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Tag: Genetics

  • 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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  • The untold history of the horse in the American Plains, a new future for the world

    The untold history of the horse in the American Plains, a new future for the world

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    Newswise — “Horses have been part of us since long before other cultures came to our lands, and we are a part of them,” states Chief Joe American Horse, a leader of the Oglala Lakota Oyate, traditional knowledge keeper, and co-author of the study. In 2018, at the instruction of her elder knowledge keepers and traditional leaders, Dr. Yvette Running Horse Collin contacted Prof Ludovic Orlando, French National Centre for Scientific Research (CNRS) scientist. She had completed her PhD, which focused on deconstructing the history of horses in the Americas. Up until that point, the field had been dominated by western academics, and Indigenous voices had been largely dismissed. She sought an opportunity to develop a research programme in which traditional Indigenous sciences could be brought forward and considered on equal footing with western science. For the Lakota, scientifically investigating the history of the Horse Nation in the Americas was a perfect starting point, as it would highlight the places of connection and disconnection between Western and Indigenous approaches. The elders were clear: working on the horse would provide a roadmap for learning how to combine the power of all scientific systems, traditional and western alike. And by doing so, eventually provide new solutions to the many challenges affecting people, communities and biodiversity around the globe. For now, as her ancestors before her, Dr. Running Horse Collin would follow the lead of the Horse Nation.

    Part of the programme was to test a narrative that features in almost every single textbook on the history of the Americas: whether European historic records accurately captured the story of Indigenous people and horses across the Great Plains and the Rocky Mountains. This narrative reflects the most popular chronicles of the Europeans who first established contact with Indigenous groups and contend a recent adoption of horses following the Pueblo Revolt of 1680.

    Archaeological science has emerged as a powerful tool to understand the past, and, if done collaboratively, a strong technique for countering biases built into historical narratives. Over the last decade, Prof. Orlando and his team of geneticists have extracted the ancient DNA molecules still preserved in archeological remains to rewrite the history of the domestic horse. They have sequenced the genomes of several hundred horses that lived on the planet thousands of years ago, up to even 700,000 years ago. This technology could, thus, be reasonably expected to reveal the genetic makeup of horses that lived in the Great Plains and the Rocky Mountains post-European contact.

    To tackle this question, Prof. William Taylor, Assistant Professor at the University of Colorado and a large team of partners including archaeologists from the University of New Mexico and University of Oklahoma set out to track down archaeological horse bones from across the American West together with his Lakota, Comanche, Pawnee and Pueblo collaborators. Using both new and established practices from the archaeological sciences, the team identified evidence that horses were raised, fed, cared for, and ridden by Indigenous Peoples. An early date from a horse specimen from Paa’ko Pueblo in New Mexico provides evidence of Indigenous control of horses at the turn of the 17th century, and possibly earlier. Direct radiocarbon dating of discoveries ranging from southern Idaho to southwestern Wyoming and northern Kansas showed that horses were present across much of the Great Plains and Rocky Mountains by the early 17th century, and conclusively before the Pueblo Revolt of 1680. Clearly, the most common narrative for the origin of the American horse needed correction.

    The genome evidence demonstrated that the horses surveyed in this study for many Plains Nations were primarily of Iberian ancestry, but not directly related with those horses that inhabited the Americas in the Late Pleistocene more than 12,000 years ago. Likewise, they were not the descendants of Viking horses, despite Viking establishing settlements on the American continent by 1021. Archaeological data show that these domestic horses were no longer in exclusive Spanish control by at least the early 1600s, and were integrated into Indigenous lifeways. Importantly, this earlier dispersal validates many traditional perspectives on the origin of the horse from project partners like the Comanche and Pawnee, who recognize the link between archaeological findings and oral traditions. Comanche Tribal Historian and study coauthor Jimmy Arterberry states: “These findings support and concur with Comanche oral tradition. Archaeological traces of our horse culture are invaluable assets that reveal a chronology in North American history, and are important to the survival of Indigenous cultures. They are our heritage, and merit honor through protection. They are sacred to the Comanche.”

    Further work involving new archaeological excavations at sites dating to or even predating the 16th century, and additional sequencing, will help shed new light on other chapters of the human-horse story in the Americas. Pawnee archaeologist and study coauthor Carlton Shield Chief Gover says: “The archaeological science presented in our research further illustrates the necessity for meaningful and genuine collaborative partnerships with Indigenous communities.”

    The genome analyses did not just address the development of horsemanship within First Nations during the first stages of the American colonization. These analyses demonstrated that the once dominant ancestry found in the horse genome became increasingly diluted through time, gaining ancestry native from British bloodlines. Therefore, the changing landscape of colonial America was recorded in the horse genome: first mainly from Spanish sources, then primarily from British settlers.

    In the future, this team is committed to continue working on the history of the Horse Nation in the Americas to include the scientific methodologies inherent in Indigenous scientific systems, as well as a greater contribution regarding migratory patterns and the effects on the genome due to climate change. This study was critical in helping to bring Western and Indigenous scientists together so that authentic dialogue and exchange may begin.

    The challenges that our modern world faces are immense. In these times of massive biodiversity crisis and global climate warming, the future of the planet is threatened. Indigenous Peoples have survived the chaos and destruction brought about by colonization, assimilation policies and genocide, and carry important knowledge and scientific approaches centered around sustainability. It is now, more than ever, time to repair history and create more inclusive conditions for co-designing strategies for a more sustainable future. Importantly, this study created a collaboration between western scientists and many Native Nations across the United States, from the Pueblo to the Pawnee, Wichita, Comanche, and Lakota. We expect to be joined by many more soon. “Our Horse Nation relatives have always brought us together and will continue to do so. Our horse societies are organized and ready. As this collaboration develops, we invite all Peoples of the Horse to join us. We call to you.” (Dr. Antonia Loretta Afraid of Bear-Cook, traditional knowledge keeper for the Oglala Lakota, a study co-author).

    This work was supported by the National Science Foundation Collaborative Research Award (#1949305, #1949304, #1949305, and #1949283), Marie Sklodowska Curie Actions (programmes HOPE and MethylRIDE), the CNRS and Université Paul Sabatier (International Research Program AnimalFarm), the French Government “Investissement d’Avenir” France Génomique (ANR-10-INBS-09), and the European Research Council (PEGASUS). All protocols for the transmission of sacred and traditional knowledge were followed, and research activities and results were endorsed by an Internal Review Board involving 10 Lakota Elder Knowledge Keepers, who now serve as the Board of Directors of Taku Škaŋ Škaŋ Wasakliyapi: Global Institute for Traditional Sciences (GIFTS).

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    CNRS (Centre National de Recherche Scientifique / National Center of Scientific Research)

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  • Story tip: A wise tool for modifying microbes

    Story tip: A wise tool for modifying microbes

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    Newswise — A DNA editing tool adapted by Oak Ridge National Laboratory scientists makes engineering microbes for everything from bioenergy production to plastics recycling easier and faster.

    The Serine recombinase-Assisted Genome Engineering, or SAGE system, lets scientists quickly insert and test new DNA designs in a variety of microorganisms. Engineered microbes hold promise for making biofuels, recycling mixed plastics, aiding soil carbon storage and treating health disorders.

    “SAGE works in virtually all microorganisms, revolutionizing what we’re able to do with microbes,” said ORNL’s Adam Guss. Microbes were modified in a few days with SAGE, compared with a tailoring process that can take weeks using existing methods.

    SAGE can advance fundamental biology as well as bioengineering, Guss said. “As a national lab, enabling science everywhere is part of our mission. SAGE is a tool that can speed the work of industry and academic researchers in their own organisms of interest.”

    UT-Battelle manages ORNL for the Department of Energy’s Office of Science, the single largest supporter of basic research in the physical sciences in the United States. The Office of Science is working to address some of the most pressing challenges of our time. For more information, please visit energy.gov.


