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Data-driven medicine

3 hours 7 min ago

UCM MOM Cover Spring 2017

Almost imperceptibly, advances in data and computation have changed our daily lives. To find the fastest route to work, you use an app that gathers live traffic data from thousands of users. A wristband keeps track of how far you’ve walked, and a diet app tells you whether you’ve earned those extra calories of dessert. And to wind down the day, another service recommends a show you’ll probably like and streams it to your television.

Behind the scenes of these now-routine applications are highly advanced developments in cloud computing, machine learning, data mining and computer simulation. Parallel to the tech industry, physicians and researchers at the University of Chicago are working to apply these same innovations in the hospital and the laboratory to improve patient care and our knowledge of health and biology.

Already, many of the same technologies that power online shopping, fitness tracking, video games and self-driving cars are changing the practice of medicine. Scientists are exploring the potential of these tools to generate new strategies for treating cancer and sepsis as well as preventing cardiac arrest and disease outbreaks. New ways of working with data promise to bring us closer to the vision of precision medicine and to solutions for some of the oldest and most difficult medical challenges.

Dr. Samuel Volchenboum

Center for Research Informatics Director Samuel L. Volchenboum, MD, PhD, MS, checks his GPS training watch during a run. Volchenboum and other researchers are applying the technology behind fitness trackers and other tools to improve patient care. (Photo: Nancy Wong)

“It is such an exciting and amazing time to be working in medical data science,” said Samuel Volchenboum, MD, PhD, MS, associate professor of pediatrics and director of the Center for Research Informatics (CRI). “The deluge of data and torrents of information from all corners of medicine and health care are overwhelming traditional analysis pipelines and storage and transfer mechanisms. By bringing together data scientists, clinician investigators and engineers, we are in an incredible and unique position to solve some of the most difficult problems facing health care.”

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By now, most of us are used to the uncannily accurate recommendations served up by online stores and streaming services. To generate these personalized picks, algorithms combine your browsing, listening and viewing history with those of similar users, looking for things others enjoyed that you have yet to try. By putting your taste and purchases in the context of a broader population of people, the process known as “machine learning” makes better predictions about what you’d like.

While the stakes are much higher, the concept behind personalized medicine follows a similar principle — combining a patient’s information with results from similar cases to find the likely best treatment. The approach has particular relevance for cancers, which can be triggered by a multitude of genetic mutations, some of which have proven, targeted therapies. But the enormous number of factors involved in the initiation and progression of cancer, combined with incomplete data on the efficacy of treatments, raises the computational bar.

Recognizing the potential and challenges of this task, the UChicago Medicine Department of Pathology formed the Division of Genomic and Molecular Pathology in 2013. Pathologists are at the center of the quest for personalized medicine, as they collect the critical information about patient tumors used in later decision-making. But as known mutations and test panels rapidly multiply, this initial step becomes more complex and data-heavy.

Working with the Center for Research Informatics’ bioinformatics group, the molecular pathology core developed SIMPL (System for Informatics in the Molecular Pathology Laboratory), an automated pipeline for handling the more than 100 steps that each tumor sample passes through while it is screened for cancer-causing gene mutations. What was once a cluttered spreadsheet is now a sleek dashboard, tracking the sample through the different genetic tests and assays, then generating a report that can suggest or rule out specific treatments for the patient.

“The ultimate goal is to support personalized medicine initiatives,” said Jeremy Segal, MD, PhD, assistant professor of pathology. “Because each patient and each cancer is different, we need to figure out, based on the genetics of each person’s cancer, how we might treat them and what information we might be able to give them.”

The SIMPL interface can also be adapted to coordinate complex multi-hospital collaborations, particularly around rare childhood cancers that lack sufficient data to discover new therapies. One such effort, the Genomic Assessment Improves Novel Therapy (GAIN) Consortium, led by Dana-Farber Cancer Institute, will use SIMPL to coordinate sample collection, genetic analysis, and knowledge generation/ aggregation for pediatric solid tumors and blood cancers at more than 20 medical centers.

“The GAIN platform facilitates and automates the query of several databases for information and annotations on genomic variants and then makes it easy for pediatric molecular pathologists to analyze and report on the significant findings,” Volchenboum said. “This ultimately allows the physician to make an informed decision about treatment. It really is changing the way in which this type of important clinical work is done.”

This is the first of a five-part series on data-driven medicine and research at the University of Chicago Medicine, originally published in the Spring 2017 issue of Medicine on the Midway.


Tagged: big data, Biological Sciences, Cancer, Deep Learning, Genetics, informatics, Jeremy Segal, machine learning, Pediatrics, Samuel Volchenboum

UCM-led studies ranked 1 and 2 in Clinical Research Forum’s Top 10 for 2016

Tue, 04/18/2017 - 23:00
Cows in an Amish barn

Cows in an Amish barn

The Clinical Research Forum, a national organization of senior researchers and thought leaders from the nation’s leading academic health centers, selected two studies headed by University of Chicago researchers as among the three best clinical research papers published in 2016.

These awards honor outstanding clinical research and identify major advances resulting from the nation’s investment in improving the health of its citizens.

Ten award winners were chosen for their innovation and creativity, advancement of science in a specific area, contribution to understanding human disease or physiology, and potential impact upon the diagnosis, prevention and treatment of disease.

The Herbert Pardes Clinical Research Excellence Award is the Clinical Research Forum’s highest honor. It is awarded to the research study that best exemplifies the spirit of the awards in that it shows a team science approach with a high degree of innovation and creativity, which advances science and has an impact upon human disease. The award comes with a cash prize of $5,000.

This year, the Pardes Award went to a team headed by geneticist Carole Ober, PhD, professor and chairman of human genetics at the University of Chicago, and immunologist Anne Sperling, PhD, associate professor of medicine at the University of Chicago.

Their study, “Innate Immunity and Asthma Risk in Amish and Hutterite Farm Children,” was published Aug. 4, 2016, in the New England Journal of Medicine.

The interdisciplinary team of researchers showed that substances in the house dust from Amish, but not Hutterite, homes were able to engage and shape the innate immune system (the body’s front-line response to most microbes) in young Amish, but not Hutterite, children in ways that appear to suppress pathologic responses leading to allergic asthma.

helmet pic1

The Distinguished Clinical Research Achievement Awards are presented to the top two studies that demonstrate creativity, innovation, or a novel approach that demonstrates an immediate impact on the health and well-being of patients. These awards come with a cash prize of $3,500.

One of those awards goes to a team led by pulmonologist John P. Kress, MD, professor of medicine at the University of Chicago, and Bhakti Patel, MD, clinical instructor of medicine at the University.

Their study on the “Effect of Noninvasive Ventilation Delivered by Helmet vs Face Mask on the Rate of Endotracheal Intubation in Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial,” was published May 15, 2016, in JAMA.

It showed that using a transparent, air-tight helmet instead of a face mask helps critically ill patients breathe better and can prevent them from needing a ventilator. Patients with helmet ventilation had better survival and spent less time in the intensive care unit.

The helmet “confers several advantages over the face mask,” the authors note. It is less likely to leak. This enables the care team to increase air pressure into the helmet, which helps keep the airway and lungs open and improves oxygen levels. It is also more comfortable, easier to tolerate because it doesn’t touch the face, and patients can see through it well enough to watch television, talk or read.

Award recipients were recognized earlier this evening at the Clinical Research Forum’s sixth annual awards ceremony on April 18 at the National Press Club in Washington, D.C. Members of the research teams will visit congressional representatives on Capitol Hill on Wednesday, April 19, to brief officials on their findings and the critical and necessary role of federal funding for clinical research.

These studies reflect major work being conducted at nearly 60 research institutions and hospitals across the United States, as well as at partner institutions from around the world, according to the Clinical Research Forum.

“The 2017 awardees represent the enormous potential that properly funded research can have on patients and the public,” said Harry P. Selker, MD, MSPH, Chairman of the CR Forum Board of Directors. “It is our hope that the significance of these projects and their outcomes can help educate the public, as well as elected officials, on the important impact of clinical research on human health.”

About the Top Ten Clinical Research Achievement Awards

Recognizing the need to celebrate our nation’s clinical research accomplishments that involve both innovation and impact on human disease, the Clinical Research Forum conducts an annual competition to determine the ten outstanding research accomplishments in the United States. These major research advances represent a portion of the annual return on the nation’s investment in the health and future welfare of its citizens.

About the Clinical Research Forum

The mission of the Clinical Research Forum is to provide leadership to the national and clinical translational research enterprise and promote understanding and support for clinical research and its impact on health and healthcare. For more information, visit www.clinicalresearchforum.org.

The National Institutes of Health, the St. Vincent Foundation and the American Academy of Allergy, Asthma & Immunology Foundation supported the asthma study. Additional authors were Michelle Stein, Cara Hrusch, Catherine Igartua and Jack Gilbert from the University of Chicago; Donata Vercelli, Justyna Gozdz, Vadim Pivniouk, Julie Ledford, Mauricius Marques dos Santos, Julia Neilson, Sean Murray, Raina Maier and Fernando Martinez from the University of Arizona; Erika von Mutius of the Dr. von Hauner Children Hospital in Munich, Germany; Nervana Metwali and Peter Thorne from the University of Iowa; and Mark Holbreich, an allergist-immunologist in Indianapolis, Indiana.

