Engineered Human Colon Model Could Aid in Cancer Research

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By Tom Fleischman

Genetic mutations are a major cause of cancer, and tracking the role of each gene in cancer pathogenesis has long been an important tool in the fight against a disease that is expected to kill more than 1.6 million people this year.

Colorectal cancer progression

The human colon model devised by researchers at Cornell and Weill Cornell Medicine recapitulated the main features of colorectal cancer progression, from in situ to invasion, in a matter of weeks.

Years ago, scientists developed the method of forward genetics – messages inserted into the genome of fruit flies to identify which genetic changes led to disease. The ability to perform the same type of study on human organs has, to date, been impossible, but a multi-institution collaboration – including researchers from Cornell and Weill Cornell Medicine – has published research on a tissue-engineering method that allows forward genetics screening on human tissue.

The paper, "A recellularized human colon model identifies cancer driver genes," was published July 11 in Nature Biotechnology. Dr. Michael Shuler, the Samuel B. Eckert Professor of Engineering and co-senior author of the paper, described his team's work as "powerful."

"You can't really do experiments very well on human tissue," he said, "so having a human system, which allows you to look at the genetics in the context of a controlled environment, is a fairly powerful technique."

The team created a human colon model by first deleting cells from normal human colon tissue, while retaining most of the molecules to which the cells adhere. The tissue is then repopulated with cells obtained from colonoscopy patient samples and from commercial sources.

"What you're really trying to do is provide a micro-environment that encourages the appropriate expression of the genes in the system," Dr. Shuler said.

Then, using a technique developed in the 1990s for inserting specific sequences of DNA into a genome – called a "Sleeping Beauty" transposon – the group tracked the genetic changes that occurred inside the colon model, which were consistent with typical early stage colorectal cancer (CRC).

Further testing confirmed that this recellularized colon model is capable of replicating key features of CRC progression. The work identified 38 driver (disease-carrying) genes, including six that had not been previously implicated in CRC progression.

Dr. Shuler admitted that while it's impossible to say the model provides an exact replica of CRC progression inside the body, "it gives you a human-based system to characterize some of the key steps in advance-stage colon cancer, and that is something that hasn't been possible."

The millimeter-scale model provides major tissue-relevant elements, including complex structure, cell-matrix interactions and physiological co-location of multiple types of differentiated cells.

Dr. Nancy Jenkins, professor of oncology at Houston Methodist Research Institute (HMRI) and co-senior author of the paper, said this technique will go a long way toward fulfilling an unmet need in cancer research.

"The recellularized human colon provides an exciting new model for identifying genes that are mutated during the earliest step in tumor metastasis," said Dr. Jenkins, a cancer geneticist. "Our hope is that a better understanding of the genetics of tumor metastasis will lead to better molecular targeted therapies and/or biomarkers for the treatment of colon cancer."

This study could lead researchers to pursue two directions, according to co-first author Dr. Joyce Chen, a former Cornell graduate student in biomedical engineering who is now a postdoctoral fellow working on a new set of problems in the lab of Dr. Harold Varmus, the Lewis Thomas University Professor at the Meyer Cancer Center at Weill Cornell Medicine.

"The first would be to improve our current colorectal tissue model and study the relationship with the immune system," she said. "We could also use this model to investigate the later stage of the disease, and the migration of cells out of the colon tissue and into other organs, such as the liver."

Other Cornell contributors included Jian Sun, research associate at Weill Cornell Medicine; Asmitta Bhattacharya, graduate student in the field of genetics, genomics and development; Pengcheng Bu, postdoctoral researcher in biomedical engineering; Lihua Wang, doctoral student in the field of biological and environmental engineering; and Shuibing Chen, assistant professor of chemical biology in surgery at Weill Cornell Medicine. Also contributing in writing the paper was Neal Copeland, professor of oncology at Houston Methodist Research Institute, and Zhubo Wei, a postdoctoral researcher in the lab of Jenkins and Copeland.

This work was supported by grants from the National Cancer Institute, the National Institutes of Health and the Cancer Prevention Research Institute of Texas.

Tom Fleischman is a physical sciences and engineering writer for the Cornell Chronicle.

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New Gene Therapy Protects Against Peanut Allergy

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A new gene therapy developed by scientists at Weill Cornell Medicine could eventually prevent the life-threatening effects of peanut allergy with just a single dose, according to a new pre-clinical study.

Peanuts are the most common food that induces fatal or near-fatal reactions in those who are allergic to them, yet preventive treatment is limited. In their study, published June 29 in the Journal of Allergy and Clinical Immunology, Weill Cornell Medicine investigators demonstrate in mice that one dose of a gene therapy boosts the efficacy of a drug that has been proven effective against peanut allergy but in its original form wears off in a matter of weeks.

"It appears that we've developed a drug that, with a single administration, might one day cure peanut allergy," said Dr. Ronald Crystal, chairman of Genetic Medicine and the Bruce Webster Professor of Internal Medicine at Weill Cornell Medicine. "If we prove that it is safe and that it works in humans, it could change the way we treat allergic people."

