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Tag: Genetics

  • How a New Blood-Vessel-on-a-Chip Can Help Researchers Further Understand Vascular Malformations

    How a New Blood-Vessel-on-a-Chip Can Help Researchers Further Understand Vascular Malformations

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    Newswise — CHAPEL HILL, N.C. – Our bodies are made up of 60,000 miles of complex pipes that play a vital role in transporting nutrients throughout our bodies, performing waste disposal, and supplying our organs with fresh oxygen and blood.

    Several things can go wrong with this complex system, including vascular malformations (VMs), a group of rare genetic disorders that causes an abnormal formation of veins, arteries, capillaries, or lymphatic vessels at birth. VMs can interfere with the duties of our precious pipes by causing blockages, poor drainage, and the formation of cysts and tangles.

    To address a need for further study, William Polacheck, PhD, an assistant professor at the UNC-NCSU Joint Department of Biomedical Engineering and the Department of Cell Biology and Physiology, and his team spanning across the UNC School of Medicine, have developed a model that mimics VMs that are specifically caused by a mutation of PIK3CA — a gene that has been implicated in multiple types of lymphatic, capillary, and venous malformations.

    Their work was published in Science Advances, an open access multidisciplinary journal from the American Association for the Advancement of Science (AAAS).

    “There are number of ‘chicken and the egg problems’ of the PIK3CA mutation,” said Polacheck. “Is it causing something else to go wrong? Or is there something else in the environment causing the mutation to have more severe effects? Working in a much more controlled environment, such as a microfluidic model, allows us to isolate and figure out how the genetics of the disease relate to what’s happening in the cells.”

    VMs are caused by mutations in the genes that direct the development of the vasculature throughout the body. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) is one of those genes. Activating mutations in PIK3CA commonly contribute to malformations of the smaller blood vessels, causing blood to pool underneath the skin.

    This specific type of vascular malformation is usually discovered at birth. These diseases start as the baby is developing. Since there are a multitude of changes happening at this point in the child’s development, it can be difficult condition for researchers to study.

    Julie Blatt, MD, professor of pediatric hematology-oncology in the UNC Department of Pediatrics, saw the need for a new approach to model the disease, which affects a majority of her patients. She has had a long-standing interest in clinical management of patients with vascular malformations, as well as an interest in repurposing cancer drugs for the disease. Impressed with his prior manuscripts, Dr. Blatt picked up the phone and cold-called Polacheck, who is a biomedical engineer by trade, to ask if he could create a microfluidic model of PIK3CA-specific vascular malformations.

    “I think the transdisciplinary aspect keeps the possibility of application to patients at the forefront, said Dr. Blatt. “The Polacheck lab has prioritized introduction of genetic mutations that are relevant to patients and to studying drugs which we know or think will have benefit.”

    Around the same time, Wen Yih Aw, PhD, was working as a postdoctoral researcher at UNC Catalyst, a research group focused on understanding rare diseases in the Eshelman School of Pharmacy. Aw was collaborating with the Polacheck lab on a vascular Ehlers Danlos Syndrome project. Eventually, Aw joined the Polacheck lab and used her molecular biology expertise to help develop the VMs model.

    In addition to Dr. Blatt and Aw, the lab has an on-going collaboration with Boyce Griffith, PhD in the Department of Mathematics and the Computational Medicine Program at the UNC College of Arts and Sciences, who is helping with analyzing the structures of the networks.

    “All those pieces were necessary to complete the work,” said Polacheck. “It does say something about UNC-Chapel Hill because there were multiple departments across campus involved. There were no barriers whatsoever to working together on this project.”

    Microfluidic models are incredibly small – about the size of a millimeter – three-dimensional devices that can be used to control or simulate the environment within the body. In this case, a small piece of blood vessel composed of healthy human endothelial cells or endothelial cells expressing the PIK3CA mutation is centered inside of the device. From there, the researchers can look into the process of vascular formation, and introduce specific chemicals and mechanical forces to the model to simulate the conditions of the body. They observed formation of enlarged and irregular vasculature with the introduction of PIK3CA mutation.

    To confirm whether or not their model accurately portrays the manifestation of the disease, the team next conducted a drug efficacy study.

    There are two drugs currently used for the treatment of vascular malformations: rapamycin and alpelisib. The latter is a newly discovered PIK3CA-specific inhibitor recently approved by the FDA to treat certain types of breast cancer and PIK3CA-related overgrowth spectrum. So far, pre-clinical studies in mouse models and in patients have shown that alpelisib is more effective in reversing vascular malformation defects.

    After selecting the two drugs, Polacheck and Aw applied the treatment to their devices. The study was a success.

    “The blood vessels used to be really dilated and large,” said Aw, first author of the study. “By imaging the vessels before and after treating with drugs, we observed the vessels shrink and, more or less, revert it back to a normal shape and function. We were very excited to be able to replicate some of the results in vitro with the model we built.”

    Moving forward, Aw and Polacheck are looking to replicate the finding in tissues from vascular malformation patients, especially those who don’t have the PIK3CA mutation or don’t have clear genetic information. Their model can now be used to evaluate new medications or to perform synergistic drug studies.

    Now that they know that their model works, Aw and Polacheck plan to use it to study the behavior of the mutated cells overtime, as well as how the mutation affects malformations of the lymphatic tissue.

    The disease initially begins with an individual cell that acquires the PIK3CA mutation. Then, much like a chain reaction, the effects of the mutation in that one cell spreads to the surrounding cells until the malformation is fully formed. As their model currently stands, the lab cannot mimic that natural process.

    Aw is currently working on a new and different approach for a microfluidic model. She aims to create a platform that will allow them to start with cells that are healthy, and then “flip on” the mutation, and watch it progress across the tissue of interest. Ultimately, it will help them understand how the mutation is able to affect other cells and move throughout space.

    Vascular malformations can also occur in lymphatic tissue. As opposed to blood vessels, lymphatic vessels have a duty to recycle excess fluid throughout the body and acts as a superhighway for immune cells to get to sites of infection. Very little is known about the basic cell biology of lymphatic endothelial cells, so Polacheck is hoping to do a study that is similar to his most recent one.

    “The outputs are slightly different because the function of the lymphatics is different from blood vessels,” said Polacheck. “By comparing and contrasting what happens on the blood side and the lymphatic side, we will also be able to learn something about the basic biology of those two types of tissues.”

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    University of North Carolina Health Care System

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  • Not Even Marfan Syndrome Can Curb One Woman’s Energy

    Not Even Marfan Syndrome Can Curb One Woman’s Energy

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    Newswise — LOS ANGELES (Feb. 24, 2023) – Her husband and their five children call Rosa Wernher “the Energizer bunny” because she is always on the go. For decades, not even her genetically inherited Marfan syndrome could keep her off her feet to prevent her from oil painting or from gliding down a ski slope–until it did.

    “I have always been active, almost manic–jumping from one activity to another, chasing my children around to their various activities and never requiring a great deal of sleep,” said Wernher, 53, who lives in Redlands, California. “But as I aged, I started quietly slowing down, needing to rest and sleep just a bit more than usual. I chalked it up to perimenopause, never attributing the new-onset symptoms to my genetic heart condition.”

    Shortly after she turned 51, Wernher decided it was time to check up on her heart. She was referred to Robert Siegel, MD, a Marfan syndrome expert and cardiologist in the Smidt Heart Institute at Cedars-Sinai.   

    After a routine exam and ultrasound imaging of her heart, Siegel discovered that Wernher had an enlarged aorta and a leaking aortic valve. These common complications of Marfan syndrome, which causes abnormalities in connective tissue, can become a life-threatening emergency.

    The aorta, which rises from the heart’s left ventricle–the major chamber that pumps blood out of the heart–is filled with oxygen-rich blood that travels throughout the body. If a tear occurs, blood spills through the inner layer tear and into the middle layers of the aorta, causing them to separate, or dissect. When that happens, it can deprive the body’s organs of vital blood supply.

    “I was told to see a cardiac surgeon, and fast,” said Wernher. “It was really scary to learn that despite my overall good health and energy, I had been a walking time bomb.”  

    Siegel sent Wernher to see Pedro Catarino, MD, director of Aortic Surgery in the Smidt Heart Institute, who confirmed that she had a large aortic root aneurysm and severe aortic valve regurgitation.  

    “A tear or rupture in the aorta is a surgical emergency,” said Catarino. “We do everything we can to avoid patients presenting in this progressive, severe way, and instead, treat them before a life-threatening complication occurs. Rosa was fortunate that her enlarged aorta had not yet reached this critical, life-threatening point.”

    A national leader in aortic surgery, the Smidt Heart Institute recently became an accredited Marfan Center of Excellence, a distinction given by the Marfan Foundation. As one of only 35 accredited medical centers in the nation, the Cedars-Sinai program utilizes a multidisciplinary team of cardiac and vascular surgeons, cardiologists, and radiologists who use advanced imaging techniques to predict patient risk and identify the best surgical options. 

    The medical consensus for Wernher: She was a candidate for a technically complex surgery called a valve-sparing aortic root replacement.

    “During Rosa’s surgery, we kept her aortic valve and reconnected it to a new section of aortic tissue,” said Catarino. “This specialized technique isn’t offered everywhere, and it really requires a team of experts who can deliver it.”

    Wernher’s four-hour surgery was a success. Although it was challenging for her energetic self to lie low after surgery, she gained more zest within six weeks. Now, nearly eight months after surgery, Wernher has already skied Mammoth Mountain and is back to standing on her feet for hours, painting nature scenes of flowers and landscapes.

    She’s also more committed than ever to staying on top of her health.

    “With my kids now grown and out of the house, I’m more vigilant about my own health and wellbeing,” said Wernher. “I’m even trying to relax and slow down a bit and offering myself grace for these changing phases of life. I’m just grateful to be alive.”

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    Cedars-Sinai

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  • Murder of Vermont woman solved after more than 50 years using DNA found on a cigarette and the victim’s clothing | CNN

    Murder of Vermont woman solved after more than 50 years using DNA found on a cigarette and the victim’s clothing | CNN

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    CNN
     — 

    More than 50 years after Rita Curran’s roommate found her strangled to death in her room, police in Vermont say they have identified the killer using DNA found on a cigarette butt and Curran’s clothing.

    Investigators identified William DeRoos, a man who lived in Curran’s Burlington apartment building, as the person responsible with the help of advances in DNA technology and genetic genealogy, police in Vermont’s most populous city announced Tuesday.

    DeRoos died of a drug overdose in San Francisco in 1986, police said. The case is now closed.

