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Study Reveals Early Molecular Signs of High-Risk Pregnancy

Pregnant woman having a ultrasound scan

Women who have healthy pregnancies tend to show distinct changes in the activities of immune genes starting early in pregnancy, while women who have complicated pregnancies tend to show clear departures from that pattern, according to a new study from a team led by researchers at Weill Cornell Medicine and Hospital for Special Surgery (HSS).

The study, published April 8 in the Journal of Experimental Medicine, was designed to find early molecular predictors of the hypertension syndrome preeclampsia, miscarriage and other adverse pregnancy outcomes in women with the autoimmune disorder lupus, who face a relatively high risk of such outcomes. Over half of the more than 200 women studied were lupus patients. But the results suggest that modulation of the immune system during pregnancy is very similar in women with and without lupus.

“These findings help us understand not only pregnancy for women with lupus but pregnancy generally,” said study co-senior author Dr. Virginia Pascual, the Drukier Director of the Gale and Ira Drukier Institute for Children’s Health and the Ronay Menschel Professor of Pediatrics at Weill Cornell Medicine. Dr. Pascual has received a research grant and consulting honorarium from Sanofi-Pasteur.

Dr. Virginia Pascual. Photo credit: John Abbott

“There are implications here for predicting adverse pregnancy outcomes and also for identifying therapeutic targets to prevent those outcomes,” said co-senior author Dr. Jane Salmon, a professor of medicine and of medicine in obstetrics and gynecology at Weill Cornell Medicine, and the Collette Kean Research Professor at HSS. Dr. Salmon has received an investigator-initiated grant from UCB Pharmaceuticals.

Lupus affects more than 500,000 people in the United States alone, and about 90 percent of them are women. The disorder features attacks by antibodies and other immune elements on the skin, heart, kidneys and other organs. Women with lupus who become pregnant face a roughly 20 percent chance of serious complications including miscarriage, preterm birth, stillbirth, and preeclampsia, a condition that endangers both the mother and unborn child. Prior research suggests that such complications, even in women without lupus, are at least partly caused by improper regulation of the maternal immune system—which must be tamed somewhat during pregnancy to allow tolerance of partly “foreign” fetal tissue.

Dr. Jane Salmon. Photo credit: Travis Curry

From 2003 and for more than a decade afterwards, Dr. Salmon and colleagues enrolled more than 700 women, about half of them pregnant women with lupus, for a multi-center study called PROMISSE designed to uncover risk factors for adverse pregnancy outcomes. For the new study, Drs. Salmon and Pascual and their colleagues made use of blood samples and other clinical data from a subset of that cohort enrolled in 2003-13, including 92 pregnant women who had lupus and 43 pregnant women who didn’t have the disorder.

Analyses of the patterns of gene activity in these women’s white blood cells during the course of pregnancy showed that in healthy women with uncomplicated pregnancies, key elements of the immune system tended to be quieted shortly after the establishment of pregnancy, and tended to remain relatively quiet throughout the pregnancy. These were largely the same sets of genes that are overactive in lupus, and include genes relating to the production of molecules called type I interferons that marshal an immune response to viral infections.

“The surprise for us was when we looked at the data for women with lupus who had uncomplicated pregnancies,” Dr. Pascual said. “They started, as expected, with a higher level of activity in these immune pathways, but once they got pregnant these immune pathways were modulated much as they were in pregnant women without lupus.”

By contrast, in pregnant women who developed preeclampsia or other serious complications, these immune pathways were downregulated to a smaller extent from their baseline levels, or not at all.

In a separate study of 25 healthy women undergoing in vitro fertilization, the researchers observed the same healthy-pregnancy and complicated-pregnancy immune-gene signatures, and found that these patterns began to emerge at the very outset of pregnancy, with embryo implantation.

The findings, if confirmed in larger groups of pregnant women, could lead to the development of early diagnostic tests predicting pregnancy complications, and ultimately treatments that quiet specific elements of the immune system to protect women from complications. “If we could identify a pathway to target with drugs to prevent preeclampsia in lupus patients,” Dr. Salmon said, “we could immediately consider the same treatment approach to protect women who don’t have lupus but have similar high-risk biomarkers early in pregnancy." 


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Gale and Ira Drukier Prize in Children’s Health Research Awarded to NIH Clinical Immunologist

Dr. Helen Su Honored for Research on Immune System Disorders in Children

Dr. Helen Su, fourth from left, was named the winner of the fourth annual Gale and Ira Drukier Prize in Children's Health Research. Pictured with him (from left): Jennifer Birnbaum, Dr. Virginia Pascual, Dr. Gale Drukier, Dr. Ira Drukier and Dr. Augustine M.K. Choi. Photo credit: Stephanie Diani

The Drukier Prize honors an early-career pediatrician whose research has made important contributions toward improving the health of children and adolescents. Dr. Su, chief of the Human Immunological Diseases Section at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, is being recognized for her innovative research into rare pediatric immunodeficiency diseases and translating findings into potential treatments for these patients. This work also extends to more common diseases such as allergies and viral infections.

“Dr. Su is a talented clinician-scientist whose discoveries have furthered our understanding of the genetic causes of rare pediatric immune diseases,” said Dr. Augustine M.K. Choi, the Stephen and Suzanne Weiss Dean of Weill Cornell Medicine. “Her innovative research using cutting-edge approaches and efforts to translate her work into new treatments has offered hope to countless children affected by these disorders and their families. For her commitment to children’s health and tireless work to advance the field of pediatric research, we are pleased to honor Dr. Su with this year’s Gale and Ira Drukier Prize in Children’s Health Research.”

“We are thrilled to be recognizing Dr. Su with this award,” said Dr. Gale Drukier and Weill Cornell Medicine Overseer Ira Drukier, who together in 2014 established the prize. “Dr. Su’s dedication to bettering the lives of young patients through her groundbreaking pediatric research into DOCK8 immunodeficiency syndrome and other rare immune disorders is exceptional. We are proud to have the opportunity to showcase the inspiring physicians and scientists making a true difference in children’s health, offering a bright future for the next generation.”

“Dr. Su’s research illustrates the value of understanding the basis of rare hereditary immune disorders,” said Dr. Virginia Pascual, the Drukier Director of the Gale and Ira Drukier Institute for Children’s Health. “Not only has her work helped to guide treatment for children with these diseases, but she has also advanced the field of immunology through her fundamental insights into how the human body protects itself from infection. Her research has the potential to help children worldwide and the Drukier Institute is pleased to honor Dr. Su for her vital contributions to pediatric research.”

Dr. Su’s research brings together clinical information with technological developments in genomics, biochemistry and molecular biology—such as sequencing all the protein-coding regions of the human genome—to identify gene mutations associated with diseases that affect the immune system. The findings may lead to improved diagnosis and better treatments.

