One of the big mysteries in biology is why cells age. Now scientists at the Salk Institute for Biological Studies report that they have discovered a weakness in a component of brain cells that may explain how the aging process occurs in the brain. The scientists discovered that certain proteins, called extremely long-lived proteins (ELLPs), which are found on the surface of the nucleus of neurons, have a remarkably long lifespan. While the lifespan of most proteins totals two days or less, the Salk Institute researchers identified ELLPs in the rat brain that were as old as the organism, a finding they reported on February 2, 2012 in Science. The Salk scientists are the first to discover an essential intracellular machine whose components include proteins of this age. Their results suggest the proteins can last an entire lifetime, without being replaced. ELLPs make up the transport channels on the surface of the nucleus; gates that control what materials enter and exit. Their long lifespan might be an advantage if not for the wear-and-tear that these proteins experience over time. Unlike other proteins in the body, ELLPs are not replaced when they incur aberrant chemical modifications and other damage. Damage to the ELLPs weakens the ability of the three-dimensional transport channels that are composed of these proteins to safeguard the cell's nucleus from toxins, says Dr. Martin Hetzer, a professor in Salk's Molecular and Cell Biology Laboratory, who headed the research. These toxins may alter the cell's DNA and thereby the activity of genes, resulting in cellular aging. Funded by the Ellison Medical Foundation and the Glenn Foundation for Medical Research, Dr. Hetzer's research group is the only lab in the world that is investigating the role of these transport channels, called the nuclear pore complex (NPC), in the aging process.
Sequencing a patient’s entire genome to discover the source of his or her disease is not routine – yet. But geneticists are getting close. A case report, published February 2, 2012 in the American Journal of Human Genetics, shows how researchers can combine a simple blood test with an “executive summary” scan of the genome to diagnose a type of severe metabolic disease. Researchers at Emory University School of Medicine and Sanford-Burnham Medical Research Institute used “whole-exome sequencing” to find the mutations causing a glycosylation disorder in a boy born in 2004. Mutations in the gene (called DDOST) that is responsible for the boy’s disease had not been previously seen in other cases of glycosylation disorders. Whole-exome sequencing is a cheaper, faster, but still efficient strategy for reading the parts of the genome scientists believe are the most important for diagnosing disease. The report illustrates how whole-exome sequencing, which was first offered commercially for clinical diagnosis in 2011, is entering medical practice. Emory Genetics Laboratory is now gearing up to start offering whole-exome sequencing as a clinical diagnostic service. It is estimated that most disease-causing mutations (around 85 percent) are found within the regions of the genome that encode proteins, the workhorse machinery of the cell. Whole-exome sequencing reads only the parts of the human genome that encode proteins, leaving the other 99 percent of the genome unread. The boy in the case report was identified by Dr. Hudson Freeze and his colleagues. Dr. Freeze is director of the Genetic Disease Program at Sanford-Burnham Medical Research Institute. A team led by Dr. Madhuri Hegde, associate professor of human genetics at Emory University School of Medicine and director of the Emory Genetics Laboratory, identified the gene responsible.
Free-flowing cancer cells have been mapped with unprecedented accuracy in the bloodstream of patients with prostate, breast, and pancreatic cancer, using a brand-new approach, in an attempt to assess and control the disease as it spreads in real time through the body, and to solve the problem of predicting response and resistance to therapies. In comparison to a previous generation of systems, the researchers state their test showed a significantly greater number of high-definition circulating tumor cells (HD-CTCs), in a higher proportion of patients, by using a computing-intensive method that enables them to look at millions of normal cells and find the rare cancer cells among them. Their results, published on February 3, 2012, in Physical Biology, could help reveal the mechanisms behind the spread of solid tumours from one organ or tissue to another – mechanisms that have, until now, remained a mystery. Dr Jorge Nieva, an oncologist at Billings Clinic (Billings, Montana) leading the study, said: "This technology will allow scientists to move away from mouse and cell culture systems and speed the delivery of cures for cancer in people. This is the technology we have been waiting for to solve the problem of resistance to chemotherapy drugs." Senior technology author of the study, Professor Peter Kuhn, said: "In the future, our fluid biopsy can effectively become the companion to the patient for life. If we can assess the disease in real time, we can make quantitative treatment decisions in real time.
