Posts Tagged ‘National Human Genome Research Institute’

Proteomics, Metabolomics, Signaling Pathways, and Cell Regulation: a Compilation of Articles in the Journal http://pharmaceuticalintelligence.com

Compilation of References by Leaders in Pharmaceutical Business Intelligence in the Journal http://pharmaceuticalintelligence.com about
Proteomics, Metabolomics, Signaling Pathways, and Cell Regulation

Curator: Larry H Bernstein, MD, FCAP


  1. The Human Proteome Map Completed

Reporter and Curator: Larry H. Bernstein, MD, FCAP


  1. Proteomics – The Pathway to Understanding and Decision-making in Medicine

Author and Curator, Larry H Bernstein, MD, FCAP


3. Advances in Separations Technology for the “OMICs” and Clarification of Therapeutic Targets

Author and Curator, Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/10/22/advances-in-separations-technology-for-the-omics-and-clarification-         of-therapeutic-targets/

  1. Expanding the Genetic Alphabet and Linking the Genome to the Metabolome

Author and Curator, Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/09/24/expanding-the-genetic-alphabet-and-linking-the-genome-to-the-                metabolome/

5. Genomics, Proteomics and standards

Larry H Bernstein, MD, FCAP, Author and Curator


6. Proteins and cellular adaptation to stress

Larry H Bernstein, MD, FCAP, Author and Curator




  1. Extracellular evaluation of intracellular flux in yeast cells

Larry H. Bernstein, MD, FCAP, Reviewer and Curator


  1. Metabolomic analysis of two leukemia cell lines. I.

Larry H. Bernstein, MD, FCAP, Reviewer and Curator


  1. Metabolomic analysis of two leukemia cell lines. II.

Larry H. Bernstein, MD, FCAP, Reviewer and Curator


  1. Metabolomics, Metabonomics and Functional Nutrition: the next step in nutritional metabolism and biotherapeutics

Reviewer and Curator, Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/08/22/metabolomics-metabonomics-and-functional-nutrition-the-next-step-          in-nutritional-metabolism-and-biotherapeutics/

  1. Buffering of genetic modules involved in tricarboxylic acid cycle metabolism provides homeomeostatic regulation

Larry H. Bernstein, MD, FCAP, Reviewer and curator

https://pharmaceuticalintelligence.com/2014/08/27/buffering-of-genetic-modules-involved-in-tricarboxylic-acid-cycle-              metabolism-provides-homeomeostatic-regulation/

Metabolic Pathways

  1. Pentose Shunt, Electron Transfer, Galactose, more Lipids in brief

Reviewer and Curator: Larry H. Bernstein, MD, FCAP


  1. Mitochondria: More than just the “powerhouse of the cell”

Ritu Saxena, PhD


  1. Mitochondrial fission and fusion: potential therapeutic targets?

Ritu saxena


4.  Mitochondrial mutation analysis might be “1-step” away

Ritu Saxena


  1. Selected References to Signaling and Metabolic Pathways in PharmaceuticalIntelligence.com

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/08/14/selected-references-to-signaling-and-metabolic-pathways-in-                     leaders-in-pharmaceutical-intelligence/

  1. Metabolic drivers in aggressive brain tumors

Prabodh Kandal, PhD


  1. Metabolite Identification Combining Genetic and Metabolic Information: Genetic association links unknown metabolites to functionally related genes

Writer and Curator, Aviva Lev-Ari, PhD, RD

https://pharmaceuticalintelligence.com/2012/10/22/metabolite-identification-combining-genetic-and-metabolic-                        information-genetic-association-links-unknown-metabolites-to-functionally-related-genes/

  1. Mitochondria: Origin from oxygen free environment, role in aerobic glycolysis, metabolic adaptation

Larry H Bernstein, MD, FCAP, author and curator

https://pharmaceuticalintelligence.com/2012/09/26/mitochondria-origin-from-oxygen-free-environment-role-in-aerobic-            glycolysis-metabolic-adaptation/

  1. Therapeutic Targets for Diabetes and Related Metabolic Disorders

Reporter, Aviva Lev-Ari, PhD, RD


10.  Buffering of genetic modules involved in tricarboxylic acid cycle metabolism provides homeomeostatic regulation

Larry H. Bernstein, MD, FCAP, Reviewer and curator

https://pharmaceuticalintelligence.com/2014/08/27/buffering-of-genetic-modules-involved-in-tricarboxylic-acid-cycle-              metabolism-provides-homeomeostatic-regulation/

11. The multi-step transfer of phosphate bond and hydrogen exchange energy

Larry H. Bernstein, MD, FCAP, Curator:

https://pharmaceuticalintelligence.com/2014/08/19/the-multi-step-transfer-of-phosphate-bond-and-hydrogen-                          exchange-energy/

12. Studies of Respiration Lead to Acetyl CoA


13. Lipid Metabolism

Author and Curator: Larry H. Bernstein, MD, FCAP


14. Carbohydrate Metabolism

Author and Curator: Larry H. Bernstein, MD, FCAP


15. Update on mitochondrial function, respiration, and associated disorders

Larry H. Bernstein, MD, FCAP, Author and Curator

https://pharmaceuticalintelligence.com/2014/07/08/update-on-mitochondrial-function-respiration-and-associated-                   disorders/

16. Prologue to Cancer – e-book Volume One – Where are we in this journey?

Author and Curator: Larry H. Bernstein, MD, FCAP


17. Introduction – The Evolution of Cancer Therapy and Cancer Research: How We Got Here?

Author and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/04/04/introduction-the-evolution-of-cancer-therapy-and-cancer-research-          how-we-got-here/

18. Inhibition of the Cardiomyocyte-Specific Kinase TNNI3K

Author and Curator: Larry H. Bernstein, MD, FCAP


19. The Binding of Oligonucleotides in DNA and 3-D Lattice Structures

Author and Curator: Larry H. Bernstein, MD, FCAP


20. Mitochondrial Metabolism and Cardiac Function

Author and Curator: Larry H. Bernstein, MD, FCAP


21. How Methionine Imbalance with Sulfur-Insufficiency Leads to Hyperhomocysteinemia

Curator: Larry H. Bernstein, MD, FCAP


22. AMPK Is a Negative Regulator of the Warburg Effect and Suppresses Tumor Growth In Vivo

Author and Curator: Stephen J. Williams, PhD

https://pharmaceuticalintelligence.com/2013/03/12/ampk-is-a-negative-regulator-of-the-warburg-effect-and-suppresses-         tumor-growth-in-vivo/