    Journal Link: Science Advances

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    Oak Ridge National Laboratory

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  • Babies or beauty?

    Babies or beauty?

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    A new study published in Science Advances has not only revealed that an ALHS in Colias butterflies has an ancient origin, but also determined the mechanisms contributing to its persistence over millions of generations.

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    Stockholm University

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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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    NYU Langone Health

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  • Scientists parse another clue to possible origins of Covid-19 as WHO says all possibilities ‘remain on the table’ | CNN

    Scientists parse another clue to possible origins of Covid-19 as WHO says all possibilities ‘remain on the table’ | CNN

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    CNN
     — 

    There’s a tantalizing new clue in the hunt for the origins of the Covid-19 pandemic.

    A new analysis of genetic material collected from January to March 2020 at the Huanan Seafood Market in Wuhan, China, has uncovered animal DNA in samples already known to be positive for SARS-CoV-2, the coronavirus that causes Covid-19. A significant amount of that DNA appears to belong to animals known as raccoon dogs, which were known to be traded at the market, according to officials with the World Health Organization, who addressed the new evidence in a news briefing on Friday.

    The connection to raccoon dogs came to light after Chinese researchers shared raw genetic sequences taken from swabbed specimens collected at the market early in the pandemic. The sequences were uploaded in late January 2023, to the data sharing site GISAID, but have recently been removed.

    An international team of researchers noticed them and downloaded them for further study, the WHO officials said Friday.

    The new findings – which have not yet been publicly posted – do not settle the question of how the pandemic started. They do not prove that raccoon dogs were infected with SARS-CoV-2, nor do they prove that raccoon dogs were the animals that first infected people.

    But because viruses don’t survive in the environment outside of their hosts for long, finding so much of the genetic material from the virus intermingled with genetic material from raccoon dogs is highly suggestive that they could have been carriers, according to scientists who worked on the analysis. The analysis was led by Kristian Andersen, an immunologist and microbiologist at Scripps Research; Edward Holmes, a virologist at the University of Sydney; Michael Worobey, an evolutionary biologist at the University of Arizona. These three scientists, who have been digging into the origins of the pandemic, were interviewed by reporters for The Atlantic magazine. CNN has reached out to Andersen, Holmes and Worobey for comment.

    The details of the international analysis were first reported Thursday by The Atlantic.

    The new data is emerging as Republicans in Congress have opened investigations into the pandemic’s origin. Previous studies provided evidence that the virus likely emerged naturally in market, but could not point to a specific origin. Some US agencies, including a recent US Department of Energy assessment, say the pandemic likely resulted from a lab leak in Wuhan.

    In the news briefing on Friday, WHO Director-General Tedros Adhanom Ghebreyesus said the organization was first made aware of the sequences on Sunday.

    “As soon as we became aware of this data, we contacted the Chinese CDC and urged them to share it with WHO and the international scientific community so it can be analyzed,” Tedros said.

    WHO also convened its Scientific Advisory Group for the Origins of the Novel Pathogens, known as SAGO, which has been investigating the roots of the pandemic, to discuss the data on Tuesday. The group heard from Chinese scientists who had originally studied the sequences, as well as the group of international scientists taking a fresh look at them.

    WHO experts said in the Friday briefing that the data are not conclusive. They still can’t say whether the virus leaked from a lab, or if it spilled over naturally from animals to humans.

    “These data do not provide a definitive answer to the question of how the pandemic began, but every piece of data is important in moving us closer to that answer,” Tedros said.

    What the sequences do prove, WHO officials said, is that China has more data that might relate to the origins of the pandemic that it has not yet shared with the rest of the world.

    “This data could have, and should have, been shared three years ago,” Tedros said. “We continue to call on China to be transparent in sharing data and to conduct the necessary investigations and share results.

    “Understanding how the pandemic began remains a moral and scientific imperative.”

    CNN has reached out to the Chinese scientists who first analyzed and shared the data, but has not received a reply.

    The Chinese researchers, who are affiliated with that country’s Center for Disease Control and Prevention, had shared their own analysis of the samples in 2022. In that preprint study posted last year, they concluded that “no animal host of SARS-CoV2 can be deduced.”

    The research looked at 923 environmental samples taken from within the seafood market and 457 samples taken from animals, and found 63 environmental samples that were positive for the virus that causes Covid-19. Most were taken from the western end of the market. None of the animal samples, which were taken from refrigerated and frozen products for sale, and from live, stray animals roaming the market, were positive, the Chinese authors wrote in 2022.

    When they looked at the different species of DNA represented in the environmental samples, the Chinese authors only saw a link to humans, but not other animals.

    When an international team of researchers recently took at fresh look at the genetic material in the samples – which were swabbed in and around the stalls of the market – using an advanced genetic technique called metagenomics, scientists said they were surprised to find a significant amount of DNA belonging to raccoon dogs, a small animal related to foxes. Raccoon dogs can be infected with the virus that causes Covid-19 and have been high on the list of suspected animal hosts for the virus.

    “What they found is molecular evidence that animals were sold at that market. That was suspected, but they found molecular evidence of that. And also that some of the animals that were there were susceptible to SARS-CoV2 infection, and some of those animals include raccoon dogs,” said Maria Van Kerkhove, WHO’s technical lead for Covid-19, in Friday’s briefing.

    “This doesn’t change our approach to studying the origins of Covid-19. It just tells us that more data exists, and that data needs to be shared in full,” she said.

    Van Kerkhove said that until the international scientific community is able to review more evidence, “all hypotheses remain on the table.”

    Some experts found the new evidence persuasive, if not completely convincing, of an origin in the market.

    “The data does point even further to a market origin,” Andersen, the Scripps Research evolutionary biologist who attended the WHO meeting and is one of the scientists analyzing the new data, told the magazine Science.

    The assertions made over the new data quickly sparked debate in the scientific community.

    Francois Balloux, director of the Genetics Institute at University College London, said the fact that the new analysis had not yet been publicly posted for scientists to scrutinize, but had come to light in news reports, warranted caution.

    “Such articles really don’t help as they only polarise the debate further,” Balloux posted in a thread on Twitter. “Those convinced by a zoonotic origin will read it as final proof for their conviction, and those convinced it was a lab leak will interpret the weakness of the evidence as attempts of a cover-up.”

    Other experts, who were not involved in the analysis, said the data could be key to showing the virus had a natural origin.

    Felicia Goodrum is an immunobiologist at the University of Arizona, who recently published a review of all available data for the various theories behind the pandemic’s origin.

    Goodrum says the strongest proof for a natural spillover would be to isolate the virus that causes Covid-19 from an animal that was present in the market in 2019.

    “Clearly, that is impossible, as we cannot go back in time any more than we have through sequencing, and no animals were present at the time sequences could be collected. To me, this is the next best thing,” Goodrum said in an email to CNN.

    In the WHO briefing, Van Kerkhove said that the Chinese CDC researchers had uploaded the sequences to GISAID as they were updating their original research. She said their first paper is in the process of being updated and resubmitted for publication.

    “We have been told by GISAID that the data from China’s CDC is being updated and expanded,” she said.

    Van Kerkhove said on Friday that what WHO would like to be able to do is to find the source of where the animals came from. Were they wild? Were they farmed?

    She said in the course of its investigation into the pandemic’s origins, WHO had repeatedly asked China for studies to trace the animals back to their source farms. She said WHO had also asked for blood tests on people who worked in the market, as well as tests on animals that may have come from the farms.

    “Share the data,” Dr. Mike Ryan, executive director of WHO’s health emergencies program, said Friday, addressing scientists around the world who might have relevant information. “Let science do the work, and we will get the answers.”

