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  • Stephen J. Galli, MD, to Receive 2024 American Society for Investigative Pathology Gold-Headed Cane Award

    Stephen J. Galli, MD, to Receive 2024 American Society for Investigative Pathology Gold-Headed Cane Award

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    Newswise — May 3, 2023 — The 2024 recipient of the American Society for Investigative Pathology (ASIP) Gold-Headed Cane Award is Dr. Stephen J. Galli, Professor of Pathology, Microbiology and Immunology, and Mary Hewitt Loveless, MD, Professor in the Stanford University School of Medicine (Stanford, CA).

    The ASIP Gold-Headed Cane Award is the society’s oldest and most prestigious award (first awarded in 1919). This award recognizes significant long-term (lifetime) contributions to the field of pathology, including meritorious experimental pathology research, outstanding teaching, general excellence in the discipline, demonstrated leadership in the field, and engagement in the activities of the ASIP. 

    Dr. Galli earned a BA magna cum laude in biology from Harvard College in 1968, a BMS with Honors from Dartmouth Medical School in 1970, and an MD from Harvard Medical School in 1973. Subsequently, Dr. Galli completed residency training in the Department of Pathology at the Massachusetts General Hospital (1973-1976), where he served as Chief Resident in 1976. Dr. Galli completed several research fellowships during the course of his training. He was appointed the Karin Grunebaum Cancer Research Foundation Fellow while working with Dr. Richard A. Adams at the Dan-Farber Cancer Institute (1971-1972). From 1974-1976, Dr. Galli worked with Dr. Harold Dvorak in the Department of Pathology at the Massachusetts General Hospital. Finally, he was supported by the Medical Foundation Inc for work at the Harvard Medical School and Massachusetts General Hospital from 1977-1978. In 1978, Dr. Galli was appointed as an Instructor in Pathology at the Massachusetts General Hospital and Harvard Medical School, and was subsequently promoted through the ranks at Harvard Medical School: Assistant Professor of Pathology in 1979, Associate Professor of Pathology in 1983, and Professor of Pathology in 1993. In 1999, Dr. Galli was appointed as Professor of Pathology and of Microbiology and Immunology, and the Mary Hewitt Loveless MD Professor in the School of Medicine at Stanford University, and became the Chair of the Department of Pathology. He remained Chair of Pathology at Stanford University until 2016, and remains active on the faculty today. Throughout his academic career, Dr. Galli has held numerous hospital appointments, including most recently Chief of Pathology Service and Director of the Pathology Residency Program at the Stanford University Medical Center. Dr. Galli has provided time and effort towards teaching at each of his institutions and across all of his faculty appointments. This teaching encompasses classroom teaching, clinical education for pathology residents, as well as teaching in the setting of the research laboratory for various kinds of learners. His efforts towards quality educational programs continued as he became Chair of Pathology at Stanford where he initiated and directed the development of many new educational programs.

    Dr. Galli joined the American Society for Investigative Pathology in 1982 and has been active in the Society since that time. He has made significant contributions to the Society over time. Dr. Galli served as the Chair of a Task Force on Research and Training Opportunities in Pathology from 1999-2000. The report from this task force was exceptionally well prepared and contained recommendations for the Society that remain valid until today, nearly twenty years later. Dr. Galli was elected into the Presidential succession in 2003 and served as Vice President (2003-2004), President-elect (2004-2005), President (2005-2006), and Past President (2006-2007). Dr. Galli was an exceptional member of the ASIP Council, always thoughtful and intentional with important decisions for the Society. Dr. Galli has provided excellent counsel to the leaders of the ASIP (elected and staff) over the years, even during times when he was not serving in an official capacity. Dr. Galli continues as an engaged member of the ASIP, currently serving on the Committee for Equal Representation and Opportunity and is a member of the newly formed President’s Circle.

    Dr. Galli has served the larger pathology community in a number of ways over the course of his career. He previously served as Associate Editor of The Journal of Immunology (1980-1984), as Advisory Editor for The Journal of Experimental Medicine (1993-2011), on the Editorial Board of The Journal of Allergy and Clinical Immunology (1996-2001), Transmitting Editor (2001-2009) and then Associate Editor (2009-2013) for International Immunology. He is currently serving on the Editorial 2 Board of Allergology International (since 1995), Laboratory Investigation (since 1997), and on the Board of Consulting Editors of the Journal of Clinical Investigation. In addition, Dr. Galli serves on the Editorial Committee for the Annual Review of Pathology: Mechanisms of Disease (since 2004). Dr. Galli has organized or co-organized 18 major national/international meetings. Most recently, he organized the 65th Annual Meeting of the Pluto Club (The American Association of University Pathologists) in Catagena, Columbia (March 2019). Dr. Galli has given significant time as a grant reviewer for the NIH, as a member of several study sections over the years, and as a member of expert panels. From 1999-2001, he chaired the NIH/NIAID Hyper-ID Scientific Review Group. Between 2019 and 2023, Dr. Galli served as Vice Chair and then Chair of the Membership Committee for the National Academy of Medicine.

    Dr. Galli has received a number of honors and awards in recognition of his excellent research and leadership within the pathology community. He was elected to the Collegium Internationale Allergologicum in 1984, to membership in the Pluto Society (Association of University Pathologists) in 1986, to the American Society for Clinical Investigation in 1991, and to the Association of American Physicians in 1997. In 2001, Dr. Galli was elected as a Foreign Member in the Physical, Mathematical, and Natural Sciences Class of the Accademia Nazionale dei Lincei. Dr. Galli was elected to the Institute of Medicine of the National Academies in 2010. Stanford University awarded Dr. Galli the President’s Award for Excellence Through Diversity in 2010. In addition, Dr. Galli received the Faculty Mentor Award for Postdoctoral Education from the Immunology Program at the Stanford University School of Medicine in 2010. In 2011, Dr. Galli received the Scientific Achievement Award from the World Allergy Organization. In 2014, Dr. Galli received the ASIP Rous-Whipple Award from the American Society for Investigative Pathology and the Karl Landsteiner Medal from the Austrian Society of Allergology and Immunology. In 2015, he was elected to membership in the American Clinical and Climatological Association. In 2017, Dr. Galli was elected to membership in Sigma Xi, and became an Overseas Fellow of the Royal Society of Medicine. In 2019, Dr. Galli was granted an honorary PhD in clinical and experimental medicine (Dottorato di Ricerca Honoris Causa in Medicina Clinica e Sperimentale) from the University of Naples Federico II, and was elected as a Foreign Member of the Societa Nazionale di Scienze Lettere e Arti (academy of Medical Sciences) in Naples, Italy. In 2020, Dr. Galli received the Distinguished Career Achievement Award from the Geisel School of Medicine at Dartmouth University (Hanover, NH). In 2022, Dr. Galli received the Lifetime Honorary Membership Award from Stanford Healthcare, and was inducted into the Alpha Omega Alpha Honor Medical Society at Stanford University School of Medicine.

    Dr. Galli’s research laboratory is interested in mast cell and basophil development and function, allergy and allergic disorders, and inflammation associated with allergic reactions. The work from Dr. Galli’s laboratory is high impact and he is regarded as an international expert in his area of research. He has given many invited lectures based upon his research around the US and abroad. His laboratory has been and continues to be very well-funded. He received a Merit Award from the National Institute of Allergy and Infectious Diseases (1995-2006). Currently, Dr. Galli is PI for a large U19 grant from the NIH/NIAID to conduct clinical trials using oral immunotherapy for childhood multi-food allergies (2019-2024). He is also PI for two R01 grants and a co-investigator on a third R01 grant. His CV lists numerous completed research projects associated with extramural funding. Dr. Galli’s research has been extremely productive over the course of his career. He holds 15 US patents for scientific developments from his laboratory. He has published 294 original research papers, 194 book chapters and reviews, 14 commentaries and meeting reports, and a few other works (reports for the National Academies). Dr. Galli’s research is highly impactful. His H-index is 133 and his papers have been cited >77,000 times. In addition to his contributions to the scientific literature, Dr. Galli has edited 12 books, including 9 volumes of the Annual Review of Pathology: Mechanisms of Disease. It is difficult to describe the remarkable body of work from Dr. Galli’s laboratory in a few sentences, and he continues to add to this body of work today.

    The letters contained in the nomination package expounded on Dr. Galli’s many contributions as an academic leader and exceptional educator, a national and international leader in the field, but also his major contributions to research throughout his career and to-date. Dr. Elaine Jaffe (NIH Distinguished Investigator, Laboratory of Pathology, National Cancer Institute/NIH) described Dr. Galli and his scientific stature in the field of experimental pathology: “He is a pathologist at the pinnacle of our discipline…His scientific achievements are outstanding…His pioneering and innovative work dealing with basic immunology and in particular the function of mast cells and basophils has been continually supported by NIH grants during the course of his career…” Dr. Tom Montine (Stanford Medicine Endowed Professor in Pathology and Chair, Department of Pathology, Stanford University School of Medicine) reinforced the impact of Dr. Galli’s research: “…Professor Galli’s research focuses on the development and function of mast cells and basophils, and the roles of these cells in health and disease. His work has had a major impact on our understanding of anaphylaxis, food allergies, and asthma, and on innate and acquired host defense against venoms. It would be difficult to over-estimate the impact that Professor Galli has had on the filed of allergy and immunology…”

    Dr. Irv Weissman (Professor of Pathology and Developmental Biology, Stanford University School of Medicine) summarized Dr. Galli’s contributions to the larger field of experimental pathology nicely: “…Dr. Galli is a longtime leader in bringing pathology to the forefront of the medical sciences…Dr. Galli is an academic visionary, and a national and international leader…” and “…Dr. Galli is the world’s leading researcher in the investigation of the biology and pathology of mast cells…”

    Dr. Galli will receive the 2024 ASIP Gold-Headed Cane Award during the 2024 Annual Meeting of the ASIP in Baltimore, MD (April 2024).

     

    About the American Society for Investigative Pathology

    The American Society for Investigative Pathology is comprised of biomedical scientists who investigate mechanisms of disease. Investigative pathology is an integrative discipline that links the presentation of disease in the whole organism to its fundamental cellular and molecular mechanisms. It uses a variety of structural, functional, and genetic techniques and ultimately applies research findings to the diagnosis and treatment of diseases. ASIP advocates for the practice of investigative pathology and fosters the professional career development and education of its members.

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    Federation of American Societies for Experimental Biology (FASEB)

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  • Quantum-Enhanced Microscope Doubles Resolution

    Quantum-Enhanced Microscope Doubles Resolution

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    Newswise — Using a “spooky” phenomenon of quantum physics, Caltech researchers have discovered a way to double the resolution of light microscopes.

    In a paper appearing in the journal Nature Communications, a team led by Lihong Wang, Bren Professor of Medical Engineering and Electrical Engineering, shows the achievement of a leap forward in microscopy through what is known as quantum entanglement. Quantum entanglement is a phenomenon in which two particles are linked such that the state of one particle is tied to the state of the other particle regardless of whether the particles are anywhere near each other. Albert Einstein famously referred to quantum entanglement as “spooky action at a distance” because it could not be explained by his relativity theory.

    According to quantum theory, any type of particle can be entangled. In the case of Wang’s new microscopy technique, dubbed quantum microscopy by coincidence (QMC), the entangled particles are photons. Collectively, two entangled photons are known as a biphoton, and, importantly for Wang’s microscopy, they behave in some ways as a single particle that has double the momentum of a single photon.

    Since quantum mechanics says that all particles are also waves, and that the wavelength of a wave is inversely related to the momentum of the particle, particles with larger momenta have smaller wavelengths. So, because a biphoton has double the momentum of a photon, its wavelength is half that of the individual photons.

    This is key to how QMC works. A microscope can only image the features of an object whose minimum size is half the wavelength of light used by the microscope. Reducing the wavelength of that light means the microscope can see even smaller things, which results in increased resolution.

