Tall Order


An ambitious study aims to understand how Crohn's disease stunts kids' growth

When Alex Bancroft was 5, it was clear that something was awry with his digestive system. During kindergarten, his mom says, he was spending a lot of time in the bathroom. Doctors first thought he had a virus, but the symptoms persisted. Then a pediatric gastroenterologist diagnosed Alex with irritable bowel syndrome and put him on medication for it. But he didn't get any better — and on top of enduring diarrhea and fatigue, he wasn't growing. "He wouldn't eat, because he was afraid that he wouldn't make it to the bathroom in school," says his mother, Caroline Bancroft. "At age 7, he dropped down to about 40 pounds."

Eventually, Alex's parents brought him to NewYork-Presbyterian/Weill Cornell Medical Center, where he saw Dr. Thomas Ciecierega, an assistant professor of pediatrics. Dr. Ciecierega made the correct diagnosis — Crohn's disease, a type of inflammatory bowel disease (IBD) that is characterized by intestinal inflammation — and put the boy on the proper course of medication. "He started gaining weight and was more active," Caroline says. "You could see the life coming back." Today, Alex is still a little short for his age, but the Long Islander is an active 9-year- old and avid lacrosse player. He'll have to stay on medication indefinitely, and the disease has other potential complications, like eye problems and arthritis. But for now, he's doing well. Says his mom: "This is the healthiest I've ever seen him in his life."

Someday, kids like Alex could benefit from research now under way at Weill Cornell Medicine. Dr. Neera Gupta, director of research and a specialist at the Weill Cornell Medicine Pediatric Inflammatory Bowel Disease Center and an associate professor of pediatrics, recently launched a study to uncover why kids with Crohn's — especially boys — are often shorter than their peers. Growth is a dynamic marker of a child's health status, she notes, and it's an issue of central importance to patients, families, and providers.

Dr. Gupta, who is also a physician-scientist at the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell Medicine, notes that roughly 25 percent of patients with IBD are diagnosed during childhood and adolescence. In the United States, there are about 5,000 new pediatric IBD cases each year — and they present unique challenges. Not only is growth impairment a major complication of pediatric-onset Crohn's disease that distinguishes it from the adult-onset version, she explains, but diffuse disease is more common in children at the time of diagnosis, and progression occurs more frequently in kids than in adults.

There are also sex differences in the presentation and course of Crohn's disease. In Dr. Gupta's previous studies, she found that girls tend to have a more severe course of disease and are more likely to need surgery, but boys are more likely to have growth problems. Her current work, funded by an NIH award of more than $3 million, aims to figure out why.

The study will follow children and adolescent boys and girls for two years. After an initial screening to make sure they qualify, participants will come in every six months for a total of five visits, either at Weill Cornell Medicine or one of the other collaborating institutions. Procedures will include height and weight measurements, assessment of pubertal status, medical history, blood draw, hand x-rays (for bone age) and nutrient intake assessments.

Dr. Gupta's team will utilize the data to develop predictive models to identify which children are most likely to have persistent growth problems caused by Crohn's disease, ultimately helping clinicians to better determine a course of treatment. "One of the debates in our field is when to introduce the most aggressive therapies for Crohn's disease," Dr. Gupta says. "Some believe we should do it at the time of diagnosis, and some believe we should start with other therapies first. Most agree there are high-risk children who would benefit from early intervention with aggressive therapy — but we need to figure out who these high-risk children are. Because there is a very narrow therapeutic window in which we can intervene to improve growth, children who are at highest risk for persistent growth impairment may be candidates for early intervention with aggressive therapy."

After data collection is completed, doctors will be able to look at a combination of variables — including sex, race/ethnicity, disease location, bone age, inflammatory markers, hormone levels and genetic markers — to determine whether a child is at high risk for growth impairment. The next step will be an interventional clinical trial assessing aggressive therapies in children who are at highest risk for remaining growth-impaired. Importantly, Dr. Gupta says, the study will improve understanding of the underlying mechanisms of growth impairment in Crohn's disease. It's known that impairment may result from inflammation, malnutrition, or the side effects of medications; despite this knowledge, it continues to occur frequently in children and adolescents. "We need to advance our understanding of the underlying mechanisms of growth impairment in Crohn's disease," Dr. Gupta says. "We hope that findings from our research will lead to improved treatments not only for the children identified as high-risk for persistent growth impairment, but for all children with IBD."

Dr. Gupta aims to complete data collection by 2019, but for now her team is still in the process of recruiting participants. The goal is 125 — but that's challenging, in part because not every Crohn's patient in the specified age range will qualify for the study. Alex, for example, hasn't qualified so far, because his bone age hasn't met the eligibility criteria. But his parents hope that work like Dr. Gupta's will someday ensure that other kids don't have to go through the ordeal that he has. "Ultimately," says his dad, Bob Bancroft, "what we're hoping for is a cure."

Keri Blakinger


This story first appeared in Weill Cornell Medicine, Vol. 15, No.2.

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Disruption of Intestinal Fungi Leads to Increased Severity of Inflammatory Disease


Fungi that live in a healthy gut may be as important for good health as beneficial intestinal bacteria, according to new research conducted at Weill Cornell Medicine.

Scientists have known for quite some time that the so-called "good" gut bacteria in the intestines, known as commensal bacteria, are a key component of a healthy body. These bacteria are critical for proper digestive and immune system function. Recent discoveries, however, have indicated that other microbes, such as fungi and viruses, may also play a part in how the body handles inflammation.

"The focus has been gut bacteria for a long time," said Dr. Iliyan Iliev, an assistant professor of immunology in medicine and a scientist at the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell Medicine. "But these bacteria share their space with fungi in the intestines, so we have to think about how the fungi can affect the human body as well."

In a study published May 26 in Cell Host & Microbe, Weill Cornell Medicine researchers found that disruption of the intestinal fungi of mice with antifungal drug treatment increases the severity of colitis and allergic airway disease. "This is evidence that a healthy intestinal fungal community definitely plays a role in immune response, both inside and outside the gut," Dr. Iliev said.

The researchers treated mice with common antifungal medications and then induced colitis, a condition characterized by inflammation in the colon. They found that the mice that received antifungal drugs developed more severe colitis than the untreated mice.

To test whether fungal disruption could affect immune response elsewhere in the body, Dr. Iliev and his colleagues again treated mice with antifungal drugs and then exposed them to household dust mites to create an allergic response in the lung. Fungal infections are actually known to worsen symptoms in severely asthmatic patients, so the investigators thought antifungal treatment might protect the mice. Instead, the treated mice developed more severe asthmatic symptoms. "Our results suggest that in addition to bacteria, a healthy fungal community is also important for regulation of immune responses throughout the body," Dr. Iliev said.

DNA analysis of the gut microbes present in the treated mice showed reduced populations of some fungi — which would be expected with antifungal treatment — but increased populations of others. Also, the researchers saw that bacterial populations changed as well—certain bacteria were found in decreased amounts from normal, others in increased amounts. "This result suggests that fungal and bacterial communities in the gut are co-dependent and that disruption of one community affects another," Dr. Iliev said.

Antifungal medications are widely prescribed to treat fungal infections throughout the body. These results suggest that researchers should take a closer look on the effects that those medications may be having.

"We know that antibiotic overuse can contribute to inflammatory disease," Dr. Iliev said. "Although antifungal medication remains the only treatment of choice against life-threatening fungal infections, these results suggest that antifungal drugs overuse may be having a similar effect on human health."

The National Institutes of Health supported this study through the grant DK098310.

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Jill Roberts Institute for Research in Inflammatory Bowel Disease Leads the Field


A string of high-profile research studies underscores the early successes of the Jill Roberts Institute for Research in Inflammatory Bowel Disease, where scientists are assiduously investigating the root causes of the disease. Now, with the official opening of its permanent laboratories, the Weill Cornell Medicine institute is poised to lead the way in advancing research to improve patient care.

Established nearly two years ago with a generous gift to Weill Cornell Medicine from longtime benefactor Jill Roberts, the institute uses a multidisciplinary approach to drive and then translate discoveries into new preventative and treatment strategies for IBD, a group of chronic inflammatory conditions of the intestine that affects an estimated 3.5 million people worldwide.

"We're in a very powerful position to accelerate basic discoveries and translate them to benefit patients," said Dr. David Artis, director of the institute and the Michael Kors Professor in Immunology at Weill Cornell Medicine. "That's really what all of this work revolves around: understanding these diseases so that we can treat and prevent them to improve the quality of life of the people who suffer from these diseases every day."