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  • Step Forward in Gene Therapy to Treat Cause of Sudden Cardiac Arrest in Athletes

    Step Forward in Gene Therapy to Treat Cause of Sudden Cardiac Arrest in Athletes

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    BYLINE: Jennifer Michalowski

    Newswise — University of Utah Health scientists have corrected abnormal heart rhythms in mice by restoring healthy levels of a protein that heart cells need to establish connections with one another. That protein, GJA1-20k, is underproduced in people with a genetic condition called arrhythmogenic cardiomyopathy, one of the leading causes of sudden cardiac arrest in athletes under the age of 35.

    The finding, reported in the journal Circulation Research, suggests a new strategy for treating the abnormal heart rhythms caused by arrhythmogenic cardiomyopathy.

    The results may also have implications for treating dangerous arrhythmias associated with more common conditions, such as those that can develop soon after a heart attack.

    “This is really a new paradigm for the treatment of heart rhythm disorders,” says Joseph Palatinus, M.D., Ph.D., an investigator at the Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI) and critical care cardiologist at Intermountain Healthcare. Palatinus is the first author of the study, which was led by U of U Health colleague Robin Shaw, M.D., Ph.D., director of the CVRTI.

    An unusual pattern in patients

    People with arrhythmogenic cardiomyopathy are born with normal hearts but begin to develop an irregular heartbeat in their 20s or 30s. These arrhythmias can raise the heart rate to dangerous levels and explain why some individuals with the condition experience sudden cardiac arrest during exercise.

    Patients diagnosed with arrhythmogenic cardiomyopathy are advised to restrict exercise. They may also benefit from an implantable defibrillator to control their heartbeat. As the disease progresses, the heart muscle becomes fatty and fibrotic. This prevents the heart from pumping blood efficiently, and eventually patients need a heart transplant.

    Palatinus, Shaw, and their colleagues studied heart tissue from patients with arrhythmogenic cardiomyopathy who underwent transplant and discovered a problem with a protein called Connexin 43. In healthy hearts, Connexin 43 forms channels between adjacent cells, facilitating communication. The diseased hearts made normal amounts of Connexin 43, but it wasn’t at the edges of cells where it belonged.

    This, the team determined, was likely because there wasn’t enough of a trafficking protein, called GJA1-20ka. The researchers knew from previous experiments that without it, the heart’s cells wouldn’t be able to get Connexin 43 to the right place.

    Fixing an abnormal heartbeat at the source

    To determine if they could restore the heart’s normal rhythm, the scientists turned to mice that have similarities to people with arrhythmogenic cardiomyopathy. They both have low levels of GJA1-20k and develop arrhythmias. Palatinus and colleagues used low doses of gene therapy to bring the trafficking protein GJA1-20k back to normal levels. This, they confirmed, enabled heart muscle cells to transport Connexin 43 to its proper locations.

    Most importantly, it gave the animals a more normal heartbeat. “The ease and low dose needed to fix the arrhythmias of even an inherited heart disease suggests that we have identified a critical pathway to stabilize cardiac electrical activity,” said Shaw.

    Although arrhythmia improved, the animals still had heart scarring, a symptom from a different underlying condition. Palatinus noted that was actually an encouraging result. It suggests arrhythmia and heart scarring can occur independently and that it could be possible to treat abnormal heart rhythms even when the heart is severely scarred. “This is a new paradigm,” he says.

    The treatment success in mice suggests that raising levels of GJA1-20k might restore normal heart rhythms in patients with arrhythmogenic cardiomyopathy, too. For patients, Palatinus says, it might be possible to deliver the therapeutic protein directly to the heart. Further research will be needed to develop the treatment for clinical use.

    Disruptions in protein trafficking are thought to contribute to arrhythmias beyond those caused by arrhythmogenic cardiomyopathy, and Palatinus is optimistic that a similar treatment strategy might be useful for those conditions, too. If so, that could one day give patients and their doctors an alternative to the ion channel-blocking drugs currently used to treat many arrhythmias, which can slow the heart and even lead to new rhythm problems for some patients.

    # # #

    The research was supported by the National Institutes of Health, The Harold Geneen Charitable Trust, and the Nora Eccles Treadwell Foundation and published as “GJA1-20k Rescues Cx43 Localization and Arrhythmias in Arrhythmogenic Cardiomyopathy.”

    About University of Utah Health

    University of Utah Health  provides leading-edge and compassionate care for a referral area that encompasses Idaho, Wyoming, Montana, and much of Nevada. A hub for health sciences research and education in the region, U of U Health has a $458 million research enterprise and trains scientists and the majority of Utah’s physicians and health care providers at its Colleges of Health, Nursing, and Pharmacy and Schools of Dentistry and Medicine. With more than 20,000 employees, the system includes 12 community clinics and five hospitals. U of U Health is recognized nationally as a transformative health care system and provider of world-class care.

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  • New gene-editing technique reverses vision loss in mice

    New gene-editing technique reverses vision loss in mice

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    Newswise — Researchers in China have successfully restored the vision of mice with retinitis pigmentosa, one of the major causes of blindness in humans. The study, to be published March 17 in the Journal of Experimental Medicine, uses a new, highly versatile form of CRISPR-based genome editing with the potential to correct a wide variety of disease-causing genetic mutations.

    Researchers have previously used genome editing to restore the vision of mice with genetic diseases, such as Leber congenital amaurosis, that affect the retinal pigment epithelium, a layer of non-neuronal cells in the eye that supports the light-sensing rod and cone photoreceptor cells. However, most inherited forms of blindness, including retinitis pigmentosa, are caused by genetic defects in the neural photoreceptors themselves.

    “The ability to edit the genome of neural retinal cells, particularly unhealthy or dying photoreceptors, would provide much more convincing evidence for the potential applications of these genome-editing tools in treating diseases such as retinitis pigmentosa,” says Kai Yao, a professor at the Wuhan University of Science and Technology.

    Retinitis pigmentosa can be caused by mutations in over 100 different genes and is estimated to impair the vision of 1 in 4,000 people. It begins with the dysfunction and death of dim light-sensing rod cells, before spreading to the cone cells required for color vision, eventually leading to severe, irreversible vision loss.

    Yao and colleagues attempted to rescue the vision of mice with retinitis pigmentosa caused by a mutation in the gene encoding a critical enzyme called PDE6β. To do this, Yao’s team developed a new, more versatile CRISPR system called PESpRY, which can be programmed to correct many different types of genetic mutation, regardless of where they occur within the genome.

    When programmed to target the mutant PDE6β gene, the PESpRY system was able to efficiently correct the mutation and restore the enzyme’s activity in the retinas of mice. This prevented the death of rod and cone photoreceptors and restored their normal electrical responses to light.

    Yao and colleagues performed a variety of behavioral tests to confirm that the gene-edited mice retained their vision even into old age. For example, the animals were able to find their way out of a visually guided water maze almost as well as normal, healthy mice and showed typical head movements in response to visual stimuli.

    Yao cautions that much work still needs to be done to establish both the safety and efficacy of the PESpRY system in humans. “However, our study provides substantial evidence for the in vivo applicability of this new genome-editing strategy and its potential in diverse research and therapeutic contexts, in particular for inherited retinal diseases such as retinitis pigmentosa,” Yao says.

     

    Qin et al. 2023. J. Exp. Med. https://rupress.org/jem/article-lookup/doi/10.1084/jem.20220776?PR

     

    # # #

     

    About Journal of Experimental Medicine

    Journal of Experimental Medicine (JEM) publishes peer-reviewed research on immunology, cancer biology, stem cell biology, microbial pathogenesis, vascular biology, and neurobiology. All editorial decisions on research manuscripts are made through collaborative consultation between professional scientific editors and the academic editorial board. Established in 1896, JEM is published by Rockefeller University Press, a department of The Rockefeller University in New York. For more information, visit jem.org.

    Visit our Newsroom, and sign up for a weekly preview of articles to be published. Embargoed media alerts are for journalists only.

    Follow JEM on Twitter at @JExpMed and @RockUPress.

