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Tag: Genetics

  • How to turn a tentacle into a foot

    How to turn a tentacle into a foot

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    Newswise — Humans, animals, plants: all multicellular organisms are made up of specialized cells called differentiated cells. Thus, the cells that make up the epidermis do not have the same identity – nor the same function – as those that line the digestive system, for example. However, the mechanisms by which these cells maintain their identity are still poorly understood. Working on the freshwater polyp named Hydra, a team from the University of Geneva (UNIGE), in collaboration with the Friedrich Miescher Institute for Biomedical Research (FMI) in Basel, discovered one of the key regulators: the transcription factor Zic4. After reducing Zic4 expression, the researchers found that Hydra tentacle cells changed their identity and turned into foot cells, forming functional feet in the animal’s head. These results can be found in the journal Science Advances.

    As a living organism develops, its stem cells divide and gradually give rise to new cells capable of performing one or more specific functions. This process of cell specialization is called differentiation. Thus, the cells that make up the surface of the skin will be different, morphologically and physiologically, from those that make up, for example, digestive tissue or the nervous system. In very rare cases, some cells that are already differentiated can change their structure and function – and therefore their identity – during their existence. This process is called transdifferentiation.

    If the mechanisms of differentiation are well known, those that allow the specialized cell to maintain its identity – and thus to prevent its dedifferentiation (loss of identity) or its transdifferentiation (change of identity) – remain mysterious. To study them, species that regenerate their organs, limbs or whole body are privileged models. In these organisms, some cells temporarily lose or change their identity before renewing themselves and performing a new function. This is particularly true of the freshwater hydra, a small invertebrate averaging 1.5 cm in length that is capable of regenerating any amputated part throughout its life.

    A key regulator identified

    Using this animal model, researchers from the University of Geneva (UNIGE), in collaboration with the Friedrich Miescher Institute for Biomedical Research (FMI) in Basel, have identified a key regulator of cell identity maintenance: the transcription factor Zic4, a protein located in the nuclei of hydra cells, responsible for regulating the expression of a series of target genes. ‘‘We show more precisely that Zic4 plays a crucial role in the formation and maintenance of the cells that make up the tentacles, and that by reducing Zic4 expression, it is possible to modify the organization and function of these cells,’’ explains Matthias Christian Vogg, senior research and teaching assistant at the Department of Genetics and Evolution of the Faculty of Science and the Institute of Genetics and Genomics (iGE3) at the UNIGE, and first author of the study.

    By reducing the level of Zic4 expression by half, the scientists found that the epithelial cells on the outer layer of the tentacles were transformed into foot epithelial cells. ‘‘In the hydra, the foot is called the basal disc of the animal. The cells that compose it are very specialized: they secrete mucus that allows it to attach to the surrounding environment. After reduction of Zic4, it took only a few days for the process of transdifferentiation of the tentacle cells to take place, leading to the development of feet in place of the tentacles,’’ says Brigitte Galliot, emeritus professor at the Department of Genetics and Evolution of the Faculty of Science and at the iGE3 of the UNIGE, who supervised the study.

    A return to the cradle

    The scientists also discovered that transdifferentiated cells return to the cell cycle beforehand, without dividing. They then lose their first identity. ‘‘These cells reactivate the process of DNA synthesis, and thus of chromosome duplication, at work during cell proliferation without going as far as mitotic division,’’ explains Charisios Tsiairis, junior group leader at the FMI and co-last author of the study.

    To reduce the expression of the Zic4 gene, molecules inhibiting its expression were ‘‘electroporated’’ into the epidermis of the animal. ‘‘Then, we detected by double labeling, both a marker specific to tentacle cells and a marker for foot cells in the same cells, proving that these cells are transdifferentiating as they go through a stage where they are still a little bit tentacle and already a little bit foot. This transitional phase is the signature of the transdifferentiation process,’’ explains Chrystelle Perruchoud, research assistant at the Department of Genetics and Evolution of the Faculty of Science and at the iGE3 of the UNIGE.

    These results provide new keys to understanding transdifferentiation. They could pave the way for new therapies to regenerate certain deficient cell types in humans. For now, many questions remain: ‘‘Does Zic4 play the same role in other animals? Would further decreasing its expression allow the generation of other cell types? And let’s not forget that there are probably other important regulators of transdifferentiation yet to be discovered,’’ concludes Brigitte Galliot.

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    Universite de Geneve (University of Geneva)

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  • Penn Medicine Awarded $9.7 Million from The Warren Alpert Foundation for Genetic Counselor Continuing Education Efforts

    Penn Medicine Awarded $9.7 Million from The Warren Alpert Foundation for Genetic Counselor Continuing Education Efforts

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    Newswise — PHILADELPHIA— Penn Medicine has received a $9.7 million grant from The Warren Alpert Foundation (WAF) that will fund continuing education efforts for genetic counselors, to ensure opportunities for continued training that will keep them on the leading edge of their profession interpreting genomic data and explaining its implications to patients. This grant will position genetic counselors to advance research to address the many critical questions in the implementation of genomic information into clinical practice.

    Spearheaded by genetics researchers and faculty members in the Perelman School of Medicine (PSOM) at the University of Pennsylvania, the WAF-Career Ladder Education Program for Genetic Counseling program will allow genetic counselors to continue their education and learn about new and emerging research trends. This advanced training will further inform their work helping individuals learn about specific hereditary disorders, assess risks, and make proactive decisions in areas from cancer prevention to family planning. Penn will lead these efforts, in close collaboration with four other leading institutions: Baylor College of Medicine, Northwestern University Feinberg School of Medicine, Vanderbilt University School of Medicine, and the University of Washington School of Medicine.

    According to the U.S. Bureau of Labor Statistic, the genetics counseling field is expected to see rapid growth over the next decade.  To enter the field, genetic counselors typically must complete a bachelors degree and a masters degree related to the field. However, unlike other health professions, there are currently few opportunities to formally continue and advance their training with this career. “Genetic counseling is only about 50 years old, and the world of genetics is moving at lightning speed. It can be challenging for genetic counselors to stay aware of the rapid changes in the field—especially for those based at smaller, community hospitals. It is vital for the field to keep genetic counselors on the forefront of research and education, and initiatives like this help to ensure genetic counselors are an integral part of the future of genomic medicine,” said Kathleen Valverde, PhD, LCGC, director of Penn’s Master of Science in Genetic Counseling Program.

    The grant funds the newly created WAF-Career Ladder Education Program for Genetic Counseling at Penn, which aims to drive continued education for genetic counselors through multiple pathways. This includes the creation of a state-of-the-art online continuing education unit (CEU) courses for genetic counselors. Each one-credit CEU course will contain 10 hours of instruction, lectures, activities, and assessments to provide in-depth coverage on designated topics in genomics and personalized medicine such as variant interpretation. Other initiatives include developing a certificate program with targeted area of advanced training, and pathways for the development of a post-graduate doctoral degree in genetic counseling, are being explored.

    “Genetic counselors are crucial for all aspects of genomic medicine, including molecular diagnostics, clinical genetics, and genomics research, and are essential to modern health care systems.  Creating a robust career ladder to support genetic counselors’ advanced training and professional development is critical in retaining genetic counselors in academic health systems, advancing genomics research, and implementing genomic information into clinical practice,” said Daniel Rader, MD, chair of Genetics and Chief of Translational Medicine and Human Genetics at Penn. “This commitment to the career development of genetic counselors will be transformational, not just at the five participating institutions but also nationally and globally.”

    PSOM will partner with four other institutions around the nation: Baylor College of Medicine, Northwestern University Feinberg School of Medicine, Vanderbilt University School of Medicine, and the University of Washington School of Medicine. These institutions, along with Penn, represent geographically diverse areas of the United States, and were chosen as recipients of a portion of the WAF grant money based on their clinical programs in genetics and genomics expertise, their existing genetic counseling masters programs, and their history of engaging in research. The five institutions will work together to create and offer programs and opportunities for genetic counselors to advance their skills.

    “Given the increasing complexity of career development and the expanded roles for genetic counselors, support in career development is imperative. We are excited to support the career ladder for genetic counselors and we are delighted to award Penn this grant,” said August Schiesser, WAF executive director.

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    Perelman School of Medicine at the University of Pennsylvania

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  • Dry eye disease alters how the eye’s cornea heals itself after injury

    Dry eye disease alters how the eye’s cornea heals itself after injury

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    Newswise — People with a condition known as dry eye disease are more likely than those with healthy eyes to suffer injuries to their corneas. Studying mice, researchers at Washington University School of Medicine in St. Louis have found that proteins made by stem cells that regenerate the cornea may be new targets for treating and preventing such injuries.

    The study is published online Jan. 2 in the Proceedings of the National Academy of Sciences.

    Dry eye disease occurs when the eye can’t provide adequate lubrication with natural tears. People with the common disorder use various types of drops to replace missing natural tears and keep the eyes lubricated, but when eyes are dry, the cornea is more susceptible to injury.

    “We have drugs, but they only work well in about 10% to 15% of patients,” said senior investigator Rajendra S. Apte, MD, PhD, the Paul A. Cibis Distinguished Professor in the John F. Hardesty, MD, Department of Ophthalmology & Visual Sciences. “In this study involving genes that are key to eye health, we identified potential targets for treatment that appear different in dry eyes than in healthy eyes. Tens of millions of people around the world — with an estimated 15 million in the United States alone — endure eye pain and blurred vision as a result of complications and injury associated with dry eye disease, and by targeting these proteins, we may be able to more successfully treat or even prevent those injuries.”

    The researchers analyzed genes expressed by the cornea in several mouse models — not only of dry eye disease, but also of diabetes and other conditions. They found that in mice with dry eye disease, the cornea activated expression of the gene SPARC. They also found that higher levels of SPARC protein were associated with better healing.

    “We conducted single-cell RNA sequencing to identify genes important to maintaining the health of the cornea, and we believe that a few of them, particularly SPARC, may provide potential therapeutic targets for treating dry eye disease and corneal injury,” said first author Joseph B. Lin, an MD/PhD student in Apte’s lab.

    “These stem cells are important and resilient and a key reason corneal transplantation works so well,” Apte explained. “If the proteins we’ve identified don’t pan out as therapies to activate these cells in people with dry eye syndrome, we may even be able to transplant engineered limbal stem cells to prevent corneal injury in patients with dry eyes.”

    Lin JB, Shen X, Pfeifer CW, Shiau F, Santeford A, Ruzycki PA, Clark BS, Liu Q, Huang AJW, Apte RS. Dry eye disease in mice activates adaptive corneal epithelial regeneration distinct from constitutive renewal in homeostasis. Proceedings of the National Academy of Sciences, Jan. 2, 2023.

