$100 million gift establishes Duchossois Family Institute to develop ‘new science’ focused on optimizing health
A Chicago-area family with a deep commitment to supporting science and medicine is giving $100 million to establish The Duchossois Family Institute at the University of Chicago Medicine, which seeks to accelerate research and interventions based on how the human immune system, microbiome and genetics interact to maintain health.
The gift from The Duchossois Group Inc. Chairman and CEO Craig Duchossois, his wife, Janet Duchossois, and The Duchossois Family Foundation will support development of a “new science of wellness” aimed at preserving health and complementing medicine’s traditional focus on disease treatment. Their investment will help build an entrepreneurial infrastructure that stimulates research, data integration, and clinical applications, while educating the next generation of young physicians and students in this new science.
By providing resources and research infrastructure, The Duchossois Family Institute: Harnessing the Microbiome and Immunity for Human Health will allow faculty and students to focus on preventing disease by optimizing the body’s own defenses and finding new ways to maintain well-being. With the embedded expertise of the university’s Polsky Center for Entrepreneurship and Innovation, they will work aggressively to bring breakthroughs to market through partnerships with industry, venture capitalists, government agencies, like-minded philanthropists, and the public.
“The Duchossois Family Institute will draw on the creativity and skill of university researchers across many fields in bringing new perspectives to medical science, oriented toward making an impact that greatly benefits human lives,” said University of Chicago President Robert J. Zimmer. “We are grateful for the Duchossois family’s remarkable level of engagement in establishing this innovative alliance between medical experts and entrepreneurs.”
The amount is the largest single gift in support of UChicago Medicine and brings the family’s lifetime charitable contributions to the academic medical center to $137 million. Ludwig Institute for Cancer Research has donated a total of $118 million since 2006, largely to support cancer research.
The Duchossois gift is also the fourth time there has been a single gift of $100 million or more to the University of Chicago. The Thomas L. Pearson and The Pearson Family Members Foundation made a grant of $100 million in 2015 to establish The Pearson Institute for the Study and Resolution of Global Conflicts and The Pearson Global Forum at the Harris School of Public Policy, and an anonymous donor gave $100 million in 2007 to fund the Odyssey Scholarship Program in support of undergraduate student aid. The university’s largest gift to date is $300 million in 2008 from investment entrepreneur David Booth, for whom UChicago’s Booth School of Business is named.‘New science of wellness’
Until now, much of the research on the microbiome — the community of bacteria, fungi, viruses and other microorganisms living in the body, primarily the digestive tract — and its relation to human health has focused on its relationship to disease. Recent discoveries, many at the University of Chicago, demonstrate that the genetic material encoded within the microbiome is a critical factor in fine-tuning the immune system and can be powerful in maintaining well-being and preventing disease. New computer technology to integrate and analyze vast amounts of biological and medical data — pioneered by the National Cancer Institute Genomic Data Commons, developed and operated by the university — also is allowing researchers from disparate disciplines and locations to work toward common interests and solutions.
The Duchossois (pronounced DUCH-ah-swah) family wanted to support the application of these discoveries to improve health, and turned to leaders at the University of Chicago for ideas.
“We wanted to find a way to be transformative in our giving and looked to the University of Chicago and asked, ‘What is the nature of what’s in our bodies that helps us stay well?’” said Ashley Duchossois Joyce, president of The Duchossois Family Foundation. “They came back with an answer that connected all the dots, confirming the potential for a new science of wellness that fundamentally explores how the immune system and microbiome interact.”
Focusing on factors crucial to maintaining wellness could greatly expand the tools available to medical researchers and entrepreneurs. Early targets identified by institute scientists envision a potential future in which:
- Peanuts, milk and eggs could safely return to school menus.
- Children with asthma play outside, confident they can breathe without inhalers.
- Inexpensive sensors help families adjust their homes to optimize health.
- Doctors guide patients to foods and probiotics to win the fight against obesity.