The institute and its five primary investigators have already made advances in describing the molecular underpinnings of IBD, exploring how host genetics, the immune system, the microbiota and pathways that control inflammation influence the disease's development and progression. In recent studies published in top-tier journals such as Science, Nature, Nature Medicine, Nature Immunology and PNAS, scientists have shown how the intestines repair themselves after daily attacks from microbes and other environmental triggers; a defect in this repair system contributes to IBD. They've revealed how the immune system learns to ignore beneficial bacteria in the gut while recognizing, eliminating and remembering foreign and harmful microbes that invade our bodies. Investigators have also discovered that starving immune cells of key nutrients prevents them from causing inflammation and allergies.

The institute's newest recruit, Dr. Iliyan Iliev from Cedars-Sinai in Los Angeles, investigates the fungi that colonize the intestine and how it operates in both healthy and unhealthy intestines — findings that researchers hope they can ultimately leverage into new therapeutic targets.

 Jessica Bibliowicz, Jill Roberts, William Roberts and Dr. David Artis

Jessica Bibliowicz, center, shakes hands with Jill Roberts during the March 17 ribbon-cutting ceremony, while William Roberts and Dr. David Artis look on. Photo credit: Studio Brooke

The close collaboration between researchers at the Roberts Institute and clinicians at the Jill Roberts Center for Inflammatory Bowel Disease at Weill Cornell Medicine and NewYork-Presbyterian is enabling the institute's scientists to "translate life to the laboratory," notes center Director Dr. Ellen Scherl, applying patients' experiences of disease to research questions — and eventually, "transforming laboratory discoveries back into patient lives."

Research at the institute, in conjunction with physicians in the Jill Roberts Center, is helping to personalize treatment for IBD patients. While patients have historically been sorted into two categories of IBD — Crohn's disease, which is characterized by inflammation in the gastrointestinal tract, and ulcerative colitis, in which inflammation is localized to the colon — scientists are beginning to understand that many more subtypes of the disease may exist. They are recording and studying how each patient's immune system and microbiota is different, and how individual patients respond to treatments. The research will help to stratify patients into increasingly specific categories so that clinicians can deliver tailored, targeted and successful care. It will also enable physicians and scientists to capture changes in the disease and its manifestations —including joint and bone pain, and inflammation in skin, the eyes and liver — in individual patients over the course of their care.

"The gastrointestinal tract is the source of all inflammation in IBD, but there are many different manifestations that patients experience," said Dr. Scherl, who published a review article on Crohn's disease in the March issue of Current Gastroenterology Reports. "What makes our center and institute unique is that we can examine the systematic inflammation that our patients live with every day and investigate what makes their gut immune response different. We can do this cross- sectionally and longitudinally, characterizing our patients."

The institute and center are also building a new IBD patient live cell bank that will provide deeper insight into disease subtypes and how best to treat them. Consenting patients who receive care at the center provide samples of blood or tissue biopsies, from which researchers isolate and freeze immune cells they can later use to investigate the disease. The institute has so far collected 300 samples from adult IBD patients, and the establishment of a pediatric IBD live cell bank is well underway.

The research and clinical arms are also jointly embarking on a clinical trial, led by Drs. Carl Crawford and Vinita Jacob, that is testing fecal microbial transplants to treat ulcerative colitis. The goal is to replace unhealthy microbiota in colitis patients with microbiota from healthy patients to treat the disease. This approach is used successfully to treat Clostridium difficile colitis, a condition in which the aggressive bacteria C. difficile grows vigorously in the intestines and causes severe inflammation. The study, now approved by the U.S. Food and Drug Administration, will begin yielding data later this year.

"This clinical trial is a cutting-edge intervention attempting to ascertain whether this could be a new approach to treating IBD," Dr. Artis said. "These types of joint approaches have benefited enormously from the partnership between the Roberts Institute and the Roberts Center. We have also joined forces with other outstanding institutional experts in digestive diseases housed in the Center for Advanced Digestive Care and The Jay Monahan Center for Gastrointestinal Health. Together, we are in the unique position of having strengths in basic research and clinical care across multiple digestive diseases, coupled with a large patient population, and we hope that these partnerships will be very fruitful moving forward."

To celebrate these accomplishments and future initiatives, the institute hosted a ribbon-cutting ceremony on March 17 to celebrate the opening of its permanent laboratory space on the seventh floor of the Belfer Research Building. Speakers including Jessica Bibliowicz, chairman of the Weill Cornell Medicine Board of Overseers, Dr. Augustine Choi, the Weill Chairman of the Weill Department of Medicine, and Drs. Artis and Scherl voiced their excitement about the institute and their deep gratitude for Jill Roberts' continued generosity towards IBD research and care.

"The institute's leadership in this field is forging a path to an understanding of IBD's molecular underpinnings in order to translate basic research breakthroughs into advanced therapies for our patients," Bibliowicz said. "There is so much that's going to change because of the work that's happening here. Jill's dedication and David's great leadership have empowered the institute's incredible work to spearhead these efforts and to transform treatment for the many patients who suffer from IBD."

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Dr. Ellen Scherl, Jill Roberts, Dr. Augustine Choi, Jessica Bibliowicz and Dr. David Artis
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Bacteria in Immune Cells May Protect Against Chronic Inflammation

A population of bacteria inhabits human and mouse immune cells and appears to protect the body from inflammation and illness, Weill Cornell Medicine scientists discovered in a new study. The findings challenge conventional wisdom about the relationship between bacteria and the human body — and about how the microbes influence health and disease.

The study, published March 15 in Immunity, focused on "good" or "commensal" bacteria that live in the human intestine and are essential for digestion and proper immune function. The majority of these commensal bacteria are found in the tube-like inner core of the intestine, called the lumen. The intestine itself acts as a barrier, keeping the bacteria inside the lumen and ensuring that they do not enter the rest of the body. Many reports have demonstrated that if commensal bacteria managed to escape the lumen, they would activate the immune system and cause disease.

But in their study, Weill Cornell Medicine investigators identified a group of commensal bacteria residing in close contact with immune cells outside of the intestinal lumen that defy this thinking. The discovery may alter the way scientists understand diseases like HIV, inflammatory bowel disease, some cancers, and cardiovascular disease.

Sonnenberg Laboratory. Front center, Dr. Gregory Sonnenberg. Back (from left, clockwise): Dr. Jeremy Goc, Thomas Fung, Xinxin Wang, Dr. Nicholas Bessman and Stephane Pourpe Photo credit: Roger Tully

"For a long time, the assumption was that the human body is essentially sterile and that a physical separation between the immune system and our commensal bacteria was necessary to prevent chronic inflammation," said lead author Dr. Gregory Sonnenberg, an assistant professor of microbiology and immunology in medicine and a member of the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell Medicine. "While this is certainly true for most types of commensal bacteria, our new data demonstrate a special class of commensal bacteria that can closely associate with immune cells in a way that is mutually beneficial for both mammals and the microbes."

To learn more about this population of microbes, the researchers studied "germ-free" mice — rodents that are bred to have no bacteria in their bodies and have no contact with outside bacteria. They added this newly identified class of bacteria, called lymphoid tissue-resident commensal bacteria (LRC), to the mice.

The LRC colonized lymphoid tissues — specifically cells in the immune system — located outside of the intestinal lumen. When Dr. Sonnenberg and his colleagues investigated what the bacteria were doing, they found that they did not cause inflammation as expected. Rather, they did exactly the opposite — they limited the inflammatory response in the immune tissue.

The researchers then tried to experimentally induce intestinal tissue damage and inflammation in the rodents. They found that the mice that had LRC in their lymphoid tissue were protected.

"So it seems that these bacteria residing in lymphoid tissue are actually protecting the mice, rather than driving disease as would be expected," said lead author Thomas Fung, a graduate student in Dr. Sonnenberg's lab. "We further found that the immune responses induced by these bacteria are mutually beneficial; they not only protected mice from experimental tissue damage, but they also facilitated bacteria colonization of lymphoid tissues."

These are early findings, but the implications for human health are important to consider, Dr. Sonnenberg added. For example, the prevailing view is that in people with inflammatory bowel disease, colorectal cancer or HIV infection, commensal bacteria disseminate from the lumen of the intestine into the periphery of the body and promote inflammation.

"Our new data indicate that some unique bacteria residing in lymphoid tissues could instead promote tissue protection and limit inflammation," he said, "and our research highlights that it will be important to consider changes in lymphoid tissue-resident microbes during human health and disease."