    On the night of the July 1971 killing, DeRoos, who lived with his wife two floors above Curran, had a fight with his spouse and left their apartment to “cool down,” according to a Burlington police investigation report.

    Curran, 24, was later found dead, severely beaten after apparently having put up a “vicious struggle,” a detective wrote at the time. Investigators are now “unanimously certain” DeRoos was responsible, the report released Tuesday says.

    But when investigators questioned DeRoos and his wife the next morning, the couple said they had been together all night and didn’t hear or see anything. After police left, DeRoos told his wife if they were questioned again, she should not admit that he had left the apartment “or they would go after him” because he had a criminal history, police said during a news conference Tuesday.

    A break in the case finally came in 2014 when a DNA profile was extracted from a cigarette butt that had been found next to Curran’s body, Detective Lt. James Trieb said at the news conference. Though the profile was submitted to a national criminal database for DNA, he said, no matches were made. That meant the person with that DNA likely never had genetic material entered into the database, possibly because the person didn’t have a felony conviction.

    In 2019, Trieb reopened the case and decided to take a new approach.

    Instead of having a single detective work the cold case alone – the department’s usual strategy – he treated the crime as if it had just been committed, bringing in a team of detectives and expert technicians to review and discuss it, his investigation report says.

    The team began retesting evidence, Trieb said, and decided to analyze the cigarette DNA using genetic genealogy – a process that uses DNA databases for genealogy research to identify possible family members of the person whose DNA is unmatched.

    An outside genetic genealogy expert then concluded that the cigarette DNA had strong connections to relatives of DeRoos, both on the paternal and maternal sides.

    “She was certain that it was William DeRoos” who put his DNA on the cigarette, the police report says.

    cnn world rugby bryan habana dnafit rugby spc_00013322.jpg

    Why your DNA may be solving cold cases

    Investigators then found a living half-brother of DeRoos who was willing to provide a DNA sample, and that sample bolstered the conclusion that the cigarette DNA belonged to DeRoos, the report says.

    Finally, investigators found that DNA left on Curran’s ripped house coat also matched the DNA on the cigarette butt, the report reads. Investigators re-interviewed his then-wife, who admitted that she had lied about DeRoos’ alibi.

    At the news conference, acting Burlington Police Chief Jon Murad said the day was “filled with mixed emotions.”

    “Ultimately, those emotions are ones of relief, of pride for me (and) for this department, but mostly of gratitude to a family that has been through an incredible ordeal for more than half a century,” he said.

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  • Vilcek Foundation Awards $100,000 Prize in Biomedical Science to Alejandro Sánchez Alvarado

    Vilcek Foundation Awards $100,000 Prize in Biomedical Science to Alejandro Sánchez Alvarado

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    Born in Venezuela, developmental and molecular biologist Alejandro Sánchez Alvarado receives the $100,000 prize for his contributions to the field of regeneration.

    Press Release
    –

    Feb 22, 2023 10:45 EST


    NEW YORK, February 22, 2023 (Newswire.com)
    –
    For his contributions to the field of regeneration, Alejandro Sánchez Alvarado receives the Vilcek Prize in Biomedical Science. The Vilcek Prize in Biomedical Science is a $100,000 prize awarded annually by the Vilcek Foundation as part of its prizes program. 

    Awarded annually since 2006, the Vilcek Foundation prizes recognize and celebrate immigrant contributions to scientific research and discovery, and to artistic and cultural advancement in the United States. The prizes provide direct support to individual immigrant scientists and artists and help to raise greater public awareness of the value of immigration for a robust society. In 2023, the Vilcek Foundation awards four prizes in Biomedical Science, comprising the $100,000 Vilcek Prize and three $50,000 prizes—the Vilcek Prizes for Creative Promise in Biomedical Science. 

    Born in Caracas, Venezuela, molecular and developmental biologist Alejandro Sánchez Alvarado grew up using the scientific method to understand the things that fascinated him in the natural world. As a budding scientist, Sánchez Alvarado moved to the United States to pursue studies in molecular biology at Vanderbilt University in Nashville, Tennessee. Now a leader in the field of regeneration, he is the executive director and chief scientific officer of the Stowers Institute for Medical Research in Kansas City, Missouri.

    “Through the combination of rigorous research and new tools and technologies, Alejandro Sánchez Alvarado has worked to illuminate the important functions that epigenetics and signaling have on the process of regeneration,” says Vilcek Foundation Chairman and CEO Jan Vilcek. “His work has important implications on the understanding of cellular and organismal regeneration, and holds enormous promise for our further understanding of core biological concepts.”

    Says Vilcek Foundation President Rick Kinsel, “Research Institutions in the United States have drawn scientists from around the globe, and many groundbreaking discoveries in research and development in biology, physics, and medicine have been by immigrant scientists. The perspective and insight that foreign-born scientists bring to research and development, and the value of diversity in seeking answers to science and medicine’s most perplexing questions, cannot be overstated.”

    Sánchez Alvarado credits being an immigrant and being bilingual as having a profound impact on his work as a scientist, noting how the syntax interpretations of problems or ideas in two different languages—English and Spanish—help him to form more nuanced ideas and hypotheses. “Because every language is an interpretation of the universe, the more interpretations one has access to, the richer our comprehension of the world becomes,” he says. 

    He also reflects on the sacrifices that immigrants make to pursue the subjects and work they are passionate about in the United States. “We left everything behind to pursue an idea,” he says. “[We were] not looking for fame or fortune. [We] are looking for answers to questions.” 

    As part of the Vilcek Foundation’s prizes campaign, the foundation has published a biographical profile and video highlighting Sánchez Alvarado’s life and work on the Vilcek Foundation website, Alejandro Sánchez Alvarado: “Making the improbable possible.”

    The Vilcek Foundation

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

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

    Source: The Vilcek Foundation

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  • Cancer: In Italy every year over 8000 patients candidate for liquid biopsy

    Cancer: In Italy every year over 8000 patients candidate for liquid biopsy

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    Newswise — Rome, 21 February 2023 – Almost 8,000 lung cancer patients are thought to qualify for a liquid biopsy each year in Italy in order to determine the best course of treatment. But in the not-too-distant future, the number of cancer patients for whom a simple blood test will choose the optimum course of treatment will grow dramatically. Blood sample enables continuous, real-time monitoring of the neoplasm’s development, much like in a video. An image of the tumour at the time of diagnosis can only be captured by a conventional biopsy, which is performed on tumour tissue. Also, even if it doesn’t currently reflect clinical practise, the difficulty is in using a blood test to make an early cancer diagnosis. The study, which is presented in the book “Liquid Biopsy: New Challenges in the Age of Immunotherapy and Precision Oncology,” by Antonio Russo, Ettore Capoluongo, Antonio Galvano, and Antonio Giordano, Ed. Elsevier, brings up truly innovative views on the use of liquid biopsy, which was presented today at a press conference in the Chamber of Deputies and has signatures from the top international experts.

    “Twenty years ago, in 2003, there were fewer than 50 publications in oncology that used the term “liquid biopsy,” but today there are more than 10,000, making it a real “hot topic,” states to Antonio Russo, COMU President, Full Professor of Medical Oncology at DICHIRONS – University of Palermo, and Treasurer of AIOM (Italian Association of Medical Oncology). The “Liquid Biopsy” manual serves as evidence of both the prominence of Sicily, specifically the University of Palermo, and the brilliance attained in this subject by Italian scholars across the globe.

    “Up to this point,“ continues Professor Russo, “the applications of liquid biopsy that have been shown effective in clinical practise involve advanced stage non-small cell lung cancer, for the assessment of the EGFR gene mutational status. In two clinical contexts, the method is suggested in these instances as a possible alternative for tumour tissue examination. 

    First of all, in patients who have just received a diagnosis and prior to beginning any kind of treatment, when the quantity or quality of tissue available is insufficient to perform the anticipated molecular analyses, when the molecular analysis of tissue has been found to be insufficient, or when it is impossible to obtain biopsy tissue due to the patient’s poor clinical conditions. It should be kept in mind that, even when used for histological diagnosis, the tissue sample is not acceptable for molecular characterization in roughly 30% of instances. In the second scenario, the liquid biopsy provides a very important contribution during the monitoring of patients with EGFR gene mutation, in progression after first-line treatment with targeted therapies, i.e. with first and second generation EGFR inhibitors. In these cases, blood sampling is very useful for searching for a specific resistance mutation and directing the change of cure, i.e. treatment with the third generation EGFR inhibitor. The latter, in light of the robust overall survival data, has now become a solid option on the front line and, given the high inhibitory activity, has made the use of liquid biopsy for the search for the resistance mutation secondary”.

    “The liquid biopsy has undoubted advantages over the traditional approach consisting of the analysis of tumor tissue – says Antonio Giordano, Director of the Sbarro Institute for Cancer Research and Molecular Medicine of Temple University in Philadelphia (USA) and Professor of Anatomy and Pathological Histology at the University of Sien, and Founder and President of the Sbarro Health Research Organization (SHRO). “It is minimally invasive, low-cost, has very fast reporting times and is practically free of complications, because it can be performed with a simple blood sample. Furthermore, it is characterized by a high level of acceptance by patients and can be repeated without problems, by performing serial sampling to highlight the onset of resistance to therapy in real time and, if necessary, modify the treatment.”

    “The liquid biopsy has undeniable advantages over the conventional method that involves the study of tumour tissue,” says Antonio Giordano, Director of the Sbarro Institute for Cancer Research and Molecular Medicine of Temple University in Philadelphia (USA) and Professor of Anatomy and Pathological Histology at the University of Siena, “It is less invasive, inexpensive, has extremely quick turnaround times, and is essentially complication-free because it can be carried out with a simple blood sample. Furthermore, serial sampling is used to highlight the development of therapy resistance in real time and, if necessary, change the treatment. It is characterised by a high level of patient acceptability and can be repeated without issues.

    Instead, very few patients opt to have a second tissue evaluation, in part because the general clinical circumstances often exclude it. Moreover, the tissue biopsy sample, particularly when it is obtained through fine-needle aspiration, may not necessarily be an accurate representation of the entire tumour. This is not the case with the liquid biopsy, which solves the issue of the heterogeneity of the tumour tissues by analysing the tumour DNA discharged into the circulation.”

    The predominant biopsy method currently utilised in clinical practise today is the examination of circulating tumour DNA, or ctDNA (circulating tumour DNA), which is a fraction of circulating free DNA (cell free DNA, or cfDNA), isolated from peripheral blood (particularly from plasma).

