

More than 200 students from Weill Cornell Medical College and the Graduate School of Medical Sciences representing the full scope of medicine — from research to clinical practice — crossed the renowned stage at the majestic Carnegie Hall May 31 to receive their degrees.

Bouquets of red and white flowers lined the stage as Cornell University President David Skorton joined with Deans Laurie H. Glimcher and David Hajjar in conferring the degrees of doctor of medicine, master of science and doctor of philosophy.

The commencement exercises recognized the triumphs of 219 students: 37 with Ph.D.s, 27 physician assistants, 11 with master of science degrees and 144 medical doctors — of who 32 are from Weill Cornell Medical College in Qatar. With the culmination of their education behind them, they will now embark on a new journey that will shape their professional careers.

"Today I share with the faculty, Board of Overseers, Board of Trustees and with family and friends in recognizing you for your achievements, drive, dedication and sacrifices that led to this day," said Cornell University President Dr. David Skorton during his commencement address. "We’re very proud of your achievements and wish you well in your days ahead."

But before parting ways, Dr. Skorton bestowed words of wisdom upon the graduates, challenging them to preserve their curiosity, seek bench-to-bedside research, maintain a work-life balance and become mentors throughout their distinguished careers.

"We are hugely proud of what you’ve accomplished," he said, "and I’m counting on your leadership in the years ahead."

This year, the graduate school student body elected one of their fellow students to address the audience and reflect on what commencement really means.

"How do you get to Carnegie Hall?" joked Manuel Viotti, the student speaker for the graduate school. "Practice, lots and lots of practice."

Each of the Ph.D. candidates practiced in their own way, but they are now unified as doctors and Weill Cornell graduates in pursuit of research that will enhance human health.

"We’ve accomplished an amazing feat, and we have the three letters at the end of our names to prove it," he said.

Sung-ho Park of South Korea, always wanted to study abroad, and with his acceptance to Weill Cornell Medical College as a Ph.D student, he got his chance. On Thursday, he earned his doctorate and is now turning his attention to his postdoctoral research at the Hospital of Special Surgery.

"Today I appreciate the opportunity I had to come to Weill Cornell," he said. "And now I’m starting my new future."

 

 

May 30, 2012

 

 

Students Honored at Convocation Ceremony

Click above to view slideshow

This years' convocation ceremony, was held on May 30, 2012 in Uris Auditorium.

Winner's of this year's Julian R. Rachele prizes and Vincent du Vigneaud awards were given special recognition at convocation.

Graduates Keith N. Brown and Drew Thacker were presented the Julian R. Rachele prize.

Jamie L. McBean and Tina El Reyes were awarded the Vincent du Vigneaud Award of Excellence for poster presentations. The Vincent du Vigneaud Award of Excellence for oral presentations was presented to Vidhya Rangaraju and Kate M. Rochlin.

The Vincent du Vigneaud First-Year Award was given to William Mills and Suranjit Mukherjee and the Vincent du Vigneaud Second-Year Award was presented to Benjamin Burnett.

Dr. Carlos Cordon-Cardo, PhD class of 1985, the Irene Heinz Given and John LaPorte Professor and Chairman of the Department of Pathology, at the Mount Sinai School of Medicine, received the 2012 Distinguished Alumnus Award in recognition of distinguished, lifelong contributions to biomedical research and education.

Dr. Katherine Hajjar and Dr. Teresa Milner received the Dean’s Award for Excellence in Teaching and Mentoring.

Graduating class members have published research papers in prestigious journals of biomedical science, and members presented their research at numerous national meetings and at the Weill Cornell Graduate School Vincent du Vigneaud Research Symposium. This class is characterized by an outstanding level of scientific scholarship together with concerned involvement with education and community outreach. The students have taken active roles in mentoring New York City public school teachers and students with medical science educational workshops, lectures, laboratory demonstrations, and personal mentoring. Many graduates will pursue post-doctoral fellowships at outstanding research institutions throughout the world. Several have chosen to directly enter the fields of biotechnology, patent law, medical writing, technology transfer, and science business consulting.

 

 

May 29, 2012

 

 

Cancerous Tumors Deliver Pro-Metastatic Information in Secreted Vesicles. Cellular Particles Fuse with Organs Establishing an Environment Ripe for the Spread of Cancer

Cancer researchers have known for well over a century that different tumor types spread only to specific, preferred organs. But no one has been able to determine the mechanisms of organ specific metastasis, the so-called "soil and seed" theory of 1889. New details that could help shed light on this hypothesis have been provided by a team of researchers from Weill Cornell Medical College, Memorial Sloan-Kettering Cancer Center, and their collaborators, proposing a new mechanism controlling cancer metastasis that offers fresh diagnostic and treatment potential.

The findings, recently published online by Nature Medicine, show how melanoma cancer cells release small "exosome" vesicles (microscopic particles like "bubbles" filled with many different molecules such as proteins and nucleic acids) that travel to the bone, liver, lung and brain. This cellular material fuses with these organs and establishes an environment ripe for spreading tumor cells.

These dangerous cancer exosomes have many effects, the researchers say, such as triggering inflammation, promoting leaky blood vessels and "educating" bone marrow progenitor cells to participate in the metastatic cascade soon to come.

The fact that these exosomes circulate in the blood — and thus are readily measurable as well as accessible — could provide an advantage to cancer diagnoses, prognoses and treatment, the researchers say.

"The exosome profile could be useful in a number of ways — to help detect cancer early, to predict the aggressiveness of a patient's tumor and response to chemotherapy or other treatments, and to understand the risk of cancer recurrence or spread before traditional methods would be able to," says Dr. David C. Lyden, the Stavros S. Niarchos Associate Professor in Pediatric Cardiology, associate professor of Pediatrics and Cell and Developmental Biology at Weill Cornell Medical College and a pediatric neuro-oncologist at Memorial Sloan-Kettering Cancer Center.

"We believe each tumor type will have its own exosomal protein profile that will represent each tumor subtype," says Dr. Jacqueline F. Bromberg, an associate attending physician at Memorial Sloan-Kettering Cancer Center and associate professor of Medicine at Weill Cornell, who studies breast cancer. "The exosomal proteins will be useful for prognosis in predicting which patients, including those who develop disease decades after their original diagnosis, will likely be at risk for future metastatic disease."

Dr. Lyden and Dr. Bromberg are the study's co-senior authors.

The study's lead author, Dr. Hector Peinado, instructor of molecular biology in the Department of Pediatrics at Weill Cornell Medical College, says the study suggests that effective cancer treatment must be multi-layered. "If, in the future, we were able to find a way to control the 'education' of bone marrow cells, as well as the release and content of tumor exosomes in cancer patients, we would be able to curtail and reduce the spread of cancer, and improve the patient's quality of life and survival," he says.

Not Just Trash Bags

Dr. Lyden and his colleagues have long been trying to decode the biochemical processes that produce the "pre-metastatic niche" — the sites in distant organs that are primed to provide a nurturing home for cells that spread from a primary tumor. He and his colleagues were first to identify that bone marrow-derived cells (BMDCs) were found to be crucial to formation of this niche. In this study they sought to understand the signals that prompt BMDCs to do their work at the niche. They looked at exosomes, microvesicles secreted by all cells, which were long thought to be just cellular trash bags to dump used proteins. Recently, however, exosomes were found to contain RNA, including nucleic acids found in cancer cells. Interest in exosomes increased due to their obvious diagnostic potential.