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  • NOVIDS: Do Some Have the Genes to Dodge COVID?

    NOVIDS: Do Some Have the Genes to Dodge COVID?

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    NOVIDS is the term some use to describe those who haven’t gotten COVID. But researchers are not overly fond of the word. They’re looking for the possible genetic underpinnings to a group of people they prefer to call “resisters.”

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  • Estrogen possible risk factor in disturbed heart rhythm

    Estrogen possible risk factor in disturbed heart rhythm

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    Newswise — The sex hormone estrogen has a negative impact on heartbeat regulation, according to an experimental study from Linköping University, Sweden, published in Science Advances. Estrogen impact seems to interact with hereditary changes causing a heart disease disturbing the heart’s rhythm, while other endogenous substances may have a protecting effect.

    In a lifetime, the heart beats around 2.5 billion times. Each heartbeat is triggered by an electrical impulse that causes the heart muscle to contract in a very well-coordinated movement. The heart’s electrical activity is regulated by small pores, ion channels, that go through the cell’s membranes and regulate the flow of electrically charged ions in and out of the cell. Some ion channels act as an accelerator and others as a brake. Together, they regulate every heartbeat throughout life.

    Diseases causing an abnormal heart rhythm may, in some cases, be deadly. Long QT syndrome, LQTS, is one such disease. In LQTS patients, the heart takes longer than normal to finish every heartbeat. This syndrome is most often due to a congenital hereditary change, or mutation, affecting one of the heart’s ion channels.

    “We’re trying to understand which substances in the body impact the function of the ion channels. If we could figure out how this regulation works, maybe we can understand why some individuals are more protected and others are hit harder,” says Sara Liin, associate professor in the Department of Biomedical and Clinical Sciences at Linköping University, LiU.

    In this study, the researchers have taken an interest in possible effects of the sex hormone estrogen. They came up with this idea when asked by heart specialists why women are not only more often affected than men, but also more severely affected, by certain hereditary diseases causing an abnormal heart rhythm, also known as arrhythmia. This in light of the fact that women are generally seen as having better protection against cardiovascular diseases. Could it have anything to do with women having more estrogen than men?

    In their study, the researchers studied the type of ion channel most often mutated in LQTS, which is called Kv7.1/KCNE1. Reduced function of this ion channel is a risk factor increasing the risk of arrhythmia. To be able to understand estrogen impact on this specific ion channel, the researchers conducted experiments where they inserted the human variant of the ion channel into frogs’ eggs, which do not have this ion channel. The researchers added the most active form of the sex hormone estrogen, estradiol, and measured the ion channel function. It turned out that ion channel function was hampered by estrogen, which the researchers interpret as an indication that estrogen may increase the risk of certain types of arrhythmia. Other sex hormones had no effect.

    The researchers also found out exactly which parts of the channel were impacted by estrogen. They further examined ion channel mutations found in families with hereditary arrhythmia syndromes. Some mutations led to high estrogen sensitivity, while others led to the ion channel completely losing estrogen sensitivity.

    “We show that some hereditary mutations that reduce ion channel function seem to contribute to high estrogen sensitivity, so there could be two risk factors that interact especially in women carriers of these mutations. We believe that our study gives good reason to look closer at this in patients,” says Sara Liin.

    The researchers point out that it is important to remember the many positive effects of estrogen, and that in women with a hereditary increased risk of LQTS, estrogen could possibly be a risk factor. LQTS is relatively rare, affecting around 1 in 2,500 people.

    The LiU researchers recently published a study in The Lancet eBioMedicine where they conducted a similar study into a group of endogenous substances known as endocannabinoids. This study showed that endocannabinoids instead seemed to function as protective factors in LQTS. According to the researchers, the findings indicate that these factors may be important to study in humans, as this may lead to ways of increasing endocannabinoid levels to counteract arrhythmia.

    The study was financed with support from, among others, the European Research Council, ERC, via the Horizon 2020 research programme.

    Article: Long-QT mutations in KCNE1 modulate the 17β-estradiol response of Kv7.1/KCNE1, Lisa-Marie Erlandsdotter, Lucilla Giammarino, Azemine Halili, Johan Nikesjö, Henrik Gréen, Katja E Odening and Sara I Liin, (2023), Science Advances, published online on 15 March 2023, doi: 10.1126/sciadv.ade7109

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  • Humans are leaving behind a ‘frozen signature’ of microbes on Mount Everest

    Humans are leaving behind a ‘frozen signature’ of microbes on Mount Everest

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    Newswise — Almost 5 miles above sea level in the Himalayan mountains, the rocky dip between Mount Everest and its sister peak, Lhotse, lies windswept, free of snow. It is here at the South Col where hundreds of adventurers pitch their final camp each year before attempting to scale the world’s tallest peak from the southeastern side.

    According to new University of Colorado Boulder-led research, they’re also leaving behind a frozen legacy of hardy microbes, which can withstand harsh conditions at high elevations and lie dormant in the soil for decades or even centuries.

    The research not only highlights an invisible impact of tourism on the world’s highest mountain, but could also lead to a better understanding of environmental limits to life on Earth, as well as where life may exist on other planets or cold moons. The findings were published last month in Arctic, Antarctic, and Alpine Research, a journal published on behalf of the Institute of Arctic and Alpine Research (INSTAAR) at CU Boulder.

    “There is a human signature frozen in the microbiome of Everest, even at that elevation,” said Steve Schmidt, senior author on the paper and professor of ecology and evolutionary biology.

    In decades past, scientists have been unable to conclusively identify human-associated microbes in samples collected above 26,000 feet. This study marks the first time that next-generation gene sequencing technology has been used to analyze soil from such a high elevation on Mount Everest, enabling researchers to gain new insight into almost everything and anything that’s in them.

    The researchers weren’t surprised to find microorganisms left by humans. Microbes are everywhere, even in the air, and can easily blow around and land some distance away from nearby camps or trails.

    “If somebody even blew their nose or coughed, that’s the kind of thing that might show up,” said Schmidt.

    What they were impressed by, however, was that certain microbes which have evolved to thrive in warm and wet environments like our noses and mouths were resilient enough to survive in a dormant state in such harsh conditions.

    Life in the cryosphere

    This team of CU Boulder researchers—including Schmidt, lead author Nicholas Dragone and Adam Solon, both graduate students in the Department of Ecology and Evolutionary Biology and the Cooperative Institute for Research in Environmental Science (CIRES)—study the cryobiosphere: Earth’s cold regions and the limits to life in them. They have sampled soils everywhere from Antarctica and the Andes to the Himalayas and the high Arctic. Usually, human-associated microbes don’t show up in these places to the extent they appeared in the recent Everest samples.

    Schmidt’s work over the years connected him with researchers who were headed to Everest’s South Col in May of 2019 to set up the planet’s highest weather station, established by the National Geographic and Rolex Perpetual Planet Everest Expedition.

    He asked his colleagues: Would you mind collecting some soil samples while you’re already there?

    So Baker Perry, co-author, professor of geography at Appalachian State University and a National Geographic Explorer, hiked as far away from the South Col camp as possible to scoop up some soil samples to send back to Schmidt.

    Extremes on Earth, and elsewhere

    Dragone and Solon then analyzed the soil in several labs at CU Boulder. Using next-generation gene sequencing technology and more traditional culturing techniques, they were able to identify the DNA of almost any living or dead microbes in the soils. They then carried out extensive bioinformatics analyses of the DNA sequences to determine the diversity of organisms, rather than their abundances.  

    Most of the microbial DNA sequences they found were similar to hardy, or “extremophilic” organisms previously detected in other high-elevation sites in the Andes and Antarctica. The most abundant organism they found using both old and new methods was a fungus in the genus Naganishia that can withstand extreme levels of cold and UV radiation.

    But they also found microbial DNA for some organisms heavily associated with humans, including Staphylococcus, one of the most common skin and nose bacteria, and Streptococcus, a dominant genus in the human mouth.

