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Tag: Genetics

  • Breast cancer by age: Study reveals early mutations that predict patient outcomes

    Breast cancer by age: Study reveals early mutations that predict patient outcomes

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    Newswise — LA JOLLA, CALIF. – June 30, 2023 – A study led by researchers at Sanford Burnham Prebys has found that in young women, certain genetic mutations are associated with treatment-resistant breast cancer. These mutations are not linked to treatment-resistant breast cancer in older women. The findings, published in the journal Science Advances, could help improve precision medicine and suggest a brand-new way of classifying breast cancer.

    “It’s well established that as you get older, you’re more likely to develop cancer. But we’re finding that this may not be true for all cancers depending on a person’s genetic makeup,” says senior author Svasti Haricharan, Ph.D., an assistant professor at Sanford Burnham Prebys. “There may be completely different mechanisms driving cancer in younger and older people, which requires adjusting our view of aging and cancer.”

    The research primarily focused on ER+/HER2- breast cancer, which is one of the most common forms of the disease. It is usually treated with hormonal therapies, but for some patients, these treatments don’t work. About 20% of tumors resist treatment from the very beginning, and up to 40% develop resistance over time.

    “Understanding how certain forms of breast cancer develop in a way that makes them eventually resist therapy can help us better classify the disease. It may also help clinicians adjust the treatment plans for patients who will likely experience resistance to standard treatments,” says Haricharan. “For scientists like myself, it can help guide research to develop new therapies to overcome these obstacles.”

    The study included an extensive analysis of a large database of breast cancer patients. It revealed that in ER+/HER2- breast cancer patients, certain gene mutations had a strong correlation with response to treatment—and the effects were dependent on age. Some gene mutations were only linked with treatment-resistant breast cancer in younger women.

    “This was a strange finding, so much so that we almost didn’t believe it at first,” says Haricharan. “But the same patterns emerged over and over again in database after database.”

    The mutations the researchers identified were in genes involved in cell replication, the process by which cells grow and divide. These genes are responsible for repairing mistakes when they happen—a process that goes awry in virtually all cancers.

    “Cell cycle dysregulation occurs so early in the development of cancer that we generally don’t consider whether the individual mutations that cause cell cycle dysregulation can affect cancer’s eventual response to treatment or its ability to spread,” says Haricharan.

    By connecting the specific type of cell cycle dysregulation that triggers cancer with the outcome of the disease many years after diagnosis, the research team proposes an entirely new paradigm for thinking about and studying all types of cancer.

    “This is a radical shift in how we look at cancer, which could have implications well beyond breast cancer,” adds Haricharan.

    To begin to test this idea, the researchers analyzed the effect of cell cycle mutations on patient outcomes in other types of cancer. In a final twist, they observed that across many cancer types, the mode of cell cycle dysregulation is significant for cancer in women, but less so for cancer in men. This suggests that the influence of cell-cycle dysregulation could depend on sex as well as age.

    “These findings emphasize why it is important to study cancer in the context of the life history of the patient,” adds Haricharan. “Too often, cancer research is focused narrowly on cells in a petri dish, forgetting the whole, complex host system in which these cells transform and grow.”

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    Additional authors on the study include Elena Oropeza, Sinem Seker, Sabrina Carrel, Aloran Mazumder, Daniel Lozano, Athena Jimenez and Nindo B. Punturi, Sanford Burnham Prebys; Sabrina N. VandenHeuvel, Dillon A. Noltensmeyer and Susan E. Waltz, University of Cincinatti; Jonathan T. Lei and Bora Lim, Baylor College of Medicine; Shreya A. Raghavan, Texas A&M University; and Matthew N. Bainbridge, Rady Children’s Institute for Genomic Medicine.

    The study was supported by grants from Susan G. Komen (CCR18548157), the American Cancer Society (978170) and the National Cancer Institute (K22 CA229613, R21 CA263768, R37 CA269224, T32 CA203690). Additional support was provided by the California Institute for Regenerative Medicine, Takeda Oncology, Merck, Genentech, Puma Biotechnology, the National Institutes of Health, the Department of Defense, the Chan Zuckerberg Institute, the Adopt a Scientist Program, and the Texas A&M Engineering Experiment Station.

    The study’s DOI is 10.1126/sciadv.adf2860.

    About Sanford Burnham Prebys

    Sanford Burnham Prebys is an independent biomedical research institute dedicated to understanding human biology and disease and advancing scientific discoveries to profoundly impact human health. For more than 45 years, our research has produced breakthroughs in cancer, neuroscience, immunology and children’s diseases, and is anchored by our NCI-designated Cancer Center and advanced drug discovery capabilities. For more information, visit us at SBPdiscovery.org or on Facebook facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.

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    Sanford Burnham Prebys

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  • Super crops are coming: Is Europe ready for a new generation of gene-edited plants?

    Super crops are coming: Is Europe ready for a new generation of gene-edited plants?

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    Brussels is finalizing a law to legalize new gene-editing technologies for crops across the European Union.

    The EU’s ultra-restrictive GMO regulation, which predates newer technologies, sets extremely high hurdles for growing genetically engineered crops and allows EU countries to ban them even after they have been proven to be safe.

    The new law aims to cut red tape and allow easier market access for plants grown with “new genomic techniques” (NGTs), such as CRISPR-Cas9, which target specific genes without necessarily introducing genetic material from outside the breeders’ gene pool.

    The rules are being pushed by multinationals such as Bayer, Syngenta and Corteva, which together control the lion’s share of the plant breeding sector, as well as a host of smaller companies, scientists and farmers’ groups such as Copa-Cogeca.

    They argue that the EU risks falling behind the rest of the world in using new crops with special traits that can make them more nutritious, efficient and better adapted to a changing climate.

    Pitted against them are green lawmakers, environmental advocacy groups, organic and small farmers, and more than 400,000 EU citizens who have signed a petition against deregulating what they call “new GMOs.”

    These groups say the rules will further tighten the grip of the handful of multinationals, allowing them to claim patents on crops that could have been obtained through conventional breeding methods, while threatening non-GM and organic production. They also argue that because NGTs have only been around for just over a decade, questions remain about their safety.

    According to a leaked draft, EU countries will no longer be able to ban the cultivation of NGT crops.

    The law simplifies rules even more for a sub-group of NGT crops that are deemed equivalent to crops obtained by traditional breeding techniques. The obligation to label foods as “GMO” will no longer apply to these “conventional-like” plants, and they won’t be subject to risk assessment by food safety regulators.

    An earlier draft of the law had a carve-out for crops engineered to tolerate herbicides — which would still have been subject to the stricter GMO rules. However, a newer draft no longer makes such a distinction.

    The European Commission is due to unveil the proposed law on gene-edited crops on Wednesday, as part of the latest package of measures under its Green Deal environment and sustainability agenda. This will include a new law on soil health, revisions of the food waste and textiles aspects in the EU Waste Framework Directive, and legislation on seeds and other plant and forest reproductive material.

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    Bartosz Brzezinski and Jakob Hanke Vela

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  • A new model allows us to see and understand human embryonic development like never before.

    A new model allows us to see and understand human embryonic development like never before.

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    Newswise — Two to three weeks after conception, an embryo faces a critical point in its development. In the stage known as gastrulation, the transformation of embryonic cells into specialized cells begins. This initiates an explosion of cellular diversity in which the embryonic cells later become the precursors of future blood, tissue, muscle, and more types of cells, and the primitive body axes start to form. Studying this process in the human-specific context has posed significant challenges to biologists, but new research offers an unprecedented window into this point in time in human development.

    A recent strategy to combat these challenges is to model embryo development using stem cell technologies, with many valuable approaches emerging from research groups across the globe. But embryos don’t grow in isolation and most previous developmental models have lacked crucial supporting tissues for embryonic growth. A groundbreaking model that includes both embryonic and extraembryonic components will allow researchers to study how these two parts interact around gastrulation stages—providing a unique look at the molecular and cellular processes that occur, and offering potential new insights into why pregnancies can fail as well as the origins of congenital disorders. The team, including Berna Sozen, PhD, and Zachary Smith, PhD, both assistant professors of genetics at Yale School of Medicine (YSM), published its findings in Nature on [tk].

    “This work is extremely important as it provides an ethical approach to understand the earliest stages of human growth,” says Valentina Greco, PhD, the Carolyn Walch Slayman Professor of Genetics at YSM and incoming president-elect of the International Society for Stem Cell Research (ISSCR), who was not involved in the study. “This stem cell model provides an excellent alternative to start to understand aspects of our own early development that is normally hidden within the mother’s body.”

    “The Sozen and Smith groups have achieved a milestone in developing in vitro models to study the earliest stages of human development that are unfeasible yet so important for understanding health and disease,” says Haifan Lin, PhD, the Eugene Higgins Professor of Cell Biology, director of the Yale Stem Cell Center, and president of ISSCR. “I commend their exceptional accomplishment as well as their sensitivity to ethical issues by limiting the model’s ability to develop further”

    The ethical questions are profound, including whether these models have the potential to develop into human beings. Sozen, the principal investigator of the study, emphasizes that they do not. The published paper demonstrates that this model lacks trophectodermal cells, which are required for an embryo to implant in the uterus. Sozen says this model also represents a developmental stage beyond the time frame in which embryos can implant. “It is very important to focus on the fact that our model cannot grow further or implant and therefore is not considered a human embryo,” she says. But as a reductionist strategy to mimic and study aspects of natural development, its potential is immense, especially where universal guidelines severely limit scientists’ ability to study actual embryos.

    New Model Contains Embryonic and Extraembryonic Tissues

    All embryos have two components—embryonic and extraembryonic. The tissues we have now in our adult bodies grew from the embryonic component. The extraembryonic component includes the tissues that offer nutritional and other support, such as the placenta and yolk sac. The majority of previous embryo models of developmental stages around gastrulation were single-tissue models that only contained the embryonic component.