The researchers were interested to see if the exosomes budding off of melanoma actually participated in the course of the cancer — and they found that they do, and to a great extent.

"Upon their release from the primary tumor, exosomes derived from melanoma cells fuse with cells in distant metastatic organs and lymph nodes, mediating vascular leakiness and inflammation, thereby promoting the formation of pre-metastatic niches that enhance future metastatic growth," Dr. Lyden says.

According to Dr. Peinado, a number of exosomal proteins are transferred by the exosomes to BMDCs where they can reprogram or "educate" the cells to participate in the metastatic cascade. "We found an oncogenic protein, called MET, that is produced by highly metastatic tumors and packaged into pro-metastatic exosomes. The tumor exosomes circulate, fuse and transfer their information, including the MET oncoprotein, to many cells, such as bone marrow cells, which in turn promote a pro-metastatic phenotype," he says.

They also discovered that the education of BMDCs by exosomes is long-lasting, and this may explain how a tumor dormant for decades suddenly develops metastatic disease. These findings are crucial, says Dr. Bromberg, because "educated bone marrow is the key in disease recurrence and may even foster a future secondary cancer."

Examining human blood samples, the scientists found a distinct signature of exosomal proteins (including MET) in patients with stage IV, widely metastatic melanoma that was not found in blood exosomes from patients with non-metastatic melanoma.

They say this protein signature could be used to predict which patients with stage III disease and local lymph node metastasis would then go on to develop distant metastatic disease. "Treatment modalities could be initiated earlier in these high-risk patients to prevent disease progression," Dr. Lyden says. "Our results demonstrated that MET oncoprotein expression, which can be easily analyzed in a simple blood test, could be used as a new marker of metastatic disease in melanoma patients."

The researchers then discovered two ways to reduce exosomal-induced metastasis. One way was to target the protein, Rab27a, responsible for production of exosomes. Another was to proactively educate BMDCs using exosomes spawned from melanoma cells that rarely metastasize.

"We have found that less or non-metastatic exosomal proteins may educate bone marrow cells not to avoid partaking in the metastatic process," says Dr. Lyden. "We are working on determining which particular exosomal proteins may be responsible for preventing metastatic participation.

"This concept may one day be applied to the clinic, where non-metastatic exosome proteins may help prevent the acceleration of tumor growth and metastatic disease, allowing patients with cancer to live longer lives," he says.

Co-authors include Dr. Irina Matei, Bruno Costa-Silva, Caitlin Williams, Dr. Guillermo García-Santos, Dr. Ayuko Nitadori-Hoshino, Dr. Karen Badal and Dr. Caitlin Hoffman from Weill Cornell Medical College; Maša Alečković, Dr. Benjamin A Garcia, and Dr. Yibin Kang from Princeton University; Dr. Simon Lavotshkin from Columbia University; Dr. Vilma R. Martins from the International Center for Research and Education, A.C. Camargo Hospital, São Paulo, Brazil; Dr. Gema Moreno-Bueno and Marta Hergueta-Redondo, Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas 'Alberto Sols', Consejo Superior de Investigaciones Científicas (CSIC)-UAM, IdiPAZ (Instituto de Investigación Sanitaria La Paz) & Fundación MD Anderson Cancer Center, Madrid, Spain; Dr. Cyrus M. Ghajar from the Lawrence Berkeley National Laboratory; Dr. Margaret K. Callahan, Dr. Jedd D. Wolchok, Dr. Paul B. Chapman, Dr. Mary Sue Brady, and Dr. Jianda Yuan from Memorial Sloan-Kettering Cancer Center; Dr. Johan Skog from Exosome Diagnostics Inc., New York; and Dr. Rosandra N. Kaplan, from the National Cancer Institute.

The research was supported by grants from the Children's Cancer & Blood Foundation, The Manning Foundation, The Hartwell Foundation, Pediatric Oncology Experimental Therapeutics Investigators Consortium, Stavros S. Niarchos Foundation, Champalimaud Foundation, The Nancy C. and Daniel P. Paduano Foundation, The Mary Kay Foundation, American Hellenic Educational Progressive Association 5th District, The Malcolm Hewitt Wiener Foundation, the National Cancer Institute, National Foundation for Cancer Research, Susan G. Komen for the Cure, Fundación para el Fomento en Asturias de la Investigación Científica Aplicada y la Tecnología, University of Oviedo Foundation, The Beth C. Tortolani Foundation, Sussman Family Fund, Charles and Marjorie Holloway Foundation, Manhasset Breast Cancer Fund, The National Institutes of Health, Fundação de Amparo a Pesquisa do Estado de São Paulo, the National Science Foundation, The George Best Costacos Foundation, and an American Society for Mass Spectrometry research award.

 

 

 

May 17, 2012

 

 

Researchers Reveal that RNA Modification Influences Thousands of Genes
Genetic Discovery Will Revolutionize Understanding of Gene Expression

Over the past decade, research in the field of epigenetics has revealed that chemically modified bases are abundant components of the human genome and has forced us to abandon the notion we've had since high school genetics that DNA consists of only four bases.
Now, researchers at Weill Cornell Medical College have made a discovery that once again forces us to rewrite our textbooks. This time, however, the findings pertain to RNA, which like DNA carries information about our genes and how they are expressed. The researchers have identified a novel base modification in RNA which they say will revolutionize our understanding of gene expression.

Their report, published May 17 in the journal Cell, shows that messenger RNA (mRNA), long thought to be a simple blueprint for protein production, is often chemically modified by addition of a methyl group to one of its bases, adenine. Although mRNA was thought to contain only four nucleobases, their discovery shows that a fifth base, N6-methyladenosine (m6A), pervades the transcriptome. The researchers found that up to 20 percent of human mRNA is routinely methylated. Over 5,000 different mRNA molecules contain m6A, which means that this modification is likely to have widespread effects on how genes are expressed.

"This finding rewrites fundamental concepts of the composition of mRNA because, for 50 years, no one thought mRNA contained internal modifications that control function," says the study's senior investigator, Dr. Samie R. Jaffrey, an associate professor of pharmacology at Weill Cornell Medical College.
"We know that DNA and proteins are routinely modified by chemical switches that have profound effects on their function in both health and disease. But biologists believed mRNA was simply an intermediate between DNA and protein," he says. "Now we know mRNA is much more complex, and defects in RNA methylation can lead to disease."

Indeed, as part of the study, the researchers demonstrated that the obesity risk gene, FTO (fat mass and obesity-associated), encodes an enzyme capable of reversing this modification, converting m6A residues in mRNA back to regular adenosine. Humans with FTO mutations have an overactive FTO enzyme, which results in low levels of m6A and causes abnormalities in food intake and metabolism that lead to obesity.

The researchers uncovered links between m6A and other diseases as well.