    The study was funded with support from the National Eye Institute, the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of General Medical Sciences of the National Institutes of Health (NIH). Grant numbers: R01 EY019287, R01 EY027844, R01 EY024704, P30 EY02687, F30 DK130282, T32 GM07200 Additional funding provided by the Jeffrey T. Fort Innovation Fund, a Centene Corp. contract for the Washington University-Centene ARCH Personalized Medicine Initiative and Research to Prevent Blindness.

    About Washington University School of Medicine

    WashU Medicine is a global leader in academic medicine, including biomedical research, patient care and educational programs with 2,700 faculty. Its National Institutes of Health (NIH) research funding portfolio is the fourth largest among U.S. medical schools, has grown 54% in the last five years, and, together with institutional investment, WashU Medicine commits well over $1 billion annually to basic and clinical research innovation and training. Its faculty practice is consistently within the top five in the country, with more than 1,790 faculty physicians practicing at over 60 locations and who are also the medical staffs of Barnes-Jewish and St. Louis Children’s hospitals of BJC HealthCare. WashU Medicine has a storied history in MD/PhD training, recently dedicated $100 million to scholarships and curriculum renewal for its medical students, and is home to top-notch training programs in every medical subspecialty as well as physical therapy, occupational therapy, and audiology and communications sciences.

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    Washington University in St. Louis

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  • New Computer Program ‘Learns’ to Identify Mosaic Mutations That Cause Disease

    New Computer Program ‘Learns’ to Identify Mosaic Mutations That Cause Disease

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    Newswise — Genetic mutations cause hundreds of unsolved and untreatable disorders. Among them, DNA mutations in a small percentage of cells, called mosaic mutations, are extremely difficult to detect because they exist in a tiny percentage of the cells.

    Current DNA mutation software detectors, while scanning the 3 billion bases of the human genome, are not well suited to discern mosaic mutations hiding among normal DNA sequences. Often medical geneticists must review DNA sequences by eye to try to identify or confirm mosaic mutations — a time-consuming endeavor fraught with the possibility of error.

    Writing in the January 2, 2023 issue of Nature Biotechnology, researchers from the University of California San Diego School of Medicine and Rady Children’s Institute for Genomic Medicine describe a method for teaching a computer how to spot mosaic mutations using an artificial intelligence approach termed “deep learning.”

    Deep learning, sometimes referred to as artificial neural networks, is a machine learning technique that teaches computers to do what comes naturally to humans: learn by example, especially from large amounts of information. Compared with traditional statistical models, deep learning models use artificial neural networks to process visually represented data. The models function in ways similar to human visual processing, with much greater accuracy and attention to detail, leading to major advances in computational abilities, including mutation detection.

    “One example of an unsolved disorder is focal epilepsy,” said senior study author Joseph Gleeson, MD, Rady Professor of Neuroscience at UC San Diego School of Medicine and director of neuroscience research at the Rady Children’s Institute for Genomic Medicine.

    “Epilepsy affects 4% of the population, and about one-quarter of focal seizures fail to respond to common medication. These patients often require surgical excision of the short-circuited focal part of the brain to stop seizures.  Among these patients, mosaic mutations within the brain can cause epileptic focus.

    “We have had many epilepsy patients where we were not able to spot the cause, but once we applied our method, called ‘DeepMosaic,’ to the genomic data, the mutation became obvious.  This has allowed us to improve the sensitivity of DNA sequencing in certain forms of epilepsy, and had led to discoveries that point to new ways to treat brain disease.”

    Gleeson said accurate detection of mosaic mutations is the first step in medical research toward developing treatments for many diseases.

    Co-first and co-corresponding author Xiaoxu Yang, Ph.D., a postdoctoral scholar in Gleeson’s lab, said DeepMosaic was trained on almost 200,000 simulated and biological variants across the genome until, “finally, we were satisfied with its ability to detect variants from data it had never encountered before.”

    To train the computer, the authors fed examples of trustworthy mosaic mutations as well as many normal DNA sequences and taught the computer to tell the difference. By repeatedly training and retraining with ever-more complex datasets and selection between a dozen of models, the computer was eventually able to identify mosaic mutations much better than human eyes and prior methods. DeepMosaic was also tested on several independent large-scale sequencing datasets that it had never seen, outperforming prior approaches.

    “DeepMosaic surpassed traditional tools in detecting mosaicism from genomic and exonic sequences,” said co-first author Xin Xu, a former undergraduate research assistant at UC San Diego School of Medicine and now a research data scientist at Novartis. “The prominent visual features picked up by the deep learning models are very similar to what experts are focusing on when manually examining variants.”

    DeepMosaic is freely available to scientists. It is not a single computer program, but rather an open-source platform that can enable other researchers to train their own neural networks to achieve a more targeted detection of mutations using a similar image-based setup, the researchers said.

    Co-authors include: Martin W. Breuss, Danny Antaki, Laurel L. Ball, Changuk Chung, Jiawei Shen, Chen Li and Renee D. George, UC San Diego and Rady Children’s Institute for Genomic Medicine; Yifan Wang, Taejeong Bae and Alexei Abyzov, Mayo Clinic; Yuhe Cheng, Ludmil B. Alexandrov and Jonathan L. Sebat, UC San Diego; Liping Wei, Peking University; and NIMH Brain Somatic Mosaicism Network.

    Funding for this research came, in part, from the National Institutes of Health (grants U01MH108898 and R01MH124890), the San Diego Supercomputer Center and UC San Diego Institute of Genomic Medicine.

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    University of California San Diego

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  • Model explains how autism arises

    Model explains how autism arises

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    Newswise — The development of autism may now become easier to understand, thanks to an explanatory model presented in a thesis from University of Gothenburg, Sweden. This model provides new insights into how various risk factors give rise to autism and why there is such great variability between individuals.

    Autism, a neurodevelopmental condition, affects how people perceive the world around them and how they interact and communicate with others. Among individuals with autism, there are major differences in terms of personal traits and manifestations alike. The disorder is therefore usually described as a spectrum, with numerous subtle variations.

    The new explanatory model is theoretical but simultaneously practical in application, since its various components are measurable through, for example, questionnaires, genetic mapping, and psychological tests. The model describes various contributing factors and how they combine to prompt an autism diagnosis and cause other neurodevelopmental conditions.

    Three contributing factors

    The model links three contributing factors. Together, these result in a pattern of behavior that meets the criteria for an autism diagnosis:

    1. Autistic personality — hereditary common genetic variants that give rise to an autistic personality.

    2. Cognitive compensation — intelligence and executive functions, such as the capacity to learn, understand others, and adapt to social interactions.

    1. Exposure to risk factors — for example, harmful genetic variants, infections, and other random events during gestation and early childhood that adversely affect cognitive ability.

    “The autistic personality is associated with both strengths and difficulties in cognition but does not, as such, mean that diagnostic criteria are fulfilled. Still, exposure to risk factors that inhibit people’s cognitive ability may affect their capacity to tackle difficulties, which contributes to individuals being diagnosed with autism,” says Darko Sarovic, physician and postdoctoral researcher at Sahlgrenska Academy, University of Gothenburg, who wrote the thesis.

    The model makes it clear that it is the many different risk factors combined that bring about the major differences among individuals on the spectrum. The various components of the model are supported by results from previous research.

    Adaptive ability

    High executive functioning skills may enable people to compensate for their impairment in such a way as to mitigate the symptoms, which reduces their risk of meeting the diagnostic criteria for autism. This may explain why, at group level, researchers observe a lower degree of intelligence among people diagnosed with autism, as well as other neurodevelopmental conditions. It also affords an understanding of why intellectual disability is more common among these groups. Thus, the model indicates that low cognitive ability is not part of the autistic personality but, rather, a risk factor that leads to diagnostic criteria being met.

    “The autistic personality is associated with various strengths. For example, parents of children with autism are overrepresented among engineers and mathematicians. The parents themselves have probably been able to compensate for their own autistic personality traits and thus not met the criteria for an autism diagnosis. The impact of the disorder has then become more noticeable in their children owing, for instance, to an exposure to risk factors and relatively low cognitive ability,” Sarovic says.

    Difference between girls and boys

    The diagnosis of autism is more common among boys than girls, and girls often get their diagnosis later in life. Some girls reach adulthood before being diagnosed, after many years of diffuse personal difficulties.

    “Girls’ symptoms are often less evident to other people. It’s well known that girls generally have more advanced social skills, which probably means that they’re better at compensating for their own difficulties. Girls also tend to have fewer autistic traits and be less susceptible to the effects of risk factors. Accordingly, the model can help to answer questions about the gender gap,” Sarovic says.

    Research and diagnostics

    The model also proposes ways of estimating and measuring the three factors (autistic personality, cognitive compensation and exposure to risk factors). This makes it possible to use the model in the planning of research studies and interpretation of their results.

    Diagnostics is another conceivable area of ​​use. In a pilot study in which 24 participants had been diagnosed with autism and 22 controls had not, measuring the three factors of the model enabled more than 93 percent to be correctly assigned to the right category. The model can also be used to explain the inception of other neurodevelopmental disorders, such as schizophrenia.

    Darko Sarovic is now a postdoctoral research fellow at Harvard Medical School in Boston, Massachusetts, while remaining affiliated to the Gillberg Neuropsychiatry Centre at the University of Gothenburg, Sweden.

    Title: A Multimodal Approach toward the Biological Categorization of Autism — Development of Theoretical Models, Classification Methods, and Biomarkers, https://hdl.handle.net/2077/73553

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    University of Gothenburg

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  • Actinidia arguta (sarunashi) juice inhibits lung cancer in mice

    Actinidia arguta (sarunashi) juice inhibits lung cancer in mice

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    Newswise — Lung cancer is the leading cause of death in Japan and across the globe. Among all the cancers, lung cancer has one of the lowest five-year survival rates. Smoking tobacco and using tobacco-based products is known to heavily contribute to the development of lung cancer. It is a clinically established fact that the active ingredients in various fruits minimize the risk of chronic diseases including cancer. “Sarunashi” (Actinidia arguta) is an edible fruit cultivated in Japan’s Okayama Prefecture. Using a mouse model, researchers from Okayama University led by Dr. Sakae Arimoto‑Kobayashi, Associate Professor in the Faculty of Pharmaceutical Sciences, Okayama University, have shown that Sarunashi juice and its constituting component isoquercetin (isoQ) help prevent and reduce lung cancer.

    A. arguta is one of the richest sources of polyphenols and vitamin C. Previously, the researchers had demonstrated the inhibitory effect of Sarunashi juice (sar-j) on mutagenesis, inflammation, and mouse skin tumorigenesis. They had identified the components of A. arguta responsible for the anti-mutagenic effects as water-soluble and heat-sensitive phenolic compounds. Subsequently, the researchers proposed the polyphenolic compound isoQ as a constituting component with anticarcinogenic potential.

