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October 10th, 2017

18-Year-Old Harvard Freshman Electrifies Scientists on Second Day of American Society for Exosomes and Microvesicles (ASEMV) 2017 Annual Meeting in Asilomar, California

On Monday, October 9, Indrani Das, an 18-year-old freshman at Harvard, electrified a crowd of 200 established scientists at the ASEMV 2017 Annual Meeting with the description of her exosome research that won the Regeneron 2017 United States Science Talent Search Grand Prize of $250,000 (this is the nation's oldest and most prestigious science and math competition for high school seniors--previous sponsors of the Talent Search were Westinghouse and Intel) (photo shows Indrani on the day her prize was awarded). Comments heard after Indrani’s Asilomar presentation included “brilliant,” “powerful,” “incredible.” Her winning project was titled “Exosomal MicroRNA-124s: Novel Translational Reactive Astrocyte Repair in Vitro.” Indrani’s early interest in neurodegenerative diseases and brain injury therapy had provided the impetus for her four-year high school study of exosomes as she had learned that these vesicles can pass through the blood-brain barrier and might perhaps be used to provide therapeutic cargo to sites of brain injury. She knew that stroke, traumatic brain injury, Alzheimer’s disease, and Parkinson’s disease all cause the behavior of glial cells to change dramatically, in particular to cause a phenomenon called reactive astrogliosis. Healthy astrocytes take up glutamate, an essential excitatory neurotransmitter, from their surroundings, but, in reactive astrogliosis, this process breaks down and glutamate accumulates in the extracellular space where it can damage surrounding neurons. In fact, neurons die when exposed to the medium that reactive astrocytes are grown in. Indrani knew that the excitatory amino acid transporter EAAT2 is one of the major glutamate transporters expressed predominantly in astrocytes and is responsible for 90% of total glutamate uptake.

October 8th

ASEMV 2017 Meeting on Exosomes & Microvesicles Opens in California

With almost 200 attendees from around the USA and world, the seventh annual American Society for Exosomes and Microvesicles (ASEMV 2017) meeting opened on Sunday, October 8, at the naturally spectacular Asilomar Conference Grounds in Pacific Grove, California. Opening remarks by Michael Graner, PhD, University of Colorado Denver, briefly outlined the history of the ASEMV meetings from the early days when just a few were working on exosomes to the present time when exosome studies are being carried out in almost every conceivable area of biology. Dr. Graner emphasized that the recurrent theme of the ASEMV meetings over the years has been “awesome science,” and he expected this year to be the same. He then introduced the evening’s three speakers: Dr. Takahiro Ochiya, Chief, Division of Molecular and Cellular Medicine, National Cancer Center, Tokyo, Japan; Dr. Christie D. Fowler, Department of Neurobiology and Behavior, University of California-Irvine; and Dr. Janos Zempleni, Department of Nutrition and Health Science, University of Nebraska-Lincoln. Dr. Ochiya spoke on “Extracellular Vesicles As a Novel Therapeutic Target for Cancer Metastasis.” Dr. Fowler spoke on “Extracellular MicroRNAs Released During Nicotine Self-Administration.” Dr. Zempleni spoke on the “Delivery and Alterations of Microbial Signals by Bovine Milk Exosomes in Non-Bovine Species.” Details of these talks will be described in an upcoming article in BioQuick News. This year’s meeting was organized by ASEMV President Dr. Stephen J.

October 5th

Scientists Sequence Genome of Taiwan Pit Viper and Examine Role of Genetic Drift in Venom Evolution