Dr. Su’s work has provided critical insights into DOCK8 immunodeficiency syndrome, a rare immune system disease that is difficult to diagnose because it masquerades as more common conditions, such as respiratory infections, middle ear infections, eczema, food allergies and skin infections. Children with DOCK8 immunodeficiency syndrome, however, reach a point at which infections of the skin and respiratory system worsen over time, and they are at increased risk for some forms of cancer. In 2014, Dr. Su and her colleagues showed that when the DOCK8 protein is missing, as occurs in these patients, white blood cells that travel to the skin and normally fight off viral infections there catastrophically die, impairing immunity within the skin. Some children with DOCK8 immunodeficiency syndrome have been successfully treated with bone marrow transplants, and Dr. Su is collaborating with other teams at NIH to determine which type of transplant—from matched siblings, matched unrelated donors, or half-matched donors, such as mothers or fathers or half-matched siblings—offer the best treatment.

Recently, Dr. Su and her colleagues identified a rare mutation in the gene that produces a protein called MDA5, which plays an important role in fighting viral infections. The faulty MDA5 protein results in a markedly increased susceptibility to infection by human rhinoviruses, the main causes of the common cold. For most people, rhinovirus infections lead to minor illness, but for people with severe asthma, chronic obstructive pulmonary disease and other health problems, rhinoviruses can cause serious complications. Insights from Dr. Su’s research may lead to new strategies for treating patients with severe rhinovirus complications and inadequate MDA5 responses.

The Gale and Ira Drukier Prize in Children’s Health Research was established in December 2014 as part of a $25 million gift to Weill Cornell Medicine. The gift also created the Gale and Ira Drukier Institute for Children’s Health – a premier, cross-disciplinary institute dedicated to understanding the underlying causes of diseases that are devastating to children. As part of its mission, the institute awards the prize, which carries an unrestricted honorarium, annually to recognize the innovative work done by young investigators in pediatric research.

Dr. Su received a Bachelor of Arts degree from Brown University in 1990. She went on to earn a medical degree and a doctorate in pathobiology, both from Brown, in 1998. After completing an internship and residency in pediatrics at St. Louis Children’s Hospital, she joined NIAID in 2002 as a clinical fellow in allergy and immunology. After completing a research fellowship in NIAID’s Laboratory of Immunology in 2007, she was appointed as a clinical investigator and chief of the Human Immunological Diseases Unit in the Laboratory of Host Defenses at NIAID. In 2016, she was named senior investigator and chief of Laboratory of Host Defenses at NIAID. In 2017, Dr. Su became senior investigator and chief of the Human Immunological Diseases Section in the Laboratory of Clinical Immunology and Microbiology at NIAID.

Dr. Su has received several awards and honors, including the NIH Director’s Award in 2010 and NIH Merit Awards in 2015 and 2018, and the Society for Pediatric Research E. Mead Johnson Award in 2018.

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New Clue to How Lupus Arises

Dr. Virginia Pascual. Photo credit: John Abbott

A previously unknown type of T lymphocyte, a class of white blood cell, contributes to the development of an autoimmune disease, called lupus, which causes the immune system to attack healthy tissues and organs and leads to chronic inflammation, according to a study led by Weill Cornell Medicine researchers.

The study, published Nov. 26 in Nature Medicine, suggests that targeting this newly discovered class of T cell, or its biochemical signals, may be a good strategy for treating lupus. Current treatments do not cure the disease and often cause broad immune suppression that increases the risk of infection and cancer.

“We’re very interested in exploring the possibility of developing new treatments based on this finding,” said senior study author Dr. Virginia Pascual, the Drukier Director of the Gale and Ira Drukier Institute for Children’s Health and the Ronay Menschel Professor of Pediatrics at Weill Cornell Medicine.

The most common form of lupus, systemic lupus erythematosus (SLE), is thought to afflict roughly 150,000 to 300,000 people in the United States. It is more prevalent among women and people of African, Hispanic, Asian or American Indian descent, and while it is often considered an adult disease, it occurs relatively frequently in children—for whom it tends to take a more severe course. The disease generally involves attacks on the body’s own tissues by antibodies and other immune elements, with symptoms ranging from skin rashes and fatigue to seizures and severe heart and kidney problems.

Investigators still do not know how lupus arises and why antibodies that react with DNA are so prevalent in this disease. Much of the research has focused on a class of T cells called T follicular helper cells, which are produced at higher levels in lupus patients and help activate many of the immune cells, called B cells, that go on to produce tissue-attacking antibodies. Dr. Pascual and colleagues also have shown in prior studies that these lupus “autoantibodies,” when they encounter immune cells called neutrophils, can cause the neutrophils to release damaged DNA. This appears to set up a vicious cycle of intensifying immune activity, as other immune cells called dendritic cells react to the damaged DNA as if it were from viruses.

For the new study, the scientists looked more closely at what these dendritic cells do when they encounter this type of damaged neutrophil DNA, taken in this case from lupus patients. The key finding was that the dendritic cells somehow activate T cells in the vicinity to become “helper” T cells, of a previously unseen type that the scientists propose calling TH10 cells. These helper T cells go on to stimulate antibody-making B cells, and they do so by producing a unique combination of signaling molecules: the immune protein IL-10, and a small molecule called succinate, which is better known as a byproduct of cellular energy production.

“This is a B-cell activation pathway that has never been described before,” said Dr. Pascual, who has received a research grant and consulting honorarium from Sanofi-Pasteur.

The scientists found relatively high levels of the new type of helper T cell in lupus patients’ blood and also in the kidneys of those affected by a serious lupus-related kidney disorder called proliferative lupus nephritis. Receptors for succinate are particularly common on kidney cells and there is evidence that their overstimulation contributes to other, non-lupus forms of kidney disease. Dr. Pascual and her colleagues therefore suspect that while the newly discovered helper T cells may harm lupus patients’ kidneys by increasing the production of lupus autoantibodies, they may also cause direct harm to the kidney by producing succinate.

The scientists are now examining the possibility of blocking succinate signaling or some other element of this new B-cell activation pathway to ameliorate lupus nephritis and other aspects of this autoimmune disease. “Our study opens up a range of potential targets for treating lupus,” Dr. Pascual said.

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Dr. David Lyden Wins NCI's Outstanding Investigator Award

Weill Cornell Medicine investigators David Lyden, MD, PhD, the Stavros S. Niarchos Professor in Pediatric Cardiology and a professor of pediatrics, and Ari Melnick, MD, the Gebroe Family Professor of Hematology/Oncology and a professor of medicine, have been awarded Outstanding Investigator Awards from the National Cancer Institute.

The NCI’s Outstanding Investigator Awards were created to support leaders in cancer research who are developing applications that may lead to major breakthroughs. Each award recipient is given $600,000 per year for seven years to fund their research. Drs. Lyden and Melnick are two of 20 researchers around the country who received Outstanding Investigator Awards this year.

Dr. David Lyden. Photo credit: Ashley Jones

Dr. Lyden’s research is aimed at understanding how cancer spreads, or metastasizes, to distant organs. His first big discovery was a microenvironment, called the pre-metastatic niche, or PMN, that tumors induce in distant organs that is favorable to the survival of tumor cells before their arrival at the site. “This emphasizes that cancer metastasis is not a late event as previously thought,” said Dr. Lyden, who is a member of the Sandra and Edward Meyer Cancer Center and the Gale and Ira Drukier Institute for Children’s Health at Weill Cornell Medicine.