    Quantum entanglement is not the only way to reduce the wavelength of light being used in a microscope. Green light has a shorter wavelength than red light, for example, and purple light has a shorter wavelength than green light. But due to another quirk of quantum physics, light with shorter wavelengths carries more energy. So, once you get down to light with a wavelength small enough to image tiny things, the light carries so much energy that it will damage the items being imaged, especially living things such as cells. This is why ultraviolet (UV) light, which has a very short wavelength, gives you a sunburn.

    QMC gets around this limit by using biphotons that carry the lower energy of longer-wavelength photons while having the shorter wavelength of higher-energy photons.

    “Cells don’t like UV light,” Wang says. “But if we can use 400-nanometer light to image the cell and achieve the effect of 200-nm light, which is UV, the cells will be happy, and we’re getting the resolution of UV.”

    To achieve that, Wang’s team built an optical apparatus that shines laser light into a special kind of crystal that converts some of the photons passing through it into biphotons. Even using this special crystal, the conversion is very rare and occurs in about one in a million photons. Using a series of mirrors, lenses, and prisms, each biphoton—which actually consists of two discrete photons—is split up and shuttled along two paths, so that one of the paired photons passes through the object being imaged and the other does not. The photon passing through the object is called the signal photon, and the one that does not is called the idler photon. These photons then continue along through more optics until they reach a detector connected to a computer that builds an image of the cell based on the information carried by the signal photon. Amazingly, the paired photons remain entangled as a biphoton behaving at half the wavelength despite the presence of the object and their separate pathways.

    Wang’s lab was not the first to work on this kind of biphoton imaging, but it was the first to create a viable system using the concept. “We developed what we believe a rigorous theory as well as a faster and more accurate entanglement-measurement method.  We reached microscopic resolution and imaged cells.”

    While there is no theoretical limit to the number of photons that can be entangled with each other, each additional photon would further increase the momentum of the resulting multiphoton while further decreasing its wavelength.

    Wang says future research could enable entanglement of even more photons, although he notes that each extra photon further reduces the probability of a successful entanglement, which, as mentioned above, is already as low as a one-in-a-million chance.

    The paper describing the work, “Quantum Microscopy of Cells at the Heisenberg Limit,” appears in the April 28 issue of Nature Communications. Co-authors are Zhe He and Yide Zhang, both postdoctoral scholar research associates in medical engineering; medical engineering graduate student Xin Tong (MS ’21); and Lei Li (PhD ’19), formerly a medical engineering postdoctoral scholar and now an assistant professor of electrical and computer engineering at Rice University.

    Funding for the research was provided by the Chan Zuckerberg Initiative and the National Institutes of Health.

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    California Institute of Technology

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  • Improved Gene Editing Method Could Power the Next Generation of Cell and Gene Therapies

    Improved Gene Editing Method Could Power the Next Generation of Cell and Gene Therapies

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    Newswise — PHILADELPHIA— A new approach to the genetic engineering of cells promises significant improvements in speed, efficiency, and reduction in cellular toxicity compared to current methods. The approach could also power the development of advanced cell therapies for cancers and other diseases, according to a study from researchers in the Perelman School of Medicine at the University of Pennsylvania.

    In the study, which appeared this week in Nature Biotechnology, researchers found that protein fragments used by some viruses to help them get into cells could also be used to get CRISPR-Cas gene editing molecules into cells and their DNA-containing nuclei with extraordinarily high efficiency and low cellular toxicity.

    The scientists expect the new technique to be particularly useful for modifying T cells and other cells from a patient’s own body to make cell therapies. One such application could be CAR T (chimeric antigen receptor T cell) therapy, which uses specially modified immune cells from a patient to treat cancer. The T cells—a type of white blood cell—are removed from the patient and reprogrammed to find and attack cancer cells when reintroduced to the bloodstream.  

    The first FDA-approved CAR T therapy was developed at Penn Medicine, and received Food & Drug Administration approval in 2017. There are now six FDA-approved CAR T cell therapies in the United States. The therapies have revolutionized the treatment of certain B cell leukemias, lymphomas, and other blood cancers, putting many patients who otherwise had little hope into long-term remission.

    “This new approach—building on Penn Medicine’s history of cell and gene therapy innovation—has the potential to be a major enabling technology for engineered cellular therapies,” said co-senior author E. John Wherry, PhD, Richard and Barbara Schiffrin President’s Distinguished Professor and chair of Systems Pharmacology & Translational Therapeutics at Penn Medicine.

    CRISPR-Cas molecules are derived from ancient bacterial antiviral defenses, and are designed to precisely remove DNA at desired locations in a cell’s genome. Some CRISPR-Cas-based systems combine the deletion of old DNA with the insertion of new DNA for versatile genome editing. This approach can be used to replace faulty genes with corrected ones or delete or modify genes to enhance cellular function. Some systems can also add genes that confer new properties to CAR T cells such as the ability to recognize tumors or withstand the harsh tumor microenvironment that normally exhausts T cells.

    Although CRISPR-Cas systems are already widely used as standard laboratory tools for molecular biology, their use in modifying patients’ cells to make cell-based therapies has been limited—in part because CRISPR-Cas molecules can be hard to get into cells and then into cells’ DNA-containing nuclei.

    “Current methods of getting CRISPR-Cas systems into cells, which include the use of carrier viruses and electric pulses, are inefficient for cells taken directly from patients (called primary cells). These methods also typically kill many of the cells they are used on, and can even cause broad unwanted changes in gene activity,” said co-senior author Shelley L. Berger, PhD, the Daniel S. Och University Professor in Cell and Developmental Biology and Genetics and director of the Penn Epigenetics Institute.

    In the study, researchers explored the use of small, virus-derived protein fragments, called peptides, to pilot CRISPR-Cas molecules more efficiently through the outer membranes of primary human cells and into their nuclei. Notably, researchers found that a fused combination of two modified peptides—one found in HIV and one in influenza viruses—could be mixed with CRISPR-Cas molecules to get them into primary human or mouse cells and their nuclei with efficiencies of up to nearly 100 percent, depending on the cell type—with almost no toxicity or gene-expression changes.

    The team demonstrated the approach, which they call PAGE (peptide-assisted genome editing), for several types of envisioned cell therapy including CAR T cell therapies.

    In addition to its potential use in cell and gene therapies, the authors note the PAGE approach could see wide application in basic scientific research. The inefficiency of standard CRISPR-Cas cell penetration methods has meant that gene-editing to create mouse models of diseases typically requires a multi-step, time-consuming process of generating transgenic mice—to introduce the gene-editing machinery into their DNA. By contrast, PAGE with its high efficiency and low toxicity might enable rapid, efficient, and straightforward gene editing in ordinary lab mice.

    “The simplicity and power of the peptide-assist concept suggests that it could potentially be adapted in the future for the delivery into primary cells of other genome-editing proteins, or even protein-based drugs,” said co-senior author Junwei Shi, PhD, an assistant professor of Cancer Biology and member of the Penn Epigenetics Institute and Abramson Family Cancer Research Institute.

    The study was a collaboration that included the laboratories of Penn co-author Rahul Kohli, MD, PhD, an associate professor of Infectious Diseases and Biochemistry and Biophysics, and co-author Gerd Blobel, MD, PhD, the Frank E. Weise III Professor of Pediatrics and co-director of the Epigenetics institute.

    This study was supported by the National Institute of Health (R01-HL119479, R01-GM138908, AI105343, AI082630, AI108545, AI155577, AI149680, U19AI082630, R35-CA263922, R01-CA258904), the Parker Institute for Cancer Immunotherapy, and institutional funds from University of Pennsylvania.

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    Perelman School of Medicine at the University of Pennsylvania

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  • New MRI method images brain glucose metabolism

    New MRI method images brain glucose metabolism

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    Newswise —

    Metabolic disorders are involved in many common health conditions such as Alzheimer’s, depression, diabetes, and cancer. Non-invasive diagnostic methods are needed to reliably detect these disorders. Until now, radioactive substances have been used to map glucose metabolism in the brain. However, a research team at MedUni Vienna has developed a new MRI approach that uses a harmless glucose solution to generate reliable results. This new method can be used with all common MRI scanners and has been published in the scientific journal Nature Biomedical Engineering.

    The research team conducted a study to improve current diagnostic methods for mapping brain glucose metabolism. They measured blood glucose levels and metabolic products in healthy subjects multiple times over 90 minutes, using a harmless glucose solution instead of radiolabeled glucose. This method indirectly measured the concentrations and metabolism of glucose based on changes in signal intensity for the product. Unlike other approaches, this method does not require additional hardware components, making it easy to use with other MRI devices. Wolfgang Bogner from MedUni Vienna explained the significance of this finding for clinical practice.

    Broad range of potential applications

    The study was conducted by researchers from the Department of Psychiatry and Psychotherapy and the Department of Medicine III at MedUni Vienna, using the university’s 7-Tesla MRI scanner, which is the only ultra-high-field MR scanner in Austria. The researchers were able to demonstrate that their new approach also works on 3-Tesla MR scanners, which are commonly used in clinical applications. This finding was an important step in validating the practicality and widespread applicability of the new method. Fabian Niess, the lead author of the follow-up study, highlighted the significance of this development.

    Further studies needed to confirm results

    Many common diseases are characterized by abnormalities in glucose metabolism. For example, cancer and tumor cells consume more glucose than normal cells, which is used in diagnosing and locating tumors through PET-CT scans. However, this requires injecting patients with radioactive glucose. While the new, less invasive MRI method developed at MedUni Vienna shows promise, further studies are needed to validate its effectiveness before it can be used for patient benefit.

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    Medical University of Vienna (MedUni Wien)

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  • New APS Leaders Take Office at Inaugural American Physiology Summit

    New APS Leaders Take Office at Inaugural American Physiology Summit

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    Newswise — Long Beach, Calif. (April 23, 2023)—The American Physiological Society (APS) is pleased to announce its new member leaders for 2023–24: President Willis K. “Rick” Samson, PhD, DSc, FAPS; President-elect Timothy Musch, PhD, FAPS, FACSM; and Councilors Michael Caplan, MD, PhD, FAPS; Karla Haack, PhD; and Gina Yosten, PhD. The new officers were elected by APS membership and took office April 23, 2023, at the American Physiology Summit, APS’ flagship annual meeting, in Long Beach, California.

    Willis K. “Rick” Samson, PhD, DSc, FAPS, is professor of pharmacology and physiology and director of biomedical science graduate programs in the School of Medicine at Saint Louis University (SLU). He earned his bachelor’s degree in chemistry from Duke University in Durham, North Carolina; his PhD from the University of Texas Health Science Center at Dallas; and his DSc from Westminster College in Fulton, Missouri. Samson is the vice chair of the SLU School of Medicine’s Pharmacology and Physiology Department. He has served on numerous study sections and editorial boards for a number of scientific organizations and journals.

    Samson served the Society on the APS Council from 2016 to 2019 and was a member of the Joint Program and Public Affairs committees as well as the Committee on Committees. He is also a former member of the Endocrinology & Metabolism Section Steering Committee. Samson is a past associate editor and editor-in-chief for the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology and is currently deputy editor of Physiological Reviews. He has been a Fellow of the American Physiological Society (FAPS) since 2015.

    Timothy Musch, PhD, FAPS, FACSM, is a University Distinguished Professor in the Departments of Kinesiology and Anatomy & Physiology at Kansas State University. He earned his PhD in exercise physiology from the University of Wisconsin and completed postdoctoral work at the University of Texas Southwestern Medical School in Dallas.

    Musch’s service to the Society includes prior roles as councilor, chair of the Animal Care & Experimentation Committee and the Committee on Committees, and as a member of the Public Affairs, Education, Fellows, Membership, Nominating, Section Advisory and Strategic Planning committees. He is on the editorial boards of the Journal of Applied Physiology and the American Journal of Physiology-Heart and Circulatory Physiology. Musch was the Guyton Educator of the Year in 2013 and received FAPS status in 2016.

