Author Interviews, Genetic Research / 26.01.2015

MedicalResearch.com Interview with: Joao Pedro de Magalhaes, PhD Institute of Integrative Biology Biosciences Building, Room 245 University of Liverpool UK Integrative Genomics of Ageing Group: http://pcwww.liv.ac.uk/~aging/ Medical Research: What is the background for this study? What are the main findings? Response: Our understanding of species differences in longevity (e.g., why can mice not live more than 5 years or dogs more than 30, yet bats can live over 40 years, humans over a century and bowheads over two centuries) is very poor and thus our findings provide novel candidate genes and mechanisms for future studies. The candidate genes we found with evidence of bowhead-specific functions may play a role in the exceptional longevity and disease resistance of these animals. In particular, we discovered changes in bowhead genes related to cell cycle, DNA repair, cancer, and aging that suggest alterations that may be biologically-relevant.  So my own view is that this points toward improved DNA repair and cell cycle regulation mechanisms to prevent DNA damage accumulation during the lifescourse which in turn promotes longevity and resistance to age-related diseases like cancer. (more…)
Author Interviews, Genetic Research, Melanoma, Nature / 25.01.2015

MedicalResearch.com Interview with: Prof Lukas Sommer. Ph.D. Cell and Developmental Biology University of Zurich Institute of Anatomy Zurich Switzerland MedicalResearch: What is the background for this study? What are the main findings? Prof. Lukas Sommer:   Melanoma, the most aggressive of all skin cancers, is often fatal for patients due to the pronounced formation of metastases. Up to date, a melanoma’s rampant growth was mainly attributed to genetic causes, such as mutations in certain genes. However, we now reveal that so-called epigenetic factors also play a crucial role in the formation of metastases in malignant skin cancer. Epigenetic factors do not influence the gene sequence directly, but rather cause certain genes and chromosomal segments to be packed in different densities – and thus make them accessible for reading. In our study we identified “EZH2” as an epigenetic control protein found very frequently in malignant melanoma cells compared to normal cells. In these cells, “EZH2” controls genes that govern both tumor growth and genes that are important for the formation of metastases. We exploited this central position of EZH2 to combat the cancer by using a pharmacological inhibitor to suppress the activity of EZH2. As a result, we were able to prevent the growth and malignant spread of the cancer in an animal model and in human melanoma cells. (more…)
Author Interviews, Genetic Research, Mental Health Research, Scripps / 25.01.2015

Dr. Gavin Rumbaug Professor (Associate) The Scripps Research InstituteMedicalResearch.com Interview with: Gavin Rumbaug Professor (Associate) The Scripps Research Institute Medical Research: What is the background for this study? What are the main findings? Response: We have developed a genetic approach that protects animal models against a type of genetic disruption that causes intellectual disability, including serious memory impairments and altered anxiety levels. The findings focus on treating the effects of mutations to a gene known as Syngap1. In our new study, we examined the effect of damaging Syngap1 mutations during development and found that the mutations disrupt a critical period of neuronal growth—a period between the first and third postnatal weeks in mouse models. We found that a certain type of cortical neuron grows too quickly in early development, which then leads to the premature formation of certain types of neural circuits. These findings help explain why genetic treatments in adult mice are not very effective. (more…)
Author Interviews, Genetic Research, JAMA, Ophthalmology / 21.01.2015

Prof. David Mackey Centre for Ophthalmology and Vision Science/Lions Eye Institute Perth Managing Director/Chair of University of Western Australia, Perth, Australia Centre for Eye Research Australia, Melbourne UniversityMedicalResearch.com Interview with: Prof. David Mackey Centre for Ophthalmology and Vision Science/Lions Eye Institute Perth Managing Director/Chair of University of Western Australia, Perth, Australia Centre for Eye Research Australia, Melbourne University MedicalResearch: What is the background for this study? What are the main findings? Prof. Mackey: Too much or too little sun? Excessive sun exposure is associated with the eye disease pterygium, while lack of outdoor activity in childhood increases the risk of myopia (short sightedness). Measuring the amount of early sun damage to a person’s eyes would be of great use to researchers and potential use in clinical practice. Over the last few years we have developed a biomarker for sun exposure to the eye by photographing Conjunctival UV Auto-Fluorescence (CUVAF). The study published in JAMA Ophthalmology looked at the genetic and environmental factors that contribute to CUVAF levels in three Australian studies from Tasmania, Perth and Brisbane. People who live in sunnier environments closer to the equator have more evidence of sun damage using CUVAF.  However, genetic factors also play a role. (more…)
AHA Journals, Author Interviews, Genetic Research, Heart Disease, Lipids / 15.01.2015