Small RNA-based nucleic acid drugs represent a promising new class of therapeutic agents for silencing abnormal or overactive disease-causing genes, and researchers have discovered new mechanisms by which RNA drugs can control gene activity. A comprehensive review article in Nucleic Acid Therapeutics, a peer-reviewed journal published by Mary Ann Liebert, Inc., details these advances. Short strands of nucleic acids, called small RNAs, can be used for targeted gene silencing, making them attractive drug candidates. These small RNAs block gene expression through multiple RNA interference (RNAi) pathways, including two newly discovered pathways in which small RNAs bind to Argonaute proteins or other forms of RNA present in the cell nucleus, such as long non-coding RNAs and pre-mRNA. Dr. Keith T. Gagnon and Dr. David R. Corey, University of Texas Southwestern Medical Center, in Dallas, Texas, review common features shared by RNAi pathways for controlling gene expression and focus in detail on the potential for Argonaute-RNA complexes in gene regulation and other exciting new options for targeting emerging forms of non-coding RNAs and pre-mRNAs in the review. "The field of RNA-mediated control of gene expression is rapidly evolving and the article by Gagnon and Corey provides a highly informative and up-to-date review of this exciting and often surprising area of biomedical research. We are delighted to publish this important review for the field," says Co-Editor-in-Chief Dr. Bruce A. Sullenger, Duke Translational Research Institute, Duke University Medical Center, Durham, North Carolina. [Press release] [Nucleic Acid Therapeutics artcle]
For decades, researchers have debated whether Alzheimer’s disease starts independently in vulnerable brain regions at different times, or if it begins in one region and then spreads to neuroanatomically connected areas. A new study by Columbia University Medical Center (CUMC) researchers strongly supports the latter, demonstrating that abnormal tau protein, a key feature of the neurofibrillary tangles seen in the brains of those with Alzheimer’s, propagates along linked brain circuits, “jumping” from neuron to neuron. The findings, published February 1, 2012 in the online journal PloS One, open new opportunities for gaining a greater understanding of Alzheimer’s disease and other neurological diseases and for developing therapies to halt its progression, according to senior author Dr. Karen E. Duff, professor of pathology (in psychiatry and in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain) at CUMC and at the New York State Psychiatric Institute. Alzheimer’s disease, the most common form of dementia, is characterized by the accumulation of plaques (composed of amyloid-beta protein) and fibrous tangles (composed of abnormal tau protein) in brain cells called neurons. Postmortem studies of human brains and neuroimaging studies have suggested that the disease, especially the neurofibrillary tangle pathology, begins in the entorhinal cortex, which plays a key role in memory. Then, as Alzheimer’s progresses, the disease appears in anatomically linked higher brain regions. “Earlier research, including functional MRI studies in humans, have also supported this pattern of spread,” said study coauthor Dr. Scott A. Small, professor of neurology in the Sergievsky Center and in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at CUMC.
Researchers at the University of Dundee in the UK have identified fexinidazole as a possible, much-needed, new treatment for the parasitic disease visceral leishmaniasis. Leishmaniasis is named after William Leishman, a Glasgwegian doctor who served with the British Army in India, and who first identified the parasite in the early 1900s. The disease is the second biggest killer in Africa, Asia, and Latin America after malaria, and affects 500,000 people, killing about 50,000-60,000 patients per year. Current drug treatments for the disease are unsatisfactory for reasons such as high cost, drug resistance, or the need for hospitalization. The disease is caused by the bite of a sand fly. Fexinidazole is already in phase 1 clinical trials for a related disease - African sleeping sickness – but a research team at Dundee, including Dr. Susan Wyllie, Professor Alan Fairlamb, and colleagues, has identified it as having potential in treating leishmaniasis. Their research was published February 1, 2012 in Science Translational Medicine, and was funded by the Wellcome Trust. Tests in mice showed that the drug has a greater than 98% rate of suppressing infection of leishmaniasis, comparable to current treatments such as miltefosine and Pentostam. These and other existing treatment options all suffer from disadvantages; they are not always safe, effective, or easy to administer. The only oral drug, miltefosine, cannot be given to women of child-bearing age due to a substantial risk of birth defects; other drugs are costly and have to be given by injection. Thus, there is a continuing need for safe and cost-effective drugs suitable for use in resource-poor settings. Professor Fairlamb said that fexinidazole has the potential to become a safe and effective oral drug therapy for treating the severest form of visceral leishmaniasis.
On January 31, 2012, the U.S. Food and Drug Administration approved Kalydeco (ivacaftor) for the treatment of a rare form of cystic fibrosis (CF) in patients ages 6 years and older who have the specific G551D mutation in the cystic fibrosis transmembrane regulator (CFTR) gene. This represents a breakthrough in the field of personalized medicine. CF is a serious genetic disorder affecting the lungs and other organs that ultimately leads to an early death. It is caused by mutations in a gene that encodes the protein CFTR that regulates ion (such as chloride) and water transport in the body. The defect in chloride and water transport results in the formation of thick mucus that builds up in the lungs, digestive tract, and other parts of the body leading to severe respiratory and digestive problems, as well as other complications such as infections and diabetes. CF, which affects about 30,000 people in the United States, is the most common fatal genetic disease in the Caucasian population. About 4 percent of those with CF, or roughly 1,200 people, are believed to have the G551D mutation. “Kalydeco is an excellent example of the promise of personalized medicine – targeted drugs that treat patients with a specific genetic makeup,” said FDA Commissioner Dr. Margaret A. Hamburg. “The unique and mutually beneficial partnership that led to the approval of Kalydeco serves as a great model for what companies and patient groups can achieve if they collaborate on drug development.” The FDA reviewed and approved Kalydeco in approximately three months under the agency’s priority review program that is designed to expedite the review of drugs. The priority review program uses a six-month review, instead of the standard 10 months, for drugs that may offer significant advances in treatment over available therapy.