23. A Second Look at the Transthyretin Nutrition Inflammatory Conundrum

Author and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/12/03/a-second-look-at-the-transthyretin-nutrition-inflammatory-                         conundrum/

24. Mitochondrial Damage and Repair under Oxidative Stress

Author and Curator: Larry H. Bernstein, MD, FCAP


25. Nitric Oxide and Immune Responses: Part 2

Author and Curator: Aviral Vatsa, PhD, MBBS


26. Overview of Posttranslational Modification (PTM)

Writer and Curator: Larry H. Bernstein, MD, FCAP


27. Malnutrition in India, high newborn death rate and stunting of children age under five years

Writer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/07/15/malnutrition-in-india-high-newborn-death-rate-and-stunting-of-                   children-age-under-five-years/

28. Update on mitochondrial function, respiration, and associated disorders

Writer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/07/08/update-on-mitochondrial-function-respiration-and-associated-                  disorders/

29. Omega-3 fatty acids, depleting the source, and protein insufficiency in renal disease

Larry H. Bernstein, MD, FCAP, Curator

https://pharmaceuticalintelligence.com/2014/07/06/omega-3-fatty-acids-depleting-the-source-and-protein-insufficiency-         in-renal-disease/

30. Introduction to e-Series A: Cardiovascular Diseases, Volume Four Part 2: Regenerative Medicine

Larry H. Bernstein, MD, FCAP, writer, and Aviva Lev- Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/04/27/larryhbernintroduction_to_cardiovascular_diseases-                                  translational_medicine-part_2/

31. Epilogue: Envisioning New Insights in Cancer Translational Biology
Series C: e-Books on Cancer & Oncology

Author & Curator: Larry H. Bernstein, MD, FCAP, Series C Content Consultant


32. Ca2+-Stimulated Exocytosis:  The Role of Calmodulin and Protein Kinase C in Ca2+ Regulation of Hormone                         and Neurotransmitter

Writer and Curator: Larry H Bernstein, MD, FCAP and
Curator and Content Editor: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/12/23/calmodulin-and-protein-kinase-c-drive-the-ca2-regulation-of-                    hormone-and-neurotransmitter-release-that-triggers-ca2-stimulated-exocy

33. Cardiac Contractility & Myocardial Performance: Therapeutic Implications of Ryanopathy (Calcium Release-                           related Contractile Dysfunction) and Catecholamine Responses

Author, and Content Consultant to e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC
Author and Curator: Larry H Bernstein, MD, FCAP
and Article Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/08/28/cardiac-contractility-myocardium-performance-ventricular-arrhythmias-      and-non-ischemic-heart-failure-therapeutic-implications-for-cardiomyocyte-ryanopathy-calcium-release-related-                    contractile/

34. Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

Author and Curator: Larry H Bernstein, MD, FCAP Author: Stephen Williams, PhD, and Curator: Aviva Lev-Ari, PhD, RN


35. Identification of Biomarkers that are Related to the Actin Cytoskeleton

Larry H Bernstein, MD, FCAP, Author and Curator

https://pharmaceuticalintelligence.com/2012/12/10/identification-of-biomarkers-that-are-related-to-the-actin-                           cytoskeleton/

36. Advanced Topics in Sepsis and the Cardiovascular System at its End Stage

Author: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/08/18/advanced-topics-in-Sepsis-and-the-Cardiovascular-System-at-its-              End-Stage/

37. The Delicate Connection: IDO (Indolamine 2, 3 dehydrogenase) and Cancer Immunology

Demet Sag, PhD, Author and Curator

https://pharmaceuticalintelligence.com/2013/08/04/the-delicate-connection-ido-indolamine-2-3-dehydrogenase-and-               immunology/

38. IDO for Commitment of a Life Time: The Origins and Mechanisms of IDO, indolamine 2, 3-dioxygenase

Demet Sag, PhD, Author and Curator

https://pharmaceuticalintelligence.com/2013/08/04/ido-for-commitment-of-a-life-time-the-origins-and-mechanisms-of-             ido-indolamine-2-3-dioxygenase/

39. Confined Indolamine 2, 3 dioxygenase (IDO) Controls the Homeostasis of Immune Responses for Good and Bad

Curator: Demet Sag, PhD, CRA, GCP

https://pharmaceuticalintelligence.com/2013/07/31/confined-indolamine-2-3-dehydrogenase-controls-the-hemostasis-           of-immune-responses-for-good-and-bad/

40. Signaling Pathway that Makes Young Neurons Connect was discovered @ Scripps Research Institute

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/26/signaling-pathway-that-makes-young-neurons-connect-was-                     discovered-scripps-research-institute/

41. Naked Mole Rats Cancer-Free

Writer and Curator: Larry H. Bernstein, MD, FCAP


42. Late Onset of Alzheimer’s Disease and One-carbon Metabolism

Reporter and Curator: Dr. Sudipta Saha, Ph.D.


43. Problems of vegetarianism

Reporter and Curator: Dr. Sudipta Saha, Ph.D.


44.  Amyloidosis with Cardiomyopathy

Writer and Curator: Larry H. Bernstein, MD, FCAP


45. Liver endoplasmic reticulum stress and hepatosteatosis

Larry H Bernstein, MD, FACP


46. The Molecular Biology of Renal Disorders: Nitric Oxide – Part III

Curator and Author: Larry H Bernstein, MD, FACP


47. Nitric Oxide Function in Coagulation – Part II

Curator and Author: Larry H. Bernstein, MD, FCAP


48. Nitric Oxide, Platelets, Endothelium and Hemostasis

Curator and Author: Larry H Bernstein, MD, FACP


49. Interaction of Nitric Oxide and Prostacyclin in Vascular Endothelium

Curator and Author: Larry H Bernstein, MD, FACP


50. Nitric Oxide and Immune Responses: Part 1

Curator and Author:  Aviral Vatsa PhD, MBBS


51. Nitric Oxide and Immune Responses: Part 2

Curator and Author:  Aviral Vatsa PhD, MBBS


52. Mitochondrial Damage and Repair under Oxidative Stress

Curator and Author: Larry H Bernstein, MD, FACP


53. Is the Warburg Effect the cause or the effect of cancer: A 21st Century View?

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/10/17/is-the-warburg-effect-the-cause-or-the-effect-of-cancer-a-21st-                 century-view/

54. Ubiquinin-Proteosome pathway, autophagy, the mitochondrion, proteolysis and cell apoptosis

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/10/30/ubiquinin-proteosome-pathway-autophagy-the-mitochondrion-                  proteolysis-and-cell-apoptosis/

55. Ubiquitin-Proteosome pathway, Autophagy, the Mitochondrion, Proteolysis and Cell Apoptosis: Part III

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2013/02/14/ubiquinin-proteosome-pathway-autophagy-the-mitochondrion-                   proteolysis-and-cell-apoptosis-reconsidered/

56. Nitric Oxide and iNOS have Key Roles in Kidney Diseases – Part II

Curator and Author: Larry H Bernstein, MD, FACP


57. New Insights on Nitric Oxide donors – Part IV

Curator and Author: Larry H Bernstein, MD, FACP


58. Crucial role of Nitric Oxide in Cancer

Curator and Author: Ritu Saxena, Ph.D.