Dr. Lyden and his team have illuminated the role of exosomes, which are comprised of tumor-derived nanoparticles, in metastatic disease progression and their contribution to creating biological conditions that are favorable to metastasis at distant organs. They found exosomes have specific molecules packaged within, including double-stranded DNA that represents the entire genome of the tumor cell of origin. “This is helpful in monitoring response to therapy and predicting the progression of cancer in patients,” said Dr. Lyden, who is also a pediatric oncologist at NewYork-Presbyterian/Weill Cornell Medical Center.  

Most recently, Dr. Lyden's group adapated a new technology called asymmetric-flow field-flow fractionation to isolate exosome subpopulations and discovered  novel, but even more prominent, particles called "exomeres," which are secreted by tumor cells. 

“This award can be a real game-changer. It allows us to explore new directions and further investigate the metastatic evolution of cancer,” Dr. Lyden said. “We also hope to conduct patient-related studies on a larger scale and develop new technologies to help identify molecular changes that occur in the pre-metastatic environment.”

Dr. Ari Melnick. Photo credit: Roger Tully

In his research, Dr. Melnick focuses on deciphering at a basic level how immune cells called B-cells – which should in theory protect the body from cancer by producing antibodies – can transform into cancer itself. It’s known that with lymphoma, a type of cancer that originates in the immune system, it’s the proteins that interact with the genome that are mutated. These proteins are analogous to the “software” of the cell, because they are responsible for writing instructions on DNA – the “hard drive” – that control how genes are expressed.

“Our preliminary results suggest a major perturbation in the software that involves changing the instructions that control how B-cells in the immune system can cross-talk with other immune cells,” said Dr. Melnick, who is also a member of the Meyer Cancer Center at Weill Cornell Medicine. “But we don’t know how that leads to cells behaving like cancer cells and we don’t know the impact on the rest of the immune system. So that’s what we’re interested in studying.”

As a next step, Dr. Melnick and his team plan on using cutting-edge genomic technologies to explore the changes affecting the readout of genetic instructions. He is also interested in developing drugs that can restore the correct instructions in immune cells to regain control and fight against the transformed cancer cells.

“It’s an honor to be considered worthy of getting an award from the National Cancer Institute,” Dr. Melnick said. “It’s very competitive so it feels gratifying that they appreciate the kind of work coming out of our group.”

This article is republished from the WCM Newsroom.

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Three Weill Cornell Medicine Physician-Scientists Inducted into Association of American Physicians


Double exposure of scientist hand holding laboratory test tube. Photo credit: Shutterstock

Three distinguished Weill Cornell Medicine physician-scientists, Dr. Daniel FitzgeraldDr. Francis Lee and Dr. Virginia Pascual, have been inducted into the Association of American Physicians (AAP).

Considered one of the top honors in the fields of health and medicine, election to the AAP  recognizes physician-scientists who have demonstrated excellence in the pursuit of medical knowledge and in the advancement of basic and clinical science discoveries and their application to clinical medicine.

Dr. Dan Fitzgerald

Dr. Dan Fitzgerald, director of the Center for Global Health and a professor of medicine at Weill Cornell Medicine, was recognized for his work evaluating and defining the optimal way to treat people with HIV/AIDS in resource-poor countries. His pioneering research in developing nations such as Haiti and Tanzania has provided rigorous scientific evidence for making antiretroviral therapy available worldwide. He also proved that treating people with HIV early, as soon as they test positive for the disease, decreases mortality four-fold and tuberculosis incidence two-fold. As a result, the World Health Organization changed international HIV treatment guidelines and early treatment became the worldwide standard of care. 

“To be invited to join the ranks of leading physician-scientists is a real honor,” Dr. Fitzgerald said. “It the importance of conducting the highest level of clinical research in resource-poor countries and developing strategies that have had a significant impact on improving care globally. People in underdeveloped countries deserve the same level of scientific effort that we undertake in developed countries.”

Dr. Francis Lee

Dr. Francis Lee, chair of the Department of Psychiatry and the Mortimer D. Sackler, M.D. Professor of Molecular Biology in Psychiatry at Weill Cornell Medicine, was recognized for his work combining molecular neuroscience with psychiatry to study anxiety disorders. His achievements include pioneering novel research strategies aimed at performing genetic mouse model studies in parallel with human behavioral and neuroimaging studies to identify how individual genetic variation contributes to risk and resilience for mental illness. Dr. Lee's findings inform how clinical treatments can be optimized based on the biological states of the developing brain, especially with regards to patients with anxiety disorders and mood disorders.

“I am incredibly honored to be elected to the Association of American Physicians,” Dr. Lee said. “As one of few psychiatrists in the organization, I look forward to mentoring and encouraging future physician-scientists to join the field.”

Dr. Virginia Pascual

Dr. Virginia Pascual, the Drukier Director of the Gale and Ira Drukier Institute for Children’s Health and the Ronay Menschel Professor of Pediatrics at Weill Cornell Medicine, was recognized for her cross-disciplinary research into the underlying causes of pediatric diseases caused by an altered immune system, and her work to find new cures. Focusing on systemic-onset juvenile arthritis, which causes joint inflammation and other symptoms in young children and had no effective therapies, one of her major contributions was identifying a molecule as the underlying driver of the disease. Through a pilot study and then larger clinical trials, her team demonstrated that a drug developed to treat adults could halt inflammation and stop disease progression in a majority of children. As a result, the U.S. Food and Drug Administration approved the drug as a treatment for the disease.

“The Association of American Physicians is a very prestigious organization, dating back to the 19th Century, and I’m very proud to become a member,” Dr. Pascual said. “I look forward to encouraging younger colleagues to follow the path of patient-oriented research and I would be delighted to help identify potential inductees in the future.”

The AAP has more than 1,700 active members and approximately 600 emeritus and honorary members from the United States, Canada and other countries. New members are elected in a competitive process by current members. Drs. Fitzgerald, Lee and Pascual were among 61 new inductees honored at the AAP’s annual meeting in April in Chicago.

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Gale and Ira Drukier Prize in Children's Health Research Awarded to Harvard Hematologist

Dr. Vijay Sankaran Honored for Research on Genetic Blood Disorders

Dr. Vijay Sankaran, fourth from left, was named the winner of the third annual Gale and Ira Drukier Prize in Children’s Health Research. Pictured with him (from left): Ira Drukier, Jennifer Birnbaum, Gale Drukier, Dr. Virginia Pascual and Dr. Augustine M.K. Choi. Photo credit: Stephanie Diani

NEW YORK (February 28, 2018) — Dr. Vijay Sankaran, a physician-scientist who investigates the molecular underpinnings of pediatric genetic blood disorders, has been awarded the third annual Gale and Ira Drukier Prize in Children’s Health Research, Weill Cornell Medicine announced today.

