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News Article | January 21, 2017
Site: www.techtimes.com

With latest developments and its cost becoming more reasonable through the years, genome sequencing promises to take newborn screening to a whole new level. Newborn screening is a mandatory medical procedure done on babies within 72 hours after delivery. It includes a newborn physical examination, where eyes are checked for cataract, heart is checked for irregular heart beat or "murmurs," and in boys, if testicles are in the right place. A newborn screening blood spot or heel prick test, where a nurse or phlebotomist will draw blood sample from the baby's heel and send it to a laboratory, is needed to identify if he's at risk for any of the nine rare diseases. A newborn hearing screening through an automated otoacoustic emission (AOAE) test will also be performed to check for possible hearing loss. It is highly recommended that a baby takes a hearing test within the first four to five weeks up to three months of age. Newborn screening has been proven effective at identifying and preventing serious congenital and genetic conditions. These include metabolic disorders (phenylketonuria or PKU), endocrine disorders (congenital hypothyroidism and congenital adrenal hyperplasia), hemoglobin disorders (sickle cell anemia), and cystic fibrosis. The Newborn Sequencing in Genomic Medicine and Public Health (NSIGHT) program, a consortium of several grants funded by the National Institutes of Health (NIH), is looking into the potential implications of genome sequencing techniques for newborn screening in diagnostic, preventative, and predictive clinical scenarios. "Genome sequencing is a new and still enormously complex process, and oftentimes the results have uncertain implications. These studies represent some of the first organized approaches to developing the best practices for determining the right information and best ways to return it to parents and their babies' doctors," Alan Beggs, PhD, of the Manton Center for Orphan Disease Research at Boston Children's Hospital and Professor of Pediatrics at Harvard Medical School said. With the ability to explore the entire genome of a newborn baby, parents will now have the opportunity to know how their child's health will fare throughout his life. But do they really want to know? According to Jonathan Berg, MD, PhD, associate professor of genetics at the UNC School of Medicine and one of the authors of a paper in the consortium, not all parents are interested in genome sequencing or the genetic information of their newborn child, although there are some who do. "Some people think this concern is an old, quaint notion that is being made obsolete by technology. And some people believe fervently that it could infringe on the child's autonomy or potentially even harm the child if parents learned or intervened too much," he said. "But the bottom line is we hope that the information we get from these studies will help us make recommendations for how to best roll out some form of newborn genomic screening in the future," Berg concluded. © 2017 Tech Times, All rights reserved. Do not reproduce without permission.


Adachi Y.,University of California at San Francisco | Mochida G.,Manton Center for Orphan Disease Research | Walsh C.,Manton Center for Orphan Disease Research | Barkovich J.,University of California at San Francisco
Neuropediatrics | Year: 2014

Microcephalies vary widely in clinical severity and in morphology. The purpose of this study is to determine the frequency of disproportion between the size of the cerebrum and the size of midbrain and hindbrain structures in infants and children with microcephaly, as analysis of such disproportions might aid understanding of these disorders and facilitate testing for specific genetic causes. The relative sizes of the forebrain, each component of the brain stem, and vermis and hemispheres of the cerebellum were analyzed visually on magnetic resonance (MR) images of 110 microcephalic patients. A disproportionally large cerebellum, compared with the cerebrum, was found in 50 cases (45.5%), a proportional cerebellum in 49 cases (44.5%), and a disproportionally small cerebellum in 11 cases (10%). Proportional cerebella were most common in mild (86%) and moderate (55%) microcephaly patients, whereas disproportionately large cerebella were most common in severe (57%) and moderate (32%) microcephaly. Disproportionately small cerebella were seen only in moderate (13%) and severe (9%) microcephaly. As genes are expressed at different times in cerebral and cerebellar development, it is postulated that analysis of relative cerebellar and brain stem size may be useful in the initial analysis of microcephaly by MR images both to categorize and to help determine likely genetic causes. © 2014 Georg Thieme Verlag KG.