59. Nitric Oxide has a ubiquitous role in the regulation of glycolysis -with a concomitant influence on mitochondrial function

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/09/16/nitric-oxide-has-a-ubiquitous-role-in-the-regulation-of-glycolysis-with-         a-concomitant-influence-on-mitochondrial-function/

60. Targeting Mitochondrial-bound Hexokinase for Cancer Therapy

Curator and Author: Ziv Raviv, PhD, RN 04/06/2013


61. Biochemistry of the Coagulation Cascade and Platelet Aggregation – Part I

Curator and Author: Larry H Bernstein, MD, FACP


Genomics, Transcriptomics, and Epigenetics

  1. What is the meaning of so many RNAs?

Writer and Curator: Larry H. Bernstein, MD, FCAP


  1. RNA and the transcription the genetic code

Larry H. Bernstein, MD, FCAP, Writer and Curator


  1. A Primer on DNA and DNA Replication

Writer and Curator: Larry H. Bernstein, MD, FCAP


4. Synthesizing Synthetic Biology: PLOS Collections

Reporter: Aviva Lev-Ari


5. Pathology Emergence in the 21st Century

Author and Curator: Larry Bernstein, MD, FCAP


6. RNA and the transcription the genetic code

Writer and Curator, Larry H. Bernstein, MD, FCAP


7. A Great University engaged in Drug Discovery: University of Pittsburgh

Larry H. Bernstein, MD, FCAP, Reporter and Curator


8. microRNA called miRNA-142 involved in the process by which the immature cells in the bone  marrow give                              rise to all the types of blood cells, including immune cells and the oxygen-bearing red blood cells

Aviva Lev-Ari, PhD, RN, Author and Curator

https://pharmaceuticalintelligence.com/2014/07/24/microrna-called-mir-142-involved-in-the-process-by-which-the-                   immature-cells-in-the-bone-marrow-give-rise-to-all-the-types-of-blood-cells-including-immune-cells-and-the-oxygen-             bearing-red-blood-cells/

9. Genes, proteomes, and their interaction

Larry H. Bernstein, MD, FCAP, Writer and Curator


10. Regulation of somatic stem cell Function

Larry H. Bernstein, MD, FCAP, Writer and Curator    Aviva Lev-Ari, PhD, RN, Curator


11. Scientists discover that pluripotency factor NANOG is also active in adult organisms

Larry H. Bernstein, MD, FCAP, Reporter

https://pharmaceuticalintelligence.com/2014/07/10/scientists-discover-that-pluripotency-factor-nanog-is-also-active-in-           adult-organisms/

12. Bzzz! Are fruitflies like us?

Larry H Bernstein, MD, FCAP, Author and Curator


13. Long Non-coding RNAs Can Encode Proteins After All

Larry H Bernstein, MD, FCAP, Reporter


14. Michael Snyder @Stanford University sequenced the lymphoblastoid transcriptomes and developed an
allele-specific full-length transcriptome

Aviva Lev-Ari, PhD, RN, Author and Curator

https://pharmaceuticalintelligence.com/014/06/23/michael-snyder-stanford-university-sequenced-the-lymphoblastoid-            transcriptomes-and-developed-an-allele-specific-full-length-transcriptome/

15. Commentary on Biomarkers for Genetics and Genomics of Cardiovascular Disease: Views by Larry H                                     Bernstein, MD, FCAP

Author: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/07/16/commentary-on-biomarkers-for-genetics-and-genomics-of-                        cardiovascular-disease-views-by-larry-h-bernstein-md-fcap/

16. Observations on Finding the Genetic Links in Common Disease: Whole Genomic Sequencing Studies

Author an curator: Larry H Bernstein, MD, FCAP


17. Silencing Cancers with Synthetic siRNAs

Larry H. Bernstein, MD, FCAP, Reviewer and Curator


18. Cardiometabolic Syndrome and the Genetics of Hypertension: The Neuroendocrine Transcriptome Control Points

Reporter: Aviva Lev-Ari, PhD, RN


19. Developments in the Genomics and Proteomics of Type 2 Diabetes Mellitus and Treatment Targets

Larry H. Bernstein, MD, FCAP, Reviewer and Curator

https://pharmaceuticalintelligence.com/2013/12/08/developments-in-the-genomics-and-proteomics-of-type-2-diabetes-           mellitus-and-treatment-targets/

20. Loss of normal growth regulation

Larry H Bernstein, MD, FCAP, Curator


21. CT Angiography & TrueVision™ Metabolomics (Genomic Phenotyping) for new Therapeutic Targets to Atherosclerosis

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/11/15/ct-angiography-truevision-metabolomics-genomic-phenotyping-for-           new-therapeutic-targets-to-atherosclerosis/

22.  CRACKING THE CODE OF HUMAN LIFE: The Birth of BioInformatics & Computational Genomics

Genomics Curator, Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/08/30/cracking-the-code-of-human-life-the-birth-of-bioinformatics-                      computational-genomics/

23. Big Data in Genomic Medicine

Author and Curator, Larry H Bernstein, MD, FCAP


24. From Genomics of Microorganisms to Translational Medicine

Author and Curator: Demet Sag, PhD

https://pharmaceuticalintelligence.com/2014/03/20/without-the-past-no-future-but-learn-and-move-genomics-of-                      microorganisms-to-translational-medicine/

25. Summary of Genomics and Medicine: Role in Cardiovascular Diseases

Author and Curator, Larry H Bernstein, MD, FCAP


 26. Genomic Promise for Neurodegenerative Diseases, Dementias, Autism Spectrum, Schizophrenia, and Serious                      Depression