    Dr. Arimoto‑Kobayashi explains, “In this study, we sought to investigate the chemo‑preventive effects of A. arguta juice and its constituting component isoQ on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in A/J mice, and identify the possible mechanisms underlying the anti-tumorigenic effects of A. arguta.”

    To this end, the team induced tumor growth in mice using NNK, a known cancer-causing compound present in tobacco products. Using a series of experiments and controls, the team studied the effects of sar-j and isoQ on lung tumorigenesis in mice.

    The results were encouraging: The number of tumor nodules per mouse lung in the group that received NNK injections and oral doses of A. arguta juice was significantly lower than that in the group injected with NNK only. Moreover, the oral administration of isoQ also reduced the number of nodules in the mouse lungs.

    Next, the team broke ground by discovering the likely mechanism of action. NNK and 1-methyl-3-nitro-1-nitrosoguanidine or “MNNG” are known mutagens—agents that trigger DNA mutations. The team therefore designed a series of experiments to study the effect of sar-j and isoQ on NNK- and MNNG-mediated mutagenesis using Salmonella typhimurium TA1535—a bacterial strain commonly used for detecting DNA mutations. As expected, the mutagenicity of NNK and MNNG detected using S. typhimurium TA1535 decreased in the presence of sar-j. However, when similar tests were conducted using S. typhimurium YG7108, a strain lacking key enzymes responsible for DNA repair, sar-j was unable to decrease the mutagenic effects of NNK and MNNG. Based on this critical observation, the researchers concluded that sar-j seems to mediate its antimutagenic effect by accelerating DNA repair.

    Finally, using cell-based experiments, the team also showed that sar-j suppressed the action of “Akt,” a key protein involved in cancer signaling. It is a known fact that Akt and an associated protein called “PI3k,” get over-activated in several human cancers.

    Co-author Katsuyuki Kiura, a Professor in the Department of Allergy and Respiratory Medicine, Okayama University Hospital, muses, “Sar-j and isoQ reduced NNK-induced lung tumorigenesis. Sar-j targets both the initiation and growth or progression steps during carcinogenesis, specifically via anti-mutagenesis, stimulation of alkyl DNA adduct repair, and suppression of Akt-mediated growth signaling. IsoQ might contribute in part to the biological effects of sar-j via suppression of Akt phosphorylation, but it may not be the main active ingredient.”

    Their findings were published on 9 December 2022 in Genes and Environment.

    In summary, the study shows that lung tumorigenesis in mice was suppressed following the oral intake of sar-j. Although clinical trials are warranted, the constituting components of sar-j, including isoQ, seem to be attractive candidates for chemoprevention.

     

    About Okayama University, Japan

    As one of the leading universities in Japan, Okayama University aims to create and establish a new paradigm for the sustainable development of the world. Okayama University offers a wide range of academic fields, which become the basis of the integrated graduate schools. This not only allows us to conduct the most advanced and up-to-date research, but also provides an enriching educational experience.

    Website: https://www.okayama-u.ac.jp/index_e.html

    About Dr. Sakae Arimoto‑Kobayashi from Okayama University, Japan

    Dr. Sakae Arimoto‑Kobayashi works as an Associate Professor at Okayama University’s Faculty of Pharmaceutical Sciences. Dr. Arimoto‑Kobayashi has multiple publications to her credit. Her research group primarily conducts studies on mutations and DNA damage induced by N-nitrosamino acids and near-ultraviolet irradiation, analysis of oxidative and alkylative DNA damage caused by the genotoxic agents, anti-carcinogenesis/anti-mutagenesis, and the chemopreventive effect of active ingredients in fruits and drinks.

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    Okayama University

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  • Understanding the “eating just one potato chip is impossible” gene

    Understanding the “eating just one potato chip is impossible” gene

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    Newswise — High-calorie foods—high in fat, oil, and sugar—can taste good but often cause overeating, leading to obesity and major health problems. But what stimulates the brain to cause overeating?

    Recently, it has become clear that a gene called CREB-Regulated Transcription Coactivator 1 (CRTC1) is associated with obesity in humans. When CRTC1 is deleted in mice, they become obese, indicating that functioning CRTC1 suppresses obesity. However, since CRTC1 is expressed in all neurons in the brain, the specific neurons responsible for suppressing obesity and the mechanism present in those neurons remained unknown.

    To elucidate the mechanism by which CRTC1 suppresses obesity, a research group led by Associate Professor Shigenobu Matsumura from the Graduate School of Human Life and Ecology at Osaka Metropolitan University focused on neurons expressing the melanocortin-4 receptor (MC4R). They hypothesized that CRTC1 expression in MC4R-expressing neurons suppressed obesity because mutations in the MC4R gene are known to cause obesity. Consequently, they created a strain of mice that expresses CRTC1 normally except in MC4R-expressing neurons where it is blocked to examine the effect that losing CRTC1 in those neurons had on obesity and diabetes.

    When fed a standard diet, the mice without CRTC1 in MC4R-expressing neurons showed no changes in body weight compared to control mice. However, when the CRTC1-deficient mice were raised on a high-fat diet, they overate, then became significantly more obese than the control mice and developed diabetes.

    “This study has revealed the role that the CRTC1 gene plays in the brain, and part of the mechanism that stops us from overeating high-calorie, fatty, and sugary foods,” said Professor Matsumura. “We hope this will lead to a better understanding of what causes people to overeat.”

    The research results were published in the FASEB Journal on November 9, 2022.

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    Osaka Metropolitan University is a new public university established by a merger between Osaka City University and Osaka Prefecture University in April 2022. For more science news, see https://www.omu.ac.jp/en/info/research-news/, and follow @OsakaMetUniv_en, or search #OMUScience. 

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    Osaka Metropolitan University

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  • UTSW researchers map activity of inherited gene variants linked to prostate cancer

    UTSW researchers map activity of inherited gene variants linked to prostate cancer

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    Newswise — DALLAS – Dec. 23, 2022 – UT Southwestern researchers have identified the molecular function of 87 inherited genetic variants that affect the risk of prostate cancer, and the majority appear to control the activity of genes located far away from the risk variants themselves. The findings, published in Cancer Discovery, could lead to better ways to assess cancer risk and new targets for anti-cancer drugs, the study authors say.

    “Traditionally, we think of regulatory elements in the genome affecting neighboring genes,” said study leader Ram Mani, Ph.D., Assistant Professor of Pathology and Urology at UTSW and a member of the Harold C. Simmons Comprehensive Cancer Center. “But these risk variants, or risk alleles, can act like a light switch. The light is on the ceiling, but the switch is on the wall on the other side of the room.”

    The findings also indicate that an individual risk allele can regulate multiple genes, he said.

    Prostate cancer is one of the most heritable cancers, Dr. Mani explained. Researchers have identified at least 185 common prostate cancer risk alleles, or snippets of DNA, passed down through families of European descent. But because the vast majority of these alleles are located in DNA’s noncoding regions – which don’t contain genes and therefore don’t produce proteins – how they affect prostate cancer risk has largely been a mystery. Previous research has suggested that they may control gene regulation, but which genes are affected and how their activity is altered has been unknown.

    To answer these questions, Dr. Mani and his colleagues used several approaches to identify which genes serve as targets for the risk alleles. A three-dimensional mapping technique using data from 565 prostate cancer tumors showed that 87 of these risk alleles affected the activity of hundreds of genes.

    Although malignant tumors typically arise in the prostate’s epithelial cells, researchers found that the affected genes were often in other tissue types, including stromal cells and smooth muscle cells that support the epithelial cells. Most of the risk alleles appeared to alter the activity of these genes, which produced proteins known to be involved in molecular pathways for development, apoptosis (programmed cell death), and metabolism, among other cellular processes.

    Dr. Mani said some alleles had opposing activity on the multiple genes they control. For example, one allele known as rs8102476 simultaneously increased the activity of one gene while decreasing the activity of a neighboring gene. The risk alleles also had significant interaction with genes that acquired nonheritable mutations associated with prostate cancer; these interactions appeared to predict how aggressive a patient’s disease became.

    Together, Dr. Mani said, these findings could lead to better risk models for patients as well as new prostate cancer treatments. Further association studies are urgently needed to identify risk alleles in populations of non-European descent so that risk models and treatments can be customized to a broader patient base, he added.

    “African American men have an elevated risk of prostate cancer, especially aggressive disease,” Dr. Mani said. “There’s a critical need for more genomewide association studies in this and other populations in which there’s an established health disparity to understand the nature of their risk and how to decrease it.”

    Other UTSW researchers who contributed to this study include Susmita G. Ramanand, Sora Lee, GuemHee Baek, and Douglas W. Strand. Jaipei Yuan, Ph.D., a former postdoctoral researcher at UT Southwestern, is first author.

    This study was funded by grants from the National Cancer Institute/National Institutes of Health (R01CA245294, P30CA016042, U01CA214194, and U24CA248265), the Cancer Prevention and Research Institute of Texas (RP190454), the Department of Defense (W81XWH-17-1-0675 and W81XWH-21-1-0114), and the Prostate Cancer Foundation.

    About UT Southwestern Medical Center

    UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 24 members of the National Academy of Sciences, 18 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,900 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 100,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 4 million outpatient visits a year.

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  • Rewriting the Textbook on Gene Regulation: It’s the Big Picture That Counts

    Rewriting the Textbook on Gene Regulation: It’s the Big Picture That Counts

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    Newswise — A fundamental principle of molecular biology governs how proteins are made within the cell, which happens in two stages called transcription and translation. During transcription, information stored in DNA is copied into messenger RNA (mRNA). Then during translation, the ribosomes assemble proteins one amino acid at a time based on the instruction specified on the mRNA.

    The understanding of this process is so fundamental that the mere direction of the information flow from DNA to mRNA to protein is called the “central dogma” of molecular biology, a term coined by Nobel laureate Francis Crick. Since the advent of systems biology 20 years ago, researchers have been trying to establish how cells regulate transcription and translation processes based on gene expression data — which mRNAs and proteins are made under what conditions. 

    Deciphering how cells regulate these activities would provide insight into how they process environmental information to modulate their behavior. It would also allow scientists to formulate strategies for the precise manipulation of protein levels — a critical step in synthetic biology, which seeks to solve problems in medicine, manufacturing and agriculture through the redesign and re-engineering of genes and their interactions.

    For the first time, researchers at the University of California San Diego have shown that changes in gene expression for the model bacterium E. coli happen almost entirely during the transcription stage while the cells are growing. The researchers have provided a simple quantitative formula linking regulatory control to mRNA and protein levels. The results and formula were published in a recent issue of Science.