    “The chance of success is dependent on the quantity of ctDNA in the peripheral blood, which may impact the test’s sensitivity,” underlines Ettore Capoluongo, Full Professor of Clinical Biochemistry and Clinical Molecular Biology and SOC Director of Clinical Pathology and Genomics, Cannizzaro Hospital of Catania, “One drawback is that, depending on the volume and locations of the disease, the amount of ctDNA in the context of cfDNA is frequently limited, and this might result in “false negative” results on the liquid biopsy sample. The size and stage of the tumour are really connected to the concentration of ctDNA in plasma, with advanced-stage neoplasms releasing more ctDNA than early-stage ones. Exosomes, platelets, circulating tumour cells, circulating tumour RNA and microRNA, as well as other biological fluids like urine, saliva, ascitic fluid, and pleural could all be used in clinical practise in the future to provide additional information beyond that provided by the analysis of ctDNA isolated from plasma.” It is crucial that the measurement of these molecular tumour markers be as consistent as possible; for this reason, using liquid biopsy as part of the diagnostic process is the perfect scenario for clinic and laboratory collaboration.

    “Due to its capability to swiftly translate laboratory discoveries into clinical applications, the liquid biopsy must only be examined in laboratories that pass quality controls and serves as a key illustration of translational medicine,” explains Marcello Ciaccio, Full Professor of Clinical Biochemistry , Dean of the School of Medicine and Surgery of the University of Palermo, Past President and President-elect of SIBioC (Italian Society of Clinical Biochemistry and Clinical Molecular Biology), “which enables the simultaneous identification of all forms of genetic changes in several genes during a single liquid biopsy study. NGS is more cost-effective than a single gene method, according to cost analyses. This advantage becomes even clearer once a threshold of patients has been evaluated in order to fully realise the potential of NGS technologies, which enable the simultaneous profiling of several individuals while optimising costs and turnaround times. The subsequent step will be to make NGS approaches accessible and convenient to utilise. Building a real network is important to accomplish this goal.”

    “The liquid biopsy definitively establishes the importance of multidisciplinarity,” says Saverio Cinieri, National President of AIOM (Italian Association of Medical Oncology), “The Molecular Tumor Boards, interdisciplinary committees where various talents are combined to govern the clinical and decision-making processes of appropriateness, are responsible for selecting the material to be exposed to molecular analysis. Yet it’s important to make a distinction between regular clinical practise and research. Although if research efforts are in the right direction, it is not yet possible to diagnose cancer from a blood sample. Nowadays, the liquid biopsy plays a significant role as a predictor of response to therapy in lung cancer. An investigation based on a novel strategy, namely the methylation signatures of circulating free DNA, was presented at the most recent Congress of the European Society of Oncology. There were more than 6,000 participants who were over 50, appeared healthy, and had never been given a cancer diagnosis. In 1.4% of the participants, the test revealed changes in the methylation profile, which are common to more than 50 distinct forms of neoplasms. Among these individuals, the oncological diagnosis was confirmed in around 40% of the instances. Yet, in more than 60% of cases, no oncological illness diagnosis was made after the positive test results.”

    “The sensitivity of the liquid biopsy, in a context of early diagnosis, is therefore still conditioned by a high rate of false positives, the causes of which are being studied,” continues the AIOM President, “The emerging clinical applications of this procedure mainly concern colorectal, breast and advanced melanoma cancers. Indeed, there is solid and reproducible information regarding the characterization of RAS and BRAF genes for colorectal, PIK3CA for breast, BRAF and NRAS in melanoma. It is likely that plasma analysis for this type of alteration will soon be recommended in clinical practice”.

    “In order to personalise treatment, a very active area of study is the use of liquid biopsy in immunotherapy. This field has the potential to produce “dynamic” and reproducible biomarkers in the near future,” highlights Antonio Galvano, Associate Professor of Medical Oncology at the University of Palermo, “Only a fraction of patients today show a significant response or long-term benefit with immunotherapy drugs. Individual biological and immune factors affect the heterogeneity in the response. For this reason, the identification of predictive biomarkers of response or resistance to treatment, for example, with immune checkpoint inhibitors, assumes an important role. Numerous studies are underway with the aim of evaluating the potential use of cfDNA, ctDNA and soluble forms of immune checkpoints as predictive biomarkers of response. In recent years, our research group has published studies conducted mainly on lung, pancreatic and melanoma tumors in important international scientific journals. It is crucial to keep moving in this direction. “.

    “One of the roles of Patients’ Associations is to support the scientific community with regard to research progress, adopting a rigorous, but informative and easy to understand method,” continues Adriana Bonifacino, President of the IncontraDonna Foundation, “It is essential that patients are increasingly involved in trials, including those on liquid biopsy. The quality of life is becoming a central element in the evaluation of the innovativeness of treatments and the liquid biopsy fits into this context. Being able to monitor the evolution of the tumor in real time with a simple blood sample also represents an element of reassurance from a psychological point of view for the patient, as well as avoiding the invasiveness of traditional procedures on tumor tissue”.

    “The “Liquid Biopsy” book is distinguished by the special focus on educational aspects and by the inclusion of the so-called “expert comments,” authored by internationally known experts,”  concludes Professor Russo, “Our group of researchers from the University of Palermo has been conducting experiments on liquid biopsy since the early 2000s and is at the forefront in this sector, today with further studies on exosomes and on the determination of circulating immunocheckpoints. The exciting data from studies may also lead to changes in the parameters used to classify cancer stages. To the TNM system, where T describes the extent of the disease, N the status of the lymph nodes and M the possible presence of metastases, the B, such as blood, should be added, which provides information on circulating tumor DNA.”

     

     

    About the Sbarro Health Research Organization

    The Sbarro Health Research Organization (SHRO) is non-profit charity committed to funding excellence in basic genetic research to cure and diagnose cancer, cardiovascular diseases, diabetes and other chronic illnesses and to foster the training of young doctors in a spirit of professionalism and humanism. To learn more about the SHRO please visit www.shro.org

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    Sbarro Health Research Organization (SHRO)

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  • Evolution: Miniproteins appeared “from nowhere”

    Evolution: Miniproteins appeared “from nowhere”

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    Newswise — Every biologist knows that small structures can sometimes have a big impact: Millions of signaling molecules, hormones, and other biomolecules are bustling around in our cells and tissues, playing a leading role in many of the key processes occurring in our bodies. Yet despite this knowledge, biologists and physicians long ignored a particular class of proteins – their assumption being that because the proteins were so small and only found in primates, they were insignificant and functionless. The discoveries made by Professor Norbert Hübner at the Max Delbrück Center and Dr. Sebastiaan van Heesch at the Princess Máxima Center for Pediatric Oncology in the Netherlands changed this view a few years ago: “We were the first to prove the existence of thousands of new microproteins in human organs,” says Hübner.

    In a new paper published in Molecular Cell, the team led by Hübner and van Heesch now describe how they systematically studied these miniproteins, and what they learned from them: “We were able to show which genome sequences the proteins are encoded in, and when DNA mutations occurred in their evolution,” explains Dr. Jorge Ruiz-Orera, an evolutionary biologist in Hübner’s lab and one of the paper’s three lead authors, who work at the Max Delbrück Center and the German Center for Cardiovascular Research (DZHK). Ruiz-Orera’s bioinformatic gene analyses revealed that most human microproteins developed millions of years later in the evolutionary process than the larger proteins currently known to scientists.

    Yet the huge age gap doesn’t appear to prevent the proteins from “talking” to each other. “Our lab experiments showed that the young and old proteins can bind to each other – and in doing so possibly influence each other,” says lead author Dr. Jana Schulz, a researcher in Hübner’s team and at the DZHK. She therefore suspects that, contrary to long-held assumptions, the microproteins play a key role in a variety of cellular functions. The young proteins might also be heavily involved in evolutionary development thanks to comparatively rapid “innovations and adaptations.” “It’s possible that evolution is more dynamic than previously thought,” says van Heesch.

    Proteins only found in humans

    The researchers were surprised to find that the vastly younger microproteins could interact with the much older generation. This observation came from experiments performed using a biotechnical screening method developed at the Max Delbrück Center in 2017. In collaboration with Dr. Philipp Mertins and the Proteomics Platform, which the Max Delbrück Center operates jointly with the Berlin Institute of Health at Charité (BIH), the miniproteins were synthesized on a membrane and then incubated with a solution containing most of the proteins known to exist in a human cell. Sophisticated experimental and computer-aided analyses then allowed the researchers to identify individual binding pairs. “If a microprotein binds to another protein, it doesn’t necessarily mean that it will influence the workings of the other protein or the processes that the protein is involved in,” says Schulz. However, the ability to bind does suggest the proteins might influence each other’s functioning. Initial cellular experiments conducted at the Max Delbrück Center in collaboration with Professors Michael Gotthardt and Thomas Willnow confirm this assumption. This leads Ruiz-Orera to suspect that the microproteins “could influence cellular processes that are millions of years older than they are, because some old proteins were present in the very earliest life forms.”

    Unlike the known, old proteins that are encoded in our genome, most microproteins emerged more or less “out of nowhere – in other words, out of DNA regions that weren’t previously tasked with producing proteins,” says Ruiz-Orera. Microproteins therefore didn’t take the “conventional” and much easier route of being copied and derived from existing versions. And because these small proteins only emerged during human evolution, they are missing from the cells of most other animals, such as mice, fish and birds. These animals, however, have been found to possess their own collection of young, small proteins.

    The smallest proteins so far

    During their work, the researchers also discovered the smallest human proteins identified to date: “We found over 200 super-small proteins, all of which are smaller than 16 amino acids,” says Dr. Clara Sandmann, the study’s third lead author. Amino acids are the sole building blocks of proteins. Sandmann says this raises the question of how small a protein can be – or rather, how big it must be to be able to function. Usually, proteins consist of several hundred amino acids.

    The small proteins that were already known to scientists are known as peptides and function as hormones or signal molecules. They are formed when they split off from larger precursor proteins. “Our work now shows that peptides of a similar size can develop in a different way,” says Sandmann. These smallest-of-the-small proteins can also bind very specifically to larger proteins – but it remains unclear whether they can become hormones or similar: “We don’t yet know what most of these microproteins do in our body,” says Sandmann.

    Yet the study does provide an inkling of what the molecules are capable of: “These initial findings open up numerous new research opportunities,” says van Heesch. Clearly, the microproteins are much too important for researchers to keep ignoring them. Van Heesch says the biomolecular and medical research communities are very enthusiastic about these new findings. One conceivable scenario would be “that these microproteins are involved in cardiovascular disease and cancer, and could therefore be used as new targets for diagnostics and therapies,” says Hübner. Several U.S. biotech companies are already doing research in this direction. And the team behind the current paper also has big plans: Their study investigated 281 microproteins, but the aim now is to expand the experiments to include many more of the 7,000 recently cataloged microproteins – in the hope that this will reveal many as-yet-undiscovered functions.