Author and Curator, Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/02/19/genomic-promise-for-neurodegenerative-diseases-dementias-autism-        spectrum-schizophrenia-and-serious-depression/

 27.  BRCA1 a tumour suppressor in breast and ovarian cancer – functions in transcription, ubiquitination and DNA repair

Sudipta Saha, PhD

https://pharmaceuticalintelligence.com/2012/12/04/brca1-a-tumour-suppressor-in-breast-and-ovarian-cancer-functions-         in-transcription-ubiquitination-and-dna-repair/

28. Personalized medicine gearing up to tackle cancer

Ritu Saxena, PhD


29. Differentiation Therapy – Epigenetics Tackles Solid Tumors

Stephen J Williams, PhD


30. Mechanism involved in Breast Cancer Cell Growth: Function in Early Detection & Treatment

     Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/17/mechanism-involved-in-breast-cancer-cell-growth-function-in-early-          detection-treatment/

31. The Molecular pathology of Breast Cancer Progression

Tilde Barliya, PhD


32. Gastric Cancer: Whole-genome reconstruction and mutational signatures

Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/12/24/gastric-cancer-whole-genome-reconstruction-and-mutational-                   signatures-2/

33. Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine –                                                       Part 1 (pharmaceuticalintelligence.com)

Aviva  Lev-Ari, PhD, RN


34. LEADERS in Genome Sequencing of Genetic Mutations for Therapeutic Drug Selection in Cancer                                         Personalized Treatment: Part 2

A Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/13/leaders-in-genome-sequencing-of-genetic-mutations-for-therapeutic-       drug-selection-in-cancer-personalized-treatment-part-2/

35. Personalized Medicine: An Institute Profile – Coriell Institute for Medical Research: Part 3

Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/13/personalized-medicine-an-institute-profile-coriell-institute-for-medical-        research-part-3/

36. Harnessing Personalized Medicine for Cancer Management, Prospects of Prevention and Cure: Opinions of                           Cancer Scientific Leaders @http://pharmaceuticalintelligence.com

Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/13/7000/Harnessing_Personalized_Medicine_for_ Cancer_Management-      Prospects_of_Prevention_and_Cure/

37.  GSK for Personalized Medicine using Cancer Drugs needs Alacris systems biology model to determine the in silico
effect of the inhibitor in its “virtual clinical trial”

Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/11/14/gsk-for-personalized-medicine-using-cancer-drugs-needs-alacris-             systems-biology-model-to-determine-the-in-silico-effect-of-the-inhibitor-in-its-virtual-clinical-trial/

38. Personalized medicine-based cure for cancer might not be far away

Ritu Saxena, PhD


39. Human Variome Project: encyclopedic catalog of sequence variants indexed to the human genome sequence

Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/11/24/human-variome-project-encyclopedic-catalog-of-sequence-variants-         indexed-to-the-human-genome-sequence/

40. Inspiration From Dr. Maureen Cronin’s Achievements in Applying Genomic Sequencing to Cancer Diagnostics

Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/10/inspiration-from-dr-maureen-cronins-achievements-in-applying-                genomic-sequencing-to-cancer-diagnostics/

41. The “Cancer establishments” examined by James Watson, co-discoverer of DNA w/Crick, 4/1953

Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/09/the-cancer-establishments-examined-by-james-watson-co-discover-         of-dna-wcrick-41953/

42. What can we expect of tumor therapeutic response?

Author and curator: Larry H Bernstein, MD, FACP


43. Directions for genomics in personalized medicine

Author and Curator: Larry H. Bernstein, MD, FCAP


44. How mobile elements in “Junk” DNA promote cancer. Part 1: Transposon-mediated tumorigenesis.

Stephen J Williams, PhD

https://pharmaceuticalintelligence.com/2012/10/31/how-mobile-elements-in-junk-dna-prote-cancer-part1-transposon-            mediated-tumorigenesis/

45. mRNA interference with cancer expression

Author and Curator, Larry H. Bernstein, MD, FCAP


46. Expanding the Genetic Alphabet and linking the genome to the metabolome

Aviva Lev-Ari, PhD, RD

https://pharmaceuticalintelligence.com/2012/09/24/expanding-the-genetic-alphabet-and-linking-the-genome-to-the-               metabolome/

47. Breast Cancer, drug resistance, and biopharmaceutical targets

Author and Curator: Larry H Bernstein, MD, FCAP


48.  Breast Cancer: Genomic profiling to predict Survival: Combination of Histopathology and Gene Expression                            Analysis

Aviva Lev-Ari, PhD, RD

https://pharmaceuticalintelligence.com/2012/12/24/breast-cancer-genomic-profiling-to-predict-survival-combination-of-           histopathology-and-gene-expression-analysis

49. Gastric Cancer: Whole-genome reconstruction and mutational signatures

Aviva  Lev-Ari, PhD, RD

https://pharmaceuticalintelligence.com/2012/12/24/gastric-cancer-whole-genome-reconstruction-and-mutational-                   signatures-2/

50. Genomic Analysis: FLUIDIGM Technology in the Life Science and Agricultural Biotechnology

Aviva Lev-Ari, PhD, RD

https://pharmaceuticalintelligence.com/2012/08/22/genomic-analysis-fluidigm-technology-in-the-life-science-and-                   agricultural-biotechnology/

51. 2013 Genomics: The Era Beyond the Sequencing Human Genome: Francis Collins, Craig Venter, Eric Lander, et al.

Aviva Lev-Ari, PhD, RD


52. Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1

Aviva Lev-Ari, PhD, RD

https://pharmaceuticalintelligence.com/Paradigm Shift in Human Genomics_/

Signaling Pathways

  1. Proteins and cellular adaptation to stress

Larry H Bernstein, MD, FCAP, Curator


  1. A Synthesis of the Beauty and Complexity of How We View Cancer:
    Cancer Volume One – Summary

Author and Curator: Larry H. Bernstein, MD, FCAP


  1. Recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes in
    serous endometrial tumors

Sudipta Saha, PhD

https://pharmaceuticalintelligence.com/2012/11/19/recurrent-somatic-mutations-in-chromatin-remodeling-ad-ubiquitin-           ligase-complex-genes-in-serous-endometrial-tumors/

4.  Prostate Cancer Cells: Histone Deacetylase Inhibitors Induce Epithelial-to-Mesenchymal Transition

Stephen J Williams, PhD

https://pharmaceuticalintelligence.com/2012/11/30/histone-deacetylase-inhibitors-induce-epithelial-to-mesenchymal-              transition-in-prostate-cancer-cells/