The Drukier Prize honors an early-career pediatrician whose research has made important contributions toward improving the health of children and adolescents. Dr. Sankaran is a pediatric hematologist and oncologist at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, and an assistant professor of pediatrics at Harvard Medical School. He is being recognized for his innovative research on red blood cell disorders, using genetic studies to understand how blood cell production occurs normally and how it goes awry in disease. His findings have led to promising new therapeutic approaches for these disorders.

“Dr. Sankaran is a talented physician-scientist whose steadfast commitment to pediatric research and clinical care exemplifies the spirit of our Gale and Ira Drukier Prize in Children’s Health Research,” said Dr. Augustine M.K. Choi, the Stephen and Suzanne Weiss Dean of Weill Cornell Medicine. “His research on the causes of genetic blood disorders and his work to translate those findings into new treatments have provided hope to children suffering from these diseases and their families. We’re delighted to honor him with this year’s Drukier Prize.”

“We are thrilled to be honoring Dr. Sankaran with this award,” said Dr. Gale Drukier and Weill Cornell Medicine Overseer Ira Drukier, who together in 2014 established the prize. “Dr. Sankaran’s innovative research and commitment to improving the health and lives of children are truly inspiring. It brings us tremendous joy to recognize those in the scientific community, like him, who are making a real impact in pediatric research and to shine a spotlight on their vital work.”

Dr. Sankaran’s research focuses on inherited diseases, such as sickle cell disease and thalassemia, that affect molecules called hemoglobin, which are present in all red blood cells and are responsible for transporting oxygen throughout the body. Humans produce two forms of hemoglobin in their lifespans: a fetal version when they are in the womb and an adult version after birth. Patients with sickle cell disease and thalassemia produce either misshapen or too few adult hemoglobin. Scientists have found that by inducing the switch back to fetal hemoglobin they can ameliorate the severity of these diseases.

Dr. Sankaran identified a key regulator of the switch, a molecule called BCL11A, which when suppressed allows fetal hemoglobin levels to increase. Dr. Sankaran and colleagues are now developing gene therapy methods to reduce the levels of BCL11A in patients’ blood stem cells, which are then reintroduced into their bodies to populate their blood with cells that can produce more fetal hemoglobin.

Dr. Sankaran’s research contributions also extend to other rare genetic blood disorders, including Diamond-Blackfan anemia, in which the bone marrow fails to produce enough red blood cells. Many patients with the disorder, which affects seven per 1 million people worldwide, have mutations that disrupt ribosomes, the cell’s general protein-making machine, leaving scientists puzzled as to why that defect causes the disease. But Dr. Sankaran discovered that a small percentage of patients with the disease have mutations in a gene called GATA1, which is a master regulator of blood production. The more common defect in ribosomes, he found, was causing Diamond-Blackfan anemia by disrupting production of GATA1. Those findings underscored that raising levels of GATA1 in cells may be an effective new treatment for Diamond-Blackfan anemia, which Dr. Sankaran is pursuing using gene therapy and small molecule approaches.

“Im incredibly humbled to be getting this award,” Dr. Sankaran said. “In addition to honoring the work that we’ve done in the lab, and the great mentorship I’ve received, I’m extremely grateful that this award is given for child health research. With increased support, there are tremendous opportunities for us to advance the work being done in this area so that we can protect the health of future generations.”

The Gale and Ira Drukier Prize in Children’s Health Research was established in 2014 as part of a $25 million gift to Weill Cornell Medicine. The gift also created the Drukier Institute for Children’s Health, a premiere, inter-disciplinary institute dedicated to understanding the underlying causes of diseases that are devastating to children. As part of its mission, the institute awards the prize, which carries a $10,000 unrestricted honorarium, annually to recognize the innovative work done by young investigators in pediatric research.

“Studying genetics is essential when focusing on childhood diseases, as so many of them have a hereditary component,” said Dr. Virginia Pascual, the Drukier Director of the Gale and Ira Drukier Institute for Children’s Health. “Dr. Sankaran’s research has illuminated some of the causes – and potential treatments – of genetic blood disorders. His dedication to treating children exemplifies why this institute and award were created and why we’re so pleased to be honoring him.”

Dr. Sankaran is board-certified in general pediatrics and pediatric hematology/oncology. He is a member of the American Academy of Pediatrics, American Society of Hematology, American Society of Clinical Investigation, American Society of Human Genetics and the Society for Pediatric Research, which awarded him its prestigious Young Investigator Award in 2015.

Dr. Sankaran received a Bachelor of Arts and a Master of Science in biochemistry from the University of Pennsylvania in 2002. He went on to earn a Master of Philosophy in biochemistry from the University of Cambridge in 2003, and a doctorate in genetics in 2009 and a medical degree in 2010, both from Harvard Medical School. For his postdoctoral training, Dr. Sankaran completed a research fellowship in molecular hematology, as well as an internship and residency in pediatrics, at Boston Children’s Hospital. He also completed a clinical fellowship in pediatric hematology and oncology at the Dana-Farber Cancer Institute and Boston Children’s Hospital, where he has served as an attending physician since 2015. He is an associate member of the Broad Institute of MIT and Harvard, and has been on faculty at Harvard Medical School since 2014. 

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Scientists Discover New Nanoparticle, Dubbed Exomeres

A new cellular messenger discovered by Weill Cornell Medicine scientists may help reveal how cancer cells co-opt the body’s intercellular delivery service to spread to new locations in the body.

In a paper  published Feb. 19 in Nature Cell Biology, the scientists show that a cutting-edge technique called asymmetric flow field-flow fractionation (AF4) can efficiently sort nano-sized particles, called exosomes, that are secreted by cancer cells and contain DNA, RNA, fats and proteins. This technology allowed the investigators to separate two distinct exosome subtypes and discover a new nanoparticle, which they named exomeres.

“We found that exomeres are the most predominant particle secreted by cancer cells,” said senior author Dr. David Lyden, the Stavros S. Niarchos Professor in Pediatric Cardiology, and a scientist in the Sandra and Edward Meyer Cancer Center and the Gale and Ira Drukier Institute for Children’s Health at Weill Cornell Medicine. “They are smaller and structurally and functionally distinct from exosomes. Exomeres largely fuse with cells in the bone marrow and liver, where they can alter immune function and metabolism of drugs. The latter finding may explain why many cancer patients are unable to tolerate even small doses of chemotherapy due to toxicity.”

Exomeres clock in at less than 50 nanometers in diameter, compared with small exosomes (Exo-S), which range from 60 to 80 nanometers in diameter, and large exosomes (Exo-L), which are 90 to 120 nanometers in diameter. “Exosomes and exomeres also have different biophysical characteristics, such as stiffness and electric charge, that likely affect their behavior in the body,” said lead author Dr. Haiying Zhang, an assistant professor of cell and developmental biology in pediatrics at Weill Cornell Medicine. “The more rigid the particle, the easier it is likely taken up by cells, rendering exomeres, which are stiffer than exosomes, the more effective messengers of transferring tumor information to recipient cells.”