- Technologies pinpoint the microbes needed to treat and prevent autoimmune diseases.
- Probiotics and prebiotics improve the effectiveness of cancer and antidepressant drugs.
- Judiciously used antibiotics reduce the impact of Alzheimer’s disease.
The institute will build on insights already gained from research at the University of Chicago.
“The family recognized the university’s and medical center’s leadership in genomics, the human immune system, data analytics and the microbiome,” said T. Conrad Gilliam, dean for basic science in the Division of the Biological Sciences, who will lead efforts to launch the institute. “The new institute will integrate these areas into this new science focused on longstanding health and the body’s natural ability to maintain wellness.”
The Duchossois Family Institute will support leading-edge technologies and services including:
- A clinical repository to maintain biological samples
- Microbial cultivation and analysis tools
- Next-generation platform to identify biomarkers that mediate between the microbiome and immune system
- Medicinal chemistry to pinpoint biomarkers and develop more effective therapies
- High-throughput genetic sequencing for microbial DNA
- A data commons for sharing large amounts of microbial, environmental and medical information
The Duchossois Family Institute’s efforts will bring together investigators across the University of Chicago as well as affiliates at Argonne National Laboratory, Marine Biological Laboratory at Woods Hole, Mass., and eventually many more partners.
In addition, the university will embed commercialization specialists from its Polsky Center for Entrepreneurship and Innovation within the institute to promote participation and support of the business community to further accelerate innovation. Polsky’s proven expertise will ensure that the intellectual property generated is protected, licensed, and potentially spun off for business development for the benefit of participating institutions and the entire region.
“Sustainability and entrepreneurship are critical to the success of this new endeavor,” said Craig Duchossois, a longtime trustee of both the university and the medical center. “The fact that we are able to leverage so many resources at one university means we can aggressively advance the progress of this new science and help society.”A history of giving
The latest gift continues a history of giving to UChicago that spans 37 years, inspired by the care that Beverly Duchossois, late wife of Richard Duchossois, received at what was then called the University of Chicago Hospital. In 1980, Richard Duchossois established the Beverly E. Duchossois Cancer Fund in memory of his wife.
In the years since, the family has given the University a total of $37 million to drive innovation and transformative care at the medical center, including a named professorship and several cancer research funds. That amount includes a $21 million gift in 1994 to establish the Duchossois Center for Advanced Medicine, which is home to outpatient specialty clinics, diagnostic centers and treatment facilities at the University of Chicago Medicine.
“We are honored and privileged to be the beneficiary of such enormous generosity and are excited by what the science can accomplish,” said Kenneth S. Polonsky, MD, dean of the Division of the Biological Sciences and the Pritzker School of Medicine and executive vice president of medical affairs. “The gift invests in a core strength of UChicago Medicine: our basic science research and our ability to quickly translate that research for the benefit of patients.”
In addition to Craig Duchossois’ service as a trustee, Janet Duchossois serves as a member of the University of Chicago Women’s Board. The Duchossois Family Foundation is made up of family members spanning three generations including patriarch Richard; son and daughter-in-law, Craig and Janet; daughters Kimberly Duchossois, a University of Chicago Cancer Research Foundation board member, and Dayle Fortino; and grandchildren, including Ashley Duchossois Joyce, a University of Chicago graduate and former member of the School of Social Service Administration Visiting Committee, Jessica Swoyer Green and Ilaria Woodward.Press Kit
Additional information, including facts about the Duchossois Family Institute and quotes from the Duchossois family, UChicago leadership and faculty:
For media inquiries, please contact the University of Chicago Medicine news office.About the University of Chicago Medicine
The University of Chicago Medicine & Biological Sciences is one of the nation’s leading academic medical institutions. It comprises the Pritzker School of Medicine, a top U.S. medical school; the University of Chicago Biomedical Sciences Division; and the University of Chicago Medical Center. Twelve Nobel Prize winners in physiology or medicine have been affiliated with the University of Chicago Medicine.About The Duchossois Family Foundation
Established in 1984 by first- and second-generation family members, The Duchossois Family Foundation strives to empower individuals to enhance their quality of life through wellness and education. Visit their website at TheDFF.org.