5. Ubiquinin-Proteosome pathway, autophagy, the mitochondrion, proteolysis and cell apoptosis

Author and Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/10/30/ubiquinin-proteosome-pathway-autophagy-the-mitochondrion-                   proteolysis-and-cell-apoptosis/

6. Signaling and Signaling Pathways

Larry H. Bernstein, MD, FCAP, Reporter and Curator


7.  Leptin signaling in mediating the cardiac hypertrophy associated with obesity

Larry H. Bernstein, MD, FCAP, Reporter and Curator

https://pharmaceuticalintelligence.com/2013/11/03/leptin-signaling-in-mediating-the-cardiac-hypertrophy-associated-            with-obesity/

  1. Sensors and Signaling in Oxidative Stress

Larry H. Bernstein, MD, FCAP, Reporter and Curator


  1. The Final Considerations of the Role of Platelets and Platelet Endothelial Reactions in Atherosclerosis and Novel

Larry H. Bernstein, MD, FCAP, Reporter and Curator

https://pharmaceuticalintelligence.com/2013/10/15/the-final-considerations-of-the-role-of-platelets-and-platelet-                      endothelial-reactions-in-atherosclerosis-and-novel-treatments

10.   Platelets in Translational Research – Part 1

Larry H. Bernstein, MD, FCAP, Reporter and Curator


11.  Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and
Cardiovascular Calcium Signaling Mechanism

Author and Curator: Larry H Bernstein, MD, FCAP, Author, and Content Consultant to e-SERIES A:
Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/09/12/disruption-of-calcium-homeostasis-cardiomyocytes-and-vascular-             smooth-muscle-cells-the-cardiac-and-cardiovascular-calcium-signaling-mechanism/

12. The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and
Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia,
Similarities and Differences, and Pharmaceutical Targets

     Author and Curator: Larry H Bernstein, MD, FCAP, Author, and Content Consultant to
e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC and
Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/09/08/the-centrality-of-ca2-signaling-and-cytoskeleton-involving-calmodulin-       kinases-and-ryanodine-receptors-in-cardiac-failure-arterial-smooth-muscle-post-ischemic-arrhythmia-similarities-and-           differen/

13.  Nitric Oxide Signalling Pathways

Aviral Vatsa, PhD, MBBS


14. Immune activation, immunity, antibacterial activity

Larry H. Bernstein, MD, FCAP, Curator


15.  Regulation of somatic stem cell Function

Larry H. Bernstein, MD, FCAP, Writer and Curator    Aviva Lev-Ari, PhD, RN, Curator


16. Scientists discover that pluripotency factor NANOG is also active in adult organisms

Larry H. Bernstein, MD, FCAP, Reporter


Read Full Post »

Gene Expression: Algorithms for Protein Dynamics

Reporter:  Aviva Lev-Ari, PhD, RN

Stanford-developed algorithm reveals complex protein dynamics behind gene expression


Michael Snyder

In yet another coup for a research concept known as “big data,” researchers at the Stanford University School of Medicine have developed a computerized algorithm to understand the complex and rapid choreography of hundreds of proteins that interact in mindboggling combinations to govern how genes are flipped on and off within a cell.

To do so, they coupled findings from 238 DNA-protein-binding experiments performed by the ENCODE project — a massive, multiyear international effort to identify the functional elements of the human genome — with a laboratory-based technique to identify binding patterns among the proteins themselves.

The analysis is sensitive enough to have identified many previously unsuspected, multipartner trysts. It can also be performed quickly and repeatedly to track how a cell responds to environmental changes or crucial developmental signals.

“At a very basic level, we are learning who likes to work with whom to regulate around 20,000 human genes,” said Michael Snyder, PhD, professor and chair of genetics at Stanford. “If you had to look through all possible interactions pair-wise, it would be ridiculously impossible. Here we can look at thousands of combinations in an unbiased manner and pull out important and powerful information. It gives us an unprecedented level of understanding.”

Snyder is the senior author of a paper describing the research published Oct. 24 in Cell. The lead authors are postdoctoral scholars Dan Xie, PhD, Alan Boyle, PhD, and Linfeng Wu, PhD.

Proteins control gene expression by either binding to specific regions of DNA, or by interacting with other DNA-bound proteins to modulate their function. Previously, researchers could only analyze two to three proteins and DNA sequences at a time, and were unable to see the true complexities of the interactions among proteins and DNA that occur in living cells.

The challenge resembled trying to figure out interactions in a crowded mosh pit by studying a few waltzing couples in an otherwise empty ballroom, and it has severely limited what could be learned about the dynamics of gene expression.

The ENCODE, for the Encyclopedia of DNA Elements, project was a five-year collaboration of more than 440 scientists in 32 labs around the world to reveal the complex interplay among regulatory regions, proteins and RNA molecules that governs when and how genes are expressed. The project has been generating a treasure trove of data for researchers to analyze for the last eight years.

In this study, the researchers combined data from genomics (a field devoted to the study of genes) and proteomics (which focuses on proteins and their interactions). They studied 128 proteins, called trans-acting factors, which are known to regulate gene expression by binding to regulatory regions within the genome. Some of the regions control the expression of nearby genes; others affect the expression of genes great distances away.

The researchers used 238 data sets generated by the ENCODE project to study the specific DNA sequences bound by each of the 128 trans-acting factors. But these factors aren’t monogamous; they bind many different sequences in a variety of protein-DNA combinations. Xie, Boyle and Snyder designed a machine-learning algorithm to analyze all the data and identify which trans-acting factors tend to be seen together and which DNA sequences they prefer.

Wu then performed immunoprecipitation experiments, which use antibodies to identify protein interactions in the cell nucleus. In this way, they were able to tell which proteins interacted directly with one another, and which were seen together because their preferred DNA binding sites were adjoining.

“Before our work, only the combination of two or three regulatory proteins were studied, which oversimplified how gene regulators collaborate to find their targets,” Xie said. “With our method we are able to study the combination of more than 100 regulators and see a much more complex structure of collaboration. For example, it had been believed that a key regulator of cell proliferation called FOS typically only works with JUN protein family members. We show, in addition to JUN, FOS has different partners under different circumstances. In fact, we found almost all the canonical combinations of two or three trans-acting factors have many more partners than we previously thought.”

To broaden their analysis, the researchers included data from other sources that explored protein-binding patterns in five cell types. They found that patterns of co-localization among proteins, in which several proteins are found clustered closely on the DNA to govern gene expression, vary according to cell type and the conditions under which the cells are grown. They also found that many of these clusters can be explained through interactions among proteins, and that not every protein bound to DNA directly.