    “Ultimately what we provide is a quantitative relationship that scientists can use to interpret how pathogenic bacteria evade antibiotic treatment and host immunity,” stated Terry Hwa, UC San Diego Distinguished Professor of Physics and Biological Sciences, and principal investigator for the project. “In the synthetic biology context, it will allow bacteria to be redesigned and rewired for uses such as detecting and cleaning up toxic waste, or being sent into the body to kill cancer cells.”

    The central dogma of molecular biology is linear, moving from DNA to mRNA to protein. It’s straightforward on an individual-gene level: turn on a gene, make mRNA, create proteins from the mRNA. Often, biologists think of gene regulation in such a linear fashion because they design experiments that change only a single gene or the few genes specific to their studies without drastically affecting the entire cell system.

    According to this line of thinking, making twice as many mRNAs would yield twice as many proteins; however, when considered at a systems level, with all the genes together, this is not true, and the linear way of thinking about the central dogma doesn’t hold.

    This is because cells must deal with certain global constraints. For example, the total protein concentration in a cell is approximately constant. When the environment changes and cells adapt by regulating the expression of certain genes, these global constraints force additional changes in the expression of not only these genes, but also others that are not directly regulated.

    While systems biologists have not considered these global constraints when writing equations to model gene expression, Hwa’s group looked at the problem from the opposite end. They started with the constraints and then made quantitative statements with absolute measurements, beyond the relative measurements that are commonly used.

    “We invested a lot of time and effort in quantifying these changes so we could filter out the small-magnitude changes that are really just distractions on a global level,” stated Hwa. “Absolute quantitative measurements will allow researchers to quantitatively relate mRNA levels to protein levels and vice versa. One cannot make these kinds of statements based on relative measurements.”

    Hwa believes this research will reframe how gene expression and regulation is taught in biology textbooks and classrooms around the world, saying it already runs contrary to things he currently teaches in his own classroom.

    Controlling gene expression is a complex process. A good design rule is essential so the same genetic circuit can work in multiple conditions. Currently scientists often see circuits they spent much effort developing in one environment fail in another.

    “We were using the wrong framework,” stated Hwa. “Now this work has provided a simple recipe that can be used to decipher gene-gene interactions in bacterial responses and can be used to design genetic circuits more effectively in synthetic biology, helping to solve some of the world’s pressing issues in biotech and health sciences.”

    Co-first authors on this paper were Rohan Balakrishnan and Matteo Mori (both UC San Diego). Other contributors include Igor Segota and Zhongge Zhang (both UC San Diego), Ruedi Aebersold (University of Zurich), and Christina Ludwig (Technical University of Munich).

    This work was supported by NIH grant R01GM109069 and NSF grant MCB1818384.

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  • Humans continue to evolve with the emergence of new genes

    Humans continue to evolve with the emergence of new genes

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    Newswise — Modern humans evolutionarily split from our chimpanzee ancestors nearly 7 million years ago, yet we are continuing to evolve. 155 new genes have been identified within the human lineage that spontaneously arose from tiny sections of our DNA. Some of these new genes date back to the ancient origin of mammals, with a few of these “microgenes” predicted to be associated with human-specific diseases. This work is publishing on December 20th in the journal Cell Reports.

    “This project started back in 2017 because I was interested in novel gene evolution and figuring out how these genes originate,” says first author Nikolaos Vakirlis (@vakirlis), a scientist at the Biomedical Sciences Research Center “Alexander Fleming” in Vari, Greece. “It was put on ice for a few years, until another study got published that had some very interesting data, allowing us to get started on this work.”

    Taking the previously published dataset of functionally relevant new genes, the researchers created an ancestral tree comparing humans to other vertebrate species. They tracked the relationship of these genes across evolution and found 155 that popped up from regions of unique DNA. New genes can arise from duplication events that already exist in the genome; however, these genes arose from scratch.

    “It was quite exciting to be working in something so new,” says senior author Aoife McLysaght (@aoifemcl), a scientist at Trinity College Dublin. “When you start getting into these small sizes of DNA, they’re really on the edge of what is interpretable from a genome sequence, and they’re in that zone where it’s hard to know if it is biologically meaningful.”

    Of these 155 new genes, 44 of them are associated with growth defects in cell cultures, demonstrating the importance of these genes in maintaining a healthy, living system. Since these genes are human specific, it makes direct testing difficult. Researchers must seek another way to explore what effects these new genes may have on the body. Vakirlis and his team examined patterns found within the DNA that can hint at if these genes play a role in specific diseases.

    Three of these 155 new genes have disease-associated DNA markers that point to connections with ailments such as muscular dystrophy, retinitis pigmentosa, and Alazami syndrome. Apart from disease, the researchers also found a new gene that is associated with human heart tissue. This gene emerged in human and chimp right after the split from gorilla and shows just how fast a gene can evolve to become essential for the body.

    “It will be very interesting in future studies to understand what these microgenes might do and whether they might be directly involved in any kind of disease,” says Vakirlis.

    “These genes are convenient to ignore because they’re so difficult to study, but I think it’ll be increasingly recognized that they need to be looked at and considered,” says McLysaght. “If we’re right in what we think we have here, there’s a lot more functionally relevant stuff hidden in the human genome.”

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    Financial support provided by the European Research Council and by Greece and the European Union. Aoife McLysaght was a member of the journal’s Advisory Board at the time of this article’s initial submission.

    Cell Reports, Vakirlis et al., “De novo birth of functional microproteins in the human lineage.” https://www.cell.com/cell-reports/fulltext/S2211-1247(22)01696-5 

    Cell Reports (@CellReports), published by Cell Press, is a weekly open access journal that publishes high-quality papers across the entire life sciences spectrum. The journal features reports, articles, and resources that provide new biological insights, are thought-provoking, and/or are examples of cutting-edge research. Visit: http://www.cell.com/cell-reports. To receive Cell Press media alerts, contact [email protected].

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  • Why aren’t all black bears black?

    Why aren’t all black bears black?

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    Newswise — Sometimes a name is just a name. Take bears, for example. In Yellowstone National Park, black bears outnumber their brownish-colored grizzly bear cousins, and in coastal areas of the Pacific Northwest, if someone says “brown bear,” they mean grizzly bear. But not all brown bears are grizzly bears.

    American black bears (Ursus americanus), which one would logically assume are, well, black, actually come in a range of colors, including brown (also known as cinnamon), blond, or bluish-grey. Others have coats that are a mixture of several colors. So, how do you tell a cinnamon-colored Ursus americanus from its brown (grizzly) Ursus arctos cousin? Differences in body shape and size can be subtle. One hypothesis for the cinnamon color of Ursus americanus is that it mimics the appearance of a grizzly bear, helping with camouflage or defense.

    Now, researchers at HudsonAlpha, the University of Memphis, and the University of Pennsylvania, have discovered what causes the cinnamon color, which sheds some light on this color confusion.

    Gene variant responsible for cinnamon morph black bear

    Emily Puckett, PhD, an Assistant Professor of Biological Sciences at the University of Memphis, has devoted her career to learning more about the evolution and genetics of bears. With help from partners in state, provincial, and federal wildlife agencies, she collected hundreds of DNA and hair samples from North American bears. She teamed up with Greg Barsh, MD, PhD, Faculty Investigator at HudsonAlpha, and animal pigmentation expert to figure out why black bears aren’t always black.

    In mammals, pigment is produced by skin cells called melanocytes. There are two types of melanin: eumelanin is black or brown, and pheomelanin is red or yellow. It is widely accepted that genetic variation in melanin biosynthesis gives rise to differences in hair, eye, and skin color. By studying photos of bears and chemically analyzing their corresponding hair samples, the team determined that cinnamon-colored black bears have reduced amounts of eumelanin, just like grizzly bears. 

    Genome sequence analysis of nearly 200 bears uncovered different missense mutations in the gene Tyrosinase-related protein 1 (TYRP1): cinnamon-colored black bears have a mutation called TYRP1R153C, while most (but not all) grizzly bears have a mutation called TYRP1R114C. The TYRP1 gene produces an enzyme within melanocytes that helps produce eumelanin, so it makes sense that the cinnamon and grizzly bears have less eumelanin. Furthermore, functional studies carried out by Mickey Marks, PhD, Professor of Pathology at the University of Pennsylvania, and his lab, determined that the TYRP1R153C and TYRP1R114C mutations interfere with melanin synthesis and distribution.

    “When we looked at other species, we were surprised to find the TYRP1R153C variant responsible for cinnamon U. americanus is identical to one previously described as a cause of oculocutaneous albinism (OCA3) in humans,” says Barsh. OCA3 is characterized by reddish skin and hair and frequent visual abnormalities and is most common in people of African or Puerto Rican ancestry. But according to Puckett, bears with TYRP1 mutations have normal skin and can see just fine.

    When and where did the cinnamon morph arise?

    The TYRP1R153C variant was primarily found in the southwest United States, at lower frequencies moving northward to Southeast Alaska and the Yukon Territory. TYRP1R153C was associated with the cinnamon color in black bears and the chocolate and light brown colors, meaning it accounts for almost all of the color diversity among U. americanus.

    The researchers used their data to learn more about the TYRP1R153C mutation. One hypothesis is that it may have started in grizzly bears and then was transferred to black bears, but demographic analysis indicated that was not the case. Instead, the TYRP1R153C mutation arose spontaneously about 9,360 years ago in black bears living in the western United States, then spread as the bears moved across their current geographic range.

    “Based on its wide range today, the TYRP1R153C mutation that arose in black bears over 9,000 years ago probably gave an advantage to the cinnamon bears,” says Puckett. “We used genetic modeling and simulations to predict the selective forces acting on the cinnamon morph. But our predictions ruled out the grizzly mimicry hypothesis as well as another hypothesis having to do with thermoregulation.”

    As to why the coat color variant arose in the first place, the team presents a new hypothesis: crypsis. Crypsis refers to the ability of an animal to conceal itself and blend into the environment. Generally, crypsis is found in prey species and ambush predators who color match within their environments. Here, the researchers suggest crypsis as a broader adaptive mechanism for large-bodied species.

    “These results illustrate how genetic variation in melanin biosynthesis can underlie iconic phenotypes and inform our understanding of color variation and recent evolution in large carnivores,” says Barsh.

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  • Screening a puppy’s DNA methylome may help predict how energetic or fearful they will be

    Screening a puppy’s DNA methylome may help predict how energetic or fearful they will be

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    Newswise — Anyone who’s ever had a dog knows how different one can be from another. For example, they can be reserved or friendly, playful or calm, fearful or bold, and prone to bark or fetch or not. Research has shown that some of these differences are genetically determined. But even within dog breeds, where line breeding and artificial selection have led to the loss of much of the original genetic variation, the behavior of individuals can differ widely.

