MedicalResearch.com Interview with:
Lynda Harris PhD
Lecturer in Pharmaceutics
University of Manchester
Manchester Pharmacy School
Maternal and Fetal Health Research Centre
Manchester
MedicalResearch.com: What is the background for this study?
Dr. Harris: Pregnancy complications such as pre-eclampsia and fetal growth restriction remain a problem despite advances in antenatal care, and impact heavily on future health: small size at birth is associated with an increased risk of cardiovascular disease and diabetes in later life. Drugs to improve pregnancy outcome are severely lacking, as pregnant women are considered a high risk cohort by drug companies, who fear expensive lawsuits associated with side effects and teratogenicity. The majority of pregnancy complications are caused by a poorly growing or poorly functioning placenta. A number of potential drugs have been identified that enhance placental function in vitro, and improve fetal growth in animal models; however, there is currently no means of restricting their actions to the placenta, and systemic administration of these drugs to pregnant women is not feasible due to the risk of adverse effects in other tissues. To address this issue, we have identified a series of placental “homing peptides” which we have used to create nanocarriers for targeted delivery of drugs to the placenta.
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MedicalResearch.com Interview with:
Lluís Ribas de Pouplana, Ph.D
IRB Barcelona
Barcelona 08028
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Ever since the discovery of the genetic code it became obvious that the system had not grown to its full theoretical potential of making proteins with 63 different amino acids.
Francis Crick called the code 'a frozen accident',
but it was unclear what had actually froze it.
In this article we offer an explanation to that, and we validate it experimentally.
What we find is that the central pieces of the genetic code, the transfer RNAs,
are unable to incorporate enough specific elements for the system to be able to
use 63 of them without confusion. Since you need a new tRNA for each new
amino acid, once the tRNA identification limit is reached you also reach the
maximum number of usable amino acids. This limit happened to be reached
at 20, and that's where it has stayed for 3 billion years.
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MedicalResearch.com Interview with:
Keir Menzies PhD
Assistant Professor
University of Ottawa Brain and Mind Research Institute
University of OttawaMedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Menzies: Currently there is significant amount of research identifying the power of stem cells to regenerate damaged or aging tissue. Our research discovered that reduced stem cell health was linked to unusually low levels of a small molecule called NAD, one of the most important cellular molecules to maintain the performance of mitochondria, the engine of the cell. Then by boosting NAD levels, using a special form of vitamin B3 called nicotinamide riboside, stem cells could be rejuvenated during aging by improving mitochondrial function. We then go on to show that by improving stem cell function we could prolong the lifespan of mice, even when the treatment began at a relatively old age.
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MedicalResearch.com Interview with:
Michael Yudell, PhD, MPH
Chair & Associate Professor
Drexel University School of Public HealthCommunity Health and Prevention
Philadelphia, PA 19104
Medical Research: What is the background for this study?
Dr. Yudell: We came together as a group of scholars from the natural sciences, social sciences, and humanities to address what we believe is a long-standing challenge: how to improve the study of human genetic diversity without recapitulating the controversial and problematic concept of race. We believe that the cross-disciplinary focus of our work—an examination of the historical, biological, and sociological aspects of the race concept—can shed new light on the long-standing debate about the use of the race concept in genetics research. We believe modern genetics remains stuck in a paradox: that on the one hand race is a tool to elucidate human genetic diversity, and on the other hand race is believedthree main concerns to be a poorly defined marker of that diversity and an imprecise proxy for the relationship between ancestry and genetics. This paradox is rooted in the nature of the field: it dates back to the evolutionary geneticist Theodosius Dozhansky, who in the 1930s redefined race in his work on what was known as biology’s evolutionary synthesis (the synthesis of population genetics with Darwinian thought). For much of his career, Dobzhansky believed race to be a useful tool to elucidate human genetic diversity. But by the end of his career he became worried that the study of human diversity had “floundered in confusion and misunderstanding” and was concerned over the nonscientific misuse of the term. He, like we and many others in genetics, anthropology, and the social sciences, have called on the field to devise better methods to improve the study of human genetic diversity.
