Give a Liver, Save a Life


Dr. Benjamin Samstein describes himself as a surgeon who prefers not to operate. But when surgery is in order, Dr. Samstein, an expert in liver transplantation, favors laparoscopic procedures that use small incisions and even smaller video cameras over large complex open surgery. The goal of the approach is to reduce pain and overall recovery time for patients.

"We treat every patient as the most important person that we are taking care of," said Dr. Samstein, the new chief of liver transplantation and hepatobiliary surgery in the Department of Surgery at Weill Cornell Medical College and NewYork-Presbyterian/Weill Cornell Medical Center. "We are always trying to think about how we can perform surgeries with less harm."

NewYork-Presbyterian Hospital is the only academic medical center in the nation that applies a full laparoscopy to donor surgery for liver transplantation, Dr. Samstein said. In his new role, Dr. Samstein will lead efforts to expand and enhance that treatment to patients with the hope that it can one day be offered routinely.

We sat down with Dr. Samstein to discuss his post, the benefit of living donor organ donations, what he envisions for the future of liver transplantation, and how he became inspired to work in this field.

Q: What brought you to Weill Cornell?

Dr. Samstein: I came to Weill Cornell because of the opportunity to not only develop really advanced surgery in my field, but also collaborate and build multidisciplinary teams that will bring the care of patients with cancers and diseases of the liver to the highest level. New York has a large population of patients with liver disease as well as a dramatic shortage of deceased donor organs. This creates demand for utilization of living donors and innovative techniques.

Q: As the new chief of liver transplant and hepatobiliary surgery here at Weill Cornell and NewYork-Presbyterian/Weill Cornell, what are your goals for the program?

Dr. Samstein: Our goals are to making treatment less invasive and more effective. Although the predominant modality that I was trained in is surgery, I like to describe myself as a surgeon who would prefer not to operate. We plan to build at NewYork-Presbyterian/Weill Cornell one of the largest liver-focused clinical programs in the country. In parallel, we will establish research programs that examine patient outcomes and strive to develop liver support therapies for acute liver failure, liver cancer, and infections of the liver.

Q: Let's talk about laparoscopic procedures and your work in this field. How are they less invasive?

Dr. Samstein: I focus on the application of laparoscopic surgery to liver surgery and, specifically, to donor hepatectomies, which are procedures in which we remove all or part of a patient's liver. Only 5 percent of liver transplants are performed from a living donor compared to half of all kidney transplants. This is predominantly because it takes longer for a liver donor than a kidney donor to recover, thus the operation has more risk and it is more technically challenging. I have been applying laparoscopic surgery to liver donors, using smaller parts of the donor liver graft to replace the diseased liver and trying to understand what makes the operation less technically challenging so that it could be done at more centers. Only about 10 percent of all donor hepatectomies in the United States are done laparoscopically — and NewYork-Presbyterian Hospital is currently the only center in the United States that uses this approach.

Q: What is advantageous about living donor transplants?

Dr. Samstein: The primary problem with organ failure today is that there aren't enough organs. If you had cancer, nobody would say to you, "Well, your cancer isn't as bad as someone else's, and I only have enough chemotherapy for one of you, and he's more likely to die, so I am going to give chemotherapy to the other person." But that's exactly how we allocate organs. There are approximately 16,000 people on the list for a liver transplant. This year, only 6,000 organs will become available. Living donation can enable patients to receive their transplants much sooner, dramatically expediting their access to new organs and cutting the risk of dying in half.

Q: Will increasing the number of living donor laparoscopic procedures you perform attract more people to become living donors?

Dr. Samstein: We hope that when we are routinely able to offer laparoscopic donation, more people will come forward, but that is an area we are actively studying. We want to learn if a reduction of invasiveness can help identify a greater number of possible donors.

Q: How does New York compare to other states when it comes to donor registration?

Dr. Samstein: In New York, less than 20 percent of the population has registered to be a donor. Most states allow people to register before the age of 18, but New York has not allowed that at this point. So if you are 16 when you get your learner's permit, you can't sign up to be an organ donor at the Department of Motor Vehicles until you get your driver's license renewed eight years later. Unfortunately, due to that loophole, New York's donor registry is among the worst in the country. We need to create systems where you can sign up online and it happens automatically. The bottom line is: New York needs to improve its donor registration. It's critically important.

Q: What's the cutting edge right now? And where is liver transplantation headed?

Dr. Samstein: We're in a transformative period of time for patients with hepatitis C — a large percentage of them are having the cause of their cirrhosis cured. We're also finding there are tremendous advances in the treatment of colorectal metastases spread to the liver. We have a lot more therapeutic options in terms of surgery and chemotherapy. There are even discussions of the utilization of liver transplant for patients with tumors that spread to the liver.

Q: What got you interested in this kind of work in the first place?