Exosomes and exomeres also differ in the way they influence cancer. Exomeres carry metabolic enzymes to the liver, an organ that is central to the breakdown of drugs into nontoxic forms. The finding suggests that exomeres target the liver to “reprogram” its metabolic function to favor tumor progression. Exomeres also carry blood-clotting factors to the liver, where they may prohibit the liver's normal function in regulating clotting. By contrast, the study suggests that Exo-L may promote metastasis to lymph nodes, while Exo-S may support distant metastasis.

“Cancer is truly a systemic disease that requires multi-organ involvement to progress,” Dr. Lyden emphasized. “Our finding that tumor cells secrete these three distinct nanoparticles, that then target cells in different organs reflects this important aspect of the disease.”

Cornell University has filed a patent application on the technology that is described in the Nature Cell Biology paper. Researchers will now study how these different types of messengers develop, exactly what molecules each of them carry, and what their functions are at their target organ sites. “Understanding these characteristics may help scientists better understand how exomeres and exosomes help cancers grow and spread to other organs, as well as what role they may play in other diseases,” Dr. Zhang said.

Exosomes and exomeres are also detectable in bodily fluids such as lymphatic fluid, which might allow development of biomarkers for early detection of cancer or other pathological conditions. “Based on our findings, the next phase will be to measure exosomes and exomeres in plasma samples to help predict organs that may be targeted for metastasis during tumor progression,” said Dr. Lyden. “This will help us better understand the biology of cancer, guide therapeutic decisions and develop novel therapies.”

“Lastly, the technique we have pioneered will likely be a valuable tool for scientists and clinicians studying the biology of complex nanoparticle populations,” Dr. Zhang said, “and may aid in the development of diagnostic tests using them as biomarkers.”

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For Kids' Sake

 John Abbott

For physician-scientist Dr. Virginia Pascual research was a revelation. After graduating from medical school in Madrid and doing a residency in pediatrics, she came to the United States for a one-year clinical fellowship at University of Texas Southwestern Medical Center—and was surprised to learn that her new post entailed a research component. “I ended up in a laboratory learning immunology, and it was life-changing,” she says. “What was supposed to be one year became five.” At UT Southwestern, where she eventually became director of pediatric rheumatology, Dr. Pascual nurtured a groundbreaking translational research program focusing on diseases such as childhood arthritis. A collaborative effort with the Baylor Institute for Immunology Research and Texas Scottish Rite Hospital for Children, the program studied diseases directly in patients—rather than in animal models, as the work had traditionally been done—and used cutting-edge technologies that gleaned high volumes of data from small samples of blood and tissue. Dr. Pascual later moved to the Baylor Institute for Immunology Research, where her work included identifying molecular drivers of disease in pediatric lupus patients. Board-certified in pediatrics and in pediatric rheumatology, she joined Weill Cornell Medicine last spring as the Drukier Director of the Gale and Ira Drukier Institute for Children’s Health, established in 2014 with a $25 million gift from Gale and Ira Drukier, and recruited as the Ronay Menschel Professor of Pediatrics.

What’s the current state of research into children’s diseases?
Unfortunately, they have suffered from a lack of translational research—which is when we go directly to patients to bring new treatments based on basic discoveries we make in the laboratory. There have been very few translational studies done directly in children, and funding has traditionally lagged behind adult diseases. But as a proponent of pediatric research, I always like to explain that in addition to the important work of finding new treatments for our patients, diseases arising in childhood are great models for study.

Why is that?
Because children normally have just one single disease. When a disease starts in adult life, individuals normally not only have that disease, like cancer, but others—such as diabetes, high blood pressure or depression—for which they are also being treated. In translational research, many times children give us more clear and direct answers about what is wrong than when we study adults.

You grew up in an unusual place: Ceuta, a small Spanish colony in the north of Morocco. How do you think that influenced you? 
Even though geographically it belongs to Africa, politically Ceuta has belonged to Spain for more than five centuries. It’s very multicultural, with different ethnicities and religions living peacefully together. I think that made it easier for me to cross the ocean to pursue my career, and when I came here, the diversity of this country was something familiar to me. And of course the diseases I study in the lab and see in the clinic impact minorities. For example, lupus—which is a complex disease in which the immune system fails to recognize the patient’s own tissues and attacks them, causing symptoms like fatigue, fever, joint pain and skin rashes—can be difficult to diagnose, because it doesn’t impact every patient the same way. It affects children who come from African American, Hispanic and Caucasian backgrounds very differently, and it has been fascinating to try to understand that. So my background might be motivating from that perspective as well.

Could you describe your vision for the Drukier Institute?
The goal is to bring together the best and brightest physician-scientists with an interest in childhood diseases; initially, our focus will be on those that are mediated by the immune system, such as diabetes, allergy, asthma and lupus. In these diseases, the immune system either over- or under-reacts to environmental triggers or pathogens, or it attacks the body’s own tissues. We want the Institute to be a highly integrated and collaborative operation, as we develop new ways to study these diseases in patients seen by clinicians at NewYork-Presbyterian/Weill Cornell Medical Center.

Why focus on immune-related disorders? 
Our immune system is there to defend us against myriads of pathogens. During human development—from embryo to fetus to baby—the immune system needs to learn how to recognize “self” from “foreign,” to know what it should and should not fight. This is a long, elaborate process that takes years; when babies are born, their immune systems are immature, so they’re more susceptible to infections. During childhood, the immune system continues to evolve, and how it “learns” in those first few years impacts an individual’s entire life. So understanding this process—even in healthy children—is a fundamental aspect of what we want to do. The immune system is at the center of a diverse array of diseases and conditions such as infections, cancer, diabetes and inflammatory bowel disease. Alterations in the immune system during pregnancy and in the early years of life may even play a role in autism and other neurological conditions.

What do you love about treating and studying kids? 
I was attracted to pediatrics because I thought that if we could understand and find better treatments for diseases that affect patients during these vulnerable years of infancy and childhood, we could have a long-term impact on their lives. As a physician, I cannot imagine any higher motivation than working with children and trying to prevent any interruption that disease can impose on their precious development. In addition, a child’s illness impacts not only the patient but the entire family. I never had kids of my own, but my patients are like my children. I’ve been very fortunate to follow many of them for years, to see them grow and have wonderful lives.

Does working with children have distinct challenges? 
Of course. When you see kids with diseases that might cut their lives short, it can be deeply affecting. But these kids and their families are amazingly resilient, and we learn a lot from them. I’ve treated lupus patients and watched them get very sick despite our best efforts; I’ve seen them experience things that children should never have to, like strokes, and try their best to go back to a normal life. My patients have inspired me in terms of continuing on and not looking back.

Are there any particular patient stories that stand out?
There are so many. Probably the most rewarding was when we were able to offer a new therapy for a devastating disease called systemic onset juvenile arthritis. These kids are very debilitated and in a lot of pain; the disease causes severe inflammation in the joints and other organs such as the heart. We developed a lab test to try to understand it and found there was a particular molecule in these patients’ blood that could be responsible for the severe inflammation. It turned out that a drug already approved by the FDA—to treat adults with rheumatoid arthritis—blocks this molecule. The drug did not help adult patients much, but when we developed a pilot clinical trial to test it in our children, the results were spectacular. Of nine kids who’d had severe disease for years, seven went into complete remission. To see kids who had been confined to a wheelchair for months or years get up and walk—and not only walk, but when kids get out of a wheelchair they want to immediately run. They are so full of energy and life.