    In the new study, the Yale-led team grew embryonic stem cells in vitro in the lab to generate their new model. They transferred these cells into a 3D culture system and exposed them to a conditions which stimulated the cells to spontaneously self-organize and differentiate. The cells diverged into two lineages—embryonic and extraembryonic precursors. The extraembryonic cells in this model were precursors for the yolk sac. The researchers grew these cellular lineages in the culture for approximately one week and analyzed how they guided each other as they developed. “We started looking into very mechanistic details, such as what signals they are giving each other and how specific genes are impacting one another,” says Sozen. “This has been limited in the literature previously.”

    The Need for Models of Human Development

    While researchers have learned a great deal from embryos of other species such as mouse, the lack of accessibility to human embryos has left significant knowledge gaps about our development. “If you want to understand human development, you need to look at the human system,” says Sozen. “This work is really important because it’s giving us direct information about our own species.” Not only does this model give access into the human gastrulation window, but will also allow for a greater quantity of research. The ability to generate as many as thousands of these models will allow for mass analysis that is not possible with human embryos. “I’m one scientist with one vision,” says Sozen. “But thinking about what other scientists are envisioning globally and what we can all accomplish is just really, really exciting to me.”

    The new model has over 70% efficiency—in other words, the stem cells aggregate correctly over roughly 70% of the time. As noted by the authors, there are some limitations to the strategy, and it is challenging to benchmark some findings against the natural embryo itself. Sozen hopes to continue to work on the models so that they become more standardized in the future.

    The team believes the models will transform scientists’ knowledge around human developmental biology. In their latest publication, the team explored some of the molecular paths underlying human gastrulation onset. In future studies, they hope to delve even deeper into the developmental pathways, including whether pregnancy loss and congenital disorders may stem from failures during gastrulation stages. Sozen believes her model can be used to look at some of these disorders and learn more about what is going awry. “Previous model systems have been able to look at this, but our model is unique because it has this extra tissue that allows us to analyze a bit deeper,” she says.  

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    Yale University

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  • توصلت أبحاث Mayo Clinic أن من يعانون من السُمنة المفرطة وأحد المتغيرات الجينية، عرضة أكثر للإصابة بارتفاع ضغط الدم

    توصلت أبحاث Mayo Clinic أن من يعانون من السُمنة المفرطة وأحد المتغيرات الجينية، عرضة أكثر للإصابة بارتفاع ضغط الدم

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    Newswise — روتشستر ، مينيسوتا – تعتبر السمنة وما يرتبط بها من مشاكل في القلب والأوعية الدموية مصدر قلق كبير في جميع أنحاء العالم. وجدت دراسة أجرتها Mayo Clinic أن الأشخاص الذين يعانون من السمنة ولديهم متغير جيني معين معرضون بشكل متزايد لخطر الإصابة بارتفاع ضغط الدم. 

    مع السمنة ، يزداد خطر الإصابة بأمراض القلب والأوعية الدموية ، والتي تشمل السكتة الدماغية وفشل القلب الاحتقاني واحتشاء عضلة القلب. السمنة مرض متعدد العوامل ينتج عن اختلال توازن الطاقة. السمنة عامل خطر قابل للتعديل لأمراض القلب والأوعية الدموية. 

    وضحت ليزيث سيفينتس، دكتور في الطب “الباحثة في علم الجهاز الهضمي في Mayo Clinic “يتم التحكم في وزن الجسم من خلال مجموعة معقدة ومتعددة من التفاعلات بين العوامل الوراثية والعوامل البيئية. “تتراوح احتمالية الإصابة بالسُمنة الوراثية بين 40% إلى 70%، ولكن فقط 10% من حالات السُمنة المفرطة المبكرة تحدث بسبب جيني.” 

    تلك المتغيرات هي نتيجة لحدوث طفرات متنحية في الجينات المسؤولة عن مسار الليبتين والميلانوكورتين، وهو المسار المسؤول عن تنظيم تناول الطعام ووزن الجسم. وتعد هذه التغيرات الجينية الأكثر انتشارًا، حيث لوحظ وجودها في 6% من الأطفال و2.5% من البالغين الذي يعانون من السُمنة المفرطة المبكرة. 

    وفي برنامج الطب الدقيق للسُمنة التابع لـ Mayo Clinic، أرادت د. سيفينتس وزملاؤها دراسة الاختلافات بين عوامل الخطر للمرض القلبي الوعائي وبين الأمراض التي تصيب من يعانون من السُمنة المفرطة، سواءً كان لديهم المتغير الجيني أو لم يكن. ووضحت “بفهم تأثير هذه المتغيرات على صحة القلب والأوعية الدموية يمكننا مساعدة الأطباء لعلاج عوامل الخطر القابلة للتعديل في مرضى السُمنة المفرطة.” 

    لتحقيق ذلك، قام الباحثون بعمل دراسة مستعرضة على المشاركين في البنك الحيوي التابع لـ Mayo Clinic ممن يعانون من سمنة مفرطة. تم تعريف السمنة المفرطة على أنها زيادة مؤشر كتلة الجسم عن 40، أو الحاجة إلى إجراء جراحة علاج السُمنة بعد ثبوت وجود متغير جيني في مسار الليبتين والميلانوكورتين للمريض. يتكون الينك الحيوي التابع لـ Mayo Clinic من مجموعة من العينات الطبية والتي تشمل عينات الدم ومشتقاته، والمعلومات الطبية التي تبرع بها مرضى Mayo Clinic لاستخدامها في الأبحاث الطبية المستمرة. 

    تم تحديد 168 حامل للمتغير الجيني MC4R. ووجد الباحثون في مايو كلينك أن الحاملين لهذا المتغير كانوا أكثر عرضة للإصابة بارتفاع ضغط الدم، كما كان لديهم عدد أكبر من عوامل الخطر لأمراض القلب والأوعية الدموية مقارنة بغير الحاملين للمتغير الجيني وعددهم 2039. ووضح د. أندريس أكوستا، دكتور في الطب، الباحث الرئيسي في معمل الطب الدقيق للسُمنة “لم يؤثر العمر أو الجنس أو مؤشر كتلة الجسم -وكلها عوامل خطر لأمراض القلب والأوعية الدموية- على النتائج، وتوصلنا في النهاية إلى أن الحاملين للمتغير الجيني أكثر عرضة للإصابة بارتفاع ضغط الدم”. 

    مع ذلك، وتبعًا للنتائج، فالحاملين للمتغير الجيني MC4R ليسو أكثر عرضة للإصابة بالمرض القلبي الوعائي أو للوفاة، تبعًا للنتائج التي عُرضت في إحدى أبحاث مجلة “مايو كلينيك بروسيدنجز – Mayo Clinic Proceedings”. استكمل د. أكوستا، كبير الباحثين، قائلًا: “توقعنا وجود زيادة أكبر في ارتفاع ضغط الدم، لأن زيادة الوزن تنبئ بالإصابة بارتفاع ضغط الدم”. 

    وأعربت د. سيفينتس عن تفاجؤ الباحثين من عدم وجود علاقة ثابتة مع المرض القلبي الوعائي. ووضحت ” نظرًا لمدى تعقيد مسببات المرض القلبي الوعائي، فببساطة قد يكون هناك قدر ضخم من البيانات التي لم يتم قياسها في تحليلاتنا”. 

    تكمن أهمية هذا البحث بالنسبة للأطباء في إدراك أن مرضى السُمنة الذين أظهر تنميطهم الوراثي وجود متغيرات متباينة الزيجوت في مسار اللبتين والميلانوكورتين قد لا يكونون محميين من ارتفاع ضغط الدم كما كان يعتقد سابقًا. ووضحت د. سيفينتس “يحتاج هؤلاء المرضى إلى مزيد من الاهتمام بعوامل الخطر القابلة للتعديل لارتفاع ضغط الدم، بما فيها أنواع العلاج الفردية للسُمنة”. 

    قد يصاب الأفراد الحاملين للمتغير الجيني بالسُمنة منذ الطفولة، لكن لم يتم توثيق الفترة الزمنية في الورقة التي قدمها الباحثون في Mayo Clinic. نحتاج إلى أبحاث أخرى لتحديد مخاطر الإصابة طويلة المدى للسمنة وللمرض القلبي الوعائي في الحاملين للمتغير الجيني. 

    من بين قيود هذا البحث أن 90% من المشاركين في بنك الحيوي لـ Mayo Clinic من البيض، لذا لا يمكننا تعميم نتائج هذا البحث على الأعراق الأخرى. 

    تلقى بحث د. أكوستا الدعم من المعاهد الوطنية للصحة، ومن البنك الحيوي التابع لـ Mayo Clinic، وشركة Rhythm لدراسة الأنماط الجينية. لم يتم الإعلان عن أي تضارب في المصالح. يقدم مركز Mayo Clinic للطب الفردي الدعم للبنك الحيوي لـ Mayo Clinic. 

    يمكنكم الرجوع إلى الورقة البحثية للتعرف على القائمة الكاملة للمؤلفين، والتمويل وتضارب المصالح، والإفصاحات. 

    لمزيد من المعلومات، يمكنك الرجوع إلى مدونة مركز Mayo Clinic للطب الفردي.  

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     نبذة عن مايو كلينك للرعاية الصحية   مايو كلينك للرعاية الصحية، الموجودة في لندن، هي شركة فرعية مملوكة بالكامل لمؤسسة مايو كلينك، وهو مركز طبي أكاديمي غير هادف للربح. تُصنَّف مايو كلينك في المرتبة الأولى بين المستشفيات وفقًا لتقرير يو إس نيوز آند وورد ريبورت بسبب: جودة الرعاية. مايو كلينك للرعاية الصحية هي المدخل الرئيسي في المملكة المتحدة لتلك التجربة التي لا مثيل لها. تفضل بزيارة مايو كلينك للرعاية الصحية لمزيد من المعلومات.   

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    Mayo Clinic

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  • 2023 Warren Alpert Foundation Prize Honors Pioneer in Computational Biology

    2023 Warren Alpert Foundation Prize Honors Pioneer in Computational Biology

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    Newswise — The 2023 Warren Alpert Foundation Prize has been awarded to scientist David J. Lipman for his visionary work in the conception, design, and implementation of computational tools, databases, and infrastructure that transformed the way biological information is analyzed and accessed freely and rapidly around the world.