    At high elevation, microbes are often killed by ultraviolet light, cold temperatures and low water availability. Only the hardiest critters survive. Most—like the microbes carried up great heights by humans—go dormant or die, but there is a chance that organisms like Naganishia may grow briefly when water and the perfect ray of sunlight provides enough heat to help it momentarily prosper. But even for the toughest of microbes, Mount Everest is a Hotel California: “You can check out any time you like/ But you can never leave.”

    The researchers don’t expect this microscopic impact on Everest to significantly affect the broader environment. But this work does carry implications for the potential for life far beyond Earth, if one day humans step foot on Mars or beyond.

    “We might find life on other planets and cold moons,” said Schmidt. “We’ll have to be careful to make sure we’re not contaminating them with our own.”

    Additional authors on this publication include: Anton Seimon, Department of Geography and Planning, Appalachian State University; and Tracie Seimon, Wildlife Conservation Society, Zoological Health Program, Bronx, New York.

    This work was supported by the National Geographic and Rolex Perpetual Planet Everest Expedition, the Department of Ecology and Evolutionary Biology, and the University of Colorado Boulder Libraries Open Access Fund.

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  • Molecular Biologist Shixin Liu Receives $50,000 Vilcek Prize for Creative Promise in Biomedical Science

    Molecular Biologist Shixin Liu Receives $50,000 Vilcek Prize for Creative Promise in Biomedical Science

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    The Vilcek Prizes for Creative Promise recognize rising immigrant scientists living and working in the United States whose work represents a significant contribution to their field.

    Press Release
    –

    Mar 14, 2023 10:45 EDT


    NEW YORK, March 14, 2023 (Newswire.com)
    –
    Shixin Liu receives the Vilcek Prize for Creative Promise in Biomedical Science for developing cutting-edge biophysical tools to directly visualize and understand the physiological function of nanometer-scale biomolecular machines such as those that carry out genome replication and gene transcription.

    The Vilcek Prize for Creative Promise is a $50,000 prize awarded annually by the Vilcek Foundation as part of its prizes program. Awarded annually since 2006, the Vilcek Foundation prizes recognize and celebrate immigrant contributions to scientific research and discovery, and to artistic and cultural advancement in the United States. In addition to providing direct support to individual immigrant professionals, the prizes support the Vilcek Foundation’s mission to raise public awareness of the value of immigration for a robust society.

    A molecular biologist, Shixin Liu is fascinated by the dynamic nature and behavior of molecules in living cells. Liu directs the Laboratory of Nanoscale Biophysics and Biochemistry at The Rockefeller University, where his research focuses on visualizing and understanding the dynamic behaviors and interactions of biomolecules using single-molecule visualization and manipulation techniques. “Our long-term goal is to establish a quantitative input-output relationship between environmental stimuli and gene expression profiles in both normal and diseased cells,” says Liu. “This research gives us fundamental knowledge and a unique angle to attack disease mutations.”

    Born in Anhui province in China, Liu began undergraduate studies at the University of Science and Technology of China when he was just 14. At 19 he immigrated to the United States to pursue his PhD at Harvard University, where his work in the laboratory of Vilcek Prize winner Xiaowei Zhuang sparked his fascination with single-molecule biophysics.

    As a postdoctoral fellow at the University of California, Berkeley, Liu continued his work in molecular biophysics, working under the mentorship of another Vilcek Prize-winning scientist, Carlos J. Bustamante. At Berkeley, Liu employed an exquisitely force-sensitive tool known as optical tweezers to investigate the operating mechanisms of molecular machines, including some of the most powerful motors found in nature.

    “My scientific trajectory was really defined by my two amazing mentors… I think that’s one of my best experiences: to be able to interact with people from around the world.”

    “My scientific trajectory was really defined by my two amazing mentors,” says Liu. “I think that’s one of my best experiences: to be able to interact with people from around the world. It’s eye-opening—both in terms of how people think about science, and how they live their life.”

    Now a mentor to his own trainees, Liu is passionate about inspiring the next generation of scientists. “The most satisfying thing is to be able to now transform my knowledge and learning from my mentors to my own mentees.”

    As part of the Vilcek Foundation’s prizes campaign, the foundation has published a biographical profile and video highlighting Liu’s life and work on the Vilcek Foundation website.

    Access the full article and video at the Vilcek Foundation: Shixin Liu: “Seeing is believing”

    The Vilcek Foundation

    The Vilcek Foundation raises awareness of immigrant contributions in the United States and fosters appreciation of the arts and sciences. The foundation was established in 2000 by Jan and Marica Vilcek, immigrants from the former Czechoslovakia. The mission of the foundation was inspired by the couple’s respective careers in biomedical science and art history. Since 2000, the foundation has awarded over $7 million in prizes to foreign-born individuals and supported organizations with over $6 million in grants.

    The Vilcek Foundation is a private operating foundation, a federally tax-exempt nonprofit organization under IRS Section 501(c)(3). To learn more, please visit vilcek.org.

    Source: The Vilcek Foundation

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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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  • Family’s participation key to advancing diabetes research

    Family’s participation key to advancing diabetes research

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    Newswise — Individuals with Type 1 diabetes have a smaller pancreas than people without diabetes. This is surprising because insulin-producing beta cells account for just a small fraction of the pancreas, so the loss of beta cells in Type 1 diabetes would not be expected to reduce pancreas size.

    Now, a study of one family from Alabama has led Vanderbilt University Medical Center researchers to discover that insulin deficiency, independent of the autoimmunity associated with Type 1 diabetes, is the principal factor leading to a markedly smaller pancreas.

    Four members of this family of eight have monogenic diabetes from a rare mutation in the insulin gene, leading to insulin deficiency without autoimmunity. Magnetic resonance imaging (MRI) of the pancreas showed a reduced size and altered shape in the individuals with diabetes. This was similar to what had previously been observed in individuals with Type 1 diabetes. These new findings are published in Diabetes Care, a journal of the American Diabetes Association.

    “This is a wonderful story about the power of a single family to inform us about the process of a disease that affects millions of people,” said Daniel Moore, MD, PhD, associate professor of Pediatrics in the Ian Burr Division of Pediatric Endocrinology and Diabetes. “There are not many families, especially not large families, who are known to have exactly this form of diabetes, who could come forward to help us answer this question. But they responded to the call, and they’ve provided a really clear answer to a fundamental biologic question.”

    About two decades ago, David Pursell and his wife, Ellen, agreed that he and three of their six children who were diagnosed with diabetes would participate in research with the hope more could be learned about the disease. It was as simple as giving a little blood.

    They were surprised years later when a researcher from the University of Chicago’s Kovler Diabetes Center called to tell them that advances in science had revealed that the four actually had monogenic diabetes due to a mutation in the insulin gene instead of Type 1 diabetes.

    Last year, the Pursells were contacted by VUMC researchers who were collaborating with Siri Greeley, MD, PhD, and colleagues at the Kovler Diabetes Center’s Monogenic Diabetes Registry. The Vanderbilt research team asked if the family could travel to Nashville to have precise measurements of their pancreas taken at the Medical Center.

    The VUMC research team, which includes Moore, Jordan Wright, MD, PhD, Jon Williams, PhD, Melissa Hilmes, MD, and Alvin C. Powers, MD, along with colleague Jack Virostko, PhD, at The University of Texas at Austin, had previously found the reduction in pancreas size was present at the time of Type 1 diabetes diagnosis. The Vanderbilt investigators had also organized an international team, the Multicenter Assessment of the Pancreas in Type 1 Diabetes (MAP-T1D), to develop a standardized MRI imaging protocol to assess pancreas volume and microarchitecture.