The Sonnenberg Laboratory is also investigating whether LRCs can be developed as an innovative therapeutic approach to limit chronic inflammation and promote tissue repair in diseases such as inflammatory bowel disease.

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Innovative Therapeutic Approach Shows Promise in Treating Inflammatory Bowel Disease

inflamed mouse intestine with longer epithelial cells and an over-abundance of immune cells

Microscopic color-enhanced image of an inflamed mouse intestine, with longer epithelial cells and an over-abundance of immune cells (shown in yellow). Credit: Drs. Greg Sonnenberg and David Withers

An investigative therapy given to mice blocks the overactive immune responses that are a hallmark of inflammatory bowel disease without impairing the body's ability to fight infection, an international research team led by Weill Cornell Medicine investigators finds in a new study. The preclinical discovery may lead to more effective treatment strategies for IBD.

The prevailing scientific view of IBD — a chronic, debilitating inflammatory disorder of the digestive tract that affects an estimated 3.5 million individuals worldwide — is an over-reactive immune system attacking the normally beneficial bacteria that colonize the intestines. Treatments for the condition have been hampered by the challenge of stopping this aberrant immune response without hindering the immune system from protecting against harmful pathogens.

To get around this conundrum, investigators used an innovative therapeutic approach to block the production of an inflammation-promoting molecule in mice, while leaving key protective immune factors intact. In their study, published Feb. 15 in Nature Medicine, the investigators found that this approach effectively prevented inflammatory immune responses without making the mice more susceptible to infection. The results suggest that the drug may be effective in people.

Dr. Gregory F. Sonnenberg

Dr. Gregory F. Sonnenberg Photo credit: Carlos Rene Perez

"We really are excited by these new findings as they suggest that this therapeutic approach could be a safe and effective way to treat chronic intestinal inflammation," said senior author Dr. Gregory F. Sonnenberg, an assistant professor of microbiology and immunology in medicine and a member of the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell Medicine.

The pro-inflammatory molecule, called IL-17, has emerged as a target for treating IBD, but clinical trials that tested blocking it with antibodies have failed. Some patients became sicker or more susceptible to opportunistic infections by fungi in the intestine, Dr. Sonnenberg said. IL-17 is produced by both white blood cells called T cells and a recently discovered class of immune cells that play a role in the immune system's surveillance of infection and in tissue repair, known as innate lymphoid cells (ILCs). Some researchers believe that blocking IL-17 not only switches off the body's attack on its own cells, but also impedes the ability of ILCs to defend against new infections or promote tissue repair.

But scientists from Weill Cornell Medicine, the Children's Hospital of Philadelphia and the United Kingdom-based University of Birmingham and Babraham Institute, tried a different approach: Using both small-molecule compounds and genetic approaches, they targeted a molecule that regulates production of IL-17 in mice, called ROR gamma-t. The investigators found that inhibition of ROR gamma-t effectively prevented inflammatory immune responses without making the mice more susceptible to infection.

"The surprising finding we made was that temporary inhibition of ROR gamma-t did not impact the function of ILCs," said lead author Dr. David Withers, a Wellcome Trust Research Fellow at the University of Birmingham. "This effectively allowed us to limit the T cell responses that are promoting chronic intestinal inflammation, while preserving the protective ILC responses that mediate tissue repair and early protection from infections."

To test if this approach could selectively inhibit pro-inflammatory T cells in human cells, the researchers applied similar approaches to immune system cells taken from intestinal biopsies of pediatric patients diagnosed with Crohn's disease, one of the major forms of IBD. Similar to their observations in mice, the investigators found a reduction in the human T cells that make pro-inflammatory molecules, and the ILCs remained intact.

"There are a number of important questions remaining here that need to be addressed prior to taking these findings forward, such as developing innovative small-molecule compounds and further understanding what is maintaining ILC responses in the absence of ROR gamma-t," Dr. Sonnenberg said. "However, these findings suggest that small molecules that inhibit ROR gamma-t may be an attractive approach for therapeutically treating inflammatory bowel disease, as well as multiple other chronic inflammatory disorders."

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Weill Cornell Medical College and NewYork-Presbyterian Hospital License Technology to Lumendi, Ltd.


Start-Up Company Dedicated to Developing and Commercializing Products Aimed At Revolutionizing Gastrointestinal Surgeries

NEW YORK (September 11, 2015)The Minimally Invasive New Technologies Program (MINT) at Weill Cornell Medical College and NewYork- Presbyterian Hospital has teamed up with entrepreneurs and investors to establish Lumendi, a new start-up company dedicated to producing next-generation endoscopic tools that make complex gastrointestinal surgeries safer and less expensive while also improving patient outcomes.

Endolumenal Surgical Platform

Rendering of the Endolumenal Surgical Platform. Image: MINT

The agreement between Weill Cornell and Lumendi will advance the development of the Endolumenal Surgical Platform (ESP), a new disposable device which fits over a standard endoscope like a sleeve and provides increased stability, control and visualization within the intestine. These enhanced features are designed to allow clinicians to remove large polyps and eventually to treat strictures, fistulas and many types of inflammatory bowel disease without necessitating open or laparoscopic surgery. The ESP is designed to transform the way gastrointestinal surgeries are performed by enabling clinicians to perform complex procedures endolumenally — from entirely within the intestine — resulting in less-invasive surgeries, quicker patient recovery and reduced healthcare costs.

Lumendi will seek to transform the ESP prototype developed at MINT into a commercial product and seek clearance by the U.S. Food and Drug Administration. In collaboration with Lumendi, the MINT team plans to develop a series of new products that are designed to enhance the ESP.

"We are defining a new era of digestive surgery, and we believe that the ESP will pave the way," said Dr. Jeffrey Milsom, chief of Colon and Rectal Surgery at Weill Cornell Medical College and NewYork-Presbyterian/Weill Cornell Medical Center and MINT co-director, who holds an equity interest in Lumendi, Ltd. and serves as a paid advisor to the company. "The ESP device and ancillary tools are all relatively simple, and clinicians who use them should be quickly able to take a leap forward in terms of what they're able to do inside the intestine."

Endolumenal Surgical Platform

Rendering of the Endolumenal Surgical Platform reaching the target location in the body. Image: MINT

The ESP design features two balloons which create a therapeutic zone inside the intestine, allowing clinicians to stretch out the intestinal wall and straighten folds and bends in order to stabilize and better visualize the colon. The design also permits stabilizing the endoscope tip at the site of the disease, allowing clinicians to target their movements precisely.

"Current endoscopes don't offer the same level of stability that ESP does," said Dr. Milsom, who is also executive director of the Center for Advanced Digestive Care at Weill Cornell and NewYork-Presbyterian/Weill Cornell Medical Center, and the Jerome J. DeCosse M.D. Distinguished Professor of Surgery at Weill Cornell Medical College. "With this device, you can better control and manipulate the surgical environment inside the intestine."

As part of the agreement, MINT plans to develop a series of new products to enhance the ESP platform and increase the number of procedures that can be performed endolumenally. These tools include flexible surgical instruments that will enable precise complex surgical procedures to be conducted within the intestinal channel.

"Creating Lumendi has opened up many new possibilities for advancing gastrointestinal surgeries," said Dr. Peter Johann, chairman and CEO of Lumendi. "This innovative relationship has the potential to transform digestive care for patients around the world."

Lumendi, Ltd. holds an exclusive worldwide license from Cornell University on the ESP platform and related ancillary products. According to Dr. Johann, Lumendi's vision is to revolutionize digestive surgery by developing and making available tools and devices enabling minimally invasive gastrointestinal interventions. Formed in December 2014, Lumendi is collaborating with MINT for the further development of these devices. For more information, visit www.lumendi.com and www.mint.weill.cornell.edu.