"We found that m6A is present in many mRNAs encoded by genes linked to human diseases, including cancer as well as several brain disorders, such as autism, Alzheimer's disease, and schizophrenia," says the study's lead investigator, Dr. Kate Meyer, a postdoctoral researcher in Dr. Jaffrey's laboratory.

"Methylation in RNA is a reversible modification that appears to be a central step in a wide variety of biological pathways and physiological processes," she says.

The first time that m6A was detected in mRNA was in 1975, but at the time scientists were unsure whether this finding was a result of contamination by other RNA molecules, Dr. Jaffrey says. Over 90 percent of RNA is either transfer RNA (tRNA) or ribosomal RNA (rRNA), cellular workhorses that are routinely modified.

But Dr. Jaffrey says he has always been interested in the idea that mRNA may be modified — "DNA, proteins, other forms of RNA are modified, so why not mRNA?" he says — so he and investigators in his laboratory developed a technique to help them uncover methylation in mRNA taken from both mouse and human samples.

They used two different antibodies that recognize and bind to m6A in mRNA in order to selectively isolate the mRNAs that contain m6A. By subjecting these mRNAs to next-generation sequencing, they were able to identify the sequence of each individual mRNA they had isolated. Co-authors Dr. Christopher Mason and Dr. Olivier Elemento, assistant professors from the Department of Physiology and Biophysics and Computational Genomics in Computational Biomedicine at Weill Cornell Medical College, then developed computational algorithms to reveal the identity of each of these methylated mRNAs.

The Weill Cornell researchers don't know how the thousands of m6As they detected in humans work to control the function of mRNAs, but they do note that the m6As are located near "stop codons" in mRNA sequences. These areas signal the end of translation of the mRNA, suggesting that m6A might influence ribosomal function. "But we really don't know yet," says Dr. Mason, a co-lead investigator on the study. "It may allow other proteins to bind to mRNA, or subject these mRNAs to a whole new regulatory pathway. Our bioinformatics analyses are providing several hints about the possible impact of methylation on RNA function."

Indeed, in their study, the investigators have already found that m6A sites frequently occur in regions of mRNA that are highly conserved across several species of vertebrates. "This shows that m6A sites are not just important for humans, but rather are maintained under selection across hundreds of millions of years of evolution, and thus are likely of critical importance for all animals," Dr. Mason says.

"This is the first demonstration of an epitranscriptomic modification — alterations in RNA function that are not due to changes in the underlying sequence," he adds.

"These findings are very, very exciting, and amazing, really, when you consider that mRNA has been around for so long and that nobody realized, in all this time, that they were being regulated in this way," Dr. Jaffrey says. "It was right under our noses."

In addition to investigating how m6A regulates mRNAs within cells, the researchers are now focused on identifying the enzymes and pathways that control mRNA methylation.

Their study already demonstrates that FTO is capable of reversing adenosine methylation and suggests that it acts on a large proportion of cellular mRNA. "FTO mutations are estimated to occur in one billion people worldwide and are a leading cause of obesity and type 2 diabetes. Our studies link m6A levels in mRNA to these major health problems and identify for the first time the mRNAs which are potentially targeted by FTO," Dr. Meyer says.

The investigators are currently working to understand how defective regulation of m6A in patients with FTO mutations causes obesity and metabolic disorders, and they are also developing tests to rapidly identify compounds that inhibit FTO activity. These compounds are expected to inhibit the overactive FTO found in humans, potentially leading to novel therapeutics for diabetes and obesity.

Other study co-authors are Yogesh Saletore and Paul Zumbo, members of Dr. Mason's Integrative Functional Genomics laboratory, in the Department of Physiology and Biophysics at Weill Cornell.

Weill Cornell Medical College has filed a provisional patent on the techniques used to detect m6A. The study was funded by National Institutes of Health grants and the Starr Cancer Consortium.

 

 

 

May 13, 2012

 

 

New Study Discovers Powerful Function of Single Protein That Controls Neurotransmission

Scientists at Weill Cornell Medical College have discovered that the single protein — alpha 2 delta — exerts a spigot-like function, controlling the volume of neurotransmitters and other chemicals that flow between the synapses of brain neurons. The study, published online in Nature, shows how brain cells talk to each other through these signals, relaying thoughts, feelings and action, and this powerful molecule plays a crucial role in regulating effective communication.
In the study, the investigators also suggest how the widely used pain drug Lyrica might work. The alpha 2 delta protein is the target of this drug and the new work suggests an approach to how other drugs could be developed that effectively twist particular neurotransmitter spigots on and off to treat neurological disorders. The research findings surprised the research team, which includes scientists from University College London.

"We are amazed that any single protein has such power," says the study's lead investigator Dr. Timothy A. Ryan, professor of Biochemistry and associate professor of Biochemistry in Anesthesiology at Weill Cornell Medical College. "It is indeed rare to identify a biological molecule's function that is so potent, that seems to be controlling the effectiveness of neurotransmission."
The researchers found that alpha 2 delta determines how many calcium channels will be present at the synaptic junction between neurons. The transmission of chemical signals is triggered at the synapse by the entry of calcium into these channels, so the volume and speed of neurotransmission depends on the availability of these channels.

Researchers discovered that taking away alpha 2 delta from brain cells prevented calcium channels from getting to the synapse. "But if you add more alpha 2 delta, you can triple the number of channels at synapses," Dr. Ryan says. "This change in abundance was tightly linked to how well synapses carry out their function, which is to release neurotransmitters."

Before this study, it was known that Lyrica, which is used for neuropathic pain, seizures and fibromyalgia, binds to alpha 2 delta, but little was understood about how this protein works to control synapses.

LIFTING UP THE HOOD

Dr. Ryan is building what he calls a "shop manual" of neurological function, much of which centers on synaptic neurotransmission. In 2007 and 2008, he discovered crucial clues to how neurons repackage the chemicals used to signal across synapses. In 2011, Dr. Ryan discovered that distinct neurons differently tune the speed by which they package these chemicals. And in a recent study published April 29 in Nature Neuroscience, he described, for the first time, the molecular mechanisms at the synapse that control the release of dopamine, a crucial neurotransmitter.

"We are looking under the hood of these machines for the first time," he says. "Many neurological diseases are considered to arise from pathologies of synaptic function. The synapse is so complex; at least a few thousand genes control how they work. Repairing them through treatment requires that we understand how they work."

Dr. Ryan and his team often use two tools to conduct these studies — they pin fluorescent tags on to molecules involved in synaptic function, and use ultra sensitive microscopy technology to watch these molecules up close and in real-time.

The researchers used the same toolkit to examine the function of calcium channels, which triggers neurotransmission. "At all synapses, the secretion of a neurotransmitter is driven by the arrival of an electric impulse, initiated by another neuron," Dr. Ryan says. When this impulse arrives at the nerve terminal it triggers the opening of calcium channels. The calcium that rushes in is the key trigger that drives a synapse to secrete its neurotransmitter.

"We have known for the past half century that calcium is a key controller of neurotransmission," he says. "Any small change in calcium influx has a big impact on neurotransmission."