Lengerke C.,University of Tuebingen Medical Center | Daley G.Q.,Childrens Hospital | Daley G.Q.,Harvard University | Daley G.Q.,Manton Center for Orphan Disease Research | And 2 more authors.
Blood Reviews | Year: 2010

The discovery of human embryonic stem cells (hESCs) raised promises for a universal resource for cell based therapies in regenerative medicine. Recently, fast-paced progress has been made towards the generation of pluripotent stem cells (PSCs) amenable for clinical applications, culminating in reprogramming of adult somatic cells to autologous PSCs that can be indefinitely expanded in vitro. However, besides the efficient generation of bona fide, clinically safe PSCs (e.g., without the use of oncoproteins and gene transfer based on viruses inserting randomly into the genome), a major challenge in the field remains how to efficiently differentiate PSCs to specific lineages and how to select cells that will function normally upon transplantation in adults. In this review, we analyse the in vitro differentiation potential of PSCs to the hematopoietic lineage by discussing blood cell types that can be currently obtained, limitations in derivation of adult-type HSCs and prospects for clinical application of PSCs-derived blood cells. © 2009 Elsevier Ltd. All rights reserved.


Shyh-Chang N.,Dana-Farber Cancer Institute | Shyh-Chang N.,Harvard University | Shyh-Chang N.,Harvard Stem Cell Institute | Shyh-Chang N.,Manton Center for Orphan Disease Research | And 38 more authors.
Cell | Year: 2013

Summary Regeneration capacity declines with age, but why juvenile organisms show enhanced tissue repair remains unexplained. Lin28a, a highly conserved RNA-binding protein expressed during embryogenesis, plays roles in development, pluripotency, and metabolism. To determine whether Lin28a might influence tissue repair in adults, we engineered the reactivation of Lin28a expression in several models of tissue injury. Lin28a reactivation improved hair regrowth by promoting anagen in hair follicles and accelerated regrowth of cartilage, bone, and mesenchyme after ear and digit injuries. Lin28a inhibits let-7 microRNA biogenesis; however, let-7 repression was necessary but insufficient to enhance repair. Lin28a bound to and enhanced the translation of mRNAs for several metabolic enzymes, thereby increasing glycolysis and oxidative phosphorylation (OxPhos). Lin28a-mediated enhancement of tissue repair was negated by OxPhos inhibition, whereas a pharmacologically induced increase in OxPhos enhanced repair. Thus, Lin28a enhances tissue repair in some adult tissues by reprogramming cellular bioenergetics. PaperClip © 2013 Elsevier Inc.


Zhu H.,Childrens Hospital Boston | Zhu H.,Harvard Stem Cell Institute | Zhu H.,Dana-Farber Cancer Institute | Shah S.,Childrens Hospital Boston | And 28 more authors.
Nature Genetics | Year: 2010

Recently, genome-wide association studies have implicated the human LIN28B locus in regulating height and the timing of menarche. LIN28B and its homolog LIN28A are functionally redundant RNA-binding proteins that block biogenesis of let-7 microRNAs. lin-28 and let-7 were discovered in Caenorhabditis elegans as heterochronic regulators of larval and vulval development but have recently been implicated in cancer, stem cell aging and pluripotency. The let-7 targets Myc, Kras, Igf2bp1 and Hmga2 are known regulators of mammalian body size and metabolism. To explore the function of the Lin28-Let-7 pathway in vivo, we engineered transgenic mice to express Lin28a and observed in them increased body size, crown-rump length and delayed onset of puberty. Investigation of metabolic and endocrine mechanisms of overgrowth in these transgenic mice revealed increased glucose metabolism and insulin sensitivity. Here we report a mouse that models the human phenotypes associated with genetic variation in the Lin28-Let-7 pathway. © 2010 Nature America, Inc. All rights reserved.


Shyh-Chang N.,Agency for Science, Technology and Research Singapore | Daley G.Q.,Dana-Farber Cancer Institute | Daley G.Q.,Harvard Stem Cell Institute | Daley G.Q.,Harvard University | And 2 more authors.
Cell Metabolism | Year: 2015

Embryonic stem cells (ESCs) manifest a unique metabolism that is intimately linked to their pluripotent state. In this issue, Moussaieff et al. (2015) find that ESCs utilize glycolysis to fuel high rates of cytosolic acetyl-CoA synthesis to maintain the histone acetylation required for pluripotency. © 2015 Elsevier Inc.