NewYork-Presbyterian Hospital

NewYork-Presbyterian Hospital, based in New York City, is one of the nation's largest and most comprehensive hospitals and a leading provider of inpatient, ambulatory and preventive care in all areas of medicine. With some 2,600 beds and more than 6,700 affiliated physicians and almost 22,000 employees, NewYork- Presbyterian had more than 2 million visits in 2014, including some 14,000 infant deliveries and more than 262,000 emergency department visits. NewYork-Presbyterian comprises six campuses: NewYork-Presbyterian/Weill Cornell Medical Center, NewYork-Presbyterian/Columbia University Medical Center, NewYork- Presbyterian/Morgan Stanley Children's Hospital, NewYork-Presbyterian/The Allen Hospital, NewYork-Presbyterian/Westchester Division and NewYork-Presbyterian/Lower Manhattan Hospital. The hospital is also closely affiliated with NewYork- Presbyterian/Hudson Valley Hospital, NewYork-Presbyterian/Lawrence Hospital and NewYork-Presbyterian/Queens. NewYork-Presbyterian is the #1 hospital in the New York metropolitan area, according to U.S. News & World Report, and consistently named to the magazine's Honor Roll of best hospitals in the nation. Affiliated with two world-renowned medical schools, Weill Cornell Medical College and Columbia University College of Physicians and Surgeons, NewYork-Presbyterian is committed to excellence in patient care, research, education and community service. For more information, visit www.nyp.org.

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.

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Restoring "Gut Health" in Patients with Inflammatory Bowel Disease May Be a Matter of Pushing Cells to Repair Our Tissues

intestinal tissue damage of intestinal inflammation

Color-enhanced histologic image showing intestinal tissue damage in a murine model of intestinal inflammation. Image credit: Drs. Laurel Monticelli and David Artis

New insight into how the intestines repair themselves after daily attacks from microbes and other environmental triggers could lead to innovative approaches to treating inflammatory bowel disease, according to new research by Weill Cornell Medical College investigators.

The findings, published Aug. 4 in PNAS, reveal a mechanism that allows the single layer of cells that line the inside of the intestines, called the gut epithelium, to signal the immune system to repair tissue damage caused by the daily onslaught of microbes and other environmental factors that the body encounters. Because a defect in that repair system underlies Crohn's disease and ulcerative colitis, the two primary forms of IBD, restoring tissue-protective repair mechanisms could reduce the diseases' hallmarks, chronic inflammation and tissue damage.

"We have to maintain gut health by protecting and repairing tissues like the intestine that are constantly exposed to environmental assaults — triggers such as food particles, microbes, pollutants, or things we might swallow — that happen every day," said senior investigator Dr. David Artis, director of the Jill Roberts Institute for Research in Inflammatory Bowel Disease and the Michael Kors Professor of Immunology at Weill Cornell Medical College. "We found one way these epithelial cells trigger the immune system to promote repair of the barrier that protects intestinal tissue from these constant assaults.

"These are early days in this research," he added, "but these findings provide the foundations for future studies to explore how therapies that promote tissue protection and repair could be developed to combat IBD and other chronic diseases." The research, led by first author Dr. Laurel Monticelli, a postdoctoral associate in Dr. Artis' lab, was designed to understand the biological processes that maintain gut health. The research team found that a component of the body's immune system, called group 2 innate lymphoid cells (ILC2), are key to orchestrating restoration of the intestinal barrier.

"While there have been many advances in understanding how the immune system is causing IBD, less is known about the processes that rebuild the gut barrier and protect against future damage," Dr. Monticelli said.

In the PNAS study, supported by the National Institutes of Health, the Crohn's and Colitis Foundation and the Burroughs Wellcome Fund, researchers have uncovered a critical feedback loop involved in maintaining intestinal health. When the gut lining is damaged during disease, epithelial cells produce and release a molecule called interleukin 33 (IL-33). The molecule belongs to a family known as the "alarmins" because they act as a chemical alarm system that activates neighboring cells at the site of the injured tissue. Group 2 innate lymphoid cells are uniquely suited to act as first responders to this alarm, rapidly producing a growth factor called amphiregulin. High levels of amphiregulin can aid in rebuilding the intestinal barrier by stimulating growth of new epithelial cells and creating a protective layer of mucus that repels future attacks.

"A very sophisticated dialogue is occurring between the gut epithelium and the innate lymphoid cell population," Dr. Artis said, "so tapping into that exchange may be key to maintaining gut health in humans."

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Color-enhanced histologic image showing intestinal tissue damage in a murine model of intestinal inflammation.  Image credit: Drs. Laurel Monticelli and David Artis
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Symbiotic Relationship


Researchers Explore the Microbiome, Medicine's Newest Frontier

By Amy Crawford

Portraits by John Abbott

intestinal epithelium lining mouse's gastro-intestinal tract

A color-enhanced image of the intestinal epithelium that lines the gastro-intestinal tract of a mouse. Scientific images: Drs. Gregory Sonnenberg and David Artis

The most exciting discoveries can begin with the humblest material — and for researchers in the lab of immunologist Dr. David Artis, that often means mouse droppings. Once an obliging rodent provides a stool sample, a technician uses a chemical buffer to break down bacterial cell walls, unleashing the coils of DNA within. After further chemical preparation to enrich the genetic information, the sample is fed into an Illumina MiSeq, a desktop machine half the size of an office photocopier that, over the course of about 48 hours, sequences billions of base pairs to reveal a catalog of hundreds of types of bacteria: the mouse's microbiome. "After painstaking collection and preparation, you load your samples and allow the machine to run overnight," explains post-doctoral researcher Dr. Lisa Osborne, who has analyzed her share of murine fecal bacteria in the name of better understanding how the microbiome works in humans. "A lot of sophisticated magic happens inside that box."

The technology may not look flashy, but it's enabling a revolution in how scientists think about the bacteria that share our bodies — no longer as mere pathogens, but as members of a tiny ecosystem that coevolved with us, and on which our health depends. Dr. Artis and his colleagues hope these communities of microbes can offer insight into one of the most confounding problems in modern medicine: the set of painful chronic conditions known as inflammatory bowel disease (IBD). But IBD is not the only reason scientists at Weill Cornell and elsewhere are increasingly interested in microbiota. It turns out that the human microbiome may have far-reaching impact throughout the body, influencing how our immune systems develop, how our food is metabolized — and even, perhaps, the peculiarities of our personalities. New knowledge about the complex web of relationships between humans and the microbes that live within us is calling into question not only our understanding of disease, but of what it means to be human. "This is one of the major topics in contemporary biomedicine, and it's profoundly reshaping the way we think about health and disease and individuality," says Dr. Carl Nathan, the R. A. Rees Pritchett Professor of Microbiology and chairman of microbiology and immunology. "I grew up thinking that a given person has one genome, one set of genes that you inherit from your two parents. That's much too simple."

intestinal tissue of healthy mouse

A stained histologic section of intestinal tissue isolated from healthy mouse.

Medical training taught Dr. Nathan that the hereditary genome he learned about in school was not the only one that makes us who and what we are. There's also the somatic genome — the accumulated mutations and re-arrangements that some cells undergo, either as part of an abnormal process that can lead to cancer or as part of a healthy immune system, which adapts to recognize the myriad pathogens a person encounters throughout life. Another code is found within mitochondria, organelles that power our cells and, scientists believe, evolved in multicellular organisms like humans from symbiotic bacteria. "Then there's the fourth genome," Dr. Nathan says. "That's the collective complement of genes of all the bacteria that normally reside in us. And the ways that this impacts medicine are almost countless."

In a suite of gleaming new labs on the fifth floor of the Belfer Research Building, some 20 people are working to unravel the mysteries of the microbiome. Some are hunched over laptops, while others collect data from a machine called a flow cytometer set up in a corner. In a culture room, several sit at biosafety cabinets, manipulating cells collected from mice or human patients.

The team is led by Dr. Artis, who was recruited as the Michael Kors Professor in Immunology. Widely considered a world leader in his field, he has recently been involved in studies that uncovered links between the immune system's response to gut bacteria and systemic allergies, as well as how the immune system keeps gut bacteria where they belong. Last year, Dr. Artis, along with some of his longtime collaborators, was lured away from the University of Pennsylvania to head Weill Cornell's new Jill Roberts Institute for Research in Inflammatory Bowel Disease.

When Dr. Artis, who grew up in Scotland, was an undergraduate in the early '90s, he took a course on evolution and became fascinated by how the mammalian immune system had evolved in conjunction with the pathogens that infect us. After earning a Ph.D. in immunology at the University of Manchester, he crossed the Atlantic to do postdoctoral work at Penn, where he would later join the faculty. Some of his early research there centered on the immune system's interaction with helminths, tiny worms that can make their home in human intestines, into which they find their way via under-cooked meat or contaminated water. Broader interest in the human microbiome as anything but pathogenic had yet to take hold, but Dr. Artis and other researchers were beginning to recognize something that ran counter to our previous understanding of these parasites as little more than uninvited passengers that make us sick. "We were interested in the pathogens that infect us, and one class of pathogens is worms," Dr. Artis explains. "The interesting thing is that to eradicate worms, the body mounts the Type 2 inflammatory response. It's the same type of response in allergies, only there it's reacting to innocuous antigens in peanuts and milk products and so forth."

healthy mouse tissue with normal microflora

A color-enhanced tissue section from a healthy mouse showing the presence of normal microflora.