Tagged: big data, Biological Sciences, Genetics, immune system, immunology, microbiome, philanthropy, The Duchossois Family Institute
Analysis of a 3.3 million-year-old fossil skeleton reveals the most complete spinal column of any early human relative, including vertebrae, neck and rib cage. The findings, published this week in the Proceedings of the National Academy of Sciences, indicate that portions of the human spinal structure that enable efficient walking motions were established millions of years earlier than previously thought.
The fossil, known as “Selam,” is a nearly complete skeleton of a 2½ year-old child discovered in Dikika, Ethiopia in 2000 by Zeresenay (Zeray) Alemseged, professor of organismal biology and anatomy at the University of Chicago and senior author of the new study. Selam, which means “peace” in the Ethiopian Amharic language, was an early human relative from the species Australopithecus afarensis—the same species as the famous Lucy skeleton.
In the years since Alemseged discovered Selam, he and his lab assistant from Kenya, Christopher Kiarie, have been preparing the delicate fossil at the National Museum of Ethiopia. They slowly chipped away at the sandstone surrounding the skeleton and used advanced imaging tools to further analyze its structure.
“Continued and painstaking research on Selam shows that the general structure of the human spinal column emerged over 3.3 million years ago, shedding light on one of the hallmarks of human evolution,” Alemseged said. “This type of preservation is unprecedented, particularly in a young individual whose vertebrae are not yet fully fused.”
Many features of the human spinal column and rib cage are shared among primates. But the human spine also reflects our distinctive mode of walking upright on two feet. For instance, humans have fewer rib-bearing vertebrae – bones of the back – than those of our closest primate relatives. Humans also have more vertebrae in the lower back, which allows us to walk effectively. When and how this pattern evolved has been unknown until now because complete sets of vertebrae are rarely preserved in the fossil record.
“For many years we have known of fragmentary remains of early fossil species that suggest that the shift from rib-bearing, or thoracic, vertebrae to lumbar, or lower back, vertebrae was positioned higher in the spinal column than in living humans. But we have not been able to determine how many vertebrae our early ancestors had,” said Carol Ward, a Curator’s Distinguished Professor of Pathology and Anatomical Sciences in the University of Missouri School of Medicine, and lead author on the study. “Selam has provided us the first glimpse into how our early ancestors’ spines were organized.”
In order to be analyzed, Selam had to take a trip. She traveled to the European Synchrotron Radiation Facility in Grenoble, France, where Alemseged and the research team used high-resolution imaging technology to visualize the bones.
“This technology provides the opportunity to virtually examine aspects of the vertebrae otherwise unattainable from the original specimen,” said coauthor of the study Fred Spoor, a professor of evolutionary anatomy in the Department of Biosciences at the University College London.
The scans indicated that Selam had the distinctive thoracic-to-lumbar joint transition found in other fossil human relatives, but the specimen is the first to show that, like modern humans, our earliest ancestors had only twelve thoracic vertebrae and twelve pairs of ribs. That is fewer than in most apes.
“This unusual early human configuration may be a key in developing more accurate scenarios concerning the evolution of bipedality and modern human body shape,” said Thierra Nalley, an assistant professor of anatomy at Western University of Health Sciences in Pomona, California, also an author on the paper.
This configuration marks a transition toward the type of spinal column that allows humans to be the efficient, athletic walkers and runners we are today.
“We are documenting for the first time in the fossil record the emergence of the number of the vertebrae in our history, when the transition happened from the rib-bearing vertebrae to lower back vertebrae, and when we started to extend the waist,” Alemseged said. “This structure and its modification through time is one of the key events in the history of human evolution.”