Dr. Samstein: I was always interested in science fiction. When I was in medical school, my colleague's brother was doing research in xenotransplantation, which is the transplantation between various species, with the idea that animals could be used to create an unlimited source of organs. I thought, ‘Wow, that could be my job? That's pretty far out.' Although my research eventually moved onto different immunologic barriers, that's what got me started.

Q: What do you enjoy most about what you do?

Dr. Samstein: I've always felt that we are a lot more than our weakest organ. It's really enjoyable to take care of patients who are made sick by a single organ and then, once that has been taken care of, they feel back to life. I also enjoy being part of a community of people who are thinking about life outside of themselves.

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Dr. Benjamin Samstein
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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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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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Stress-Fighting Proteins Could Be Key to New Treatments for Asthma

Immune cells called eosinophils store granule proteins in a form known as amyloid. Linked to Alzheimer's disease.

Immune cells called eosinophils store granule proteins in a form known as amyloid. Regulated amyloid formation is a stable way to compress proteins together to save space, but irregular formation can be linked to disease, such as Alzheimer's disease. The Glimcher lab discovered that a deficiency in the protein XBP1 prevents amyloid formation within eosinophil granules, suggeting that eosinophil amyloid formation might be critical to the immune cells' development, and that XBP1 is linked to this process. This image illustrates wild-type bone marrow-derived eosinophils. In blue is the nucleus, red is a stain for specific eosinophil proteins and green is a dye that reacts with amyloid structures. Scientific images: Sarah Bettigole and Raphael Lis

Investigators have discovered the precise molecular steps that enable immune cells implicated in certain forms of asthma and allergy to develop and survive in the body. The findings from Weill Cornell Medical College reveal a new pathway that scientists could use to develop more effective treatments and therapies for the chronic lung disorder.

More than 1 in 12 Americans are affected by asthma, a disorder characterized by an overactive immune response to normally harmless substances such as pollen or mold. Scientists had previously discovered that an overabundance of immune cells that help defend the body against parasites and infection, called eosinophils, were implicated in certain forms of asthma, as well as in allergic reactions. But little was known about how eosinophils develop and survive.

In their study, published July 6 in Nature Immunology, the investigators discovered that a signaling pathway, formed by two proteins that help cells survive stressful conditions, also plays a critical role in eosinophil development. When the investigators altered the function of either of those proteins, the eosinophils, but not other cell types, underwent excess stress and were completely wiped out, suggesting that this pathway could serve as a new therapeutic target for patients who respond poorly to current asthma therapies.

"Our findings demonstrate that individual cell types, particularly eosinophils, interpret and manage stress in distinct ways," said lead author Dr. Sarah E. Bettigole, a postdoctoral fellow at Weill Cornell. "If we disrupt the ability to respond to stress, sensitive cells like eosinophils die off. These subtle differences could be leveraged to develop novel therapies for diseases like asthma and eosinophilic leukemia."

Eosinophils belong to a group of cells called granulocytes, which develop in the bone marrow before migrating into blood. During early stages of development, these cells produce a large number of proteins that are critical for survival, as well as toxic proteins that are later released in response to an immune trigger, such as bacteria or viruses. Intense bursts of protein production during normal biological processes put strain on a cell structure called the endoplasmic reticulum, which plays a crucial role in protein synthesis and transport. If the ER is overwhelmed by such strain, the cell enters a state known as ER stress.

In response to ER stress, a protein called IRE1α helps to generate a highly active form of a second protein called XBP1, which in turn regulates the activity of various genes involved in the cell stress response. This signaling pathway reduces ER stress and prevents cell death by enhancing the ER's protein synthesis capacity while reducing overall protein production.

"Because XBP1 supports the survival of certain mature cell types that make a lot of protein throughout their lives, we suspected that XBP1 might also help cells like eosinophils cope with intense bursts of protein production during development," said senior author Dr. Laurie H. Glimcher, the Stephen and Suzanne Weiss Dean of Weill Cornell Medical College.

XBP1-deficient bone marrow-derived eosinophils without amyloid structures.

This image illustrates XBP1-deficient bone marrow-derived eosinophils without amyloid structures. The nucleus is colored in blue and specific eosinophil proteins are stained red.

In support of this idea, the research team found that the IRE1α/XBP1 pathway became increasingly active in differentiating eosinophils as they produced more and more proteins during progressive developmental stages. Moreover, genetically modified mice that were deficient in XBP1 completely lacked eosinophils in the bone marrow, spleen and blood, while other granulocytes were unaffected.

"So far, XBP1 is the only transcription factor to our knowledge that distinguishes the development of eosinophils from that of other granulocytes," Dr. Glimcher said. "This suggests that subtle differences in cellular biological processes provide a previously unappreciated handle for fine-tuning the production of different types of granulocytes."