Jean-Claude Tardif MD Professor of Medicine Director of the Research Centre Montreal Heart Institute Montreal, Quebec CanadaMedicalResearch.com Interview with: Jean-Claude Tardif MD Professor of Medicine Director of the Research Centre Montreal Heart Institute Montreal, Quebec Canada MedicalResearch.com: What is the background for this study? What are the main findings? Dr. Tardif: Epidemiological and mechanistic studies have suggested that high-density lipoproteins (HDL) could have beneficial cardiovascular properties. However, several medications targeting HDL have failed in recent clinical trials, including the CETP inhibitor dalcetrapib in the dal-Outcomes trial. We hypothesized that dalcetrapib would be beneficial in the subset of patients with the appropriate genetic profile. We conducted the pharmacogenomic analysis of approximately 6000 patients from the dal-Outcomes study which showed that patients with the AA genotype at a specific genetic location (rs1967309) of the adenylate cyclase (ADCY9) gene benefited from a 39% reduction in cardiovascular events including cardiovascular death, myocardial infarction, stroke, unstable angina and the need for coronary revascularization when treated with dalcetrapib compared to placebo. In contrast, patients with the GG genotype had a 27% increase in cardiovascular events. We then obtained confirmatory evidence from the dal-Plaque-2 imaging study which revealed that patients with the protective genotype (AA) had a reduction in their carotid artery wall thickness and that those with the genotype associated with clinical harm (GG) had an increase in their wall thickness. (more…)
Author Interviews, Genetic Research, PTSD, UCLA / 15.01.2015

Armen K. Goenjian, M.D., L.D.F.A.P.A., F.A.C.G.S. Research Professor of Psychiatry Department of Psychiatry and Biobehavioral Sciences David Geffen School of Medicine at UCLAMedicalResearch.com Interview with: Armen K. Goenjian, M.D., L.D.F.A.P.A., F.A.C.G.S. Research Professor of Psychiatry Department of Psychiatry and Biobehavioral Sciences David Geffen School of Medicine at UCLA Medical Research: What is the background for this study? Response: Post-traumatic stress disorder (PTSD) is a psychiatric disorder that develops after exposure to a traumatic event such as rape, war, natural disaster, and accident. Symptoms include recurrent intrusive traumatic memories, flashbacks, nightmares, hyper-vigilance, jumpiness, and anxiety. Dopaminergic and serotonergic systems have been implicated in PTSD. Catechol-O-methyltransferase (COMT) is an enzyme that degrades dopamine, an important brain neuro-hormone that regulates human behavior, thoughts and emotions.  Tryptophan hydroxylase is the rate limiting step in the synthesis of serotonin, another important neuro-hormone that regulates arousal, sleep, anxiety, and mood. This study evaluated the association of four COMT gene loci, and the joint effect of COMT and tryptophan hydroxylase 2 (TPH-2) genes on PTSD symptoms. (more…)
Author Interviews, BMC, Genetic Research, Heart Disease, Pharmacology / 12.01.2015

Caroline Attardo Genco, PhD Professor Department of Medicine, Section of Infectious Diseases Department of Microbiology Boston University School of Medicine Boston MA 02118MedicalResearch.com Interview with: Caroline Attardo Genco, PhD Professor Department of Medicine, Section of Infectious Diseases Department of Microbiology Boston University School of Medicine Boston MA MedicalResearch: What is the background for this study? What are the main findings? Dr. Genco: Atherosclerosis is a common cardiovascular disease associated with heart attack and stroke. Although it has been shown that a diet high in fat as well as exposure to certain bacteria can cause atherosclerosis (the buildup of fats, cholesterol, and other substances on artery walls which can restrict blood flow), we have for the first time identified distinct gene pathways that are altered by these different stimuli. One of these bacteria, Porphyromonas gingivalis, is found in the mouth of humans with periodontal disease. Another is the bacteria Chlamydia pneumoniae, which causes pneumonia. We found that even though these three different stimuli all cause atherosclerosis, the gene pathways are distinct depending upon stimulus. This is the first study that has performed side-by-side comparison of genome-wide gene expression changes to address this issue. In this study, we used four experimental groups to compare genome-wide expression changes in vascular tissue. The first group was subjected to Porphyromonas gingivalis, while the second group received Chlamydia pneumoniae. The third group was placed on a high-fat Western style diet, while the fourth group was the control group. In collaboration with the Clinical and Translational Science Institute (CTSI) at Boston University, we performed genome-wide microarray profiling and analysis of vascular tissue from all groups to reveal gene pathways altered in vascular tissue by each treatment group. These findings may explain how specific infections or high-fat diet may cause atherosclerotic plaques to undergo changes that affect their size and stability and may ultimately lead to a heart attack. (more…)
Author Interviews, Breast Cancer, Genetic Research, Nature / 11.01.2015

MedicalResearch.com Interview with: Dr. Pentao Liu PhD and Dr. Walid Khaled PhD Wellcome Trust Sanger Institute Cambridgeshire United Kingdom Medical Research: What is the background for this study? What are the main findings? Dr. Pentao Liu: The significance of this research is that it aims to tackle the worst type of breast cancer. Triple Negative Breast Cancer (TNBC) has the poorest patient survival rate compared to other forms of breast cancer.  At present there are no targeted therapies available for TNBC, leaving the non-specific chemotherapy as the only treatment option. In this study we identify a new key gene in  Triple Negative Breast Cancer which could potentially be inhibited for the targeted treatment of TNBC. In this study we report the identification of a novel gene for Triple Negative Breast Cancer. By analyzing genomics data from 3,000 patients we find BCL11A to be highly expressed in TNBC. We then demonstrate experimentally that upregulation of BCL11A drives tumour development while its downregulation leads to reduction in tumour size. In the experimental mouse model, inactivation of this gene completely abolishes breast tumour development. (more…)
Author Interviews, Breast Cancer, Genetic Research / 10.01.2015

