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February 25th, 2018

Cutting-Edge Technology Enables Identification of Novel Nanoparticles (Exomeres) Released by Cancer Cells and Similar to Exosomes, But Smaller and with Different Functions

A new cellular messenger discovered by Weill Cornell Medicine scientists may help reveal how cancer cells co-opt the body’s intercellular delivery service to spread to new locations in the body. In a paper published online on February 19, 2018 in Nature Cell Biology, the scientists show that a cutting-edge technique called asymmetric flow field-flow fractionation (AF4) can efficiently sort nano-sized particles, called exosomes, that are secreted by cancer cells and contain DNA, RNA, fats, and proteins. This technology allowed the investigators to separate two distinct exosome subtypes and discover a new nanoparticle, which they named an “exomere.” The article is titled "Identification of Distinct Nanoparticles and Subsets of Extracellular Vesicles by Asymmetric Flow Field-Flow Fractionation." Also published online on February 19, 2018 was a description of the protocol used to identify the nanoparticles. “We found that exomeres are the most predominant particle secreted by cancer cells,” said senior author Dr. David Lyden, the Stavros S. Niarchos Professor in Pediatric Cardiology, and a scientist in the Sandra and Edward Meyer Cancer Center and the Gale and Ira Drukier Institute for Children’s Health at Weill Cornell Medicine. “They are smaller and structurally and functionally distinct from exosomes. Exomeres largely fuse with cells in the bone marrow and liver, where they can alter immune function and metabolism of drugs.

Mutation in Gene Controlling RNA Lariat Metabolism Implicated in Susceptibility to Lethal Brain Stem Infections by Common Viruses

For previously healthy children, brain infections are rare. But about one out of every 10,000 people who are exposed to common viruses like herpes simplex or influenza will develop a potentially deadly disease, encephalitis. Rockefeller's Dr. Jean-Laurent Casanova has identified mutations in a single gene that may explain what goes wrong in cases of encephalitis of the brain stem, the part of the brain that controls many basic functions including heart rate and breathing. Shen-Ying Zhang, Assistant Professor of Clinical Investigation in the Casanova lab, evaluated seven children from unrelated families who had been exposed to a common virus (herpes simplex virus 1, influenza virus, or norovirus) and developed a life-threatening or lethal infection of the brain stem. The scientists discovered mutations in a gene called DBR1, which is responsible for producing a protein (image) that helps process the loops formed in RNA during a step called mRNA splicing. Without it, immunity to viruses is selectively impaired in the brain stem. Dr. Casanova's experiments, published in the February 22, 2018 issue of Cell, point to an almost complete loss of DBR1 (debranching RNA lariats 1) as the culprit, enabling brain stem virus invasion in all seven patients. The findings also reveal an unexpected connection between an RNA processing mechanism and protective immunity in a specific region of the brain. The Cell article is titled “Inborn Errors of RNA Lariat Metabolism in Humans with Brainstem Viral Infection.” The study is a new example of the Casanova lab's ongoing work to identify mutations that underlie infectious diseases in otherwise healthy individuals. Previous work has found genetic factors that cause increased vulnerability to staph infections, the flu, and fungal infections, among others.

February 19th

Genome of Asexually Reproducing Amazon Molly Fish Sequenced

No species is immune from the suffering of unrequited love, but scientists expect to learn volumes about the biological basis of sex from the newly sequenced genome of an all-female, asexual Texas native - the Amazon molly - that has thrived over millennia. The fresh waters along the Texas-Mexico border serve as home to this evolutionary anomaly - a fish that has flourished by defying nature's odds to reproduce asexually through a natural form known as parthenogenesis in which growth and development of embryos occurs without fertilization, resulting only in daughters that are true clones of their mothers. Texas A&M University Hagler Institute for Advanced Study (HIAS) Faculty Fellow Dr. Manfred Schartl led the international team that recently sequenced the first Amazon molly genome and the genomes of the original parental species that created this unique fish in an effort to better understand how its reproduction deviates from the male-female sexual norm and why the Amazon molly as a species has fared so well in the process. The findings from their National Institutes of Health-funded research were published online on February 12, 2018 in Nature Ecology & Evolution. The open-access article is titled” Clonal Polymorphism and High Heterozygosity in the Celibate Genome of the Amazon Molly.” "The existence of two sexes, male and female, is one of the oldest and most widespread phenomena in biology," says Dr. Schartl, a world leader in cellular and molecular biology of Xiphophorus model systems, including platyfish and swordtails. "Studies on the exceptional case of asexuality helps us to better understand the biological meaning and evolution of sex." Animals that reproduce asexually are rare, compared to the overwhelming majority of species that exist as males and females and reproduce sexually.