    Michael Caplan, MD, PhD, FAPS, is the C.N.H. Long Professor and chair of the Department of Cellular and Molecular Physiology at the Yale University School of Medicine in New Haven, Connecticut. He earned his MD and PhD degrees from Yale University. Caplan has been honored with awards for his work in renal physiology from numerous organizations, including APS, the American Society of Nephrologists and the National Science Foundation. Caplan is editor-in-chief of the journal Physiology and is a member of the Physiology Summit Leadership Committee. He received FAPS status in 2019.

    Karla Haack, PhD, is a medical writer at Merck and Co., where she collaboratively authors pre-approval regulatory documents. Prior to joining Merck in 2021, Haack taught anatomy and physiology and pathophysiology courses at Kennesaw State University (KSU) in Georgia. She earned her PhD in molecular biology from Georgia Institute of Technology and completed postdoctoral research at the University of Nebraska Medical Center. Haack was a member of the College of Science and Mathematics Inclusion and Diversity Committee and liaison to the chief diversity officer at KSU. She is the outgoing chair of the APS Diversity, Equity & Inclusion Committee.

    Gina Yosten, PhD, is a tenured associate professor of pharmacology and physiology at SLU, where she also earned her PhD. She is a longtime APS member and has served the Society in multiple capacities, including as the chair of the Endocrinology & Metabolism Section and a member of the Section Advisory and Joint Program committees. Yosten is the editor-in-chief of the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology and was APS’ 2023 Henry Pickering Bowditch Award Lecturer.

    Physiology is a broad area of scientific inquiry that focuses on how molecules, cells, tissues and organs function in health and disease. The American Physiological Society connects a global, multidisciplinary community of more than 10,000 biomedical scientists and educators as part of its mission to advance scientific discovery, understand life and improve health. The Society drives collaboration and spotlights scientific discoveries through its 16 scholarly journals and programming that support researchers and educators in their work.

     

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    American Physiological Society (APS)

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  • Improved control of blood sugar levels

    Improved control of blood sugar levels

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    Newswise — Patients with type 1 diabetes live with a constant risk of hyper- or hypoglycemia. Precisely controlled insulin release could help to improve regulation of their blood sugar levels. In the journal Angewandte Chemie, a research team has now introduced a novel insulin formulation that can be switched on by glucose: Lipid nanoparticle carriers release more or less insulin depending on the blood sugar level.

    In our bodies, the insulin level in our plasma is primarily regulated by β-cells in the pancreas and reflects fluctuations in the blood sugar level. Patients with type 1 diabetes can produce very little or no insulin and require several daily injections of a fast-acting insulin as well as one or two injections of a long-acting insulin to keep their blood sugar at a normal level. Alternatively, they wear an insulin pump that provides continuous infusion. The insulin formulations cannot react to changes in the blood sugar level and thus do not allow for the precise regulation of blood sugar. If an insulin overdose is administered, a meal is missed, or too little carbohydrate consumed before strenuous physical activity, there is increased risk of acute, life-threatening hypoglycemia.

    Insulin formulations that respond to glucose, mimicking the function of β-cells, could improve insulin therapy. Various approaches with insulin “carriers” made of polymers with incorporated glucose oxidase as a glucose detector suffer from two problems: The polymer carriers are not of uniform molecular weight and glucose oxidase is toxic if released into the body.

    A Chinese team led by Jinqiang Wang and Zhen Gu at Zhejiang University, Zhejiang Cancer Hospital, and the University of Hong Kong chose a different approach based on biocompatible lipid nanoparticles used as carriers with lipids with uniform chemical structures. Lipid nanoparticles are already in wide clinical use as drug carriers.

    A section of the lipids was modified so that the surfaces of the self-aggregated nanoparticles carry many positive charges. Insulin molecules with a negative charge electrostatically bind to the nanoparticles and are released slowly when the blood sugar level is normal. If the blood sugar level is high, certain lipids in the nanoparticles form chemical bonds with the glucose, reducing the positive charge at the surface and significantly accelerating the release of insulin. In diabetic mice treated with the new insulin formulation, it was possible to maintain a normal blood sugar level for six hours. After injection of glucose, the blood sugar in the treated diabetic mice decreased to a normal level just as rapidly as that of healthy mice.

    In the Future, a combination of this glucose-responsive insulin formulation with a dispensation device controlled by a wearable electronic sugar detector could significantly improve regulation of the blood sugar level in diabetes patients.

     

    About the Author

    Dr Zhen Gu is a Qiushi Distinguished Chair Professor and Dean of the College of Pharmaceutical Sciences at Zhejiang University (China). His research is focused on the design of bioinspired materials for physiological-signal-responsive drug delivery for treating various diseases including cancer and diabetes.

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    Wiley

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  • Safe Bioink for Artificial Organ Printing

    Safe Bioink for Artificial Organ Printing

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    Newswise — The development of biomaterials for artificial organs and tissues is active due to an increase in accidental injuries and chronic diseases, along with the entry into a super-aged society. 3D bioprinting technology, which uses cells and biomaterials to create three-dimensional artificial tissue structures, has recently gained popularity. However, commonly used hydrogel-based bioinks can cause cytotoxicity due to the chemical crosslinking agent and ultraviolet light that connect the molecular structure of photocuring 3D-printed bioink.

    Dr. Song Soo-chang’s research team at the Center for Biomaterials, Korea Institute of Science and Technology (KIST, President Yoon Seok-jin), revealed the first development of poly(organophosphazene) hydrogel-based temperature-sensitive bioink that stably maintained its physical structure only by temperature control without photocuring, induced tissue regeneration, and then biodegraded in the body after a certain period of time.

    Current hydrogel-based bioinks must go through a photocuring process to enhance the mechanical properties of the 3D scaffold after printing, with a high risk of adverse effects in the human body. In addition, there have been possibility of side effects by transplanting externally cultured cells within bioink to increase the tissue regeneration effect. Accordingly, the research team developed a new bioink material using a temperature-sensitive poly(organophosphazene) hydrogel, which existed in a liquid form at low temperatures and changed to a hard gel at body temperature. This enabled the regeneration of tissues only by temperature control without chemical crosslinking agents or UV irradiation and the manufacture of a three-dimensional scaffold with a physically stable structure, minimizing the possibility of immune adverse effects in the human body.

    The developed bioink also had a molecular structure that could interact with growth factors, which were proteins that help in tissue regeneration to preserve growth factors that regulated cell growth, differentiation, and immune responses for a long period of time. The research team was able to maximize the effect of tissue regeneration by creating an environment in which cell differentiation could be autonomously regulated within the 3D scaffold printed with bioink.

    The research team fabricated the 3D scaffold by printing it with a 3D bioprinter using bioink containing transforming growth factor beta 1 (TGF-β1) and bone morphogenetic protein-2 (BMP-2), which were required for cell infiltration and bone regeneration, and conducted an experiment by implanting it into a damaged bone in a rat. As a result, cells from the surrounding tissue were migrated into the scaffold, and the defected bone was regenerated to a normal tissue level, and the implanted 3D scaffold slowly biodegraded in the body over 42 days.

    Dr. Song Soo-Chang of KIST said, “The research team has transferred technology for the thermo-sensitive polyphosphazene hydrogel to NexGel Biotech Co., Ltd. in June 2022, and the development of products such as bone graft materials and cosmetic fillers is underway.” “As the bioink developed this time has different physical properties, follow-up research to apply it to the regeneration of other tissues besides bone tissue is being conducted, and we expect to finally be able to commercialize bioink tailored to each tissue and organ,” he said.

     

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    KIST was established in 1966 as the first government-funded research institute in Korea. KIST now strives to solve national and social challenges and secure growth engines through leading and innovative research. For more information, please visit KIST’s website at https://eng.kist.re.kr/

    This research was conducted through the KIST Major Projects supported by the Ministry of Science and ICT (Minister Lee Jong-ho), and the research results were published as the inside back cover in the latest issue of “Small” (IF: 15.153, top 7.101% in the JCR field), an international academic journal in the field of materials.

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    National Research Council of Science and Technology

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  • Blind dating in bacteria evolution

    Blind dating in bacteria evolution

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    Newswise — Proteins are the key players for virtually all molecular processes within the cell. To fulfil their diverse functions, they have to interact with other proteins. Such protein-protein interactions are mediated by highly complementary surfaces, which typically involve many amino acids that are positioned precisely to produce a tight, specific fit between two proteins. However, comparatively little is known about how such interactions are created during evolution.

    Classical evolutionary theory suggests that any new biological feature involving many components (like the amino acids that enable an interaction between proteins) evolves in a stepwise manner. According to this concept, each tiny functional improvement is driven by the power of natural selection because there is some benefit associated with the feature. However, whether protein-protein interactions also always follow this trajectory was not entirely known.

    Using a highly interdisciplinary approach, an international team led by Max Planck researcher Georg Hochberg from the Terrestrial Microbiology in Marburg have now shed new light on this question. Their study provides definitive evidence that highly complementary and biologically relevant protein-protein interactions can evolve entirely by chance.

    Proteins cooperate in a photoprotection system

    The research team made their discovery in a biochemical system that microbes use to adapt to stressful light conditions. Cyanobacteria use sunlight to produce their own food through photosynthesis. Since much light damages the cell, cyanobacteria have evolved a mechanism known as photoprotection: if light intensities become dangerously high, a light intensity sensor named Orange Carotenoid Protein (OCP) changes its shape. In this activated form, OCP protects the cell by converting excess light energy into harmless heat. In order to return into its original state, some OCPs depend on a second protein: The Fluorescence Recovery Protein (FRP) binds to activated OCP1 and strongly accelerates its recovery.

    ‘Our question was: Is it possible that the surfaces that allow these two proteins to form a complex evolved entirely by accident, rather than through direct natural selection?’ says Georg Hochberg. ‘The difficulty is that the end result of both processes looks the same, so we usually cannot tell why the amino acids required for some interaction evolved – through natural selection for the interaction or by chance. To tell them apart, we would need a time machine to witness the exact moment in history these mutations occurred, ’Georg Hochberg explains.

    Luckily, recent breakthroughs in molecular and computational biology has equipped Georg Hochberg and his team with a laboratory kind of time machine: ancestral sequence reconstruction. In addition, the light protection system of cyanobacteria, which is under study in the group of Thomas Friedrich from Technische Universität Berlin since many years, is ideal for studying the evolutionary encounter of two protein components. Early cyanobacteria acquired the FRP proteins from a proteobacterium by horizontal gene transfer. The latter had no photosynthetic capacity itself and did not possess the OCP protein.

    To work out how the interaction between OCP1 and FRP evolved, graduate student Niklas Steube inferred the sequences of ancient OCPs and FRPs that existed billions of years ago in the past, and then resurrected these in the laboratory. After translation of the amino acid sequences into DNA he produced them using E. coli bacterial cells in order to be able to study their molecular properties.

    A fortunate coincidence

    The Berlin team then tested whether ancient molecules could form an interaction. This way the scientists could retrace how both protein partners got to know each other. ‘Surprisingly, the FRP from the proteobacteria already matched the ancestral OCP of the cyanobacteria, before gene transfer had even taken place. The mutual compatibility of FRP and OCP has thus evolved completely independently of each other in different species, says Thomas Friedrich. This allowed the team to prove that their ability to interact must have been a happy accident: selection could not plausibly have shaped the two proteins’ surfaces to enable an interaction if they had never met each other. This finally proved that such interactions can evolve entirely without direct selective pressure.

    ‘This may seem like an extraordinary coincidence,’ Niklas Steube says. ‘Imagine an alien spaceship landed on earth and we found that it contained plug-shaped objects that perfectly fit into human-made sockets. But despite the perceived improbability, such coincidences could be relatively common. But in fact, proteins often encounter a large number of new potential interaction partners when localisation or expression patterns change within the cell, or when new proteins enter the cell through horizontal gene transfer.’ Georg Hochberg adds, ‘Even if only a small fraction of such encounters ends up being productive, fortuitous compatibility may be the basis of a significant fraction of all interactions we see inside cells today. Thus, as in human partnerships, a good evolutionary match could be the result of a chance meeting of two already compatible partners.’