Funding for the helmet study was supplied by the National Heart Lung and Blood Institute. The helmets were purchased using funds from an unrestricted grant from the Daniel J. Edelman family. Additional authors were Krysta Wolfe, Anne Pohlman and Jesse Hall, all from the University of Chicago.


Tagged: allergies, Amish, Anne Sperling, asthma, Bhakti Patel, Biological Sciences, Carole Ober, critical care, Hutterites, intensive care, John Kress, microbiome, pulmonology, respiratory distress

As fins evolve to help fish swim, so does the nervous system

Mon, 04/10/2017 - 14:00
Red-breasted wrasse, or Cheilinus fasciatus, on a coral reef in Palau Parrotfish, a common Labrid species Bird wrasse, or Gomphosus varius, on a coral reef in Palau

The sensory system in fish fins evolves in parallel to fin shape and mechanics, and is specifically tuned to work with the fish’s swimming behavior, according to new research from the University of Chicago. The researchers found these parallels across a wide range of fish species, suggesting that it may occur in other animals as well.

The study, published April 10, 2017 in the Proceedings of the National Academy of Sciences, combined measurements of fin shape from hundreds of specimens of the Labridae family with fin mechanical properties and neural responses recorded from eight different Labrid species, commonly known as wrasses. These measurements were then mapped on an evolutionary tree of 340 wrasses to determine how the mechanical properties and nervous systems of the fins evolved over time.

“As pectoral fins evolve different shapes, behaviors, and mechanical properties, we’ve shown that the sensory system is also evolving with them,” said Brett Aiello, a PhD student in the Department of Organismal Biology and Anatomy, and the lead author of the study. “This allows the sensory system to be tuned to the different stimuli relevant to the locomotor behaviors and fin mechanics of different species.”

When animals use appendages for movement, they rely on sensory feedback from those limbs to control motion. Nerves in the pectoral fins of fish detect the fin rays’ position and how much they bend as they move through the water, which helps the fish sense speed and the relative position of their fins.

The shape of the fin affects how the fish will move too. Scientists use a number called aspect ratio (AR) to measure this shape. High AR means the fin is long and narrow, or more wing-like; low AR means the fin is broad or round, and more paddle-like. Wrasses with high AR, wing-like fins flap them to maximize efficiency and thrust as they propel themselves forward, while those with the broader, low AR, paddle-like fins use rowing movements to maneuver close to reef bottoms.

Brett Aiello, Department of Organismal Biology and Anatomy

Brett Aiello, Department of Organismal Biology and Anatomy

Aiello and his colleagues collected fin aspect ratio measurements from hundreds of Labrid species at the Field Museum, and combined that data with a genetic phylogeny of 340 Labrids developed by Mark Westneat, PhD, professor of Organismal Biology and Anatomy and co-author on the study. Using DNA from living fishes, Westneat constructed a family tree of relationships between these species, tracing how they evolved through time. The researchers then mapped the fin shape of each species on the phylogeny, allowing them to track fin evolution from their ancestral state to living species. The ancestral state reconstruction revealed patterns of convergent evolution, with high AR fins originating independently at least 22 times.

With this history of fin evolution in place, the researchers also tested the mechanical properties and sensory system sensitivity in the pectoral fins of four pairs of closely related Labrid species, one with low AR fins and one with independently evolved high AR fins. The team tested the sensory response by measuring the neural response from the pectoral fin nerves as they bent the fin, and then repeated the process, bending the fins a different amount each time.

What they found gave more clues about the utility of each kind of fin. The low AR, paddle-like fins tended to be more flexible, and the high AR fins were more stiff or rigid. But the sensory system of the wing-like, high AR fins was also more sensitive, meaning the fins were more responsive to a smaller magnitude of bending. Aiello said he believes that a more sensitive nervous system evolved in the high AR fins because it needed to be more responsive to smaller movements as the fish use these stiff, less flexible fins to swim.

The work is the product of collaboration across disciplines, a hallmark of the Organismal Biology and Anatomy program at UChicago. The resulting PNAS study could have been three separate papers: the archival research of specimens from the Field Museum, the genetic phylogeny, and the neurobiological study of the living species.

“Collaboration among scientists with different perspectives and expertise can take research in whole new directions,” said Melina Hale, the William Rainey Harper Professor of Organismal Biology and Anatomy and senior author of the study. “It is also a lot of fun because we learn about each other’s fields. For experimentalists, like us, working with colleagues and natural history collections at the Field Museum has been particularly important as they bring key insights on evolution and biodiversity.”

Besides giving biologists a better understanding of how fish have optimized their swimming mechanics, the results of the study could also be useful to engineers developing underwater autonomous vehicles. The propulsion systems of these devices need to be both efficient and responsive, and there are perhaps no better designs to copy than those perfected through evolution over millions of years.

“A lot of the problems that engineers run into are similar to the type of things that animals have already evolved solutions to over time,” Aiello said. “If we start to look more towards bio-inspired technology and incorporating some of the things we see in nature in our engineered devices, I think it will help advance and solve some of these problems more quickly.”


Tagged: Biological Sciences, Brett Aiello, Evolution, fish, marine biology, Mark Westneat, Melina Hale, nervous system, sensory system, swimming

Paleoanthropologist Zeray Alemseged explores the origins of our shared humanity

Fri, 04/07/2017 - 11:34
Zeray Alemseged

Zeray Alemseged, professor of organismal biology and anatomy at the University of Chicago

In July 2015, Zeray Alemseged had the rare opportunity to meet President Barack Obama and the prime minister of his native country of Ethiopia, Hailemariam Dessalegne. Obama was making a historic visit as the first ever sitting US president to visit Ethiopia, and Alemseged, a paleoanthropologist, was tasked with showing him artifacts from the country’s rich heritage of humanity.

Our species, Homo sapiens, was born in Ethiopia about 200,000 years ago, and our ancestors lived there long before that. Alemseged showed the two leaders some of the world’s most famous fossils, including “Lucy,” the 3.2 million year old Australopithecus skeleton discovered in Ethiopia in 1974 by Donald Johanson, and “Selam,” a nearly complete, 3.3 million year old skeleton of an Austraolopithecus juvenile known as “the world’s oldest child,” discovered by Alemseged himself in the Dikika region of Ethiopia in 2000.

As Alemseged proudly showed off his country’s heritage, he worked in a few digs at the then long-shot presidential candidate Donald Trump that impressed even Jon Stewart; but he left Obama with a message about humanity’s shared history, dating back to when Lucy and Selam’s descendants evolved in the Horn of Africa and spread across the globe. He wrote about the encounter later in Discourse, an East African humanities journal:

“We’ve come this far, a long odyssey since our species was born 200,000 years ago in Africa. All of us, particularly those in power and the aspiring ones, need to be reminded of a simple truth: the oneness of humanity.”

Alemseged Obama

Zeray Alemseged with US President Barack Obama and Ethiopian Prime Minister Hailemariam Dessalegne (right) (Image: Comedy Central)

It took six years of careful research and preparation before Alemseged revealed Selam to the world in a landmark publication in Nature in 2006. At the time, he was a senior scientist at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, before settling in at the California Academy of Sciences two years later, where he worked for eight years as a senior curator and educator.

But in the fall of 2016, amidst stiff competition from other suitors, the University of Chicago convinced him to leave the California coast for the Midwest. The decision—joining U.S. News & World Report’s top-ranked paleontology program in the country—was made easy by UChicago’s storied history. The Walker Museum of Geology and Paleontology was established on campus in 1893, and some of the most famous names in the field, including Donald Johanson, Francis Clark Howell, and Sherwood Washburn trained or served on the faculty at UChicago. Continuing that history was appealing, Alemseged said, but so was the opportunity for collaboration offered at UChicago.

“The study of human evolution here has very deep roots,” he said. “Continuing that legacy and thinking into the future is exciting, but when you leverage that with the ability to work with some of the brightest students in the world, the opportunity to collaborate with them is one of the great legacies a scientist could have.”

Alemseged fills a niche in the Department of Organismal Biology and Anatomy as its resident paleoanthropologist, studying human origins and the environmental context of human evolution. The other senior researchers on the faculty occupy key branches on the evolutionary tree of life. Michael Coates studies the origins of early vertebrates and fish. Neil Shubin studies the first tetrapods and their transition to land. Paul Sereno covers dinosaurs and the emergence of flight, and Zhe-Xi Luo studies the origins of mammals.

uchicago-paleontology-tree

Alemseged extends this expertise to the species that dominates our planet today, with a new breed of research that combines high-tech imaging analysis of fossils with traditional geology and field work. Using these tools, he explores the milestone events in human evolution since our split from the apes.

“With one foot in the field, he’s a top-notch scientist who can use geology, biology and the latest technology in his work, and has a very good sense of public outreach,” said Sereno. “I’m so happy he chose to come here, putting UChicago at the cutting edge of the newest research in human evolution.”

Alemseged returns to Ethiopia every year for several months to continue work in the Afar, a paleoanthropological hotspot, collaborating with researchers from across the globe, including the National Museum of Ethiopia where the fossils are prepared and curated. “You can say that one-half of my lab is back there,” he said. Despite the excitement of meeting world leaders and media coverage of major discoveries, Alemseged prefers the meticulous, painstaking labor of the field site and laboratory.