PROTEIN ACTS LIKE A SHIPPING LABEL

But the number of calcium channels at the synapse is not static. Neurons constantly replace worn out channels, and to do this, they build the channels in the neuron's cell body and then package them up and ship them to the nerve terminal. In some cases, that is a very long journey — as much as a few feet, such as the distance between the brain and the base of the spinal cord or the length of a leg.

In the study, researchers tagged fluorescent proteins onto a gene that encodes protein that makes a calcium channel and delivered it to neurons. They then watched the progress of the newly formed channels as they made their way, from day four to day seven, from the bodies of neurons to the synapse.

They also manipulated the levels of alpha 2 delta, a suspected calcium channel partner, and discovered that when the protein was increased, more calcium channels were moved to the synapse. Less alpha 2 delta reduced the flow. "We discovered that alpha 2 delta made the decision of how many calcium channels should be shipped the length of the neuron to the synapse," Dr. Ryan says. "It's like the channels couldn't be transported without an alpha 2 delta shipping label."

The research team found however that alpha 2 delta must work in at least two steps. When they impaired a piece of alpha 2 delta that resembles proteins that are involved in how cells bind to each other, they found that this broken alpha 2 delta could still help get calcium channels shipped down to synapses. But once there, they no longer helped drive neurotransmitter release. "This means that not only does alpha 2 delta help to get calcium channels shipped out, but it also implies that something at the synapse has to sign-off on receiving the calcium channels, putting them in the right place for them to do their job," Dr. Ryan says.

The researchers suggest that Lyrica might work by interfering with this final step since the piece of alpha 2 delta they "broke" that prevents the signing-off resembles parts of proteins that allows them to stick to each other in a kind of handshake.

These findings suggest that future therapies designed to manipulate neurotransmission could try to target this handshaking process, Dr. Ryan says. To do this will require that researchers identify the missing partner in the handshake.

"We hope these exciting findings are providing a new direction in how to make better drugs to control communication between brain cells," Dr. Ryan says.

The study was funded by the National Institutes of Mental Health and the Welcome Trust. Co-authors of the study include Dr. Michael B. Hoppa from Weill Cornell Medical College, and Dr. Beatrice Lana, Dr. Wojciech Margas, and Dr. Annette C. Dolphin from University College London.

 

 

 

May 3, 2012

 

 

Researchers Discover First Gene Linked to Missing Spleen in Newborns

NEW DISCOVERY OF A GENETIC MUTATION IN CONGENITAL ASPLENIA MAY LEAD TO GENETIC PRENATAL SCREENING IN PATIENTS WITH THE RARE, BUT DEADLY, DISORDER

Researchers at Weill Cornell Medical College and Rockefeller University have identified the first gene to be linked to a rare condition in which babies are born without a spleen, putting those children at risk of dying from infections they cannot defend themselves against. The gene, Nkx2.5, was shown to regulate genesis of the spleen during early development in mice.

The study, published online May 3 in Developmental Cell, raises the hope that a simple genetic screening test for Nkx2.5 mutations can be developed that will alert parents that their developing child may be missing the organ, which could then be confirmed with a diagnostic scan.

"The great news is that with the appropriate preventive antibiotic treatment these children will not succumb to fatal infections. This test could potentially save lives," says the study's lead investigator, Dr. Licia Selleri, an associate professor in the Department of Cell and Developmental Biology at Weill Cornell Medical College.

Because defense against infections depends, in part, on the spleen, children known to be born without the organ require treatment with a regimen of antibiotic therapy throughout their lives. But most diagnoses of this condition, congenital asplenia, are made during an autopsy after a child dies, suddenly and unexpectedly, from a rapidly lethal infection, usually from bacteria that causes pneumonia or meningitis, Dr. Selleri says. "For those reasons, we believe this condition is not quite as rare as believed. Not every child who dies from an infection is given an autopsy."

 

LONG SEARCH FOR GENETIC CULPRITS

 

Patients with congenital asplenia usually lack a spleen as the sole abnormality, but sometimes have abnormalities of the heart and blood vessels. The majority of those cases arise sporadically, so are not believed to be inherited. One form of this disorder is known as Isolated Congenital Asplenia (ICA), characterized by a spleen that is missing but with no other developmental abnormalities. The cause is believed to be genetic, but no candidate genes in humans had been found before this study.

This research project was a collaboration between Dr. Selleri and her colleagues, and Rockefeller University's Dr. Jean-Laurent Casanova, professor in the St. Giles Laboratory of Human Genetics of Infectious Diseases. Dr. Casanova had led a previous study describing 20 ICA patients, of which most children suffered their first serious infection by age one, and nine died of an invasive pneumonia.

Dr. Selleri has long been studying congenital asplenia in the laboratory using the mouse as a model system and had previously discovered that a transcription factor known as Pbx is the prime regulator of spleen development in mouse models. Dr. Matthew Koss, a recent Ph.D. graduate who had studied in Dr. Selleri's lab, led the effort to create a strain of mice that lacked Pbx in the spleen, and were born without a spleen. He identified a regulatory module that is controlled by Pbx and targets Nkx2.5, a gene downstream of Pbx, in the developing spleen of the mouse embryo. He also discovered that Pbx controls the growth of the spleen by directly regulating the expression of Nkx2.5, which in turn controls cell proliferation within the primitive spleen organ.

Then, in Dr. Casanova's lab, Alexandre Bolze, a graduate student, sequenced genetic samples from ICA patients and analyzed them using whole exome sequencing technology, which allows sequencing of the entire coding genome of multiple patients — a technique routinely employed by Dr. Casanova. Bolze found that Nkx2.5 was mutated in a family of asplenic patients, some of which died from lethal infections — confirming the importance of Nkx2.5 in human congenital asplenia as in the mouse model of the disorder.

"This study illustrates the unique strength in using mouse models and human genetics hand-in-hand," says Dr. Selleri. "It demonstrates how genetic pathways identified in mouse models can be exploited to further understand the pathogenesis of human disease towards a better prenatal diagnosis."

She says that other patients and families with this disorder need to be studied in order to develop a comprehensive prenatal test. "It may be that there are other mutations that are acting in concert or independently of Nkx2.5 in other asplenic patients," Dr. Selleri says. Those studies in human patients are currently underway in the Rockefeller University lab, while at the Weill Cornell lab additional studies on mouse models are ongoing.

The research was funded by the National Institutes of Health, the March of Dimes and Birth Defects Foundation, the Associazione Italiana Ricera Cancro, the Marie Curie Foundation and the St. Giles Foundation.

Other co-authors include Dr. Andrea Brendolan, Dr. Matilde Saggese, Dr. Terence D. Capellini and Dr. Ekaterina Bojilova from Weill Cornell Medical College; Dr. Bertrand Boisson from Rockefeller University; Dr. Owen W.J. Prall, Dr. David Elliott, Dr. Mark Solloway and Dr. Richard P. Harvey from the Victor Chang Cardiac Research Institute in Darlinghurst, Australia; Dr. Elisa Lenti from the Fondazione Centro San Raffaele Del Monte Tabor in Milan, Italy; Dr. Chisa Hidaka from the Hospital of Special Surgery; Dr. Ching-Pin Chang from Stanford University School of Medicine; and Dr. Nizar Mahlaoui from Necker Hospital in Paris, France.