Can the race concept in genetics elucidate the relationship between humans and their evolutionary history, between humans and their health? In the wake of the human genome project the answer seemed to be a pretty resounding “no.” In 2004, for example, Francis Collins, then head of the National Human Genome Research Institute and now Director of the National Institutes of Health called race a “flawed” and “weak” concept and argued that science needed to move beyond race. Yet, as our paper highlights, the use of race persist in genetics, despite voices like Collins, like Craig Venter—leaders in the field of genomics-who have called on the field to move beyond it. They, of course, were not the first to do, but we hope they are among the last. We believe it is time to revisit this century-long debate and bring biologists, social scientists, and scholars from the humanities together in a to find better ways to study the ever-important subject of human diversity.
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More on Allergies on MedicalResearch.comMedicalResearch.com Interview with:
Yuxia Zhang PhD
Population Healthy and Immunity Division
Walter + Eliza Hall Institute
Parkville VIC 3052 AustraliaMedical Research: What is the background for this study?
Dr. Zhang: There has been a dramatic increase in hospital presentations due to food allergy over recent decades, most among children under five years of age. In Melbourne Australia, up to one in every 10 babies develop food allergy during the first year of life. To understand the mechanisms underlying the increased incidences of allergy and other diseases in children, Associate Professor Peter Vuillermin and colleagues established the Barwon Infant Studies (BIS), following and collecting bio-speciments from pregnant mothers and their babies. Together with my colleagues Prof. Leonard Harrison and Mr. Gaetano Naselli from the Walter and Eliza Hall Institute of Medical Research, we examined the immune cell composition and function in cord blood in babies who developed food allergy compared to allergy-free babies at one year of age. Medical Research: What are the main findings?
Dr. Zhang: Our initial observation was that in cord blood the proportions of CD14+ monocytes and CD4+T cells were inversely associated. In infants who developed food allergy, there was a higher ratio of CD14+monoctypes/CD4+T cells and a lower ratio of naive natural regulatory T cells (nTreg). The reduced nTreg frequency was also independently discovered by Dr. Fiona Collier in the BIS fresh blood cohort. CD14+ monocytes are the foot-solders of the immune system, which immediately release inflammatory cytokines upon infection. These inflammatory cytokines then guide the unexperienced CD4+T cells down to different paths to control infection. nTreg cells police the immune system to prevent unwanted damages during the elimination of the infections. Despite this widely accepted view of how our immune system are activated, we do not know if and how these interactions may cause an allergic reaction in babies. Through a series of in vitro experiments, we found that the inflammatory cytokines- most likely in the mucosal sites where food allergy was initiated-could lead the development of both CD4+T cells and nTregs towards a Th2-type immune phenotype. These Th2-type immune cells secrete large amount of IL-4, a cytokine through which may cause allergic reactions to some foods.
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MedicalResearch.com Interview with:
Jonathan Kaltman, MD
Chief, Heart Development and Structural Diseases Branch
Division of Cardiovascular Sciences
National Heart, Lung, and Blood Institute
Medical Research: What are the main findings?
Dr. Kaltman: Congenital heart disease (CHD) is the most common birth defect but the cause for most defects is unknown. Surgery and clinical care of patients with congenital heart disease has improved survival but now we are learning that many patients have neurodevelopmental abnormalities, including learning disability and attention/behavioral issues.
Medical Research: What are the main findings?
Using exome sequencing we found that patients with congenital heart disease have a substantial number of de novo mutations. This finding is especially strong in patients with CHD and another structural birth defect and/or neurodevelopmental abnormalities.
Many of the genes identified are known to be expressed in both the heart and the brain, suggesting a single mutation may contribute to both congenital heart disease and neurodevelopmental abnormalities.