“I took six years to patiently work on Selam before even telling the world that I had this discovery. Six years, and then the moment came. We published our paper on the cover of Nature, and National Geographic came, the BBC sent a special envoy, CNN sent a special envoy. The moment of the announcement was fascinating, but then it passed and the following day was another stressful day,” he said. “So what I enjoy the most is the quiet moments that I have in my lab in the process of making the little incremental discoveries, that when combined will allow me to tackle questions pertaining to those milestone events.”

alemseged-field

As he told Obama, the work of paleoanthropologist helps us understand humanity’s shared past, and ideally, emphasize less (or balance out) the cultural, linguistic, and political differences that drive so much conflict today. But equally important is understanding humanity’s connection to nature. After all, we are just another animal, and our behavior has dire consequences for the entire planet.

“Today’s humans, you and I, are so distinct, so far removed both anatomically and behaviorally from other animals. There is no other animal that has your brain. There is no other animal that uses computers and reflects on its origins,” Alemseged said. “So, the key transitional moments in our evolutionary history that we paleoanthropologists establish will allow us to understand our links to our animal origins. Establishing those milestones allows us as scientists to know what the process was like, and allows the lay person to understand the links we have with nature.”


Tagged: Biological Sciences, Ethiopia, Evolution, human evolution, organismal biology and anatomy, paleoanthropology, paleontology, Paul Sereno, Zeray Alemseged

How chewing like a cow helped early mammals thrive

Wed, 03/22/2017 - 12:07

You probably haven’t given much thought to how you chew, but the jaw structure and mechanics of almost all modern mammals may have something to do with why we’re here today. In a new paper published this week in Scientific Reports, David Grossnickle, a graduate student in the Committee on Evolutionary Biology at the University of Chicago, proposes that mammal teeth, jaw bones and muscles evolved to produce side-to-side motions of the jaw, or yaw, that allowed our earliest ancestors to grind food with their molars and eat a more diversified diet. These changes may have been a contributing factor to their survival of the mass extinction at the end of the Cretaceous Period 66 million years ago.

Cow chewingThe terms “pitch” and “yaw” usually describe movements of airplanes, but biologists also use them to describe basic movements of body parts such as the jaw. Pitch rotation results in basic up and down movement, and yaw rotation results in side-to-side, crosswise motion (think of a cow munching away on some grass). Almost all modern mammals, including placental mammals, like humans and deer, and marsupials, like kangaroos and opossums, share similarities in their jaw structures and musculature that allow for both pitch and yaw movements. This allows mammals to have especially diverse diets today, from cutting pieces of meat to grinding tough plants and vegetables. For early mammals, these characteristics meant they could be more resourceful during tough times.

“If you have a very specialized diet you’re more likely to perish during a mass extinction because you’re only eating one thing,” Grossnickle said. “But if you can eat just about anything and 90 percent of your food goes away, you can still live on scraps.”

Using 2D images of early mammal fossils from previous publications and 3D data collected from modern specimens at the Field Museum, Grossnickle analyzed the structure of teeth, jaw bones, and how the muscles that control them were attached to the skull. He saw that as species began to develop a projection on the upper molars that fit into a corresponding cup or basin on their lower counterparts, the musculature of the jaw also changed to provide greater torque for side-to-side yaw movements. This way the animal could grind its food between the molars like a mortar and pestle, as opposed to cutting it with simple up and down pitch movements.

David Grossnickle, Committee on Evolutionary Biology, UChicago

David Grossnickle, Committee on Evolutionary Biology, UChicago

Grossnickle, who works in the lab of Zhe-Xi Luo, PhD, professor of organismal biology and anatomy, studies the early origins of mammals, and is interested in broader questions about why certain mammal groups have diversified through time and survived extinction events. He says the adaptations of the jaws and teeth may have been key.

“Mammals rebounded from those events and kept diversifying and persisting, and that’s one of my interests. Why are we in the Age of Mammals, not still in the Age of Dinosaurs?” he said.  “This study begins to address that question from a functional perspective, looking at what changes occurred that might’ve given some mammals functional or dietary advantages over other groups.”


Tagged: Biological Sciences, chewing, David Grossnickle, Evolution, mammals, paleontology
David Grossnickle explains the evolution of jaw yaw

Explore Urban Nature with biologist Marcus Kronforst and WTTW

Mon, 03/20/2017 - 11:55

Urban Nature logo

If you know where to look, you’ll find the most surprising slices of nature thriving amidst the urban jungles of America’s largest cities. In Chicago, drive down Lake Shore Drive late at night and you might see a coyote trotting out of the bushes, or visit a vacant lot on the South Side to find an amazing array of birds, bees, butterflies and native prairie plants.

In WTTW’s new 16-episode digital series Urban Nature, University of Chicago evolutionary biologist Marcus Kronforst leads audiences on a tour of these overlooked ecosys­tems in Chicago, New York and San Francisco. He’ll hop on a bike, grab a kayak, or even take the subway to seek out the unlikely habitats that are hidden among the skyscrapers. He’ll talk with the passionate conservationists who are ensuring that these ur­ban oases survive despite the constant dangers posed by the surrounding city. And he’ll discover how these havens are essential to the health of our cities—and the future of our planet.

Marcus Kronforst

Marcus Kronforst, PhD, Neubauer Family Assistant Professor of Ecology and Evolution

“It’s really amazing. As a biologist, of course I knew that there was nature around us in the city,” said Kronforst, who is the Neubauer Family Assistant Professor of Ecology and Evolution at UChicago, “but I had no appreciation for just how much ecology is happening out there, and how important cities actually are in driving some natural systems.”

The series is now posted in its entirety on wttw.com/urbannature, and was written and produced by WTTW’s Dan Protess. It consists of 16, four to 10 minute episodes featuring everything from birds, butterflies and coyotes in Chicago to sea lions in San Fransciso and a deserted island hospital just a mile from Manhattan.

WTTW is also hosting a screening and discussion about Urban Nature this Saturday, March 25, from 3:00 to 4:30 p.m. at the Field Museum in Chicago. Kronforst, Protess, and the Field Museum’s Abigail Derby Lewis will discuss the making of the series and answer questions. Click here for more information and to RSVP.


Tagged: Biological Sciences, ecology and evolution, Marcus Kronforst, Urban Nature, WTTW

How cells communicate to move together as a group

Mon, 03/13/2017 - 13:00
Drosophila egg chambers

Drosophila egg chamber rotates as it develops into an egg. This rotation occurs because the epithelial cells that form the egg chamber’s outer layer outer collectively migrate along the extracellular matrix (green) that surrounds each organ-like structure.

When an individual cell needs to move somewhere, it manages just fine on its own. It extends protrusions from its leading edge and retracts the trailing edge to scoot itself along, without having to worry about what the other cells around it are doing. But when cells are joined together in a sheet of tissue, or epithelium, they have to coordinate their movements with their neighbors. It’s like walking by yourself versus navigating a crowded room. To push through the crowd, you have to communicate with others by talking (“Pardon me”) or tapping them on the shoulder. Cells do the same thing, but instead of verbal cues and hand gestures, they use proteins to signal to each other.

This kind of coordinated migration is important during embryonic development when cells migrate to form organs, during healing when they move to close a wound, and unfortunately during the spread of many cancers. Scientists already knew about some of the proteins involved in this process, but research from the University of Chicago has identified a new signaling system that epithelial cells use to coordinate their individual movements and efficiently move tissues.

In a study published Mar. 13, 2017 in the journal Developmental Cell, cell biologist Sally Horne-Badovinac, PhD, and colleagues describe how two cell membrane proteins work together to coordinate epithelial migration in the fruit fly Drosophila. One, called Fat2, localizes at the trailing edge of cells; the other, called Lar, localizes at the leading edge of cells. As cells migrate, Fat2 signals to Lar in the cell behind it, which causes that cell to extend its leading edge, tucking under the cell in front of it. In response, Lar signals back to Fat2, which retracts its trailing edge. Step-by-step, the neighboring cells work together in this coordinated fashion to move the entire tissue.

“The protrusion of one cell goes underneath edge of the cell ahead, so you get what looks like overlapping shingles on a roof,” said Horne-Badovinac, who is an assistant professor of molecular genetics and cell biology and senior author of the study. “This process is understood really well at the single cell level, but when you hook these cells all together in a tight sheet, it becomes something more coordinated.”

Cell migration

Fat2 and Lar are large transmembrane signaling proteins that promote the migration of the epithelial cells. When the epithelium’s outer surface is visualized, Fat2 localizes to the trailing edge of each cell and Lar localizes to the leading edge of each cell. These proteins then interact across cell-cell boundaries to coordinate individual cell migratory behaviors.

Horne-Badovinac and her team, which included postdoctoral scholars Kari Barlan, PhD, lead author of the paper, and Marueen Cetera, PhD, now at Princeton University, used a fruit fly model to study the signaling process. As female fly embryos develop, the tissues that form egg chambers elongate and rotate into position. Scientists knew that both Fat2 and Lar were involved in this process, but it wasn’t clear that cells were migrating because they were rotating around the circumference of the circular chamber, not moving in a straight line from one point to another.

Using new cell culturing techniques, the researchers could grow the egg chambers separately outside the female flies to study them more closely. They saw that when Fat2 was missing from a patch of cells with normal cells behind it, the normal cells didn’t make their usual leading edge protrusions. If Lar was missing in a patch of cells behind a normal patch, the normal cells didn’t retract their trailing edges to move.