Peanut allergies occur when a person's immune system overreacts to the allergen by producing an antibody called Immunoglobulin E (IgE), which stimulates the release of inflammatory chemicals. The most serious allergic reaction is anaphylaxis, which can cause severe respiratory effects that can be fatal.

The drug omalizumab, which is a type of protein called a monoclonal antibody that binds to IgE and neutralizes it, has been shown to protect against peanut allergy. Unfortunately, it has significant limitations, Dr. Crystal said. The drug must be injected and is only effective for two to four weeks, he said. "And it is expensive. It's not a practical preventative treatment for peanut allergy, even though it works."

In their study, Dr. Crystal and colleagues describe a new version of the drug that is effective in peanut-allergic mice with just a single dose. They took the genetic sequence from the monoclonal antibody in omalizumab and placed it in a virus, which they then injected into allergic mice.

"We essentially use the virus as a Trojan horse," Dr. Crystal said, "to transfer the monoclonal antibody into the mouse."

The researchers found that one dose of the gene therapy effectively prevented allergic reaction both in mice that were allergic but had never had a reaction, as well as in mice that had already been exposed to peanuts and had anaphylactic reactions.

"This scenario mirrors that of an allergic person who is accidentally exposed to peanuts," Dr. Crystal said. "If the therapy works as well in humans as in rodents, a single therapy may provide protection against allergic reactions for a lifetime."

The technique could also be effective against other IgE-mediated allergies, such as bee sting and shellfish, he added.

All of the work in this study was supported by Department of Genetic Medicine internal funds. Subsequent to the completion of this work, Weill Cornell licensed a patent disclosure relating to this work to Adverum Biotechnologies, a biotechnology company.  Dr. Crystal holds equity in Adverum as well as serves as a member of its scientific advisory board and a paid consultant to the company.  Drs. Crystal, Odelya Pagovich and Maria Chiuchiolo are inventors on the patent disclosure.

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Sequencing Reveals Molecular Underpinnings of Aggressive Prostate Cancer Subtype

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treatment-resistant prostate cancer

A subset of treatment-resistant prostate cancer pathologically resembles small cell lung cancer rather than typical prostate cancer, Weill Cornell Medicine and University of Trento investigators discovered in a new study. The scientists say their findings may lead to more effective ways to diagnose and treat neuroendocrine prostate cancer.

Therapies that cut off the hormone androgen, which fuels tumor growth, are commonly used to treat patients with advanced prostate cancer. While this is initially effective, patients often stop responding and develop treatment resistance. Some of these tumors transform from typical prostate cancer, called adenocarcinoma, into neuroendocrine prostate cancer — an event that scientists have increasingly observed but knew little about how or why it happened.

For their large study, published Feb. 8 in Nature Medicine, Weill Cornell Medicine investigators collaborated with scientists at the University of Trento. They used next-generation sequencing technologies to examine resistance across a spectrum of patients and discovered the genetic, epigenetic and molecular features that underlie neuroendocrine prostate cancer. Their findings illuminate the disease's distinctive characteristics, which may enable researchers to develop biomarkers to help identify this subset of patients with prostate cancer less likely to respond to the next line of hormonal-based therapies. This large dataset can now also be used by researchers to develop new therapeutic approaches for patients.

"We used genomics to better understand how neuroendocrine prostate tumors develop," said lead author Dr. Himisha Beltran, an assistant professor of medicine at Weill Cornell Medicine and director of clinical activities at its Caryl and Israel Englander Institute for Precision Medicine. "These tumors seem to arise clonally from a typical prostate cancer (adenocarcinoma) cell of origin."

Prostate cancer is the leading cause of male cancer death worldwide. The American Cancer Society estimated that 220,000 new cases of prostate cancer were diagnosed in the United States in 2015, and nearly 28,000 men died from the disease.

images of treatment-resistant prostate cancer

Microscopic images of treatment-resistant prostate cancer. The top panel shows typical prostate cancer, known as adenocarcinoma, while the bottom depicts neuroendocrine prostate cancer. The investigators also used a technique to detect a genetic deletion associated with prostate cancer; the blue images on the bottom right hand side of the top and bottom panels show the genetic changes between the two forms of cancer. Image credit: Dr. Himisha Beltran/Nature Medicine

While patients with advanced prostate cancer typically respond well to initial and even subsequent hormonal therapies, understanding why patients stop responding can help identify new therapeutic options. Most commonly, tumors remain driven by androgen even during treatment resistance; only a small fraction of patients develop truly androgen-independent disease associated with neuroendocrine features, the investigators said. To discern these differences, scientists examined 114 metastatic tumor samples from 81 patients with resistant prostate cancer enrolled at the Englander Institute for Precision Medicine, including 30 patients with neuroendocrine prostate cancer.