Dr. Chao Cheng PhD Department of Genetics Geisel School of Medicine at Dartmouth Hanover 03755, NHMedicalResearch.com Interview with: Dr. Chao Cheng PhD Department of Genetics Geisel School of Medicine at Dartmouth Hanover 03755, NH   MedicalResearch: What is the background for this study? What are the main findings? Dr. Chao Cheng: Cancer survival prognosis—“How long do I have, Dr.?” is a topic of great importance to cancer patients and their families. While clinical and pathological variables, such as cancer type, stage, grade, and patient demographics, have long been used to predict survival outcomes, only recently have molecular signatures become incorporated into survival prediction. A molecular approach holds great promise for improving prediction accuracy and additionally elucidating mechanisms of disease, however it is fraught with difficulty due to assay “noise” and “big data” statistical issues, such as the multiple comparisons problem In this study, we began by analyzing transcription factor binding profiles across available cell lines. By restricting our analysis to transcription factors, DNA expression regulators known to be involved in tumor genesis, we reasoned that we could avoid many of the “big data” issues and achieve results that would make mechanistic and biological sense. We first employed a statistical method we described previously to calculate which genes were the major downstream targets of our transcription factors. With these targets identified, we then analyzed gene expression data using a bioinformatics method to infer the relative activity of each transcription factor based upon the overall expression levels of their gene targets. From here, we incorporated cancer survival data and examined how each transcription factor’s regulatory activity did, or did not, correlate with survival. The most prognostic transcription factor was E2F4, a member of the E2F family and a known regulator of the cell cycle. We therefore restricted our analysis to E2F4 and examined how its activity level impacted survival in breast cancer patients. We found that tumors with high E2F4 regulatory activity as compared to low E2F4 regulatory activity had much worse survival outcomes. These results were stable even after controlling for tumor stage, grade, patient age, and treatment, and were based on data from over 1900 patients across eight independent datasets. These results demonstrate that E2F4 is an independent and enhancing predictor of survival above the currently examined variables. (more…)
Author Interviews, Case Western, Genetic Research / 05.01.2015

Michael A. Weiss, MD, PhD The Cowan-Blum Professor and Chairman of the Department of Biochemistry Distinguished Research Professor andMedicalResearch.com Interview with: Michael A. Weiss, MD, PhD The Cowan-Blum Professor and Chairman of the Department of Biochemistry Distinguished Research Professor and Professor of Medicine in the Endocrine Division at the Case Western Reserve School of Medicine in Cleveland, Ohio. Joseph Racca Researcher and graduate student Department of BiochemistryJoseph Racca Researcher and graduate student Department of Biochemistry Case Western Reserve School of Medicine in Cleveland, Ohio. Medical Research: What is the background for this study? What are the main findings? Response: The function of the gene responsible for male differentiation, sex-determining region of the Y chromosome (SRY), was first demonstrated in transgenic mouse models by P. Koopman, R. Lovell-Badge and colleagues in the early 1990s. These findings were corroborated by identification of mutations in human SRY that are associated with human sex reversal: XY, 46 gonadal dysgenesis leading to somatic sex reversal (Swyer’s Syndrome). Such mutations may occur spontaneously in spermatogenesis or be inherited. The characterization of the molecular defects associated with these mutations has unmasked novel biological and biochemical activities of SRY. More broadly, such studies have also increased our understanding of an entire family of related transcription factors (Sry-box related; SOX), which broadly function in metazoan development (from worms, fish and flies to mammals). Within human SRY, the majority of clinical mutations occur in the region of the protein responsible for specific DNA binding and DNA bending, the primary molecular actions of SRY at target genes. Our study bridges structure (i.e., protein folding and stability) and function (i.e., transcriptional activation of target genes and related cell-biological processes such as trafficking and proteosomal degradation). In our current study, we highlighted the importance of a structural scaffold in human SRY, specifically a key single amino acid that buttresses the unique L-shape structure of this domain. The mutation of interest represents a “perfect storm” leading to deleterious effects on multiple activities, including specific DNA binding, cellular localization, and both protein and cellular stability (lifetime), among other properties, together leading to sex reversal and cancer (gonadoblastoma) in the proband patient. Our integrated multi-disciplinary approach allowed us to characterize these various facets of SRY in the context of its biological site of action: the pre-Sertoli cell in an embryonic gonadal ridge just prior to its morphological differentiation into a testis. We are grateful to Prof. Patricia K. Donahoe (Harvard Medical School and the Massachusetts General Hospital), who generously provided this micro-dissected pre-Sertoli cell line. (more…)
Author Interviews, Genetic Research, Neurological Disorders, PNAS, Scripps / 26.12.2014