“It was surprising, because what we knew was that the protein [Fat2] was at the trailing edge of the cell, but we were seeing an effect at the leading edge of the cell. So initially that made absolutely no sense,” said Horne-Badovinac. “It required careful analysis along those cloned boundaries to really figure it out.”

Horne-Badovinac said she still has a lot of questions about how these proteins interact with each other, and believes that there may be other proteins involved that signal to the cytoskeletal machinery that actually drives cellular movement.

“This is just the tip of the iceberg for figuring out how this signaling system works,” she said. “I absolutely love thinking about collective behaviors of cells, how they communicate with one another, and how groups of cells can make decisions to move in uniform in complicated ways. By studying this process in a simple Drosophila system, we might generate information that’s going to be useful for understanding wound healing or the spread of cancer.”

The study, “Fat2 and Lar Define a Basally Localized Planar Signaling System Controlling Collective Cell Migration,” was supported by the National Institutes of Health (T32 GM007183 and R01 GM094276) and the Life Sciences Research Foundation.


Tagged: Biological Sciences, cellular biology, epithelial migration, Genetics, Kari Barlan, molecular biology, Sally Horne-Badovinac

Parallel cellular pathways activate the process that controls organ growth

Mon, 03/13/2017 - 11:00
Microscopic image of the fruit fly wing imaginal disc, with cell junctions and medial apical cortices illuminated by fluorescent protein tags

Microscopic image of the fruit fly wing imaginal disc, with cell junctions and medial apical cortices illuminated by fluorescent protein tags

There is an old axiom among cell biologists meant to caution against making assumptions about how certain proteins function, and it involves a hypothetical Martian. If that Martian came to Earth and looked down at a school from its spaceship, it would assume the main job of the school buses is to sit in a parking lot all day, because except for a few hours in the morning and afternoon, that’s all they do.

Likewise, if someone (whether Martian or Earthling) looked through a microscope for proteins that help control organ growth, they would assume they only functioned at the edges, or junctions, of cells, because that’s where they mostly accumulate. But a new study from the University of Chicago suggests that while these proteins do accumulate around the edges of cells, they actually function at a different cellular site.

‘Tumor suppressors’ are genes that normally function to restrict tissue growth. When these genes are inactivated by mutations, cancerous tumors can result. Researchers have taken advantage of the power of genetic experimentation in the fruit fly Drosophila melanogaster to exhaustively identify all of the tumor suppressor genes in flies. In the early 2000s, researchers determined that most of these genes were all part of the same system, dubbed the Hippo signaling pathway. Remarkably, these genes are not exclusive to flies and function similarly in a host of other organisms, including humans, suggesting that the system goes far back in evolutionary time as a critical controller of cell function. Early returns also indicate that the Hippo pathway is a likely contributor to human cancers and other tumor syndromes, including neurofibromatosis.

While the Hippo pathway has been firmly established, scientists are still looking for how elements upstream turn the pathway on and off. Three different proteins associated with the cell membrane—Kibra, Merlin and Expanded—regulate pathway activity, but scientists aren’t sure how. The conventional wisdom is that all three operate together at the intracellular junctions, but using a combination of advanced imaging and genetic tools to observe and manipulate these proteins in live tissues, UChicago postdoctoral researcher Ting Su, PhD, discovered that Merlin and Kibra work together to activate the Hippo pathway in a separate area called the medial apical cortex. Meanwhile, Expanded works independently to activate the pathway at the junctions.

“There has been some evidence that these components interact with one another biochemically, but genetically they seem to form two independent inputs into the pathway,” Su said. The results of this work were published Mar. 13, 2017 in the journal Developmental Cell.

Su said that the key to understanding the activity of these proteins was being able to observe them endogenously, or as they occur normally in living epithelial tissues that form the wing of the fly, fused to fluorescent protein tags. Using a high-sensitivity, confocal microscope, Su and his colleagues could see a honeycomb-like mesh of circles, where the glowing proteins gathered at cell junctions—i.e. the school bus parking lots—as expected. But looking carefully, they also saw clusters of activity at a non-junctional site called the medial apical cortex, meaning that the proteins were functioning in another cellular region at the same time.

The downstream results seem to be the same whether the process is initiated by the proteins in the center of the cell or those at the junctions—when the Hippo pathway is activated, it acts as a throttle, signaling that it’s time for organs to stop growing. What’s not clear are the upstream inputs, or what causes one means of activating the pathway to be triggered over the other. One possibility may be mechanical tension in the cells. As tissues grow, cells stretch and squeeze against each other, generating tension across the tissue that cells might sense through junctions with their neighbors.

“The current thinking is that might be one way the tissues sense how big they are. As they grow, that generates mechanical tension, and it’s clear that tension feeds into pathway activity through the junctions,” said Rick Fehon, PhD, professor and chair of the Department of Molecular Genetics and Cell Biology, and senior author on the study.

At the same time, each cell can generate internal tension using a motor protein called myosin, a mechanism cells use to change shape. “We’re interested in the possibility that this medial localization might be a way to sense tension generated within cells,” he said.

Tissue growth is an inherent part of developmental biology, but only recently have researchers focused on understanding the cellular mechanisms that regulate it.

“The really great thing about working with flies is the genetic tools that make this possible,” Fehon said. “It’s the ability to combine those with new, advanced microscopy approaches to figure out whether the school bus functions when it’s in the parking lot, or when driving around.”

The study “Kibra and Merlin activate the Hippo pathway spatially distinct from and independent of Expanded,” was supported by the National Institutes of Health (R01NS034783) and the Children’s Tumor Foundation (2013-01-020 and 2014-01-020). Additional authors include Michael Ludwig and Jiajie Xu, both from the University of Chicago.


Tagged: Biological Sciences, Cancer, cellular biology, developmental biology, Genetics, Hippo pathway, molecular biology, neurofibromatosis, organ growth, Rick Fehon, Ting Su, tumor suppressors

Molecules form gels to help cells sense and respond to stress

Thu, 03/09/2017 - 11:00
phase separation

During phase separation, two mixed liquids separate, like oil and vinegar in a salad dressing. The new UChicago study showed that normal levels of the protein Pab1 could phase-separate and form hydrogel droplets.

A specific protein inside cells senses threatening changes in its environment, such as heat or starvation, and triggers an adaptive response to help the cell continue to function and grow under stressful conditions, according to a new study by scientists from the University of Chicago.

When cells experience stress, such as heat or starvation, groups of proteins and RNA molecules inside the cells form clumps. These clumps have long been thought to be a sign of cellular damage, piles of melted, dysfunctional molecules that need to be discarded. This matches with observations that in many human neurological diseases, such as Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis (ALS), clumps of proteins accumulate in dying nerve cells.

drummond2

D. Allan Drummond, PhD, assistant professor in the Department of Biochemistry and Molecular Biology and of Human Genetics

In the new study, published Mar. 9, 2017 in the journal Cell, D. Allan Drummond, PhD, and colleagues show that a molecule called poly(A)-binding protein (Pab1) forms clumps in response to stressful conditions inside budding yeast cells, and when only the protein is isolated in a test tube. What look like clumps are instead a hydrogel—like a jelly or toothpaste—which under the microscope appear as round droplets. Most importantly, when the researchers interfered with the formation of this stress-associated hydrogel in living cells, those cells couldn’t cope with stress. Hydrogel formation, in other words, is not damage, but an adaptive response.

“It appears to be an organized emergency procedure, like a fire alarm when people move away from their normal jobs and collect in large groups at specific places, unhurt and out of the way of danger,” said Drummond, who is an assistant professor in the Department of Biochemistry and Molecular Biology and of Human Genetics at UChicago. “When these molecules gather into large groups—forming a gel—they’re not just doing it for protection, but to do crucial work, like calling firefighters and paramedics.”

The study is the result of a five-year collaboration between Drummond and Tobin Sosnick, PhD, Chair of the Department of Biochemistry and Molecular Biology, and spearheaded by two graduate students, biophysicist Joshua Riback and biochemist Chris Katanski.

Cellular oil and vinegar

In recent years, a surge of research has focused on the formation of protein liquids and hydrogels as a way in which cells organize and remodel themselves. In one process, called “phase separation,” two mixed liquids separate, like oil and vinegar in a salad dressing. To get phase separation to occur, previous studies generally used extreme test-tube conditions (high concentrations of the protein or additives). The new UChicago study showed that normal levels of Pab1 could phase-separate—if confronted with temperature or pH changes that accompany cell stress.

Fluorescently labeled Pab1 protein in hydrogel droplets

Fluorescently labeled Pab1 protein in hydrogel droplets

“Surprisingly, we don’t actually know how these cells sense that it’s gotten hotter,” Drummond said. Animals use temperature-sensing nerve channels, but yeast cells lack those channels. “The temperature-sensitivity of this phase separation process is much greater than any other molecular temperature-sensing system that’s been described,” Drummond said. “We suspect that this kind of molecular mechanism for cells to sense thermal and other environmental changes will be widespread.”

Drummond and his colleagues are continuing to study how this phase separation process helps cells survive stress. In the paper, the researchers suggest this may be because when Pab1 releases specific messenger RNAs during stress response, this triggers translation of those mRNAs to encode new, stress-responsive proteins that help the cells grow.