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    Max Planck Society (Max-Planck-Gesellschaft)

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  • Fred Hutch at AACR: New targets for cancer therapies, experts available in diversity and cancer screening tests — and Fred Hutch’s Philip Greenberg becomes AACR president

    Fred Hutch at AACR: New targets for cancer therapies, experts available in diversity and cancer screening tests — and Fred Hutch’s Philip Greenberg becomes AACR president

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    Newswise — SEATTLE — April 6, 2023 — Experts from Fred Hutchinson Cancer Center will present their latest findings on targets in RIT1-driven cancers, ROR1 CAR T-cell immunotherapy, interplay of the microbiome and genetics in colorectal cancer and more at the annual meeting of the American Association for Cancer Research, to be held April 14-19 in Orlando, Florida. 

    Other meeting highlights include:

    Philip Greenberg, M.D. of Fred Hutch will become AACR president.

    Public health researcher and biostatistician Ruth Etizioni, Ph.D. will discuss new and emerging tests for early detection of cancer.

    Christopher Li, M.D., MPH, a national leader in diversity, equity and inclusion efforts at cancer centers, will best practices and strategies to enhance diversity. 

    Below are highlights of work to be presented, and you can follow Fred Hutch’s AACR updates on Twitter #AACR23.

    For media requests during AACR, please contact . 

    AACR news

    Meet and Greet: Meet the editors-in-chief of Cancer Immunology Research Monday, April 17, 2023, 9:30-10:30 a.m. 

    Meeting: Meet the 2023-2024 AACR President, Philip Greenberg Tuesday, April 18, 2023, 1:30-2:30 p.m.

    Fred Hutch’s Philip Greenberg, M.D., one of two editors-in-chief of AACR’s Cancer Immunology Research, will participate in an April 17 discussion of the scope and types of research manuscripts they’re looking to publish. Greenberg, currently president-elect of AACR, will become AACR president during the meeting and be at the April 18 “Meet the 2023-2024 AACR President” session. He leads the Program in Immunology at Fred Hutch and holds the Rona Jaffe Foundation Endowed Chair.  

    Early detection and screening

    Educational session: How can we realize the promise of novel technologies for early cancer detection? Presentation: Developing realistic expectations for new cancer screening tests Friday, April 14, 2023, 3:01-3:21 p.m. Presenter: Ruth Etzioni, Ph.D.

    Public health researcher and biostatistician Ruth Etzioni, Ph.D. will join an educational session to talk about novel cancer screening tests based on liquid biopsies, with a particular focus on multi-cancer early detection testing. She said that while there are some studies that show how well the tests detect different cancers, the extent to which this will translate into lives saved is still unclear. Etzioni, who holds the Rosalie and Harold Rea Brown Endowed Chair at Fred Hutch and received a $7.4 million National Cancer Institute grant to study cancer diagnostics, will discuss the process by which population screening leads to reduction in cancer deaths, why some past cancer screening trials have led to disappointing results and what needs to be done now to generate convincing evidence that population screening using the new tests will reduce cancer deaths. 

    Precision oncology

    Educational session: Tumor heterogeneity: Rapid autopsy to longitudinal biopsies Presentation: Intra and inter-tumor heterogeneity across cancer metastases: A reality check for targeted therapeutics and the utility of non-invasive biomarkers Saturday, April 15, 2023, 3:16-3:33 p.m. Presenter: Peter Nelson, M.D.

    In a session on the use of rapid autopsies to understand cancer metastasis, Peter Nelson, M.D. will discuss the impact of tumor heterogeneity on treatment resistance. Nelson, who is a prostate cancer expert and is the vice president of Precision Oncology at Fred Hutch, will also explain how studies of metastatic tumors improve our understanding of molecular imaging such as PET scans as well as minimally-invasive diagnostic methods including circulating tumor DNA. Nelson directs the Stuart and Molly Sloan Precision Oncology Institute at Fred Hutch and holds an endowed chair with the same name.  

    Session: Small cell lung cancer: Moving biology to the clinic Presentation: Measuring and modulating SCLC transcriptional heterogeneity from murine models to clinical trials Monday, April 17, 2023, 1:00-1:20 p.m. Presenter: Joseph Hiatt, M.D., Ph.D. (On Twitter and LinkedIn)

    Physician-scientist Joseph Hiatt, M.D., Ph.D. will give an update on Fred Hutch preclinical research that has identified a molecular pathway that could make more cases of small cell lung cancer responsive to checkpoint inhibition. The approach is now being studied in a clinical trial. Hiatt, who is a research fellow in the MacPherson lab at Fred Hutch, will also present a new liquid biopsy method to predict subtypes of small cell lung cancer using cell-free DNA. This could be used to link patients’ subtypes to their treatment outcomes to help personalize clinical trial enrollment. The work is part of the Fred Hutch Lung Specialized Project of Research Excellence (SPORE), a five-year $13 million grant from the National Cancer Institute to expedite lung cancer research from the lab to the clinic. 

    Session: Ras-related signaling Poster: Protein-level regulation of wild-type and mutant RIT1 by the deubiquitinase USP9X Monday, April 17, 2023, 1:30-5 p.m. Presenter: Amanda Riley (On LinkedIn)

    Mutations in the gene RIT1 account for about 13,500 cases of non-small cell lung cancer diagnoses each year, with limited treatment options. Graduate student Amanda Riley, working in the Fred Hutch lab of Alice Berger, Ph.D., will give an update on their work to find targeted therapies for RIT1-driven cancers. They’ve identified a regulator of RIT1, a protein called USP9X. Using mouse models and existing inhibitors of USP9X, the researchers are evaluating this potential drug target. The project is part of Berger’s 7-year NIH MERIT award to pursue targeted therapies for mutations in lung cancer. Berger holds the Innovators Network Endowed Chair at Fred Hutch, follow her on Twitter. 

    Cancer biology

    Major symposium: Targeting RNA splicing in cancer and the immune system Presentation: From splicing to polyadenylation in tumor immunity Sunday, April 16, 2023, 1:55-2:15 p.m. Presenter: Robert Bradley, Ph.D. (On Twitter)

    Computational biologist and biophysicist Robert Bradley, Ph.D. will present new work on a biological process that’s growing in attention for its role in controlling cancer growth. Alternative polyadenylation is part of making mRNA and it’s disrupted in many cancers, though it’s not clear how the dysregulation contributes to tumors. Bradley, who holds the McIlwain Family Endowed Chair in Data Science at Fred Hutch, will discuss a CRISPR-Cas9-based screen to test the functional importance of alternative polyadenylation to tumor growth. 

    Cellular immunotherapy

    Minisymposium: Genetically engineered anticancer T cells Presentation: NKTR-255, a polymer-conjugated IL-15, dramatically improves ROR1 CAR-T cell persistence and anti-tumor efficacy in an autochthonous model of ROR1+ lung cancer Sunday, April 16, 2023, 4:10-4:25 p.m. Presenter: Sam Nutt

    Using a mouse model of lung cancer that closely resembles human disease, graduate student Sam Nutt in the Fred Hutch lab of Shivani Srivastava, Ph.D. (on Twitter) will present a study on whether NKTR-255, a drug that stimulates the immune system to fight cancer, can improve the anticancer effects of chimeric antigen receptor (CAR) T cells. The Fred Hutch team is using a CAR-T cell targeting the tumor antigen ROR1, which is a marker on many breast and lung cancer patients. Their findings suggest that NKTR-255 treatment improves the persistence and function of ROR1 CAR T cells, and that these two therapies work together to boost immune function in the tumor microenvironment, resulting in significantly improved tumor control. The team is continuing to evaluate the combined approach for treatment of solid tumors. Read more about the lab’s work to develop cellular therapies for solid tumors.

    Colorectal cancer risk and prevention

    Session: Biological and behavioral factors in cancer surveillance, prevention and survivorship Poster: Evaluation of intra-tumoral pks+ E. coli, enterotoxigenic B. fragilis and Fusobacterium nucleatum and in early onset disease, in colorectal cancer cases Monday, April 17, 2023, 1:30-5:00 p.m. Presenter: Meredith Hullar, Ph.D. 

    Meredith Hullar, Ph.D., a principal staff scientist at Fred Hutch, studies the gut microbiome and its interplay with diet and cancer risk. She will present a new study that revealed different patterns of microbes in colorectal cancer tumors that are present in patients with early onset colorectal cancer, which has increased in incidence in people who are 50 years old and younger. Since some microbes can help tumors grow, understanding the microbiome may help predict which colorectal cancer patients will have increased odds of lower survival and may support targeted intervention strategies to improve survivorship. Learn more about her work in a Fred Hutch news story.

    Session: Aging, immune factors and metabolomics Poster: Association between HLA-KIR allele interaction combinations and density of T-cell subsets in colorectal cancer Monday, April 17, 2023, 1:30-5:00 p.m. Presenter: Claire E. Thomas, Ph.D., MPH (On Twitter)

    Session: Diet, alcohol, tobacco use, and other lifestyle factors Poster: Lifestyle and environmental factors in relation to colorectal cancer risk and survival by colibactin tumor mutational signature status Wednesday, April 19, 2023, 9:00 a.m.-12:30 p.m. Presenter: Claire E. Thomas, Ph.D., MPH (On Twitter)

    Claire E. Thomas, Ph.D., MPH, a post-doctoral researcher at Fred Hutch, will present two posters looking at genetic and molecular risks underlying colorectal cancer. In the first poster, she examines whether immune function gene combinations are related to T-cell density within colorectal cancer tumors. The findings could help determine how an individual’s genetic background is related to T-cells and immune response to fight cancer. 

    In a second poster, Thomas will present a study examining whether lifestyle and environmental factors are differentially associated with colorectal cancer risk and survival for cases with and without the mutational signature SBS88. SBS88 is present in some colorectal cancer tumors and is related to production of the genotoxin colbactin from exposure to some strains of Escherichia coli. The findings show that among cases with the SBS88 signature, higher BMI category was associated with worse colorectal cancer outcomes. 

    Thomas works with Fred Hutch’s Ulrike Peters, Ph.D., MPH, who is a molecular and genetic epidemiologist and holds the Fred Hutch 40th Anniversary Endowed Chair, and with Amanda Phipps, Ph.D., MPH, an epidemiologist. The research team aims to understand underlying genetic risks in cancer and how to intervene. A recent Nature Genetics study from the Peters team identified 100 new genetic risk variants in colorectal cancer.

    Diversity, equity and inclusion

    Meet-the-expert session: Plan to enhance diversity: Opportunities, challenges, best practices and innovative strategies to advance a culture of inclusive excellence at cancer centers Tuesday, April 18, 2023, 7:00-7:45 a.m. Presenter: Christopher Li, M.D., Ph.D. (On LinkedIn)

    Christopher Li, M.D., Ph.D., vice president of Faculty Affairs and Diversity at Fred Hutch, is a nationally recognized leader in efforts to ensure that cancer research benefits all people. At AACR, he will insights from his efforts to help build and maintain a diverse, equitable and inclusive workforce at Fred Hutch and to collaborate with leaders at other cancer centers. Li, who holds the Helen G. Edson Endowed Chair for Breast Cancer Research, is also an epidemiologist who studies breast cancer risk factors, breast cancer recurrence and cancer health disparities.