Elizabeth A. Thomas, Ph.D. Associate Professor Department of Molecular and Cellular Neuroscience The Scripps Research InstituteMedicalResearch.com Interview with: Elizabeth A. Thomas, Ph.D. Associate Professor Department of Molecular and Cellular Neuroscience The Scripps Research Institute   Medical Research: What is the background for this study? What are the main findings? Response: Increasing evidence has demonstrated that epigenetic factors can profoundly influence gene expression, and in turn, influence resistance or susceptibility to disease.  Epigenetic drugs, such as histone deacetylase (HDAC) inhibitors, are finding their way into clinical practice, and are being proposed for therapeutic use in several neurological disorders.  Our previous studies have shown that selective HDAC inhibitors can cause beneficial effects in mouse models of Huntington’s disease, improving symptoms, and reducing severity of the disease.  Our current studies show that one such compound can alter DNA methylation, an epigenetic mark that can be inherited, leading to changes in gene expression that are seen in the parent mouse exposed directly to the drug, as well as in offspring from the drug-treated male mice.  Concurrent with these changes, we observed that offspring from drug-treated males shown improved disease symptoms, showing a delay in disease onset and a reduction of motor and cognitive symptoms that included improved performance in tests of balance, speed and memory. These finding have significant implications for human health as they enforce the concept that ancestral drug exposure may be a major molecular factor that can affect disease outcome in a subsequent generation.  One exciting aspect of our study is that the parental drug treatment made the offspring better, not worse, like other compounds known to cause transgenerational effects. (more…)
Author Interviews, Cognitive Issues, Genetic Research, JAMA / 13.12.2014

David H. Ledbetter, Ph.D., FACMG Executive Vice President & Chief Scientific Officer, Geisinger Health System Danville, PA 17822MedicalResearch.com Interview with: David H. Ledbetter, Ph.D., FACMG Executive Vice President & Chief Scientific Officer, Geisinger Health System Danville, PA 17822 Medical Research: What is the background for this study? What are the main findings? Dr. Ledbetter: One of the biggest challenges in clinical care and research of children with autism and related neurodevelopment disorders is the remarkable clinical variability between individuals. This heterogeneity is reduced, but still significant, when considering individuals who have neurodevelopment disorders due to the identical genetic mutation such as deletion 16p11.2. We proposed that family background, genetic or environmental, may contribute to the variability in cognitive, behavioral and motor performance profiles of children with a sporadic (new) mutation in 16p11.2. Our study confirmed that a significant portion of the clinical variability seen in these children is due to the performance level of their parents and unaffected siblings and suggested that this may be due in part to genetic background effects as these traits are all known to have very high heritability. (more…)
Author Interviews, Genetic Research, NEJM, NIH / 13.12.2014

Dr. Constantine A. Stratakis, M.D., D.Sc National Institutes of Health, Clinical Research Center Bethesda, MD 20892-1862MedicalResearch.com Interview with: Dr. Constantine A. Stratakis, M.D., D.Sc National Institutes of Health, Clinical Research Center Bethesda, MD 20892-1862 Medical Research: What is the background for this study? What are the main findings? Dr. Stratakis: We have been working for years on the genetics of pituitary tumors in association with other conditions. A few years ago (attached), we studied for the first time a series of pediatric giants that we sequenced for then known genes. We found a few MEN1 and AIP mutations but all mutations were present in older kids with gigantism. This left out the youngest among the giants without any genetic defect. This was the first time I realized that I was dealing with a different disease. We started looking for additional genetic defects and when we found the Xq26 microduplications in 3 kindreds. We contacted the custodians of the largest series in the world - Dr. Beckers in Liege. He screened his cases, once we gave him the coordinates, and boom - it was there... The most significant thing here is that this is a new disease really: the early pediatric gigantism is almost exclusively due to Xq26 microduplications unless it is part of a family with another syndrome (AIP, MEN1, Carney complex). If there is no family history and you are dealing with a toddler with gigantism, based in these data, there is a more than 80% chance of having an Xq26 defect. This is pretty amazing! In addition, assuming that GPR101 is the responsible gene (which needs to be confirmed with additional studies) this identifies a new molecular pathway of increasing growth hormone secretion, most likely due to upregulation of GHRH - all of this needs to be confirmed in further human and animal studies. The Xq26 genomic micro-arrangements (which contain the GPR101, but also 3 other genes) is the big news here... (more…)
Author Interviews, Genetic Research, Memory / 09.12.2014

Sandra Barral Rodriguez, Ph.D Assistant Professor G. H. Sergievsky Center & Taub Institute Columbia University Medical Center New York, NY 10032MedicalResearch.com Interview with: Sandra Barral Rodriguez, Ph.D Assistant Professor G. H. Sergievsky Center & Taub Institute Columbia University Medical Center New York, NY 10032 Medical Research: What is the background for this study? What are the main findings? Dr. Barral: We already know that there is a substantial genetic contribution to the variability observed in different cognitive tasks including memory performance. Previous work reported heritability estimates for episodic memory ranging between 30% and 60%. However, we can’t fully explain why some individuals demonstrate a better memory performance in late life, while others do not. We have previously defined a cognitive endophenotype based on exceptional episodic memory performance (EEM) and demonstrated that there is a familial aggregation of EEM in families selected on their basis of their exceptional survival, the Long Life Family Study. We performed genome-wide linkage analysis of long-lived families selected on the basis of their exceptional episodic memory and the follow-up SNP association analysis with episodic memory in four independent cohorts of more than 4,000 non-demented elderly cohorts. Our results provide strong evidence for potential candidate genes related to exceptional episodic memory on 6q24. (more…)
Author Interviews, General Medicine, Genetic Research, Nature / 03.12.2014