 

 

May 1, 2012

 

 

IMP Faculty Member Dr. Alexander Rudensky Elected a Member of the National Academy of Sciences

The National Academy of Sciences today announced the election of 84 new members and 21 foreign associates from 15 countries in recognition of their distinguished and continuing achievements in original research.

Those elected today bring the total number of active members to 2,152 and the total number of foreign associates to 430. Foreign associates are nonvoting members of the Academy, with citizenship outside the United States.

Weill Cornell Graduate School Professor in the Immunology and Microbial Pathogenesis Program and Howard Hughes Medical Institute Investigator Dr. Alexander Rudensky, Ph.D. was elected as a member for his excellence in scientific research. Membership in the NAS is one of the highest honors given to a scientist in the United States.

 

 

May 1, 2012

 

 

Weill Cornell Researcher Wins Prestigious Award Supporting Epigenomic Study

Dr. Olivier Elemento, an assistant professor in the Department of Physiology and Biophysics and an assistant professor of computational genomics in the Institute for Computational Biomedicine at Weill Cornell Medical College, recently received the National Science Foundation Faculty Early Career Development Award.

The most prestigious award bestowed by the National Science Foundation, it honors junior faculty who exemplify excellence as teacher-scholars through research, education and the integration of education and research.

The award will support Dr. Elemento's research to develop novel computational methodologies to better understand how the epigenome regulates genes expression in normal and malignant cells through a five-year $1.5 million grant, effective May 1.

"It's really one of the most prestigious awards the National Science Foundation gives, so it's obviously great to be awarded this grant," said Dr. Elemento.

This is the second time in four years that a researcher in the Department of Physiology and Biophysics garnered the Foundation’s Faculty Early Career Development Award. Dr. Scott Blanchard, associate professor of physiology and biophysics, received the honor in 2008 for his groundbreaking work in cell biology, focusing specifically on the ribosome, the complex molecular machine responsible for translating DNA-encoded instructions into usable proteins.

Dr. Elemento and his lab are engaged in a large scale effort to better understand how the epigenome, which controls the differential expression of genes in specific cells by learning how the combined effects of modifications to chromatin, the combination of DNA and proteins that comprise the nucleus of a cell, together with chromatin folding, which brings chromatin regions that are normally far away from each other on a chromosome close to each other, influence gene expression in malignant and normal cells. Because the epigenome is known to be massively reprogrammed in cancer cells, the knowledge gained from this research should ultimately lead to more targeted therapeutic strategies in the treatment and diagnosis of cancer.

In the awarded project, Dr. Elemento will develop computational methods to analyze and interpret epigenomics and chromatin interaction datasets obtained from deep sequencing. Dr. Elemento believes these computer models in conjunction with experimentation will enable him to discover and characterize the principles by which regulatory elements located far away from genes contribute to transcriptional activation, the first step leading to gene expression. The National Science Foundation award will also support additional researchers hired by Dr. Elemento for the project as well as necessary computational equipment and infrastructure. Finally, funds provided by this award will go towards organizing epigenomic data analysis workshops to teach members of the Weill Cornell community how to analyze complex epigenomic datasets.

Dr. Elemento received a bachelor's degree in mechanical engineering from the Paul Sabatier University in Toulouse, France; a master's degree in mechanical engineering from INSA Toulouse, one of the largest engineering schools in France, and Nottingham University in England; a master's in computer science and artificial intelligence from Dauphine University in Paris, France; and a doctorate in computational biology from CNRS/University of Montpellier in France. An author of numerous articles on epigenomics, Dr. Elemento joined Weill Cornell in 2008 as an Institute for Computational Biomedicine Institute Fellow and group leader and was promoted to assistant professor a year later.

 

 

 

April 17, 2012

 

 

 

32nd Annual Vincent du Vigneaud Memorial Symposium

On April 17, 2012 the 32nd Annual Vincent du Vigneaud Memorial Symposium was hosted by the Weill Cornell Graduate School of Medical Sciences of Cornell University. Since 1981, the symposium has been a showcase of Ph.D. students’ original research. This year more than 80 posters and talks were presented by students to their colleagues and to the faculty of the school.

The keynote address was delivered by Dr. Karl Deisseroth, M.D., Ph.D.. Dr. Deisseroth is an Associate Professor of Bioengineering and Psychiatry at Stanford University as well as a Howard Hughes Medical Institute Early Career Investigator who has received numerous awards for developing optogenetics. His speech was entitled “Optogenetics: Development and Application”. At each Du Vigneaud Symposium students receive awards for both poster and oral presentations. Below is the list of this year’s winners.

2012 Vincent du Vigneaud Awards of Excellence

Poster Presentation:

Jamie L. McBean, “Elucidation of the Substrate Profile of Protein Methyltransferase SET7/9.” (Professor Minkui Luo)

Tina El Rayes, “Metastasis-Incompetent Tumors Systemically Generate Metastasis-Suppressive Niche.” (Professor Vivek Mittal)

Oral Presentation:

Vidhya Rangaraju, “Syn-ATP a Novel Optical Reporter of Presynaptic ATP Levels.” (Professor Timothy A. Ryan)

Kate M. Rochlin, “Identification of a Novel Splicing Factor is Required for Proper Myotendenous Junction Formation and Maintenance in Drosophila.” (Professor Mary Baylies)

2012 Vincent du Vigneaud First-Year Awards:

William Mills, “Characterization of Szeto-Schiller Tetrapeptide/Phospholipid Binding.” (Professor Hazel Szeto)

Suranjit Mukherjee, “Development of New Heteroclitic Peptides for B702 and A3/A11 HLA
Types for WT1.” (Professor David Scheinberg)

2012 Vincent du Vigneaud Second-Year Award:

Burnett, Benjamin, “Kinetic Properties of Elongation Factor-Tu, GTP, and Aminoacyl-tRNA Ternary Complex from Escherichia coli.” (Professor Scott C. Blanchard)

 

 

April 10, 2012

 

 

Weill Cornell Graduate School of Medical Sciences' Seventh Postdoctoral Research Day

For Dr. Peter Grunert, a native of Austria, the decision to come to Weill Cornell Medical College for postdoctoral research in neurosurgery was an easy one.

"I knew Weill Cornell's Neurological Surgery Department is famous for spine surgery," he said. "This is one of the best places to do research."

Dr. Grunert has, since last year, delved into research evaluating the impact of tissue–engineered spinal discs implanted in rats, the results of which may have clinical implications for patients with disc degeneration who now depend on metal prostheses.

"It's hard work and a lot of commitment, but it's very rewarding," said Dr. Marisa Carbonaro, who completed graduate school at Weill Cornell and decided to stay on for her postdoctoral training with research focusing on oncology drugs. "I'm learning something new all the time."

Dr. Grunert and Dr. Carbonaro joined 52 of their fellow postdocs at Weill Cornell on April 10, to present their research during the Medical College's seventh annual Postdoctoral Research Day, a four–hour long event that offers postdocs the opportunity to share their research with their colleagues, faculty and other investigators. Nearly 300 people packed Griffis Faculty Club to learn about the work being done at Weill Cornell, including Dr. Laurie H. Glimcher, the Stephen and Suzanne Weiss Dean of Weill Cornell Medical College.