    “We know the pancreas is much smaller in individuals with Type 1 diabetes, but there haven’t been good models to understand exactly what’s going on,” said Wright, an instructor in the Division of Diabetes, Endocrinology and Metabolism and first author on the manuscript. “This is the first time we can actually demonstrate in humans that insulin is a major factor in determining pancreas size and the loss of it leads to a much smaller pancreas.”

    David and Ellen and their now adult children, Peggy Rice, Vaughan Spanjer, Chrissy Adolf, Ramsey Nuss, and twin sons Parker and Martin Pursell, each had their pancreas size measured using the standardized Vanderbilt MRI protocol. David, Chrissy, Parker and Martin have monogenic diabetes.

    “When we talked to the doctors at Kovler, they asked if we’d be interested in participating in some trials or research and we said, ‘Of course, anything we can do,’” said David Pursell. “When we learned our diabetes was not caused by an immune response due to our islet cells being attacked by antibodies, then we thought maybe we’ve got the chance of getting an islet cell transplant.

    “But also, we’re obviously all in this together. If, by virtue of our family volunteering for this research we can help anyone else, we felt like it would be worth it.”

    This research was performed with assistance from the Vanderbilt University Institute of Imaging Sciences (National Institutes of Health [NIH] project 1S10OD021771-01), the Vanderbilt Institute for Clinical and Translational Research (UL1-TR000445) and the Institute for Translational Medicine (UL1-TR000430) and with the support of the Leona M. and Harry B. Helmsley Charitable Trust, the Juvenile Diabetes Research Foundation, the Doris Duke Charitable Foundation, the NIH (DK104942, DK129979) and the Vanderbilt and Chicago Diabetes Research and Training Centers (DK20593, DK20595).

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  • Elite athletes with genetic heart disease can safely return to play with diagnosis and treatment, early study suggests | CNN

    Elite athletes with genetic heart disease can safely return to play with diagnosis and treatment, early study suggests | CNN

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    CNN
     — 

    In a new study, most elite athletes with a diagnosed genetic heart disease did not experience serious or fatal symptoms of their condition, such as sudden cardiac death. The research suggests it can be “feasible” and “safe” for athletes to continue to participate in their sport.

    Among a sample of 76 elite athletes with a genetic heart disease who had competed or are still competing in either Division I university or professional sports, 73 out of the 76 did not experience a cardiac event triggered by their disease during the study period, according to researchers behind a late-breaking clinical trial presented Monday at the American College of Cardiology’s Annual Scientific Session Together With the World Congress of Cardiology.

    Among those elite athletes with a genetic heart disease, 40 of them – 52% – were asymptomatic, the study abstract finds.

    Over the years, researchers have become more aware of alarming reports about elite athletes experiencing heart problems, or even suddenly collapsing during games.

    “For athletes with genetic heart conditions, and I would add non-athletes, the tragedies occur when we don’t know of their condition,” said Dr. Michael Ackerman, a genetic cardiologist at Mayo Clinic in Rochester, Minnesota, who was a senior author of the new research. “When we know of their condition, and we assess the risk carefully and we treat it well, these athletes and non-athletes, they can expect to live and thrive despite their condition.”

    The new research has not yet been published in a peer-reviewed journal, but the findings suggest that many athletes with a genetic heart disease can decide with their health care professionals on whether to continue competing in their sport and how to do so safely, instead of being automatically disqualified due to their health conditions.

    “In sports, historically, we’ve been paternalistic and de-emphasize patient preference and risk tolerance, but we know that athletes come from all walks of life. They are intelligent and when there’s scientific uncertainty, their values should be incorporated in medical decision-making,” Dr. J. Sawalla Guseh, cardiologist at Massachusetts General Hospital, who was not involved in the new study, said during Monday’s scientific session.

    “Shared decision-making when done well can have very favorable outcomes,” he said.

    Elite basketball, hockey, soccer and football players, were among the 76 athletes included in the new study, conducted by researchers at Mayo Clinic and other institutions in the United States. They wrote in their study abstract that this is the first study to their knowledge describing the experience of athletes competing at the NCAA Division I level or in professional sports with a known genetic heart disease that puts them at risk of sudden cardiac death.

    The athletes in the study were cleared for return-to-play at either a NCAA Division I school or at the professional level. They were studied over an average of seven years, and all had been diagnosed with a genetic heart disease in the past 20 years, being treated at either Mayo Clinic, Morristown Medical Center, Massachusetts General Hospital or Atrium Health Sports Cardiology Center.

    “Only three of them had a breakthrough cardiac event, which means after they were diagnosed and treated, they were still having an event,” said Katherine Martinez, an undergraduate student at Loyola University in Baltimore, who helped conduct the research as an intern in the Mayo Clinic’s Windland Smith Rice Sudden Death Genomics Laboratory.

    Fainting was the most common event, and one athlete received a shock with an implantable cardioverter defibrillator, or ICD. None of the athletes died.

    “The majority of these athletes went on to continue their career with no events at all,” Martinez said. But most of the athletes in the study – 55 of them, or 72% – were initially disqualified from competing by their primary provider or institution after their diagnosis. Most ultimately opted to return to play with no restrictions after undergoing comprehensive clinical evaluations and talking with their doctors.

    While each sports league has its own set of rules, historically, some people diagnosed with a genetic heart disease that puts them at an increased risk for sudden cardiac death have been restricted from competitive sports, the researchers wrote in their study abstract.

    “Just because you were given this diagnosis, doesn’t mean that your life, your career, the future that you see for yourself is over, but taking a second opinion from an expert who knows what they’re doing and is comfortable with shared decision-making is the next step,” said Martinez, who worked on the new research alongside her father, Dr. Matthew Martinez, director of Atlantic Health System Sports Cardiology at Morristown Medical Center and an author of the new research.

    Regarding the new study, “the take-home message is, if you have one of these findings, seek out an expert who’s going to help you identify a safe exercise plan for you and determine what level you can continue to safely participate in,” he said. “This is the next best step – the next evolution – of how we manage athletes with genetic heart disease.”

    Leaving their sport due to a genetic heart disease can be “very destructive” for athletes who have devoted their lives to excelling in competitions, said Dr. Lior Jankelson, director of the Inherited Arrhythmia Program at NYU Langone Heart in New York, who was not involved in the new research.

    Yet he added that these athletes still need to consult with their doctors and be watched closely because some genetic diseases could be more likely to cause a serious cardiac event than others.

    The new study highlights that “the majority of athletes with genetic heart disease could probably – after careful, meticulous expert risk-stratification and care strategy – participate in sports,” Jankelson said. “But at the same time, this is exactly the reason why these patients should be cared only in high-expertise genetic cardiology clinics, because there are other conditions that are genetic, that could respond very adversely to sports, and have a much higher risk profile of developing an arrhythmia during intense activity.”

    Separately, the NCAA Sports Science Institute notes on its website, “Though many student-athletes with heart conditions can live active lives and not experience health-related problems, sudden fatality from a heart condition remains the leading medical cause of death in college athletes.”

    For athletes with a genetic heart disease, their symptoms and their family history of cardiac events should be considered when determining their risks, said Dr. Jayne Morgan, a cardiologist with Piedmont Healthcare in Atlanta, who was not involved in the new research.

    “Certainly, there is concern with elite athletes competing and whether or not they are being screened appropriately,” Morgan said. But she added that the new research offers “some understanding” to the mental health implications for athletes with a genetic heart disease who may be required to step away from a competitive sport that they love.

    “This study, I think, begins to go a long way in identifying that we may not need to pull the trigger so quickly and have athletes step away from something that they love,” Morgan said.

    The new study is “timely” given the recent national attention on athletes and their risk of sudden cardiac death, Dr. Deepak Bhatt, director of Mount Sinai Heart in New York City, who was not involved in the research, said in an email.

    “These are some of the best data showing that the risk of return to play may not be as high as we fear,” Bhatt said about the new research.