The researchers are also studying how the hydrogel droplets of Pab1 get dispersed back into individual molecules. Understanding the reversal of phase separation could provide clues to how the process can go awry. In neurodegenerative disease like Alzheimer’s or ALS, for example, the presence of protein clumps in nerve cells may be a sign that the phase separation process began as a protective response to stress, but something went wrong and prevented the cells from returning to their normal state.

“This is the first example of those clumps being useful,” Drummond said. “These studies get at the broader questions of how cells use the reversible formation of massive groups of molecules to carry out important functions, and how these good clumping processes might go haywire, resulting in diseases where clumping has run amok.”

stress granules

“Stress granules” forming inside the cell

The study, “Stress­triggered phase separation is an adaptive, evolutionarily tuned response,” was supported by the Pew Charitable Trusts, the National Institutes of Health, the Protein Translation Research Network, the National Science Foundation, the U.S. Army Research Office, and the Department of Energy. Additional authors include Jamie Kear-Scott, Evgeny Pilipenko, and Alexandra Rojek, all from the University of Chicago.


Tagged: Allan Drummond, ALS, Alzheimer's disease, Biological Sciences, cell biology, Chris Katanski, Joshua Riback, molecular biology, Parkinson's disease, phase separation, Tobin Sosnick

Brain plasticity and phantom limbs: Does amputation rewire the sense of touch?

Tue, 02/14/2017 - 12:51

Bensmaia hand brain

In October 2015, 28-year-old Nathan Copeland used a robotic prosthetic arm to give President Obama a fist bump at a scientific conference in Pittsburgh. Copeland, who was paralyzed from the chest down in a car accident in 2004, also showed the President how he could “feel” with the hand, which sent realistic sensory feedback through electrodes implanted in his brain.

It was a feat of engineering and neuroscience by a team of researchers from the University of Pittsburgh and Sliman Bensmaia, associate professor of organismal biology and anatomy at the University of Chicago—and a feat that was made possible by the resilience of the sensory parts of the brain.

Bensmaia has spent years researching how the nervous system interprets sensory feedback as we touch or grasp objects, move our limbs and run our fingers along textured surfaces. He believes that the best way to restore the sense of touch in patients like Copeland is to use a “biomimetic” approach that mimics the natural, intact nervous system. By studying how the brain normally encodes and responds to sensory information, scientists can reproduce those signals through a prosthetic limb connected directly to the brain.

This approach assumes that the part of the brain responsible for processing the sense of touch, the somatosensory cortex, is relatively stable—i.e., that if someone loses a limb or becomes paralyzed, the somatosensory cortex is still there, intact and ready to respond to stimulation. But Bensmaia says that every time he gives a presentation about his prosthetics research, someone invariably challenges him with a different idea—that after amputation, the brain reorganizes and uses that part of the somatosensory cortex for something else.

This notion was popularized by a series of famous studies in the 1990s by V.S. Ramachandran at the University of California, San Diego. Three amputees reported that when they were touched on the face, they felt sensations that corresponded to their missing, or “phantom” hand. This curious phenomenon was taken as direct evidence for brain reorganization–once input to the brain territory of the (now missing) hand is lost, this territory is claimed by the face.

referred-sensations

In some studies, amputees reported that when they were touched on the face, they felt sensations that corresponded to their missing hand (A). But in others, different locations evoked the missing limb (B).

Ramachandran went on to become a popular scientific speaker and author of several books, most notably Phantoms in the Brain in 1998. His ideas added to a broader school of thought on the brain’s “plasticity,” or ability to change and accommodate for learning new skills or responding to trauma like losing a limb. This supposed malleability is what troubled Bensmaia.

“If the somatosensory cortex were so labile, then the biomimetic approach wouldn’t work,” he said. “Instead, the design of the neural interface would depend on the idiosyncratic neural representations of each individual, rather than based on general principles of organization, which we work to uncover.”

In response, he teamed up with Tamar Makin, an associate professor at the University of Oxford, United Kingdom, and an expert on the brains of amputees, to write a paper that challenges the notion of massive reorganization of sensory representations in the brain after amputation. Based on a reexamination of the existing literature and on their own work, Makin and Bensmaia argue that while other parts of the brain may indeed be plastic, the somatosensory cortex for processing the sense of touch is relatively stable.

“Previous researchers studying amputees focused on representations of body parts that are not directly affected by the amputation, such as the face, to study brain plasticity,” Makin said, but she thinks this is just one piece of the puzzle.

“Amputees ubiquitously report very vivid sensations of their missing hand, called ‘phantom sensations’. In my research, we take advantage of this remarkable phenomenon to study the persistent representation of the missing hand,” she said.

For instance, the body parts that are thought to benefit from the brain resources previously devoted to the missing hand do not gain any functionality by having access to that additional sensory processing power. In experiments, the skin surfaces of the face that trigger these sensations are no more sensitive to touch than before amputation.

University of Pittsburgh researchers perform a sensory test on a blindfolded Nathan Copeland who demonstrates his ability to feel by correctly identifying different fingers through a mind-controlled robotic arm. (Credit: UPMC/Pitt Health Sciences Media Relations)

Second, as in Bensmaia’s research, both amputees and paralyzed patients like Copeland reported realistic, natural-feeling sensations in their missing or otherwise insensate arm when stimulated through residual nerves or directly in the brain. This suggests that the portions of the brain responsible for that arm are still there, ready and waiting for sensory input from the arm.

“Even if they haven’t had an arm for 10 years, the way they report it is not as a phantom or vague sensation of the arm. They would describe it as, ‘My arm is still present. I can’t see it. I know it’s not really there, but it feels like it’s there,’” Bensmaia said.

Instead of the somatosensory cortex reorganizing and creating a new representation of the face, Bensmaia and Makin point to research showing that new nervous system circuits develop in the brain stem. After loss of input from the hand following amputation, parts of the brain stem that used to carry signals from the arm form new connections to neighboring areas, which can result in receiving input from a new source, like the face. However, the hand sensations generated by touching the face result from echoes of this new input, reverberating through the hand portion of the somatosensory cortex.

Bensmaia acknowledges that much of the brain is plastic of course, but suggests that we should have a more nuanced view of plasticity than is often taken for granted in the public imagination.

“You can learn how to play guitar, for example, even as an adult, so that implies that the motor parts of your brain can learn and are plastic,” he said. “And right next to these motor regions, you have somatosensory regions that are relatively fixed, at least in their coarse organization. This region carries the ground truth of what your body is doing at any time.”


Tagged: artificial touch, Biological Sciences, Brain, brain plasticity, neuroprosthetics, Neuroscience, prosthetics, Sliman Bensmaia, somatosensory cortex, touch
UPMC Pitt BCI Demonstration

National Academy of Sciences Honors Prof. Bernard Roizman for microbiology research

Mon, 02/13/2017 - 10:52

Bernard Roizman

Bernard Roizman holding a model of the herpes simplex virus, 1978 (University of Chicago Library / Chicago Maroon)

Bernard Roizman, ScD, the Joseph Regenstein Distinguished Service Professor of Virology, has been awarded the 2017 Selman A. Waksman Award in Microbiology for his pivotal research on how herpes viruses replicate and cause disease.

Supported by the Waksman Foundation for Microbiology, the National Academy of Sciences gives the award biannually to recognize a major advance in the field of microbiology. The honor is accompanied by a $20,000 prize.

“I am deeply honored to be a recipient of an award bearing Selman Waksman’s name,” Roizman said. “His research laid the foundations for discoveries of potent antibiotics, and over the course of half a century his pioneering research saved billions of lives. He continues to be an inspiration for scientists involved in research to curb the spread of infectious agents.”

Over the past five decades, Roizman’s contributions to the scientific understanding of herpes viruses have helped to improve human health. His research first identified viral herpes genes and proteins, as well as the structure of viral DNA, and defined the principles of herpes simplex virus gene regulation. He also constructed the first recombinant virus specifically targeted to malignant cells.

Using biochemistry, novel genetic strategies and cell biology, Roizman’s ongoing research focuses on how the herpes simplex virus, which has fewer than 100 genes, can take over a much more complex human cell, which contains more than 20,000 genes. This led to the first engineered virus, which has been used to study and target lethal tumors in humans.

Roizman’s role as a mentor has extended his research beyond his lab, with dozens of graduate student and postdoctoral fellows energizing the field of virology in premier universities in the United States, Europe, and Asia.

A member of the University faculty since 1965, Roizman was elected as a member of the National Academy of Sciences in 1979 and to the National Academy of Medicine in 2001. He is a Foreign Associate of the Chinese Academy of Engineering and the recipient of honorary degrees in the United States, France, Italy, and Spain. He will be honored in a ceremony on Sunday, April 30, during the National Academy of Sciences’ 154th annual meeting.


Tagged: Bernard Roizman, Biological Sciences, herpes, Microbiology, National Academy of Sciences, Selman Waksman Award, viruses

UChicago startups focus on microbiome medicine

Wed, 02/01/2017 - 10:39
Jack Gilbert

Prof. Jack Gilbert co-founded Gusto Global to better understand microorganisms inside humans and harness them to treat disease. (Photo: Andrew Collings)

Two startup companies founded by UChicago faculty are leveraging the microbiome to develop new medications that could prevent food allergies, stop infections, and treat disease.