"I think you’ll find the research impressive," said Dr. Randi B. Silver, associate dean of the Graduate School of Medical Sciences, professor of Physiology and Biophysics and faculty director of the Office of Postdoctoral Affairs. "We are very proud of the contributions of the postdocs to the institution's research and today they have the opportunity to showcase their efforts."

The postdocs presented posters on research in six categories: oncology; neuroscience; cardiology and hematology; microbiology and immunology; metabolic diseases; and computational biology. Leaders of the Medical College's Postdoctoral Association say the sheer number of presenters is a testament to the dedication they bring to their work.

"It's a major accomplishment considering it takes a lot to put these posters together," said Dr. Giovanni Passiatore, a board member of the association and chair of the association's Research Day Organizing Committee.

The Postdoctoral Research Day was created to give postdoctoral trainees the opportunity to present their current research to peers and mentors through oral and poster presentations. The Research Day Organizing Committee, comprised of nearly a dozen postdoctorates, met biweekly since November to plan the event.

It also featured addresses from two prominent scientists, Dr. David P. Hajjar, dean of the Graduate School of Medical Sciences and the Frank H.T. Rhodes Professor of Cardiovascular Biology and Genetics who spoke of the future of postdoctoral research, and Dr. David C. Lyden, the Stavros S. Niarchos Associate Professor of Pediatrics and Cell and Developmental Biology at Weill Cornell and a pediatric neuro–oncologist at Memorial Sloan–Kettering Cancer Center, whose talk was titled, "Tumor–derived Exosomes 'Educate' Bone Marrow Progenitor Cells Towards a Pro–metastatic Phenotype."

"Today is about celebrating the research efforts of postdocs here at Weill Cornell, as well as giving everyone a sense of where they can go next in their careers," said Dr. Amanda Sadacca, vice president of the association.

It's on that last point that Dr. Hajjar pledged to postdocs that the institution will do whatever it can to help them in their burgeoning careers.

"It's no secret that federal budgets are going to be flat, and they are going to be flat for a while," he said to a standing–room–only crowd. "We recognize that the job market is going to be tough. But we will think about how we can help mentors 'package' you to get the right job."

Members of the Medical College's Postdoctoral Association Research Day Organizing Committee: Giovanni Passiatore, Leigh Amanda Sadacca, Kwame Osei–Sarfo, Frances Gratacos, Harvey Chin, Manu Jain, Mayako Michino, Ronald Perez, Madhumitha Nandakumar, Marin Schlossberg, Georgette Yandolino.

 

 

March 27, 2012

 

 

IMP Student Wins 2012 Joanna M. Nicolay Melanoma Foundation Scholarship Award

Award winner photo

New York, New York –The Joanna M. Nicolay Melanoma Foundation (JMNMF) presented Judith Murphy, attending the Weill Cornell Graduate School of Medical Sciences with one of nine, nationally competitive, "Research Scholar Awards" (RSA). The $10,000 melanoma research grants support exceptional graduate students and provide recognition to their lab directors/PIs, schools, and cancer research institutions across the U.S. The JMNMF grants increased dramatically, by nearly 30% in 2012 (following a 40% funding increase in 2011), to significantly enhance the potential for advancements in the melanoma cancer field.

The 2012 RSA applicant pool and cancer research centers represented grew to include 42 of the country’s most promising young melanoma researchers, and 28 prominent National Cancer Institute (NCI)-Designated Cancer Centers or members of the Association of American Cancer Institutes (AACI). This represents a dramatic 60% increase in students and 75% growth in research institutions participating over 2011. As first in the U.S. to fund graduate student melanoma researchers, the JMNMF program is celebrating the program’s sixth anniversary. The Research Scholar Award program was initially piloted with the Johns Hopkins Sidney Kimmel Cancer Center in 2006, and expanded nationally to benefit the broader academic, scientific, clinical and patient communities and encourage larger numbers of students to choose melanoma research as their professional career path.

"Applying for and receiving the Research Scholar Award from the Joanna M. Nicolay Melanoma Foundation was not only rewarding from an academic perspective, it was also an inspiring way to learn more about efforts made outside of the lab to fight melanoma through education and legislation."-Judith Murphy

According to Robert E. Nicolay, JMNMF Chairman, "Our Foundation’s ‘Research Scholar Awards’ are invaluable at the grassroots level, to specifically grow interest in melanoma research, at qualified cancer centers across the country. If we can attract the brightest minds that are considering, or already within, the nation’s cancer research pipelines, to pursue a career in melanoma research – we’re that much closer to better understanding the disease, identifying the means for effective treatments and, most importantly, finding a cure for this deadly and very prevalent disease."

The Foundation continues to experience tremendous growth in this valuable student research program in both depth and breadth of funding, and in the diversity of candidates and institutions participating.

The JMNMF proudly recognizes the RSA Professional Advisory Panel that unselfishly review student researcher applications thoroughly, and provide extensive expertise and professionalism in objectively evaluating candidate applications. In 2012 the RSA Panel members were expanded to
accommodate the program’s growth, and are as follows:


Rhoda M. Alani, M.D.
Herbert Mescon Professor and Chair
Department of Dermatology
Boston University School of Medicine
Dermatologist-in-Chief
Boston Medical Center
Boston, MA

Marcus Bosenberg, M.D., Ph.D.
Associate Professor Dermatology and Pathology
Melanoma Program, Yale Cancer Center
Yale University School of Medicine
New Haven, CT

Jeffrey E. Gershenwald, M.D., FACS
Professor of Surgery
Professor of Cancer Biology
Depts. of Surgical Oncology and Cancer Biology
Medical Director, Melanoma and Skin Center
The University of Texas M. D. Anderson Cancer Center
Houston, TX

Meenhard Herlyn, D.V.M., D.Sc.
Caspar Wistar Professor in Melanoma Research
Director, The Wistar Institute Melanoma Research Center
Professor and Co-program Leader, Tumor Microenvironment
and Metastasis Program
The Wistar Institute
Philadelphia, PA

John M. Kirkwood, M.D.
Usher Professor of Medicine, Dermatology and
Translational Science
Vice Chair for Clinical Research, Dept of Medicine
University of Pittsburgh School of Medicine
Director, Melanoma Program
University of Pittsburgh Cancer Institute
Pittsburgh, PA

Gavin P. Robertson, Ph.D.
Prof. of Pharmacology, Pathology, Dermatology and Surgery
Department of Pharmacology and Penn State Cancer Institute
Director, Penn State Melanoma Center
Director, Penn State Melanoma Therapeutics Program
Director, Foreman Fdn. Melanoma Research Laboratory
Penn State University
Hershey, PA

Yardena Samuels, Ph.D.
Head, Molecular Cancer Genetics Section
National Human Genome Research Institute
National Institutes of Health
Bethesda, MD

All 42 RSA candidates were objectively evaluated in two stages utilizing a quantifiable rating spreadsheet tool: First, independently by the RSA Professional Advisory Panel members; and, secondly, on an independent basis by the Foundation’s RSA Committee comprised of Board of Director members. Independent results for both groups were then separately compiled and utilized by the RSA Committee for final awards discussion and selection.