     

    Further information

    Unchartered territory in the human genome

    Unknown miniproteins in the heart

    Hübner Lab

    Van Heesch Lab

     

    Literature

    Clara-L. Sandmann, Jana F. Schulz, Jorge Ruiz-Orera, et al. (2023): “Evolutionary origins and interactomes of human, young microproteins and small peptides translated from short open reading frames,” Molecular Cell, DOI: 10.1016/j.molcel.2023.01.023
     

    Downloads

    An evolutionarily young protein that arose de novo in Old World monkeys: The microprotein in the mitochondria (green) and in the nucleus (blue) was overexpressed in human cells. The yellow and pink areas show that the signal of the microprotein overlaps with the mitochondrial and nuclear signals. Photo: Clara Sandmann, MDC

     

    Max Delbrück Center

    The Max Delbrück Center for Molecular Medicine in the Helmholtz Association (Max Delbrück Center) is one of the world’s leading biomedical research institutions. Max Delbrück, a Berlin native, was a Nobel laureate and one of the founders of molecular biology. At the Center’s locations in Berlin-Buch and Mitte, researchers from some 70 countries analyze the human system – investigating the biological foundations of life from its most elementary building blocks to systems-wide mechanisms. By understanding what regulates or disrupts the dynamic equilibrium in a cell, an organ, or the entire body, we can prevent diseases, diagnose them earlier, and stop their progression with tailored therapies. Patients should benefit as soon as possible from basic research discoveries. The Max Delbrück Center therefore supports spin-off creation and participates in collaborative networks. It works in close partnership with Charité – Universitätsmedizin Berlin in the jointly run Experimental and Clinical Research Center (ECRC), as well as with the Berlin Institute of Health (BIH) at Charité and the German Center for Cardiovascular Research (DZHK). Founded in 1992, the Max Delbrück Center today employs 1,800 people and is funded 90 percent by the German federal government and 10 percent by the State of Berlin. www.mdc-berlin.de

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  • Reimagining drugs for rare brain disorder

    Reimagining drugs for rare brain disorder

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    BYLINE: Marissa Locke Rottinghaus

    Newswise — A team of researchers has developed a new method to screen FDA-approved drugs to determine if they could be repurposed or improved to help patients with a rare, debilitating disease of the nervous system.

    Spinocerebellar ataxia type 5 causes cerebellar neurodegeneration. Loss of coordination, impaired gait and slurred speech are just a few of the debilitating symptoms, which usually emerge between the ages of 20 and 30. There is no cure or even a targeted therapy. SCA5 affects around 1,000 people in the U.S. but is a part of a group of diseases that plagues tens of thousands more.

    Despite the nature and broad reach of SCA5 and related diseases, few researchers are trying to find a cure. However, one ataxia-focused research group published a study on Jan. 30 detailing a new method to screen for drugs that might help.

    “Not only is there no known therapeutic to treat these diseases, but, to our knowledge, there is no other research campaign to identify potential therapies for a lot of these ataxias,” said Robyn Rebbeck, a postdoctoral researcher at the University of Minnesota and one of the lead authors on the study.

    SCA5 is inherited and is sometimes called “Lincoln’s ataxia” because it has been passed down over 10 generations in one family with traces to President Abraham Lincoln’s grandparents. It is caused by a mutation in the β-III-spectrin gene, which is critical for creating connections between neurons in the central nervous system.

    Adam Avery, the assistant professor at Oakland University who oversaw the work, said: “Our goal is to improve the conditions of these patients within the next 10­­ to 20 years. … (W)e are family people. We want to provide SCA5 patients and their families with the hope of an effective treatment.”

    The mutation studied by the researchers causes β-III-spectrin and a structural protein called actin to stick together. This abnormally tight interaction results in a traffic jam inside neurons, which prevents them from carrying out their normal functions, such as controlling speech and movement.

    The research team created a pipeline to screen FDA-approved drugs against the mutated β-III-spectrin protein to find out if any can restore its normal function. This assay uses cutting-edge spectroscopy to examine whether and how drugs change the interaction of mutant β-III-spectrin with actin and is at least five-times more sensitive than methods used previously. The drugs that dampen β-III-spectrin’s binding to actin initiate a unique florescent signal. This high-throughput screening method allows the team to evaluate 1,536 drugs in about six minutes.

    Of the 3,000 FDA-approved drugs analyzed, two immediately stood out to the researchers for their high efficacy and potency: ginsenoside Rb1 and micafungin. However, this is just the beginning. The researchers plan to screen thousands more compounds to get their best shot at finding an effective drug.

    Piyali Guhathakurta, an assistant professor at the University of Minnesota and a lead author, said the team is now “primed for screening much larger libraries for compounds that can lead us to drugs that have the potential to treat SCA5. Our assay is the start of the drug-discovery campaign, with collaborators preparing to test these compounds in systems more akin to the human patients that we hope to treat.”

    The researchers plan to develop a cell culture and mouse model to more definitively test their hits from the drug screen. If the hits are successful in ameliorating disease in future models, they would be that much closer to a drug specific for SCA5 patients.

    “Our study is proof that the binding of this mutant spectrin to actin is a druggable target,” Avery said. “This work establishes that we can modulate this interaction using small molecule drugs.”

    Though there is much work to be done, the team is optimistic about the prospects that this new pipeline presents for studying mutations in β-III-spectrin-related proteins that cause other rare diseases like muscular dystrophy.

    “Our findings may pave the way for the development of a new class of drugs that will provide relief to patients suffering from SCA5 and additional diseases due to mutations in spectrin-related proteins,” Avery explained. “Our technology is adaptable for drug discovery for treatment of other diseases associated with disrupted actin binding.”

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  • Major genetic study reveals unexpectedly high variation in T-cell receptor genes between persons

    Major genetic study reveals unexpectedly high variation in T-cell receptor genes between persons

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    Newswise — T-cells that are part of our immune system are central in the protection against infections and cancer. With the help of TCRs, the cells recognize foreign invaders and tumor cells.

    “It was previously unknown how variable human TCR genes are”, says Gunilla Karlsson Hedestam, professor at the department of microbiology, tumor and cell biology at Karolinska Institutet and the study’s lead author.

    Using deep sequencing of blood samples, the researchers examined TCR genes in 45 people originating from sub-Saharan Africa, East Asia, South Asia and Europe. The researchers showed that these genes vary greatly between different persons and population groups. The results were confirmed by analyses of several thousand additional cases from the 1000 Genomes project.

    “We found that every individual, other than identical twins, has a unique set of TCR gene variants. These differences reveal possible mechanisms underlying the wide range of responses to infections and vaccines that we observe at the population level”, says Martin Corcoran, the first author of the study.

    “We discovered 175 new gene variants, which doubles the number of known TCR gene variants. An unexpected and surprising finding is that certain gene variants originate from Neanderthals and one of these is present in up to 20% of modern humans in Europe and Asia.”

    Gunilla Karlsson Hedestam explains that the variation in these genes cannot be detected with the standard methods used in whole genome sequencing, but with the development of specialized deep sequencing methods and analysis software that allow highly precise definition of B- and T-cell receptor genes, this is now possible.

    “As these genes are among the most variable in our genome, the results also provide new information about how our immune system has developed over the course of history, says Martin Corcoran. We are particularly interested in uncovering the function of the TCR variants we have inherited from Neanderthal ancestors. The frequency of these variants in modern humans suggests an advantageous function in our biology and we are keen to understand this”, adds Martin Corcoran.

    The findings and the new TCR gene database the researchers now publish can be of great importance in the development of new therapeutic approaches in the future.

    “Understanding human genetics is fundamental for the development of targeted treatments. The methods described in the study provide new opportunities, not the least in the cancer field where T-cells are central to several promising forms of immunotherapy”, says Gunilla Karlsson Hedestam.

    The results can also shed light on other areas of research.

    “The findings can lead to the development of new diagnostics and therapies in a range of medical disciplines, including precision medicine”, says Gunilla Karlsson Hedestam.

    What is the next step in your research?

    “We are now investigating the functional significance of several of the newly discovered gene variants and how this variation impacts our T-cell responses. We are also planning extended studies involving large groups of individuals to examine the role of TCR gene variation in diseases we know involve T cells, such as infectious diseases, cancer, and autoimmune disorders”, says Gunilla Karlsson Hedestam.

    Main funding for the study comes from an ERC Advanced Grant and the Swedish Research Council.  

    Publication: “Archaic humans have contributed to large-scale variation in modern human T cell receptor genes”, Martin Corcoran, Mark Chernyshev, Marco Mandolesi, Sanjana Narang, Mateusz Kaduk, Kewei Ye, Christopher Sundling, Anna Färnert, Taras Kreslavsky, Carolina Bernhardsson, Maximilian Larena, Mattias Jakobsson, Gunilla B. Karlsson Hedestam, Immunity, online February 15, doi: 10.1016/j.immuni.2023.01.026

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  • Mosquito’s DNA could provide clues on gene expression, regulation

    Mosquito’s DNA could provide clues on gene expression, regulation

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    Newswise — HOUSTON – (Feb. 9, 2023) – When it comes to DNA, one pesky mosquito turns out to be a rebel among species.

    Researchers at Rice University’s Center for Theoretical Biological Physics (CTBP) are among the pioneers of a new approach to studying DNA. Instead of focusing on chromosomes as linear sequences of genetic code, they’re looking for clues on how their folded 3D shapes might determine gene expression and regulation.

    For most living things, their threadlike chromosomes fold to fit inside the nuclei of cells in one of two ways. But the chromosomes of the Aedes aegypti mosquito — which is responsible for the transmission of tropical diseases such as dengue, chikungunya, zika, mayaro and yellow fever — defy this dichotomy, taking researchers at the CTBP by surprise.

    The Aedes aegypti’s chromosomes organize as fluid-yet-oriented “liquid crystals,” different from all other species, according to their study published in Nature Communications.

    “Understanding DNA is a key to understanding how life works,” said Rice theoretical physicist Peter Wolynes, a co-author on the study. “We are only just beginning to learn how the 3D architecture of chromosomes influences the functioning of genomes.”

    A 2021 collaborative study co-led by a team from the CTBP and published in Science reported that chromosomes display one of two structural patterns when cells are not dividing, the stage in the cell life cycle known as interphase.