    Now, researchers show that part of the differences in temperament – in particular  their ‘energy’ level and fear-related behaviors – depend on acquired differences in the epigenome. The epigenome, an individual’s unique set of chemical tags on DNA and its associated histone complexes (nucleosomes), can dial the expression of local genes up or down. Because the epigenome is known to depend on age, diet, exercise, training, socialization, and other environmental factors, it can impact the activity and wiring of nerve cells and thus alter behavior.

    Corresponding author Dr Matteo Pellegrini, a professor at the University of California at Los Angeles, said: “Here we show that the behavior of dogs is associated with their epigenome, in particular DNA methylation. Our results open the door to using epigenetics to screen and select for desired behavioral traits in companion or service dogs.”

    Behavioral questionnaire 

    Pellegrini and his colleagues quantified the epigenetic, genetic, and behavioral differences between 46 female and male dogs from 31 different breeds, with an age between one and 16 years. Behavioral differences were quantified based on how the owners rated their dog in the Canine Behavioral and Research Assessment Questionnaire (C-BARQ) questionnaire, a widely used standardized tool that consists of 101 questions. The researchers used a form of machine learning, Partial Least Squares (PLS) regression, to identify significant associations between genetic or epigenetic variants and behavioral traits.

    The epigenome is known to differ strongly between tissues. In principle, nervous tissue would be the best place to look for associations between behavior and the epigenome. But for ease of collection, the researchers studied the epigenome of epithelial and immune cells obtained from swabs inside the dogs’ cheeks. For this proof-of-concept study, they focused on DNA methylation at 3,059 CG sites, as this is easier to quantify than other types of epigenetic marks, for example methylation or acetylation of histones. 

    Epigenetics are more informative than genetics for behavior

    The results showed that the epigenome was a better predictor of behavior than the genotype at the sites they measured. Even within the most represented breed – Australian shepherds with 12 dogs in the sample – only two of the 930 selected Single-Locus Polymorphisms (SNP) examined were strongly associated with behavioral traits. Two SNPs on chromosome 12 could partly predict a dog’s degree of stranger-directed fear (ie, fear of unfamiliar people).

    But when the authors corrected for the potential confounding effect of differences in age, differences in DNA methylation between dogs explained a far greater proportion of observed variation in energy, attention seeking, nonsocial fear, and stranger-directed fear than genetic differences did. These results imply that the epigenome helps to shape behavioral differences in dogs, even in tissues that aren’t part of the nervous system. 

    Surprising results

    “These associations between the DNA methylation of cells in the mouth and dog behaviors were surprising, and suggests that future studies that examine DNA methylation in nerve tissues may identify similar patterns,” said Pellegrini.

    “We plan to conduct much larger studies in the future, with the goal of developing biomarkers that allow us to better identify dogs with specific behavioral predispositions.”

    He concluded: “Ultimately, we would be very interested in examining the epigenomes of highly specialized dogs such as guide dogs or sled dogs, to be able to assist in the selection of dogs that might be more likely to successfully complete their training.”

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    For editors / news media:

    Please link to the open access original research article “Association of DNA methylation with energy and fear-related behaviors in canines” in Frontiers in Psychology in your reporting: https://www.frontiersin.org/articles/10.3389/fpsyg.2022.1025494/full

    Corresponding author 1: Prof Matteo Pellegrini

    Corresponding author 1’s institution: Professor, David Geffen School of Medicine, University of California, Los Angeles, USA

     

     

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  • NEJM study: Researchers Discover Hidden Genetic Anomaly Behind Common Late-Onset Cerebellar Ataxia

    NEJM study: Researchers Discover Hidden Genetic Anomaly Behind Common Late-Onset Cerebellar Ataxia

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    Hello –This new scientific discovery, published today in the New England Journal of Medicine, should interest you for coverage. Below, please find link to full press release.

    Co-Senior Author Dr. Stephan Zuchner and Co-Primary Author, Dr. Matt Danzi, with the University of Miami are available for interviews.  Broll and high rez photos are also available.

    Full press release

    A copy of the study can be found here.

     

     

     

     

     

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    University of Miami Health System, Miller School of Medicine

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  • CRISPR Technology Improves Huntington’s Disease Symptoms in Models

    CRISPR Technology Improves Huntington’s Disease Symptoms in Models

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    Newswise — Huntington’s disease (HD) is a neurological disorder that causes progressive loss of movement, coordination and cognitive function. It is caused by a mutation in a single gene called huntingtin or HTT. More than 200,000 people worldwide live with the genetic condition, approximately 30,000 in the United States. More than a quarter of a million Americans are at risk of inheriting HD from an affected parent. There is no cure.

    But in a new study, published December 12, 2022 in Nature Neuroscience, researchers at University of California San Diego School of Medicine, with colleagues elsewhere, describe using RNA-targeting CRISPR/Cas13d technology to develop a new therapeutic strategy that specifically eliminates toxic RNA that causes HD.

    CRISPR is known as a genome-editing tool that allows scientists to add, remove or alter genetic material at specific locations in the genome. It is based on a naturally occurring immune-defense system used by bacteria. However, current strategies run the risk of off-target edits at unintended sites that may cause permanent and inheritable chromosomal insertions or genome alterations. Because of this, significant efforts have focused on identifying CRISPR systems that target RNA directly without altering the genome.

    In the case of HD, the condition is caused by repetitive and damaging sequences in the HTT gene.

    Our cells have a hard time copying repetitive DNA, and these copying errors can cause repetitive sequences to grow longer with each generation,” said senior study author Gene Yeo, PhD, professor of cellular and molecular medicine at UC San Diego School of Medicine.

    “In the Huntingtin gene, these repeats can sometimes grow to many times their normal length, with the resulting repeat-expanded protein tending to aggregate and form toxic clumps in a part of the brain called the striatum that is important for regulating movement. The loss of functional neurons in the striatum ultimately leads to HD symptoms.”

    With colleagues at UC Irvine and Johns Hopkins University, Yeo and his team investigated whether recently described RNA-targeting CRISPR technology could be used to affect RNA (a chemical intermediate between DNA instructions and protein production) accumulation associated with HD.

    They used viral vehicles to deliver the therapy to neuronal cultures, which were developed from stem cells derived from patients with HD, and found that the approach not only targeted and destroyed mutant RNA molecules, but also cleared out toxic protein buildup. They also demonstrated that expression of other human genes was generally not disrupted by the therapy.

    “Our goal was to engineer a type of therapy that would only target the toxic RNA that causes HD and could keep the rest of the human genome and transcriptome intact,” said co-first author Kathryn Morelli, PhD, a research fellow in Yeo’s lab. “We specifically screened our top therapeutic constructs in HD patient cell lines to make sure of it.”

    Development of effective therapies for HD has proven challenging. In 2021, for example, two clinical trials for promising gene therapies were halted following disappointing results performance. Both potential drugs had been touted as game-changers for HD. Currently, no treatments can alter the course of the disease, though medications can lessen some symptoms.

    “The Huntington’s community was devastated when the clinical trials failed, primarily due to target specificity and toxic effects,” said Yeo. “But their termination has only re-energized the scientific community to find alternative strategies.”

    Yeo’s lab collaborated with Wenzhen Duan, MD, PhD, professor of psychiatry and behavioral sciences, at Johns Hopkins Medicine to conduct preclinical testing in mice. Duan, with co-first author Qian Wu, PhD, found that the therapy improved motor coordination, attenuated striatal degradation and reduced toxic protein levels in a mouse model of HD. The improvements lasted for at least 8 months without adverse effects and minimal off-target effects on other RNA molecules.

    Co-authors include: Maya L. Gosztyla, Ryan J. Marina, Kari Lee, Krysten L. Jones, Megan Huang and Allison Li, all at UC San Diego; Hongshuai Liu, Minmin Yao and Chuangchuang Zhang, Johns Hopkins University; Jiaxu Chen, Beijing University of Chinese Medicine; and Charlene Smith-Geater and Leslie M. Thompson, UC Irvine.

    Funding for this research came, in part, from the National Institutes of Health (grants EY029166, NS103172,MH107367, AI132122, HG004659, HG009889, NS099397, NS124084, T32GM008666 ) the Bev Hartig Huntington’s Disease Foundation, an NIH NS112654-03 postdoctoral fellowship, a University of California President’s Postdoctoral Fellowship, the Paul G. Allen Foundation, the China Scholarship Council and the National Natural Science Foundation of China (82174278 and 81973748), the Hereditary Disease Foundation, an NIH predoctoral fellowship (NS111859), a National Science Foundation Graduate Research Fellowship (DGE-2038238),a Myotonic Dystrophy Foundation Doctoral Research Fellowship, an Association for Women in Science Scholarship and a Triton Research and an Experiential Learning Scholarship from Eureka! Research Scholarship.

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    Disclosures: Gene Yeo is a scientific advisory board member of Jumpcode Genomics and a co-founder, member of the Board of Directors, scientific advisory board member, equity holder and paid consultant for Locanabio and Eclipse BioInnovations. He is also a Distinguished Visiting Professor at the National University of Singapore.

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  • Scientists Map Genetic Evolution of Chronic Lymphocytic Leukemia to Richter’s Syndrome

    Scientists Map Genetic Evolution of Chronic Lymphocytic Leukemia to Richter’s Syndrome

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    Newswise — Every year, up to 1% of patients with chronic lymphocytic leukemia (CLL), a slow-growing blood cancer, have their disease transform into a far more aggressive cancer, a form of lymphoma known as Richter’s Syndrome. For the most part, the genomic changes that underlie this metamorphosis and push it forward have been obscure, hindering advances in treatment. 

    In a new study, scientists at Dana-Farber and the Broad Institute of MIT and Harvard trace these changes in unprecedented detail, revealing for the first time the genomic differences between CLL and Richter’s, the molecular pathways by which Richter’s emerges, and the existence of multiple subtypes of the disease.

    The findings, presented today at the annual meeting of the American Society of Hematology (ASH) and published online in the journal Nature Medicine, not only break open what was once a “black box” of molecular change but point the way to an earlier diagnosis of the disease, when treatments may be more effective.

    “The treatments for CLL and Richter’s Syndrome are very different, so it’s critical that doctors be able to determine, as early as possible, when CLL has ‘crossed over’ to become Richter’s,” says study co-senior author Catherine Wu, MD, of Dana-Farber, the Broad Institute, and Brigham and Women’s Hospital. “The traditional method of diagnosing Richter’s has a number of shortcomings, which can lead to delays in patients’ receiving the appropriate treatment. Our findings in this study hold the promise of an earlier, more definitive diagnosis based on the molecular makeup of the tumor cells.”