    The $500,000 award is bestowed by The Warren Alpert Foundation in recognition of work that has improved the understanding, prevention, treatment, or cure of human disease. The prize is administered by Harvard Medical School. 

    Lipman will be honored at a scientific symposium on Oct. 11, 2023, hosted by HMS. For further information, visit The Warren Alpert Foundation Prize symposium website.

    Lipman, who is currently a senior science adviser for bioinformatics and genomics for the Food and Drug Administration, is receiving the award for work he did in the 1980s and 1990s prior to and after becoming the founding director of the National Center for Biotechnology Information (NCBI), a position he held until 2017.

    Lipman led the development of a powerful computational program called BLAST for the analysis and comparison of newly identified DNA and protein sequences against all known DNA and protein sequences. The tool transformed researchers’ ability to access and interpret DNA, RNA, and protein sequence data and propelled the fields of computational biology and molecular biology. While at the NCBI, Lipman also conceptualized and then oversaw the design and implementation of PubMed, the web-based database for biomedical literature used daily by millions of scientists, physicians, students, teachers, and the public. Today, NCBI houses multiple biotechnology databases and resources that, over the years, have reshaped biology, medicine, and other fields of science.

    “At a time when computation was deemed an exotic pursuit by most biomedical researchers, David was prescient because he understood the potential of computation to propel biomedical science forward,” said George Q. Daley, dean of HMS and chair of the Warren Alpert Foundation Prize scientific advisory board. “His vision, creativity, and rigor have transformed how scientists analyze and share data and, indeed, how we do science.”

    Lipman’s pioneering achievements not only democratized access to scientific information but also helped catalyze critical discoveries by enabling vital exchanges and collaborations among scientists in multiple fields of biomedicine and beyond.

    “The foundational work of David Lipman in the field of computational biology and the tools that he envisioned and created have an impact that is nearly impossible to measure on the fields of biology, medicine, and beyond,” said David M. Hirsch, director and chairman of the board of The Warren Alpert Foundation. “His contributions exemplify the mission and vision of the Warren Alpert Foundation.”

    Significance of the work

    Over the past 40 years, advances in DNA sequencing, computation, and the internet have transformed biomedical research, public health, and the practice of medicine. Lipman developed many of the most important computational tools and infrastructure for making discoveries with these technologies.  

    In the 1980s, as understanding of DNA and genes began to accelerate, elucidating the evolutionary relationships across genes and proteins within and between species became a major focus of Lipman’s scientific curiosity and research efforts. Such knowledge is critical in elucidating evolutionary relationships that provide essential clues about the function of genes and proteins.

    Early on, Lipman realized that the rapid emergence of new genetic sequencing data would require powerful and efficient computer programs to compare one DNA or protein sequence against all known sequences.

    In a series of papers published between 1983 and 1990, Lipman pioneered the design of multiple methods for comparative sequence analysis. This culminated in the development of an algorithm called BLAST, described in a now seminal 1990 paper. Today, BLAST and subsequent programs, gapped BLAST, and PSI-BLAST remain among the most widely used tools in biology and medicine and are deemed among the most significant achievements in the field of computational biology of the past 40 years.

    BLAST enabled understanding of the interplay between genes, biology, physiology, and the environment across organisms and has led to important discoveries in nearly all areas of biomedical research, from the molecular basis of cancer to identifying the source of a foodborne outbreak. 

    Furthermore, Lipman became one of the most ardent supporters of and key figures in the move toward open-access science. He was instrumental in the design of PubMed, the open-access scientific publication resource of the NCBI and the largest and most widely used resource for scientific research in the world.

    As director of NCBI, Lipman oversaw GenBank, the world’s largest DNA and protein sequence repository, an international collaboration among the United States, Japan, and Europe. Under his direction, NCBI brought GenBank into the era of genomics and the internet, vastly augmenting its capabilities.

    From the winner

    “Through the creation of computational tools and information systems, my goal and that of the wonderful collaborators I’ve had the honor to work with has been to enable biomedical researchers to make discoveries. The scientists involved in the nomination and selection process have a deep understanding of the field and have themselves made some of the most important biomedical discoveries. So, this honor holds a special significance to me.”

                -David J. Lipman

    The prize

    The Warren Alpert Foundation Prize recognizes the research of scientists throughout the world. Including the 2023 prize, the foundation has awarded more than $7.5 million to 79 individuals. Since the inception of the award in 1987, 12 honorees have gone on to receive Nobel prizes.

    The 2022 Warren Alpert Foundation Prize was awarded to Drew Weissman, Katalin Karikó, Uğur Şahin, Özlem Türeci, and Eric Huang for pioneering discoveries into the biology of mRNA, for its modification for medicinal use, and for the design of mRNA-based COVID-19 vaccines that set the stage for other mRNA vaccines and a variety of mRNA-based therapies.

    Other past recipients include:

    • Lynne Maquat and Joan Steitz for discoveries in the biology and function of RNA that reshaped the understanding of RNA’s various roles in healthy cell function and disease-causing dysfunction.
    • Daniel Drucker, Joel Habener, and Jens Juul Holst for elucidating the function of key intestinal hormones, their effects on metabolism, and the subsequent design of treatments for type 2 diabetes, obesity, and short bowel syndrome.
    • Edward Boyden, Karl Deisseroth, Peter Hegemann, and Gero Miesenböck for pioneering work in the field of optogenetics.
    • Francis Collins, Paul Negulescu, Bonnie Ramsey, Lap-Chee Tsui, and Michael Welsh for discoveries in cystic fibrosis.
    • James Allison, Lieping Chen, Gordon Freeman, Tasuku Honjo, and Arlene Sharpe for discoveries into cancer’s ability to evade immune surveillance, which led to the development of a class of cancer immunotherapies. Allison and Honjo shared the 2018 Nobel Prize in Physiology or Medicine.
    • Rodolphe Barrangou, Emmanuelle Charpentier, Jennifer Doudna, Philippe Horvath, and Virginijus Siksnys for CRISPR-related discoveries. Doudna and Charpentier shared the 2020 Nobel Prize in Chemistry.
    • Tu Youyou, who went on to receive the 2015 Nobel Prize in Physiology or Medicine with two others, and Ruth and Victor Nussenzweig for their pioneering discoveries in the chemistry and parasitology of malaria and the translation of that work into the development of drug therapies and an antimalarial vaccine.
    • Oleh Hornykiewicz, Roger Nicoll, and Solomon Snyder for research into neurotransmission and neurodegeneration.
    • Alain Charpentier and Robert Langer for innovations in bioengineering.
    • Harald zur Hausen and Lutz Gissmann for work on the human papillomavirus (HPV) and its role in cervical cancer. Zur Hausen and others were honored with the Nobel Prize in Physiology or Medicine in 2008.

    The Warren Alpert FoundationEach year the Warren Alpert Foundation receives between 30 and 50 nominations from scientific leaders worldwide. Prize recipients are selected by the foundation’s scientific advisory board, which is composed of distinguished biomedical scientists and chaired by the dean of Harvard Medical School. Warren Alpert (1920-2007), a native of Chelsea, Mass., established the prize in 1987 after reading about the development of a vaccine for hepatitis B. The inaugural recipient of the award was Kenneth Murray of the University of Edinburgh, who designed the hepatitis B vaccine. To award subsequent prizes, Alpert asked Daniel Tosteson (1925-2009), then dean of Harvard Medical School, to convene a panel of experts to identify scientists from around the world whose research had a direct impact on the treatment of disease. 

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    Harvard Medical School

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  • Researchers achieve ultra-high DNA resolution by slowing down and scanning individual DNA molecules multiple times

    Researchers achieve ultra-high DNA resolution by slowing down and scanning individual DNA molecules multiple times

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    Newswise — Aleksandra Radenovic, head of the Laboratory of Nanoscale Biology in the School of Engineering, has worked for years to improve nanopore technology, which involves passing a molecule like DNA through a tiny pore in a membrane to measure an ionic current. Scientists can determine DNA’s sequence of nucleotides – which encodes genetic information – by analyzing how each one perturbs this current as it passes through. The research has been published today in Nature Nanotechnology.

    Currently, the passage of molecules through a nanopore and the timing of their analysis are influenced by random physical forces, and the rapid movement of molecules makes achieving high analytical accuracy challenging. Radenovic has previously addressed these issues with optical tweezers and viscous liquids. Now, a collaboration with Georg Fantner and his team in the Laboratory for Bio- and Nano-Instrumentation at EPFL has yielded the advancement she’s been looking for – with results that could go far beyond DNA.

    “We have combined the sensitivity of nanopores with the precision of scanning ion conductance microscopy (SICM), allowing us to lock onto specific molecules and locations and control how fast they move. This exquisite control could help fill a big gap in the field,” Radenovic says.The researchers achieved this control using a repurposed state-of-the-art scanning ion conductance microscope, recently developed at the Lab for Bio- and Nano-Instrumentation.

    Improving sensing precision by two orders of magnitude
    The serendipitous collaboration between the labs was catalyzed by PhD student Samuel Leitão. His research focuses on SICM, in which variations in the ionic current flowing through a probe tip are used to produce high-resolution 3D image data. For his PhD, Leitão developed and applied SICM technology to the imaging of nanoscale cell structures, using a glass nanopore as the probe. In this new work, the team applied a SICM probe’s precision to moving molecules through a nanopore, rather than letting them diffuse through randomly.

    Dubbed scanning ion conductance spectroscopy (SICS), the innovation slows molecule transit through the nanopore, allowing thousands of consecutive readings to be taken of the same molecule, and even of different locations on the molecule. The ability to control transit speed and average multiple readings of the same molecule has resulted in an increase in signal-to-noise ratio of two orders of magnitude compared to conventional methods.