MedicalResearch.com Interview with:
Stephen A. Krawetz, Ph.D.
Associate Director C.S. Mott Center for Human Growth and Development,
Charlotte B. Failing Professor of Fetal Therapy and Diagnosis,
Department of Obstetrics and Gynecology,
Center for Molecular Medicine and Genetics,
Wayne State University School of Medicine,
Detroit, MI, 48201
Medical Research: What is the background for this study? What are the main findings?
Dr. Krawetz: The current study developed over approximately the past 20 years of work in my laboratory. In the mid 1990s, along with David Miller, we independently discovered that sperm contain RNA. This was followed by our joint publication in The Lancet that began to describe the RNAs in normal fertile males along with our paper in Nature that showed that RNA was delivered to the oocyte at fertilization. Following these studies we assessed the ability of RNAs to be used as markers of morphologically abnormal sperm (teratozoospermia). My laboratory then had the opportunity to explore the complexity of the population of sperm RNAs using Next Generation Sequencing. We recently began the translation of this work from the bench to bedside which takes us to the current paper in Science Translational Medicine that was a multi-institutional collaborative effort. Members of the team include Dr. Meritxell Jodar, Edward Sendler, Robert Goodrich, from my laboratory, along with Dr. Clifford L. Librach, Dr. Sergey I. Moskovtsev, and Sonja Swanson - CReATe Fertility Center, University of Toronto; Dr. Russ Hauser -Harvard University and Dr. Michael P. Diamond, Georgia Regents University. Here we tackled the issue of idiopathic infertility, that is, unknown infertility, since the couple appears normal in all respects. We specifically framed our study as the contribution of the male and female as a couple towards the birth of a healthy child focusing on male idiopathic infertility within the setting of a Reproductive Clinic. Representative publications from my laboratory that outline this part of my research program appear below.
1) Jodar, M., Sendler, E., Moskovtsev, S. Librach, C., Goodrich, R., Swanson, S., Hauser, R., Diamond, M. and Krawetz, S.A. (2015) Absence of sperm RNA elements correlates with idiopathic male infertility. Science Translational Medicine, 7(295):295re6.
2) Sendler, E., Johnson, G.D., Mao, S., Goodrich, R.J., Diamond, M.P., Hauser, R., and Krawetz, S.A. (2013) Stability, Delivery and Functions of Human Sperm RNAs at Fertilization. Nucleic Acids Research 41:4104-4117. PMID: 23471003
3) Platts, A.E., Dix, D. J., Chemes, H.E., Thompson, K.E., Goodrich, R., Rockett, J. C., Rawe, V.Y., Quintana, S., Diamond, M.P., Strader, L.F. and Krawetz, S.A. (2007) Success and failure in human spermatogenesis as revealed by teratozoospermic RNAs. Human Molecular Genetics. 16:763-773. PMID: 17327269
4) Ostermeier, G.C., Miller, D., Huntriss, J.D., Diamond, M.P. and Krawetz, S.A. (2004) Delivering spermatozoan RNA to the oocyte. Nature 429:154. PMID: 15141202
5) Ostermeier, G.C., Dix, D.J., Miller, D., Khatri, P. and Krawetz, S.A. (2002) Spermatozoal RNA profiles of normal fertile men. The Lancet. 360:773-777. PMID: 12241836
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MedicalResearch.com Interview with:Dr. Leonard Petrucelli Ph.D
Mayo Clinic
Jacksonville, FL 32224
MedicalResearch: What is the background for this study?Dr.Petrucelli: According to the ALS Association, more than 30,000 Americans live with amyotrophic lateral sclerosis (ALS), a condition that destroys motor neuron cells that control essential muscle activity such as speaking, walking, breathing and swallowing. After Alzheimer’s disease, frontotemporal dementia (FTD) is the most common form of early onset dementia. It is characterized by changes in personality, behavior, and language due to loss of neurons in the brain’s frontal lobe. Once considered rare, frontotemporal dementia is now thought to account for up to 10 to 15 percent of all dementia cases, according to the Alzheimer’s Association.