Researchers in Lille and Paris have demonstrated that mutations in the melatonin receptor gene (melatonin or the "hormone of darkness" induces sleep) lead to an almost seven-fold increase in the risk of developing type 2 diabetes. This research, which was published online in Nature Genetics on January 29, 2012, could contribute to the development of new drugs for the treatment or prevention of this metabolic disease. Type 2 diabetes is characterized by excess blood glucose and increased resistance to insulin. It is the most common form of the disease and affects 300 million people in the world, including 3 million in France. This figure should double in the next few years, driven by the obesity epidemic and the disappearance of ancestral lifestyles. It is known that genetic factors, combined with a high-fat, high-sugar diet and lack of exercise, can also contribute to the onset of the disease. Furthermore, several studies have shown that sleeping disorders that affect the duration and quality of sleep are also high risk factors. Shift workers, for example, are at greater risk of developing the disease. No previous research has described any mechanism linking the biological clock to diabetes. The researchers focused their attention on the receptor of a hormone called melatonin, which is produced by the pineal gland as light fades. Melatonin, also known as the hormone of darkness, can be seen as a biological "time-keeper," synchronizing biological rhythms with nightfall. The research teams sequenced the MT2 gene, which encodes a melatonin receptor, in 7,600 diabetics and persons with normal glycemia. They found 40 rare mutations that modify the protein structure of the MT2 melatonin receptor, 14 of which made the receptor in question non-functional.
Researchers studying a rare, lethal childhood tumor of the brainstem discovered that nearly 80 percent of the tumors have mutations in genes not previously tied to cancer. Early evidence suggests the alterations play a unique role in other aggressive pediatric brain tumors as well. The findings from the St. Jude Children's Research Hospital – Washington University Pediatric Cancer Genome Project (PCGP) offer important insight into a poorly understood tumor that kills more than 90 percent of affected patients within two years. The tumor, diffuse intrinsic pontine glioma (DIPG), is found almost exclusively in children and accounts for 10 to 15 percent of pediatric tumors of the brain and central nervous system. "We are hopeful that identifying these mutations will lead us to new selective therapeutic targets, which are particularly important since this tumor cannot be treated surgically and still lacks effective therapies," said Dr. Suzanne Baker, co-leader of the St. Jude Neurobiology and Brain Tumor Program and a member of the St. Jude Department of Developmental Neurobiology. She is a corresponding author of the study published in the January 29, 2012 online edition of Nature Genetics. DIPG is an extremely invasive tumor that occurs in the brainstem, which is at the base of the skull and controls such vital functions as breathing and heart rate. DIPG cannot be cured by surgery and is accurately diagnosed by non-invasive imaging. As a result, DIPG is rarely biopsied in the U.S. and little is known about it. Cancer occurs when normal gene activity is disrupted, allowing for the unchecked cell growth and spread that makes cancer so lethal.
An international research team led by the Research Institute of the McGill University Health Centre (RI MUHC) in Montreal, Canada has made a major genetic breakthrough that could change the way pediatric cancers are treated in the future. The researchers identified two genetic mutations responsible for up to 40 per cent of glioblastomas in children - a fatal cancer of the brain that is unresponsive to chemotherapy and radiotherapy treatment. The mutations were found to be involved in DNA regulation, which could explain the resistance to traditional treatments, and may have significant implications on the treatment of other cancers. The study was published online on January 29, 2012 in Nature. Another article, by a different research team, independently reported related findings online on January 29, 2012 in Nature Genetics (see separate article in BioQuick News, “Histone Mutations Associated with Aggressive Childhood Brain Tumors”). Using the knowledge and advanced technology of the team from the McGill University and Génome Québec Innovation Centre, the researchers identified two mutations in an important gene known as the histone H3.3 gene. This gene, one of the guardians of our genetic heritage, is key to modulating the expression of our genes. "These mutations prevent the cells from differentiating normally and help protect the genetic information of the tumor, making it less sensitive to radiotherapy and chemotherapy," says Dr. Nada Jabado, hematologist-oncologist at The Montreal Children's Hospital of the MUHC and principal investigator of the study. "This research helps explain the ineffectiveness of conventional treatments against cancer in children and adolescents – we've been failing to hit the right spot," says Dr. Jabado, who is also an Associate Professor of Pediatrics at McGill University.