    “What’s particularly exciting is that this increased detection capability with SICS may be transferable to other solid-state and biological nanopore methods, which could significantly improve diagnostic and sequencing applications,” Leitão says.

    Fantner summarizes the logic of the approach with an automotive analogy: “Imagine you are watching cars drive back and forth as you stand in front of a window. It’s a lot easier to read their license plate numbers if the cars slow down and drive by repeatedly,” he says. “We also get to decide if we want to measure 1,000 different molecules each one time or the same molecule 1,000 times, which represents a real paradigm shift in the field.”

    This precision and versatility mean that the approach could be applied to molecules beyond DNA, such as protein building blocks called peptides, which could help advance proteomics as well as biomedical and clinical research.

    “Finding a solution for sequencing peptides has been a significant challenge due to the complexity of their “license plates”, which are made up of 20 characters (amino acids) as opposed to DNA’s four nucleotides,” says Radenovic.”For me, the most exciting hope is that this new control might open an easier path ahead to peptide sequencing.”

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    Ecole Polytechnique Federale de Lausanne (EPFL)

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  • DNA shape and packing manipulation: groundbreaking method

    DNA shape and packing manipulation: groundbreaking method

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    Newswise — A human cell harbors roughly 2 meters of DNA, encompassing the essential genetic information of an individual. If one were to unwind and stretch out all the DNA contained within a single person, it would span a staggering distance – enough to reach the sun and back 60 times over. In order to manage such an astounding volume of biological information, the cell compacts its DNA into tightly packed chromosomes.

    “Imagine DNA as a piece of paper upon which all our genetic information is written.” Says Minke A.D. Nijenhuis, co-corresponding author. “The paper is folded into a very tight structure in order to fit all of that information into a small cell nucleus. To read the information, however, parts of the paper have to be unfolded and then refolded. This spatial organization of our genetic code is a central mechanism of life. We therefore wanted to create a methodology that allows researchers to engineer and study the compaction of double-stranded DNA.”

    Triple helical structure provides protection and compactness

    Natural DNA is often double-stranded: one strand to encode the genes and one backup strand, intertwined in a double helix. The double helix is stabilized by Watson-Crick interactions, which allow the two strands to recognize and pair with one another. Yet there exists another, lesser-known class of interactions between DNA. These so-called normal or reverse Hoogsteen interactions allow a third strand to join in, forming a beautiful triple helix (Figure 2).

    In a recent paper, published in Advanced Materials, researchers from the Gothelf lab debut a general method to organize double-stranded DNA, based on Hoogsteen interactions. The study unambiguously demonstrates that triplex-forming strands are capable of sharply bending or “folding” double-stranded DNA to create compacted structures. The appearance of these structures range from hollow two-dimensional shapes to dense 3D constructs and everything in-between, including a structure resembling a potted flower. Gothelf and co-workers have named their method triplex origami (Figure 3).

    With triplex origami, scientists can achieve a level of artificial control over the shape of double-stranded DNA that was previously unimaginable, thereby opening new avenues of exploration. It has recently been suggested that triplex formation plays a role in the natural compaction of genetic DNA and the current study may offer insight into this fundamental biological process.

    Potential in gene therapy and beyond

    The work also demonstrates that the Hoogsteen-mediated triplex formation shields the DNA against enzymatic degradation. Hence, the ability to compact and protect DNA with the triplex origami method may have large implications for gene therapy, wherein diseased cells are repaired by encoding a function that they are missing into a deliverable piece of double-stranded DNA.

    This biological marvel of DNA sequence and structure has also been applied in nanoscale materials engineering, yielding applications in therapeutics, diagnostics, and many other areas. “For the past four decades, DNA nanotechnology has almost exclusively relied on Watson-Crick base interactions to pair up single DNA strands and organize them into custom nanostructures.” Says Professor Kurt V. Gothelf. “We now know that Hoogsteen interactions have the same potential to organize double-stranded DNA, which presents a significant conceptual expansion for the field.”

    Gothelf and co-workers demonstrated that Hoogsteen-mediated folding is compatible with state-of-the-art Watson-Crick-based methods. Due to comparative rigidity of double-stranded DNA, however, triplex origami structures require fewer starting materials. This allows larger structures to be formed at significantly lower cost.

    The new method has the limitation that triplex formation typically requires long stretches of purine bases within the double-stranded DNA and the researchers have therefore used artificial DNA sequences, instead of natural genetic DNA. However, in the future they will work towards overcoming this limitation.

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    Aarhus University

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  • Genes Define Eyebrow Look: Study

    Genes Define Eyebrow Look: Study

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    Newswise — Philadelphia, June 5, 2023 – The first gene mapping study on eyebrow thickness in Europeans discovered three previously unreported genetic loci, as reported in a Letter to the Editor in the Journal of Investigative Dermatology, published by Elsevier. The study conducted by the International Visible Trait Genetics (VisiGen) Consortium demonstrates that eyebrow appearance has partly the same and partly different underlying genes in people from different parts of the world.

    The appearance of human eyebrows is not just a matter of grooming but is in the genes. Eyebrow thickness, as any other appearance trait, is highly heritable. Thus far, genetic knowledge on eyebrow thickness has been very limited and solely restricted to non-Europeans. This study is the first genome-wide association study (GWAS) on eyebrow thickness in Europeans. By identifying new genes and rediscovering some of the genes previously identified in non-Europeans, the study expands genetic knowledge on human eyebrow variation, which is of broad interest and has implications for dermatology and other fields.

    Previous studies were performed among Latin American and Chinese individuals, establishing four eyebrow thickness -associated genetic loci. Because no European eyebrow thickness GWAS had been reported, researchers did not know whether the genetic eyebrow thickness effects described in non-Europeans persist in Europeans, or whether there are European-specific genetic loci involved in eyebrow thickness, or both.

    Lead investigator Prof. Dr. Manfred Kayser, Department of Genetic Identification, Erasmus MC University Medical Center Rotterdam, and co-chair of the VisiGen Consortium responsible for this study, commented, “Despite the immense efforts in mapping genes underlying human complex traits, we still know much more about the genes that make us sick than about those behind our healthy looks. For the first time, we performed a gene mapping study on eyebrow thickness variation in Europeans. Previous genetic knowledge on eyebrow thickness was limited and solely restricted to non-Europeans. We discovered new genes involved in eyebrow variation in Europeans and rediscovered some of the genes previously identified in non-Europeans.”

    The study among 9,948 individuals from four groups of European ancestry not only discovered three previously unreported genetic loci associated with eyebrow thickness, but also rediscovered two of the four genetic loci previously found in non-Europeans. Two other genetic loci previously reported in non-Europeans had minimal effects in Europeans, due to very low allele frequencies in Europeans.

    Prof. Dr. Kayser concluded, “Our study significantly improves the genetic knowledge of human eyebrow appearance by increasing the number of known genes from four to seven and delivers new targets for future functional studies. By having demonstrated that eyebrow variation is determined by both shared and distinct genetic factors across continental populations, our findings underline the need for studying populations of different ancestries for unveiling the genetic basis of human traits, including, but not restricted to, physical appearance.”

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    Elsevier

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  • UC San Diego Scientists Find Treatment for Severe Genetic Skin Disorder

    UC San Diego Scientists Find Treatment for Severe Genetic Skin Disorder

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    Newswise — In a true example of bench-to-bedside science, researchers at UC San Diego have identified the cause of a rare skin disorder, disabling pansclerotic morphea, and swiftly identified a treatment that dramatically improved patients’ symptoms. 

    The scientists discovered that the patients have an overactive version of a protein called STAT4, and that the drug ruxolitinib improved patients’ rashes and ulcers. 

    The results were published in the New England Journal of Medicine.

    DOI: 10.1056/NEJMoa2202318

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    University of California San Diego

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  • WHO chief warns of deadlier post-COVID disease

    WHO chief warns of deadlier post-COVID disease

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    Newswise — The leader of the World Health Organization (WHO) emphasized the need for global readiness in addressing a disease outbreak with a potential even greater than COVID-19. This statement came following the launch of a worldwide network by the UN agency to closely monitor and respond to threats posed by various diseases.

    During his address at the World Health Assembly (WHA) held in Geneva, Switzerland, on Monday, May 22, the Director-General of the WHO, Tedros Adhanom Ghebreyesus, cautioned that the conclusion of the COVID-19 pandemic as a global health emergency did not imply that the global health risks had subsided.

    Addressing the annual decision-making meeting of the World Health Organization’s 194 member states, he stressed that the possibility of another variant arising and leading to fresh waves of illness and fatalities persists.

    Furthermore, the persistent risk of another pathogen emerging, possessing an even greater capacity for devastation, continues to loom.

    Commencing the 76th session of the World Health Assembly (WHA) on Saturday, May 20, the WHO inaugurated the International Pathogen Surveillance Network (IPSN). This global initiative leverages genomics to facilitate the detection and timely response to emerging disease threats.

    Genetic data derived from viruses, bacteria, and other pathogens responsible for diseases plays a vital role in enabling scientists to identify and monitor diseases, as well as in developing effective treatments and vaccines. This information provides insights into the infectiousness and lethality of specific strains, as well as their patterns of transmission.

    During the launch, Tedros emphasized that the objective of the network is to provide every country with access to pathogen genomic sequencing and analytics as an integral component of their public health system.

    The IPSN Secretariat, which will be housed within the WHO Hub for Pandemic and Epidemic Intelligence, will serve as a collaborative platform uniting genomics and data analysis experts from various regions across the globe. This inclusive network will comprise governments, philanthropic foundations, multilateral organizations, civil society, academia, and the private sector.

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    SciDev.Net

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  • Ancient viruses found in coral symbionts’ DNA

    Ancient viruses found in coral symbionts’ DNA

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    Newswise — HOUSTON – (June 1, 2023) –A group of marine biologists from various countries has made a remarkable finding, uncovering the traces of ancient RNA viruses integrated into the DNA of symbiotic organisms residing within coral reefs.