    Clinical trials

    Major symposium: Sex hormones and cancer Presentation: Sex differences in severe adverse events in patients receiving immunotherapy, targeted therapy, or chemotherapy in Cancer clinical trials: An evidentiary perspective Tuesday, April 18, 2023, 1:25-1:45 p.m. Presenter: Joseph Unger, Ph.D. (On Twitter)

    Biostatistician and health services researcher Joseph Unger, Ph.D. will insights based on findings he published in Journal of Clinical Oncology in how women experience greater adverse effects from cancer treatment, whether it’s chemotherapy, targeted therapy or immunotherapy. The data came from more than 23,000 people participating in 202 clinical trials as part of the SWOG Cancer Research Network, which described the study in a blog post. Unger uses big data to understand treatment outcomes and disparities in cancer, with the aim of revealing problems in cancer care that then allow for ways to predict and prevent the issues before they impede patients.  

    Late-breaking poster session: Clinical research 3 Poster: Biomarker analysis from AMPECT correlating response to nab-sirolimus with TSC1 and TSC2 inactivating alterations Wednesday, April 19, 9 a.m.-12:30 p.m. Presenter: Lee Cranmer, M.D., Ph.D.

    Lee Cranmer, M.D., Ph.D. leads the Bob and Eileen Gilman Family Sarcoma Research Program at Fred Hutch. A recent Fred Hutch news story featured a patient Cranmer treated for a type of cartilage cancer, called chondrosarcoma.

    Note: Fred Hutch and its scientists who contributed to these discoveries may stand to benefit from their commercialization. See links above to AACR abstracts for more details on individual researchers’ disclosures.

    The clinical trials referenced above involve investigational products and/or therapies that have not been approved for commercial marketing by the U.S. Food and Drug Administration or any other regulatory authority. Results may vary, and encouraging results from early-stage clinical trials may not be supported in later-stage clinical trials. No conclusions should be drawn from the information in this report about the safety, efficacy or likelihood of regulatory approval of these investigational products and/or therapies.

    # # #

    Fred Hutchinson Cancer Center unites individualized care and advanced research to provide the latest cancer treatment options and accelerate discoveries that prevent, treat and cure cancer and infectious diseases worldwide.

    Based in Seattle, Fred Hutch is an independent, nonprofit organization and the only National Cancer Institute-designated cancer center in Washington. We have earned a global reputation for our track record of discoveries in cancer, infectious disease and basic research, including important advances in bone marrow transplantation, immunotherapy, HIV/AIDS prevention, and COVID-19 vaccines. Fred Hutch operates eight clinical care sites that provide medical oncology, infusion, radiation, proton therapy and related services and has network affiliations with hospitals in four states. Fred Hutch also serves as UW Medicine’s cancer program.

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    Fred Hutchinson Cancer Center

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  • How do we know if our brain is capable of repairing itself?

    How do we know if our brain is capable of repairing itself?

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    Newswise — Is our brain able to regenerate? And can we harness this regenerative potential during aging or in neurodegenerative conditions? These questions sparked intense controversy within the field of neuroscience for many years. A new study from the Netherlands Institute for Neuroscience shows why there are conflicting results and proposes a roadmap on how to solve these issues.

    The notion of exploiting the regenerative potential of the human brain in aging or neurological diseases represents a particularly attractive alternative to conventional strategies for enhancing or restoring brain function, especially given the current lack of effective therapeutic strategies in neurodegenerative disorders like Alzheimer’s disease. The question of whether the human brain does possess the ability to regenerate or not has been at the center of a fierce scientific debate for many years and recent studies yielded conflicting results. A new study from Giorgia Tosoni and Dilara Ayyildiz, under the supervision of Evgenia Salta in the laboratory of Neurogenesis and Neurodegeneration, critically discusses and re-analyzes previously published datasets. How is it possible that we haven’t yet found a clear answer to this mystery?

    Previous studies in which dividing cells were labeled in postmortem human brain, showed that new cells can indeed arise throughout adulthood in the hippocampus of our brain, a structure that plays an important role in learning and memory, and is also severely affected in Alzheimer’s disease. However, other studies contradict these results and cannot detect the generation of new brain cells in this area. Both conceptual and methodological confounders have likely contributed to these seemingly opposing observations. Hence, elucidating the extent of regeneration in the human brain remains a challenge.

    New state-of-the-art technologies

    Recent advances in single-cell transcriptomics technologies have provided valuable insights into the different cell types found in human brains from deceased donors with different brain diseases. To date, single-cell transcriptomic technologies have been used to characterize rare cell populations in the human brain. In addition to identifying specific cell types, single-nucleus RNA sequencing can also explore specific gene expression profiles to unravel full the complexity of the cells in the hippocampus.

    The advent of single-cell transcriptomics technologies was initially viewed as a panacea to resolving the controversy in the field. However, recent single-cell RNA sequencing studies in human hippocampus yielded conflicting results. Two studies indeed identified neural stem cells, while a third study failed to detect any neurogenic populations. Are these novel approaches – once again – failing to finally settle the controversy regarding the existence of hippocampal regeneration in humans? Will we eventually be able to overcome the conceptual and technical challenges and reconcile these -seemingly- opposing views and findings?

    Technical issues

    In this study, the researchers critically discussed and re-analyzed previously published single-cell transcriptomics datasets. They caution that the design, analysis and interpretation of these studies in the adult human hippocampus can be confounded by specific issues, which ask for conceptual, methodological and computational adjustments. By re-analyzing previously published datasets, a series of specific challenges were probed that require particular attention and would greatly profit from an open discussion in the field.

    Giorgia Tosoni: ‘We analyzed previously published single-cell transcriptomic studies and performed a meta-analysis to assess whether adult neurogenic populations can reliably be identified across different species, especially when comparing mice and humans. The neurogenic process in adult mice is very well characterized and the profiles of the different cellular populations involved are known. These are actually the same molecular and cellular signatures that have been widely used in the field to also identify neurogenic cells in the human brain. However, due to several evolutionary adaptations, we would expect the neurogenesis between mice and humans to be different. We checked the markers for every neurogenic cell type and looked at the amount of marker overlap between the two species.’

    ‘We found very little, if no, overlap between the two, which suggests that the mouse-inferred markers we have been long using may not be suitable for the human brain. We also discovered that such studies require enough statistical power: if regeneration of neuronal cells does happen in the adult human brain, we expect it to be quite rare. Therefore, enough cells would need to be sequenced in order to identify those scarce, presumably neurogenic populations. Other parameters are also important, for example the quality of the samples. The interval between the death of the donor and the downstream processing is critical, since the quality of the tissue and of the resulting data drops over time.’

    Reproducibility is key

    Dilara Ayyildiz: ‘These novel technologies, when appropriately applied, offer a unique opportunity to map hippocampal regeneration in the human brain and explore which cell types and states may be possibly most amenable to therapeutic interventions in aging, neurodegenerative and neuropsychiatric diseases. However, reproducibility and consistency are key. While doing the analysis we realized that some seemingly small, but otherwise very critical details and parameters in the experimental and computational pipeline, can have a big impact on the results, and hence affect the interpretation of the data.’

    ‘Accurate reporting is essential for making these single-cell transcriptomics experiments and their analysis reproducible. Once we re-analyzed these previous studies applying common computational pipelines and criteria, we realized that the apparent controversy in the field may in reality be misleading: with our work we propose that there may actually be more that we agree on than previously believed.’

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    Netherlands Institute for Neuroscience

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  • Small proteins in heart play big role

    Small proteins in heart play big role

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    BYLINE: Beth Miller

    Newswise — A heartbeat is a carefully coordinated series of electrical signals led by sodium ion channels, which tell the heart when to contract and to relax. Any disruption to these signals may lead to cardiac diseases such as an irregular heartbeat, or arrhythmia. Two researchers at Washington University in St. Louis have taken a closer look at this process at the molecular level and have found what may provide new insights into different heart conditions and how to develop better therapies.

    Jonathan Silva, the Dennis & Barbara Kessler Career Development Associate Professor at the McKelvey School of Engineering, and Jeanne Nerbonne, Alumni Endowed Professor of Molecular Biology & Pharmacology in Medicine and Developmental Biology at the School of Medicine, and their labs found distinct effects of novel proteins, known as intracellular fibroblast growth factors (iFGF), on the regulation of the kinetics of cardiac sodium channel gating. Their results were published in the Journal of General Physiology March 21.

    Intracellular fibroblast growth factors are small proteins that are known to bind to sodium channels and to influence how these channels open and close, or “gate.” The gating properties of cardiac sodium channels affect how the electromechanical propagate through the heart. In addition, drugs interact differently with the sodium channels in different gating (i.e., open and closed) states, Silva said.

    The team sought to determine how one intracellular fibroblast growth factor, iFGF12, works in a healthy human heart by observing how the iFGFs change the sodium channel at the molecular level. Nerbonne’s lab generated a mouse model with iFGF12 to observe how it modulates the sodium channel in myocytes. Using electrophysiology methods, they found that it modulated the channel differently than the comparable iFGF in the mouse heart and changed the properties of the sodium current.

    “One of the reasons we want to define how the iFGFs and other sodium channel accessory proteins affect channel properties at the molecular level is that we know from previous work that the protein components of functional channels influence the pharmacology of these channels,” said Nerbonne, who also is the director of the Center for Cardiovascular Research. “These channels are potential therapeutic targets for people with arrhythmias.”

    Silva’s lab looked at how the iFGF affects channel function through methods they have developed to watch the voltage sensing domains.

    “We looked at how these subunits affect native cell electrophysiology, and that’s an exciting part of our collaboration with the Nerbonne lab,” Silva said. “We were able to determine how these subunits change the channel at the molecular level to cause those cell-level effects.”

    Going forward, the team plans to take a closer look at how different drugs interact with sodium channels that have different iFGF compositions.

    ***

    Originally published by the McKelvey School of Engineering.

    Angsutararux P, Dutta AK, Marras M, Abella C, Mellor RL, Shi J, Nerbonne JM, Silva JR. Differential regulation of cardiac sodium channels by intracellular fibroblast growth factors. Journal of General Physiology, March 21, 2023. https://doi.org/10.1085/jgp.202213300

    This research was supported by the National Institutes of Health’s National Heart, Lung, and Blood Institute (R01 142520 and R01 HL150637); the NIH National Center for Research Resources (UL1 RR024992) and the Children’s Discovery Institute Pediatric Disease Mouse Models Core at Washington University.

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    Washington University in St. Louis

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  • خبراء السرطان في مايو كلينك يسلطون الضوء على التقدم المحرز في علاج الورم النقوي المتعدد

    خبراء السرطان في مايو كلينك يسلطون الضوء على التقدم المحرز في علاج الورم النقوي المتعدد

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    Newswise — مدينة روتشستر، ولاية مينيسوتا— يشارك دكتور سكندر العوضي، دكتور في الطب، اختصاصي الدَّمَويات والأورام في مركز مايو كلينك الشامل لعلاج للسرطان تفاصيل حول تطورات جديدة توصلت إليها الأبحاث ستفضي إلى نتائج أفضل لمرضى الورم النقوي المتعدد.  

    الورم النقوي المتعدد هو نوع غير شائع نسبيًا من أنواع سرطان الدم التي تصيب نخاع العظم. رغم أنه لا يوجد علاج نهائيًا للمرض، إلا إنه يمكن التعامل معه بالعلاجات المتاحة مثل الأدوية، والعلاج الكيميائي، والإشعاع، أو حتى بزراعة نخاع العظم للمساعدة في إطالة جودة حياة المرضى.  

    يشارك دكتور العوضي في قيادة فريق من الباحثين في مايو كلينك لتجربةعلاج مستقبلات المستضد الخيمرية، والتي تسمى أيضًا علاج الخلايا التائية ذات مستقبلات المستضد الخيمرية (CAR-T cell)، لعلاج المرضى المصابين بالورم النقوي المتعدد، وتطوير أدوية جديدة لاستهداف الواسِمات السرطانية المختلفة مثل مستضد نضج الخلايا البائية وغيره.  

    يقول دكتور العوضي “التطورات في الأدوية والعلاجات الجديدة لعلاج الورم النقوي في حالة تطور وتغير مستمرين. وإنه لوقت باعث على الحماسة لإجراء أبحاث على أدوية السرطان لاكتشاف علاجات جديدة ستمنح الأمل لمرضى السرطان.”  