Over most of human history, the Type 2 response was an effective way to combat common parasites, and it's still called into action in much of the world, where helminths remain a problem. But in the United States and other industrialized countries, sanitation and medicine have virtually eliminated intestinal worms, leaving the Type 2 response a weapon without a proper target. That mismatch may contribute to the startling increase in allergic disease, asthma and other immune disorders, including certain forms of IBD.

As Dr. Artis' research looked at the ways in which immunity in the presence or absence of parasites could be involved with allergic reactions and chronic inflammation, a great shift was taking place in how researchers, doctors and even the general public think about other organisms that live in our bodies. It was a shift that paralleled the discovery of microorganisms themselves in the late 17th century, when the Dutch scientist Antonie van Leeuwenhoek trained his homemade microscopes on droplets of rainwater. "Like most discoveries in science," Dr. Artis says, "these quantum leaps are triggered by new technologies that allow us to see differently." A decade ago, studying the organisms living in someone's colon would have required culturing them in a petri dish, a time-consuming technique that could only begin to reveal the multitudes of bacteria that make up a complete human microbiome. That has changed, largely thanks to an international science project that some have compared to the 1969 moon landing in both its historical importance and its legacy of innovation.

In 2000, President Bill Clinton and British Prime Minister Tony Blair appeared on television to announce that an international team of scientists had completed a rough draft of the human genome, some 3 billion base pairs that make up roughly 20,500 genes. The project had been a massive undertaking, involving researchers in six countries working for more than a decade. In addition to the invaluable information about our own DNA that the project provided, it also spurred the development of new technology that would enable further discoveries. Today, commercially available genetic sequencing platforms like the Illumina MiSeq are considered de rigueur for any well-stocked research institution — Weill Cornell's Genomics Resources Core Facility has several — and what took the Human Genome Project years to accomplish can be done overnight. Now, researchers are using that technology to read and understand that fourth human genome, that of the bacteria that make their homes in our bodies. "Sequencing technology allows us to identify the microbiota at a level that we would never have been able to understand before," Dr. Artis says. "That technology has really accelerated our ability to profile the organisms in this complex ecosystem, and it also allows us to report how their composition changes in the context of disease."

Much as the sequencing of the human genome inspired the popular imagination a decade ago, today studies of the human microbiome have filtered from scientific journals and into the popular press. Breathless newspaper articles have told us how gut bacteria influence the workings of the mind, and that they might determine why some of us get fat while others stay slim on the same diet. In a 2013 New York Times Magazine cover story, the writer Michael Pollan recounted how sequencing the genes of the 100 trillion bacteria in his own body led him to think of himself "in the first-person plural — as a superorganism, that is, rather than a plain old individual human being."

Dr. Greg Sonnenberg, an assistant professor of microbiology and immunology in medicine, sees this as an asset to science. "The current level of excitement is fantastic," says Dr. Sonnenberg, who has collaborated on seminal studies with Dr. Artis and who was also recruited to lead a lab at the Roberts Institute. "The more you learn about the microbiome, the more it just touches upon everything; it is involved in probably every human disease out there. It's like the rainforest, where you can go through and find different bugs that may have the ability to provide therapeutic benefit in many diseases. And that's where the field is today. Now we need to get down to the nitty gritty in determining which species are important, which species are doing what and how are they interacting with each other. It's an extremely complex system."

Dr. Sonnenberg cautions that many recent papers based on sequencing data have likely uncovered mere correlations. While some members of the microbiome are clearly associated with certain medical conditions, he explains, that doesn't mean the bacteria caused the conditions. Much more work must be done to understand the functions of the bacteria that make up the human microbiome, and how the chemical signals and byproducts they produce affect us and each other. "Hopefully," he says, "that's going to translate to more research being done that advances us to the point where it will benefit patients more directly."

There is already one way in which doctors are using knowledge of the microbiome to benefit patients. Clostridium difficile (C. diff.) is a highly antibiotic-resistant bacterium that causes severe diarrhea and kills some 14,000 Americans each year. Patients most at risk are those in whom antibiotics have wiped out beneficial gut bacteria, leaving the coast clear for C. diff. to grow unimpeded. So far the most successful treatment involves replacing those good bugs with a fecal transplant — that is, inserting the stool of a healthy volunteer into the colon of a C. diff. sufferer — and restoring the normal, healthy balance of gut bacteria. "The concept is both intriguing and somewhat repulsive," admits Dr. Charlie Buffie, who will finish his medical degree at Weill Cornell in 2016, having completed his doctoral work at Sloan Kettering through the Tri-Institutional M.D.-Ph.D. program. "But the efficacy of a fecal transplant has been strikingly high under the right circumstances." Fecal transplant cures about 90 percent of C. diff. patients, but doctors aren't sure exactly why. And because the treatment by its very nature is impossible to standardize, government regulators are uneasy and doctors are reluctant to use it in immunocompromised patients. Dr. Buffie, however, may have found a partial answer to those quandaries.

Dr. Charlie Buffie

The components of a fecal transplant are as numerous as those of the human microbiome itself. But one that seems to be especially effective in controlling a C. diff. infection is a related species called Clostridium scindens. In a study published last year in Nature, Dr. Buffie and colleagues in the Sloan Kettering lab of immunologist Dr. Eric Pamer used C. scindens to defeat C. diff. in mice whose normal microbiomes had been disrupted with antibiotics. In the future, Dr. Buffie says, patients with C. diff. might be given precisely calibrated mixtures of beneficial bacteria or drugs that mimic the metabolic products of C. scindens that seem to prevent C. diff. from propagating. That would allow patients to avoid the potential safety risks — not to mention the ick factor — of a fecal transplant. Says Dr. Buffie: "Being able to isolate, define and construct compositions of bacteria that we know have positive effects and that do not have negative effects — that's definitely an attractive solution."

This line of research also holds promise for IBD patients, says Dr. Randy Longman '07, an assistant professor of medicine in gastroenterology and alumnus of the Tri-Institutional M.D.-Ph.D. Program who joined the Jill Roberts Center for Inflammatory Bowel Disease in 2013. Preliminary evidence suggests that fecal transplantation could help those with a form of IBD called ulcerative colitis, and Dr. Longman and his colleagues are working to figure out why. "The idea is to be able to get specific about the microbes," he says. "If we isolate some of these bugs from patient samples and then put them into gnotobiotic mice we may be able to understand how these microbes interact with the immune system within the intestine."

Although Dr. Longman's primary occupation is research, he spends one day a week in clinical practice, working to help patients manage their illness. "Inflammatory bowel disease, epidemiologically, affects people in the prime of life," Dr. Longman notes. "So many of the patients that I'm seeing for initial diagnoses are young people with so much of their lives in front of them. There is a tremendous need for new medicines and new therapeutic strategies." Like his colleagues, Dr. Longman is optimistic that cracking the secrets of the microbiome will lead to better treatments, and his patients will one day get relief from the stress of living with a chronic condition. "Right now, treating IBD is a management thing," he says. "We don't cure it right now. But we do hope for that."

Today, fecal transplantation remains the best microbiome-based treatment available. But as research points to gut bacteria's involvement with a variety of other ailments, scientists are hoping that future patients could be helped by targeted probiotics or drugs modeled after the chemical signaling of good bacteria. "There may be a point where it isn't necessary to cultivate certain bacteria in your body," Dr. Nathan says, "but rather to take a pill that provides the compounds those bacteria are making — to do the job they do, but in a more orderly, defined, predictable, consistent, safe way." In the future, such treatments might be used not only for C. diff. and IBD, but eventually for metabolic disorders, obesity and even neurological problems. "Whether the food you eat influences a predisposition to atherosclerosis — that's controlled by the bacteria in the body," Dr. Nathan says. "There are influences on behavior, on weight gain, probably on asthma. There's a connection to autism that's recently been reported." The microbiome may have an impact on every system in the human body, he stresses, and its importance is inestimable.

Dr. Artis echoes Dr. Nathan's enthusiasm, and notes that most breakthroughs are yet to come. He draws an analogy to the years after van Leeuwenhoek's microscope first revealed the hidden world in a water droplet. "The pace of discovery is so rapid; this field has really exploded," he says. "But in terms of understanding the complexities of microbiota in the body, we're in our infancy."