    In a groundbreaking revelation, it has been revealed that the RNA fragments derived from viruses had infected the symbiotic organisms as far back as 160 million years. The astonishing discovery, highlighted in a recent open-access publication in the journal Communications Biology by Nature, holds immense potential for enhancing our understanding of the ongoing battle against viral infections in corals and their associated organisms. This finding has taken scientists by surprise since the integration of RNA viruses into the DNA of their host organisms is an uncommon phenomenon.

    Through the study, it has been revealed that endogenous viral elements (EVEs) are prevalent in the genetic makeup of coral symbionts. These symbionts, known as dinoflagellates, are single-celled algae residing within corals, imparting vibrant colors to their hosts. The identification of EVEs reinforces recent findings that viruses, not limited to retroviruses, have the ability to incorporate fragments of their genetic material into the genomes of their host organisms.

    “Then how did it happen?” inquired Adrienne Correa, one of the co-authors of the study from Rice University. She further explained, “While it might seem accidental, researchers are increasingly discovering that such occurrences are more common than previously thought. These ‘accidents’ have been identified in various hosts, ranging from bats and ants to plants and algae.”

    The presence of an RNA virus within coral symbionts came as an unexpected revelation.

    “I found this project particularly intriguing,” expressed Alex Veglia, the lead author of the study and a graduate student in Correa’s research team. Veglia continued, “Based on our current understanding, there is truly no logical explanation for the presence of this virus within the genome of the symbionts.”

    The research, funded by the Tara Ocean Foundation and the National Science Foundation, was spearheaded by Correa, Veglia, along with two scientists from Oregon State University: postdoctoral scholar Kalia Bistolas and marine ecologist Rebecca Vega Thurber. By unraveling crucial insights, this study offers valuable clues for scientists to enhance their comprehension of the ecological and economic ramifications of viruses on reef well-being.

    During their investigation, the researchers did not detect any endogenous viral elements (EVEs) derived from RNA viruses in the samples of filtered seawater or within the genomes of dinoflagellate-free stony corals, hydrocorals, or jellyfish. However, EVEs were found extensively in coral symbionts gathered from numerous coral reef locations. This indicates that the pathogenic viruses were, and likely still are, selective in their choice of target hosts.

    Correa, an assistant professor of biosciences, emphasized the vast diversity of viruses that exist on our planet. She explained, “While we have extensive knowledge about certain viruses, the majority of viruses remain uncharacterized. We may be able to detect their presence, but we are still unaware of their host organisms.”

    Correa highlighted the various methods by which viruses, including retroviruses, can replicate through host infections. She stated, “One intriguing aspect of our study is that this RNA virus is not classified as a retrovirus. Considering this, one wouldn’t anticipate it to integrate into the host’s DNA.”

    Correa remarked, “Over the past several years, we have observed a multitude of viruses within coral colonies, but it has been challenging to definitively determine their specific targets.” She further stated, “Therefore, this discovery provides us with the most reliable and conclusive data regarding the actual host of a virus associated with coral colonies. With this knowledge in hand, we can now delve into understanding why the symbiont retains that DNA or a portion of the genome. The question arises: Why hasn’t it been lost over time?”

    The revelation that the endogenous viral elements (EVEs) have been preserved over millions of years implies that they might hold some advantageous role for the coral symbionts. It also suggests the existence of a mechanism that actively promotes the genomic integration of EVEs.

    Veglia expressed the multitude of possibilities for further exploration, such as investigating whether these elements serve as antiviral mechanisms within dinoflagellates and assessing their potential impact on reef health, particularly in the context of rising ocean temperatures.

    Veglia raised important questions related to the potential influence of rising seawater temperatures on the presence of endogenous viral elements (EVEs) within Symbiodiniaceae species. He pondered whether the presence of EVEs in their genomes enhances their ability to combat infections caused by present-day RNA viruses. These queries emphasize the need for further research to unravel the intricate connections between EVEs, symbiont genomes, and the response to viral infections under changing environmental conditions.

    “In another study, we demonstrated that there is a rise in RNA viral infections during episodes of thermal stress in corals. Hence, there are numerous interconnected factors at play. The current discovery provides another valuable piece to complete the puzzle,” Veglia explained. The intricate relationship between thermal stress, viral infections, and coral health requires comprehensive examination to gain a holistic understanding of the dynamics involved.

    Correa cautioned against making assumptions about the virus having a negative impact, but she also noted that there is evidence suggesting its increased productivity under conditions of temperature stress. This highlights the complexity of the situation and the need for further investigation to better understand the potential effects of the virus on coral health.

    Thurber holds the distinguished position of Emile F. Pernot Professor in the Department of Microbiology at Oregon State University.

    The study included more than 20 co-authors from the University of Konstanz, Germany; the Institute of Microbiology and Swiss Institute of Bioinformatics, Zürich; the University of Perpignan, France; the Scientific Center of Monaco; the Université Paris-Saclay, Evry, France; the Tara Ocean Foundation, Paris; the University of Maine; Sorbonne University, France; the University of Tsukuba, Japan; Paris Science and Letters University, France; the University of Paris-Saclay; the Weizmann Institute of Science, Rehovot, Israel; Côte d’Azur University, Nice, France; the European Bioinformatics Institute, University of Cambridge, England; Ohio State University; and the National University of Ireland, Galway.

    National Science Foundation support was provided by three grants (2145472, 2025457, 1907184).

    -30-

    Peer-reviewed paper:

    “Endogenous viral elements reveal associations between a non-retroviral RNA virus and symbiotic dinoflagellate genomes” | Communications Biology | DOI: 10.1038/s42003-023-04917-9

    Authors: Alex J. Veglia, Kalia S.I. Bistolas, Christian R, Voolstra, Benjamin C. C. Hume, Hans-Joachim Ruscheweyh, Serge Planes, Denis Allemand, Emilie Boissin, Patrick Wincker, Julie Poulain, Clémentine Moulin, Guillaume Bourdin, Guillaume Iwankow, Sarah Romac, Sylvain Agostini, Bernard Banaigs, Emmanuel Boss, Chris Bowler, Colomban de Varga, Eric Douville, Michel Flores, Didier Forcioli, Paola Furla, Pierre Galand, Eric Gilson, Fabien Lombard, Stéphane Pesant, Stéphanie Reynaud, Matthew B. Sullivan, Shinichi Sunagawa, Olivier Thomas, Romain Troublé, Didier Zoccola, Adrienne M.S. Correa, and Rebecca L. Vega Thurber

    https://doi.org/10.1038/s42003-023-04917-9

     

     

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    Rice University

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  • Synthetic DNA: Fueling Gene Mods & Biofuel Innovation

    Synthetic DNA: Fueling Gene Mods & Biofuel Innovation

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    Unlocking the potential of laboratory-crafted DNA, known as synthetic DNA, holds the key to groundbreaking advancements across multiple domains, according to quantum biologists from the University of Surrey.

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    University of Surrey

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  • DNA tech reveals wild dingoes mostly pure

    DNA tech reveals wild dingoes mostly pure

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    Newswise — Wild dingo populations have less dog lineage, with a significantly greater proportion of pure dingoes than previously thought, according to new research, challenging the view that pure dingoes are on the decline due to crossbreeding.

    The findings, published in Molecular Ecology, suggest previous studies significantly overestimated the prevalence of dingo-dog mixes in the wild and that lethal methods to control ‘wild dogs’ target pure dingoes.

    Dingoes are genetically distinct from domestic dogs but can interbreed. Cross-species breeding, or hybridisation, can threaten pure species, which may become vulnerable to extinction by genetic dilution. 

    “For decades, there was fear that dingoes were breeding themselves into extinction. But our findings suggest this isn’t the case, and dingoes are largely maintaining their identity, which has implications for their management and conservation,” says Dr Kylie Cairns, a conservation biologist from UNSW Science and lead author of the study. 

    More pure dingoes than hybrids

    For the study, the research team led by UNSW Sydney investigated the extent of dingo hybridisation in different regions across Australia. They used a new genome-wide test to analyse the DNA of 391 wild and captive dingoes and conducted detailed ancestry modelling and biogeographic analysis to find wild dingoes had far less dog ancestry than suggested by prior genetic studies. 

    “The old method, which relied on a relatively small number of genetic markers and limited reference population, overestimates the amount of dog ancestry in dingo samples – sometimes by over 30 per cent,” Dr Cairns says. “This meant it often identified an animal as crossbred when it was a pure dingo or historical backcross.

    “But with the new test, we can look at 195,000 points across the genome compared with just 23 previously. So, it’s a huge step up in reliability and accuracy.”

    In Victoria, where previous reports suggested the pure dingo population was as small as 4 per cent, the study found 87.1 per cent of animals tested were pure dingoes and 6.5 per cent were historical dingo backcrosses with more than 93 per cent dingo ancestry.

    Similarly, in New South Wales and Queensland, where dingo-dog hybridisation is assumed to be pervasive, most animals were found to be pure dingoes, and only two wild canids had less than 70 per cent dingo ancestry.

    Little evidence of hybridisation in the dingo population was also found in the Northern Territory, South Australia, and Western Australia.

    “Reliance on outdated DNA testing methods has led to the belief that dingo–dog hybridisation is much more common in Australia than it really is,” Dr Cairns says. “Most dingoes in the wild are pure dingoes, and the remaining animals are more dingo than anything else.

    “Even in the parts of Australia where dingo-dog hybridisation is higher, it is not the pervasive threat we’ve been led to believe.”

    No animals in the sample were 50 per cent hybrids – meaning none were direct offspring of a dog and a dingo in the wild. The few animals that weren’t pure dingoes were mostly historical backcrosses with a single dog ancestor four or five generations in the past.

    “While there has been some hybridisation in the past, it’s not occurring at a rapid pace today,” Dr Cairns says. “Where it does happen, we can see the offspring of the hybrids returning to their dingo roots over time.” 

    The study also found significant regional variation in dingoes, with four distinct wild dingo populations across mainland Australia.

    “We didn’t have samples from every single corner of Australia. So, there may be even more variation in dingoes,” Dr Cairns says. “There’s also a chance some dog DNA has been integrated into the dingo genome because it’s provided an evolutionary advantage, so that’s something we plan to investigate in future research using the new testing.”