Five broad candidate evaluation categories included: Scope & Innovation; Feasibility; Organization; Future Collaboration & Application; and, Overall panel/committee recommendations of individual applicants that also ruled out any applicant/evaluator bias/conflicts. Each category for all applicants was scored within a range of metrics to reach a summary score. Though difficult, the final evaluations and awards are the result of a broad collective analysis.

The Foundation continues to refine and improve the process in each successive award year. All RSA recipients, and the entire pool of applicants, represent the forefront of compelling research to further the understanding of melanoma biology, develop effective treatments and, to definitively find a cure.

JOANNA M. NICOLAY MELANOMA FOUNDATION
The Joanna M. Nicolay Melanoma Foundation is a non-profit public charity founded in January, 2004 to foster melanoma education, advocacy and research. In just eight years, the Foundation has grown dramatically to become an influential voice in the melanoma community and is now established as a national, and international, "voice for melanoma prevention, detection, care and cure."

JMNMF Contact:
Gregory Safko
President
Joanna M. Nicolay Melanoma Fdn.
(410) 857-4890
gsafko@melanomaresource.org

255 Clifton Blvd., Suite 203
Westminster, MD 21157
www.melanomaresource.org

Weill Cornell Contact:
Xiaoai Chen, Ph.D.
Fellowships and Outreach Director
Weill Cornell Graduate School of Medical Science
(212) 746-6585
xic2001@med.cornell.edu

1300 York Avenue, A-131
New York, NY 10065
http://weill.cornell.edu/gradschool

 

March 27, 2012

 

 

New Gene Therapy Approach Developed for Red Blood Cell Disorders. Researchers Say Their Method, Tested in Human Cells, May Offer the First Viable Approach to Gene Transfer in Sickle Cell Anemia

A team of researchers led by scientists at Weill Cornell Medical College has designed what appears to be a powerful gene therapy strategy that can treat both beta-thalassemia disease and sickle cell anemia. They have also developed a test to predict patient response before treatment.
This study's findings, published in PLoS ONE, represents a new approach to treating these related, and serious, red blood cells disorders, say the investigators.

"This gene therapy technique has the potential to cure many patients, especially if we prescreen them to predict their response using just a few of their cells in a test tube," says the study's lead investigator, Dr. Stefano Rivella, Ph.D. , an associate professor of genetic medicine at Weill Cornell Medical College. He led a team of 17 researchers in three countries.
Dr. Rivella says this is the first time investigators have been able to correlate the outcome of transferring a healthy beta-globin gene into diseased cells with increased production of normal hemoglobin — which has long been a barrier to effective treatment of these disease.

So far, only one patient in France has been treated with gene therapy for beta thalassemia, and Dr. Rivella and his colleagues believe the new treatment they developed will be a significant improvement. No known patient has received gene therapy yet to treat sickle cell anemia.

A Fresh Approach to Gene Therapy

Beta-thalassemia is an inherited disease caused by defects in the beta-globin gene. This gene produces an essential part of the hemoglobin protein, which, in the form of red blood cells, carries life-sustaining oxygen throughout the body.

The new gene transfer technique developed by Dr. Rivella and his colleagues ensures that the beta-globin gene that is delivered will be active, and that it will also provide more curative beta-globin protein. "Since the defect in thalassemia is lack of production of beta-globin protein in red blood cells, this is very important," Dr. Rivella says.

The researchers achieved this advance by hooking an "ankyrin insulator" to the beta-globin gene that is carried by a lentivirus vector. During the gene transfer, this vector would be inserted into bone marrow stem cells taken from patients, and then delivered back via a bone marrow transplant. The stem cells would then produce healthy beta-globin protein and hemoglobin.

This ankyrin insulator achieves two goals. First, it protects delivery of the normal beta-globin gene. "In many gene therapy applications, a curative gene is introduced into the cells of patients in an indiscriminate fashion," Dr. Rivella explains. "The gene lands randomly in the genome of the patient, but where it lands is very important because not all regions of the genome are the same." For example, some therapeutic genes may land in an area of the genome that is normally silenced — meaning the genes in this area are not expressed. "The role of ankyrin insulator is to create an active area in the genome where the new gene can work efficiently no matter where it lands," Dr. Rivella says. He adds that the small insulator used in his vector should eliminate the kind of side effects seen in the French patient treated with beta-thalassemia gene therapy.

The research team also discovered that the insulator increases the efficiency by which the beta-globin gene is transcribed during the process of making the red blood cells. "We found the gene is integrated into cells which have not yet begun to make red blood cells, and when they do, the beta-globin gene is activated," Dr. Rivella says. "We showed that if the insulator is present, activation of the curative gene is more efficient. This provides more curative protein to red blood cells."

The study further provides evidence that the vector had different rates of efficiency depending on the beta-thalassemia mutation it was used in — thus providing the basis for a predictive test in patients. The investigators tested 19 different beta-thalassemia samples comprising the two types commonly found in patients — "beta-zero" cells that do not produce any beta-globin (forcing patients to receive blood transfusions throughout life), and "beta-plus" cells that produce suboptimal levels of hemoglobin. On average, they found that one copy of the vector in beta-zero cells produced 55 percent of the adult hemoglobin seen in normal individuals. Beta-plus cells, after treatment, produced hemoglobin comparable to a healthy individual, and were thus cured.

"The variable nature of the beta-thalassemia mutations suggests that some patients would be better candidates for gene therapy than others, and that success of gene therapy depends on the ability of a specific vector to make hemoglobin," Dr. Rivella says. "This is something we can test in advance using a little bit of a patient's blood — which is quite extraordinary."

The issue in sickle cell anemia is very different, Dr. Rivella says. The hemoglobin protein is made in the right quantities, but it is not normal — the red cell is shaped like a sickle and is abnormal in function. "One of the problem in gene therapy of sickle cell anemia is to add a new gene without increasing too much the total amount of protein, both normal and sickle. This would cause other problems," he says.

By treating eight cell specimens taken from sickle cell anemia patients, the investigators discovered that attaching the ankyrin insulator to a normal beta-globin gene increases the amount of normal beta globin protein while reducing the quantity of sickled protein. "The total amount of protein stays the same, which is very important," says first author Dr. Laura Breda, pediatric research associate at Weill Cornell Medical College.
The researchers say that their advances will likely make a substantial impact on a number of fields, including gene regulation and transfer and the design of gene therapy trials. "This study represents a fresh departure from previously published work in the field of gene therapy," Dr. Rivella says. The PLoS ONE article may be found online at after the embargo lifts.
The study was funded by the Cooley's Anemia Foundation (CAF), the Veneta Association for the Fight Against Thalassemia (AVLT-Italy), the Children's Cancer and Blood Foundation, the Clinical and Translational Science Center, the Carlo and Micol Schejola Foundation, Telethon, and grants from the National Institutes of Health.