— Beth Saulnier

This story first appeared in Weill Cornell Medicine, Vol. 16. No. 4

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Dr. Virginia Pascual Wins Lupus Insight Prize

Dr. Virginia Pascual. Photo credit: John Abbott

Dr. Pascual received the award, which includes a $150,000 monetary prize, at FOCIS 2017, the Federation of Clinical Immunological Societies’ 17th annual meeting in Chicago. The award recognizes a significant, new insight or discovery with the potential to change the thinking about lupus and generate advances in diagnosis and treatment of the disease.

“I’m very honored to have been selected by my peers, and am committed to understanding the disease and bringing new therapies to children with lupus,” said Dr. Pascual, who was recruited as the Ronay Menschel Professor of Pediatrics at Weill Cornell Medicine.

Lupus is an autoimmune disease that occurs when a person’s immune system attacks healthy organs, tissues and cells. It leads to chronic inflammation in various parts of the body, including the skin, kidneys and brain. Although lupus is found mainly in women of childbearing age, an estimated 5,000-10,000 children are diagnosed with the disease in the United States.

In the past, most research by scientists on lupus has focused on what is happening to the immune system at the time of flares. While this is valuable knowledge, it has been unsuccessful in explaining why a patient with lupus might feel well one day and then have flares the next day, Dr. Pascual said.

To better understand how lupus flares develop, Dr. Pascual will analyze blood samples taken from children with lupus on a frequent basis, even in between clinical visits, using innovative sequencing technology. By doing so, she hopes to capture what is happening at the earliest stages of disease activity – weeks or even months before symptoms appear.

“If we can identify what is changing in the immune system of each patient before symptoms appear, we will be able to develop personalized treatments,” Dr. Pascual said. “The ultimate goal is to prevent a flare from happening.”

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Daedalus Fund Supports 15 Investigators

Fifteen winners (fourteen projects) have been selected for the fourth round of the Daedalus Fund for Innovation awards, a pioneering Weill Cornell Medicine program that helps advance promising applied and translational research projects and emerging technologies that have commercial potential.

In an expansion of the program, winners are now selected twice annually and are eligible for two levels of funding: $100,000 and $300,000 (the latter, subject to the satisfaction of certain specified pre-defined milestones).

The researchers — Drs. Francis Barany, Jochen Buck in collaboration with Lonny Levin, Ethel Cesarman, Shuibing Chen, David Cohen, Ronald Crystal, Lukas Dow, Katherine Hajjar, Samie Jaffrey, Gang Lin, David Lyden, Xiaojing Ma, John Pena, and Nicholas Schiff — have each won a Daedalus award to fund proof-of-concept studies that will enhance the data package, thereby helping to upgrade their technologies and translate their early-stage discoveries into new therapeutic modalities and hopefully more effective treatments for patients.

The fund’s independent external Scientific Advisory Committee, comprised of seasoned technology analysts from the biopharmaceutical and venture capital industries, selected the projects.

“The Daedalus Fund helps our investigators bridge the ‘development gap’ and accelerate their projects to the point at which they are strong candidates for business development and licensing,” said Larry Schlossman, managing director of BioPharma Alliances and Research Collaborations at Weill Cornell Medicine, who manages the Daedalus Fund. “By providing philanthropic support at this critical juncture, we are helping to advance early-stage research projects that have significant commercial potential.”

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Concentrated Effort

Colin Ogilvie '18 (center left) and Marta Dzyadyk '18 (center right) with mentors Dr. Harjot Kaur Singh (left), and Dr. Laura Kirkman

By Anne Machalinski 
Photos By John Abbott

On a Tuesday in early June, just days before summer break, dozens of third-year medical students gathered in the Belfer Research Building to present findings from independent research projects they’d been working on since February. One student compared the use of palliative care in oncology in the United States and India; another presented findings on a promising biomarker that might allow physicians to track the progression of a pediatric brain tumor; and a third described her investigations into whether large polyps are a risk factor for metastatic colorectal cancer.

The poster session was the culmination of the first part of a six-month, dedicated research block that all Weill Cornell Medical College students now participate in during their third year. Begun in 2014, this capstone requirement is called the Areas of Concentration (AOC) program. It requires students — with the exception of MD-PhDs — to pick an area in which they’d like to gain in-depth knowledge, then complete original research related to it before graduation under the tutelage of a one-on-one mentor. “The more we can educate students in how to conduct original research,” says Dr. Anthony Brown, an associate professor of cell and developmental biology and the director of medical student research, “the more likely our graduates will be to challenge the status quo, make advances in their fields and become better doctors.”

The AOC is the latest in a continuum of changes to the curriculum at Weill Cornell Medical College — which, like many of its peer institutions, has shifted away from a classroom-focused system for the early years of medical school. Today, medical educators generally accept that students should be exposed to clinical work as early as possible. Protected research time, a relatively new concept in medical education, is also considered a benefit for physicians-in-training. Although many schools only require a few weeks or months, often broken up by other coursework, Weill Cornell Medical College — which previously didn’t require any research at all — opted to add six months. Students now do four months of research in the spring of their third year and two in the fall of their fourth, then report their work in a scholarly paper. “As a med student, I’ve sometimes felt like I’m memorizing all this information and just trying to retain as much as I can,” says Marta Dzyadyk ’18, who presented research on beneficial microbes that live in the gastrointestinal tract. “But the AOC program allowed me to ask a research question and think a little more creatively. I loved being in a basic science lab and taking ownership of my project.”

Professor of Medicine Dr. Andrew Schafer, who is the program’s director, stresses that in no way is the AOC intended to pressure students to choose a specialty prematurely, or push them into full-time research. Instead, he says, it gives medical students a chance to do what PhD candidates have been doing all along: thinking about the big picture, and creating — rather than just absorbing — knowledge. “A lot of medicine today ends up being very technical,” he says, “but we want all of our graduates, including doctors going into clinical practice, to maintain a scholarly and scientific perspective in their careers.” This means continuing to ask fundamental questions that might advance clinical standards; working with scientists to translate promising research into improved treatments for patients; and maintaining strong ties with a scholarly scientific community, like the one that the AOC program invites students to join. “Medical school is the perfect time to ingrain this out-of-the-box way of thinking,” Dr. Schafer says, adding that the AOC also builds confidence, grounds students in the fundamentals of the research process and strengthens their CVs, giving them a boost when they apply for fellowships and residencies.