    إن علاج مستقبلات المستضد الخيمرية هو أحدث علاج مناعي للسرطان يحتوي على خلايا تائية مُعدّلة وراثيًا لاستهداف واسِمات الخلايا السرطانية تحديدًا، ولتنشيط الجهاز المناعي للتعرف على الخلايا السرطانية والقضاء عليها.  

    في دراسة نُشرت مؤخرًا في في مجلة نيو إنجلاند الطبية، والتي شاركت فيها مايو كلينك، قارن الباحثون نتائج علاج مستقبلات المستضد الخيمرية بنتائج نُظُم العلاج القياسية المتوفرة حاليًا لدى المرضى الذين عولجوا سابقًا من الورم النقوي المتعدد والذين عاودهم المرض بعد الشفاء منه. وقاس الباحثون معدلات البقاء على قيد الحياة التي خلت من تقدّم المرض، وهي الفترة التي يتعايش فيها المريض مع المرض خلال العلاج وبعده، ولكن دون أن يتفاقم المرض.  

    وأشارت الدراسة أنه بإجراء متابعة تفقدية بمتوسط 18.6 شهرًا، بلغ متوسط البقاء على قيد الحياة دون تقدّم المرض لدى المجموعة التي تلقت علاج مستقبلات المستضد الخيمرية 13.3 شهرًا، مقارنة بمتوسط بلغ 4.4 شهور فقط لدى المجموعة التي عولجت بنُظُم العلاج القياسية.  

    يضيف دكتور العوضي قائلاً: “تشير هذه النتائج إلى أننا نمضي في الطريق البحثي الصحيح الذي سيحدث تغييرًا في الممارسة العلاجية والتي ستقدم علاج مستقبلات المستضد الخيمرية في مرحلة مبكرة من علاج المرضى الذين عاودتهم الإصابة بالورم النقوي المتعدد — والذي أتمنى أن يصبح معيار الرعاية في المستقبل.”  

    يواصل باحثو مايو كلينك اختبار أدوية جديدة تستهدف الورم النقوي المتعدد حيث تقود فرق متخصصة التجارب السريرية مستخدمين طرق علاج مستقبلات المستضد الخيمرية الحديثة. يشمل ذلك استخدام العلاجات الجاهزة وعلاج مستقبلات المستضد الخيمرية في وقت مبكر من رحلة العلاج المرضى.  

    يوجد حاليًا ما يزيد عن 40 تجربة سريرية متاحة في مايو كلينك لمرضى الورم النقوي المتعدد. 

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    نبذة عن مايو كلينك 
    مايو كلينك هي مؤسسة غير ربحية تلتزم بالابتكار في الممارسات السريرية والتعليم والبحث وتوفير التعاطف والخبرة لكل مَن يحتاج إلى الاستشفاء والرد على استفساراته. لمعرفة المزيد من أخبار مايو كلينك، تفضَّل بزيارة شبكة مايو كلينك الإخبارية.  

    جهة الاتصال الإعلامية: 

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  • New insights into an old drug: Scientists discover why aspirin works so well

    New insights into an old drug: Scientists discover why aspirin works so well

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    Newswise — New research has revealed important information about how aspirin works. Even though this drug has been available commercially since the late 1800s, scientists have not yet fully elucidated its detailed mechanism of action and cellular targets. The new findings could pave the way to safer aspirin alternatives and might also have implications for improving cancer immunotherapies.

    Aspirin, which is a nonsteroidal anti-inflammatory drug, is one of the most widely used medications in the world. It is used to treat pain, fever and inflammation, and an estimated 29 million people in the U.S. take it daily to reduce the risk of cardiovascular diseases.

    Scientists know that aspirin inhibits the cyclooxygenase enzyme, or COX, which creates messenger molecules that are crucial in the inflammatory response. Researchers led by Subhrangsu Mandal, a professor of chemistry and biochemistry at the University of Texas at Arlington, have discovered more about this process.

    Prarthana Guha, a graduate student in Mandal’s lab, will present the team’s findings at Discover BMB, the annual meeting of the American Society for Biochemistry and Molecular Biology, March 25–28 in Seattle. Avisankar Chini also made significant contributions to the study.

    “Aspirin is a magic drug, but long-term use of it can cause detrimental side effects such as internal bleeding and organ damage,” Mandal said. “It’s important that we understand how it works so we can develop safer drugs with fewer side effects.”

    The team found that aspirin controls transcription factors required for cytokine expression during inflammation while also influencing many other inflammatory proteins and noncoding RNAs that are critically linked to inflammation and immune response. Mandal said this work has required a unique interdisciplinary team with expertise in inflammation signaling biology and organic chemistry.

    They also showed that aspirin slows the breakdown of the amino acid tryptophan into its metabolite kynurenine by inhibiting associated enzymes called indoleamine dioxygenases, or IDOs. Tryptophan metabolism plays a central role in the inflammation and immune response.

    “We found that aspirin downregulates IDO1 expression and associated kynurenine production during inflammation,” Mandal said. “Since aspirin is a COX inhibitor, this suggests potential interplay between COX and IDO1 during inflammation.”

    IDO1 is an important target for immunotherapy, a type of cancer treatment that helps the body’s immune system seek out and destroy cancer cells. Because COX inhibitors modulate the COX–IDO1 axis during inflammation, the researchers predict that COX inhibitors might also be useful as drugs for immunotherapy.

    Mandal and his team are now creating a series of small molecules that modulate COX–IDO1 and will explore their potential use as anti-inflammatory drugs and immunotherapeutic agents.

     

    Prarthana Guha will present this research from 4 to 5:30 p.m. PDT on Tuesday, March 28, in Exhibit Hall 4AB of the Seattle Convention Center (Poster Board No. 185) (abstract). Contact the media team for more information or to obtain a free press pass to attend the meeting.

     

    Image available.

     

    Research in Mandal’s lab is funded by National Institute of Health grant R15 HL142032-01.

     

    About the American Society for Biochemistry and Molecular Biology (ASBMB)

    The ASBMB is a nonprofit scientific and educational organization with more than 12,000 members worldwide. Founded in 1906 to advance the science of biochemistry and molecular biology, the society publishes three peer-reviewed journals, advocates for funding of basic research and education, supports science education at all levels, and promotes the diversity of individuals entering the scientific workforce. www.asbmb.org

    Find more news briefs and tipsheets at: https://discoverbmb.asbmb.org/newsroom.

     

     

     

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  • Human cells help researchers understand squid camouflage

    Human cells help researchers understand squid camouflage

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    INDIANAPOLIS, March 27, 2023 — Squids and octopuses are masters of camouflage, blending into their environment to evade predators or surprise prey. Some aspects of how these cephalopods become reversibly transparent are still “unclear,” largely because researchers can’t culture cephalopod skin cells in the lab. Today, however, researchers report that they have replicated the tunable transparency of some squid skin cells in mammalian cells, which can be cultured. The work could not only shed light on basic squid biology, but also lead to better ways to image many cell types. 

    The researchers will present their results at the spring meeting of the American Chemical Society (ACS). ACS Spring 2023 is a hybrid meeting being held virtually and in-person March 26–30, and features more than 10,000 presentations on a wide range of science topics. 

    For many years, Alon Gorodetsky, Ph.D., and his research group have been working on materials inspired by squid. In past work, they developed “invisibility stickers,” which consisted of bacterially produced squid reflectin proteins that were adhered onto sticky tape. “So then, we had this crazy idea to see whether we could capture some aspect of the ability of squid skin tissues to change transparency within human cell cultures,” says Gorodetsky, who is the principal investigator on the project.

    The team at the University of California, Irvine focused their efforts on cephalopod cells called leucophores, which have particulate-like nanostructures composed of reflectin proteins that scatter light. Typically, reflectins clump together and form the nanoparticles, so light isn’t absorbed or directly transmitted; instead, the light scatters or bounces off of them, making the leucophores appear bright white.

    “We wanted to engineer mammalian cells to stably, instead of temporarily, form reflectin nanostructures for which we could better control the scattering of light,” says Gorodetsky. That’s because if cells allow light through with little scattering, they’ll seem more transparent. Alternatively, by scattering a lot more light, cells will become opaque and more apparent. “Then, at a cellular level, or even the culture level, we thought that we could predictably alter the cells’ transparency relative to the surroundings or background,” he says.

    To change how light interacts with cultured cells, Georgii Bogdanov, a graduate student in Gorodetsky’s lab who is presenting the results, introduced squid-derived genes that encoded for reflectin into human cells, which then used the DNA to produce the protein. “A key advance in our experiments was getting the cells to stably produce reflectin and form light-scattering nanostructures with relatively high refractive indices, which also allowed us to better image the cells in three dimensions,” says Bogdanov.

    In experiments, the team added salt to the cells’ culture media and observed the reflectin proteins clumping together into nanostructures. By systematically increasing the salt concentration, Bogdanov got detailed, time-lapse 3D images of the nanostructures’ properties. As the nanoparticles became larger, the amount of light that bounced off the cells increased, consequently tuning their opacity.

    Then, the COVID-19 pandemic hit, leaving the researchers to wonder what they could do to advance their investigation without being physically in the lab. So, Bogdanov spent his time at home developing computational models that could predict a cell’s expected light scattering and transparency before an experiment was even run. “It’s a beautiful loop between theory and experiments, where you feed in design parameters for the reflectin nanostructures, get out specific predicted optical properties and then engineer the cells more efficiently — for whatever light-scattering properties you might be interested in,” explains Gorodetsky.

    On a basic level, Gorodetsky suggests that these results will help scientists better understand squid skin cells, which haven’t been successfully cultured in a laboratory setting. For example, previous researchers postulated that reflectin nanoparticles disassemble and reassemble to change the transparency of tunable squid leucophores. And now Gorodetsky’s team has shown that similar rearrangements occurred in their stable engineered mammalian cells with simple changes in salt concentration, a mechanism that appears analogous to what has been observed in the tunable squid cells.

    The researchers are now optimizing their technique to design better cellular imaging strategies based on the cells’ intrinsic optical properties. Gorodetsky envisions that the reflectin proteins could act as genetically encoded tags that would not bleach inside human cells. “Reflectin as a molecular probe provides a lot of possibilities to track structures in cells with advanced microscopy techniques,” adds Bogdanov. For example, the scientists propose that imaging approaches based on their work could also have implications for better understanding cell growth and development.

    The researchers acknowledge funding from the Defense Advanced Research Projects Agency and the U.S. Air Force Office of Scientific Research.

    A recorded media briefing on this topic will be posted Monday, March 27, by 10 a.m. Eastern time at www.acs.org/acsspring2023briefings. Reporters can request access to media briefings during the embargo period by contacting [email protected].

    For health and safety information for ACS Spring 2023, please visit the FAQ webpage.  

    The American Chemical Society (ACS) is a nonprofit organization chartered by the U.S. Congress. ACS’ mission is to advance the broader chemistry enterprise and its practitioners for the benefit of Earth and all its people. The Society is a global leader in promoting excellence in science education and providing access to chemistry-related information and research through its multiple research solutions, peer-reviewed journals, scientific conferences, eBooks and weekly news periodical Chemical & Engineering News. ACS journals are among the most cited, most trusted and most read within the scientific literature; however, ACS itself does not conduct chemical research. As a leader in scientific information solutions, its CAS division partners with global innovators to accelerate breakthroughs by curating, connecting and analyzing the world’s scientific knowledge. ACS’ main offices are in Washington, D.C., and Columbus, Ohio.

    To automatically receive news releases from the American Chemical Society, contact [email protected].

    Note to journalists: Please report that this research was presented at a meeting of the American Chemical Society.