    “In a ‘type two’ genome architecture — like that found in humans and chickens, for instance — chromosomes form territories and don’t mix together that much,” said Vinícius Contessoto, a CTBP research scientist who is a lead co-author on the latest study and was also a co-author on the 2021 study.

    The still-unknown forces that keep active and inactive parts of “type two” chromosomes separate from each other during interphase behave like those that prevent oil and water from mixing together.

    “In a ‘type one’ architecture, like that found in yeast or in many plants, the regions of the chromosomes known as centromeres come together, folding them into an intermeshed, hairpin-like structure, polarized with telomeres ” said José Onuchic, Rice’s Harry C. and Olga K. Wiess Professor of Physics and Astronomy, and a professor of chemistry and biosciences.

    “Something that’s surprising to me is that even though so many different species have been mapped, they still largely fall into one of these two different classes,” Wolynes said. “The Aedes aegypti mosquito is the first real outlier.”

    The genome of the Aedes aegypti is roughly half the length of the human genome and is organized into six large chromosomes, as opposed to humans’ 46. “We used to think that the chromosomes of the mosquito did not form territories, but in fact they do form these elongated territories,” Contessoto said.

    “During interphase, ‘type two’ chromosomes are really very fluid, disordered things balled up into droplet-shaped territories,” said Wolynes, Rice’s Bullard-Welch Foundation Professor of Science and a professor of chemistry, of biochemistry and cell biology, of physics and astronomy, and of materials science and nanoengineering and co-director of the CTBP.

    The chromosomes of the Aedes aegypti mosquito display fluid characteristics, separating from one another like liquid droplets of oil and water. At the same time, they are partially condensed by compaction forces, which gives them an unusual shape, oriented like an overlong football, suggesting their consistency is also similar to that of a crystal.

    Moreover, if force is applied to a regular “type two” nucleus and it is deformed, the organization of the chromosomes inside remains unaffected. “It’s like poking a water balloon — it reverts to its prior shape. But when we poke the nucleus of the mosquito cells, the chromosomes’ patterns inside change dramatically,” said Onuchic.

    “This is an intriguing feature of ‘type one’ chromosome architecture that suggests there is a possible mechanism linking gene regulation to mechanical inputs on the cell,” said Onuchic. In 2020, he and collaborators confirmed the existence of a mechanism connecting genome structure to gene expression.

    Other co-authors of the new study are Erez Lieberman Aiden, a Rice adjunct assistant professor of computer science and an assistant professor of computational and applied mathematics, an associate professor of molecular and human genetics and a principal investigator in the joint Rice/Baylor College of Medicine Center for Genome Architecture; Olga Dudchenko, an assistant professor in the Center for Genome Architecture and former CTBP postdoctoral fellow; and Michele Di Pierro, an assistant professor of physics at Northeastern University. All are CTBP members.

    The research was supported by the National Science Foundation (2019745, 2210291, 2019276, 2021795); the Welch Foundation (C-1792, Q-1866); the Cancer Prevention and Research Institute of Texas; the São Paulo State Research Foundation and Higher Education Personnel, and Higher Education Personnel Improvement Coordination (2016/13998-8, 2017/09662-7); the D.R. Bullard-Welch Chair at Rice (C-0016); the McNair Medical Institute Scholar Award; the National Institutes of Health (UM1HG009375, RM1HG011016-01A1, R35GM146852); and the AMD HPC Fund.

    -30-

    This release can be found online at news.rice.edu.

    Follow Rice News and Media Relations via Twitter @RiceUNews.

    Peer-reviewed paper:

    Interphase chromosomes of the Aedes aegypti mosquito are liquid crystalline and can sense mechanical cues | Nature Communications | DOI: 10.1038/s41467-023-35909-2

    https://doi.org/10.1038/s41467-023-35909-2

    Authors: Vinícius Contessoto, Olga Dudchenko, Erez Lieberman Aiden, Peter Wolynes, José Onuchic and Michele Di Pierro

    Image downloads:

    https://news-network.rice.edu/news/files/2023/02/CTBP_NatureCommunications_image1_LG.jpg

    CAPTION: 3D simulation of the genome structure of the Aedes aegypti mosquito. The elongated territories formed by each of the six chromosomes are color-coded and shown separately (bottom) and together as part of the whole genome (top). (Image adapted from Nature Communications, https://doi.org/10.1038/s41467-023-35909-2, under a Creative Commons Attribution 4.0 International License.)

    https://news-network.rice.edu/news/files/2023/02/CTBP_NatureCommunications_image2_LG.jpg
    CAPTION: The image shows the effects of applying tension to cell nuclei on contacts between the chromosomes of both the human and mosquito genomes (red and white squares), with corresponding 3D simulations (colorful stringlike structures). The human interphase chromosome is less sensitive to mechanical cues than the mosquito interphase chromosome. (Image adapted from Nature Communications, https://doi.org/10.1038/s41467-023-35909-2, under a Creative Commons Attribution 4.0 International License.)

    https://news-network.rice.edu/news/files/2023/02/230203_Vinicius-Contessoto_LG.jpg
    CAPTION: Vinícius Contessoto is a researcher in the Center for Biological Theoretical Physics at Rice University. (Photo by Gustavo Raskosky/Rice University)

    https://news-network.rice.edu/news/files/2023/02/230203_Onuchic_LG.jpg
    CAPTION: José Onuchic is the Harry C. and Olga K. Wiess Chair of Physics and professor of chemistry and biosciences at Rice University. (Photo by Gustavo Raskosky/Rice University)

    https://news-network.rice.edu/news/files/2023/02/230203_ContessotoOnuchic_LG.jpg
    CAPTION: Vinícius Contessoto (left) and José Onuchic are lead co-authors on the study published last month in Nature Communications. (Photo by Gustavo Raskosky/Rice University)

    Related stories:

    NSF extends Physics of Living Systems network at Rice:
    https://news2.rice.edu/2021/09/27/nsf-extends-physics-of-living-systems-network-at-rice/

    Biologists construct a ‘periodic table’ for cell nuclei:
    https://news.rice.edu/news/2021/biologists-construct-periodic-table-cell-nuclei

    At our cores, we’re all strengthened by ‘dumbbells’:
    https://news.rice.edu/news/2020/our-cores-were-all-strengthened-dumbbells

    Snake-like proteins can wrangle DNA:
    https://news.rice.edu/news/2020/snake-proteins-can-wrangle-dna

    Ring-shaped protein complex wrangles DNA:
    https://news2.rice.edu/2018/11/02/ring-shaped-protein-complex-wrangles-dna/

    Links:

    BioScience Research Collaborative: https://brc.rice.edu/

    Center for Theoretical Biological Physics: https://ctbp.rice.edu/

    Department of Chemical and Biomolecular Engineering: https://chbe.rice.edu/

    Department of Chemistry: https://chemistry.rice.edu/

    Department of Physics and Astronomy: https://physics.rice.edu/

    George R. Brown School of Engineering: https://engineering.rice.edu

    Ken Kennedy Institute: https://kenkennedy.rice.edu/

    Wiess School of Natural Sciences: https://naturalsciences.rice.edu

    Wolynes Research Lab: https://wolynes.rice.edu/

    Located on a 300-acre forested campus in Houston, Rice University is consistently ranked among the nation’s top 20 universities by U.S. News & World Report. Rice has highly respected schools of Architecture, Business, Continuing Studies, Engineering, Humanities, Music, Natural Sciences and Social Sciences and is home to the Baker Institute for Public Policy. With 4,552 undergraduates and 3,998 graduate students, Rice’s undergraduate student-to-faculty ratio is just under 6-to-1. Its residential college system builds close-knit communities and lifelong friendships, just one reason why Rice is ranked No. 1 for lots of race/class interaction and No. 1 for quality of life by the Princeton Review. Rice is also rated as a best value among private universities by Kiplinger’s Personal Finance.

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  • Yellow evolution: Unique genes led to new species of monkeyflower

    Yellow evolution: Unique genes led to new species of monkeyflower

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    Newswise — Monkeyflowers glow in a rich assortment of colors, from yellow to pink to deep red-orange. But about 5 million years ago, some of them lost their yellow. In the Feb. 10 issue of Science, UConn botanists explain what happened genetically to jettison the yellow pigment, and the implications for the evolution of species.

    Monkeyflowers are famous for growing in harsh, mineral-rich soils where other plants can’t. They are also famously diverse in shape and color. And monkeyflowers provide a textbook example of how a single-gene change can make a new species. In this case, a monkeyflower species lost the yellow pigments in the petals but gained pink about 5 million years ago, attracting bees for pollination. Later, a descendent species accumulated mutations in a gene called YUP that recovered the yellow pigments and led to production of red flowers. The species stopped attracting bees. Instead, hummingbirds pollinated it, isolating the red flowers genetically and creating a new species.

    UConn botanist Yaowu Yuan and postdoctoral researcher Mei Liang (currently a professor at South China Agricultural University), with collaborators from four other institutes, have now shown exactly which gene it is that changed to prevent monkeyflowers from making yellow. Their research, published this week in Science, adds weight to a theory that new genes create phenotypic diversity and even new species.

    The YUP gene in question is found at a locus, or region, of the monkeyflower genome that has three new genes. These new genes are not found in species outside of this group. They are duplicates of other genes from other parts of the monkeyflower genome. In particular, YUP is a partial duplicate of a pre-existing gene that has nothing to do with color.

    Standard genetics thought is that partial duplicate genes regulate the genes they are derived from; it was very unlikely that these genes would affect an unrelated gene. Liang decided to investigate what these genes were doing anyway, against the advice of Yuan, who thought it was a waste of time.  But Liang’s persistence paid off: she discovered that the YUP gene was actually targeting the plants’ master regulator of carotenoids, the pigments that make monkeyflowers and other plants yellow. YUP produced many small RNAs that suppressed the carotenoid gene. There are very few examples of genes that produce small RNAs affecting traits important to the creation of a new species.

    “This experience really taught me how important it is not to constrain oneself with ‘conventional wisdom’,” Yuan says. Not only does YUP regulate a gene it is entirely unrelated to it; the other two genes at this same locus also affect monkeyflower color, Yuan says.

    The uniqueness of these three genes, only found in a few closely related monkeyflowers, is an important clue as to how new species evolve.

    “Almost every single species has unique genes,” called ‘taxon specific’ because they are only found in a small group of species. “For the most part, we have no idea what these genes do,” says Yuan. This research shows that these taxon specific genes can be the keys to the new species. Previously, many geneticists and evolutionary biologists thought that it was changes in the expression of common genes shared by many different species that differentiated them, and that the small number of idiosyncratic genes were unlikely to be important.