Prof Dr Isabelle Mansuy Lab of Neuroepigenetics University/ETH Zürich Brain Research Institute Zürich, SwitzerlandMedicalResearch Interview with: Prof Dr Isabelle Mansuy Lab of Neuroepigenetics University/ETH Zürich Brain Research Institute Zürich, Switzerland   MedicalResearch: What is the background for this study? What are the main findings? Prof. Mansuy: It is recognised that being exposed to traumatic stress in early life increases the susceptibility to psychiatric and metabolic diseases later in life. This is true for people directly exposed but also for their progeny across generations. It is also known that sometimes, stress exposure in early life can help an individual develop response strategies and be better prepared for later stressful experiences. The mechanisms of such beneficial effects and the question of whether they can be transmitted or not are not known. This study in mice was designed to answer these questions. The main findings are that exposure to traumatic stress of mouse newborns makes the animals and their progeny more efficient in challenging tasks when adult. For instance, they are more able to adapt to rules that change in a complex task to get a water ration when they are thirsty. This suggests more adaptive behaviours in challenging situations that are transmitted across generation. The study identifies the mineralocorticoid receptor, a stress hormone receptor in the brain, as an important molecular mediator of this effect and demonstrates that its expression is altered in the brain by epigenetic mechanisms. (more…)
Allergies, Author Interviews, Genetic Research / 28.11.2014

Dr. Hakon Hakonarson MD PhD The Center for Applied Genomics, The Children’s Hospital of Philadelphia Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania Philadelphia, Philadelphia, PennsylvaniaMedicalResearch.com Interview with: Dr. Hakon Hakonarson MD PhD The Center for Applied Genomics, The Children’s Hospital of Philadelphia Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania Philadelphia, Philadelphia, Pennsylvania Medical Research: What is the background for this study? What are the main findings? Dr. Hakonarson: We have built the world’s largest pediatric biobank at the Center for Applied Genomics at CHOP. Eosinophilic esophagitis (EoE) is among the projects we have sampled in collaboration with the EoE Center in collaboration with Dr. Spergel. We have nearly 1,000 samples now of this relatively rare disorder, which is now well powered for GWAS.  We previously  reported association of the TSLP locus with Eosinophilic esophagitis. Here we report genome-wide significant associations at four additional loci; c11orf30 and STAT6, which have been previously associated with both atopic and autoimmune diseases, and two EoE-specific loci, ANKRD27 that regulates the trafficking of melanogenic enzymes to epidermal melanocytes and CAPN14, that encodes a calpain whose expression is highly enriched in the esophagus in EoE.  This discovery not only improves our understanding of the pathobiology of  EoE, but also represents novel targets for the development of new therapies to treat the disease. (more…)
Author Interviews, BMJ, Genetic Research, Vitamin D / 19.11.2014

MedicalResearch.com Interview with: Børge G Nordestgaard, MD, DMSc Professor, University of Copenhagen Chief Physician, Herlev Hospital, Copenhagen University Hospital Dept. Clinical Biochemistry Herlev Ringvej Herlev, Denmark Medical Research: What is the background for this study? What are the main findings? Prof. Nordestgaard: Many people take vitamin D supplements with the hope of reducing morbidity and mortality. However, it is unclear whether low vitamin D per se is a direct cause of increased mortality or whether it is simply a marker of poor lifestyle in general and/or underlying hidden disease. Our study involved 95,766 white participants of Danish descent from three cohorts in Copenhagen, who had genetic variants known to affect vitamin D levels. We found that genetically low vitamin D levels were associated with increased all-cause mortality, cancer mortality, and other mortality, but not with cardiovascular mortality. This is important as such genetics studies cannot be explained by poor lifestyle or hidden disease, as neither can change your genes. (more…)
Author Interviews, Genetic Research, Nature, NYU / 06.11.2014

Leslie Mitchell, PhD New York University Langone Medical Center Boeke Lab, Institute for Systems Genetics NY NY, 10016MedicalResearch.com Interview with: Leslie Mitchell, PhD New York University Langone Medical Center Boeke Lab, Institute for Systems Genetics NY NY, 10016 Medical Research: What is the background for this study? What are the main findings? Dr. Mitchell: One of our major interests is building synthetic chromosomes. Typically we construct synthetic chromosomes using a bottom-up approach, first designing the sequence in silico and then synthesizing and piecing together the DNA to build the designer molecule. While eukaryotic chromosomes are usually linear in structure, oftentimes we build our designer synthetic chromosomes as circular molecules to take advantage of cloning technologies available in E. coli, an organism that tolerates only circular chromosomes. We developed the telomerator as a means by which to convert circular synthetic chromosomes into linear molecules, which more closely resemble the native chromosomes found in eukaryotic cells. We discovered that the telomerator is an extremely effective tool for generating linear derivatives of circular synthetic chromosomes. There are two main reasons for this.
  • First, the action of the telomerator can be assessed using a simple phenotypic assay so it is easy to differentiate cells that encode linear synthetic chromosomes from those with the circular format.
  • Second, the telomerator encodes ‘telomere seed sequences’ that are exposed and recognized by the cell upon linearization, thus the ends of a newly linearized chromosome are protected, which ensures its stability over generations. We put the telomerator to the test by integrating it in 54 different positions on a circular synthetic yeast chromosome called synIXR (Dymond et al. 2011). In 51 of the 54 positions we could successfully linearize the synIXR chromosome and recover viable cells, however many of the different linear derivatives conferred growth defects. We determined the mechanism underlying both the growth defects and lethality associated with linearization to be telomere position effect. In other words, when essential genes were re-positioned near telomeres their reduction in expression due to subtelomeric silencing was detrimental to the cell.
(more…)
Alcohol, Author Interviews, Genetic Research / 05.11.2014