In 2011, Mayo investigator Rosa Rademakers, Ph.D., identified the most common genetic mutation known to cause ALS and FTD, namely a repeat expansion in the gene C9ORF72. The C9ORF72 repeat expansion leads to the generation of toxic RNA species that form abnormal foci, as well as inclusions of c9RAN proteins in affected cells in the central nervous system. Prior to this research study lead by Leonard Petrucelli, Chair of the Department of Neuroscience at the Mayo Clinic Florida, no animal model existed that fully recapitulated the known clinicopathological features of what is now collectively referred to as c9FTD/ALS. Without such an animal it has remained difficult to identify important mechanisms by which the repeat expansion leads to neurodegeneration and putative therapeutic targets that may mitigate disease in patients where currently there are no curative treatments.
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MedicalResearch.com Interview with:
Lee Zou, Ph.D.
Professor of Pathology, Harvard Medical School
The Jim & Ann Orr MGH Research Scholar
Associate Scientific Director, MGH Cancer Center
Medical Research: What is the background for this study? What are the main findings?
Dr. Lee Zou: Cancer cells must rely on telomerase or the alternative lengthening of telomere (ALT) pathway to maintain telomeres and bypass replicative senescence. The ALT pathway is active in about 10-15% of human cancers, and it is particularly prevalent in specific cancer types, such as osteosarcoma, glioblastoma, and neuroendocrine pancreatic tumors. ALT is a recombination-mediated process. Whether the reliance of cancer cells on alternative lengthening of telomere can be exploited therapeutically was not known.
In our study, we discovered that the ATR kinase is a key regulator of alternative lengthening of telomere. We found that ATR inhibitors disrupt ALT effectively. Furthermore, we found that ATR inhibitors selectively kill ALT-positive cancer cells in a panel of caner cell lines. These findings have suggested the first rational therapeutic strategy for the treatment of ALT-positive cancer. (more…)
MedicalResearch.com Interview with:
Melanie Blokesch PhD
Assistant Professor (tenure-track)
Laboratory of Molecular Microbiology
Global Health Institute, School of Life Sciences
Swiss Federal Institute of Technology Lausanne (EPFL)
Lausanne Switzerland
Medical Research: What is the background for this study? What are the main findings?Dr. Blokesch: We have been studying the cholera-causing bacterium Vibrio cholerae for many years in my laboratory. Our main focus has always been on elucidating how this pathogen acquires new genetic material that allows it to evolve. This is often accomplished through a mechanism known as horizontal gene transfer (HGT). There are three main modes of horizontal gene transfer in bacteria and the one we are primarily interested in is called natural competence for transformation. When the bacterium enters the state of natural competence it can take up free genetic material from its surrounding and in case it recombines this new material into its own genome the bacterium is considered to be naturally transformed. Notably, natural competence/transformation was first described in 1928 by Fred Griffith, who showed that transformation can render harmless bacteria pathogenic. These early experiments can be considered a milestone in molecular biology as it later led to the discovery of DNA as the carrier of genetic information.
Medical Research: What are the main findings?
Dr. Blokesch: The main finding of our study is that the pathogen V. cholerae does not solely rely on free DNA floating around but that it actively kills neighbouring bacteria followed by the uptake of their DNA. Indeed, we were able to show that the two processes - killing of other bacteria and DNA uptake - are co-regulated by the same proteins within the bacterial cell. We also used imaging techniques to visualize the killing of other bacteria by V. cholerae, followed by the release of their genetic material, which the predator then pulled into its own cell. We further quantified these HGT events by following the transfer of an antibiotic resistance gene from the killed bacterium to the predatory V. cholerae cell. Notably, the spread of antibiotic resistances is a major health concern and HGT is a major driver of it.
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