"Usually patients only have one biopsy — the one that leads to a diagnosis — and no more. For this study, we examined cancers that had been rebiopsied after they spread to see how the tumors changed," said Dr. Beltran, who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine and an oncologist at NewYork-Presbyterian/Weill Cornell Medical Center.

The investigators first compared adenocarcinoma and neuroendocrine prostate cancer tumors under the microscope. The difference was stark: The neuroendocrine tumors looked pathologically different than the adenocarcinoma tumors, Dr. Beltran said. The investigators then sequenced the two tumor types to see if they were genetically and epigenetically the same.

"While the two resistant tumor types (adenocarcinoma and neuroendocrine prostate cancer) were genomically similar, they had distinct epigenomic profiles," said co-senior author Dr. Mark Rubin, director of the Englander Institute for Precision Medicine, the Homer T. Hirst III Professor of Oncology in Pathology and a member of the Meyer Cancer Center at Weill Cornell Medicine. "These changes could potentially explain why the altered cells no longer respond to anti-hormonal therapies."

The investigators found that the features of a person's tumor can evolve over time, and the tumor cells can acquire molecular changes affecting cancer-associated pathways.

"Neuroendocrine tumors evolved from adenocarcinomas, but they are being activated in different ways," said co- senior author Dr. Francesca Demichelis, an associate professor at the University of Trento and an adjunct professor of computational biomedicine in the Institute for Computational Biomedicine and a member of the Meyer Cancer Center at Weill Cornell Medicine, whose laboratory led the computational analyses for this study. "Because of this difference in activation, it may be possible to find new drug targets that can shut down these previously untreatable cells."

These findings may help scientists develop biomarkers to help predict which patients are developing this disease transformation. With that information, physicians may be able to diagnose the condition earlier and intervene with different therapeutic approaches.

"The goal of precision medicine — our goal — is to identify which therapies are most effective for an individual patient and to understand why some patients stop responding to the available therapies that we have," Dr. Beltran said. "This study identifies distinct molecular characteristics associated with neuroendocrine prostate cancer, one subset of treatment resistant prostate cancer. This study is an excellent example of current collaborative and multidisciplinary team science, and the results of this effort between Weill Cornell Medicine, University of Trento, and the Broad Institute, will serve as an important resource for future research focused on how to more effectively treat patients that have developed this aggressive subtype."

"The Prostate Cancer Foundation applauds the work of Dr. Beltran and colleagues in understanding genomic alterations for patients with severe treatment resistance," said Dr. Howard R. Soule, chief science officer of the foundation. "This work addresses a significant unmet medical need and may ultimately result in improved disease control."

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The Power of Two

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Identical twin astronauts offer a rare chance to study how space affects the human genome

Some 220 miles above our collective heads, astronaut Scott Kelly is orbiting the planet on the International Space Station. Awaiting his return here on Earth is his twin brother, Mark — six minutes his elder, and himself a retired astronaut.

During the run-up to Scott Kelly's launch last March, NASA officials realized they had a potential scientific bonanza on their hands: a natural experiment involving two people with all-but-identical genes, one of whom would spend a full year in space. So they put out a call for proposals, offering a total of $1.5 million in grants to scientists eager to investigate the effects of long-term space travel on the human body. Among the 10 winners of the three-year awards: Dr. Christopher Mason, an associate professor of physiology and biophysics at the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Al-Saud Institute for Computational Biomedicine and an assistant professor of neuroscience at the Feil Family Brain and Mind Research Institute.

Dr. Mason is principal investigator of a study entitled "The Landscape of DNA and RNA Methylation Before, During, and After Human Space Travel." Essentially, it's an exploration of how an astronaut's environment affects how his or her genes are expressed — an area known as epigenetics — and whether any such changes are temporary or permanent. The other nine funded projects address such wide-ranging topics as cognition, immune response, and the composition of gut, skin and oral bacteria. "This is probably the most integrated biological portrait of a human ever made — on Earth and then again in space," Dr. Mason says of the overall effort, known as the NASA Twins Study. At the same time, he acknowledges the project's inherent limitations: it does, after all, have only two research subjects. "Statistically, it's the lowest power you could ever have," he notes. "So no one in the study, myself included, believes it's the be-all and end-all. This is the first step on a long stairway toward understanding human physiology in space and helping NASA and humanity prepare for long-duration missions."

It's a step that Dr. Mason was thrilled to take; he's a lifelong astronaut fan who, as a kid, dreamed of applying to NASA and attended space camp twice. Similarly, colleague Dr. Francine Garrett-Bakelman, who'd once contemplated a career in aerospace medicine, leapt at the chance when Dr. Mason and his co-investigators — Dr. George Grills, assistant dean of research resources, and Dr. Ari Melnick, the Gebroe Professor of Hematology-Oncology and director of the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences — asked her to take on the project's bench work. "This is a way to participate in space science that I never imagined I'd be able to do," says Dr. Garrett-Bakelman, an instructor in medicine and a mentee of both Drs. Mason and Melnick. "Very few people are astronauts; only 500-plus have actually been in space, but there are hundreds of thousands who support that work. And being part of that group is pretty special."