Living Underground

The New York Subway System Hosts a Complex Bacterial Ecosystem, Too

Infographic of DNA in New York subway forming bacteria in human body

Infographic showing the relative amount of DNA found in the New York subway system form bacteria associated with the human body. Click to enlarge.

Just as each human body holds a complex ecosystem of bacteria in the gut, every major metropolis is home to a medley of bacteria and pathogens, coexisting with that city's residents. Until recently, little was known about these native microbial communities, which surround us in streets, buildings and public transit areas.

Using the subway system as their testing ground, Weill Cornell investigators fanned out beginning in June 2013 and collected samples of hundreds of DNA from bacterial, viral, fungal, and animal species — like insects and domestic pets — in the underbelly of New York City. They then compiled the data and turned it into an interactive pathogen map, dubbed PathoMap, and recently published their findings in Cell Systems.

While most of the collected microbes are harmless, some are not — including live, antibiotic- resistant bacteria, which were found in 27 percent of the samples. Two samples included DNA fragments of anthrax, and three carried a plasmid associated with Bubonic plague. Reassuringly, those five were discovered at very low levels and showed no evidence of being alive. Other DNA — half of what was collected, in fact — could not be identified as any known organism, because the databases against which they are compared are still incomplete.

While this might sound troubling, there's no need to worry right now, says the study's senior investigator, Dr. Christopher Mason, the WorldQuant Foundation Research Scholar and an associate professor in Weill Cornell's Department of Physiology and Biophysics and in the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Al-Saud Institute for Computational Biomedicine. These apparently virulent organisms are not linked to widespread sickness or disease in this environment, Dr. Mason says. "They are instead likely just the co-habitants of any shared urban infrastructure and city," he says, "but additional testing is needed to confirm this."

The knowledge that these bacteria are present and having no obvious negative effect on the 5.5 million daily subway riders demonstrates that most of them are neutral to human health, he adds. They may even be helpful, as they can out-compete dangerous bacteria. "The presence of these microbes and the lack of reported medical cases is truly a testament to our body's immune system," Dr. Mason says, "and our innate ability to continuously adapt to our environment." Would these pathogens be typical for other cities? With the aim of answering that question, collaborators are collecting samples from airports, taxis and public parks in 15 other cities around the world under a recent grant from the Sloan Foundation.

The PathoMap project involved investigators from Weill Cornell, five additional New York City medical centers and more than a dozen national and international institutions. Over the course of 17 months, medical students and other volunteers used nylon swabs to collect DNA from turnstiles, benches, railings, trashcans and kiosks in all operating subway stations across the five boroughs. The team also collected samples from inside trains, swabbing seats, doors, poles and handrails. They time-stamped each sample and tagged it using a GPS system, later sequencing about 1,500 samples (out of more than 4,200 collected) and analyzing those results. "PathoMap establishes the first baseline data for an entire city," Dr. Mason says, "revealing that 'molecular echoes' of commuters appear on all surfaces — from the bacteria on their skin to the food they eat, and even from the human DNA left behind, which matched U.S. Census data."

The data on New York City's ecosystem — an ingredient in building a smart city — already has potential real-world applications. Researchers could monitor the system for changes that would signal disease or a potential threat, or someday create a live model tracking real-time changes to this urban microbiome. The PathoMap, Dr. Mason says, is just the beginning.

— Anne Machalinski

This story first appeared in Weill Cornell Medicine, Vol. 14, No. 1.

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In the lab: Dr. David Artis with postdoc Dr. Anne-Laure Flamar
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Weill Cornell Investigators Discover a New Pathway that Prevents Chronic Inflammation in the Gut


Investigators Show How Immune Cells are "Educated" Not to Attack Beneficial Bacteria

color-enhanced microscopic image of a mouse intestine demonstrates the presence of the immune system and intestinal barrier.

This color-enhanced microscopic image of a mouse intestine demonstrates the presence of the immune system and intestinal barrier. Image credit: Drs. Mario Noti, Matthew R. Hepworth and Gregory F. Sonnenberg

New York (April 23, 2015) — An international research team led by Weill Cornell Medical College investigators has discovered an answer to why the human immune system ignores roughly 100 trillion beneficial bacteria that populate the gastrointestinal tract. The findings, published April 23 in the journal Science, advance investigators' understanding of how humans maintain a healthy gastrointestinal tract, and may provoke new ways to treat inflammatory bowel disease — including Crohn's disease and ulcerative colitis — whose origins have been mysterious and treatment difficult.

The investigators studied T cells — critical components of the adaptive immune system — which have the capacity to recognize, eliminate and remember foreign microbes that invade our bodies. T cells are named after the thymus, an organ where they develop and are taught not to attack normal human tissues and organs, leaving them free to target and eradicate disease-causing foreign invaders. One question that had puzzled scientists until now is how these cells learn to ignore beneficial bacteria in the intestine that are also foreign, but not harmful.

In the study, the research team discovered that once they leave the thymus, T cells are again educated in the gastrointestinal tract, or gut, to leave beneficial bacteria alone. This dual education strategy is vital to supporting healthy immune function, the investigators say. Disruption in the pathway that facilitates this education, they add, causes the immune system to attack beneficial bacteria in the intestine, which is often linked to the development and progression of diseases like inflammatory bowel disease, HIV, viral hepatitis, cardiovascular disease, obesity, diabetes and cancer. Therapeutic strategies to promote and boost the activity of this education pathway may be beneficial in treating patients with these chronic inflammatory disorders, the investigators say.

"In many chronic human diseases, the immune system attacks bacteria in the intestine that are normally beneficial. Although we do not yet know whether this is a cause or consequence of these complex diseases, experimental evidence suggests that this inflammatory process contributes to disease progression," says senior author Dr. Gregory F. Sonnenberg, an assistant professor of microbiology and immunology in medicine and a member of the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell. "Our study demonstrates that there may be an efficient way to eliminate pro-inflammatory T cells in the intestine that attack beneficial bacteria. This would not only help our patients with inflammatory bowel disease, but also might give us clues about how to treat other chronic inflammatory diseases caused by abnormal T cell responses, such as allergic and autoimmune disorders."

A microscopic image of a severely inflamed mouse colon lacking molecule MHCII

A microscopic image of a mouse colon that is severely inflamed because the animal lacked a molecule, called Major Histcompatibility Complex class II (MHCII), that is found on the surface of cells that regulate immune cell interactions with bacteria, called innate lymphoid cells (ILCs). MHCII teaches T cells to ignore beneficial bacteria in the intestine. Immune responses waged against these bacteria are linked to the development and progression of disease like inflammatory bowel disease. Image credit: Drs. Matthew R. Hepworth and Gregory F. Sonnenberg

In earlier research, Dr. Sonnenberg and his team identified that a recently discovered member of the innate immune system — innate lymphoid cells (ILCs) — critically regulate immune cell interactions with bacteria. These ILCs, and other cells of the immune system, are found in the intestine, which is constantly exposed to and colonized by beneficial bacteria. "There is a physical separation between the immune system and most beneficial bacteria," Dr. Sonnenberg says.

The researchers had previously found that ILCs reinforce a physical barrier between the immune system and intestinal beneficial bacteria, but in this study, they uncovered a new key role for these cells — that they act like the cells in the thymus that educate T cells.

In a process that developed over evolution, bits of human tissues and organs are introduced to T cells in the thymus so they "know" what not to attack after leaving the organ. Specialized cells in the thymus teach T cells this behavior by interacting with a molecule known as the Major Histocompatibility Complex class II (MHCII). Any T cells with the potential to attack the human body and organs and cause auto-immunity are destroyed before they can leave the thymus. However, T cells with the potential to attack beneficial bacteria are not educated or eliminated in the thymus. It was therefore unclear what stopped these T cells from attacking beneficial bacteria in the intestine.

The scientists found a similar process happening directly within the GI tract, an organ that contains the majority of the body's total immune system.

"Due to the similarities of what we know happens in the thymus, we have called this new process 'intestinal selection,'" says first author Dr. Matthew R. Hepworth, a postdoctoral associate in medicine who works in Dr. Sonnenberg's laboratory. "ILCs also interact with T cells through MHCII machinery to educate T cells in the intestine.

"In the thymus, T cells are educated not to attack our organs," he adds, "and in the GI tract, using ILCs, they are further educated not to attack beneficial bacteria."