The loss of XBP1 in eosinophils also altered the activity of genes that are critical for the ER stress response, leading to the accumulation of incorrectly processed proteins, substantial ER swelling and severe granule dysfunction. Without XBP1, the researchers discovered that developing eosinophils underwent too much stress. This stalled their differentiation by blocking a molecule called GATA1, which ensures that young eosinophils finish maturing into adult eosinophils. The researchers found that too much stress and not enough GATA1 eventually killed the eosinophils. Taken together, the findings suggest that ER health is crucial for eosinophil development and survival, highlighting the IRE1α/XBP1 pathway as a potential therapeutic target in a wide variety of eosinophil-mediated diseases.

The investigators are currently testing whether experimental XBP1 or IRE1α inhibitors can be effective treatments for asthma and eosinophil leukemia.

"We now know that XBP1 is required for normal eosinophil development, but we need to figure out whether eosinophil-mediated respiratory illnesses and cancers are also dependent on this pathway," Dr. Bettigole said. "If these diseases are eosinophil- dependent, blocking IRE1α or XBP1 with pharmaceuticals would be an exciting new treatment strategy."

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Drs. Sarah Bettigole and Dr. Laurie H. Glimcher plan their paper on eosinophil development
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Study Finds Lipid Mediator Associated with Good Cholesterol Promotes More Than Just Good Heart Health


High-density lipoprotein (HDL) is often referred to as "good" cholesterol because it transports fat molecules out of blood vessels, protecting against stroke and heart disease. Now, researchers at Weill Cornell Medical College have discovered that HDL in blood also carries a protein that powerfully regulates immune function. Together they play an important role in preventing inflammation in the body.

In the study, published June 8 in Nature, the investigators found that a lipid molecule called sphingosine 1-phosphate (S1P) that is bound to HDL suppresses the formation of T and B immune cells in the bone marrow. In doing so, HDL and S1P block these cells from launching an abnormal immune response that leads to damaging inflammation, a hallmark of many disorders including autoimmune diseases, cardiovascular disease and neuroinflammatory disease, such as multiple sclerosis.

"Our study shows that S1P that is bound to HDL helps prevent inflammation in many tissues," said senior investigator Dr. Timothy Hla, director of the Center for Vascular Biology and a professor of pathology and laboratory medicine at Weill Cornell. "When there is less S1P that is bound to HDL in blood, there are more B and T cells that can be activated to produce unwanted inflammation."

Dr. Hla has been studying S1P for more than two decades. He discovered that it is a key regulator of vascular function, and that about 65 percent of S1P in blood is bound to apolipoprotein M (ApoM), a member of the lipoprotein family, within the HDL particle. But until this study, the researchers did not know what specific function HDL-bound S1P served.

The team, including first author Dr. Victoria Blaho, an instructor in pathology and laboratory medicine, and researchers from the National Institutes of Health and Stanford University, studied mice that lacked HDL-bound S1P.

Dr. Timothy Hla

Dr. Timothy Hla. Photo credit: Carlos Rene Perez

Mice lacking HDL-bound S1P developed worse inflammation in a model of multiple sclerosis. The reason for this, the investigators found, is that HDL-bound S1P suppresses the formation of T and B immune cells in the bone marrow. While both immune cells help fight infection, an overabundance of these cells can also trigger unwanted inflammation.

The findings help explain why blood HDL levels are such an important measure of cardiovascular health, Dr. Hla said.

"Blood HDL levels are associated with heart and brain health — the higher the HDL in blood, the less risk one has for cardiovascular diseases, stroke, and dementia," Dr. Hla said. "The corollary is that the lower the HDL, the higher the risk of these diseases." Blood levels of ApoM and S1P have not been studied in these diseases.

The findings further suggest that molecules that mimic HDL-bound S1P could be useful in reducing damaging inflammation that has gone awry, Dr. Hla said. Such molecules are not known and will need to be developed in the future.

However, a related S1P1 receptor inhibitor called Gilenya, has already been approved for use in multiple sclerosis, a condition in which the immune system attacks nerve fibers due to unwanted inflammation, Dr. Hla said.

"The unique function of HDL-S1P could be further exploited for innovative therapeutic opportunities," he said.

For this research, Dr. Blaho received funding from the National Institutes of Health (F32 CA14211), the New York Stem Cell Foundation (C026878) and the Leon Levy Foundation (supported through the Feil Family Brain and Mind Research Institute). Dr. Hla received funding from the NIH (HL67330 and HL89934), as well as through Fondation Leducq.

Featured Image: 
Left: T and B cells are types of white blood cells that develop from stem cells (progenitor cells) in the bone marrow. When HDL (good cholesterol) containing the protein ApoM (in yellow) binds to the surface of their progenitor cells, it prevents them from proliferating. Right: Mice that lack the ApoM protein on their HDL develop more severe brain inflammation in a mouse model of multiple sclerosis. This inflammation is illustrated by leakage of a red fluorescent dye from blood vessels into the brain. Image
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