Dr. Christopher Mason

Ultimately, the team's investigations could have implications both on Earth and beyond. Studying how the epigenome responds to the stresses of space travel — with its microgravity, increased radiation exposure, and lack of conventional days and nights — could offer insights into such topics as aging, cancer and circadian rhythm function. On a logistical level, the Twin Study is spurring the creation of a computational infrastructure to integrate findings from all ten projects, which Dr. Mason says could serve as a model for researchers in other data-heavy fields. And as NASA contemplates long-range space travel, including a mission to Mars, the study could influence how future generations of astronauts live and work. "This could help us understand how to design a space station so it can be a healthy environment," Dr. Mason says. "As for the long-term goals, the sky's the limit. NASA is planning to send humans to Mars and beyond."

Before Scott Kelly launched, he and his twin underwent a battery of physical tests; some are ongoing during his stay, and both brothers will have follow-up exams after Scott returns. During the yearlong mission, the Kellys are giving regular blood samples for analysis — though, obviously, Scott's are harder to obtain. Some of his specimens are frozen for transport back to Earth during scheduled astronaut return trips, while others are delivered via space capsule: a fresh sample splashes down in the ocean, gets picked up by helicopter, and is transported to the Johnson Space Center in Houston. There, Drs. Mason, Melnick, Garrett-Bakelman and fellow Twins Study researchers collect and process it, and some of the samples are brought back to Weill Cornell Medicine. Dr. Garrett-Bakelman confesses that the first time she did so — handling blood that just a matter of hours earlier had flowed through the veins of an orbiting astronaut — was rather mind-blowing. "It was a very high-quality sample," she recalls. "It was as though the cells didn't even care that they'd traveled down from the International Space Station, landed in Kazakhstan, and flown through Ireland to Houston to the lab. It was a little surreal, to be honest. But it was really cool, because it was from space."

— Beth Saulnier

This story first appeared in Weill Cornell Medicine, Vol. 14, No.3.

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$25 Million Gift from Gale and Ira Drukier Creates the Drukier Institute for Children's Health at Weill Cornell Medical College

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NEW YORK (December 4, 2014) — Weill Cornell Medical College announced today that it has received a $25 million gift from Gale and Ira Drukier to establish a premier, cross-disciplinary institute dedicated to understanding the underlying causes of diseases that are devastating to children. Its goal will be to rapidly translate basic research breakthroughs into the most advanced therapies for patients.

The extraordinary gift names the Gale and Ira Drukier Institute for Children's Health and will enable the medical college to recruit a team of leading scientists, including a renowned expert who will serve as the Gale and Ira Drukier Director, to pursue innovative research that improves treatments and therapies for the littlest patients. The Drukier Institute, a marquee program that will be headquartered on the 12th floor of Weill Cornell's new Belfer Research Building, will also expand and enhance the medical college's already-distinguished research and clinical care programs that strive to end diseases and disorders that affect children and adolescents, including asthma, autism, cancer, cardiovascular disease, infectious diseases and schizophrenia."We couldn't be more grateful to Gale and Ira, whose generous gift exemplifies their commitment to advancing human health and their steadfast support of Weill Cornell Medical College," said Sanford I. Weill, chairman of the Weill Cornell Board of Overseers. "The Drukiers' investment will better the lives of children in New York and beyond, and will leave a lasting mark on our next generation."

"We are greatly appreciative of Gale and Ira Drukier, whose remarkable gift will enable Weill Cornell to expand its world-class research and clinical care programs for children, who can't be treated like little adults," said Dr. Laurie H. Glimcher, the Stephen and Suzanne Weiss Dean of Weill Cornell Medical College. "The Drukiers' generosity is critical in allowing us to attract the best and brightest minds in pediatric research, who will lead the way as we pursue innovative treatments and therapies that will ensure the health of children now and in the future."

"As parents and grandparents, Gale and I appreciate the tremendous impact medicine can have on growing children," said Dr. Ira Drukier, a member of the Weill Cornell Board of Overseers. "When you cure children, you give them their entire life back. It's with immense pride that we are able to make this investment, which will empower Weill Cornell Medical College to focus and direct all of its outstanding pediatric research under the auspices of one institute and provide vital resources to develop tomorrow's treatments and cures."

"It gives us great joy to be able to support Weill Cornell Medical College and make such a tremendous difference in children's lives," Dr. Gale Drukier said. "This gift also continues our enduring relationship with Cornell University, with which we have been connected for 40 years."

The Drukiers have a legacy of philanthropy at Cornell University, having provided generous support to its Herbert F. Johnson Art Museum and College of Architecture, Art and Planning.

"We at Cornell are immensely grateful to Gale and Ira Drukier for their extraordinary leadership and generosity, which has already been felt across the university," President David Skorton said. "With this spectacular new gift, the Drukiers are enabling us to achieve an unprecedented level of excellence in pediatric research. The bench-to-bedside approach of the Drukier Institute will have a lasting impact on children and their families, giving hope when they need it most."