Ancient Fused Gene Offers Insight into How Mosses Build Cell Walls

Researchers have identified a fused gene in moss that provides insight into how moss cells build their external walls. The same discovery raises questions about the one-of-a-kind gene that codes for two distinct proteins that participate in two distinct functions. The research team identified the novel gene, known as For1F, while studying exocytosis. Exocytosis is the process by which cells secrete packets of protein and carbohydrates outside their membranes to support extracellular processes like the construction of cell walls. The gene discovered in the research couples the exocytosis-regulating protein Sec10 with formin, a protein that regulates the remodeling of the actin cytoskeleton critical to forming cell shapes. The new study also shows that the gene fusion occurred early in moss evolution and has been retained for more than 170 million years. "We were surprised to find this fused gene in the moss genome," said Magdalena Bezanilla, PhD, the Ernest Everett Just 1907 Professor of Biology at Dartmouth College. "Through our research, we know that the analysis is correct; now it will be interesting to explore the advantage of this coupling of proteins." Dr. Bezanilla led a team at Dartmouth and the University of Massachusetts-Amherst to conduct the study. The research was published online on January 26, 2018 in the Journal of Cell Biology. The article is titled “An Ancient Sec10–Formin Fusion Provides Insights into Actin-Mediated Regulation of Exocytosis.” Once For1F was observed, Dr. Bezanilla and her team set out to determine how unique this particular conjoined arrangement is. By consulting the database of the 1000 Genomes Project, the researchers found that the fused gene was evident in many diverse species of mosses, but not in other plants.

Progress Reported in Using CRISPR/Cas9 Editing to Correct Sickle Cell Mutation

Scientists have successfully used gene editing to repair 20 to 40 percent of stem and progenitor cells taken from the peripheral blood of patients with sickle cell disease, according to Rice University bioengineer Gang Bao., PhD. Dr. Bao, in collaboration with colleagues at the Baylor College of Medicine, Texas Children's Hospital, and Stanford University, is working to find a cure for the hereditary disease. A single DNA mutation causes the body to make sticky, crescent-shaped red blood cells that contain abnormal hemoglobin and can block blood flow in limbs and organs. In his talk on February 16, 2018 at the annual American Association for the Advancement of Science (AAAS) meeting ( in Austin, Texas, Dr. Bao revealed results from a series of tests to see whether CRISPR/Cas9-based editing can fix the mutation. His presentation was part of a scientific session titled "Gene Editing and Human Identity: Promising Advances and Ethical Challenges." ( "Sickle cell disease is caused by a single mutation in the beta-globin gene (in the stem cell's DNA)," Dr. Bao said. "The idea is to correct that particular mutation, and then stem cells that have the correction would differentiate into normal blood cells, including red blood cells. Those will then be healthy blood cells." Dr. Bao's lab collaborated with Dr. Vivien Sheehan, an Assistant Professor of Pediatrics and Hematology at Baylor and a member of the Sickle Cell Program at Texas Children's, to collect stem and progenitor cells (CD34-positive cells) from patients with the disease. These cells were then edited in the Bao lab with CRISPR/Cas9 together with a custom template, a piece of DNA designed to correct the mutation.

February 17th

Dynamic Ligand Discrimination Shown in Notch Signaling Pathway

Multicellular organisms like ourselves depend on a constant flow of information between cells, coordinating their activities in order to proliferate and differentiate. Deciphering the language of intercellular communication has long been a central challenge in biology. Now, Caltech scientists have discovered that cells have evolved a way to transmit more messages through a single pathway, or communication channel, than previously thought, by encoding the messages rhythmically over time. The work, conducted in the laboratory of Michael Elowitz (photo), PhD, Professor of Biology and Bioengineering, Howard Hughes Medical Institute Investigator, and Executive Officer for Biological Engineering, is described in a paper in the February 8, 2018 issue of Cell. The open-access paper is titled "Dynamic Ligand Discrimination in the Notch Signaling Pathway." In particular, the scientists studied a key communication system called "Notch," which is used in nearly every tissue in animals. Malfunctions in the Notch pathway contribute to a variety of cancers and developmental diseases, making it a desirable target to study for drug development. Cells carry out their conversations using specialized communication molecules called ligands, which interact with corresponding molecular antennae called receptors. When a cell uses the Notch pathway to communicate instructions to its neighbors--telling them to divide, for example, or to differentiate into a different kind of cell--the cell sending the message will produce certain Notch ligands on its surface. These ligands then bind to Notch receptors embedded in the surface of nearby cells, triggering the receptors to release gene-modifying molecules called transcription factors into the interior of their cell.

February 13th

ASHG Disappointed by Proposed NIH Budget for FY 2019

On February 13, 2018, The American Society of Human Genetics (ASHG) announced that it is disappointed by the Administration’s proposed Fiscal Year 2019 National Institutes of Health (NIH) budget released on February 12, 2018. This budget would impose cuts to the budgets of most NIH institutes and centers, including those institutes supporting most genetics research. “NIH funding is the lifeblood of genetics research in the United States,” said ASHG President David L. Nelson, PhD. “It connects our nation to global collaborations that are advancing science and improving health. Because of crucial federal support for such research, we are making remarkable progress in understanding how the human genome operates and how this knowledge can enhance patient care. Yet there are still fundamental questions that researchers are working to answer, which will pave the way for better health for future generations,” he added. “Whether for pioneering projects like the All of Us Research Program or for innovative investigator-initiated research, this investment is essential for discovering breakthrough diagnostics and treatments. We are heartened that there is broad bipartisan consensus in Congress to increase federal funding for biomedical research, and we thank and look forward to working with Congressional leaders to support sustained investment.”