    “Some caveats include that the majority of these athletes were not symptomatic and about a third had an implantable defibrillator,” he added. “Any decision to return to the athletic field should be made after a careful discussion of the potential risks, including ones that are hard to quantify. Input from experts in genetic cardiology and sports cardiology can be very helpful in these cases.”

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  • Israel: the origin of the world’s grapevines

    Israel: the origin of the world’s grapevines

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    Newswise — A recent study on the genetic makeup of grapevine has revealed fascinating insights into its domestication and evolution. The study, published in the journal Science, suggests that the harsh climate during the Pleistocene era resulted in the fragmentation of wild ecotypes, which paved the way for the domestication of grapevine about 11,000 years ago in the Near East (Israel) and the Caucasus.

    The research team sequenced the genomes of 3525 grapevine accessions (2503 V. vinifera (domesticated) and 1022 V. sylvestris (wild) accessions of grapevine, to identify the genetic changes that occurred during domestication and evolution of grapevine in Euro-Asia.

    According to the study, the Near East (Israel) wild grapevine population (Syl-E1) is the source for the domestication of table grapes, which then dispersed into Europe with early farmers, introgressed with ancient wild western ecotypes, and diversified into unique western wine grape ancestries by the late Neolithic.

    Furthermore, the study shows that hybridization with local V. sylvestris was common in creating extant European wine grapes. However- when these introgression events occurred, remain unknown.

    Dr Elyashiv Drori, Head of the Samson Family Grape and Wine Research Centre at Ariel University and Eastern Regional R&D Center says, “Our findings provide important insights into the domestication and evolution of grapevine, which is a religiously, culturally and economically important crop.

    The indigenous grapevine population we have collected in the last 12 years, containing both wild and domesticated subpopulations, have central importance in this research. The Israeli wild grapevines (Syl -E1) were found to be the source of domestication for all the cultivated group of table grapes (CG1), which includes the Israeli domesticated grapevines. This initial group of grapevine varieties then were dispersed to eastern and western Europe, to form most of the known winegrapes.  We now aim to deeply study the characteristics of Israel’s indigenous grapevine, which were developed in the dry and harsh conditions of the Levant, and may pose a repository for resistance genes.

    With climate change and emerging diseases threatening vineyards worldwide, the study’s findings may help in developing new strategies to protect and sustain the wine industry for future generations.

    Prof Ehud Weiss, head of the archaeobotanical lab at Martin (Szuss) Department of Land of Israel, Bar Ilan University, a specialist in the domestication of crops and archaeobotany, gave important insights as to the domestication history. Prof Weiss adds “this is a research breakthrough in the field of the beginning of agriculture as well. The accepted view was that annual crops, like wheat, barley, and legumes, were domesticated some 10,000 years ago, while perennials were domesticated thousands of years later. Current research changes this view and demonstrates these transitions occurred simultaneously, and moreover, with the same species, some 1,600 kilometers apart – a phenomenon we have never met.”

    Two Israeli scientists collaborated with Dr. Drori’s team in this project. Prof Ehud Weiss collaborated with Dr. Drori to identify the varieties used by ancestors in the land of Israel using genetic and morphological tools. Dr. Sariel Hubner from Migal is a bioinformatician. Dr. Hubner is working with Dr. Drori’s group on the population genetics of the Israeli wild and domesticated grapevines. This collaborative research group published the first research paper describing the possible local domestication of grapevine in Israel in 2021 (Sivan 2021). 

    This is a ground-breaking study also in the field of the beginnings of agriculture. This is the first research proof that the domestication of a perennial plant happened at the same time as the domestication of annuals, wheat, barley, legumes, and flax. Until today, it was common to say that fruit trees were domesticated several thousand years later. In addition, the double domestication of the same species into two varieties, in our case the edible grape variety and the wine grape variety, happened at the same time in two separate geographical centers – a phenomenon we had not known until now.

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    Ariel University

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  • New link between fatal muscle wasting disease gene and cancer discovered

    New link between fatal muscle wasting disease gene and cancer discovered

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    Newswise — Mutations of the gene encoding dystrophins have long been known to cause the debilitating muscle-wasting disease DMD, which affects one in every 5,000 boys born. People with the condition will usually only live into their 20s or 30s.

    Now, a study, led by the University of Portsmouth, has found that the same gene has a role in oncology. A team of international researchers analysed a broad spectrum of malignant tissues, including from breast, ovarian, and gastrointestinal cancer patients. 

    The DMD gene expression was reduced in 80 per cent of these tumours. This low expression of dystrophins was associated with a more advanced stage of cancer and reduced survival across different tumours.

    The paper, published in Cancers, calls for a re-evaluation of the current view that dystrophin expression is only important in muscles, and when found across numerous tissues is the result of an “illegitimate transcription”.

    Senior author, Professor Darek Gorecki from the School of Pharmacy and Biological Sciences at the University of Portsmouth, said: “The findings that the DMD gene has a role in tumours, expands the growing evidence of its significance beyond Duchenne muscular dystrophy.

    “Further investigation is needed to better understand the role of DMD in malignancies and how it may be exploited in  monitoring cancer progression and treatment.”

    Moreover, these findings build on the recent discovery that the disease begins much earlier than previously thought. In 2021, the team published results of modelling DMD to look at its development, from its initial trigger and first manifestation. They found evidence of abnormalities even before birth in the embryo. 

    Given the similarities between early embryo development and cancer formation, including invasive potential, changes in gene expression and other vital behaviours, the team decided to investigate the DMD gene across the spectrum of tumours, which led to this discovery.

    Most boys with DMD are diagnosed between two and five years old by which time the damage to their bodies is already significant. 

    Professor Gorecki says these new findings should be taken into consideration as delay in identifying the condition may be preventing therapeutic interventions that could help slow, if not stop, disease progression.

    “The job of DMD, the largest human gene known, is far more complex than previously believed”,  he explained.

    “It must be better understood if we want to find effective treatments for pathologies caused by its mutations.”

    ENDS

    Notes to editors:

    The study ‘Downregulation of Dystrophin Expression Occurs across Diverse Tumors, Correlates with the Age of Onset, Staging and Reduced Survival of Patients’ can be viewed online here: https://www.mdpi.com/2072-6694/15/5/1378

    About the University of Portsmouth

    • The University of Portsmouth is a progressive and dynamic university with an outstanding reputation for innovative teaching and globally significant research and innovation.
    • The University’s research and innovation culture is impacting lives today and in the future and addressing local, national and global challenges across science, technology, humanities, business and creative industries. http://www.port.ac.uk/
    • The University actively promotes the incredible work being carried out here, including through the Life Solved podcast series. Search ‘Life Solved’ on your podcast streaming platform or visit our pod follow page: https://podfollow.com/uoplifesolved/view

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    University of Portsmouth

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  • Risk of cancer remains high for women over 50 with genetic BRCA1 or BRCA2 mutation

    Risk of cancer remains high for women over 50 with genetic BRCA1 or BRCA2 mutation

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    Newswise — Although genetic mutations in BRCA1 or BRCA2 are associated with a younger onset of breast and ovarian cancer, women with these genetic mutations continue to face a high risk of cancer incidence after age 50, even if they have not been previously diagnosed with cancer. This is according to a new study led by Kelly Metcalfe, a professor at the Lawrence S. Bloomberg Faculty of Nursing.

    The study published recently in the American Cancer Society Journal Cancer, followed over 2000 women between the ages of 50 to 75, from 16 countries, who were aware they had a BRCA mutation and had no previous diagnosis of cancer. The study found that the cumulative risk of these women developing any type of cancer after the age of 50 was 49 percent for those with a BRCA1 mutation and 43 per cent for those with a BRCA2 mutation.  For those in the study cohort who had not undergone a cancer risk-reduction surgery, the risk was even greater at 77 per cent for those with a BRCA1 mutation and 67 per cent for those with a BRCA2 mutation.