“We’d like to understand how these interactions work together to make different cell types and how they gain their unique identities in development,” Snyder said. “Furthermore, diseased cells will have a very different type of wiring diagram. We hope to understand how these cells go astray.”

Other Stanford co-authors include life science research assistant Jie Zhai and life science research associate Trupti Kawli, PhD.

The research was supported by the National Human Genome Research Institute (grants U54HG004558 and U54HG006996).

Information about Stanford’s Department of Genetics, which also supported the work, is available at http://genetics.stanford.edu.

Krista Conger | Tel (650) 725-5371
M.A. Malone | Tel (650) 723-6912

Stanford Medicine integrates research, medical education and patient care at its three institutions – Stanford University School of MedicineStanford Hospital & Clinics and Lucile Packard Children’s Hospital. For more information, please visit the Office of Communication & Public Affairs site at



Dynamic trans-Acting Factor Colocalization in Human Cells

Cell, Volume 155, Issue 3, 713-724, 24 October 2013
Copyright © 2013 Elsevier Inc. All rights reserved.


    • Highlights
    • Colocalization patterns of 128 TFs in human cells
    • An application of SOMs to study high-dimensional TF colocalization patterns
    • Colocalization patterns are dynamic through stimulation and across cell types
    • Many TF colocalizations can be explained by protein-protein interaction


    Different trans-acting factors (TFs) collaborate and act in concert at distinct loci to perform accurate regulation of their target genes. To date, the cobinding of TF pairs has been investigated in a limited context both in terms of the number of factors within a cell type and across cell types and the extent of combinatorial colocalizations. Here, we use an approach to analyze TF colocalization within a cell type and across multiple cell lines at an unprecedented level. We extend this approach with large-scale mass spectrometry analysis of immunoprecipitations of 50 TFs. Our combined approach reveals large numbers of interesting TF-TF associations. We observe extensive change in TF colocalizations both within a cell type exposed to different conditions and across multiple cell types. We show distinct functional annotations and properties of different TF cobinding patterns and provide insights into the complex regulatory landscape of the cell.


    Personalized medicine aims to assess medical risks, monitor, diagnose and treat patients according to their specific genetic composition and molecular phenotype. The advent of genome sequencing and the analysis of physiological states has proven to be powerful (Cancer Genome Atlas Research Network, 2011). However, its implementation for the analysis of otherwise healthy individuals for estimation of disease risk and medical interpretation is less clear. Much of the genome is difficult to interpret and many complex diseases, such as diabetes, neurological disorders and cancer, likely involve a large number of different genes and biological pathways (Ashley et al., 2010,Grayson et al., 2011,Li et al., 2011), as well as environmental contributors that can be difficult to assess. As such, the combination of genomic information along with a detailed molecular analysis of samples will be important for predicting, diagnosing and treating diseases as well as for understanding the onset, progression, and prevalence of disease states (Snyder et al., 2009).

    Presently, healthy and diseased states are typically followed using a limited number of assays that analyze a small number of markers of distinct types. With the advancement of many new technologies, it is now possible to analyze upward of 105 molecular constituents. For example, DNA microarrays have allowed the subcategorization of lymphomas and gliomas (Mischel et al., 2003), and RNA sequencing (RNA-Seq) has identified breast cancer transcript isoforms (Li et al., 2011,van der Werf et al., 2007,Wu et al., 2010,Lapuk et al., 2010). Although transcriptome and RNA splicing profiling are powerful and convenient, they provide a partial portrait of an organism’s physiological state. Transcriptomic data, when combined with genomic, proteomic, and metabolomic data are expected to provide a much deeper understanding of normal and diseased states (Snyder et al., 2010). To date, comprehensive integrative omics profiles have been limited and have not been applied to the analysis of generally healthy individuals.

    To obtain a better understanding of: (1) how to generate an integrative personal omics profile (iPOP) and examine as many biological components as possible, (2) how these components change during healthy and diseased states, and (3) how this information can be combined with genomic information to estimate disease risk and gain new insights into diseased states, we performed extensive omics profiling of blood components from a generally healthy individual over a 14 month period (24 months total when including time points with other molecular analyses). We determined the whole-genome sequence (WGS) of the subject, and together with transcriptomic, proteomic, metabolomic, and autoantibody profiles, used this information to generate an iPOP. We analyzed the iPOP of the individual over the course of healthy states and two viral infections (Figure 1A). Our results indicate that disease risk can be estimated by a whole-genome sequence and by regularly monitoring health states with iPOP disease onset may also be observed. The wealth of information provided by detailed longitudinal iPOP revealed unexpected molecular complexity, which exhibited dynamic changes during healthy and diseased states, and provided insight into multiple biological processes. Detailed omics profiling coupled with genome sequencing can provide molecular and physiological information of medical significance. This approach can be generalized for personalized health monitoring and medicine.


    Read Full Post »

    ENCODE (Encyclopedia of DNA Elements) program: ‘Tragic’ Sequestration Impact on NHGRI Programs

    Reporter: Aviva Lev-Ari, PhD, RN

    NHGRI’s Green Sees ‘Tragic’ Sequestration Impact on NHGRI Programs

    September 13, 2013

    NEW YORK (GenomeWeb News) – The funding squeeze from the sequestration of the US federal budget, now more than half-a-year old, has already had a sizable impact at the National Human Genome Research Institute, leading to cuts to ongoing programs, scaling back of new ones, and the deferring of efforts that have not yet launched.

    The five percent cut in funding this year at NHGRI has led not only to trimmed-down renewal grants and fewer, smaller awards broadly, but also has chopped the budget for some of the institute’s important programs, according to NHGRI Director Eric Green.

    The programs that have either had their funding reduced, and in one case delayed, include the ENCODE (Encyclopedia of DNA Elements) program, projects focused on using genome sequencing in newborns and in clinical medicine, and other initiatives, Green said in his Director’s Report to the National Advisory Council on Human Genomics Research this week.

    In addition, many renewal grants have been trimmed, and there are “numerous examples of detrimental cuts” to the institute’s intramural research program, said Green. These cuts to large and small NHGRI programs come at a pivotal time for genomics, he noted, as the products of such research are beginning to translate into clinical possibilities.

    “It is tragic. [That] is the word I would use,” Green told GenomeWeb Daily News this week.