[Press release]

Huntington’s Disease Provides Potentially Powerful New Cancer Weapon; Small Interfering RNAs (siRNAs) Based on Huntingtin Trinucleotide Repeats (TNRs) Are Highly Toxic to Cancer Cells

Patients with Huntington’s disease, a fatal genetic illness that causes the breakdown of nerve cells in the brain, have up to 80 percent less cancer than the general population. Northwestern Medicine scientists have discovered why Huntington’s is so toxic to cancer cells and have harnessed some of the disease’s characteristics for a novel approach to treat cancer, according to a new study published online on February 12, 2018 in EMBO Reports. The article is titled “Small Interfering RNAs Based on Huntingtin Trinucleotide Repeats Are Highly Toxic to Cancer Cells.” Huntington’s is caused by a prominent trinucleotide repeat (TNR) expansion in the numbers of the CAG triplets in the huntingtin (HTT) gene responsible, when mutated, for Huntington's disease (HD). Pathology is caused by protein and RNA generated from the TNR regions, including small interfering RNA (siRNA)‐sized repeat fragments. The HTT gene is present in every cell and the defect that causes the disease is also highly toxic to tumor cells. These siRNAs from the mutated huntingtin gene attack genes in the cell that are critical for survival. Nerve cells in the brain are vulnerable to this form of cell death, however, cancer cells appear to be much more susceptible. “This molecule is a super assassin against all tumor cells,” said senior author Marcus Peter, PhD, the Tom D. Spies Professor of Cancer Metabolism and of Medicine in the Division of Hematology and Oncology. “We’ve never seen anything this powerful against cancer cells.” The researchers showed that siRNAs based on the CAG TNR are toxic to cancer cells by targeting genes that contain long reverse complementary TNRs in their open reading frames. Of the 60 siRNAs based on the different TNRs, the six members in the CAG/CUG family of related TNRs are the most toxic to both human and mouse cancer cells.

February 12th

Machine-Learning Algorithm Uses Time-Series Data to Reveal Underlying Gene Regulatory Networks in Cells

Biologists have long understood the various parts within the cell. But how these parts interact with and respond to each other is largely unknown. "We want to understand how cells make decisions, so we can control the decisions they make," said Northwestern University's Neda Bagheri (photo), PhD. "A cell might decide to divide uncontrollably, which is the case with cancer. If we understand how cells make that decision, then we can design strategies to intervene." To better understand the mysterious interactions that occur inside cells, Dr. Bagheri and her team have designed a new machine learning algorithm that can help connect the dots among the genes' interactions inside cellular networks. Called "Sliding Window Inference for Network Generation," or SWING, the algorithm uses time-series data to reveal the underlying structure of cellular networks. Supported by the National Science Foundation, the National Institutes of Health, and Northwestern's Biotechnology Training Program, the research was published online on February 12, 2018 in PNAS. Justin Finkle and Jia Wu, graduate students in Dr. Bagheri's laboratory, served as co-first authors of the paper, which is titled “Windowed Granger Causal Inference Strategy Improves Discovery of Gene Regulatory Networks.” In biological experiments, researchers often perturb a subject by altering its function and then measure the subject's response. For example, researchers might apply a drug that targets a gene's expression level and then observe how the gene and downstream components react. But it is difficult for those researchers to know whether the change in genetic landscape was a direct effect of the drug or the effect of other activities taking place inside the cell.

National Alliance for Hispanic Health Brings NIH's All of Us Journey to Oregon State University Feb 15

Oregon State University and the National Alliance for Hispanic Health will host the National Institutes of Health's All of Us Journey ( on Thursday, February 15, 2018. The traveling, hands-on exhibit raises awareness about the All of Us Research Program (—an ambitious effort to gather data from 1 million or more people living in the United States to accelerate precision medicine research and improve health. "We are glad the National Alliance for Hispanic Health recognizes our region as an important stop on the national tour and they are taking on a national effort to focus on the Hispanic population. If you look at most biomedical, behavioral, or social science research, it doesn't involve the Hispanic population," said Javier Nieto, Dean of the College of Public Health and Human Sciences at Oregon State. "Most clinical trials and large population health studies do not include Hispanic participants. It is our duty to figure out how we can better their lives through science." Campus and community members are invited to come learn about the NIH’s All of Us program and get information on healthy living and preventing disease. Corvallis is one stop on the All of Us Journey's 37-week national tour. "All of Us is so important to shaping the future of health in the United States," said Dr. Jane L. Delgado, President and CEO of the National Alliance for Hispanic Health, the nation's leading Hispanic health advocacy group.