    “We think we understand evolution well enough to make predictions. But now we are realizing we really don’t. Evolution is just so unpredictable,” Yuan says.

    His lab is now looking at how the monkeyflower genome controls the production of pigment spatially. For example, some monkeyflowers have upper petals that are entirely white, but lower petals with color. Yuan and his colleagues want to know how the plants suppress pigment only in certain parts of the flower.

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    University of Connecticut

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  • Protein droplets may cause many types of genetic disease

    Protein droplets may cause many types of genetic disease

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    Newswise — Most proteins localize to distinct protein-rich droplets in cells, also known as “cellular condensates”. Such proteins contain sequence features that function as address labels, telling the protein which condensate to move into. When the labels get screwed up, proteins may end up in the wrong condensate. According to an international team of researchers from clinical medicine and basic biology, this could be the cause of many unresolved diseases. The findings appeared in the journal Nature.

    Patients with BPTA syndrome have characteristically malformed limbs featuring short fingers and additional toes, missing tibia bones in their legs and reduced brain size. As the researchers found out, BPTAS is caused by a special genetic change that causes an essential protein to migrate to the nucleolus, a large proteinaceous droplet in the cell nucleus. As a result, the function of the nucleolar condensate is inhibited and developmental disease develops.

    “What we discovered in this one disease might apply to many more disorders. It is likely not a rare unicorn that exists only once. We just could not see the phenomenon until now because we did not know how to look for it,” says Denise Horn, a clinical geneticist at the Institute of Medical and Human Genetics at Charité – Universitätsmedizin Berlin.

    In collaboration with scientists at the Max Planck Institute for Molecular Genetics (MPIMG) in Berlin, the University Hospital Schleswig-Holstein (UKSH), and contributors from all around the world, the team is pushing open a door to new diagnoses that could lead to the elucidation of numerous other diseases as well as possible future therapies.

    “We discovered a new mechanism that could be at play in a wide range of diseases, including hereditary diseases and cancer,” says Denes Hnisz, Research Group Leader at the MPIMG. “In fact, we have discovered over 600 similar mutations, 101 of which are known to be associated with different disorders.”

    “The actual work is just starting now,” adds human geneticist Malte Spielmann of UKSH in Lübeck and Kiel. “We will find many more genes with such disease-causing mutations and can now test their mode of action.”

    An unusual mutation

    Affected individuals have complex and striking malformations of the limbs, face, and nervous and bone systems, only partially described by the already-long disease name “brachyphalangy-polydactyly-tibial aplasia/hypoplasia syndrome” (BPTAS).

    “With fewer than ten documented cases worldwide, the disease is not only rare, but ultra-rare,” says Martin Mensah, clinical geneticist at the Institute of Medical and Human Genetics at Charité. To track down the cause, he and his colleagues decoded the genome of five affected individuals and found that the gene for the protein HMGB1 was altered in all patients.

    This protein has the task of organizing the genetic material in the cell nucleus and facilitates the interaction of other molecules with the DNA, for example to read genes.

    In mice, a complete loss of the gene on both chromosomes is catastrophic and leads to death of the embryo. In some patients with only one copy mutated, however, the cells are using the intact copy on the other chromosome, resulting only in mild neurodevelopmental delay. But the newly discovered cases did not fit this scheme.

    “All five unrelated individuals featured the same ultra-rare disorder and had virtually the same mutation”, says Mensah, who is a fellow of the Clinician Scientist Program operated by the Berlin Institute of Health at Charité (BIH) and Charité. “This is why we are sure that the HMGB1 mutation is the cause of the disease. However, at that point, we had no clue how the gene product functionally caused disease, especially given that loss-of-function mutations were reported to result in other phenotypes.”

    Charged protein extensions

    A closer look revealed that different mutations of HMGB1 have different consequences. The sequencing data showed that in the affected individuals with the severe malformations, the reading frame for the final third of the HMGB1 gene is shifted.

    After translation to protein, the corresponding region is now no longer equipped with negative but with positively charged amino acid building blocks. This can happen if a number of genetic letters not divisible by three is missing in the sequence, because exactly three consecutive letters always code for one building block of the protein.

    However, the tail part of the protein does not have a defined structure. Instead, this section hangs out of the molecule like a loose rubber band. The purposes of such protein tails (also called “intrinsically disordered regions”) are difficult to study because they often become effective only in conjunction with other molecules. So how might their mutation lead to the observed disease?

    Protein droplets in the cell

    To answer this question, the medical researchers approached biochemists Denes Hnisz and Henri Niskanen at the MPIMG, who work with cellular condensates that control important genes. These droplet-like structures behave much like the oil and vinegar droplets in a salad dressing. Composed of a large number of different molecules, they are separated from their surroundings and can undergo dynamic changes.

    “We think condensates are formed in the cell for practical reasons,” Niskanen explains. Molecules for a specific task are grouped together in this way, say to read a gene. For this task alone, he says, several hundred proteins need to somehow make their way to the right place.

    “Intrinsically disordered regions, which tend not to have an obvious biochemical role, are thought to be responsible for forming condensates,” Niskanen says, giving an example to describe how important the physical properties of the protein extensions are in this regard. “I can easily make a ball from many loose rubber bands that holds together relatively tightly and that can be taken apart with little effort. A ball of smooth fishing line or sticky tape, on the other hand, would behave quite differently.”

    Solidifying droplets

    The nucleolus within the cell nucleus is also a condensate, which appears as a diffuse dark speck under the microscope. This is where many proteins with positively charged tails like to linger. Many of these provide the machinery required for protein synthesis, making this condensate essential for cellular functions.

    The mutant protein HMGB1 with its positively charged molecular tail is attracted to the nucleolus as well, as the team observed from experiments with isolated protein and with cell cultures.

    But since the mutated protein region has also gained an oily, sticky part, it tends to clump. The nucleolus loses its fluid-like properties and increasingly solidifies, which Niskanen was able to observe under the microscope. This impaired the vital functions of the cells – with the mutated protein, more cells in a culture died compared to a culture of cells without the mutation.

    Combing through databases

    The research team then searched databases of genomic data from thousands of individuals looking for similar incidents. In fact, the scientists were able to identify more than six hundred similar mutations in 66 proteins, in which the reading frame had been shifted by a mutation in the protein tail, making it both more positively charged and more “greasy”. Of the mutations, 101 had previously been linked to several different disorders.

    For a cell culture assay, the team selected 13 mutant genes. In 12 out of 13 cases, the mutant proteins had a preference to localize into the nucleolus. About half of the tested proteins impaired the function of the nucleolus, resembling the disease mechanism of BPTA syndrome.

    New explanations for existing diseases

    “For clinical research, our study could have an eye-opening effect,” says Malte Spielmann, who led the research together with Denes Hnisz and Denise Horn. “In the future, we can certainly elucidate the causes of some genetic diseases and hopefully one day treat them.”

    However, “congenital genetic diseases such as BPTAS are almost impossible to cure even with our new knowledge”, says Horn. “Because the malformations already develop in the womb, they would have to be treated with drugs before they develop. This would be very difficult to do.”

    But tumor diseases are also predominantly genetically determined, adds Hnisz: “Cellular condensates and the associated phase separation are a fundamental mechanism of the cell that also plays a role in cancer. The chances of developing targeted therapies for this are much better.”

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    Max Planck Society (Max-Planck-Gesellschaft)

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  • Omics and AI May Help Predict Lung Disease Risk in Premature Babies

    Omics and AI May Help Predict Lung Disease Risk in Premature Babies

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    Research Alert

    Article title: Development of a peripheral blood transcriptomic gene signature to predict bronchopulmonary dysplasia

    Authors: Alvaro Moreira, Miriam Tovar, Alisha M. Smith, Grace C. Lee, Justin A. Meunier, Zoya Cheema, Axel Moreira, Caitlyn Winter, Shamimunisa B. Mustafa, Steven Seidner, Tina Findley, Joe G. N. Garcia, Bernard Thébaud, Przemko Kwinta, Sunil K. Ahuja

    From the authors: “In conclusion, we show that the combination of omics and artificial intelligence can potentially predict [bronchopulmonary dysplasia (BPD)] and stratify neonates at risk for severe BPD.”

    This study is highlighted as one of February’s “best of the best” as part of the American Physiological Society’s APSselect program.


    Journal Link: American Journal of Physiology-Lung Cellular and Molecular Physiology

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    American Physiological Society (APS)

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  • A new understanding of reptile coloration

    A new understanding of reptile coloration

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    Newswise — Snakes and mice don’t look alike. But much of what we know about skin coloration and patterning in vertebrates generally, including in snakes, is based on lab mice. However, there are limits to what mice can tell us about other vertebrates because they don’t share all of the same types of color-producing cells, known as chromatophores. For example, snakes have a type of chromatophore called iridophores that can generate iridescent colours by reflecting light.

    To gain a better understanding of the genetic basis of coloration in vertebrates, a McGill University-led research team combined a range of techniques (whole gene sequencing, gene-editing, and electron microscopy) to look more closely at color variations and patterning in the skin shed by ball pythons bred in captivity. They were able to identify a particular gene (tfec) that plays a crucial role in reptile pigmentation generally and more specifically in a classic color variant found across vertebrates and distinguished by blotches of white, the piebald.

    Crowdsourcing biological data with the help of snake breeders

    The sale of captive-bred reptiles is a $1.4 billion industry within the U.S. alone. Over 4.5 million American households keep reptiles, and close to one in five of these are snakes bred in captivity. Due to the spectacular color variations produced through captive breeding, an individual ball python (Python regius – originally found in West and Central Africa) can sell for tens of thousands of dollars.

    “Ball pythons show incredible variation in skin coloring and patterning, which is part of their appeal for hobbyists, but also makes them really useful for researchers who want to understand the genetic basis of coloration,” says Rowan Barrett, Interim Director of McGill University’s Redpath Museum, the Canada Research Chair in Biodiversity Science, and the senior author on the recent paper in Current Biology. “The pet trade has created a huge pool of colour variation that would not have existed otherwise. This provides a catalogue for us to figure out the many ways that genes produce the amazing diversity of colors, spots, and stripes we see across different animals.”

    Gene-editing confirms role of mutation in reptile colouration

    To identify the genes that control a particular trait, scientists look for genetic variants that are present in animals that have the trait and absent in animals that don’t. Using shed skin collected from snake breeders, Barrett’s team found that piebald snakes carried the same mutation in the tfec gene.