An Evolving Educational Landscape

Introduced in the first weeks of medical school, the AOC program starts by linking students with one of four “exploratory advisers”: Dr. Brown (who works with students wanting to focus on laboratory research); Dr. Mark Pecker, clinical professor of medicine (clinical research); Dr. Madelon Finkel, professor of clinical healthcare policy and research (global and public health, health policy, and population research); and Dr. Schafer, who takes students who are undecided. As students work through their foundational science classes, they periodically meet with their adviser to pinpoint their choice from a list of about 50 areas of concentration including nanomedicine, communication disorders, geriatrics and addiction medicine. Their adviser also helps them find a faculty mentor, who will work with them on the scholarly project they propose in the fall of their third year. Dr. Brown notes that after having completed 12 months of clinical clerkships, most students are ready to slow down and think creatively — a reprieve that the research block, which begins in February, provides. “Students look at this as a breath of fresh air in what is an otherwise very stressful curriculum,” he says. “They take advantage of what is essentially a giant block of unstructured time, and enjoy the process of creating knowledge.”

Vince Raikhel ’18 (center) with mentors Dr. Susan Ball (left), and Dr. Milagros Silva

Vince Raikhel ’18 (center) with mentors Dr. Susan Ball (left), and Dr. Milagros Silva

For Sydney Ariagno ’18, a Dallas native who came straight to medical school from her undergraduate studies at Washington University in St. Louis, the AOC program was a major reason she chose to attend Weill Cornell Medical College. She conducted neuropsychology research in college, studying biomarkers that turn up in the blood of pediatric patients after a concussion to see how they correlate with cognitive function later on. At Weill Cornell Medical College, she decided to try basic science research, to learn new skills and see if she enjoyed the process. Dr. Schafer guided her toward cancer research; then Dr. Brown introduced her to her eventual mentor, Dr. David Lyden, the Stavros S. Niarchos Professor in Pediatric Cardiology at Weill Cornell Medicine and a pediatric neuro-oncologist at Memorial Sloan Kettering Cancer Center. After learning about his work on exosomes — microparticles released by tumor cells — she knew she’d found the right fit. “Dr. Lyden’s research interests are very much in line with what I was hoping to focus on,” says Ariagno, who plans on going into pediatrics or pediatric oncology after graduation. “Our meeting went so well that I didn’t need to consider working with anyone else.”

The project Ariagno focused on during her research block — which she has extended into a full year, after which she’ll return to her medical studies — is on medulloblastoma, the most common malignant pediatric brain tumor. Along with Dr. Lyden and co-mentor Dr. Praveen Raju, an assistant professor of pediatrics at Weill Cornell Medicine, Ariagno is looking at whether exosomes released by this tumor could be detected by a blood test — not only to diagnose it, but to monitor whether it has grown or spread after treatment. “This is a really collaborative project; I get to work with both of my mentors equally,” says Ariagno. “Dr. Lyden’s lab is focused on general cancer biology and the mechanisms of cancer progression, and Dr. Raju focuses on medulloblastoma and brain tumors. It’s been illuminating to see both the broad and more narrow questions play out in the research, and consider how this lab-based work could lead to a safer, non-invasive way of diagnosing and monitoring kids with this type of tumor.”

Dr. Andrew Schafer (left), with students Caitlin Gribbin ’18 (center) and Aditi Gupta ’18

Dr. Andrew Schafer (left), with students Caitlin Gribbin ’18 (center) and Aditi Gupta ’18

While AOC leaders say it’s too early for a comprehensive assessment of the program’s benefits, it seems to be paying off. This year, five third-year students, including Ariagno, received Howard Hughes Medical Institute fellowships, each providing $32,000 to support a year of research. Two more third-years received other prestigious fellowships, one from the Sarnoff Cardiovascular Research Foundation and another from the Doris Duke Charitable Foundation. In the past, only one or two students per year were likely to receive such honors, Dr. Schafer says. “We can’t take full credit for this increase — but we did get students to start thinking about research early, made them aware of these opportunities, helped them with their applications and urged them to apply,” he says. “This is an early indicator of success that shows we’re on to something.”

Shooting for the Stars

While many incoming students are unsure about their future specialty, Tim Donahoe ’19 stands out for his singular focus: he wants to be an astronaut. Even before he matriculated, he outlined what he hoped to do in aerospace medicine and reached out to Weill Cornell Medicine’s three astronaut alumni. He also identified a faculty mentor: Dr. Christopher Mason, an associate professor of physiology and biophysics who is one of the lead investigators of the NASA Twins Study, which studies how long-term space flight affects the human body (in astronaut brothers Scott and Mark Kelly) and is developing new technology for DNA diagnostics in space. After Dr. Mason eagerly took him under his wing and they brainstormed a research outline, Donahoe set up a meeting with Dr. Schafer to describe his plan. “He was a little surprised, because no student had visited him yet — and I came in with this whole plan that I was super excited about,” says Donahoe. “But he was also extremely supportive, and within a month the school launched an aerospace medicine and space genetics area of concentration.” The summer before his third year, Donahoe spent a week shadowing an astronaut who’s also a physician at the Johnson Space Center — an experience facilitated by Dr. Ellen Baker, (MD ’78), a veteran of three space missions. Now, he’s deciding whether to spend his upcoming research block studying genomic changes in astronauts during space flight or comparing zero-gravity exercise regimens — knowledge that’s meant to elucidate what would happen to the human body on a long-duration mission to Mars, for example.

Eugene Carragee ’18 (left) and Tom Donahoe ’19 with mentor Dr. Chris Mason(right)

Eugene Carragee ’18 (left) and Tom Donahoe ’19 with mentor Dr. Chris Mason (right)

While such research may seem distant from the practice of medicine on Earth, it provides practical insights for future doctors, says Eugene Carragee ’18, an aspiring anesthesiologist who also is pursuing an aerospace AOC. “Learning what happens when someone goes into space, and the compensatory mechanisms that kick in because of a micro-gravity environment, has helped me understand much better how the body works and how the organ systems interact with one another,” says Carragee , who is working with Dr. Mason on the Twins Study. “I see this in-depth knowledge as a bridge between what I’ve done in this concentration and what I’ll pursue as a specialty.”

Joining a Research Community

When AOC leadership unveiled the program in 2014 after a long planning process, Dr. Schafer feared it would be challenging to find faculty willing to participate. But he had the opposite problem: there was a rush of volunteers. Among them was Dr. Harjot Kaur Singh, an assistant professor of clinical medicine who leads the infectious diseases AOC with Dr. Laura Kirkman, the William Randolph Hearst Foundation Clinical Scholar in Microbiology and Infectious Diseases. The pair welcomed six students by inviting them to participate in division meetings and to share their work at a gathering two days after the poster session. “We thought this was a great opportunity — not only for students to showcase what they’ve done, but also for the infectious diseases group to offer mentorship, support and advice,” Dr. Singh says.

For Dzyadyk, the third-year student who studied gut microbes as part of the infectious diseases AOC, the program’s biggest benefit has been developing close relationships with her mentors at Memorial Sloan Kettering Cancer Center: Dr. Eric Pamer, an infectious diseases physician, and Dr. Miriam Torchinsky, a fellow. Both not only guided her through her research, but shared details about their professional paths and advised her on topics like identifying her own interests and choosing a specialty. Says Dzyadyk: “Graduating from medical school, we’ll earn an MD — but there’s still so much more to learn about medicine, ourselves and what we want to do in our careers.” Vince Raikhel ’18 had a similarly powerful mentorship experience — halfway around the world. After spending two months shadowing a palliative care physician in New York, he spent six weeks doing the same in Vellore, India. From both, he learned the importance of slowing down to get to know the patient and involving families in the medical decision-making process, an experience he calls “very inspiring.”