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    Title
    Dynamic optical systems inspired by cephalopods 

    Abstract
    Cephalopods (e.g., squids, octopuses, and cuttlefish) have captivated the imagination of both the general public and scientists alike due to their sophisticated nervous systems, complex behavioral patterns, and visually stunning coloration changes. By drawing inspiration from the structures and functionalities of tunable cephalopod skin cells, we have designed and engineered human cells that contain reconfigurable protein-based photonic architectures and, as a result, possess tunable transparency-changing and light-scattering capabilities (1). In turn, we have visualized the refractive index distributions of analogous engineered cells with three-dimensional label-free holotomographic microscopy techniques, and as a consequence, we have developed a detailed understanding of the relationship between their global optical characteristics and subcellular ultrastructures (2). We have moreover extended these efforts to the predictive engineering of the refractive indices and light-scattering properties of multiple self-assembled protein-based platforms, both in vitro and in vivo (2,3). Finally, we have developed improved chemical and genetic strategies for manipulating the sizes, numbers, and refractive indices of our subcellular structures (4). Our combined findings may facilitate an improved understanding of cephalopod camouflage mechanisms and lead to the development of unique tools for applications in biophotonics and bioengineering.

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    American Chemical Society (ACS)

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  • Global analysis of coronavirus protein research reveals how countries respond to disease

    Global analysis of coronavirus protein research reveals how countries respond to disease

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    Newswise — In a new study, researchers examined how a country’s number of published 3D protein structures for coronaviruses, including the one responsible for COVID-19, correlated with its economic output and population. The findings reveal important insights into how different countries’ research establishments respond to disease outbreaks and could be useful for planning responses to future pandemics.

    The study showed that countries with larger economies generated more 3D structure determinations for the protein components of coronaviruses, although there were many outliers. For example, some advanced and prosperous countries published few or no coronavirus structures while some countries strongly affected by COVID-19 published far more such structures than would be expected based on their populations and economies.

    Manfred Philipp, professor emeritus at the City University of New York, will present the new research at Discover BMB, the annual meeting of the American Society for Biochemistry and Molecular Biology, March 25–28 in Seattle.

    The 3D structures of proteins, such as those that make up coronaviruses, are determined using techniques such as X-ray crystallography and nuclear magnetic resonance. This information is then deposited into the Protein Data Bank (PDB) database so that it can be used to develop new drug treatments and new vaccines. Protein structure information is also key for understanding how viruses infect cells and interact with our immune system.

    “We asked ourselves how different countries respond to disease, not in terms of treatment and medical care, but in terms of the research needed to study those diseases and to develop new treatments,” said Philipp. “Structure determinations provide a clear metric in terms of research response without any vagaries of interpretation.”

    Although a great deal of research has examined levels of coronavirus research funding in various countries, most of this work has focused either on coronavirus-related patents or financial inputs. However, relating research to patents is complex, in part, because some nonprofits perform considerable amounts of research but rarely apply for patents while some patent-generating organizations don’t conduct a lot of research. Financial-based analyses don’t provide a complete picture because it is difficult to capture both public and private funds. Also, private research funds are not always publicly disclosed and some funds that are reported may be used for administrative and overhead costs instead of directly for research.

    “Because we did not look at levels research funding, we didn’t have to figure out how much research funding was devoted to disease and how much to something else,” said Philipp. “Our metric only sees research successes and provides a clear indication of the amount of research applied to this topic alone.”

    In the work, the researchers collected and cataloged 3D structure determinations for all proteins and nucleic acids that are components of coronaviruses. This included viruses from animal infections as well as those responsible for the 2003 SARS epidemic in Asia, the 2012 MERS epidemic in the Middle East, the worldwide COVID-19 pandemic and other coronaviruses that have been studied.

    Of the approximately 40 countries the researchers examined, the United States, United Kingdom and China had the highest number of protein structures. They found that population size contributed very little to the number of coronavirus protein deposits while countries with a higher GDP did tend to deposit more protein structures. The number of confirmed COVID-19 cases was positively associated with the number of PDB deposits per country, especially in the U.S. Although South Africa and Brazil are not in the top 10 research-producing countries, they had a high number of COVID-19 cases and PDB deposits, suggesting that the high number of cases experienced in these countries influenced their research output.

    “Our research on the country distribution of coronavirus-related structure determinations is intended to give research administrators in various countries the tools to redirect research funds in the most productive direction,” said Philipp. “For example, it can help countries with large research budgets but few if any structure determinations to redirect the focus of their research. This should not be the only such metric, but it is a key metric since it is independent of administrative and overhead costs.”

    Next, the researchers plan to examine whether the number of structure publications for coronaviruses will continue to increase as the COVID-19 pandemic subsides and whether the countries that have led in depositing coronavirus structures into the PDB will continue to lead. 

     

    Manfred Philipp will present this research from 4:30–6:30 p.m. PDT on Sunday, March 26, in Exhibit Hall 4AB of the Seattle Convention Center (Poster Board No. 177) (abstract). Contact the media team for more information or to obtain a free press pass to attend the meeting.

     

    Image available.

     

    About the American Society for Biochemistry and Molecular Biology (ASBMB)

    The ASBMB is a nonprofit scientific and educational organization with more than 12,000 members worldwide. Founded in 1906 to advance the science of biochemistry and molecular biology, the society publishes three peer-reviewed journals, advocates for funding of basic research and education, supports science education at all levels, and promotes the diversity of individuals entering the scientific workforce. www.asbmb.org

    Find more news briefs and tipsheets at: https://discoverbmb.asbmb.org/newsroom.

     

     

     

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  • Cancer cells with thicker glycocalyx barrier are better at evading immune cells

    Cancer cells with thicker glycocalyx barrier are better at evading immune cells

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    Newswise — One of the ways that cancer cells hide from the body’s immune system is by forming a thin surface barrier called the glycocalyx. In a new study, researchers examined the material properties of this barrier with unprecedented resolution, revealing information that could help improve current cell-based cancer immunotherapies.

    Cancer cells often form the glycocalyx with high levels of cell-surface mucins, which are thought to help protect the cancer cell from immune cell attack. However, a physical understanding of this barrier has remained limited, especially as it relates to cell-based cancer immunotherapies, which involve removing immune cells from a patient, modifying them to seek and destroy cancer, and then putting them back into the patient’s body.

    “We found that changes in the thickness of the barrier that were as small as 10 nanometers could affect the antitumor activity of our immune cells or the engineered cells used for immunotherapy,” said Sangwoo Park, a graduate student in Matthew Paszek’s Lab at Cornell University in Ithaca, New York. “We used this information to engineer immune cells that can get through the glycocalyx, and we hope this approach could be used to enhance current cell-based immunotherapies.”

    Park will present the findings at Discover BMB, the annual meeting of the American Society for Biochemistry and Molecular Biology, March 25–28 in Seattle.

    “Our lab has advanced a powerful strategy called scanning angle interference microscopy (SAIM) for measuring the nanoscale dimensions of the cancer cell glycocalyx,” said Park. “This imaging technique allows us to understand the structural relationship of cancer-associated mucins to the biophysical properties of the glycocalyx.”

    The researchers generated a cellular model to precisely control the cell-surface mucin expression to mimic the cancer cell glycocalyx. They then combined SAIM with genetic approaches to study how the surface density, glycosylation and crosslinking of cancer-associated mucins affect the thickness of the barrier at the nanoscale. They also analyzed how the glycocalyx thickness affected a cell’s resistance to attack by immune cells.

    The study revealed that the thickness of cancer cells’ glycocalyx is one of the major parameters determining immune cell evasion and that engineered immune cells worked better if the glycocalyx was thinner.

    Based on this knowledge, the researchers engineered immune cells with special enzymes on their surface to allow them to attach to and interact with the glycocalyx. Experiments performed at the cellular level showed that these immune cells were able to overcome the glycocalyx armor of cancer cells.

    Next, the researchers plan to determine whether these findings can be replicated in the laboratory and, eventually, in clinical trials.

     

    Sangwoo Park will present this research during the Regulatory Glycosylation Spotlight Session from 2–3 p.m. PDT on Sunday, March 26, in Room 608 of the Seattle Convention Center (abstract). Contact the media team for more information or to obtain a free press pass to attend the meeting.

     

    Image available.

     

    This investigation was supported by National Institute of Health New Innovator DP2 GM229133, National Cancer Institute (NCI) U54 CA210184, NCI R33 CA193043, National Institute of General Medical Sciences (NIGMS) R01 GM138692, NIGMS R01 GM137314, National Science Foundation 1752226, and Breast Cancer Coalition of Rochester 07.1922Research.

     

    About the American Society for Biochemistry and Molecular Biology (ASBMB)

    The ASBMB is a nonprofit scientific and educational organization with more than 12,000 members worldwide. Founded in 1906 to advance the science of biochemistry and molecular biology, the society publishes three peer-reviewed journals, advocates for funding of basic research and education, supports science education at all levels, and promotes the diversity of individuals entering the scientific workforce. www.asbmb.org

    Find more news briefs and tipsheets at: https://discoverbmb.asbmb.org/newsroom.

     

     

     

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  • Genes that form specific bones in the womb heal them later in life

    Genes that form specific bones in the womb heal them later in life

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    Newswise — Genes long known to control the formation of bones before birth also control bone healing later in life, a new study found.  

    Led by researchers at NYU Langone Health, a new study pinpointed key Hox genes, specific to each location in the body, as the controllers of stem cells involved in both forming and repairing bone. HOX proteins act like the body’s “zip code,” specifying the position of limbs in the fetus by encoding instructions for transcription factors, which attach to DNA and influence the action of genes.

    Such adjustments guide immature stem cells as they multiply and mature in the womb, say the study authors, to become heart muscle, nerves, bones, etc., and in the right places. Bone is among the tissues that keep pools of stem cells on hand into adulthood, ready to mature into needed replacement cells that maintain healthy tissue and heal broken bones.

    Published online recently in the journal Development, the new work found that Hox genetic programs in adulthood control a bone stem cell type called periosteal stem and progenitors cells or PSCPs. These cells play a central role in healing bones according to the womb-determined positions in which they first formed. Already known to encode the spatial code that sets the body’s formation plan, HOX genes were shown in the study to give adult stem cells from different locations the properties needed to regenerate the particular bone in which they reside.

    During aging, such stem cells become depleted, the researchers say, resulting in weaker bones that are more likely to fracture and slower to heal. In an effort to counter this loss in healing, the research team demonstrated that increasing the activity of the gene that directs the building of the Hoxa10 transcription factor in the tibia, the larger of the two “shin bones,” in aging mice caused a 32.5% restoration of fracture repair capacity.

    “Our data revealed a previously unknown function for Homeobox or Hox genes as essential location-specific regulators of stem cell maturity in adulthood, with short-term local increases in their expression able to drive healing,” said corresponding study author Philipp Leucht, MD, PhD, the Raj-Sobti-Menon Associate Professor in the Department of Orthopedic Surgery at NYU Langone Health. “The therapeutic promise of adult stem cells as a source of bone-making cells in healing-compromised people is massive.”

    Bone Requires Attention

    A fundamental question in the field has been whether bone healing is driven more by stem cells in the marrow in a bone’s center, or by those known to pool in the nearby periosteum, the outer bone layer made of up tough connective tissue and cell-filled areas. Both stem cell types have the capacity to mature into osteoblasts, the cells that lay down new bone in response to a fracture, but the current study argues that stem cells in the periosteum, the PSPCs, are the important contributors to bone repair.

    The study result builds on the understanding that, to keep stem cells pools on hand, they must get signals to continually divide and multiply without maturing, maintaining their “stemness” until needed. The body regulates bone repair by controlling the degree to which stem cells stay immature, with the most primitive cells playing the largest role in healing due to their flexibility and ability to quickly multiply.

    In the current study, the researchers found that Hox deficiency leads to an increase in the stem cells’ propensity to differentiate into mature bone cell types. Conversely, when the team increased Hoxa10 expression in tibia stem and progenitor cells, it reprogrammed them into a more stem-cell-like state, a needed step if they are to become new bone-making cells as part of healing.