The study, “Thoracic Vertebral Count and Thoracolumbar Transition in Australopithecus afarensis” was supported by Margaret and Will Hearst, the National Science Foundation and the European Synchrotron Radiation Facility.
Jeff Sossamon from the University of Missouri contributed to this story
Tagged: Biological Sciences, Ethiopia, Evolution, fossils, human evolution, paleoanthropology, paleontology, Selam, Zeray Alemseged
In 2015, scientists announced they had discovered 15 skeletons of an unusual new species of human cousins, clustered together deep in a remote chamber of the Rising Star cave system in South Africa. Homo naledi, as the species was named, was an enigma to researchers. Some of its features, like its long legs, small teeth and dexterous wrists, resembled modern humans; but its small brain size and curved fingers suggested it was more closely related to our ape-like Australopithecus ancestors.
This week we have one answer about the history of these fossils: how old they are. In a series of papers published in the journal eLife, a team led by Professor Lee Berger of The University of the Witwatersrand in Johannesburg, South Africa, announced that the Homo naledi fossils are between 335,000 and 236,000 years old. That means these primitive, long-lost cousins lived at the same time as Homo sapiens, the first time it has been shown that another species of hominin survived alongside the first humans in Africa.
Myra Laird, a postdoctoral scholar at the University of Chicago, worked on the project, studying the features of the Homo naledi skulls and comparing them to other fossils to determine whether a new set of specimens, found in second cave near the original site, were of the same species. She began the work as a graduate student at New York University, and continued after she moved to UChicago, where she also published a paper about the skull in the Journal of Human Evolution last fall.
One of the most memorable moments, Laird said, was putting together the face of Neo, one of the newly discovered skulls.
“Fossil hominins rarely preserve the face because the bones are quite fragile, so it was really exciting when my colleagues and I finally pieced together the bones of the face,” she said. “We all stood back and just stared for a couple of minutes. It was like fitting the final piece into a complicated puzzle.”
Tagged: Biological Sciences, Evolution, Homo naledi, Myra Laird, paleoanthropology, paleontology
Neil H. Shubin, PhD, the Robert R. Bensley Distinguished Service Professor of Organismal Biology and Anatomy and Associate Dean for Academic Strategy at the University of Chicago, has been elected to the American Philosophical Society. Members are nominated and elected by their peers in the Society.
Founded by Benjamin Franklin in 1743, the APS is the nation’s oldest learned society. An eminent, internationally known scholarly organization, the American Philosophical Society “promotes useful knowledge in the sciences and humanities through excellence in scholarly research.”
Shubin was elected for his discoveries involving the evolution of limbs and the transition from water to dry land. One of his most significant discoveries, the 375-million-year-old Tiktaalik roseae fossil, is an important transitional form between fish and land animals.
Shubin, Who was elected to the National Academy of Sciences in 2011, has written two popular science books: the best-selling “Your Inner Fish” (2008), named best book of the year by the National Academy of Sciences and made into a celebrated PBS series, and “The Universe Within: The Deep History of the Human Body” (2013). He spent much of last December and January hunting for fossils in Antarctica.
Two other current or former University of Chicago faculty members were also elected to the APS this year: Michael S. Turner, the Bruce V. and Diana M. Rauner Distinguished Service Professor and director of the Kavli Institute for Cosmological Physics; and former law school senior lecturer, Barack Obama, the 44th President of the United States.
Tagged: American Philosophical Society, Biological Sciences, Evolution, Neil Shubin, paleontology
A study involving more than 600 children living in a small village in southeast Gabon, near the border with the Republic of Congo, found that each infected child in one African village had a different strain of the malaria parasite and a distinctly different set of the up to 60 genes that the human immune system focuses on to detect and control this infection.
The findings help explain why people can’t develop immunity to malaria and indicate that control programs should now focus on looking at the impact not just on the number of infections but the structure of diverse strains of the parasite.
Researchers from the University of Melbourne and the University of Chicago, working with scientists from the US, Europe and Australia, published their findings in the journal PNAS on May 1, 2017.