A bite from a pit viper, locally known in Taiwan and Okinawa as habu, can cause permanent disability and even death. Yet, much about its venom remains an enigma. Highly variable in composition, even between littermates, this toxic cocktail keeps changing over generations. A recent study published online on September 27, 2017 in Genome Biology and Evolution sheds light on the evolution of snake venoms. For the first time, researchers have sequenced a habu genome, that of the Taiwan habu (Protobothrops mucrosquamatus), and compared it to that of its sister species, the Sakishima habu (Protobothrops elegans). The article is titled “Population Genomic Analysis of a Pitviper Reveals Microevolutionary Forces Underlying Venom Chemistry.” More than 50 instances of snake bites were recorded in the past year on Okinawa alone, prefectural government figures show. Globally, snake bites cause between 81,000 and 138,000 mortalities per year, according to the World Health Organization. In developing countries and rural areas with high exposure to venomous species and scant medical resources, snake bites can be especially devastating. For such places, creating effective antivenom can be a matter of life or death. "For many years it was known that snake venoms evolve very rapidly, and the most common explanation for this has been natural selection," said Dr. Alexander Mikheyev, senior author on the paper and head of the Ecology and Evolution Unit at the Okinawa Institute of Science and Technology (OIST), "but there are reasons to suspect that this might not be the only evolutionary force at work."

Nobel Prize in Chemistry 2017 Awarded for Cryo-Electron Microscopy

We may soon have detailed images of life’s complex machineries at atomic resolution. The Nobel Prize in Chemistry 2017 has been awarded to three European-born scientists: Jacques Dubochet, Joachim Frank, and Richard Henderson; for the development of cryo-electron microscopy, which both simplifies and improves the imaging of biomolecules. This method has moved biochemistry into a new era. A picture can be a key to understanding. Scientific breakthroughs often build upon the successful visualization of objects invisible to the human eye. However, biochemical maps have long been filled with blank spaces because the available technology has had difficulty generating images of much of life’s molecular machinery. Cryo-electron microscopy changes all of this. Researchers can now freeze biomolecules mid-movement and visualize processes they have never previously seen, which is decisive for both the basic understanding of life’s chemistry and for the development of pharmaceuticals. Electron microscopes were long believed to only be suitable for imaging dead matter, because the powerful electron beam destroys biological material. But in 1990, Richard Henderson succeeded in using an electron microscope to generate a three-dimensional image of a protein at atomic resolution. This breakthrough proved the technology’s potential. Joachim Frank made the technology generally applicable. Between 1975 and 1986, he developed an image-processing method in which the electron microscope’s fuzzy two-dimensional images are analyzed and merged to reveal a sharp three-dimensional structure. Jacques Dubochet added water to electron microscopy. Liquid water evaporates in the electron microscope’s vacuum, which makes the biomolecules collapse.

October 5th

Study Finds Non-Protein-Coding Fusion Genes Are Frequent in Breast Cancer

A fusion gene occurs when a chromosomal break brings two separate genes together into a new functioning gene. So far, the research has focused on protein-coding fusion genes. However, human genes consist not only of protein-coding components, but also of components that lack this ability. The latter have not attracted any interest so far, argues Dr. Carlos Rovira (photo), cancer researcher and Associate Professor of Oncology at Lund University in Sweden. "We study genes that lack the ability to produce proteins, and we were very surprised to discover that this type of study has not been done before - the 'non-coding' components of fusion genes have never been analyzed globally in this context. This means that previous analyses have ruled out important genetic components, and that fusion gene data should be re-analyzed to possibly find more markers and potential targets for cancer treatment", says Dr. Rovira, who has been researching breast cancer for many years. "In our study, we discovered a new class of fusion genes that primarily affect the activity of microRNA. These genes are small and often located inside larger protein-coding genes, but they are very short and lack the code required to control protein production. It has already been shown that microRNAs are important for the development of cancer, but the relationship between them and fusion genes was previously unexplored." Fusion genes are commonly found in patients with leukemia and soft tissue cancers, and are of great value in terms of diagnosis and treatment. They have also been used for many years for targeted cancer treatment. The new work was reported online on October 5, 2017 in Nature Communications.