Using mice to test their findings, the researchers discovered that ILCs destroy T cells with the potential to attack beneficial bacteria, and that impairing ILC function led to severe intestinal inflammation. Then, with the help of researchers at Children's Hospital of Philadelphia, the team looked at intestinal biopsies of pediatric patients diagnosed with Crohn's disease, one of the major forms of inflammatory bowel disease.

"We found ILCs in intestinal biopsies from pediatric patients diagnosed with Crohn's disease, but they were not functioning properly because, in many cases, they were lacking MHCII machinery, so T cells were not educated to ignore beneficial bacteria," Dr. Sonnenberg says. "In fact, we found the loss of MHCII correlated with an increase in pro-inflammatory cells from matched biopsies of children with Crohn's disease. That tells us that this education process may be impaired in patients with inflammatory bowel disease, and that restoring adequate levels of MHCII might help to eliminate pro-inflammatory T cells and reduce chronic intestinal inflammation."

This microscopic image illustrates a healthy mouse colon and a severely inflamed mouse colon

This microscopic image illustrates a healthy mouse colon (top), and a severely inflamed mouse colon resulting from a lack of a molecule, called Major Histcompatibility Complex class II, found on the surface of a member of the innate immune system, which teaches T cells to ignore beneficial bacteria in the intestine (bottom). Inflammation occurs when the immune system incorrectly attacks beneficial bacteria. Image credit: Drs. Matthew R. Hepworth and Gregory F. Sonnenberg. Dr. Sonnenberg says there are likely many causes of inflammatory bowel disease, and other pathways that help control T cells in the gut. "But our work shows a previously unrecognized pathway whereby ILCs educate our immune system not to attack beneficial bacteria," he says.

Dr. Sonnenberg, his laboratory and the Jill Roberts Institute for Research in IBD are now exploring how scientists can utilize this knowledge and design novel therapeutic strategies to boost MHCII on ILCs and limit chronic intestinal inflammation.

Co-authors include Thomas C. Fung from Weill Cornell Medical College; Terri M. Laufer from the University of Pennsylvania; Samuel H. Masur, Judith R. Kelsen and Robert N. Baldassano from Children's Hospital of Philadelphia; Fiona M. McConnell and David R. Withers from University of Birmingham, United Kingdom; Juan Dubrot, Stephanie Hugues and Walter Reith from the University of Geneva Medical School in Switzerland; Michael A. Farrar from the University of Minnesota; Gerard Eberl from Institut Pasteur, France; and Charles O. Elson from the University of Alabama at Birmingham.

Research in Dr. Sonnenberg's laboratory is supported by the National Institutes of Health (DP5OD012116), the NIAID Mucosal Immunology Studies Team (MIST), Scholar Award in Mucosal Immunity and the Institute for Translational Medicine and Therapeutics, Transdisciplinary Program in Translational Medicine and Therapeutics (UL1-RR024134 from the U.S. National Center for Research Resources). Other investigator support includes a research fellowship from the Crohn's, and Colitis Foundation of America (CCFA, #297365), a Cancer Research Institute Student Training and Research in Tumor immunology (STaRT) grant, a Wellcome Trust Research Career Development Fellowship, and the National Institutes of Health (DK071176).

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.

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Daedalus Fund Selects Six Projects for Funding in Program's First Round


Six Weill Cornell scientists have been selected as winners of the Daedalus Fund for Innovation, a new medical college program that helps advance promising early-stage applied and translational research that has commercial potential.

The investigators, Drs. Peter Goldstein, Gang Lin, David Lyden, Stefano Rivella, Enrique Rodriguez-Boulan and Vladislav Sandler will each receive up to $100,000 one-year grants that fund studies demonstrating that their early-stage discoveries can be translated into effective treatments for patients. An independent advisory committee comprised of a Weill Cornell faculty member and experts from the biopharmaceutical and venture capital industries selected the projects from nearly 30 applications for the Daedalus Fund's first round of funding.

"The Daedalus Fund is helping us mobilize and innovate," said Larry Schlossman, managing director of BioPharma Alliances and Research Collaborations at Weill Cornell, who manages the Daedalus Fund. "That's incredibly exciting. I see so much rich opportunity in Weill Cornell's research enterprise, but some of the projects need a little help getting across the finish line or getting to the proverbial take-off point where they will be viewed favorably by industry as potential candidates for further development."

Established by Weill Cornell Dean Dr. Laurie H. Glimcher earlier this year, the Daedalus Fund is designed to help Weill Cornell investigators make their research more appealing to the biopharmaceutical industry. Investors require "proof of concept" — for instance, data derived from testing in animal models or the development of a new biomarker — as the standard by which they determine whether a project is ready for funding.

While grants from the National Institutes of Health or other agencies fund basic science research, they often don't provide enough money to cover these "proof of concept" studies. This funding gap is one of the greatest obstacles scientists face when trying to advance early-stage discoveries into next- generation treatments.

"We are extremely thankful that Weill Cornell came up with this program," said Dr. Rodriguez-Boulan, the Charles and Margaret Dyson Professor in Ophthalmology Research and a professor of cell and developmental biology, who up until now has received small, short-term grants from small foundations to investigate a new drug to treat incurable blinding diseases, such as Stargardt disease and age-related macular degeneration.

"With this grant from the Daedalus Fund, we will really be able to study the most important aspects in terms of developing drugs for human use. That means showing in animals that our drug can cure these diseases. Once you show that, you are one long step closer to a treatment in humans."

A Potential New Treatment for Nerve Pain

Dr. Peter Goldstein

At least 20 million adults in the United States suffer from chronic and often intense nerve pain caused by the abnormal activation of the control system for a group of cells in the peripheral nervous system. This channel protein, known as HCN, helps regulate how neurons function and react to stimuli. While the most common treatment is one or more pain medications, none of them work particularly well and often carry risk of serious side effects including addiction.

Weill Cornell anesthesiologist Peter Goldstein and colleagues at Weill Cornell Medical College found that the general anesthetic propofol can block the activity of the protein, potentially offering relief to pain sufferers — but at a cost. Used by anesthesiologists for surgical sedation and anesthesia, propofol is too powerful a drug for use outside of an operating room setting and, if abused or misused, can be fatal. (King of Pop Michael Jackson died from an overdose.) But with this preliminary finding, supported by the Weill Cornell Department of Anesthesiology, too promising to dismiss, the collaborators dug deeper and discovered a molecule that is structurally similar to propofol — it blocks the same channel protein and provides pain relief — but lacks its sleep-inducing properties.

The Daedalus award will allow Dr. Goldstein's lab to test novel, related compounds synthesized in the lab of co-investigator Dr. Anthony Sauve, an associate professor of pharmacology at Weill Cornell, in an animal model of chronic pain to see if they have the same pain-relieving effects as propofol and the related non-anesthetic compound. If successful, Dr. Goldstein hopes at least one of them can then be developed into a new drug to treat the condition.

"This is a lifeline," said Dr. Goldstein, a professor of anesthesiology and an associate professor of medical ethics (in medicine), of the grant award. "This keeps the project going to pursue what we think is a very promising line of investigation."

Innovative Treatments for Inflammatory Bowel Disease

Dr. Gang Lin

A few years back, Weill Cornell scientist Gang Lin designed a class of inhibitors that selectively targeted an enzyme expressed in tuberculosis. While the proteasome is also present in various forms in the human body, tuberculosis is the only known pathogenic bacterium to express it. The enzyme is critical to TB's ability to defend itself against its human host. Dr. Lin, an associate research professor of microbiology and immunology, designed drugs that inhibited the bacterium's proteasome more potently than its host's, killing the parasite while likely avoiding collateral damage in the patient.

At the time, inflammatory bowel diseases were the furthest thing from Dr. Lin's mind. Then in 2009, a paper was published in Nature Medicine describing the therapeutic potential of an immunoproteasome inhibitor in autoimmune diseases.

One form of proteasome in humans is called the immunoproteasome, which plays pivotal roles in immune responses. The 2009 paper showed that immunoproteasome selective inhibitors effectively reduced inflammation in mice that had type I diabetes and arthritis. Later research confirmed that finding, and also showed efficacy in mice with colitis, multiple sclerosis and lupus. While the inhibitors were groundbreaking in their therapeutic potency, scientists found them to be reactive, irreversible and unstable.