"The gift from Gale and Ira Drukier establishing the Drukier Institute for Children's Health makes a powerful statement about the importance of focusing the energies of a major research institution on improving the health and wellbeing of children," said Dr. Gerald M. Loughlin, the Nancy C. Paduano Professor of Pediatrics and chairman of the Department of Pediatrics at Weill Cornell Medical College and pediatrician-in-chief at NewYork-Presbyterian/Weill Cornell Medical Center. "It is a wonderful legacy for these visionary philanthropists."

Caring for children is particularly challenging because their bodies are constantly changing as they grow, and their metabolisms and immune systems are vastly different than those of adults. Understanding the factors that spur growth in children can present possible lines of inquiry into other diseases, such as cancer, because tumors are also programmed to grow. There are also many genetic and developmental diseases that arise in childhood and pose serious health risks during adulthood. But treating these conditions can be arduous for pediatric patients. Many of the common treatments and therapies available to adults have toxic effects on children, making it critical to devise new and better interventions.

Using genomics and other cutting-edge research approaches, the cross-disciplinary Drukier Institute will drive excellence and innovation in pediatrics, seeking to rapidly and seamlessly catalyze research breakthroughs into the most advanced, safe and effective patient care. The Drukiers' generosity will empower the medical college to recruit five top-flight investigators — including a faculty member who conducts clinical research in pediatric genetics — to augment the distinguished team of physician-scientists already at Weill Cornell, as well as train the next generation of researchers in the field.

To help realize this vision, the Drukiers' gift will enable Weill Cornell to secure the latest research equipment, such as sequencing and informatics technology, as well as develop an infrastructure to establish a biobank. Investigators at the institute will work in close collaboration with clinicians in Weill Cornell's Department of Pediatrics to ensure that children immediately benefit from the latest research advances.

To encourage and support faculty development, research and education, the gift will endow the Drukier Lectureship, an annual lecture at Weill Cornell on a research or clinical topic in the field of children's health. It will also establish the Drukier Prize, which will be awarded once a year to a junior faculty member in the United States or abroad for excellence and achievement in advancing research on childhood diseases or disorders.

About Gale and Ira Drukier

A Cornell University graduate, Ira Drukier is co-owner of BD Hotels, LLC, a real estate development company that owns and operates more than two-dozen hotel properties in New York City, including the Mercer, Hotel Elysee and the Maritime.

Dr. Drukier graduated from Cornell in 1966 with a Bachelor of Science in Engineering with a focus on solid-state physics and in 1967 with a Master in Engineering, earning a doctorate in electrical engineering in 1973 from the Polytechnic Institute of Brooklyn. Upon graduation, he joined RCA Corporation's David Sarnoff Research Center, conducting research in the field of microwave semiconductors, which culminated in his development of the first high-power compound semiconductor field effect transistor. In 1976, he joined Microwave Semiconductor Corporation (MSC) and established a division to develop and manufacture high-power microwave transistors for commercial and military use. Siemens Corporation acquired MSC in 1981, and Dr. Drukier stayed on as corporate vice president until 1983, when he ventured into a career in real estate.

Dr. Drukier has served on the Weill Cornell Board of Overseers since 2012, sat on Cornell University's Board of Trustees for eight years and was a member of the Cornell Tech Task Force to help develop the Cornell NYC Tech campus on Roosevelt Island. He is chair of the council for the Johnson Art Museum at Cornell, chair of the board of trustees building committee of the Parrish Art Museum in Southampton, N.Y., and serves on the Metropolitan Museum of Art's President's Council. Dr. Drukier is vice-chair of the American Society for Yad Vashem and is a member of the Museum of Jewish Heritage's Board of Overseers. He has also published numerous papers and given lectures in the field of microwave electronics and has contributed a chapter to a book on Gallium Arsenide Field Effect Transistors.

Gale Drukier graduated from New York University's Steinhardt School of Culture, Education and Human Development in 1972 with a degree in speech pathology and audiology, later earning a Master of Science ('73) and a Doctor of Education degree ('79) in audiology from Teacher's College at Columbia University. Dr. Drukier began her career as an audiologist at Bellevue Hospital and at Veterans Affairs hospitals in metropolitan New York, later joining Trenton State University — now the College of New Jersey — as a professor. During her 17-year tenure there, Dr. Drukier conducted research, taught and developed the college's nationally accredited graduate program in audiology. She was consistently recognized by her students as the "Best Teacher." After retiring from teaching, Dr. Drukier joined her family's business, BD Hotels, and has managed and renovated properties on Manhattan's West Side for more than 12 years.

Dr. Drukier has continued to serve NYU since her graduation. She has been a member of the Steinhardt Dean's Council since 2005 as a supporter of the educational and fundraising initiatives of the school. In 2007, Dr. Drukier joined the NYU Board of Trustees and presently chairs its Academic Affairs Committee. In 2010, Dr. Drukier endowed and named the deanship of NYU's Steinhardt School of Education. She was awarded the Meritorious Service Award by NYU in 2013.