Shyh-Chang N.,Dana-Farber Cancer Institute | Shyh-Chang N.,Harvard Stem Cell Institute | Shyh-Chang N.,Harvard University | Daley G.Q.,Dana-Farber Cancer Institute | And 4 more authors.
Cell Stem Cell | Year: 2013

In recent years, the highly conserved Lin28 RNA-binding proteins have emerged as factors that define stemness in several tissue lineages. Lin28 proteins repress let-7 microRNAs and influence mRNA translation, thereby regulating the self-renewal of mammalian embryonic stem cells. Subsequent discoveries revealed that Lin28a and Lin28b are also important in organismal growth and metabolism, tissue development, somatic reprogramming, and cancer. In this review, we discuss the Lin28 pathway and its regulation, outline its roles in stem cells, tissue development, and pathogenesis, and examine the ramifications for re-engineering mammalian physiology. © 2013 Elsevier Inc.


Loh Y.-H.,Childrens Hospital Boston | Loh Y.-H.,Harvard Stem Cell Institute | Yang L.,Childrens Hospital Boston | Yang L.,Harvard Stem Cell Institute | And 12 more authors.
Annual Review of Genomics and Human Genetics | Year: 2011

Embryonic stem cells (ESCs) first derived from the inner cell mass of blastocyst-stage embryos have the unique capacity of indefinite self-renewal and potential to differentiate into all somatic cell types. Similar developmental potency can be achieved by reprogramming differentiated somatic cells into induced pluripotent stem cells (iPSCs). Both types of pluripotent stem cells provide great potential for fundamental studies of tissue differentiation, and hold promise for disease modeling, drug development, and regenerative medicine. Although much has been learned about the molecular mechanisms that underlie pluripotency in such cells, our understanding remains incomplete. A comprehensive understanding of ESCs and iPSCs requires the deconstruction of complex transcription regulatory networks, epigenetic mechanisms, and biochemical interactions critical for the maintenance of self-renewal and pluripotency. In this review, we will discuss recent advances gleaned from application of global "omics" techniques to dissect the molecular mechanisms that define the pluripotent state. © 2011 by Annual Reviews. All rights reserved.


Kahle K.T.,Harvard University | Kahle K.T.,Howard Hughes Medical Institute | Kahle K.T.,Manton Center for Orphan Disease Research | Khanna A.,Harvard University | And 4 more authors.
JAMA Neurology | Year: 2014

Peripheral neuropathic pain, typified by the development of spontaneous pain or pain hypersensitivity following injury to the peripheral nervous system, is common, greatly impairs quality of life, and is inadequately treated with available drugs. Maladaptive changes in chloride homeostasis due to a decrease in the functional expression of the potassium-chloride cotransporter KCC2 in spinal cord dorsal horn neurons are a major contributor to the central disinhibition of ã-aminobutyric acid type A receptor- and glycine receptor-mediated signaling that characterizes neuropathic pain. A compelling novel analgesic strategy is to restore spinal ionotropic inhibition by enhancing KCC2-mediated chloride extrusion.We review the data on which this theory of alternative analgesia is based, discuss recent high-throughput screens that have searched for small-molecule activators of KCC2, and propose other strategies of KCC2 activation based on recent developments in the basic understanding of KCC2's functional regulation. Exploiting the chloride-dependent functional plasticity of the ã-aminobutyric acid and glycinergic system by targeting KCC2 may be a tenable method of restoring ionotropic inhibition not only in neuropathic pain but also in other "hyperexcitable"diseases of the nervous system such as seizures and spasticity. © Copyright 2014 American Medical Association. All rights reserved.


Kumar R.M.,Wyss Institute for Biologically Inspired Engineering | Kumar R.M.,Howard Hughes Medical Institute | Cahan P.,Manton Center for Orphan Disease Research | Shalek A.K.,Harvard University | And 14 more authors.
Nature | Year: 2014

Pluripotent stem cells (PSCs) are capable of dynamic interconversion between distinct substates; however, the regulatory circuits specifying these states and enabling transitions between them are not well understood. Here we set out to characterize transcriptional heterogeneity in mouse PSCs by single-cell expression profiling under different chemical and genetic perturbations. Signalling factors and developmental regulators show highly variable expression, with expression states for some variable genes heritable through multiple cell divisions. Expression variability and population heterogeneity can be influenced by perturbation of signalling pathways and chromatin regulators. Notably, either removal of mature microRNAs or pharmacological blockage of signalling pathways drives PSCs into a low-noise ground state characterized by a reconfigured pluripotency network, enhanced self-renewal and a distinct chromatin state, an effect mediated by opposing microRNA families acting on the Myc/Lin28/let-7 axis. These data provide insight into the nature of transcriptional heterogeneity in PSCs. © 2014 Macmillan Publishers Limited. All rights reserved.

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