ClostraBio, started by Cathryn Nagler, PhD, the Bunning Food Allergy Professor, and Jeffrey Hubbell, the Barry L. MacLean Professor of Molecular Engineering Innovation and Enterprise, is working to develop microbiome-based treatments for food allergies.

In 2014 Nagler and her team discovered that the presence of Clostridia, a common class of gut bacteria, protects against food allergies by acting as a barrier that prevents the trigger foods from entering the bloodstream and sparking an allergic reaction. Nagler’s group also identified the differences between the bacteria in the guts of healthy infants and those who were allergic to cow’s milk in 2015, and has created mouse models that mimic the human microbiome by transferring bacteria from infants into mice.

ClostraBio will use these special mice and controlled UChicago lab environments, such as the Gnotobiotic Mouse Facility, to test their potential treatments.

A second startup, Gusto Global, launched by Jack Gilbert, PhD, faculty director of the Microbiome Center, and John Alverdy, MD,  the Sarah and Harold Lincoln Thompson Professor of Surgery and executive vice chair of the Department of Surgery, is using computer models to predict how the trillions of bacteria in the body interact with each other and influence health. The company’s proprietary platform uses databases from human studies to run thousands of simulations to bolster the research and development of microbiome-based drugs.

Both companies have been supported by the Polsky Center for Entrepreneurship and Innovation, which provides resources for UChicago researchers to help commercialize their work.


Tagged: Biological Sciences, Cathryn Nagler, Food Allergies, Gastroenterology, Jack Gilbert, John Alverdy, microbiome, Surgery

Regulating “gasotransmitters” could improve care for sleep apnea

Mon, 01/23/2017 - 14:00

NP mice 1

Unbalanced signaling by two molecules that regulate breathing leads to sleep apnea in mice and rats, researchers report in the Jan. 23, 2017, Proceedings of the National Academy of Sciences. They show, working with rodents, that injection of a substance that reduces production of one of those signals, hydrogen sulfide, can prevent apneas. This approach has the potential to help people suffering from multiple forms of sleep-disordered breathing.

Apnea, the periodic cessation of breathing during sleep, is a major health problem. It affects more than 10 million people in the United States, often disrupting their sleep hundreds of times each night. This profoundly fragmented sleep causes daytime drowsiness, curtails academic achievement and professional productivity, and is a common cause of motor-vehicle or on-the-job accidents. It can lead to life-threatening health issues, including hypertension and stroke.

Current apnea treatments, such as the use of continuous positive airway pressure (C-PAP) while sleeping, are difficult for many patients to maintain and provide only limited benefits.

NP.01

Nanduri Prabhakar, PhD

“We believe we have found an approach that could significantly improve the clinical management of sleep apneas by restoring the balance between two key gasotransmitters in the blood – carbon monoxide and hydrogen sulfide,” said Nanduri Prabhakar, PhD, the Harold Hines Jr. Professor of Medicine and Director of the Institute for Integrative Physiology and Center for Systems Biology of O2 at the University of Chicago.

Prabhakar and colleagues from the University of Chicago, the Illinois Institute of Technology, Beth Israel Deaconess Medical Center (Boston), and Johns Hopkins University (Baltimore), focused on the carotid bodies, a tiny cluster of cells embedded in the left and right carotid arteries, which pass through the neck.

The carotid bodies are the primary organ for sensing oxygen and carbon dioxide levels in arterial blood. Glomus cells in the carotid bodies produce the enzymes heme oxygenase 2 (HO-2), which generates carbon monoxide (CO) when oxygen levels are appropriate, and cystathionine-γ-lyase (CSE), which generates hydrogen sulfide (H2S) when oxygen levels dip.

During normal breathing during sleep, CO prevents the production of H2S by inhibiting CSE. When apnea begins and oxygen levels drop, however, CSE produces H2S, which stimulates the carotid bodies to increase breathing, heart rate and blood pressure. This leads to a sudden awakening.

carotidPrabhakar and colleagues tested two ways to manipulate this system by modulating the enzymes, CSE and HO-2, involved in CB signaling. When they gave a CSE inhibitor, L-propargyl glycine (L-PAG) by injection or by mouth to mice lacking HO-2 or rats predisposed to heightened CB activity – it reduced the frequency of apnea, underscoring the role of H2S in triggering apnea.

The response to L-PAG was “rapid, reversible, and did not result in overt toxicity within the dose range tested,” the investigators wrote. Conversely, administering CORM3 – a compound that releases carbon monoxide gas – to HO-2 deficient mice, restored normal breathing within 10 minutes. Notably, L-PAG reduced the number of both obstructive and central apneas in a dose-dependent and reversible manner.

The findings “demonstrate the salutary effects of blocking CSE during apnea and point to a potential therapeutic strategy for human sleep apnea,” according to the authors. “Our results suggest that pharmacologic targeting of the CB with a CSE inhibitor, such as L-PAG, might prevent apneas.”

These observations “provide proof-of-concept for the therapeutic potential of CSE inhibitors,” the authors wrote, but the doses of L-PAG required to normalize breathing were relatively high. More studies are needed to develop and test more potent CSE inhibitors.

“Nonetheless,” they conclude, “pharmacologic modulation of the CB chemoreflex by an inhibitor of H2S synthesis, as shown in the present study, has the potential to significantly improve the clinical management of sleep apnea.”

The study, “Gasotransmitters in Sleep Apnea: Complementary Roles of CO and H2S,” was funded by the National Institutes of Health’s Heart, Lung and Blood Institute. Additional authors were Ying-Jie Peng, Xiuli Zhang, Anna Gridina, Irina Chupikova, Gene Kim, Jayasri Nanduri and Ganesh Kumar of UChicago; David L. McCormick of IIT; Robert Thomas and Thomas Scammel of Beth Israel Deaconess; and Gregg Semenz, Chirag Vasavda and Solomon Snyder of Johns Hopkins University.


Tagged: Biological Sciences, Nanduri Prabhakar, Sleep, sleep apnea

How the chemical signals that shape animal bodies evolve

Thu, 01/19/2017 - 10:29
picture1

Representative images of Megaselia embryos with labeled RNA probes for tissue-type specific gene expression. Mab-eve is expressed in embryonic cells, Mab-doc in both amnion and serosa, and Mab-zen in serosa alone. Note the gradual repression of Mab-eve, first in the serosa and then also in the amnion. (Image: Chun Wai Kwan.)

The question of how the enormous range of animal diversity that surrounds us came to exist has fascinated scientists for centuries. Since the 1930s, Charles Darwin’s theory of evolution by natural selection has been broadly accepted as the process that shapes new species. Many people, myself included, usually imagine natural selection only during an organism’s adult lifetime – say, one finch’s beak might have superior digging power, allowing it to outcompete its fellow finches and pass on this trait to the next generation. However, an entire field of science studies evolution by examining variations in embryonic development between species, an area of work known as evolutionary developmental biology.

Two UChicago researchers in this field, Urs Schmidt-Ott, associate professor of Organismal Biology and Anatomy, and Chun Wai Kwan, a graduate student in the Schmidt-Ott lab, along with their colleagues Edwin L. Ferguson, professor of Molecular Genetics and Cell Biology, and postdoctoral scholar Jackie Gavin-Smyth (a former graduate student in the Ferguson lab), have provided evidence for a novel evolutionary mechanism during development in a study recently published in eLife.

As an embryo develops, chemical signals determine how distinct tissues form over time and space. Bone Morphogenetic Proteins (BMPs), found in organisms from fruit flies to humans, belong to a class of signaling molecules known as morphogens, essential factors in directing the arrangement of tissue types as an embryo grows. By comparing the distribution of BMP signaling during the development of two different fly species, Schmidt-Ott and his team have identified the BMP gradient as a target for evolution.

Urs Schmidt-Ott, PhD, professor of organismal biology and anatomy

During development, the fly embryo’s cells spit out BMPs into the extracellular space, where they diffuse around the embryo. Cells lining the back, or dorsal, region of the embryo carry receptors that bind the BMPs, which in turn sets off chemical signals within the cells that drive tissue specification. Generally, the intensity of BMP signaling follows a gradient pattern: most intense at the dorsal region and decreasing in magnitude in cells spread further to the sides. In Drosophila melanogaster, the fruit fly commonly used as a model organism, cells experiencing high BMP signaling early in development become an extraembryonic tissue called amnioserosa, which plays important roles in protecting the embryo and directing the movement of tissue in late developmental stages.

However, in most insects, including many fly species, BMP signaling promotes the formation of two separate tissue types, the serosa and the amnion. These extraembryonic tissues fulfil functions similar to those of the amnioserosa, as well as mediating key elements of embryo immunity. In Megaselia abdita, a fly closely related to Drosophila, the serosa develops from the most dorsal region and the amnion from surrounding tissue. As Schmidt-Ott, Kwan, and their team demonstrate in the new paper, the BMP signaling gradient in Megaselia first becomes narrow and steep, and then broadens as development progresses. By observing and manipulating levels of tissue-specific genetic markers as well as the changing BMP gradient in Megaselia embryos, they found that a positive feedback loop in pre-amnion cells amplifies BMP signaling after the serosa has begun forming, widening the range of BMP signaling and thus determining amnion.