Dr. Drukier has also been active at Cornell University, chairing the Herbert F. Johnson Museum of Art's Program Committee and is a member of the Plantations Council. Dr. Drukier and her husband endowed the deanship at Cornell's College of Architecture, Art and Planning, endowed the curator of prints and drawings at the Herbert F. Johnson Museum and created a garden at Plantations at Cornell University. The couple is also active in the Parrish Art Museum in Southampton, N.Y., and serves on the Metropolitan Museum of Art's President's Council. Dr. Drukier is an animal lover, particularly of felines, and is on the board of directors of the Animal Rescue Fund of the Hamptons. The Drukiers have one daughter and four grandchildren.

Weill Cornell Medical College

Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, Cornell University is the first in the U.S. to offer a M.D. degree overseas. Weill Cornell is the birthplace of many medical advances — including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with Houston Methodist. For more information, visit weill.cornell.edu.

This release was updated on Dec. 16, 2014.

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Single Gene Mutation Can Cause Abnormally Large Brain

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Finding Provides Clues to How the Human Brain Regulates Its Own Construction, Strategies for Improving Developmental Disorders

Head size in an infant is a marker of proper brain development, which is why pediatricians measure head circumference at every clinic visit during a baby's first year of life. But 1 out of 50 infants have a head circumference that exceeds what a normal growth curve would predict – a possible sign of pressure on the brain or "faulty wiring" that could create cognitive malfunctions as the child grows up.

While scientists already knew some of the genes that contribute to aberrations in brain size, research by Weill Cornell Medical College scientists reveals a new genetic route to megalencephaly, or MEG — a growth and development disorder in which the brain is abnormally large. The findings, published April 6 in Nature Genetics, suggest that it may be possible to disrupt that pathway, reverting infant brains that are growing too large or in an irregular fashion back to more normal development, says the study's co-lead investigator, Dr. M. Elizabeth Ross, a professor of neurology and neuroscience at the Feil Family Brain and Mind Research Institute at Weill Cornell.

"Previous studies have associated these mutations with various cancers, but this is the first proof that this kind of genetic alteration has a major impact on human brain size, shape and organization during development," Dr. Ross says.

The discovery of the gene mutation by Dr. Ross with colleagues at the University of Washington, the Leeds Institute of Biomedical and Clinical Science in the United Kingdom and elsewhere offers potential therapeutic possibilities. There are investigational cancer drugs that may alter the previously known pathway responsible for MEG, raising hope that similar therapies could help children improve their development and neurological function, she says.

While unusually large head size is not a problem in itself, it can reflect a mismatch of particular types of neurons that disrupts normal organization of these brain cells generated in utero, she says. The research team, which included investigators from five countries, knew that a mutation in the PI3K-AKT signaling pathway is one cause of megalencephaly. Regulation of this pathway is important in apoptosis, or cell death, in cell division and is overactive in a number of cancers, including breast and lung. The pathway also plays a key role in brain growth and development. But scientists knew little about the specifics of which molecules in this complicated pathway affect normal brain growth.

Dr. Ross has long studied a different gene and its protein — cyclin D2 — that is part of the cell-division cycle. She discovered that the protein regulates brain size and organization, and found that inactivating cyclin D2 in mice produces animals with smaller brains (microcephaly). Knowing that, the scientists were surprised to find that infants with a single letter change in their cyclin D2 gene had bigger brains — MEG — not smaller brains.

Dr. Ross and her laboratory team, which included Dr. Kristin Giamanco, a postdoctoral fellow and co-first author on the study, thought the tiny genetic change must make cyclin D2 too active. To find out, Dr. Giamanco made a mini-gene that would provide instructions for a cell to make the mutant form of cyclin D2 and a fluorescent green protein that would identify the cells making the mutated version of cyclin D2. She then compared the effect of introducing normal or mutant versions of cyclin D2 into mouse embryo brains to study how the gene mutation worked.

Dr. Giamanco found signs that the mutant protein both stimulated cell division and blocked the ability of an enzyme, GSK3beta, to tag cyclin D2 for degradation in the cell, leaving more cyclin D2 to actively promote the proliferation of brain cells.

Now the story came together. Scientists knew that an overactive PI3K-AKT pathway can turn off GSK3beta, which places PI3-AKT and cyclin D2 genes in the same signaling pathway. The researchers thought mutations in cyclin D2 alone might be enough to produce megalencephaly, and found this was true in 12 megalencephaly patients who did not have mutations in either PIK3 or AKT proteins. The new findings implicate a different and more direct route from PI3K to the cell cycle in a developing brain, suggesting ways that the system might be brought back into a proper balance, Dr. Ross says.