    But a common problem for scientists is that finding a correlation between a gene and a particular trait, such as the piebaldism, does not imply causation. To make that functional link, the McGill researchers collaborated with Doug Menke’s lab at the University of Georgia to modify tfec in a different reptile species, the brown anole lizard, using the gene-editing technology CRISPR. They found that genetically modified lizards do indeed show altered colouration, proving that mutations to tfec cause changes to color-producing cells. 

    “Our research advances knowledge of the genetics of vertebrate colouration generally and particularly of the development of iridescent cells, which haven’t been studied as much as other color pathways” adds Alan Garcia-Elfring, a PhD student in McGill’s Biology Department and the first author on the paper. “It also highlights the potential benefits of working with non-academic communities like ball python breeders to accelerate discoveries in fundamental science. Our job, at this point, is to figure out what other mutations underlie all this variation seen in captivity, and how these mutations interact. It’s an exciting time for both researchers and reptile hobbyists.”

     

    “Piebaldism and chromatophore development in reptiles are linked to the tfec gene” in Current Biology by Alan Garcia-Elfring et al

    https://doi.org/10.1016/j.cub.2023.01.004

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    McGill University

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  • Researchers use Artificial Intelligence to personalise cancer patient treatments

    Researchers use Artificial Intelligence to personalise cancer patient treatments

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    Newswise — Researchers at the University of Sussex are using Artificial Intelligence (AI) technology to analyse different types of cancer cells to understand different gene dependencies, and to identify genes that are critical to a cell’s survival. Sussex researchers have done this by developing a prediction algorithm that works out which genes are essential in the cell, by analysing the genetic changes in the tumour. This can be used to identify actionable targets that in time could guide oncologists to personalise cancer patient treatments

    Dr Frances Pearl, Senior Lecturer in Bioinformatics in the School of Life Sciences at the University of Sussex says

    “Our vision is to take advantage of the decreasing cost of DNA sequencing and to harness the power of AI to understand cancer cell differences and what they mean for the individual patient’s treatment. Through our research, we were able to identify cell-specific gene dependencies using only the DNA sequence and RNA levels in that cell, which are easily and cheaply obtainable from tumour biopsy samples.

    “This is an incredibly exciting step in our research which means that we can now work to improve the technology so that it can be offered to oncologists and help in the treatment pathways for their patients.”

    Cancer treatments are primarily prescribed on the basis of the location and type of cancer. Genetic differences in tumours can make standard cancer treatments ineffective. Using a personalised approach to guide treatment could improve life expectancy, quality of life and reduce unnecessary side effects of cancer patients.

    In each cell,  there are around 20,000 genes that contain the information needed to make proteins. Around 1,000 of those genes are essential, meaning they are required for the cell to survive. When normal cells become cancer cells, oncogenes (that is, those genes with the potential to cause cancer) become activated and tumour suppressor genes become inactivated, causing a rewiring of the cell. This causes the cell to become dependent on a new set of genes to survive, and this can then be exploited to kill the cancer cells.

    By using this new technology to target protein products of tumour-specific dependent genes, cancer cells can be killed, leaving the normal cells which are not dependent on these genes relatively unharmed. Although dependencies can be determined using intensive laboratory techniques, it is costly and time consuming and would not be feasible to analyse all tumour samples in this way.

    – End –

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    University of Sussex

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  • How age and sex influence our body clocks

    How age and sex influence our body clocks

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    Newswise — The human body runs on a finely tuned clock synchronized to the 24-hour cycle of Earth’s rotation, known as the circadian clock, which controls various physiological processes such as the sleep-wake cycle, hormone production, and metabolism.

    In a new study, researchers led by Felix Naef at EPFL were able to uncover the organization of tissue-specific gene expression rhythms in humans, and shed light on how our body clocks depend on sex and age.

    In model organisms, analyzing molecular rhythms is usually done using time-stamped measurements – but such data are not readily available in humans. To work around this, the researchers used existing measurements from a large cohort of post-mortem donors, combined with a novel computer algorithm that was designed to assign internal clock times to nearly one thousand donors.      

    “Interestingly, the data-science algorithm we developed turned out to resemble models from magnetic systems, which are well studied in statistical physics,” says Felix Naef. Using this innovative approach, the researchers obtained the first comprehensive and accurate whole-organism view of 24-hour gene expression rhythms in 46 human tissues.

    The study found that the core clock machinery properties are conserved across the body and do not change significantly with sex and age. On the other hand, the analysis revealed extensive programs of gene expression rhythms across major compartments of metabolism, stress response pathways and immune function, and these programs peaked twice a day.

    In fact, the emerging whole-body organization of circadian timing shows that rhythmic gene expression occurs as morning and evening waves, with the timing in the adrenal gland peaking first, while brain regions displayed much lower rhythmicity compared to metabolic tissues.

    Dividing the donors by sex and age revealed a previously unknown richness of sex- and age- specific gene expression rhythms spread across biological functions. Strikingly, gene expression rhythms were sex-dimorphic (different in males and females) and more sustained in females, while rhythmic programs were generally reduced with age across the body.

    Sex-dimorphic rhythms – referring to the differences between males and females – were particularly noticeable in the liver’s “xenobiotic detoxification”, the process by which liver breaks down harmful substances. Additionally, the study found that as people grow older, the rhythm of gene expression decreases in the heart’s arteries, which may explain why older people are more susceptible to heart disease. This information could be useful in the field of “chronopharmacology,” which is the study of how a person’s internal clock affects the effectiveness and side effects of medication.

    This study provides new insights into the complex interplay between our body clock, sex, and age. By understanding these rhythms, we might find new ways of diagnosing and treating pathologies such as sleep disorders and metabolic diseases.

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    Ecole Polytechnique Federale de Lausanne (EPFL)

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  • Researchers identify the neurons that synchronise female preferences with male courtship songs in fruit flies

    Researchers identify the neurons that synchronise female preferences with male courtship songs in fruit flies

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    Newswise — When it comes to courtship, it is important to ensure that one is interacting with a member of the same species. Animals use multiple sensory systems to confirm that potential mates are indeed suitable, with acoustic communication playing an important role in their decision making.   

    Although these differences have previously been reported at the behavioral level, it is not known how the neuronal circuitry underlying this decision-making has diverged between species. Now, in a new publication in Scientific Reports, a research group at Nagoya University in Japan has investigated how the auditory processing pathway has evolved and diverged between fruit fly species.  

    Males of several species of Drosophila (fruit flies), which are regularly used in neuroscience research, vibrate their wings rhythmically during courtship, producing a courtship song. The temporal components of these songs differ between species, allowing female flies to distinguish between potential mates. 

    “Identifying complex features, such as rhythm, requires information processing that involves not only the auditory organs but also neural circuits,” explains Yuki Ishikawa, the lecturer leading the project. “However, interspecies comparisons of the mechanism of rhythm discrimination have not been studied before because they require a more precise approach than just studying peripheral auditory organs.” 

    To find out what happens in the neural circuits during courtship, Professor Azusa Kamikouchi, Lecturer Yuki Ishikawa, and Graduate Student Takuro Ohashi of the Graduate School of Science first played songs with different rhythms to females of two closely related species of fruit flies (Drosophilia melanogaster and Drosophilia simulans), which have different courtship songs, to see which tones the females found acceptable. Confirming previous reports, the researchers found that Drosophilia simulans females preferred songs with distinct temporal components to those of Drosophilia melanogaster. 

    Building on these behavioral data, the researchers next used calcium imaging to determine how a specific subset of auditory neurons, called AMMC-B1, responded to different courtship songs between the species. They found that the responses of these neurons did indeed differ between species, and that these differences were consistent with previously observed behavioral responses.  

    “This is the first study to clarify how the evolution of the mechanism for distinguishing between rhythms of the same sound occurs,” explains Dr. Ishikawa. “Rhythmic information processing in neural circuits differs between fruit fly species. Using mathematical modeling, we have shown that this species difference may be due to a change in the balance between facilitation and inhibition in neural circuits.” 

    Despite the differences at the behavioral level, the group found that the overall characteristics of AMMC-B1 neurons are similar between the two species. This suggests that the properties of the neural circuit, at least in its early stages, are evolutionarily conserved. Thus, even in different species, they appear to be encoded by similar genes. These findings support the theory that the species-specificity of such neuronal cell groups emerged at a later stage of the auditory information- processing neural circuits. 

    “Drosophila melanogaster has neural mechanisms that are widely shared among animals,” Ishikawa said. “It is one of the most advanced animals for brain research because of the wealth of existing genetic tools. By introducing these tools into Drosophila simulans, this study was the first to make detailed interspecies comparisons of auditory neural circuits. By transferring these methods and results to closely related species, we can begin to study how information processing has evolved in the animal brain. We hope that the method established in this study will contribute to understanding the full picture of how mechanisms in the auditory brain have evolved.” 

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    Nagoya University

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  • Decades-old crustaceans coaxed from lake mud give up genetic secrets revealing evolution in action

    Decades-old crustaceans coaxed from lake mud give up genetic secrets revealing evolution in action

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    Newswise — Human actions are changing the environment at an unprecedented rate. Plant and animal populations must try to keep up with these human-accelerated changes, often by trying to rapidly evolve tolerance to changing conditions.

    University of Oklahoma researchers Lawrence Weider, professor of biology, and Matthew Wersebe, a biology doctoral candidate, demonstrated rapid evolution in action by sequencing the genomes of a population of Daphnia pulicaria, an aquatic crustacean, from a polluted lake.  

    The research, which was conducted as part of Wersebe’s doctoral dissertation, was recently published in the Proceedings of the National Academy of Sciences.  Wersebe and Weider revived decades-old Daphnia resting eggs from lake sediments, a method known as resurrection ecology, which has been refined in Weider’s lab over the past several decades. They then sequenced the entire genomes of 54 different Daphnia individuals from different points-in-time, allowing them to study the genetics and evolution of the population.

    The Daphnia were collected from Tanners Lake, located in Oakdale, Minnesota. Tanners Lake has suffered significant salt pollution, stemming from the widespread use of road deicing salts in its watershed.  

    Daphnia, also known as water fleas, play critical roles in environmental monitoring. For example, they have served as important test organisms in laboratories around the world for over a century because of their sensitivity to many environmental stressors such as chemicals. In nature, Daphnia act as a keystone species in freshwater food webs globally, where they feed on algae to help keep lake and reservoir water clean and serve as a food item for recreational and commercially important fish species.