    One of the biggest obstacles to diagnosing Richter’s Syndrome is that patients don’t have either CLL or Richter’s cells, but a mixture of both. And unlike CLL, which is diagnosed from a blood sample, a formal diagnosis of Richter’s requires a biopsy, in which a small piece of tissue is removed and examined under a microscope for telltale changes in the structure and markings of the cells. But because a biopsy collects tissue from just one area, it may find CLL cells but miss Richter’s cells lurking right nearby. As a result, a patient may have classic symptoms of Richter’s such as swollen lymph nodes, fever, night sweats, but the biopsy – which ultimately determines the diagnosis – indicates CLL.

    To understand Richter’s at the molecular level and track how it evolves from CLL, researchers began with tissue samples gathered from 52 patients over a period of years. Samples collected when the patients had CLL were paired with samples taken when they were diagnosed with Richter’s. The researchers then performed whole exome sequencing, reading the protein-coding sections of DNA in the samples.  Because the samples likely had a mix of cells, they used computational methods on these sequencing data to estimate the proportion of CLL and Richter’s cells in each one. Knowing the relative levels of different cell types within the samples, they were able to identify the genetic changes that drive the evolution from CLL to Richter’s.

    The researchers discovered a motley assortment of such changes, including mutations in multiple genes, missing or added copies of other genes, duplication of cell genomes, and ‘chromothripsis’, a splintering and haphazard reassembly of entire chromosomes.

    “We see myriad differences between CLL and Richter’s at the molecular level, with a much more complex genome in Richter’s, as well as additional driver events,” remarks study co-senior author, Dr. Gad Getz of the Broad Institute and Massachusetts General Hospital. “In addition, we’ve found that Richter’s exists in a number of different subtypes.”

    The subtypes are distinguished by their molecular signatures, the specific pattern of genomic anomalies within their cells. These DNA-level differences suggest that the subtypes arrived by taking different routes in evolving from CLL. “The formation of multiple subtypes can give us insights into the ‘archaeology’ of the disease: what was the molecular make-up of CLL before it transformed into one subtype or another?” Wu explains.

    Being able to identify different subtypes of Richter’s can be helpful in the clinic: patients with certain subtypes generally fare better than those with others, although the outlook at the present time is poor for all patients with Richter’s. Scientists hope that advances can improve those prospects.

    Plasma diagnosis

    Once researchers knew the genomic features of Richter’s, they explored whether the disease could be detected by analyzing DNA in patients’ plasma, the liquid portion of blood. They sequenced the DNA in 46 plasma samples from 24 patients with Richter’s. The samples had been collected over a period of years, beginning within three years of a diagnosis of Richter’s and extending through treatment and relapse of the disease. The researchers then sequenced the DNA floating freely within the samples. “We found that genomic features of Richter’s were indeed detectable in the plasma,” Wu relates.

    “We then asked whether such changes could be detected before patients had been diagnosed with Richter’s based on a biopsy,” she continues. “For some patients, we clearly detected Richter’s-related DNA alterations in plasma that had been collected one to ten months prior to their Richter’s diagnosis – a time at which they had been undergoing treatment for what was presumed to be aggressive CLL.” The upshot is that it may become possible to diagnose Richter’s through a simple blood test, potentially earlier than it would show up on a biopsy and at a stage where it may be more treatable.

    “The current therapies for Richter’s are of very limited effectiveness, yet there is hope that patients may benefit from novel, more effective agents. Clinical trials of these agents and of stem cell transplant can explore that promise,” Wu notes. “By the time Richter’s is diagnosed, however, patients may be very sick, at which point transplant or other new therapies may not be an option. So detecting it early may make a critical difference.”

    Learning the molecular hallmarks of Richter’s led researchers to one further discovery. In a substantial portion of patients, their Richter’s cells didn’t share a genetic history with their CLL cells, meaning Richter’s arose independently, with no connection to the earlier disease.

    “Looking ahead to future work, we would like to analyze even larger cohorts of RS patients to obtain a comprehensive characterization of the genomic and microenvironmental landscape of RS; from this, we can discover new and robust therapeutic targets as well as refined molecular subtypes, getting us closer to applying precision medicine to this disease,” adds Dr. Getz

    “Our findings suggest that in many patients, the genomic changes in CLL that lead to Richter’s occur before patients develop symptoms of lymphoma,” Wu says. “Being able to trace the transition from CLL to Richter’s at a molecular level impacts not only our understanding of the disease but, potentially, our ability to treat it and improve outcomes for patients.”

    The co-senior authors of the study are Gad Getz, PhD, of Massachusetts General Hospital and the Broad Institute, and Stephan Stilgenbauer, MD, of Ulm University, Ulm, Germany. The lead authors are Erin Parry, MD, PhD, of Dana-Farber and the Broad Institute; Ignaty Leshchiner, PhD, of the Broad Institute and Boston University School of Medicine; and Romain Guieze, MD, PhD, of Dana-Farber, the Broad Institute, CHU de Clermont-Ferrand and Université Clermont Auvergne, both in France. The co-authors are: Camilla Lemvigh, Shanye Yin, PhD, Teddy Huang, Shuqiang Li, PhD, Geoff Fell, Robert Redd, Neil Ruthen, Stacey Fernandes, Annabelle J Anandappa, MD, Kenneth J. Livak, PhD, Donna Neuberg, ScD, Matthew S. Davids, MD, and Jennifer R. Brown, MD, PhD, of Dana-Farber; Noelia Purroy-Zuriguel, MD, PhD, of Dana-Farber and the Broad Institute; Connor Johnson, Conor Messer, Liang Li, Daniel Rosebrock, Kara Slowik, Raquel Jacobs, Ziao Lin, Binyamin A. Knisbacher, PhD, Dimitri Livitz, Liudmilla Elagina, Amaro Taylor-Weiner, PhD, Bria Persaud, Aina Martinez, Jialin Ma, Julian Hess, Brian P. Danysh, PhD, and Chip Stewart, PhD, of the Broad Institute; Eugen Tausch, MD, and Christof Schneider of Ulm University; Sameer A. Parikh, MD, and Neil E. Kay, MD, of the Mayo Clinic; Julien Broséus, MD, PhD, Sébastien Hergelant, and Pierre Feugier of Université de Lorraine, Nancy, France; Filippo Utro, PhD, Chaya Levovitz, MD, PhD, Kahn Rhrissorrakrai, PhD, and Laxmi Parida, PhD, of IBM Research, Yorktown Heights, N.Y.; Laura Z Rassenti,, PhD, and Thomas J Kipps MD, PhD, of Moores Cancer Center, Medicine, University of California, San Diego; Nitin Jain, MD, and William Wierda, MD, PhD, of the University of Texas MD Anderson Cancer Center; and Florence Cymbalista, MD, PhD, of Université Sorbonne Paris Nord, Bobigny, France.

    The study was supported by the National Institutes of Health/National Cancer Institute (grants # P01 CA206978, 1U10CA180861-01, R01 CA 213442, and P01 CA 206978); a DDCF Physician-Scientist Fellowship; Dana-Farber Flames FLAIR fellowship; ASCO Conquer Cancer Young Investigator Award; the Broad/IBM Cancer Resistance Research Project; the Fishman Family Fund; Force Hemato; a long-term EMBO fellowship (ALTF 14-2018); Deutsche Forschungsgemeinschaft; an NCI Research Specialist Award; and the Melton Family Foundation.

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    Dana-Farber Cancer Institute

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  • Genetic barriers, a warming ocean, and the uncertain future for an important forage fish

    Genetic barriers, a warming ocean, and the uncertain future for an important forage fish

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    Newswise — In the vast oceans, one would assume their inhabitants can travel far and wide and, as a result, populations of a species would mix freely. But this doesn’t appear to be the case for a vital forage fish called the sand lance.

    Sand lance are small schooling fish impressively rich in lipids, which makes them a fantastic and significant food source for at least 70 different species ranging from whales and sharks to seabirds, says UConn Associate Professor of Marine Sciences Hannes Baumann.

    The Northern sand lance can be found from the waters off New Jersey all the way north to Greenland. Researchers, including Baumann and Ph.D. student Lucas Jones, were interested to see if sand lance constitute a massive, homogenous population, or whether there are genetically distinct groups. Their findings are published in the ICES Journal of Marine Science.

    Baumann explains these are important questions to answer when considering conservation and sustainable management of the species, especially since the regions where sand lance live are warming faster than many areas of the planet due to climate change.

    Sampling fish from such a broad range is no small task, but two years ago, Baumann and Jones began reaching out to other researchers to see if they had tissue samples to spare. Baumann credits the work to the international group of colleagues who contributed samples including co-authors from Canada and Greenland, and who helped sequence and analyze the data including co-authors from Cornell University.

    In all, Baumann, Jones, and the team were able to sequence and analyze nearly 300 samples from a variety of locations across the sand lance’s range using a technique called low-coverage whole genome sequencing. They also sequenced the first reference genome for sand lance.

    In a nutshell, Baumann says they found an area on the Scotian Shelf, off the coast of Nova Scotia, where a genetic break occurs. The researchers distinguished two distinct groups, one north and one south of the divide, with parts of the genome differing quite dramatically – namely on chromosomes 21 and 24. Without obvious physical barriers like a mountain range separating the groups, Baumann says it’s logical to ask how these differences are possible.

    “That is the scientific conundrum,” says Baumann, and the answer, it appears, lies in the currents.

    “When fish from the north reproduce and drift south, they are genetically less adapted to warmer southern waters, even if it’s five or six degrees warmer in the winter, they are just not surviving,” Baumann says. “These populations may be linked by the ocean currents, but the realized connectivity is basically zero.”

    This finding is a first for the sand lance, but it has been shown in other species such as lobsters, cod, and scallops, and this research adds further evidence to an apparent temperature divide at the Scotian Shelf, and helps demonstrate that temperature is an important factor in survival.

    “Example after example shows that the ocean is not as homogeneous a place as expected, and there are all kinds of things that prevent that constant mixing,”Baumann says. “We found another striking example of that.”

    When researchers find adaptation in an environment where mixing is continuous, like in the ocean, Baumann says, the question is how it is possible that groups stay different, even though they are constantly encountering other genotypes. That is where powerful genomic methods, like the ones used in this paper, come in handy.

    “Parts of the genome in many species have what we call a ‘genetic inversion,’ which means that the genes on the chromosome from one parent have a certain order and the genes on the same chromosome that come from the other parent that code for the same thing, and they’re the same area, but they’re flipped,” Baumann says.

    These inversions mean recombination cannot occur; therefore, the genes are passed down through the generations and play an important role in adaptation.