    “What is striking about our results is that breast and ovarian cancers were the most frequently observed cancers occurring and that is concerning, considering we know how to reduce the risk of cancer in women who have these genetic risk factors,” says Metcalfe who is also a Senior Scientist at Women’s College Hospital.

    Of the women included in the study only 15 percent underwent a preventative bilateral mastectomy, and 43 percent a bilateral salpingo‐oophorectomy (BSO) – removal of both ovaries and fallopian tubes – before the age of 50. The study found that these women had the lowest risk of any occurrence of cancer at just 9 per cent.

    “Our analysis highlights the effectiveness of these risk reduction surgeries, and emphasizes the need for individuals as well as health care providers, to consider clinical guidelines and recommendations for their cancer risk, including how their genetics might impact them even at a later age,” says Metcalfe.

    She acknowledges that there are some limitations to the study including the fact that in some countries access to risk reduction surgeries may be limited, and knowledge of how often or whether these women received genetic counselling was not assessed.

    “We are not aware of whether the participants in our study received additional counselling about their elevated risk of cancer as they age and we are also unable to determine why some of these women chose to forgo preventative surgery before the age of 50,” says Metcalfe. “However, it is important to point out that screening alone only reduces mortality risk by increasing the chances of detecting the cancer early, it does not reduce the risk of cancer occurring.”

    Understanding the limitations of screening is of particular importance for women with either a BRCA1 or BRCA2 mutation especially in assessing their risk of ovarian cancer, as no good screening method exists to detect the cancer early enough. Metcalfe’s study references the National Comprehensive Cancer Network (NCCN) guidelines where it is recommended that women with a BRCA1 mutation undergo a BSO between ages 35-40 and those with BRCA2 mutation between 40-45.

    Future studies says Metcalfe, will look at exploring women’s decision-making around whether or not to undergo surgery and their own understanding of risk. For now, Metcalfe is hopeful that advances in genetic testing will help make it more accessible to all women who want to know their risk status.

    The Screen Project Canada, housed at Women’s College Hospital, is one example of a consumer-based model of testing where individuals can pay to access genetic testing that allows anyone, regardless of family history, to find out if they carry a BRCA1 or BRCA2 mutation. While it currently operates at a small cost to the patient, Metcalfe believes that lower barriers to genetic testing will not only save lives, but eventually become a mainstay of cancer care in Canada.

    “It has been over 25 years since clinical testing for BRCA1 and BRCA2 began in Canada and the United States, we have come a long way in reducing cancer incidence, but not far enough,” says Metcalfe. “The majority of cancers resulting from these two genes are preventable, we need to be offering women the best chance at a cancer-free life.”

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    University of Toronto

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  • Making engineered cells dance to ultrasound

    Making engineered cells dance to ultrasound

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    Newswise — Let’s say you needed to move an individual cell from one place to another. How would you do it? Maybe some special tweezers? A really tiny shovel?

    The fact is that manipulating individual cells is a difficult task. Some work has been done on so-called optical tweezers that can push cells around with beams of light, but while they are good at moving a single cell around, they are not intended for manipulating larger numbers of cells.

    New research conducted at Caltech has created an alternative: air-filled proteins, produced by genetically engineered cells, that can be pushed around—along with the cells containing them—by ultrasound waves. A paper describing the work appears in the journal Science Advances.

    The work builds on previous work conducted in the lab of Mikhail Shapiro, professor of chemical engineering and medical engineering and investigator with the Howard Hughes Medical Institute.

    Shapiro has for years worked with gas vesicles derived from bacteria as an acoustic tag. These vesicles, which are air-filled capsules of protein, provide buoyancy to some species of aquatic bacteria. But they also have another useful quality: Because of their air-filled interiors, they show up quite strongly in ultrasound imagery. Shapiro’s discovery of this quality has led his lab to develop gas vesicles as a genetic marker for tracking the location of individual bacterial cells, and for observing gene-expression activity in mammalian cells deep inside the body.

    Now, Shapiro and his colleagues have shown that these vesicles can push and pull cells into specific locations under the influence of ultrasound. The phenomenon is very similar to how ultrasound in air can be used to suspend and/or move small, light objects. This is due to the fact that sound waves create pressure zones that act on objects in their vicinity. The physical properties of an object or material determine whether it will be attracted to a high-pressure zone or repulsed by it. Normal cells are pushed away from areas of higher pressure, but cells containing gas vesicles are attracted to them.

    “We’ve used these vesicles for imaging previously, and this time we’ve shown that we can actually use them as actuators so we can apply force to these objects using ultrasound,” says Di Wu (MS ’16, PhD ’21), a research scientist in Shapiro’s lab and the study’s lead author. “What this allows us to do is to move cells around in space using ultrasound and to be able to do so in a very selective manner.”

    Shapiro and Wu say there a few reasons you might want to be able to move cells around. For one, tissue engineering—the creation of artificial tissues for research or medical purposes—requires cells of specific types to be arranged in complex patterns. An artificial muscle might need multiple layers of muscle cells, cells that create tendons, and nerve cells, for example.

    Another case in which you might want to move cells around is in cell-based therapy, a field of medicine in which cells with desirable properties are introduced into the body.

    “You’re introducing engineered cells into the body, and they go all over the place to find their target,” Di says. “But with this technology, we potentially have a way to guide them to the desired location into the body.”

    As a demonstration, the team showed that cells containing gas vesicles can be forced to clump into a small ball, or arranged as thin bands, or pushed to the edges of a container. When they changed the ultrasound pattern, the cells “danced” to take up new positions. They also developed an ultrasound pattern that pushed the cells into the shape of the letter “R” in a gel that held them in that shape after it solidified. They call the resulting figure an “acoustic hologram.”

    Wu says one area where their research has the potential for immediate impact is in cell sorting, a process necessary for various kinds of biological and medical research.

    “A common way people sort cells now is to engineer them to express a fluorescent protein and then use a fluorescent-activated cell sorter (FACS),” he says. “That is a $300,000 piece of equipment that is bulky, often lives in a biosafety cabinet, and doesn’t sort cells very fast.”

    “In contrast, acousto-fluidic sorting can be done with a tiny little chip that costs maybe $10. The reason for this difference is that in fluorescent sorting, you have to separately measure the gene expression of the cells and then move them. This is done one cell at a time. With gas vesicle expression, the cell’s genetics are directly linked to the force that’s being applied to the cell. If they express gas vesicles, they will experience a different force, so we don’t need to separately check if they’re expressing gas vesicles and then move them; we can move them all at once. That greatly simplifies things.”

    The paper describing the research, titled “Biomolecular actuators for genetically selective acoustic manipulation of cells,” appears in the February 22 of Science Advances. Additional co-authors are former Caltech medical engineering PhD students Colin Cook (MS ’16, PhD ’19), who is now a staff scientist at City of Hope; and David R. Mittelstein (MS ’16, PhD ’20), who is now a resident physician at Scripps Health; former postdoctoral fellow David Maresca, who is now an assistant professor at Delft University of Technology, Netherlands; Caltech chemical engineering graduate student Maria Abundo and bioengineering graduate students Mengtong Duan, Justin Lee, and Shirin Shivaei; Dina Malounda of the Howard Hughes Medical Institute, Diego Baresch of the University of Bordeaux in France; Zhichao Ma of the Max Planck Institute for Intelligent Systems in Stuttgart, Germany; Tian Qiu of the University of Stuttgart, Germany; and Peer Fischer of the Max Planck Institute for Medical Research and Heidelberg University in Heidelberg, Germany.

    Funding for the research was provided by the National Institutes of Health, the U.S. Army’s Institute for Collaborative Biotechnologies, the David and Lucile Packard Foundation, and the Pew Charitable Trust. Mikhail Shapiro is an affiliated faculty member with the Tianqiao and Chrissy Chen Institute for Neuroscience at Caltech.

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    California Institute of Technology

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