    “[The field of genomics] is just so exciting. There are so many opportunities,” he said. “This is precisely the time that we should be pushing the accelerator hard, and we just cannot do it because we don’t have enough fuel in our fuel tank.

    “It’s frustrating. I think the opportunities now are just spectacular,” said Green. “It’s tragic because it is just so obvious that we could do some remarkable things in genomics and we are not being able to do it.”

    ENCODE, a decade-old flagship project at NIH that aims to identify all of the functional elements in the human genome, had its budget reduced by 16 percent.

    The Genomic Sequencing and Newborn Screening Disorders program was cut by half, which left the program to fund fewer research projects than planned and its research consortium to go forward without the benefit of a data coordinating center. This new initiative, an effort to support pioneering studies on how sequencing might be used in the care of newborns and in neonatal care that was created jointly with the Eunice Kennedy Shriver National Institute of Child Health and Human Development, had its budget cut from $10 million to $5 million.

    The Genomic Medicine Pilot Demonstration Projects program had its budget cut by 20 percent, and NHGRI’s Bioinformatics Resources and Analysis Research Portfolio had $5 million sliced out of its budget. The new Genomics of Gene Regulation (GGR)request for applications was bumped out of this funding year entirely, and has been delayed until 2014, according to Green.

    Because the sequestration plan was concocted and agreed to well in advance of its arrival earlier this year, Green told GWDN that the institute did have some time to try to react to the sequestration and mitigate the pain from the cuts, spreading them around fairly and evenly while maintaining priorities. He said leadership at the institute tried to prepare for the possibility of sequestration by being conservative in its planning.

    Programs that were already ongoing, like ENCODE, were likely to take priority over those that were not yet launched, like GGR, in part because the infrastructure is already in place for ongoing projects and because it is easier to plan for how they operate and generate outputs, like data.

    “With ENCODE you know for every million dollars you invest you get so much back,” said Green. “With a program like newborn sequencing … we don’t totally know what it’s going to look like or play out like. We won’t know what we are missing because we won’t be able to launch it to the scale that we wanted to launch it originally.”

    Green said some of the projects being cut or delayed were created under NHGRI’sstrategic plan, a program it laid out in 2011 that involves restructuring of the institute’s divisions and some shifting in its research portfolio to include more efforts in applying genomics to medicine and healthcare.

    “Some of these RFAs that we delayed really represent key elements that we started to anticipate two years ago,” said Green. “We knew we wanted to do more in sequencing, we knew we wanted to do some pilot projects in genomic medicine. We knew we wanted to continue to accelerate efforts in understanding how the genome works … ENCODE, GGR, and so forth. It just had to be slowed down,” he said.

    Anastasia Wise, program director for the Genomic Sequencing and Newborn Screening Disorders program, told GWDN that the program was supposed to be much larger than the $5 million in awards unveiled last week, which funded a consortium of four research projects.

    Wise said NHGRI and NICHD were each initially planning to provide double the amount of funding they were actually awarded, which is now expected to be a total of $25 million over five years, although that total could be subject to the availability of funding.

    “There were definitely more scientifically meritorious applications than we were able to fund,” she said. “Even the four awards that we made ended up being cut an additional five percent because of the sequestration.”

    She said the program “wanted to be able to make more awards, and we wanted to be able to fund a coordinating center to be able to bring the network together and help provide some harmonization of data and coordination of logistics between the different members of the consortium,” but it was unable to fund that part of the effort.

    Although the fractured fiscal culture in Washington engenders caution at NHGRI as the agency looks forward, Green sees many scientific opportunities right now, as genomics begins to hit the clinic.

    “Some people are saying we are not even going fast enough,” he said. “Lots of people have been discussing what the world is going to look like when somebody gets their genome sequenced in the newborn period, and [they] think about what the implications of that are for the patient for the rest of their lives. We want to start studying this,” he said.

    “And we are starting to … but we’re not starting as aggressively as we wanted to,” Green said. “I mean, we took a big hit this year.”

    Matt Jones is a staff reporter for GenomeWeb Daily News. He covers public policy, legislation, and funding issues that affect researchers in the genomics field, as well as the operations of research institutes. E-mail Matt Jones or follow GWDN’s headlines at @DailyNewsGW.

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    ASHG to Maintain Information of to shut down National Genetics Coalition

    Reporter: Aviva Lev-Ari, PhD, RN


    National Genetics Coalition to Shut Down,

    July 30, 2013

    NEW YORK (GenomeWeb News) – The National Coalition for Health Professional Education in Genetics (NCHPEG), an interdisciplinary group of leaders from a range of public and private organizations funded by the National Institutes of Health, will shut down next month due to funding constraints, according to the National Human Genome Research Institute.

    The genetics and genomics education information that NCHPEG has compileds and made available via its website will be maintained by the American Society of Human Genetics, ASHG executive VP and former NCHPEG executive director Joseph McInerney said.

    NCHPEG launched in 1996 after current NIH Director Francis Collins and Kathy Hudson, current NIH director for science, outreach, and policy, began talking with the American Medical Association and the American Nurses Association about the need for educating healthcare providers about genetics and genomics. Those discussions led to the creation of the group, which has been funded by NHGRI, the National Center for Advancing Translational Sciences, the NIH Office of Rare Diseases, and several other government agencies and non-profit foundations.

    NCHPEG is slated to close down on Aug. 31. When the coalition began, there were few applications for genomics-related applications in healthcare that doctors encountered.

    “A lot has changed since then,” NCHPEG Executive Director Joan Scott said in a statement. “There are many more clinical applications of genomics available and a growing awareness within the healthcare provider community that they need to be thinking about incorporating them into practice. We see more institutions and organizations developing initiatives to bring genomics into the clinic.”

    The coalition’s core aim has been to provide genetics and genomics professional education tools through partnerships with specific communities and collaborations.

    To that end, it has developed a number of documents, products, and programs to provide core competencies and educational programs in genetics, genomics, and family history for healthcare professionals.

    The group has developed special programs aimed at helping physicians recognize increased genetic risk for cancer, and helping nutritionists, physician’s assistants, dentists, nurses, and others understand genetics and genomics.

    McInerney said that ASHG will work over the next six months to determine whether the society wants to become more deeply involved in offering educational programs to healthcare providers.

    “But we have to be thoughtful. NCHPEG is closing as a direct result of the current funding climate. We have to determine where our funding for education programs would come from if our board decides to take this on,” he explained.

    McInerney said that during his time at NCHPEG, the group distributed thousands of publications on genomics education.