Taking advantage of his expertise in proteasome inhibitor design, Dr. Lin's team investigated and synthesized two classes of compounds that do not react with the immunoproteasome. Now, armed with funding from the Daedalus Fund, he will test them on mice that mimic human Crohn's disease — a common form of debilitating inflammatory bowel disease. He is working with Dr. Carl Nathan, chairman of Microbiology and Immunology and the R.A. Rees Pritchett Professor of Microbiology; Dr. Xiaojing Ma, a professor of microbiology and immunology and of microbiology and immunology in pediatrics; Dr. Jane Salmon, a professor of medicine and of medicine in obstetrics and gynecology, as well as a rheumatologist at Hospital for Special Surgery; and Dr. Franck Barrat, a professor of microbiology and immunology at Weill Cornell and a senior scientist in Hospital for Special Surgery's Autoimmunity and Inflammation Program.

"We are extremely grateful and very pleased to receive a grant from the Daedalus Fund," Dr. Lin said. "The fund really provides us an opportunity to demonstrate these compounds' efficacy and lack of toxicity in mice — a critical step in drug research and development."

A Liquid Biopsy for Cancer

Dr. David Lyden

Invasive needle biopsies are the only way to tell whether a patient's cancer is responding to its prescribed treatment — and oftentimes the answer comes too late. By the time oncologists learn that the treatment isn't working, likely due to a mutation causing resistance, the cancer has likely already spread.

But that may soon change. David Lyden, the Stavros S. Niarchos Professor in Pediatric Cardiology and a professor of pediatrics and of cell and developmental biology, together with Dr. Hector Peinado Selgas, an assistant professor of molecular biology in pediatrics, have developed a blood test that isolates small, spherical tumor-secreted packages containing protein, RNA and DNA from patients' bloodstreams. Cancer cells release these vesicles, known as exosomes, which use the bloodstream to travel around the body and spread the seeds for metastasis.

Dr. Lyden believes his liquid biopsy can quickly determine how effective a cancer patient's treatment is by measuring the number and content of exosomes circulating in that patient's blood, ultimately leading to personalized treatment approaches. He also hypothesizes that the test can predict future cancer metastasis. The Daedalus Fund grant will enable Dr. Lyden to characterize and analyze the protein and DNA content of tumor exosomes. Ultimately, he will use that information to develop a platform that can identify and screen patients for biomarkers in melanoma, breast and prostate cancers.

"I was pleased that the reviewers funded a project that's considered ‘out of the box,'" Dr. Lyden said. "This is a whole new cancer field in which discoveries regarding the properties of cancer vesicles have been made by a few groups of investigators including work in our laboratory. This fund is helping us overcome a lot of obstacles and accelerate our projects so we can connect with drug companies to rapidly translate our discovery into a clinical application."

Curing Blood Disorders

Dr. Stefano Rivella

Transfusions offer a lifeline to children who have the blood disorders sickle cell anemia and beta-thalassemia, but they are often cumbersome and hardly a panacea. For these children, whose conditions are characterized by misshapen or too few of the oxygen-carrying molecules present in all red blood cells, their only hope for survival is bone marrow transplants.

But that, too, is fraught with risk. A bone marrow transplant requires a compatible donor — a minority of patients locate one — and a match doesn't guarantee a successful outcome.

Stefano Rivella, an associate professor of genetic medicine in pediatrics at Weill Cornell, believes that a new gene therapy technique that he's developing with collaborators may cure these conditions.

Sickle cell anemia and beta-thalassemia result from a mutation in the beta-globin gene, which is charged with producing an essential part of hemoglobin molecules that carry life-sustaining oxygen throughout the body. A piece of DNA, called the locus control region, activates the beta-globin gene after a baby is born, and shuts down a second gene, called the gamma globin gene, which is tasked with making a critical part of fetal hemoglobin when a baby is in the womb.

Dr. Rivella is investigating whether he can combine a classical gene therapy approach with an innovative technology. Using gene therapy, Dr. Rivella will insert a new and functional copy of the beta-globin gene into patient cells while also introducing a new gene that reprograms the genome in the locus control region. By reprogramming the genome, Dr. Rivella hopes to shut down the mutant beta-globin gene and reactivate the gamma globin gene, enabling the gamma globin gene to generate fetal hemoglobin, which can also sustain life. He's theorized that a genetically modified HIV virus that's been stripped of its viral properties could be used to transmit these new instructions to the genome. This approach would leave behind two healthy, therapeutic genes, while shutting down the toxic mutant gene.

The Daedalus Fund will support Dr. Rivella and his lab's efforts to develop this modified virus and test its efficacy in petri dishes using patient-donated cells.

"I cannot be more grateful to Weill Cornell, Dean Laurie Glimcher and Larry Schlossman for sponsoring our faculty's research ideas and helping us move them forward," Dr. Rivella said.

Ending Juvenile Blindness

Dr. Enrique Rodriguez-Boulan

For children born with sight, the thought of losing their vision by the time they are 30 years old is terrifying. But that's exactly what happens with children born with Stargardt disease, the most common form of inherited juvenile macular degeneration for which there is no treatment.

Some 100,000 Americans have Stargardt disease, which is characterized by a genetic mutation that enables a yellowish-brown pigment composed of mostly fats to accumulate in the eye. The pigment, known as lipofuscin, is a product of cellular wear and tear that is often found in muscle, kidney, liver, heart and nerve cells. Lipofuscin detected in the eye is particularly worrisome, says Weill Cornell cell biologist Enrique Rodriguez-Boulan. Researchers believe it to be toxic to a support cell for the light-sensitive photoreceptors cells that allow people to see, known as the retinal pigment epithelium.

Using basic science methods, Dr. Rodriguez-Boulan, the Charles and Margaret Dyson Professor in Ophthalmology Research, and collaborators Dr. Marcelo Nociari, an assistant research professor of immunology in ophthalmology, and Dr. Fred Maxfield, chairman of Biochemistry and the Vladimir Horowitz and Wanda Toscanini Horowitz Distinguished Professor in Neuroscience, discovered that the drug beta cyclodextrin can successfully bind to lipofuscin and remove it from the eye. The Daedalus Fund will enable the research team to see if the same effect is true in animal models before blindness occurs.

"So far we have been able to show that these drugs remove lipofuscin from the eye, but that's not the same as showing that we can prevent model mice from becoming blind," said Dr. Rodriguez-Boulan, also a professor of cell and developmental biology and of cell biology in ophthalmology. "We're getting a chance to go for it and try to cure the blinding disease. This is a big step forward in showing that this is eventually good for humans."

Dr. Rodriguez-Boulan hopes that his findings can be applied to age-related macular degeneration, a leading cause of vision loss among people age 65 and older that is not well understood and has no treatment. While lipofuscin accumulates dramatically in the retinal pigment epithelium with age, it's not clear if it also plays a role in this condition. Dr. Rodriguez-Boulan hopes that a successful treatment for Stargardt, where lipofuscin is a clear cause of disease, could ultimately be tested on macular degeneration patients to see if it makes a difference.

A New Bone Marrow Transplant

Dr. Vladislav Sandler

Search a textbook for adult hemogenic endothelial cells and one would likely come up empty. In scientific literature, these cells — which give rise to blood and enable the body to regenerate it for the duration of life — exist only during fetal development and disappear soon after birth.

But Weill Cornell biologist Vladislav Sandler is challenging conventional wisdom. After scouring blood vessels in various organs through the human body, Dr. Sandler recently spotted a small cluster of cells in an adult liver that has the same signature of these progenitor cells — including their regenerative abilities. Using advanced research techniques, Dr. Sandler, a faculty instructor at Weill Cornell who is being recruited for the Department of Medicine, demonstrated that adult hemogenic endothelial cells can reactivate and generate blood cells that closely resemble bone marrow stem cells — the building blocks of blood necessary for life. He then transplanted them into immune-deficient mice and discovered that the engineered cells were capable of regenerating the rodents' blood system, just as they do during embryonic development. The Daedalus Fund grant will allow Dr. Sandler to further test these cells in mice to determine how fast they take hold and how many are needed for successful regeneration.

If the regenerative and transplantable properties of adult hemogenic endothelial cells can be replicated in humans, the finding could benefit the millions of patients with blood disorders — thalassemia, sickle cell and other genetic diseases, blood cancers and even infections like HIV — for which the most common cure is matched bone marrow transplants. Dr. Sandler hopes that patients' own cells can be used to generate blood stem cells free of the defects that caused the original disease, and then re-transplanted into the patients' bodies to treat their conditions.

"This grant is the greatest validation to any doubts that I may have had," Dr. Sandler said. "This gives me an opportunity to check this hypothesis. And it says that Weill Cornell is interested in promoting its own people, giving them the opportunity to do something both fundamentally important for science and potentially important for patients."

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