    Wersebe’s and Weider’s results indicate that rapid adaptation to salt pollution may allow lake Daphnia to persist in the face of anthropogenic salinization, maintaining the food webs and ecosystem services that Daphnia support. However, the ability of these populations to adapt will depend on the speed at which these changes are occurring and the underlying genetic makeup of the impacted populations. 

    Over the past several years, many researchers have published results defining the scope and scale of lake salinization and recent research has highlighted the ecological impacts. However, to date, the evolutionary implications are not well known. Through their study, Wersebe and Weider reported signatures of natural selection throughout the genome near genes related to osmoregulation and ion regulation, key processes for dealing with high salt. Characterizing clones for salinity tolerance revealed evidence that genetic changes may underlie rapid evolution.  

    “Work like this is the first step in designing future studies incorporating recent technological advances, such as CRISPR gene editing, allowing the creation of comprehensive genotype-to-phenotype maps and predicting the role that genetic variation plays in creating diverse forms and functions,” Wersebe said. “In fact, we found a promising gene that appears not to work properly in the older Daphnia, but a functional copy of the gene is increasing in frequency – true evolution in action.”

    Future research using these advanced technologies for cutting and pasting the non-functional gene into Daphnia would be one way to better probe the effects that mutations have on complex phenotypic traits like salinity tolerance.  

    The work was funded by the OU Department of Biology Adams Summer Scholarship, Robberson OU Graduate College Grant, Hill Fund for Research in Biology, OU Graduate Student Senate Research Grant, American Museum of Natural History Theodore Roosevelt Grant and the National Science Foundation Biogeography of Behavior student seed grant awarded to Wersebe in support of graduate research. The study was facilitated by material and technical assistance from the University of Oklahoma Biological Station in Kingston, Oklahoma, and the St. Croix Watershed Research Station in Marine-on-St. Croix, Minnesota.  

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    University of Oklahoma

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  • Establishing cell lines to improve iPSC research

    Establishing cell lines to improve iPSC research

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    Newswise — Farmington, CT– iPSC lines have become essential for determining the underlying genetic drivers of human disease. Genomes of iPSCs can be easily edited using the bacteria-based CRISPR/Cas9 technology to introduce or correct disease-associated variants. 

    By focusing on one gene variation at a time, results of experiments have a clear genetic cause and effect to be easily compared to previous data. What poses a challenge for accurate disease modeling is the inherent variation between iPSC lines, as well as the wide variety of cell lines used in research between institutions, creating unwanted obstacles in data interpretation.

    Jackson Laboratory (JAX) Professor of Cellular Engineering Bill Skarnes, Ph.D., and colleagues have developed a cell line to address the challenges facing cellular modeling of disease. The study, published in Cell Stem Cell, details genetic properties characterization of eight iPSC lines, with one rising above the rest. 

    The cell line KOLF2.1J proved to be an all-around well-performing iPSC line with high genomic stability in post-edited clones. Meeting all the criteria for cellular engineering research, KOLF2.1J can act as a stable foundation for modeling hundreds of genetic alterations relevant to Alzheimer’s disease, rare disease, cancer, and more.

    Through the partnership between the iPSC Neurodegenerative Disease Initiative and the Chan Zuckerberg Initiative, KOLF2.1J is available as both a reference parental line and with selected single nucleotide variants (SNVs) as part of the catalog of human iPSCs at JAX. 

    By selecting KOLF2.1J as a cell line of choice, researchers will be able to generate consistent, integratable data and help accelerate human disease research. In collaboration with UConn Health, Skarnes and fellow JAX researchers are now planning to derive additional similarly well-characterized iPSC lines from healthy individuals of diverse genetic backgrounds.

    About The Jackson Laboratory

    The Jackson Laboratory is an independent, nonprofit biomedical research institution with a National Cancer Institute-designated Cancer Center and nearly 3,000 employees in locations across the United States (Maine, Connecticut, California) and Japan, as well as a joint venture in China. Its mission is to discover precise genomic solutions for disease and empower the global biomedical community in the shared quest to improve human health. For more information, please visit www.jax.org​​​​​​​.

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    Jackson Laboratory

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  • Targeted therapy momelotinib provides significant symptom and anemia improvements in patients with myelofibrosis

    Targeted therapy momelotinib provides significant symptom and anemia improvements in patients with myelofibrosis

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    Newswise — Patients with myelofibrosis had clinically significant improvement in disease-related symptoms, including anemia and spleen enlargement, when treated with the targeted therapy momelotinib, according to results from the international Phase III MOMENTUM trial led by researchers at The University of Texas MD Anderson Cancer Center.

    The findings, published today in The Lancet, support the use of momelotinib – a potent ACVR1/ALK2 and JAK1/2 inhibitor – over the standard therapy danazol in treating myelofibrosis patients that were resistant, refractory or intolerant to firstline therapy, especially symptomatic patients and those with anemia.

    “Current options for managing anemia in our myelofibrosis patients provide only modest and temporary benefits, so we are excited about these findings,” said study lead Srdan Verstovsek, M.D., Ph.D., professor of Leukemia. “The trial results suggest that momelotinib is safe, well-tolerated and can improve one of the most common and debilitating clinical problems for this patient population.”

    Myelofibrosis is an uncommon bone marrow cancer that is part of a group of diseases known as myeloproliferative neoplasms. A hallmark of the disease is dysregulated JAK signaling, which disrupts the body’s normal production of blood cells and leads to common symptoms, including an enlarged spleen and anemia. Chronic anemia in these patients is associated with poor prognoses.

    Currently approved JAK inhibitors can improve spleen responses and other disease-related symptoms, but they also can worsen anemia. In this trial, momelotinib improved anemia and reduced transfusion dependency in myelofibrosis patients previously treated with a JAK inhibitor. Momelotinib can be administered and maintained at full dose because it does not suppress bone marrow activity like other JAK inhibitors.  

    The MOMENTUM trial is the first randomized Phase III study to evaluate a JAK1/2 and ACVR1/ALK2 inhibitor in patients with myelofibrosis and anemia. The trial was designed to compare the clinical benefits of momelotinib to danazol, a synthetic androgen currently used to treat anemia in symptomatic myelofibrosis patients.

    The study enrolled 195 adult patients from 107 research sites across 21 countries. Trial participants were randomly assigned (2:1) to receive momelotinib plus placebo or danazol plus placebo. Sixty-three percent of participants were male and 37% were female. The median age of participants for the momelotinib group was 71 years and for the danazol group 72 years.

    The trial’s primary endpoint was symptom reduction after 24 weeks of treatment, defined as a 50% or more reduction in Myelofibrosis Symptom Assessment Form Total Symptom Score. A significantly greater proportion of patients who received momelotinib saw benefits in their disease symptoms (25%) compared to those receiving danazol (9%).

    Patients treated with momelotinib also experienced a significant reduction in their spleen size, with 25% responding after 24 weeks of therapy. Additionally, these patients required fewer blood transfusions compared to those receiving danazol.

    The safety profile of momelotinib was comparable to previous clinical trials. The most common non-hematological side effects experienced by trial participants in the momelotinib group included diarrhea, nausea, weakness and itching or irritated skin.

    “If approved, momelotinib could offer an effective option for patients with myelofibrosis to improve anemia, splenomegaly and other disease-related symptoms over other approved medications so far,” Verstovsek said. “Momelotinib may also be an ideal partner for combinations with other investigational agents in development to further control myelofibrosis symptoms.”

    Patient follow-up is ongoing and long-term survival continues to be monitored.

    The research was supported by Sierra Oncology. A full list of collaborating authors and their disclosures can be found with the full paper here.

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    University of Texas M. D. Anderson Cancer Center

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  • Discovering Unique Microbes Made Easy with DOE Systems Biology Knowledgebase (KBase)

    Discovering Unique Microbes Made Easy with DOE Systems Biology Knowledgebase (KBase)

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    The Science

    Microbes are foundational for life on Earth. These tiny organisms play a major role in everything from transforming sunlight into the fundamental molecules of life. They help to produce much of the oxygen in our atmosphere. They even cycle nutrients between air and soil. Scientists are constantly finding interactions between microbes and plants, animals, and other macroscopic lifeforms. As genomic sequencing has advanced, researchers can investigate not only isolated microbes, but also whole communities of microorganisms – known as microbiomes – based on DNA found in an environment. The genomes extracted from these communities (metagenomic sequences) can identify the organisms that carry out biogeochemical processes, contribute to health or disease in human gastrointestinal microbiomes, or interact with plant roots in the rhizosphere. The Department of Energy Systems Biology Knowledgebase (KBase) recently released a suite of features and a protocol for performing sophisticated microbiome analysis that can accelerate research in microbial ecology.

    The Impact

    The widespread adoption of DNA sequencing in microbiology has generated huge amounts of genomic data. Researchers need computational tools to recover high-quality genomes from environmental samples to understand which organisms live in an environment and how they might interact. The combination of usability, data, and bioinformatics tools in a public online resource makes KBase a uniquely powerful web platform for performing this task. These new features in KBase will allow biologists to obtain genomes from microbiome sequences with easy-to-use software powered by Department of Energy computational resources. This will reduce the time required to process sequencing data and characterize genomes. Scientists can use KBase to collaboratively analyze genomics data and build research communities to solve common problems in microbial ecology.

    Summary

    Obtaining genomes of uncultivated microbes directly from the environment using DNA sequencing is a recent advance that allows scientists to discover and characterize novel organisms. Sequencing the DNA of all the microbes in a given environment produces a “metagenome.” Performing genetic analysis of metagenomes has emerged as a way to explore microbial traits and behaviors and community interactions in an environmental context. Methods for obtaining metagenome-assembled genomes (MAGs) have varying degrees of success, depending on the techniques used. An increasing number of researchers generate microbiome sequences, but many do not have ready access to the expertise, tools, and computational resources necessary to extract, evaluate, and analyze their genomes.

    The KBase team added and updated several metagenome analysis tools, data types, and execution capabilities to provide researchers the tools that accelerate the discovery of microbial genomes and uncover the genetic potential of microbial communities. A recent paper in Nature Protocols presents a series of analysis steps, using KBase apps and data products for extracting high quality MAGs from metagenomes. These capabilities, including computing, data storage, and sharing of data and analyses, are provided free to the public via the KBase web platform. This protocol allows scientists to both generate putative genomes from organisms only found in the environment and analyze them with tools to understand who they are, what they are doing, who they are interacting with, and their role in the ecosystem.

     

    Funding

    KBase is funded by the Genomic Science Program in the Department of Energy Office of Science, Office of Biological and Environmental Research.


    Journal Link: Nature Protocols

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    Department of Energy, Office of Science

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