"This MEG syndrome is rare but teaches us that subtle perturbations of the PI3K-AKT-cyclin D2 pathway can significantly alter the course of brain development," she says. "It is possible that events that influence the activity of this pathway at critical time windows in brain development could contribute to other, more common disorders like those in the autism spectrum or schizophrenia. The more we learn about how the developing brain regulates its own cell growth and differentiation, the better able we will be to optimize each child's developmental potential."

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NASA Grant to Shed Light on Effects of Human Space Travel

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Dr. Christopher Mason is boldly going where no man has gone before.

Suited-up (though not yet for the cosmos) with a three-year grant from NASA, the Weill Cornell Medical College geneticist will study the biology of the only set of identical twins who've ever left Earth's atmosphere, scouring their genetically identical DNA and RNA to see if human space travel leaves a genetic fingerprint.

"I often find that you can learn the most about fundamental aspects of the human genome or biology by looking at how it responds in extreme situations," said Dr. Mason, assistant professor of physiology and biophysics at the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Al-Saud Institute for Computational Biomedicine and assistant professor of neuroscience at the Feil Family Brain and Mind Research Institute. "This is one of the most extreme situations the body can go through."

NASA will send veteran astronaut Scott Kelly to the International Space Station next March for a one-year mission, while his brother, retired astronaut Mark Kelly, remains on Earth. To capitalize on this opportunity, the space agency selected and awarded a team of 10 principal investigators a combined $1.5 million to study the molecular, physiological and psychological effects of humans rocketing into space.

The brothers will give blood samples at various intervals before, during and after the mission. Dr. Mason and co-investigators Dr. Ari Melnick at Weill Cornell and Dr. George Grills at Cornell University will then study those samples to see how DNA and RNA change during space travel. They will investigate how genes respond to microgravity and whether gene expression and behavior change while in space. They also will explore whether space travel drives changes between different cells in the body that carry new mutations — or changes to DNA and RNA.

"Human space travel is a long dream for humanity," Dr. Mason said, "and if we can contribute to this goal by understanding how the body responds at the molecular level, that will make me very happy."

And he's ready to jump on a rocket if it aids the scientific cause.

"NASA hasn't said if they will need to send me to space," Dr. Mason said with a chuckle. "But I'm still hopeful they need me to help with the blood draw in zero gravity or to write some zero-G code."

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Researchers Reveal Link Between COPD Risk Genes and Lung Cells

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It has long been a mystery: Why do breathing difficulties develop in one out of five smokers? What puts these smokers at risk for development of chronic obstructive pulmonary disease (COPD), the third-leading killer of Americans, while 80 percent seem to be protected against the damaging effects to airways of trillions of oxidants and chemicals in each cigarette puff?

Genetics plays a role, but one that has remained enigmatic — until now. In a study in the Feb. 3 issue of PLoS ONE, a team of researchers at Weill Cornell Medical College has discovered a biological link between genes known to be associated with COPD and lung function that may explain both the development of the disease and the disparate respiratory effects of cigarettes on their users.

They found, when comparing genetic expression between healthy smokers and non-smokers, that four genes previously associated with COPD are being abnormally expressed in the airway basal cells, the progenitor cells critical to airway function. These genes were among the 676 genes the researchers found were either being over- or under-expressed in the basal cells lining the airways in smokers. These basal cells are crucial to the health of the lung, and the first cells that show damage from smoking.

"This is the first demonstration of COPD risk genes to an actual mechanism within cells that are critical for the maintenance of lung health," says Dr. Ronald G. Crystal, chairman of genetic medicine at Weill Cornell Medical College. "We doubt these four genes are completely responsible for COPD. They are likely part of the story — we believe they play a central role in the very early events that lead to COPD, but they act within a very complex genetic-environment interaction."

COPD and lung disease

A biological link between four genes known to be associated with COPD and lung function may explain the development of the disease. Image courtesy of Dr. Ronald Crystal

The researchers also found that not every smoker had the same level of abnormal expression in the four COPD risk genes (as well as in many of the other genes whose expression differed), which may explain inherited susceptibility to COPD.

"We believe that smoking reprograms basal cells, making some smokers with a certain genetic variant more susceptible to COPD, but we don't know the details yet," Dr. Crystal says. "We are now studying how the basal cells are disordered by smoking."

Basal cells make up 5 to 15 percent of the cells that line the branching airways of the lungs, as well as the windpipe. They contain the critical stem cells that produce the other three kinds of cells that make up, and clean, that protective sheath. "The basal cells replace cells in that lining that are injured or that die, so without them, your lungs will become sick," Dr. Crystal says.

"These abnormal biologic changes are going on in the lungs of smokers who appear to be healthy, but whose lungs show evidence of massive reprogramming," says the study's senior investigator," Dr. Crystal adds.

Dr. Ronald G. Crystal

For this study, the researchers studied 10 non-smokers as well as 10 smokers. Both groups were judged to have healthy lungs, based on chest X-rays, lung function tests and the lack of symptoms of breathing difficulty. Using fiberoptic bronchoscopy — a thin, tube-like instrument threaded through the nose or mouth into the lungs — the scientists sampled the lining of the airway in both groups, retrieving basal cells deep in the lungs.