    The findings are consistent with studies in other species demonstrating genome-wide analysis performs more accurate identification of ancestry, which policymakers can use to inform dingo management.

    “Existing management decisions have been based on the findings from old DNA testing technology with limited resolution,” says Professor Mike Letnic, a conservation biologist from UNSW Science and senior author of the study. “We now have a more advanced approach using higher-density genomic data that can be applied to dingoes to assess populations more accurately and inform management strategies with best-available evidence.”

    Informing evidence-based dingo management

    In Australia, the term “wild dog” is widely used in policy under the assumption there is widespread dingo–dog hybridisation and very few remaining pure dingoes. 

    Under the name “wild dog”, dingoes, dingo-hybrids, and feral domestic dogs are all considered invasive species under biosecurity legislation and subject to eradication measures like aerial baiting or trapping across parts of the Australian mainland, including National Parks where native animals are protected. 

    “It’s convenient to paint all dingoes as wild dogs. But the term obscures the reality that many pure dingoes and dingo-dominant backcrosses are being killed,” Dr Cairns says. “In fact, no other native species is treated in quite the same way as the dingo, which is subject to lethal control measures across all landscapes, including ones where they should be protected.”

    Environments without dingoes can get overrun by kangaroos, foxes and feral cats that threaten other native animals and can change vegetation significantly.

    “Dingoes are a threat to some livestock, but they’re not a pest in all contexts. They play a crucial role as apex predators in maintaining ecosystem function and biodiversity,” Prof. Letnic says. “So, there’s a real need find a balance in management and ensure there are places in the landscape where we maintain populations.”

    Lethal control methods, particularly during dingo breeding season, may inadvertently increase the risk of hybridisation by reducing the availability of pure dingo mates. However, more research is needed to confirm the link.

    “While we don’t have many hybrids running around like previously suggested, where dingo-dog hybridisation does occur, it’s in regions where intensive lethal control is used and where there are higher numbers of domestic pet dogs,” Dr Cairns says.

    The researchers suggest that the definition of “dingoes” in conservation policy should be revised to include historical dingo backcrosses with 93 per cent or more dingo ancestry and distinguish them from “feral domestic dogs.” 

    “Doing so will more accurately reflect the identity of wild canids in Australia and acknowledge the value of dingoes as a native and culturally significant species,” Dr Cairns says.

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    University of New South Wales

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  • Lung infection may be less transmissible than thought

    Lung infection may be less transmissible than thought

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    Newswise — A little-known bacterium — a distant cousin of the microbes that cause tuberculosis and leprosy — is emerging as a public health threat capable of causing severe lung infections among vulnerable populations, those with compromised immunity or reduced lung function.

    Recent research found that various strains of the bacterium, Mycobacterium abscessus, were genetically similar, stoking fears that it was spreading from person to person.

    But a new study by Harvard Medical School researchers published May 22 in PNAS, calls those findings into question, offering an alternative explanation behind the genetic similarity of clinical clusters. This suggests that the pathogen may not be that prone to person-to-person transmission after all.

    “Our findings make a strong case for a different explanation behind the observed genetic similarities across strains,” said study senior author Maha Farhat, the Gilbert S. Omenn Associate Professor of Biomedical Informatics at HMS and a pulmonary disease expert at Massachusetts General Hospital. Farhat conducted the work in collaboration with Eric Rubin’s lab at the Harvard T.H. Chan School of Public Health.

    The results, Farhat added, argue against direct person-to-person transmission in clinical settings and instead point to M. abscessus infections being acquired from the home or other environmental exposures.

    In addition to having implications for the precautions that hospitals take to prevent outbreaks, it’s an important new clue into the behavior of a relatively unknown pathogen that poses serious risks for vulnerable populations.

    The research not only contributes to the understanding of M. abscessus transmission, but also suggests scientists should be cautious about assuming human transmission when they see genetic similarities in pathogens more generally, said study first author Nicoletta Commins, who conducted the research as a doctoral candidate at HMS and is now a postdoctoral fellow at the Broad Institute.

    “Our results certainly do not refute the possibility of person-to-person transmission of Mycobacterium abscessus in some cases, and more research is needed to inform best clinical practice for vulnerable patients,” she said. “However, our work supports a model in which person-to-person transmission may not be as common as it is sometimes suggested to be.”

    M. abscessus is a hardy microbe highly resistant to antibiotics and can infect the lungs of immunocompromised people. While it doesn’t pose a threat to most healthy individuals, it can cause severe infection in those with suppressed immunity or people with compromised lung function such as patients with cystic fibrosis, a genetic condition marked by recurrent lung infections and lung scarring. Notably, patients with CF who become infected with this organism become ineligible for lifesaving lung transplants.

    The earlier study that sounded the alarm about person-to-person transmission was based on genetic sequencing of M. abscessus samples obtained from cystic fibrosis patients at clinics in the United States, Australia, and Europe, including the United Kingdom. Researchers found few genetic mutations across the samples — a possible sign that the pathogen was spreading directly between humans.

    For many pathogens such as TB, for example, recent person-to-person transmission leads to only a few or no mutations between any pair of samples simply because the pathogen does not have much time to acquire genetic mutations, Farhat explained.

    “Understandably, observing the genetic similarity between M. abscessus samples caused a great deal of anxiety and fear around how these organisms could be transmitting,” she said.

    Clinicians, especially in clinics that treat cystic fibrosis patients, began taking extra precautions to avert transmission. However, follow-up investigations failed to find supporting evidence that human-to-human transmission was happening, raising questions about other possible explanations for the genetic similarities across samples.

    Farhat’s team set out to investigate a hypothesis that the samples appeared genetically similar because the pathogen was evolving at a very slow rate.

    “We thought, yeah, you observed a small number of mutations, but we don’t know how quickly these mutations are acquired, she explained. “It may be slower than we think, and links between samples that appear recent may not be.’”

    The scientists first used a large dataset of M. abscessus genomes to create a “tree of life,” a kind of genetic family tree for the bacterium.

    They looked at branches of the tree with clusters of genetically similar strains, then tried to calculate their evolutionary rate. They found that these genetically similar clusters were evolving around 10 times more slowly than typical M. abscessus strains.

    Next, they used computer modeling to determine whether the genetic similarities could be explained by the relatively small population size of these bacteria. But even when they simulated extreme population sizes, the result didn’t change. This was an indicator that the high genetic similarity is best explained by a slower evolutionary rate.

    Finally, researchers conducted experiments to see how fast different strains of M. abscessus evolved to develop resistance when exposed to antibiotics in the lab. They found that the genetically similar strains evolved much more slowly than other strains.

    “These are three separate lines of evidence supporting this idea that these clustered isolates of Mycobacterium abscessus are evolving at a slower rate,” Farhat said.

    In addition to reducing concern about person-to-person transmission, the findings provide new insight into a poorly understood pathogen.

    In particular, the results offer clues about how a bug found primarily in the environment adapts and changes after it enters the human body — information that could help scientists eventually understand how to prevent and treat infections.

    Farhat is now planning follow-up studies that would compare bacteria in the environment with samples taken from patients, to better understand why certain patients become infected.

    Authorship, funding, disclosures

    Additional authors included Mark R. Sullivan, Kerry McGowen

    Evan Koch, and Eric Rubin. The work was partly supported by the Damon Runyon Cancer Research Foundation, DRG-2415-20, with additional support from the Orchestra High Performance Compute Cluster at Harvard Medical School, funded by the NIH NCRR 1S10RR028832-01.

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    Harvard Medical School

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  • Genetic Risk Information May Help People Avoid Alcohol Addiction

    Genetic Risk Information May Help People Avoid Alcohol Addiction

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    Newswise — Today’s substance use prevention efforts ignore individual genetic risk, but Rutgers research suggests DNA test results may eventually enhance prevention and treatment and improve outcomes. 

    Investigators recruited 325 college students, provided them with varying levels of information about alcohol use disorder and how genetics affect addiction risk and asked them how they would react to learning they had high, medium and low genetic tendencies toward alcoholism.

    The results provided two significant supports for eventually using real genetic risk scores in actual addiction prevention efforts. First, participants understood what those scores indicated; they recognized that higher genetic risk scores meant a higher likelihood of developing alcohol problems. Second, most participants said they would drink less and take other steps to prevent addiction if actual scores showed high risk. 

    “There are a lot of steps between the discovery of addiction-related genes and the effective use of genetic information in prevention and treatment,” said Danielle Dick, director of the Rutgers Addiction Research Center and senior author of the study published in the American Journal of Medical Genetics. “This trial paves the way for studies using real genetic data and for integrating genetic information into prevention and intervention efforts.”

    Adoption and twin studies indicate addiction risk is roughly half genetic, Dick said, but there’s no single addiction gene that’s either present or absent. Instead, there are thousands of interacting genes, so each person’s genetic risk falls somewhere on a continuum.

    Risk isn’t distributed evenly along that continuum: It’s distributed in a bell curve. A small number of people have high or low genetic risk (at the tail ends of the curve), but most people fall in the middle of the curve, she said. Knowing one’s level of genetic risk can help people make the best choices for their health and well-being. Individuals at higher genetic risk are more likely to develop problems with alcohol use, so they can take precautionary steps with their substance use.

    Despite the relative complexity of the risk calculation, study participants formed relatively accurate impressions of the risk for addiction associated with various genetic results. Future research will investigate whether other populations understand risk scores as well as the college students in this trial.

    Another important finding was that individuals reported they would experience moderate distress if they learned they were at high genetic risk for addiction. This suggests that providers should be mindful of how to return high-risk genetic results and consider accompanying this information with counseling. Encouragingly, as individuals received increasing levels of genetic risk, they also reported greater intentions to seek additional information, such as talking with a healthcare provider and engaging in harm reduction practices.   

