News and Events
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
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
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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.