Timing as well as spatial distribution of BMP signaling is key for the formation of distinct tissue types. In Megaselia, early low-level BMP signaling activates genes in nested domains that mark, but do not specify, the two extraembryonic tissue types. Rather, target genes of the early BMP gradient function in a positive feedback loop, first concentrating BMP signaling in the prospective serosa and then– after serosa specification – in the prospective amnion. In Drosophila, with its single extraembryonic tissue, the BMP gradient also becomes narrow and steep in the process of amnioserosa specification, but fails to broaden thereafter.

These results suggest that at some point in its evolution, Drosophila lost the broadening of the BMP gradient. Rather than identifying a gene downstream of the BMP gradient that directly produces a trait that has changed between species, this study indicates that genes responsible for the spatiotemporal dynamics of the BMP gradient during development were targeted in evolution to alter tissue. In Kwan’s words, “we found that by changing the shape of the morphogen gradient, the morphology or tissue type in different species can also change. This is a different way of looking at how evolution can occur.”

The subtlety of the interplay between extracellular signals like BMP and the responding cells, and the implications in determining animal forms demonstrated by this work support a theory of body patterning proposed by Alan Turing, the famous mathematician, in the 1950s. A simple model of signaling in development posits that a field of cells responds to a static signaling gradient. In this model, evolutionary change of tissue types or the organization of the animal’s body plan would be mediated by changing the nature of the responding cells.

As Schmidt-Ott explains it, Turing instead imagined that pattern and form depend primarily on the form of the morphogen gradients. Turing envisioned multiple diffusing signaling molecules interacting with each other in a concentration-dependent manner, and thereby defining their respective gradient shapes. By modeling the diffusion and reactivity of morphogens mathematically, he illustrated how a stable pattern can emerge from random fluctuations. From Turing’s consideration of the importance of a dynamic signaling gradient in animal body plans, the potential for a change in a morphogen gradient to advance evolution naturally follows.

“What was interesting for us here is that it was the morphogens themselves that were driving the evolutionary process,” said Schmidt-Ott. “By changing the parameters by which they are distributed in time and space, you get different animal forms.”

Next, Kwan and Schmidt-Ott plan to examine a group of flies that have two tissue types, like Megaselia, but have a reversed morphology towards the end of development – the amnion tissue ends up on the ventral side, rather than the dorsal as in Megaselia. They plan to determine whether different signaling gradients play a role in determining the ultimate arrangement of tissues as well as specifying tissue types, and to determine the genetic elements involved. They plan to pursue this goal – once again – in close collaboration with the Ferguson laboratory to combine their work with new experimental with research in Drosophila.

Schmidt-Ott hopes that these results will inspire the consideration of signaling gradients as targets of evolution more broadly.

“We could imagine this being applicable to the neural tube of vertebrates or the eyespots on butterfly wings – the same principle in which morphogens control the evolution of the complexity of a trait through feedback loops,” he said. “As evolutionary targets, feedback loops would change the dynamic of these gradients and that would provide a mechanism for diversification of the trait in question.”

Kwan and Schmidt-Ott would like to acknowledge the contributions of the additional authors on the paper, Jackie Gavin-Smyth, a postdoctoral scientist in the Reinitz lab, and Edwin L. Ferguson, professor of Molecular Genetics and Cell Biology, whose work on body patterning in Drosophila provided insight into the signaling pathway that promotes formation of amnioserosa tissue.

 


Tagged: Biological Sciences, Chun Wai Kwan, developmental biology, Evolution, evolutionary biology, molecular biology, organismal biology, Urs Schmidt-Ott

Scientists engineer animals with ancient genes to test causes of evolution

Fri, 01/13/2017 - 10:00
A transgenic fruit fly

A transgenic fruit fly engineered to carry the alcohol dehydrogenase gene as it existed about 4 million years ago. Thousands of these “ancestralized” flies were bred and studied for their ability to metabolize alcohol and to survive on an alcohol-rich food source. (Photo: Kathleen Gordon)

Scientists at the University of Chicago have created the first genetically modified animals containing reconstructed ancient genes, which they used to test the evolutionary effects of genetic changes that happened in the deep past on the animals’ biology and fitness.

The research, published early online in Nature Ecology & Evolution on Jan. 13, is a major step forward for efforts to study the genetic basis of adaptation and evolution. The specific findings, involving the fruit fly’s ability to break down alcohol in rotting fruit, overturn a widely-held hypothesis about the molecular causes of one of evolutionary biology’s classic cases of adaptation.

“One of the major goals of modern evolutionary biology is to identify the genes that caused species to adapt to new environments, but it’s been hard to do that directly, because we’ve had no way to test the effects of ancient genes on animal biology,” said Mo Siddiq, a graduate student in the Department of Ecology and Evolution at the University of Chicago, one of the study’s lead scientists.

“We realized we could overcome this problem by combining two recently developed methods—statistical reconstruction of ancient gene sequences and engineering of transgenic animals,” he said.

Until recently, most studies of molecular adaptation have analyzed gene sequences to identify “signatures of selection”—patterns suggesting that a gene changed so quickly during its evolution that selection is likely to have been the cause.  The evidence from this approach is only circumstantial, however, because genes can evolve quickly for many reasons, such as chance, fluctuations in population size, or selection for functions unrelated to the environmental conditions to which the organism is thought to have adapted.

Joe Thornton, PhD

Siddiq and his advisor, Joe Thornton, PhD, professor of ecology and evolution and human genetics at the University of Chicago, wanted to directly test the effects of a gene’s evolution on adaptation.  Thornton has pioneered methods for reconstructing ancestral genes—statistically determining their sequences from large databases of present-day sequences, then synthesizing them and experimentally studying their molecular properties in the laboratory. This strategy has yielded major insights into the mechanisms by which biochemical functions evolve.

Thornton and Siddiq reasoned that by combining ancestral gene reconstruction with techniques for engineering transgenic animals, they could study how genetic changes that occurred in the deep past affected whole organisms–their development, physiology, and even their fitness.

“This strategy of engineering ‘ancestralized animals’ could be applied to many evolutionary questions,” Thornton said.  “For the first test case, we chose a classic example of adaptation–how fruit flies evolved the ability to survive the high alcohol concentrations found in rotting fruit.  We found that the accepted wisdom about the molecular causes of the flies’ evolution is simply wrong.”

The fruit fly Drosophila melanogaster is one of the most studied organisms in genetics and evolution.  In the wild, D. melanogaster lives in alcohol-rich rotting fruit, tolerating far higher alcohol concentrations than its closest relatives, which live on other food sources. Twenty-five years ago at the University of Chicago, biologists Martin Kreitman and John McDonald invented a new statistical method for finding signatures of selection, which remains to this day one of the most widely used methods in molecular evolution.  They demonstrated it on the alcohol dehydrogenase (Adh) gene—the gene for the enzyme that breaks down alcohol inside cells—from this group of flies.  Adh had a strong signature of selection, and it was already known that D. melanogaster flies break down alcohol faster than their relatives. So, the idea that the Adh enzyme was the cause of the fruit fly’s adaptation to ethanol became the first accepted case of a specific gene that mediated adaptive evolution of a species.

Drosophila melanogaster

In the wild, D. melanogaster lives in alcohol-rich rotting fruit, tolerating far higher alcohol concentrations than its closest relatives, which live on other food sources.

Siddiq and Thornton realized that this hypothesis could be tested directly using the new technologies.  Siddiq first inferred the sequences of ancient Adh genes from just before and just after D. melanogaster evolved its ethanol tolerance, some two to four million years ago. He synthesized these genes biochemically, expressed them, and used biochemical methods to measure their ability to break down alcohol in a test tube.  The results were surprising:  the genetic changes that occurred during the evolution of D. melanogaster had no detectable effect on the protein’s function.

Working with collaborators David Loehlin at the University of Wisconsin and Kristi Montooth at the University of Nebraska, Siddiq then created and characterized transgenic flies containing the reconstructed ancestral forms of Adh.  They bred thousands of these “ancestralized” flies, tested how quickly they could break down alcohol, and how well the larvae and adult flies survived when raised on food with high alcohol content.  Surprisingly, the transgenic flies carrying the more recent Adh were no better at metabolizing alcohol than flies carrying the more ancient form of Adh.  Even more strikingly, they were no better able to grow or survive on increasing alcohol concentrations. Thus, none of the predictions of the classic version of the story were fulfilled. There is no doubt that D. melanogaster did adapt to high-alcohol food sources during its evolution, but not because of changes in the Adh enzyme.

“The Adh story was accepted because the ecology, physiology, and the statistical signature of selection all pointed in the same direction. But three lines of circumstantial evidence don’t make an airtight case,” Thornton said. “That’s why we wanted to test the hypothesis directly, now that we finally have the means to do so.”

Siddiq and Thornton hope that the strategy of making ancestralized transgenics will become the gold standard in the field to decisively determine the historical changes in genes to their changes on organisms’ biology and fitness.

For his part, Kreitman, who is still a professor of ecology and evolution at UChicago, has been supportive of the new research, helping advise Siddiq on the project and sharing his vast knowledge about molecular evolution and Drosophila genetics.

“From the beginning, Marty was excited about our experiments, and he was just as supportive when our results overturned well-known conclusions based on his past work,” Siddiq said. “I think that’s extremely inspiring.”

The study, “Experimental test and refutation of a classic case of molecular adaptation in Drosophila melanogaster,” was supported by the National Science Foundation, the National Institutes of Health, the Howard Hughes Medical Institute, and the Life Sciences Research Foundation.