    “Overall, the results strongly encourage the notion that real genetic risk scores may prove helpful in preventing and treating alcohol addiction,” Dick said. “Comprehension of test results was high. Psychological distress remained at manageable levels. The vast majority of individuals indicated that they’d take action to reduce their risk if they learned they were at elevated genetic risk, and, fortunately, there was no indication that people would interpret low-risk scores as an invitation to take fewer precautions.”

    Dick emphasized we still know little about how real-world genetic information will affect real-world behavior. Most known addiction genes were discovered in the past few years, and many more remain to be discovered. No commercial genetic testing service provides information about addiction risk, so very few people have ever received genuine information about their genetic tendency toward addiction. What’s more, stated intentions often differ from subsequent actions.

    “There was a hope that compelling information about elevated genetic risk would get people to change behavior, but we haven’t seen that happen for other aspects of health,” Dick said. “Initial studies suggest that receiving genetic feedback for heart disease, lung cancer, and diabetes does not get people to change their behavior. Getting people to alter their behavior is hard. Providing them with good risk information is just the first step. We then need to connect individuals to resources and support to help them reduce risk. That’s what my team is currently working on — helping people understand their addiction risk and how they can reduce that risk and avoid developing problems.”

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    Rutgers University-New Brunswick

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  • Yeast screen reveals chromosomal mutation genes

    Yeast screen reveals chromosomal mutation genes

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    Newswise — Osaka, Japan – While developing a computer program, coding mistakes can lead to software bugs. Likewise, errors in our body’s genetic code, DNA, housed within structures called chromosomes, can trigger alterations in the body. These alterations are responsible for numerous fatal illnesses, including cancer. Presently, Japanese researchers have unveiled fresh insights into a specific kind of genetic alteration: extensive chromosomal reconfiguration (ECR).

    In an article published in Communications Biology, a team of researchers from multiple institutions, led by scientists from Osaka University, conducted an analysis on fission yeast to discover two crucial genes associated with the mechanism of ECR.

    The scientists were particularly focused on studying the centromere, a crucial region responsible for the separation of chromosomes during cell division. The centromere consists of repetitive DNA sequences, and it is known that ECR tends to happen in regions with repeated DNA sequences. Rad51, an essential enzyme involved in DNA recombination and the exchange of genetic material, was of specific interest. Surprisingly, contrary to expectations, Rad51 actually inhibits rather than facilitates ECR at the centromere. The mechanism by which ECRs occur using the centromere repeat remains mysterious.

    “By inducing mutations in Rad51-deficient yeast, which are known to have elevated GCR levels, we aimed to identify genes associated with GCR occurrence,” explained senior author Takuro Nakagawa. “We observed cells with decreased GCR levels and identified mutations in the Srr1 and Skb1 genes. This finding suggests that these genes are involved in the occurrence of GCR.”

    Subsequently, the researchers proceeded to delete the Srr1 and Skb1 genes in Rad51-deficient yeast and assessed the occurrence of GCR. The cells lacking Srr1 as well as those lacking Skb1 demonstrated decreased rates of GCR. Furthermore, cells lacking both Srr1 and Skb1 exhibited even lower rates of GCR.

    Lead author Piyusha Mongia explained, “Through our analysis, we discovered that Srr1 and Skb1 are implicated in the formation of isochromosomes, a specific type of structural mutation found in chromosomes. Deletion of either Srr1 or Skb1 resulted in a significant decrease in the occurrence of isochromosomes.”

    The findings of the research team mark a significant advancement in unraveling the mechanisms that drive GCR at the centromere. Since GCRs are implicated in various genetic disorders, including cancer, gaining insights into the process of GCR formation has the potential to enhance our capacity to treat specific genetic diseases. This represents a crucial step forward in our understanding of GCR and its broader implications for human health.

     

    ###

    The article, “Fission yeast Srr1 and Skb1 promote isochromosome formation at the centromere,” will be published in Communications Biology at DOI: https://doi.org/10.1038/s42003-023-04925-9

     

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    Osaka University

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  • Epigenetic landscape modulates pioneer transcription factor binding

    Epigenetic landscape modulates pioneer transcription factor binding

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    Newswise — Memphis, Tenn.—May 24, 2023) Like thread tightly wrapped around a spool, DNA is wrapped around histones and packaged into structures called nucleosomes. Scientists at St. Jude Children’s Research Hospital are exploring how a type of transcription factor called a pioneer transcription factor accesses DNA even when it is tightly wound. Their work revealed how the epigenetic landscape influences transcription factor binding. Problems with transcription have been implicated in numerous cancers, so this more detailed understanding of the process may aid in developing future therapeutics. The study was published today in Nature.  

    The nucleosome packaging of DNA can physically block transcription factors that regulate gene expression from accessing their binding sites. Restricting access to DNA is an integral part of how transcription is regulated. However, pioneer transcription factors can bind to their target piece of DNA even within compacted chromatin and are also known to promote the binding of other transcription factors. 

    Among pioneer transcription factors are the so-called Yamanaka factors which include Oct4 and are used to induce pluripotency (the ability to give rise to different cell types). How pioneer transcription factors access tightly wound DNA was unclear. To better understand the process, scientists at St. Jude used cryo-electron microscopy (cryo-EM) and biochemistry to investigate how Oct4 interacts with nucleosomes.  

    “Building on prior work to understand the dynamic behavior of nucleosomes, we wanted to understand how other factors might utilize those dynamic changes to access chromatin,” said corresponding author Mario Halic, Ph.D., St. Jude Department of Structural Biology. “Oct4 did not bind where we anticipated it might — rather than binding inside the nucleosome, we found that it bound a little bit outside.” 

    “One of the main findings is that epigenetic modifications can affect transcription factor binding and cooperativity,” Halic added. “The existing epigenetic state of chromatin can determine how transcription factors will cooperatively bind to chromatin.” 

    The epigenetic impact 

    Results show that the first Oct4 molecule binding “fixes” the nucleosome in a position that increases the exposure of other binding sites, thus promoting the binding of additional transcription factors and explaining transcription factor cooperativity. They also found that Oct4 contacts histones, and these interactions promote chromatin opening and influence cooperativity. Their work also showed that modifications at histone H3K27 affect the positioning of DNA by Oct4. These findings explain how the epigenetic landscape can regulate Oct4 activity to ensure proper cell programming.  

    Notably, the researchers used endogenous human DNA sequences instead of artificial sequences to assemble their nucleosomes. This allowed them to study the dynamic nature of the nucleosome, despite it being more challenging to work with.  

    “In this work, we used real genomic DNA sequences to study transcription factors in the context of where they function,” said first author Kalyan Sinha, Ph.D., St. Jude Department of Structural Biology. “This strategy allowed us to discover that the first binding event of Oct4 positions the nucleosomal DNA in a manner that allows cooperative binding of additional Oct4 molecules to internal sites. In addition, we observed exciting interactions with histone tails and have seen that histone modifications can alter those interactions. Together, these findings provide new insights into the pioneering activity of Oct4.” 

    “Histone modifications affect how DNA is positioned and how transcription factors can bind cooperatively,” Sinha added, “which means in cells, if you have the same DNA sequence, different epigenetic modifications can result in different, combinatorial effects on transcription factor binding.” 

    Authors and funding 

    The study’s other authors are Silvija Bilokapic, Yongming Du and Deepshikha Malik of St. Jude. 

    The study was supported by the National Institutes of Health (1R01GM135599-01 and 1R01GM141694-01) and ALSAC, the fundraising and awareness organization of St. Jude.  

     

      

    St. Jude Children’s Research Hospital 

    St. Jude Children’s Research Hospital is leading the way the world understands, treats and cures childhood cancer, sickle cell disease and other life-threatening disorders. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 60 years ago. St. Jude shares the breakthroughs it makes to help doctors and researchers at local hospitals and cancer centers around the world improve the quality of treatment and care for even more children. To learn more, visit stjude.org, read St. Jude Progress blog, and follow St. Jude on social media at @stjuderesearch. 

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  • Study reveals unique molecular machinery of woman who can’t feel pain

    Study reveals unique molecular machinery of woman who can’t feel pain

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    Newswise — The biology underpinning a rare genetic mutation that allows its carrier to live virtually pain-free, heal more rapidly and experience reduced anxiety and fear, has been uncovered by new research from UCL.

    The study, published in Brain, follows up the team’s discovery in 2019 of the FAAH-OUT gene and the rare mutations that cause Jo Cameron to feel virtually no pain and never feel anxious or afraid. The new research describes how the mutation in FAAH-OUT ‘turns down’ FAAH gene expression, as well as the knock-on effects on other molecular pathways linked to wound healing and mood. It is hoped the findings will lead to new drug targets and open up new avenues of research in these areas.

    Jo, who lives in Scotland, was first referred to pain geneticists at UCL in 2013, after her doctor noticed that she experienced no pain after major surgeries on her hip and hand. After six years of searching, they identified a new gene that they named FAAH-OUT, which contained a rare genetic mutation. In combination with another, more common mutation in FAAH, it was found to be the cause of Jo’s unique characteristics.

    The area of the genome containing FAAH-OUT had previously been assumed to be ‘junk’ DNA1 that had no function, but it was found to mediate the expression of FAAH, a gene that is part of the endocannabinoid system and that is well-known for its involvement in pain, mood and memory.

    In this study, the team from UCL sought to understand how FAAH-OUT works at a molecular level, the first step towards being able to take advantage of this unique biology for applications like drug discovery.

    This included a range of approaches, such as CRISPR-Cas9 experiments on cell lines to mimic the effect of the mutation on other genes, as well as analysing the expression of genes to see which were active in molecular pathways involved with pain, mood and healing.

    The team observed that FAAH-OUT regulates the expression of FAAH. When it is significantly turned down as a result of the mutation carried by Jo Cameron, FAAH enzyme activity levels are significantly reduced.

    Dr Andrei Okorokov (UCL Medicine), a senior author of the study, said: “The FAAH-OUT gene is just one small corner of a vast continent, which this study has begun to map. As well as the molecular basis for painlessness, these explorations have identified molecular pathways affecting wound healing and mood, all influenced by the FAAH-OUT mutation. As scientists it is our duty to explore and I think these findings will have important implications for areas of research such as wound healing, depression and more.”