    “We discovered on chromosomes 21 and 24 there are whole regions that are completely different and that is like the trademark signature of what we call an inversion because there’s no recombination going on.”

    Baumann says that knowing there are genetic and ecological barriers on the Scotian Shelf is important, because with climate change, this barrier may move north and while that may be good news for southern fish, it’s bad news for the fish currently there.

    The researchers were also a little relieved in finding two clusters, because had there been many smaller clusters, it could make management and conservation more challenging, especially considering scenarios like the construction of offshore wind parks. Areas potentially well situated for wind turbines can also be habitats for sand lance, and construction disrupts habitats. If there were many, smaller population clusters, a single construction project could pose the risk of completely wiping out a cluster, whereas with more widely dispersed populations, though the local population may be temporarily disturbed, it will not be long before they are able to re-establish after construction is completed.

    Baumann plans to focus further research on studying the genetic basis of the thermal divide.

    “We want to make sure that this fish is productive and resilient, despite climate change, so we should make sure these areas where they are occurring are protected,” Bauman says. “These decisions should include experts to ensure if there’s an area that is very critical to sand lance, that any disturbance is temporary.”

    It isn’t an unsolvable conflict, but it is something that we need to do, says Baumann, who also notes that it is possible that sand lance north of the thermal divide are already suffering more from warming because the region is warming faster.

    “It could be that these two clusters have different vulnerabilities to climate change,” he says. “We don’t know that yet but that’s something that should be pursued.”

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    University of Connecticut

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  • Genetic profiling may identify patients with breast cancer who can safely omit radiation therapy after breast-conserving surgery

    Genetic profiling may identify patients with breast cancer who can safely omit radiation therapy after breast-conserving surgery

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    Newswise — SAN ANTONIO – Patients with invasive breast cancer who had low scores on an investigational gene molecular signature had similar rates of local recurrence whether or not they received adjuvant radiation therapy after breast-conserving surgery, according to results of a meta-analysis presented at the San Antonio Breast Cancer Symposium, held December 6-10, 2022.

    Patients with breast cancer who undergo breast-conserving surgery are recommended to receive adjuvant radiation therapy to reduce the risk of local recurrence. “However, many patients will not experience a local recurrence even without radiation therapy,” said Per Karlsson, MD, a professor of oncology at the Sahlgrenska Comprehensive Cancer Center and the University of Gothenburg in Sweden.

    “Currently, we do not have any reliable predictive classifiers to identify patients who might be able to skip radiation therapy,” he added. “Since radiation therapy can be associated with problematic side effects in some patients, it is of clinical importance to identify those patients for whom radiation therapy can be safely omitted.”

    In this study, Karlsson and colleagues evaluated the predictive potential of POLAR (Profile for the Omission of Local Adjuvant Radiotherapy), an investigational 16-gene molecular signature that was developed based on gene expression differences between patients with and without local recurrence after breast-conserving surgery. Genes included in the signature have known roles in cellular proliferation and the immune response.

    The researchers performed a meta-analysis of 623 patients with lymph node-negative, estrogen receptor-positive, HER2-negative breast cancer who were enrolled in one of three randomized clinical trials examining the efficacy of breast-conserving surgery with and without local breast radiation therapy. The clinical trials included in the meta-analysis were the Swedish SweBCG91RT trial, the Scottish Conservation Trial (SCT), and a trial from the Princess Margaret Hospital (PMH) in Canada. Among the 623 patients in the meta-analysis, 354 were from SweBCG91RT, 137 from SCT, and 132 from the PMH trial.

    To evaluate the predictive capability of POLAR, the researchers analyzed gene expression in patient breast tumor samples to assign each patient a POLAR score; they then examined the impact of radiation therapy for patients with high and low POLAR scores. Among the 429 patients with high POLAR scores, those who received adjuvant radiation therapy after breast-conserving surgery had a 63 percent reduction of local recurrence compared with those who did not receive adjuvant radiation therapy, suggesting that adjuvant radiation therapy was beneficial for these patients.

    In contrast, for the 194 patients with low POLAR scores, there was no significant difference in local recurrence rate between those who received adjuvant radiation therapy and those who did not. After 10 years, 5 percent of patients who received radiation therapy experienced a local recurrence, compared with 7 percent of those who did not receive radiation therapy.

    “In a patient-level meta-analysis of three independent randomized clinical trials, the POLAR gene profile successfully predicted which patients would and would not benefit from local radiation therapy, thereby identifying a group of breast cancer patients where radiation therapy may be safely omitted after breast-conserving surgery,” summarized Karlsson.

    “Although only a minority of patients experience severe side effects to breast radiation, this adds up to a fair number of patients once you consider how prevalent breast cancer is,” he added. “The POLAR gene profile may, therefore, help mitigate toxicities and improve quality of life for many patients.” Karlsson noted that the POLAR gene profile will need further validation and additional streamlining before it could be used in the clinic.

    Future research from Karlsson and colleagues will examine whether the POLAR gene profile can also identify patients who could safely avoid regional radiation therapy, which is associated with more severe toxicities than local radiation therapy.

    A limitation of the study is its retrospective design. Additionally, the POLAR gene profile was developed using samples from patients who did not receive currently available endocrine therapies; however, validation trials included patients who received such therapies.

    The study was supported by funds from the Swedish Cancer Society, the Swedish Research Council, the King Gustaf V Jubilee Clinic Foundation, the ALF Agreement of the Swedish government, PFS Genomics, and Exact Sciences.

    Karlsson has pending patents with and receives royalties from Exact Sciences and PreludeDX.

     

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    American Association for Cancer Research (AACR)

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  • Aging is driven by unbalanced genes

    Aging is driven by unbalanced genes

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    • New study finds that most molecular-level changes that occur during aging are associated with gene length
    • Organisms balance the activity of short and long genes
    • Aging is accompanied by a shift in gene activity toward short genes, which are associated with accelerated aging
    • Researcher: ‘Aging is a subtle imbalance, away from equilibrium’ that requires your cells to expend more effort to function properly
    • Findings could lead to medical interventions that slow or even reverse the biological hallmarks of aging

    Newswise — EVANSTON, Ill. — Northwestern University researchers have discovered a previously unknown mechanism that drives aging.

    In a new study, researchers used artificial intelligence to analyze data from a wide variety of tissues, collected from humans, mice, rats and killifish. They discovered that the length of genes can explain most molecular-level changes that occur during aging.

    All cells must balance the activity of long and short genes. The researchers found that longer genes are linked to longer lifespans, and shorter genes are linked to shorter lifespans. They also found that aging genes change their activity according to length. More specifically, aging is accompanied by a shift in activity toward short genes. This causes the gene activity in cells to become unbalanced.

    Surprisingly, this finding was near universal. The researchers uncovered this pattern across several animals, including humans, and across many tissues (blood, muscle, bone and organs, including liver, heart, intestines, brain and lungs) analyzed in the study.

    The new finding potentially could lead to interventions designed to slow the pace of — or even reverse — aging.

    The study will be published on Dec. 9 in the journal Nature Aging.

    “The changes in the activity of genes are very, very small, and these small changes involve thousands of genes,” said Northwestern’s Thomas Stoeger, who led the study. “We found this change was consistent across different tissues and in different animals. We found it almost everywhere. I find it very elegant that a single, relatively concise principle seems to account for nearly all of the changes in activity of genes that happen in animals as they age.”

    “The imbalance of genes causes aging because cells and organisms work to remain balanced — what physicians denote as homeostasis,” said Northwestern’s Luís A.N. Amaral, a senior author of the study. “Imagine a waiter carrying a big tray. That tray needs to have everything balanced. If the tray is not balanced, then the waiter needs to put in extra effort to fight the imbalance. If the balance in the activity of short and long genes shifts in an organism, the same thing happens. It’s like aging is this subtle imbalance, away from equilibrium. Small changes in genes do not seem like a big deal, but these subtle changes are bearing down on you, requiring more effort.”

    An expert in complex systems, Amaral is the Erastus Otis Haven Professor of Chemical and Biological Engineering in Northwestern’s McCormick School of Engineering. Stoeger is a postdoctoral scholar in Amaral’s laboratory.

    Looking across ages

    To conduct the study, the researchers used various large datasets, including the Genotype-Tissue Expression Project, a National Institutes of Health-funded tissue bank that archives samples from human donors for research purposes.

    The research team first analyzed tissue samples from mice — aged 4 months, 9 months, 12 months, 18 months and 24 months. They noticed the median length of genes shifted between the ages of 4 months and 9 months, a finding that hinted at a process with an early onset. Then, the team analyzed samples from rats, aged 6 months to 24 months, and killifish, aged 5 weeks to 39 weeks.

    “There already seems to be something happening early in life, but it becomes more pronounced with age,” Stoeger said. “It seems that, at a young age, our cells are able to counter perturbations that would lead to an imbalance in gene activity. Then, suddenly, our cells are no longer able to counter it.”

    After completing this research, the researchers turned their attention to humans. They looked at changes in human genes from ages 30 to 49, 50 to 69 and then 70 and older. Measurable changes in gene activity according to gene length already occurred by the time humans reached middle age.

    “The result for humans is very strong because we have more samples for humans than for other animals,” Amaral said. “It was also interesting because all the mice we studied are genetically identical, the same gender and raised in the same laboratory conditions, but the humans are all different. They all died from different causes and at different ages. We analyzed samples from men and women separately and found the same pattern.”

    ‘Systems-level’ changes

    In all animals, the researchers noticed subtle changes to thousands of different genes across samples. This means that not just a small subset of genes that contributes to aging. Aging, instead, is characterized by systems-level changes.

    This view differs from prevailing biological approaches that study the effects of single genes. Since the onset of modern genetics in the early 20th century, many researchers expected to be able to attribute many complex biological phenomena to single genes. And while some diseases, such as hemophilia, do result from single gene mutations, the narrow approach to studying single genes has yet to lead to explanations for the myriad changes that occur in neurodegenerative diseases and aging.

    “We have been primarily focusing on a small number of genes, thinking that a few genes would explain disease,” Amaral said. “So, maybe we were not focused on the right thing before. Now that we have this new understanding, it’s like having a new instrument. It’s like Galileo with a telescope, looking at space. Looking at gene activity through this new lens will enable us to see biological phenomena differently.”

    Lengthy insights

    After compiling the large datasets, many of which were used in other studies by researchers at Northwestern University Feinberg School of Medicine and in studies outside Northwestern, Stoeger brainstormed an idea to examine genes, based on their length.

    The length of a gene is based on the number of nucleotides within it. Each string of nucleotides translates to an amino acid, which then forms a protein. A very long gene, therefore, yields a large protein. And a short gene yields a small protein. According to Stoeger and Amaral, a cell needs to have a balanced number of small and large proteins to achieve homeostasis. Problems occur when that balance gets out of whack. 