Victor M. Karpyak, M.D., Ph.D.  Medical Director, Intensive Addiction Treatment Program Director, Mayo Clinic Addiction Services Consultant, Department of Psychiatry and Psychology  Assistant Professor of Psychiatry Mayo Clinic College of Medicine MedicalResearch.com Interview with: Victor M. Karpyak, M.D., Ph.D.  Medical Director, Intensive Addiction Treatment Program Director, Mayo Clinic Addiction Services Consultant, Department of Psychiatry and Psychology Assistant Professor of Psychiatry  Mayo Clinic College of Medicine Medical Research: What is the background for this study? Dr. Karpyak: The staggering costs of alcohol use disorders call for the development and implementation of evidence-based treatment strategies. Several medications (acamprosate, naltrexone, and disulfiram) were approved for treatment of alcohol use disorders; yet, only a fraction of patients respond to each medication. Clearly, response predictors are needed to improve treatment efficacy and personalize recommendations for treatment selection. It is expected that pharmacogenomic research will aid the discovery of such predictors. (more…)
Author Interviews, Genetic Research, Infections / 25.10.2014

Dr R.E.W. (Bob) Hancock, OC, OBC, FRSC {Canada Research Chair and Professor, Department of Microbiology and Immunology,UBC} Director, Centre for Microbial Diseases and Immunity Research University of British Columbia, Vancouver, British Columbia,  CanadaMedicalResearch.com Interview with: Dr R.E.W. (Bob) Hancock, OC, OBC, FRSC {Canada Research Chair and Professor, Department of Microbiology and Immunology,UBC} Director, Centre for Microbial Diseases and Immunity Research University of British Columbia, Vancouver, British Columbia,  Canada MedicalResearch: What is the background for this study? What are the main findings? Dr. Hancock: We wanted to understand how patients transitioned from the hyperinflammatory phase (cytokine storm) of sepsis to the hypoinflammatory (immunosuppressive) phase of sepsis (inability to respond appropriately to infections). About 15% of patients die in this first phase and 20% in the second phase, making sepsis one of the most deadly syndromes (35% overall mortality, 5 million deaths [8.3% of all deaths] annually worldwide). We hypothesized that immunosuppression was characterized by a state termed endotoxin tolerance a cellular amnesia (termed cellular reprogramming) in which cells fail to respond to microbial cues. Overall we found that an Endotoxin Tolerance gene signature is significantly associated with the subsequent development of confirmed sepsis and new organ dysfunction in patients who had suspected sepsis. All 620 sepsis patients in retrospective and new analyses presented with an expression profile strongly associated with the endotoxin tolerance signature (p<0.01; AUC 96.1%). This occurred in fact very early in sepsis and in a new clinical study we found that the signature could be detected already in the emergency ward at first clinical  presentation and 24-48 hours prior to definitive diagnosis. Importantly, this signature further differentiated between suspected sepsis patients who did, or did not, go on to develop confirmed sepsis, and predicted the development of organ dysfunction. (more…)
Author Interviews, Genetic Research / 24.10.2014

Dr. Toomas Kivsild PhD Department of Archaeology and Anthropology University of Cambridge, CambridgeMedicalResearch.com Interview with: Dr. Toomas Kivsild PhD Department of Archaeology and Anthropology University of Cambridge, Cambridge Medical Research: What is the background for this study? What are the main findings? Dr. Kivsild: Native populations of Siberia are known to have certain physiological characteristics such as high basal metabolic rate, and high blood pressure and low levels of serum lipids, that have been explained as traits that have evolved as a consequence of the adaptation of Siberians to their cold environment. Genetic basis of cold adaptation is still poorly understood. In our previous study using genome-wide genotyping scans we detected a 3 Mbp region of high haplotype homozygosity in chromosome 11 as a candidate of strong positive selection in Northeast Siberians. There were 79 protein coding genes mapping to this homozygosity region but we could not determine which of the genes was driving the signal we observed. In this forthcoming paper we have used high coverage whole genome sequences from 25 individuals from Northeast Siberia and we were able to determine the most likely SNP that is responsible for the high haplotype homozygosity in the chromosome 11 in Northeast Siberians maps to CPT1A gene which is a key regulator of long-chain fatty-acid oxidation in mitochondria. What makes this finding most interesting is that the same SNP had previously been found in Greenland and Canadian Inuits in association with high infant mortality and hypoketotic hypoglycemia. There are only a few other similar cases, like the sickle cell and APOL1 alleles, where disease associated genetic variants may have risen to high frequency in modern day populations due to the adaptive advantage they have presented in the past populations. (more…)
Author Interviews, Bipolar Disorder, Genetic Research, Nature / 21.10.2014