    The authors looked at fibroblasts taken from patients to study the effects of the FAAH-OUT-FAAH axis on other molecular pathways. While the mutations that Jo Cameron carries turn down FAAH, they also found a further 797 genes that were turned up and 348 that were turned down. This included alterations to the WNT pathway that is associated with wound healing, with increased activity in the WNT16 gene that has been previously linked to bone regeneration.

    Two other key genes that were altered were BDNF, which has previously been linked to mood regulation and ACKR3, which helps to regulate opioid levels. These gene changes may contribute to Jo Cameron’s low anxiety, fear and painlessness.

    Professor James Cox (UCL Medicine), a senior author of the study, said: “The initial discovery of the genetic root of Jo Cameron’s unique phenotype was a eureka moment and hugely exciting, but these current findings are where things really start to get interesting. By understanding precisely what is happening at a molecular level, we can start to understand the biology involved and that opens up possibilities for drug discovery that could one day have far-reaching positive impacts for patients.”

    This research was supported by the Medical Research Council (MRC) and Wellcome.

     1 So called ‘junk’ DNA describes regions of the genome or non-coding genes that don’t create proteins. They were once thought redundant, but in recent years researchers have begun to discover the role of ‘dark’ regions of the genome in regulating coding genes.

    Publication:

    Hajar Mikaeili et al. ‘Molecular basis of FAAH-OUT-associated human pain insensitivity’ will be published in Brain and is strictly embargoed until 24 May 2023 01:01 BST / 23 May 2023 20:01 ET.

    The DOI for this paper will be: https://doi.org/10.1093/brain/awad098

     

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    University College London

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  • Fungus puppeteers hijack zombie flies

    Fungus puppeteers hijack zombie flies

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    Newswise — In a new study published in eLife, lead author Carolyn Elya, postdoctoral researcher in the Department of Organismic and Evolutionary Biology at Harvard, reveals the molecular and cellular underpinnings behind the parasitic fungus, Entomophthora muscae’s (E. muscae), ability to manipulate the behavior of fruit flies.

    Elya first described the manipulated behavior, called summiting, in a study published in eLife in 2018. Elya, who was studying microbes carried by fruit flies while a graduate student at University of California (UC) Berkeley, set out rotting fruit to capture wild fruit flies. When she later checked to see is she had captured any, she found instead zombie flies, with a banding pattern on their abdomen, that had died striking an interesting pose. Through extraction and sequencing of DNA Elya confirmed the suspected cause, E. muscae.

    Summiting occurs at sunset when the infected flies climb to an elevated location and extend their proboscises to the surface. A sticky droplet that emerges from the proboscis adheres the fly to the surface right before the wings raise up and away from the body and the flies die.

    “The climbing is very important as it positions the fly in an advantageous location for the fungus to spread to the most possible hosts,” says Elya. “The fungus jumps to the new host by forming very specialized and temporary structures that burst through the fly’s skin and shoots spores into the environment that are only good for a handful of hours. It’s a fleeting process, so an advantageous position is everything to survival.”

    While at UC Berkeley, Elya developed a laboratory model she refers to as the Entomophthora muscae-Drosophila melanogaster ‘zombie fly’ system using the wild fungal isolate she found in her backyard. With this system, Elya could continuously infect fruit flies – a laboratory staple, as well as culture the fungus independently of the fly host in media thought to mimic the internal environment of the fly.

    Summiting has appeared several times in scientific literature, but studies had only been observations of dead house flies. No one had ever observed how flies behave in their last hours of life. Elya set out to fill this knowledge gap of what happens when flies summit by developing a high-throughput behavioral assay to automatically track hundreds of infected flies. While using this platform to monitor the behavior of flies becoming zombies, she encountered a surprise. “We found that summiting is not about climbing,” said Elya, “it’s actually this burst of locomotor activity that starts about two and a half hours before the flies die.”

    With this discovery, Elya and co-authors paired her system to create on-demand zombie flies with the lab’s powerful fruit fly genetic toolkit. With these and the author’s new behavior assay they could identify genes and neurons required for flies to summit.

    “Overall, we found the flies hormonal axes was mediating summiting behavior. When we silenced these neurons the flies were really bad at summiting,” Elya says. These neurons send projections to a neurohemal organ that produces juvenile hormone, a hormone conserved in insects. “We think the fungus is actually driving the activity of these neurons in order to drive the release of this hormone, which is causing the flies to have this burst of locomotor activity.”

    Elya and co-authors were then able to collect a behavioral dataset consisting of hundreds of infected flies, which they then used to train a computer to identify flies as they are summiting. This classifier tool enabled the team to discover that fungal cells invade the fly’s brains in an organized way, occupying specific regions of the brain during summiting.

    Interestingly, the team also discovered that the flies blood brain barrier is compromised when exposed to the fungus. Normally the neurons are protected from the blood that’s circulating through the fly’s body. The breakdown of the blood brain barrier has important consequences for what the neurons are being exposed to, potentially allowing  things that are circulating in the blood to interact with neurons in the brain, thus providing a route for modulating neural activity.

    “We think this could be important for the way that the fungus is driving behavioral changes,” Elya said, “and we actually found that you can pull blood from flies that are doing the summiting behavior, put it into naive flies and drive some of this increased locomotion. So we’ve shown that there’s at least the partial ability to recapitulate this summiting behavior just by transferring fly blood.” Elya says that these experiments show some blood-borne factors can drive summiting behavior, though it’s not yet clear what the identity of these factors are or who produces them (the fungus or the fly).

    Elya hopes to next develop transgenics to help modulate things from the fungus side in addition to perturbations that can already be made in the flies. “There are still a lot of open questions here,” she says, “what the fungus is doing is still a mystery.”

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    Harvard University, Department of Organismic and Evolutionary Biology

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  • Ribosomal jam: Heartbreaking traffic

    Ribosomal jam: Heartbreaking traffic

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    Newswise — Fukuoka, Japan—A team of researchers have discovered that a mutation in a ribosomal protein found specifically in heart and skeletal muscle leads to impaired cardiac contractility in mice.

    The mutation was found to delay the rate of translating mRNA, leading to ribosomes colliding and causing protein folding abnormalities. The abnormal proteins would then be targeted and degraded by the cell’s quality control system. Moreover, while the deficiency in the ribosomal protein, known as RPL3L, altered translation dynamics for the entire tissue, its effects were most pronounced for proteins related cardiac muscle contraction.

    The study, published in Nature Communications, shines new insight into the dynamics of a molecule as fundamental as ribosomes. Furthermore, since RPL3L gene deficiencies have been found in humans with cardiomyopathy and atrial fibrillation, the team hopes their new findings can lead to future treatments.

    You are likely familiar with the process of how cells produce the proteins and molecules that make the body function. DNA is transcribed into messenger RNA, or mRNA, which is then used as a blueprint to link amino acids together and build a protein. At the heart of the protein building process is the ribosome which reads the mRNA and translates that code into proteins.

    Because of its fundamental function, ribosomes are found within all cells and were thought to be generally the same. However, recent studies have revealed the existence of differences in ribosomal structures.

    “These differences in a ribosomal structure have shown to lead to translation specificity. For example, some ribosomes are better at producing proteins that control metabolism, or the cell cycle. It’s a new concept called Ribosome Heterogeneity,” explains Keiichi I. Nakayama of Kyushu University’s Medical Institute of Bioregulation who led the study. “We hypothesized that this heterogeneity exists between tissues. After screening for tissue-specific ribosomal proteins we found one that was only expressed in heart and skeletal muscle: RPL3L.”

    To elucidate the function of RPL3L, the team studied the hearts of mice with a mutated RPL3L gene. As expected, echocardiographic analysis showed that they had reduced cardiac contractility. Their next step was to study why exactly this mutation led to such a condition. As it turns out, the RPL3L mutation was causing a ‘translational traffic jam’ for proteins critical in proper heart function.

    “We found that the mutant RPL3L would delay translation for the proline and alanine codons on mRNA. This delay caused ribosomes to collide, resulting in proteins not folding correctly,” continues Nakayama. “Misfolded proteins would then be cleared out from the cell by its quality control system. More importantly, much of the misfolded proteins were ones involved in cardiac contraction.”

    The team hopes that by deepening our understanding of the translation dynamics of ribosome such as RPL3L, they can better understand how its genetic mutations—found in patients with dilated cardiomyopathy and atrial fibrillation—can lead to heart disease.

    “We are developing new understandings in the field of biology and medicine every day, even in something as fundamental as ribosomes. I’m exciting to see what we’ll find next,” concludes Nakayama.

    ###

    For more information about this research, see “RPL3L-containing ribosomes determine translation elongation dynamics required for cardiac function,” Chisa Shiraishi, Akinobu Matsumoto, Kazuya Ichihara, Taishi Yamamoto, Takeshi Yokoyama, Taisuke Mizoo, Atsushi Hatano, Masaki Matsumoto, Yoshikazu Tanaka, Eriko Matsuura-Suzuki, Shintaro Iwasaki, Shouji Matsushima, Hiroyuki Tsutsui, Keiichi I. Nakayama Nature Communications, https://doi.org/10.1038/s41467-023-37838-6

    About Kyushu University 
    Kyushu University is one of Japan’s leading research-oriented institutes of higher education since its founding in 1911. Home to around 19,000 students and 8,000 faculty and staff, Kyushu U’s world-class research centers cover a wide range of study areas and research fields, from the humanities and arts to engineering and medical sciences. Its multiple campuses—including one of the largest in Japan—are located around Fukuoka City, a coastal metropolis on the southwestern Japanese island of Kyushu that is frequently ranked among the world’s most livable cities and historically known as Japan’s gateway to Asia. Through its Vision 2030, Kyushu U will ‘Drive Social Change with Integrative Knowledge.’ Its synergistic application of knowledge will encompass all of academia and solve issues in society while innovating new systems for a better future.

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    Kyushu University

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