Mystery of BRCA1 Breast Cancer Risk Gene Solved, 20 Years After Its Discovery; Interaction With BARD1 Is Key

More than 20 years after scientists revealed that mutations in the BRCA1 gene predispose women to breast cancer, Yale scientists have pinpointed the molecular mechanism that allows those mutations to wreak their havoc. The findings, reported online on October 4, 2017 in Nature, will not only help researchers design drugs to combat breast and ovarian cancers, but also help identify women who are at high risk of developing them, the authors say. The Nature article is titled “BRCA1–BARD1 Promotes RAD51-Mediated Homologous DNA Pairing.” "There have been about 14,000 papers written about BRCA1, and you would think we already know everything about the gene, but we don't," said senior author Dr. Patrick Sung, Professor of Molecular Biophysics and Biochemistry and of Therapeutic Radiology and member of the Yale Cancer Center. The discovery of BRCA1's role in DNA repair and suppression of tumors was the first evidence that the risk of cancer could be inherited. It was originally thought that mutations in BRCA1 and the related BRCA2 gene might account for 7% to 8% of breast and ovarian cancers, Dr. Sung said. However, the cancer risk is likely much higher because in many cancer cases the expression of the BRCA genes is silenced even though no mutation can be found, he added. Dr. Sung and colleagues showed in their Nature paper that the interaction of BRCA1 with its partner BARD1 is necessary to recruit the exact genetic sequence needed to repair breaks in DNA caused by endogenous stress and environmental insults such as radiation exposure. "Defining the mechanism of the BRCA-dependent DNA repair pathway will help scientists design drugs to kill cancer cells more efficiently," Dr. Sung said.

Gene Therapy Halts Progression of Cerebral Adrenoleukodystrophy (ALD) in Clinical Trial; Impact Has Been “Phenomenal” Physician States

In a recent clinical trial, a gene therapy to treat cerebral adrenoleukodystrophy (CALD) -- a neurodegenerative disease that typically claims young boys' lives within 10 years of diagnosis -- effectively stabilized the disease's progression in 88 percent of patients, researchers from the Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Massachusetts General Hospital report today. According to their results, published online on October 4, 2017 in the New England Journal of Medicine, 15 of 17 patients had stable neurologic functioning more than two years on average after receiving the gene therapy, which was administered in a clinical trial sponsored by bluebird bio. It is one of the largest gene therapy trials targeting a single-gene disease to be published to date. The NEJM article is titled “Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy.” "Although we need to continue to follow the patients to determine the long-term outcome of the gene therapy, so far it has effectively arrested the progress of cerebral adrenoleukodystrophy in these young boys," says David A. Williams, MD, Chief Scientific Officer and Senior Vice-President for Research at Boston Children's Hospital and President of Dana-Farber/Boston Children's Cancer and Blood Disorders Center and the lead author of the study. "This is a devastating disease, and we are all quite grateful that the patients and their families chose to participate in the trial." The treatment leverages Bluebird Bio's proprietary Lenti-D gene therapy to deliver the functional gene to patients' stem cells in the laboratory. "The clinical experience with Lenti-D demonstrates the potential for gene therapy to benefit patients with CALD," said David Davidson, MD, Chief Medical Officer of Bluebird Bio.

October 4th

Experiment of Nature: Regeneration of Beta Cells in Human Insulinomas Offers Clues to Molecular Pathways in Beta Cell Regeneration

Rare benign tumors known as insulinomas contain a complicated wiring diagram for regeneration of insulin-producing human beta cells, which may hold the key to diabetes drug development, researchers at the Icahn School of Medicine at Mount Sinai in New York report. The study, titled "Insights into Beta Cell Regeneration for Diabetes via Integration of Molecular Landscapes in Human Insulinomas," was published as an open-access article on October 3, 2017 in Nature Communications. With the help of an international group of investigators, the Mount Sinai team collected 38 human insulinomas -- rare pancreatic tumors that secrete too much insulin -- and analyzed their genomics and expression patterns. "For the first time, we have a genomic recipe -- an actual wiring diagram in molecular terms that demonstrates how beta cells replicate," said Andrew Stewart, MD, Director of the Diabetes, Obesity, and Metabolism Institute at the Icahn School of Medicine and lead author of the study. Approximately 30 million people living in the United States have diabetes and nearly 50 to 80 million are living with prediabetes. Diabetes occurs when there are not enough beta cells in the pancreas, or when those beta cells secrete too little insulin, the hormone required to keep blood sugar levels in the normal range. Diabetes can lead to major medical complications: heart attack, stroke, kidney failure, blindness, and limb amputation. Loss of insulin-producing beta cells has long been recognized as a cause of type 1 diabetes, in which the immune system mistakenly attacks and destroys beta cells. In recent years, researchers have concluded that a deficiency of functioning beta cells also contributes importantly to type 2 diabetes--the primary type that occurs in adults.