Edward I. Ginns, MD, PhD, Director Program in Medical Genetics and Lysosomal Disorders Treatment and Research Program University of Massachusetts Medical School Reed Rose Gordon Building, Room 137 Shrewsbury, MA 01545MedicalResearch.com: Interview with: Edward I. Ginns, MD, PhD, Director Program in Medical Genetics and Lysosomal Disorders Treatment and Research Program University of Massachusetts Medical School Reed Rose Gordon Building, Room 137 Shrewsbury, MA 01545 Medical Research: What are the main findings of the study? Dr. Ginns: Our study identified that sonic hedgehog signaling, an important brain pathway, is involved in bipolar affective disorder. This finding shows a mechanism and provides new targets for drug development. It suggests that sonic hedgehog signaling can be modulated to help manage bipolar symptoms in adults by using drugs already being studied in clinical trials for other medical conditions. The new findings were uncovered by decades of translational research in the Old Order Amish families of Pennsylvania, where in a few special families in the Amish Study there is a high incidence of both bipolar disorder and a rare genetic dwarfism, Ellis van‐Creveld (EvC) syndrome. No person with EvC had bipolar disorder despite forty years of documented research across multiple generations, suggesting that the genetic cause of this rare dwarfism was protective of bipolar affective disorder. (more…)
Author Interviews, Diabetes, Diabetologia, Exercise - Fitness, Genetic Research / 01.10.2014

Dr. Yann C Klimentidis, PhD Assistant professor of Epidemiology and Biostatistics Mel and Enid Zuckerman College of Public Health University of Arizona Medical CenterMedicalResearch.com Interview Invitation with: Dr. Yann C Klimentidis, PhD Assistant professor of Epidemiology and Biostatistics Mel and Enid Zuckerman College of Public Health University of Arizona Medical Center   Medical Research: What are the main findings of the study? Dr. Klimentidis: The main finding is that the association of physical activity with type-2 diabetes risk is weakest among those who are at high genetic risk for type-2 diabetes. Furthermore, we find that this trend is stronger among women as compared to men, and that it appears to be driven mainly by genetic risk to insulin resistance, as opposed to genetic risk for reduced beta-cell function. (more…)
Author Interviews, Genetic Research, Nature, Prostate Cancer / 18.09.2014

Dr. Jyotsna Batra QUT Institute of Health and Biomedical Innovation's  Queensland University of Technology Queensland, AustraliaMedicalResearch.com Interview with: Dr. Jyotsna Batra QUT Institute of Health and Biomedical Innovation's Queensland University of Technology Queensland, Australia   Medical Research: What are the main findings of the study? Dr Batra: Prostate cancer is a disease with upto 40% genetic component. Previous Genome-wide association studies have identified 77 risk loci associated with prostate cancer. This study is further extension of previous GWASs and also involved meta-analysis of multi-ethnic populations. Through this large study involving approximately 90,0000 individuals, 23 new susceptibility loci were identified to be associated with prostate cancer, 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. (more…)
Author Interviews, Cancer Research, Genetic Research, University of Pennsylvania / 12.09.2014

Renata Afi Rawlings-Goss, Ph.D. Postdoctoral Fellow Tishkoff Lab, University of PennsylvaniaMedicalResearch.com Interview with: Renata Afi Rawlings-Goss, Ph.D. Postdoctoral Fellow Tishkoff Lab, University of Pennsylvania   Medical Research: What are the main findings of the study? Dr. Rawlings-Goss: We found genetic mutations in key gene regulators that have been linked to ethnic disparities in cancer. Our investigation identified more than 30 previously undescribed mutations in important regulatory molecules called microRNAs. Individual microRNA molecules can regulate large numbers of genes in some cases over 6000 genes at once. Therefore, mutations in these genes have been linked to numerous diseases. By and large, however, microRNA mutations have not been studied in people of diverse ethnic backgrounds. (more…)
Author Interviews, Genetic Research, Hematology, Johns Hopkins, NEJM / 27.08.2014

Jerry Spivak, M.D Professor of Medicine and Oncology Director, Center for the Chronic Myeloproliferative Disorders John Hopkins MedicineMedicalResearch.com Interview with: Jerry Spivak, M.D Professor of Medicine and Oncology Director, Center for the Chronic Myeloproliferative Disorders John Hopkins Medicine Medical Research: What are the main findings of the study? Dr. Spivak: The main findings of this study are that polycythemia vera occurs in two clinical forms: an indolent form in which only phlebotomy may be necessary and a more aggressive form requiring myelosuppressive therapy and that these two forms of the disease can be distinguished genetically. (more…)
Aging, Author Interviews, Genetic Research / 26.08.2014

Dr. Manuel Serrano PhD Tumour Suppression Group CNIO, Melchor Fernandez Almagro 3, 28029 Madrid, Spain.MedicalResearch.com Interview with: Dr. Manuel Serrano PhD Tumour Suppression Group CNIO, Melchor Fernandez Almagro 3, 28029 Madrid, Spain. Medical Research: What are the main findings of the study? Dr. Serrano: We investigated the contribution of rare genetic variation to human exceptional longevity (EL, individuals with ≥100 years of age) by exome-sequencing long-lived siblings in three different families where exceptional longevity clustered. We found only one gene that harbored rare variants that was likely to contribute to human longevity across all three families and this gene was the Apolipoprotein B gene (APOB). We further found that the frequency of these rare APOB variants associated with familial exceptional longevity was greater in a cohort of 206 nonfamilial cases of exceptional longevity compared to the control population, though this association did not reach statistical significance. In addition, we found rare variants in many genes within individual families that are likely to contribute to human longevity given previous studies in animals. (more…)
Author Interviews, Breast Cancer, Genetic Research, NEJM / 07.08.2014