Co-authors include: Laura Breda, Carla Casu, Sara Gardenghi, Dorothy A. Kleinert, Robert W. Grady, and Patricia J. Giardina (Weill Cornell Medical College); Nicoletta Bianchi, and Roberto Gambari, from Universita' di Ferrara, Ferrara, Italy; Luca Cartegni, from Memorial Sloan Kettering Cancer Center; Mohandas Narla, Karina Yazdanbakhsh, from the New York Blood Center; Marco Musso, from Ospedali Galliera, Genova, Italy; Deepa Manwani, from the Albert Einstein College of Medicine; Jane Little, from Montefiore Medical Center now at the UH Seidman Cancer Center, Cleveland; Lawrence B. Gardner, from New York University, and Eugenia Prus, and Eitan Fibach, from Hadassah–Hebrew University Medical Center, Jerusalem, Israel.


Contact Info
Richard Pietzak
riz2008@med.cornell.edu

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March 8, 2012

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Weill Cornell Researchers Develop Powerful Tool to Measure Metabolites in Living Cells

Glowing "Spinach" Produces a Snapshot of Abnormal Molecules Inside Diseased Cells, Providing Clues About How to Treat Disorders.

By engineering cells to express a modified RNA called "Spinach," researchers have imaged small-molecule metabolites in living cells and observed how their levels change over time. Metabolites are the products of individual cell metabolism. The ability to measure their rate of production could be used to recognize a cell gone metabolically awry, as in cancer, or identify the drug that can restore the cell's metabolites to normal.

Researchers at Weill Cornell Medical College say the advance, described in the March 9 issue of Science, has the potential to revolutionize the understanding of the metabolome, the thousands of metabolites that provide chemical fingerprints of dynamic activity within cells.

"The ability to see metabolites in action will offer us new and powerful clues into how they are altered in disease and help us find treatments that can restore their levels to normal," says Dr. Samie R. Jaffrey, an associate professor of pharmacology at Weill Cornell Medical College. Dr. Jaffrey led the study, which included three other Weill Cornell investigators.

"Metabolite levels in cells control so many aspects of their function, and because of this, they provide a powerful snapshot of what is going on inside a cell at a particular time," he says.

For example, biologists know that metabolism in cancer cells is abnormal; these cells alter their use of glucose for energy and produce unique breakdown products such as lactic acid, thus producing a distinct metabolic profile. "The ability to see these metabolic abnormalities can tell you how the cancer might develop," Dr. Jaffrey says. "But up until now, measuring metabolites has been very difficult in living cells."

In the Science study, Dr. Jaffrey and his team demonstrated that specific RNA sequences can be used to sense levels of metabolites in cells. These RNAs are based on the Spinach RNA, which emits a greenish glow in cells. Dr. Jaffrey's team modified Spinach RNAs so they are turned off until they encounter the metabolite they are specifically designed to bind to, causing the fluorescence of Spinach to be switched on. They designed RNA sequences to trace the levels of five different metabolites in cells, including ADP, the product of ATP, the cell's energy molecule, and SAM (S-Adenosyl methionine), which is involved in methylation that regulates gene activity. "Before this, no one has been able to watch how the levels of these metabolites change in real time in cells," he says.

Delivering the RNA sensors into living cells allows researchers to measure levels of a target metabolite in a single cell as it changes over time. "You could see how these levels change dynamically in response to signaling pathways or genetic changes. And you can screen drugs that normalize those genetic abnormalities," Dr. Jaffrey says. "A major goal is to identify drugs that normalize cellular metabolism."

This strategy overcomes drawbacks of the prevailing method of sensing molecules in living cells using green fluorescent protein (GFP). GFP and other proteins can be used to sense metabolites if they are fused to naturally occurring proteins that bind the metabolite. In some cases, metabolite binding can twist the proteins in a way that affects their fluorescence. However, for most metabolites, there are no proteins available that can be fused to GFP to make sensors.

By using RNAs as metabolite sensors, this problem is overcome. "The amazing thing about RNA is that you can make RNA sequences that bind to essentially any small molecule you want. They can be made in a couple of weeks," Dr. Jaffrey says. These artificial sequences are then fused to Spinach and expressed as a single strand of RNA in cells.

"This approach would potentially allow you to take any small molecule metabolite you want to study and see it inside cells," Dr. Jaffrey says. He and his colleagues have expanded the technology to detect proteins and other molecules inside living cells.

He adds that uses of the technology to understand human biology can be applied to many diseases. "We are very interested in seeing how metabolic changes within brain neurons contribute to developmental disorders such as autism," Dr. Jaffrey says. "There are a lot of opportunities, as far as this new tool is concerned."

Co-authors of the study include Dr. Jeremy S. Paige, Mr. Thinh Nguyen Duc, and Dr. Wenjiao Song from the Department of Pharmacology at Weill Cornell Medical College.

The study was funded by the National Institute of Biomedical Imaging and Bioengineering of the NIH, and the McKnight Foundation. The Cornell Center for Technology Enterprise and Commercialization (CCTEC), on behalf of Cornell University, has filed has filed for patent protection on this technology. Dr. Samie Jaffrey is the founder and scientific advisor to Lucerna Technologies, and holds equity interests in this company. In addition, Lucerna Technologies has a license that is related to technology described in this press release.

Office of Public Affairs
Weill Cornell Medical College
525 East 68th Street, Box 144
New York, NY 10065

tel: 212.821.0560
fax: 212.821.0576
email: pr@nyp.org

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March 6, 2012

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PBSB Student Wins Student Research Achievement Award

Sayan Mondal, a 4th year PBSB student in Dr. Harel Weinstein's lab won the 2012 Student Research Achievement Award (SRAA) in Molecular Biophysics at the Biophysical Society's 56th annual meeting in San Diego for his poster entitled: "Interaction with the membrane uncovers essential differences between highly homologous GPCRs" Sayan Mondal, George Khelashvili, Jennifer M. Johnston, David Provasi, Hao Wang, Olaf S. Anderson, Marta Filizola, Harel Weinstein.

To view Sayan Mondal's poster, please click here.

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January 18, 2012

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BCMB Student Completes Christine Mirzayan Science and Technology Policy Graduate Fellowship

Naira Rezende (PhD candidate in the BCMB program) has just completed the prestigious Christine Mirzayan Science and Technology Policy Graduate Fellowship with the Committee on Science Technology and Law (CSTL) at the National Academy of Sciences (NAS). The fellowship was first designed by Bruce Alberts (Current Editor-in-Chief of Science Magazine) in 1997 and is a competitive 12 week program at The National Academies designed to engage its Fellows in the analytical process that informs U.S. science and technology policy. The National Academy of Sciences (NAS) was signed into being by President Abraham Lincoln on 1863 to "investigate, examine, experiment, and report upon any subject of science or art" whenever called upon to do so by any department of the government. It is also the highest scientific honorific society within the United States. Fellows earn the privilege of working with Committees and Boards within the National Academy of Sciences (NAS), the National Academy of Engineering (NAE) and/or the Institute of Medicine (IOM). Prior to becoming a Mirzayan Fellow, Naira brought to Cornell a 5-year Howard Hughes Medical Institute (HHMI) Gilliam Fellowship for Advanced Studies, which supported the first 5 years of her graduate studies.

 

     

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