“The study began with collection of blood from 641 children, aged 1 to 12 years, living in the small village of Bakoumba, Gabon. Children in the area are frequently exposed to malaria, receiving about 100 bites from infected mosquitos each year,” said study author Karen Day, Professor of Population Science and Dean of Science, University of Melbourne.
“We produced a genetic fingerprint of malaria parasites from small amounts of blood based on what are called var or variant antigen genes. These genes encode proteins that coat the surface of the red blood cells when infected by a parasite, and are important because they allow the parasite to disguise itself from the human immune system,” added Prof. Day.
The malaria parasite is a single-celled microorganism (known as a Plasmodium) that infects red blood cells and is transferred from human to human via mosquitoes. Every parasite has approximately 60 of these var genes and can switch between them.
“Looking down the microscope you would think all of the infections look the same, but when we did the genetic fingerprinting with this variant antigen gene system, we could see that every child had a different parasite fingerprint, and importantly, each fingerprint was highly unrelated to all other fingerprints.”
“Our results show that the parasite has evolved this enormous diversity with limited overlap between the sets of var genes. This structure allows each parasite to look different to the immune system, and provides the possibility for the malaria parasite to keep re-infecting the same people because it exists as different “strains” that can persist for many months.
Computer analyses of the variation in these sets of genes and how they might respond to control efforts with anti-malarial drugs showed that these patterns were not random. The extremely high level of diversity helps explain how the parasite evades its host’s immune system.
The non-random pattern has “implications for the success of malaria-control programs,” the authors note. It supports the notion that a large number of strains of the disease, each characterized by a significantly different combination of surface-coat proteins, could result in many children remaining infected even after aggressive efforts to intervene, such as mass drug administration.
“If strain theory is correct,” said study author Mercedes Pascual, PhD, professor of ecology and evolution at the University of Chicago, “we would want to rethink how we approach treatment for malaria in regions such as Gabon, where multiple highly diverse strains are the rule. Also, we would need to rethink how we model malaria transmission, rather than relying on existing mathematical models designed for a much less diverse parasite population.”
“There are tens of thousands of different var gene types,” Pascual said. “Some are conserved and others are highly variable.” Are parasites basically random combinations, a random mixture of all this variation, or are they instead different combinations with a special structure?
When she and colleagues analyzed gene sequences of multiple parasites they found a structure of minimal overlap, far less than expected.
“They form niches,” Pascual said. “They diversify. They try not to compete with each other, to distance themselves from each other. This opens the way to a better understanding of the parasites’ success, a clue to help us disrupt its persistence,” she said. “But it can be difficult to intervene in a system with such a diverse ensemble of strains.”
The researchers are now var code fingerprinting and modelling malaria strains in larger human populations through time. Dr Kathryn Tiedje, a researcher in Professor Day’s team at the University of Melbourne and one of the study authors, is currently looking at how control methods might impact the diversity of malaria.
“Will reducing the prevalence of malaria in any way reshape the var gene diversity,” she asked, “and can interventions also reduce the number of malaria strains in the population?”
“Ultimately, the question we all want to answer is, how can we defeat humanity’s most unrelenting enemy?”
The National Institutes of Health, including the Fogarty International Center and the National Institute of Allergy and Infectious Diseases, funded this study. Additional authors were Karen P. Day, Kathryn E. Tiedje, Virginie Rougeron, Donald Chen and Thomas S. Rask from the University of Melbourne, Australia and formerly New York University; Yael Artzy-Randrup from the University of Amsterdam, the Netherlands; Mary M. Rorick, from the University of Michigan; and Florence Migot-Nabiasi, Philippe Deloroni, and Adrian J. F. Luty from Institut de Recherche pour le Développement, UMR 216 Mère et EnfantFace aux Infections Tropicales, 75006 Paris, France; Virginie Rougeron from the Université de Montpellier, France.