Dr Marc Tischkowitz MD PhD University Lecturer (Associate Professor) and Honorary Consultant  Physician in Medical Genetics Department of Medical Genetics, University of CambridgeMedicalResearch.com Interview with: Dr Marc Tischkowitz MD PhD University Lecturer (Associate Professor) and Honorary Consultant  Physician in Medical Genetics Department of Medical Genetics, University of Cambridge Medical Research: What are the main findings of the study? Dr. Tischkowitz: The PALB2 gene was first identified in 2006 and linked to breast cancer in 2007 but until now we have not had good breast cancer risk estimates for women who have inherited PALB2 mutations. This study was started in 2009 by an group of research institutions (The PALB2 Interest Group) in Canada, US, Europe (UK, Belgium, Greece, Italy, Finland) and Australia. We studied 362 individuals with PALB2 mutations from 154 families. We found that awomen with a PALB2 mutation will on average have a 35% risk of developing breast cancer by the age of 70, rising to 58% if there is a strong family history. Our study will help clinicians to better advise and manage such women. There are several new aspects.
  • It is by far the largest study to date and provides the most accurate risk estimates for PALB2 mutation carriers.
  • It shows that the breast cancer risk is modified by the family history. (more…)
Author Interviews, Genetic Research, JAMA, Schizophrenia / 31.07.2014

Dr Angelica Ronald Genes Environment Lifespan (GEL) laboratory Centre for Brain and Cognitive Development Department of Psychological Sciences Birkbeck, University of London London WC1E 7HXMedicalResearch.com Interview with: Dr Angelica Ronald Genes Environment Lifespan (GEL) laboratory Centre for Brain and Cognitive Development Department of Psychological Sciences Birkbeck, University of London London WC1E 7HX Medical Research: What are the main findings of the study? Dr. Ronald: Psychotic experiences, such as paranoia, hallucinations and disorganised thinking, are commonly reported by adolescents. Until now it has not been understood whether mild variations in psychotic experiences in the community are part of the same construct as more severe psychotic experiences in adolescence. Our findings suggest that they are. In our study, over 10,000 16-year-old adolescents in England and Wales were assessed on measures of psychotic experiences. The study identified a close link between normal, less frequent psychotic experiences and more severe and frequent experiences in the general population. A classic twin design was employed, which enabled us to conduct analyses investigating the role of genetic and environmental influences on psychotic experiences. The same genetic influences appeared to play a role across the spectrum of severity of psychotic experiences. The study found that psychotic experiences are moderately heritable in adolescence in the general population. This suggests it would be worth directing molecular genetic endeavours towards this area, which has so far received very little attention in terms of causal explanations. We also show that psychotic experiences have considerable environmental influence; in fact, environmental influence appears to play a larger role in causing psychotic experiences in adolescence than for diagnosed psychotic disorders in adults, such as schizophrenia. This result suggests a fruitful avenue will be to tackle what environmental risk factors influence adolescents to have psychotic experiences. (more…)
Author Interviews, Genetic Research, JCEM, Weight Research / 31.07.2014

Dr. Agatha van der Klaauw, PhD Wellcome Trust Postdoctoral Clinical Fellow Wellcome Trust-MRC Institute of Metabolic Science University of Cambridge Metabolic Research Laboratories Addenbrooke's Hospital Cambridge, United KingdomMedicalResearch.com Interview with: Dr. Agatha van der Klaauw, PhD Wellcome Trust Postdoctoral Clinical Fellow Wellcome Trust-MRC Institute of Metabolic Science University of Cambridge Metabolic Research Laboratories Addenbrooke's Hospital Cambridge, United Kingdom   Medical Research: What are the main findings of the study? Dr. van der Klaauw: Obesity occurs when we eat more calories than we burn which is often easy to do as many foods are highly palatable and high in calories. Highly palatable foods such as chocolate trigger signals in the brain that give a feeling of pleasure and reward (sometimes called cravings) which can contribute to overeating. These signals are processed in the reward centres in the brain, where sets of neurons release chemicals such as dopamine. However, very little is known about whether the reward centres of the brain work differently in some people who are overweight. In this study, we were interested in studying overweight people who had a problem with the melanocortin 4 receptor (MC4R) gene. About 1% of obese people have a problem in this gene which contributes to weight gain from a young age. We compared three groups of people: people who were overweight due to a problem in the MC4R gene, people who were overweight but the gene was normal and some people who were normal weight. We performed functional Magnetic Resonance Imaging (fMRI) scans to look at how the reward centres in the brain were activated by pictures of appetizing food such as chocolate cake compared to bland food such as rice or broccoli and non-food items such as staplers. We found that in normal weight people, the reward centres are activated (light up) when they are shown pictures of cake or chocolate and the same was seen in overweight people with a problem in the MC4R gene. But we found that the reward centres were underactive in overweight volunteers (in whom the gene was normal). (more…)