    Specifically, say the authors, PSPCs exist as a mixed stem cell population that includes those with the most stemness, naïve periosteal stem cells (PSCs), alongside more mature periosteal progenitor 1 (PP1s) and periosteal progenitor 2 (PP2s) cells. The current study authors found that Hoxa10 expression was most abundant in PSCs and was significantly reduced as cells progressed along the lineage hierarchy to PP1 and PP2. Experiments that increased the activity of the Hox genes in these more mature progenitors brought about a 3-fold increase of PSCs as cells were reprogrammed into a more primitive stem cell identity.  

    “PSPCs have distinguishing characteristics that form the basis for future cell-based therapies, including their greater tendency to naturally regenerate bone than many related stem cell groups,” said co-corresponding lead author Kevin Leclerc, a post-doctoral scholar in Leucht’s lab. “By modifying Hox activity in these cells, we can help them regenerate bone more effectively in individuals with deficient bone-healing capacity.”     

    Along with Leucht and Leclerc, study authors from the Department of Orthopedic Surgery are Lindsey Remark, Malissa Ramsukh, Anne Marie Josephson, Laura Palma, Paulo EL Parente, Margaux Sambon, Sooyeon Lee, Emma Muiños Lopez, and co-senior author Sophie Morgani. The study was funded by National Institutes of Health grants R01AG056169, K08AR069099, S10OD010751, 5P30CA016087 642, and P41 EB017183, as well as by Perlmutter Cancer Center support grant P30CA016087, the Patricia and Frank Zarb Family, and the CTSI TL1 post-doctoral scholarship of the New York Stem Cell Foundation.

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  • Antibiotic resistance is an increasing problem. Learn all about it in the Drug Resistance channel.

    Antibiotic resistance is an increasing problem. Learn all about it in the Drug Resistance channel.

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    Staphylococcus aureus, Clostridioides difficile, Candida auris, Drug-resistant Shigella. These bacteria not only have difficult names to pronounce, but they are also difficult to fight off.  These bacteria may infect humans and animals, and the infections they cause are harder to treat than those caused by non-resistant bacteria. Antimicrobial resistance is an urgent global public health threat. According to the World Health Organization, antibiotic resistance leads to higher medical costs, prolonged hospital stays, and increased mortality. It kills at least 1.27 million people worldwide and they are associated with nearly 5 million deaths in 2019, according to the CDC. In the U.S., more than 2.8 million antimicrobial-resistant infections occur each year. Careful prescribing of antibiotics will minimize the development of more antibiotic-resistant strains of bacteria. Staying informed is another way to fight these dangerous “superbugs.” Below are some of the latest news updates on the topic of Drug Resistance.

    Scientists make critical progress toward preventing C. diff infections (embargoed until 26-Mar-2023 5:00 PM EDT)

    Resistant bacteria are a global problem. Now researchers may have found the solution

    Potential Treatment Target for Drug-Resistant Epilepsy Identified

    Brazilian researchers investigate diversity of E. coli bacteria in hospitalized patients

    A Quick New Way to Screen Virus Proteins for Antibiotic Properties

    New Class of Drugs Could Prevent Resistant COVID-19 Variants

    The world’s first mRNA vaccine for deadly bacteria

    From anti-antibiotics to extinction therapy: how evolutionary thinking can transform medicine

    St. Jude approach prevents drug resistance and toxicity

    Restricting antibiotics for livestock could limit spread of antibiotic-resistant infections in people

    Resistance Is Futile

    Bacteria communicate like us – and we could use this to help address antibiotic resistance

    Study reveals how drug resistant bacteria secrete toxins, suggesting targets to reduce virulence

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    Newswise

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  • A common metabolite may help treat autoimmune diseases

    A common metabolite may help treat autoimmune diseases

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    Newswise — Researchers have revealed the modulatory effect of the anti-inflammatory metabolite itaconate on T helper and T regulatory cells, which may lead to new therapeutic approaches to treating some autoimmune diseases.

    Autoimmune diseases occur when the immune system attacks its own body. There are more than eighty known types of autoimmune diseases. In many cases, autoimmune diseases can be treated by suppressing the immune system; however, a side effect of such treatment is that the patient has an increased risk of severe infectious diseases, which is a leading cause of death. Hence there is a need to establish novel therapies for autoimmune diseases to reduce the risk of infectious diseases. 

    A research team led by Professor Tatsuya Atsumi, Assistant Professor Michihito Kono and graduate student Kuniyuki Aso at Hokkaido University, along with Senior Lecturer Masatoshi Kanda at Sapporo Medical University, has studied the effect of the molecule itaconate on the immune system. Their findings, which have implications for treating autoimmune disorders, were published in the journal Nature Communications.

    “Multiple sclerosis (MS) and systemic lupus erythematosus are two of the many autoimmune diseases caused by a dysregulation of T cells,” Kono explained. “We were interested in two types of T cells: T helper 17 (Th17) and regulatory T (Treg) cells. These cells have the same origin but have opposite functions in autoimmune diseases, and cell metabolites modulate their action. The metabolite we focused on was itaconate (ITA), as it has been shown to have anti-inflammatory, antiviral, and antimicrobial effects.”

    The researchers showed that, in cell cultures, ITA inhibited the differentiation of Th17 cells which have the potential to elaborate autoimmune diseases, and promoted that of Treg cells, which can ameliorate them. Further, in mice models with experimental autoimmune encephalomyelitis, ITA reduced the disease symptoms. Further tests were conducted to confirm that this effect was due to its effect on T cells.

    Investigations into the mechanism of action of ITA revealed that it inhibits essential metabolic pathways, glycolysis, oxidative phosphorylation, and methionine metabolism in Th17 and Treg cells. “ITA inhibits these pathways by directly inhibiting the enzymes methionine adenosyltransferase and isocitrate dehydrogenase, resulting in change of S-adenosyl-L-methionine/S-adenosylhomocysteine ratio and 2-hydroxyglutarate levels,” Kono elaborated. “The altered cell metabolites also indirectly affect the chromatin accessibility of essential transcription factors and the synthesis of proteins required for the differentiation of Th17 and Treg cells.”

    “Our results explain the mechanisms that underlie the modulation of T cell differentiation,” he concluded. “This could eventually lead to simple therapeutic approaches which regulate T cell differentiation, thereby treating T cell-mediated autoimmune diseases.”

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    Hokkaido University

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  • New Class of Drugs Could Prevent Resistant COVID-19 Variants

    New Class of Drugs Could Prevent Resistant COVID-19 Variants

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    Newswise — The constant evolution of new COVID-19 variants makes it critical for clinicians to have multiple therapies in their arsenal for treating drug-resistant infections. Researchers have now discovered that a new class of oral drugs that acts directly on human cells can inhibit a diverse range of pathogenic SARS-CoV-2 strains.

    In their newly published study, the team found a novel mechanism through which the gene that expresses angiotensin converting enzyme-2 (ACE-2)—the cellular receptor to which SARS-CoV-2 binds so that it can enter and infect the cell—is turned on. They also found that a class of oral drugs currently in human clinical trials can block this pathway and potentially be a therapeutic for all SARS-CoV-2 variants, as well as any newly emerging SARS-like viruses. The team published its findings in Nature Genetics on March 8.

    Targeting these master regulatory complexes complements existing approaches and fills a need for a new drug class that can be exploited to help combat drug resistance and infection. -Craig Wilen, MD, PhD

    “Because of drug-resistant variants, we’re down to only one drug, Paxlovid, as far as our oral options,” says Craig Wilen, MD, PhD, associate professor of laboratory medicine and of immunobiology, and a member of Yale Cancer Center. “Targeting these master regulatory complexes complements existing approaches and fills a need for a new drug class that can be exploited to help combat drug resistance and infection.” Wilen and Cigall Kadoch, PhD, of Dana-Farber Cancer Institute, are co-senior authors of the study. The co-first authors are Jin Wei, PhD, postdoctoral scholar in the Wilen Lab, and Ajinkya Patil, MS, graduate student in the Kadoch Lab and the Program in Virology at Harvard Medical School.

    Researchers Identify Potential Anti-Viral Targets

    In a previous study published in 2021, Wilen’s team at Yale performed genetic screening to identify host factors that are essential for SARS-CoV-2 infection. One of the key players was the mammalian switch/sucrose non-fermentable (mSWI/SNF, also called BAF) chromatin remodeling complex, a group of over a dozen very conserved proteins that allow certain genes to turn on.

    “At that point, I’d never heard of it in the setting of virus infection, and we couldn’t understand why it was important for coronaviruses,” says Wilen. Thus, the group teamed up with experts on this complex, the Kadoch Lab at the Dana-Farber Cancer Institute and Harvard Medical School to find out how the protein complex acts to make cells susceptible to infection and if newly emerging drugs against these complexes could stunt viral infection.

    At the time they embarked on their collaborative work, the U.S. Food and Drug Administration had authorized six monoclonal antibody treatments for emergency use, yet none of these treatments work against the newest Omicron variants. This leaves clinicians with remdesivir, which can only be administered through an IV, limiting its use; molnupiravir, an oral drug that works similarly to remdesivir but only has 30 percent efficacy; and Paxlovid, an oral antiviral that works through inhibiting the viral protease. Paxlovid, Wilen says, is the mainstay of current treatment.

    “It’s a great drug that works well, but there has been some emerging drug resistance to it,” he says. “And currently, that is the only drug in our toolbox that we can give as an oral form.” The dwindling of effective treatments further highlights the critical need for a new class of drugs to add to the toolbox, and ideally, ones that are less susceptible to quick-acting resistance mechanisms.

    Blocking mSWI/SNF Protects Cells Against SARS-CoV-2

    First, the team discovered that disrupting mSWI/SNF complexes prevented viral entry into human cells. Because mSWI/SNF is known to regulate genes turning on and off, they then hypothesized that it might also play a role in activating the ACE-2 receptor. Next, they uncovered its mechanism: mSWI/SNF binds to another protein called HNF1A, a transcription factor, which directs it to the gene that encodes ACE-2. Upon disrupting mSWI/SNF complexes, the cell could no longer make ACE-2 and became resistant to infection by any virus that uses that receptor. This includes many coronaviruses.

    Small molecule inhibitors that target mSWI/SNF have already been developed by Kadoch-founded Foghorn Therapeutics and are in phase I clinical trials as a therapeutic for several cancers. Wilen and Kadoch found that this class of drugs was effective against multiple variants of SARS-CoV-2—including a remdesivir-resistant strain isolated from a Yale patient—without any adverse effects on the cell. “This is proof of principle that this can be a really important first- or second-line tool to combat drug resistance,” says Wilen.

    “Further, this speaks to the wide, multi-disease potential for pharmacologic modulation of chromatin remodeling complexes,” says Kadoch. “These molecular machines sit at the top of the pyramid in governing gene expression programs that go awry in many different human diseases—we are just at the tip of the iceberg in identifying and exploring their utility”.

    Wilen believes the drugs in these clinical trials can potentially be repurposed to inhibit both current and future coronaviruses. Furthermore, Wilen and Kadoch hope the work can provide insight into why certain people and specific cell types may be more susceptible to coronavirus than others. “Future work is needed to look at the underlying biology of why some people are asymptomatic while others experience severe infection and death,” Wilen says.

    COVID-19 will not be the last severe viral outbreak. Wilen’s lab studies coronaviruses circulating in wild bats, which he believes pose the highest risk for infecting humans and causing the next pandemic. Many of these viruses use ACE-2 as a receptor, which means that this new study may hold the key to slowing or stopping the next outbreak. “We’re going to have another pandemic, whether it’s in a few years or a decade. And we’re underprepared for it,” he says. “The best way to prepare is to have as many vaccines and drugs as possible ready to go so that we can combat the outbreak early with maximum effectiveness.”

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    Yale Cancer Center/Smilow Cancer Hospital

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