Tagged: Africa, Biological Sciences, Gabon, Global Health, Infectious Disease, malaria, Mercedes Pascual
Artist Kentaro Yamada wanted to contribute something positive to the world, so he created The Uplifted photography project. The series highlights “joy, accomplishment and success” through portraits of leaders and visionaries levitating objects that represent their life’s work.
Several UChicago physicians and researchers are among the first 100 subjects captured for the project, and in this video we go behind the scenes as Kentaro photographs neuroscientists Sliman Bensmaia and Nicho Hatsopoulos, and biologist Marcus Kronforst.
Photos from The Uplifted will be on display on the bridge between Bernard A. Mitchell Hospital and the Duchossois Center for Advanced Medicine until the end of May. You can also see more of Kentaro’s work at TheUplifted.net, and on Facebook and Instagram.
Tagged: Biological Sciences, butterflies, Kentaro Yamada, Marcus Kronforst, Neuroscience, Nicho Hatsopoulos, photography, prosthetics, Sliman Bensmaia, The Uplifted
Currently, only a small minority of cancers has a known relationship between mutation and treatment that can inform today’s clinical decisions. The University of Chicago is at the epicenter of the search for new cancer targets and therapies in the massive — and rapidly growing — data of the National Cancer Institute (NCI).
The Genomic Data Commons (GDC), led by Robert Grossman, PhD, the Frederick H. Rawson Professor in Medicine and the College and chief research informatics officer for the Biological Sciences Division, launched in June 2016 with an announcement by Vice President Joe Biden. In the months since, the GDC has expanded to hold over five petabytes of data, accessed by more than 1,500 users a day.
The GDC unlocks the potential of the NCI’s vast archive of genomic and clinical data. Because these datasets have grown too large for most laboratories to download or analyze, the GDC provides a centralized and standardized repository and advanced tools so that researchers can work remotely. By working with this extensive data, scientists can find subtle cancer-related genetic effects and probe whether various combinations of drugs might be effective for particular cancer subtypes.
Since the launch of the GDC, Grossman has also led the development of a new commons for cancer data called the Blood Profiling Atlas for Cancer (BloodPAC), which will be a home for liquid biopsy data with the goal of accelerating the discovery of new biomarkers. Future projects will apply the data commons concept to other conditions, such as psychological disorders and traumatic brain injuries.
“We’re trying to change the way scientific discoveries are made by democratizing access to this large-scale data,” Grossman said. “We’ve been happy to see our community develop tools that allow these kinds of discoveries to be made on software applications that run on researchers’ desktop computers, with the needed data streaming from the GDC in real time.”
But data is only half the story. Fulfilling the promise of personalized medicine will also require powerful computation, beyond even the level of today’s most powerful supercomputers.
As part of the Exascale Computing Project, a Department of Energy initiative to push the frontier of supercomputer speed to one quintillion (or a billion billion) calculations per second, researchers at UChicago and Argonne National Laboratory will help extract clinically relevant discoveries from the huge and rapidly growing landscape of cancer data. The CANcer Distributed Learning Environment, or CANDLE, will develop “deep learning” methods” — similar to those used to train self-driving cars — on clinical, experimental and molecular data in the hope of finding new hypotheses, drug targets and treatments for different types of cancers.
“It’s a huge computational problem,” said principal investigator Rick Stevens, PhD, associate laboratory director for computing, environment and life sciences at Argonne and professor of computer science at UChicago. “We have lots of data — millions of millions of experiments and expression data from 20,000 patients. But the models we need are still an open question. Once we train and develop the models, clinics can deploy them on relatively small systems and start using models to predict which drugs to give to a given patient.”
This is the second 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, Genomic Data Commons, machine learning, Rick Stevens, Robert Grossman
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.
“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.”Recommended for you
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
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.
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.
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
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.
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
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.”
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.
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.”
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
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.
The 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.
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
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.
“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
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.”
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
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
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.
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.
“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.”
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
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.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
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