October 3rd

CRISPR-Gold Delivery Vehicle for CRISPR-Cas9 Fixes Duchenne Muscular Dystrophy Mutation in Mouse Model

Scientists at the University of California, Berkeley, have engineered a new way to deliver CRISPR-Cas9 gene-editing technology inside cells and have demonstrated in a mouse model that the technology can repair the mutation that causes Duchenne muscular dystrophy, a severe muscle-wasting disease. A new study shows that a single injection of CRISPR-Gold, as the new delivery system is called, into mice with Duchenne muscular dystrophy led to an 18-times-higher correction rate and a two-fold increase in a strength and agility test compared to control groups. Since 2012, when study co-author Dr. Jennifer Doudna, a Professor of Molecular and Cell Biology and of Chemistry at UC Berkeley, and colleague Emmanuelle Charpentier, of the Max Planck Institute for Infection Biology, repurposed the Cas9 protein to create a cheap, precise, and easy-to-use gene editor, researchers have hoped that therapies based on CRISPR-Cas9 would one day revolutionize the treatment of genetic diseases. Yet developing treatments for genetic diseases remains a big challenge in medicine. This is because most genetic diseases can be cured only if the disease-causing gene mutation is corrected back to the normal sequence, and this is impossible to do with conventional therapeutics. CRISPR/Cas9, however, can correct gene mutations by cutting the mutated DNA and triggering homology-directed DNA repair. However, strategies for safely delivering the necessary components (Cas9, guide RNA that directs Cas9 to a specific gene, and donor DNA) into cells need to be developed before the potential of CRISPR-Cas9-based therapeutics can be realized. A common technique to deliver CRISPR-Cas9 into cells employs viruses, but that technique has a number of complications. CRISPR-Gold does not need viruses.

Genetic Targets for Potential Reduction of the Development of Chemo-Resistance in Triple-Negative Breast Cancer Identified

Research led by Dr. Carlos Arteaga, Director of the Harold C. Simmons Comprehensive Cancer Center, has identified potential targets for treatment of triple negative breast cancer, the most aggressive form of breast cancer. Increased activity of two genes, MCL1 and MYC, is associated with the development of chemotherapy resistance. The increased action of these two genes boosts mitochondrial oxidative phosphorylation, which promotes the growth of chemotherapy-resistant cancer stem cells, the research showed. "Alterations in these two genes are easily detectable with tumor gene tests in current use. Combinations of drugs that inhibit MCL1 or MYC, or both, have the potential to reduce the development of chemotherapy resistance and should be studied in clinical trials," said Dr. Arteaga, Professor of Internal Medicine at UT Southwestern Medical Center. Dr. Arteaga holds The Lisa K. Simmons Distinguished Chair in Comprehensive Oncology. Most breast cancers can be treated with hormone therapy, but about 15 percent of cases are triple-negative breast cancer, meaning the cancer cells are not influenced by hormones like estrogen or progesterone. These triple-negative breast cancers must, therefore, be treated with chemotherapy, which is toxic to healthy cells as well as cancer cells. Furthermore, most triple negative breast cancers eventually become resistant to chemotherapy and the cancer then spreads unchecked. Drugs that inhibit activity of the MCL1 or MYC genes are in development, Dr. Arteaga said. These drugs, given in conjunction with standard chemotherapies, could potentially slow or even prevent the development of chemotherapy resistance, improving the outlook for this aggressive form of breast cancer.