In addition to faculty mentorship, a key part of the AOC is that students help and support each other. At biweekly meetings during the research block, groups of seven to 10 students brainstorm solutions to research problems, with a faculty facilitator on hand to offer advice. Natalie Wong ’18 needed that peer input — as well as guidance from her mentor, Dr. Heather Yeo, an assistant professor of surgery and the Nanette Laitman Clinical Scholar in Healthcare Policy and Research/Clinical Evaluation — when she realized that her proposed project wasn’t going to work out. Wong originally set out to study complications related to colorectal cancer screening procedures using a massive national database, but realized that the dataset was missing a lot of variables that she needed to do the correct analysis. So, working with her mentor, she shifted to another question, for which the data was more helpful: are large polyps a risk factor for metastatic colorectal cancer that has spread to the lymph nodes? Physicians working with Dr. Yeo’s group are keenly interested in the answer, which could impact clinical practice. Says Wong, who’s continuing her research this fall: “Hitting roadblocks and working through them has been an important part of my experience.”

This story first appeared in Weill Cornell Medicine, Vol. 16. No. 3

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Five Weill Cornell Medical Students Win Prestigious Howard Hughes Fellowships

Double exposure of scientist hand holding laboratory test tube. Photo by PowerUp.

Five Weill Cornell Medical College students have been named 2017 Medical Research Fellows from the Howard Hughes Medical Institute (HHMI). It’s the most HHMI fellowships awarded to Weill Cornell students since the award’s inception in 1989.

The institute offers the prestigious fellowship to develop exceptional medical, veterinary and dental students into future physician-scientists. Third-year Weill Cornell medical students Sydney Ariagno, Aditi Gupta, Solomon Levin, Aaron Oswald and Yoshiko Toyoda are among 79 students nationwide to receive the honor, which will provide them with a year of full-time, mentored laboratory research training. Fellows, funded by a $32,000 stipend and additional allowances for travel and other expenses, will share their research at the American Society of Clinical Investigation-Association of American Physicians Joint Meeting April 20-22, 2018, in Chicago.

“This is a tremendous accolade and illustrates the growing importance of original research as a component of medical education at Weill Cornell Medicine,” says Dr. Anthony Brown, director of medical student research at Weill Cornell Medicine. “Our students are extremely talented and they have an extraordinary choice of faculty mentors to guide their research, be it in basic science, translational, clinical or population-based studies.”

Ariagno will work to develop a non-invasive blood test, based on identifying small tumor-secreted packages or exosomes, which can diagnose the most common malignant brain tumor in children, called medulloblastoma. By identifying the characteristics of the exosomes as the tumor develops, Ariagno hopes to be able to monitor the disease’s growth and predict its future progression. She will be mentored by Dr. David Lyden, the Stavros S. Niarchos Professor in Pediatric Cardiology, and Dr. Praveen Raju, assistant professor of pediatrics, both at Weill Cornell Medicine.

Gupta will study the expression pattern of a protein called TGF beta in melanoma, working to characterize whether inhibiting TGF beta prevents cancer growth. Gupta will be mentored by Memorial Sloan Kettering Cancer Center investigators Dr. Jedd Wolchok, the Lloyd J. Old/Virginia and Daniel K. Ludwig Chair in Clinical Investigation and chief of the Melanoma and Immunotherapeutics Service, and Dr. Taha Merghoub, co-director of the Ludwig Collaborative Laboratory and the Swim Across America Laboratory.

Levin will seek to develop a drug to inhibit an enzyme mutated in most cases of the rare liver cancer fibrolamellar hepatocellular carcinoma, which usually affects adolescents and young adults who have no history of liver disease. There is currently no effective treatment outside of liver resection surgery. Levin will be mentored by Dr. Sanford Simon, who is a professor at The Rockefeller University.

Oswald will investigate the mechanical properties of components of the inner ear called tip links, which help convert sound waves into electrical signals sent to the brain, resulting in hearing. Also, by analyzing the mechanical properties of tip links affected by mutations that can cause hearing loss in genetic diseases, Oswald hopes to be able to understand the development of these diseases while working toward devising therapies for treatment. Oswald will be mentored by Dr. A. James Hudspeth, the F.M. Kirby Professor at The Rockefeller University and an investigator for the Howard Hughes Medical Institute.

Toyoda will investigate mechanisms of blood vessel development, called angiogenesis, and cancer metabolism by studying the interplay between breast cancer cells and the microenvironment in a novel model that recreates a blood vessel in collagen. Toyoda will be mentored by Dr. Jason Spector, a professor of plastic surgery and otolaryngology at Weill Cornell Medicine and adjunct professor of bioengineering at Cornell University, and Dr. Shahin Rafii, director of the Ansary Stem Cell Institute and the Arthur B. Belfer Professor in Genetic Medicine at Weill Cornell Medicine.

The awardees are part of the first class at Weill Cornell Medicine to learn under the institution’s new curriculum. Launched in fall 2014, the curriculum, through the Areas of Concentration Program, carves out a six-month period that students can devote to a scholarly project. Some students can also elect to extend this into an additional year. Dr. Brown says the new curriculum has helped students connect to potential faculty mentors and make plans for their research earlier in their studies.

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Dr. David Lyden Receives Grants from the Sohn Conference Foundation

Researchers from Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center have received two grants from the Sohn Conference Foundation to advance their investigation into how cancer spreads in children.

Dr. David Lyden, the Stavros S. Niarchos Professor in Pediatric Cardiology and a professor of pediatrics, Dr. Haiying Zhang, an assistant professor of cell and developmental biology in pediatrics, both of Weill Cornell Medicine, and Dr. Michael Berger, associate director of the Marie-Josee and Henry R. Kravis Center for Molecular Oncology at Memorial Sloan Kettering, will receive a $600,000 grant from the foundation to fund three years of research isolating and characterizing tumor cell-derived “packages” called exosomes.

These packages, shed by pediatric cancer tumors, carry proteins and nucleic acids such as RNA or DNA, and circulate through the body to distant tissues. Dr. Lyden hopes that by characterizing the exosomes, his team can determine which cancers will metastasize — and where — in these cancer patients. The team’s investigation could also lead to the establishment of new biomarkers and targeted therapies for pediatric cancer patients, plus an improved understanding of metastasis in all cancers.

“It will also help us identify novel biological macromolecules including proteins, lipids and genes as therapeutic targets,” Dr. Lyden said. “If we learn something in the pediatric cancer setting, it could help us learn more about other cancers.”

The team also received a $100,000 equipment grant from the Sohn Foundation to fund the upgrading of an instrument that has the unique capacity to separate nanoparticles and is further adapted and optimized to separate the components of tumor exosomes with a higher resolution and a rate faster than the previous equipment.

The Sohn Conference Foundation funds pediatric cancer research, technology and programs to target cures and improve patient care.

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