They then sequenced the genome of these cells, looking at genetic expression of messenger RNA — the molecule each gene makes to produce proteins. The researchers found 676 genes that produced aberrant levels of messenger RNA in smokers. "Smoking essentially reprograms basal cells to have an output of messenger RNA that is different from that of non-smokers," Dr. Crystal says.

To their surprise, they found that 166 genes (25 percent) were found in chromosome 19, known to be home to genes linked to COPD. And in the precise location of these risk genes — an area known as 19q13.2 — 13 aberrantly expressed genes were discovered. Four of these genes were previously linked to development of COPD.

When the science is further defined, the researchers may be able to find targets for potential drug therapy that could protect at-risk smokers against COPD.

"It may be possible to protect basal cells from the toxic effects of cigarette smoke if you shield them in some way, perhaps by shutting off, or modifying the output, of certain genes," Dr. Crystal says.

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Interview with the Dean: Fighting for Genetic Liberty

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Even at a young age, Dr. Christopher Mason was struck by the idea of spending the rest of his life unraveling the mysteries of the human genome.

"By the time I was in eighth grade, I knew I wanted to be a geneticist," said Dr. Mason, an assistant professor of physiology and biophysics and an assistant professor of computational genomics in computation biomedicine at the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Al-Saud Institute for Computational Biomedicine at Weill Cornell Medical College. "I was fascinated by how you start life as a single cell, and that in that one cell there is a complete genetic, dynamic recipe to create an entire human being that eventually is composed of trillions of cells. But, we do not yet understand the grammar of life's molecular code, even if we can see the letters in the book."

Dr. Mason has spent his career looking for genetic mutations that are responsible for aggressive diseases. It was while he was a postdoctoral fellow at Yale University that he made a discovery that would lead him down an unexpected path to the U.S. Supreme Court.

"I was looking for specific genes that were associated with brain malformations," he said. "It became clear that you often don't know the cause of the disease, so you'll look at five or 20 genes at a time; sometimes you'll have a list of 100. And I came across a study indicating that as many as 19 percent of human genes were patented. That was surprising. For one, I didn't realize that you could patent genes; and two, it meant that just by doing my normal research in the lab I would have a one in five chance of infringing on a patent."

Concerned that these patents could debilitate research, Dr. Mason started approaching members of the U.S. House of Representatives and U.S. Senate, supporting a bipartisan bill introduced in early 2007 called the "Genomic Research and Accessibility Act" that would have prevented further gene patents. While making his rounds on Capitol Hill, he found likeminded individuals from the American Civil Liberties Union, the Public Patent Foundation, the American Medical Association and the Association for Molecular Pathologists. Together, they filed a lawsuit in 2009 to challenge the patents.

In March, Dr. Mason published a study in Genome Medicine that showed that as much as 100 percent of human DNA could be considered off-limits to researchers due to the broad scope of many patents that companies hold on genes.

"Just as we enter the era of personalized medicine, we are ironically living in the most restrictive age of genomics," Dr. Mason said. "You have to ask, how is it possible that my doctor cannot look at my DNA without being concerned about patent infringement?"

Three months later, the Supreme Court answered that question in the case Association for Molecular Pathology vs. Myriad Genetics, which had the patents to the BRCA1 and BRCA2 genes. Mutations in the BRCA1 and BRCA2 have been linked to markedly increased chances of hereditary breast and ovarian cancer. And since Myriad had the patents, they also had a monopoly on genetic testing for the BRCA1 and BRCA2 genes.

The nine justices ruled unanimously that human genes can't be patented, saying in their brief: "A naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated..."

"This is the fulfillment of a seven-year long struggle and dream that we can liberate the genome, as I like to say," Dr. Mason said. "It's a clear, gigantic win for patients. It means if you want to have additional research, cutting edge research, second opinions on any of your breast cancer associated or other disease related genes, you now have that freedom. It opens the floodgates of research for other people who want to work on these genes."

The Supreme Court, however, also decided that a synthetic version of DNA created in a laboratory called complementary DNA, or cDNA, is eligible for patents because it does not occur organically in nature. But Dr. Mason doesn't think the fight is over just yet. In fact, a new round of patent lawsuits have already been launched against companies that wanted to offer independent testing of the genes, both for work on DNA and also cDNA.

However, Dr. Mason suspects that these other methods and even cDNA will be ruled ineligible for patents because of the ease with which cDNA is developed. Simply adding an enzyme to DNA essentially creates synthetic DNA, which Dr. Mason and many other geneticists think isn't a distinct enough difference to be considered patent-eligible.

Regardless of what happens with cDNA, Dr. Mason's advocacy for genetic liberty has helped bring a breath of fresh air to an area of medicine that was suffocating under patent burdens, and this should help expedite the use of genomics for personalized medicine.

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