Tagged: Biological Sciences, ecology and evolution, Evolution, fruit flies, Genetics, Joe Thornton, Mo Siddiq

Universal flu vaccines could offer key benefits over seasonal shots

Thu, 01/05/2017 - 10:30

20131105_Flu drill_0674

Universal vaccines that protect against multiple strains of influenza (flu) virus at once could offer substantial advantages over conventional seasonal flu vaccines, when deployed on a large scale in the human population, according to research published in PLOS Computational Biology. The new study from the University Chicago, Princeton University and Imperial College London demonstrates potential effects of new vaccines that target multiple flu strains using mathematical modeling.

Current flu vaccines provide good protection, but only if they are well matched against a specific flu strain. Flu-causing viruses are continually evolving and cause annual epidemics. Scientists must update vaccines regularly to provide protection against whichever seasonal strains pose the greatest health risk. To keep from updating the vaccines every year, researchers are now working to develop universal vaccines that could protect against multiple flu strains instead.

According to the Centers for Disease Control, it is not possible to predict with certainty if the vaccine will be a good match for circulating viruses. The vaccine is made to protect against the flu viruses that research and surveillance indicate will be most common. However, experts pick which viruses to include in the vaccine many months in advance in order for vaccine to be produced on time.

In addition, every few decades a new virus emerges in the human population that causes a global pandemic, and the current flu vaccines cannot be used to protect the population against the next pandemic virus.

“There are certain proteins that are shared across a wide range of flu viruses. Only now with recent advances in biotechnology has it been possible to develop vaccines targeting these ‘conserved antigens’,” said UChicago graduate student Rahul Subramanian, the lead author of the study.

These universal flu vaccines currently being developed in the laboratory could protect against a broad range of seasonal flu viruses without having to be updated, as well as protecting against pandemic flu strains.

Research on universal flu vaccines has mostly focused on their potential effects in individual patients. To better understand their effects at the population level, Subramanian and colleagues mathematically modeled the interactions between vaccination, flu transmission and flu virus evolution.

“We asked the question – How would a universal flu vaccination program compare against a similar program using only current flu vaccines?” said Subramanian. “We wanted to know how would each compare in their ability to control seasonal flu, reduce the pace of flu evolution, and protect against the next influenza pandemic.”

The model revealed that deployment of universal vaccines across large populations could reduce flu transmission more effectively than conventional flu vaccines. It could also slow the evolution of new strains of flu virus and bolster the immunity of a population, allowing protection against the emergence of dangerous pandemic strains.

“New flu vaccines could, for the first time, maintain their effectiveness in the face of viral evolution,” said Subramanian. “In doing so they could transform the way we manage flu in future.”

However, when conventional vaccines are well matched against circulating flu strains they are highly effective at blocking infection and are likely to continue to play an important role. Strategic decisions about their deployment, alongside novel vaccines, could be guided by anticipated population impact, as well as their effectiveness in individuals.

“Our work suggests an optimal approach may be to strategically use universal vaccines alongside conventional vaccines to protect the health at-risk groups while promoting immune defense of the whole population,” said Subramanian.

Additional authors include Andrea Graham and Bryan Grenfell from Princeton University, and Nimalan Arinaminpathy from Imperial College London. This work was supported by: Health Grand Challenges Program, Center for Health and Wellbeing, Princeton University; Bob and Cathy Solomon Undergraduate Research Fund, Princeton Environmental Institute, Princeton University, and MRC Centre for Outbreak Analysis and Modeling.


Tagged: Biological Sciences, computational modeling, flu vaccine, health, Infectious Disease, influenza, mathematics, Rahul Subramanian, universal vaccine, vaccines

280 million-year-old fossil reveals origins of chimaeroid fishes

Wed, 01/04/2017 - 12:00

High-definition CT scans of the fossilized skull of a 280 million-year-old fish reveal the origin of chimaeras, a group of cartilaginous fish related to sharks. Analysis of the brain case of Dwykaselachus oosthuizeni, a shark-like fossil from South Africa, shows telltale structures of the brain, major cranial nerves, nostrils and inner ear belonging to modern-day chimaeras.

This discovery, published early online in Nature on Jan. 4, allows scientists to firmly anchor chimaeroids—the last major surviving vertebrate group to be properly situated on the tree of life—in evolutionary history, and sheds light on the early development of these fish as they diverged from their deep, shared ancestry with sharks.

“Chimaeroids belong somewhere close to the sharks and rays, but there’s always been uncertainty when you search deeper in time for their evolutionary branching point,” said Michael Coates, PhD, professor of organismal biology and anatomy at the University of Chicago, who led the study.

“Chimaeras are unusual throughout the long span of their fossil record,” Coates said. “Because of this, it’s been difficult to understand how they got to be the way they are in the first place. This discovery sheds new light not only on the early evolution of shark-like fishes, but also on jawed vertebrates as a whole.”

 

vertebrate family tree

Chimaeras include about 50 living species, known in various parts of the world as ratfish, rabbit fish, ghost sharks, St. Joseph sharks or elephant sharks. They represent one of four fundamental divisions of modern vertebrate biodiversity. With large eyes and tooth plates adapted for grinding prey, these deep-water dwelling fish are far from the bloodthirsty killer sharks of Hollywood.

For more than 100 years, they have fascinated biologists. “There are few of the marine animals that on account of structure and relationships to other forms living and extinct have as great interest for zoologists and palaeontologists as the Chimaeroids,” wrote Harvard naturalist Samuel Garman in 1904. More than a century later, the relationship between chimaeras, the earliest sharks, and other early jawed fishes in the fossil record continues to puzzle paleontologists.

Chimaeras—named for their similarities to a mythical creature described by Homer as “lion-fronted and snake behind, a goat in the middle”—are unusual. Their anatomy comprises features reminiscent of sharks, ray-finned fishes and tetrapods, and their form is shaped by hardened bits of cartilage rather than bone. Because they are found in deep water, they were long considered rare. But as scientists gained the technology to explore more of the ocean, they are now known to be widespread, but their numbers remain uncertain.

After a 2014 study detailing their extremely slow-evolving genomes was published in Nature, interest in chimaeras blossomed. Of all living vertebrates with jaws, chimaeras seemed to offer the best promise of finding an archive of information about conditions close to the last common ancestor of humans and a Great White.

Like sharks, also reliant on cartilage, chimaeras rarely fossilize. The few known early chimaera fossils closely resemble their living descendants. Until now, the chimaeroid evolutionary record consisted mostly of isolated specimens of their characteristic hyper-mineralized tooth plates.

Rock nodule containing the Dwyka fossil Rock nodule containing the Dwyka fossil Rock nodule containing the Dwyka fossil Rock nodule containing the Dwyka fossil Roy Oosthuizen

The Dwykaselachus fossil resolves this issue. It was originally discovered by amateur paleontologist and farmer Roy Oosthuizen when he split open a nodule of rock on his farm in South Africa in the 1980s. An initial description named it based on material visible at the broken surface of the nodule. It was carefully archived in the South African Museum in Cape Town, where its splendor awaited technology able to unwrap its long-shrouded secrets.

In 2013, when the University of the Witwatersrand Evolutionary Studies Institute obtained a micro CT scanner, Dr. Robert Gess, a South African Centre of Excellence in Palaeosciences partner and co-author of this study, began scanning Devonian shark fossils while he was based at the Rhodes University Geology Department. Coates encouraged him to investigate Dwykaselachus.

Reconstruction of Dwykaselachus oosthuizeni

Reconstruction of Dwykaselachus oosthuizeni (Image: Kristen Tietjen)

At the surface, Dwykaselachus appeared to be a symmoriid shark, a bizarre group of 300+ million-year-old sharks, known for their unusual dorsal fin spines, some resembling boom-like prongs and others surreal ironing boards.

CT scans showed that the Dwykaselachus skull was remarkably intact, one of a very few that had not been crushed during fossilization. The scans also provide an unprecedented view of the interior of the brain case.

“When I saw it for the first time, I was stunned,” Coates said. “The specimen is remarkable.”

The images, one reviewer commented, are “almost dripping with data.”

They show a series of telltale anatomical structures that mark the specimen as an early chimaera, not a shark. The braincase preserves details about the brain shape, the paths of major cranial nerves and the anatomy of the inner ear. All of which indicate that Dwyka belongs to modern-day chimaeras. The scans reveal clues about how these fish began to diverge from their common ancestry with sharks.

A large extinction of vertebrates at the end of the Devonian period, about 360 million years ago, gave rise to an explosion of cartilaginous fishes. Instead of what became modern-day sharks, Coates said, revelations from this study indicate that “much of this new biodiversity was, instead, early chimaeras.”

“We can now say that the first radiation of cartilaginous fishes after the end Devonian extinction was chimaeras, in abundance.” Coates said. “It’s the inverse of what we’ve got today, where sharks are far more common.”

The study, “A symmoriiform chondrichthyan braincase and the origin of chimaeroid fishes,” was supported by the National Science Foundation, the National Research Foundation (NRF) / Department of Science and Technology South African Centre of Excellence in Palaeosciences, and the NRF African Origins Programme. Additional authors include John Finarelli from the University College Dublin, Ireland, and Katharine Criswell and Kristen Tietjen from the University of Chicago.


Tagged: Biological Sciences, chimaeras, Evolution, fossils, Michael Coates, paleontology, sharks
Dwykaselachus oosthuizeni CT scan