    Although the researchers did find that long genes are associated with increased lifespans, short genes also play important roles in the body. For example, short genes are called upon to help fight off pathogens.

    “Some short genes could have a short-term advantage on survival at the expense of ultimate lifespan,” Stoeger said. “Thus, outside of a research laboratory, these short genes might help survival under harsh conditions at the expense of shortening the animal’s ultimate lifespan.”

    Suspected ties to long COVID-19

    This finding also may help explain why bodies take longer to heal from illnesses as they age. Even with a simple injury like a paper cut, an older person’s skin takes a longer time to recover. Because of the imbalance, cells have fewer reserves to counteract the injury. 

    “Instead of just dealing with the cut, the body also has to deal with this activity imbalance,” Amaral hypothesized. “It could explain why, over time with aging, we don’t handle environmental challenges as well as when we were younger.”

    And because thousands of genes change at the system-level, it doesn’t matter where the illness starts. This could potentially explain illnesses like long COVID-19. Although a patient might recover from the initial virus, the body experiences damage elsewhere.

    “We know cases where infections — predominantly viral infections — lead to other problems later in life,” Amaral said. “Some viral infections can lead to cancer. Damage moves away from the infected site and affects other areas of our body, which then is less able to fight environmental challenges.”

    Hope for medical interventions

    The researchers believe their findings could open new venues for the development of therapeutics, designed to reverse or slow aging. Current therapeutics to treat illness, the researchers argue, are merely targeting the symptoms of aging rather than aging itself. Amaral and Stoeger compare it to using Tylenol to reduce a fever instead of treating the illness that caused the fever.

    “Fevers can occur for many, many reasons,” Amaral said. “It could be caused by an infection, which requires antibiotics to cure, or caused by appendicitis, which requires surgery. Here, it’s the same thing. The issue is the gene activity imbalance. If you can help correct the imbalance, then you can address the downstream consequences.”

    Other Northwestern co-senior authors include Richard Morimoto, a professor of molecular biosciences in the Weinberg College of Arts and Sciences; Dr. Alexander Misharin, an associate professor of medicine at Feinberg; and Dr. G.R. Scott Budinger, the Ernest S. Bazley Professor of Airway Diseases at Feinberg and chief of pulmonary and critical care at Northwestern Medicine. 

    The study, “Aging is associated with a systemic length-associated transcriptome imbalance,” was supported by the Office of the Assistant Secretary of Defense for Health Affairs, the U.S. Department of Defense, the National Institutes of Health (grant numbers AG068544, AG049665, AG054407, AG026647, AG057296, AG059579), the Veterans Administration, the National Science Foundation and a gift from John and Leslie McQuown.

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    Northwestern University

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  • Researchers discover rare form of premature-aging syndrome

    Researchers discover rare form of premature-aging syndrome

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    Newswise — DALLAS – Dec. 8, 2022 – UT Southwestern researchers have discovered a new form of progeria, a rare premature-aging syndrome, in a man from Malaysia and traced its cause to a novel gene mutation. The finding, reported in the Journal of Clinical Investigation, could lead to new therapies for more common conditions that share features with this ultra-rare disorder.

    “We realized that this is not like the progeroid syndromes we have seen in the past. It is a completely new subtype,” said study leader Abhimanyu Garg, M.D., Professor of Internal Medicine at UTSW, Section Chief of Nutrition and Metabolic Diseases in the Division of Endocrinology, and Director of Metabolic Diseases in the Center for Human Nutrition. “We wanted to see whether we could find the gene behind it.”

    Dr. Garg explained that colleagues in Malaysia had encountered a patient of Chinese descent with a highly unusual combination of physical characteristics. The 21-year-old male was 3.8 feet tall, weighed 46 pounds, and had a head circumference of 21 inches, all below the lowest 3% of the general population. He also had a unique set of facial features, with a pointed nose, thin lips, a small lower jaw, and severe dental crowding, as well as very low body fat – a condition known as lipodystrophy – and extremely poor vision.

    Because Dr. Garg’s lab focuses on lipodystrophy research and had previously discovered the genetic mutations behind a condition called mandibuloacral dysplasia (MAD), which the Malaysian researchers believed this patient had, they sent Dr. Garg the patient’s blood samples to confirm their tentative diagnosis. However, when Dr. Garg and his colleagues performed genetic testing, they found the patient lacked mutations in either of the two genes linked to MAD.

    Suspecting the patient might have an undiscovered condition, Dr. Garg and his collaborators scanned the entire genomes of the patient and his immediate family members for any unusual gene variants. They quickly narrowed their search to a single gene known as TOMM7.

    From animal studies, this gene was known to produce a protein that comes together in a complex with related proteins to form a pore in the outer membrane of mitochondria, the power-generating organelles of cells.

    To better understand its function in humans, the researchers grew skin cells from a sample derived from the patient and compared them to skin cells from healthy volunteers. Tests showed that the patient’s cells consumed far more oxygen than the healthy cells and produced greater amounts of proteins related to oxygen metabolism. They also produced fewer proteins related to phospholipid metabolism, a process involved in the formation of body fat.

    Further experiments showed that the mutant TOMM7 protein from the patient didn’t interact well with other proteins that form the mitochondrial pore complex. This functional defect, Dr. Garg said, could limit the transportation of proteins through the pore, pointing to a mechanism for the patient’s symptoms.

    Dr. Garg said that more common variants in this gene could help explain population-wide differences in characteristics exaggerated in this patient, such as height, jaw size, body fat, and vision. In addition, because the patient had an older sister who appeared to have the same genetic syndrome and died at age 10, further research on this gene variant could clarify genetic factors that affect aging – and may also eventually lead to a cure for this individual, who may be in danger, Dr. Garg said.

    “We don’t know what his life span may be, but based on what we know about his sister, he may be at risk of premature death,” he said. “I hope other scientists will take it to the next level and figure out a specific treatment that could save this patient from that fate.”

    Dr. Garg holds the Distinguished Chair in Human Nutrition Research.

    Other researchers who contributed to this study include Adwait Amod Sathe, Chao Xing, Anil K. Agarwal, and Prashant Mishra of UTSW; Yanqiu Shao of UTSW and Southern Methodist University; Wee-Teik Keng of Kuala Lumpur Hospital in Malaysia; Zhenkang Chen, Nicholas P. Lesner, and Claire B. Llamas of Children’s Medical Center Research Institute at UT Southwestern; and Pavithira Devi Kailasam of Hospital Pakar Sultanah Fatimah in Malaysia.

    About UT Southwestern Medical Center

    UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 24 members of the National Academy of Sciences, 18 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,900 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 100,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 4 million outpatient visits a year.

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    UT Southwestern Medical Center

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  • Oldest DNA reveals life in Greenland 2 million years ago

    Oldest DNA reveals life in Greenland 2 million years ago

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    NEW YORK — Scientists discovered the oldest known DNA and used it to reveal what life was like 2 million years ago in the northern tip of Greenland. Today, it’s a barren Arctic desert, but back then it was a lush landscape of trees and vegetation with an array of animals, even the now extinct mastodon.

    “The study opens the door into a past that has basically been lost,” said lead author Kurt Kjær, a geologist and glacier expert at the University of Copenhagen.

    With animal fossils hard to come by, the researchers extracted environmental DNA, also known as eDNA, from soil samples. This is the genetic material that organisms shed into their surroundings — for example, through hair, waste, spit or decomposing carcasses.

    Studying really old DNA can be a challenge because the genetic material breaks down over time, leaving scientists with only tiny fragments.

    But with the latest technology, researchers were able to get genetic information out of the small, damaged bits of DNA, explained senior author Eske Willerslev, a geneticist at the University of Cambridge. In their study, published Wednesday in the journal Nature, they compared the DNA to that of different species, looking for matches.

    The samples came from a sediment deposit called the Kap København formation in Peary Land. Today, the area is a polar desert, Kjær said.

    But millions of years ago, this region was undergoing a period of intense climate change that sent temperatures up, Willerslev said. Sediment likely built up for tens of thousands of years at the site before the climate cooled and cemented the finds into permafrost.

    The cold environment would help preserve the delicate bits of DNA — until scientists came along and drilled the samples out, beginning in 2006.

    During the region’s warm period, when average temperatures were 20 to 34 degrees Fahrenheit (11 to 19 degrees Celsius) higher than today, the area was filled with an unusual array of plant and animal life, the researchers reported. The DNA fragments suggest a mix of Arctic plants, like birch trees and willow shrubs, with ones that usually prefer warmer climates, like firs and cedars.

    The DNA also showed traces of animals including geese, hares, reindeer and lemmings. Previously, a dung beetle and some hare remains had been the only signs of animal life at the site, Willerslev said.

    One big surprise was finding DNA from the mastodon, an extinct species that looks like a mix between an elephant and a mammoth, Kjær said.

    Many mastodon fossils have previously been found from temperate forests in North America. That’s an ocean away from Greenland, and much farther south, Willerslev said.

    “I wouldn’t have, in a million years, expected to find mastodons in northern Greenland,” said Love Dalen, a researcher in evolutionary genomics at Stockholm University who was not involved in the study.

    Because the sediment built up in the mouth of a fjord, researchers were also able to get clues about marine life from this time period. The DNA suggests horseshoe crabs and green algae lived in the area — meaning the nearby waters were likely much warmer back then, Kjær said.

    By pulling dozens of species out of just a few sediment samples, the study highlights some of eDNA’s advantages, said Benjamin Vernot, an ancient DNA researcher at Germany’s Max Planck Institute for Evolutionary Anthropology who was not involved in the study.

    “You really get a broader picture of the ecosystem at a particular time,” Vernot said. “You don’t have to go and find this piece of wood to study this plant, and this bone to study this mammoth.”

    Based on the data available, it’s hard to say for sure whether these species truly lived side by side, or if the DNA was mixed together from different parts of the landscape, said Laura Epp, an eDNA expert at Germany’s University of Konstanz who was not involved in the study.

    But Epp said this kind of DNA research is valuable to show “hidden diversity” in ancient landscapes.

    Willerslev believes that because these plants and animals survived during a time of dramatic climate change, their DNA could offer a “genetic roadmap” to help us adapt to current warming.

    Stockholm University’s Dalen expects ancient DNA research to keep pushing deeper into the past. He worked on the study that previously held the “oldest DNA” record, from a mammoth tooth around a million years old.

    “I wouldn’t be surprised if you can go at least one or perhaps a few million years further back, assuming you can find the right samples,” Dalen said.

    ———

    The Associated Press Health and Science Department receives support from the Howard Hughes Medical Institute’s Science and Educational Media Group. The AP is solely responsible for all content.

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