    “Our premise was that healthcare professionals want to be up-to-date on all areas of medicine. Many of them already felt like the field of genetics and genomics was snowballing and they wanted to be ready,” he said.





    Read Full Post »

    Reporter: Aviva Lev-Ari, PhD, RN

    Genome.gov National Human Genome Research Institute National Institutes of Health

    Online Research Resources


    From NHGRI
    Online Research Resources Developed at NHGRI
    NHGRI Reports and Publications
    The NHGRI Genome Sequencing Program (GSP)
    Beyond NHGRI
    The Completed Human Sequence
    Other Federal Agencies Involved in Genomics
    Human Genome Sequence Assemblies and Other Genomic Data Resources
    Underlying Map Information
    Sequencing Centers of the International Human Genome Sequencing Consortium
    Model Organism Genome Projects
    Archaea and Bacteria
    National Center for Biotechnology Information (NCBI) Databases and Tools
    Nucleotide Sequence Databases
    Trace Archives (Raw Sequence Data Repositories)
    Single Nucleotide Polymorphisms (SNPs)
    cDNAs and Expressed Sequence Tags (ESTs)
    Model Organism Databases
    Additional Sequence, Gene and Protein Databases
    Ethical, Legal and Social Implications (ELSI) Information
    Funding Agencies
    Additional Genome Resources
    Biology Resources
    Selected Journals

    From NHGRI

    Online Research Resources Developed at NHGRI
    Software, databases and research project Web sites from NHGRI’s Division of Intramural Research (DIR).

    NHGRI Reports and Publications

    The NHGRI Genome Sequencing Program (GSP) 
    Genome sequencing projects currently in production and funded by NHGRI.

    Beyond NHGRI

    The Completed Human Sequence:
    Other Federal Agencies Involved in Genomics
    Human Genome Sequence Assemblies and Other Genomic Data Resources


    Underlying Map Information
    Sequencing Centers of the International Human Genome Sequencing Consortium

    (Listed in order of total sequence contributed to the draft human sequence published February 15, 2001, Nature, 409:860-921)

    Model Organism Genome Projects

    Archaea and Bacteria



    National Center for Biotechnology Information (NCBI) Databases and Tools

    Nucleotide Sequence Databases

    Trace Archives (Raw Sequence Data Repositories)

    Single Nucleotide Polymorphisms (SNPs)

    cDNAs and Expressed Sequence Tags (ESTs)

    Model Organism Databases

    Additional Sequence, Gene and Protein Databases

    • InterPro protein sequence analysis & classification [ebi.ac.uk]
      An integrated database of predictive protein signatures used for the classification and automatic annotation of proteins and genomes.
    • Eukaryotic Promoter Database [epd.isb-sib.ch]
    • PROSITE [expasy.org]
      A database of protein families and domains.
    • SWISS-PROT [web.expasy.org]
      A protein knowledgebase.
    • BioMagResBank [bmrb.wisc.edu]
      NMR spectroscopy data on proteins, peptides, and nucleic acids.
    • Protein Data Bank (PDB) [rcsb.org]
      The repository for 3-D biological macromolecular structure data.
    • DSSP [swift.cmbi.ru.nl]
      A database of secondary structure protein assignments.
    • FSSP [biocenter.helsinki.fi]
      A database of fold classifications based on structure-structure alignment of proteins.
    • HSSP [cmbi.kun.nl]
      A database of homology-derived secondary structure of proteins.
    • Nucleic Acid Database Project (NDB) [ndbserver.rutgers.edu]
      Structural information about nucleic acids.
    • The I.M.A.G.E. Consortium [image.hudsonalpha.org]
      A public collection of genes.
    Ethical, Legal and Social Implications (ELSI) Research Program
    Funding Agencies
    Additional Genome Resources
    Biology Resources
    Selected Journals

    Last Updated: October 16, 2012



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    Reporter: Aviva Lev-Ari, PhD, RN

    The reader is encourage to review the following ANALYSIS of this subject matter:

    Genomics & Genetics of Cardiovascular DiseaseDiagnoses: A Literature Survey of AHA’s Circulation Cardiovascular Genetics, 3/2010 – 3/2013


    10 Years On, Still Much To Be Learned From Human Genome Map

    Advances made in genetics of disease, but creating new drugs more complex than first thought

    By Amanda Gardner
    HealthDay Reporter

    FRIDAY, April 12 (HealthDay News) — As scientists mark the 10th anniversary Sunday of the completion of the Human Genome Project, they will note how that watershed effort has led to the discovery of the genetic underpinnings of almost 5,000 diseases.

    And it has made it possible to develop personalized treatments that have prolonged the lives of many.

    But the scientists will also acknowledge that, while the project has unlocked many mysteries that once shrouded diseases, there’s still much to be learned before new drugs can be developed to target illness-causing mutations in human DNA.

    “What we’ve learned over the past 10 years is that we’re still far from really understanding the complexity of the human genome,” said Eric Schadt, chairman of genetics and genomic sciences at Mount Sinai Icahn School of Medicine in New York City. “Human disease is way more complicated than the old view that single hits to single genes cause diseases.

    “In most forms of diseases, it’s whole constellations of genes operating in networks,” Schadt explained. “That becomes a much harder problem. How do you target networks with a single drug?

    “We keep learning how much we really don’t know and how much further we need to go,” he added. “That’s the big story.”

    A decade ago, the Human Genome Project was hailed as a major milestone because researchers identified all of the nearly 25,000 genes in human DNA and sequenced the 3 billion chemical base pairs comprising that DNA.

    The feat took 13 years and cost close to $3 billion, but the genetic information gleaned from the project gave scientists the tools needed to pinpoint how changes in specific genes could kick-start some diseases.

    One of the most tangible benefits of the project has been the development of ever more sophisticated sequencing technology and a dramatic lowering of the cost of using that technology.

    Today, the cost of sequencing one human genome is closer to $5,000 and can be done in a day or two, said Dr. Eric Green, director of the National Human Genome Research Institute in Bethesda, Md.

    What that means is that the pace of research, and its attendant discoveries, has been accelerated.

    When the project first began, scientists knew the genetic basis of about 53 diseases. Today, that number is close to 5,000, Green noted. That means doctors can now test patients to see if they carry gene mutations that raise their risk for certain diseases, and counsel them accordingly on ways they might prevent or delay illness. There are currently almost 2,000 genetic tests for specific diseases or conditions, according to the U.S. National Institutes of Health.

    There have also been breakthroughs with some rare diseases.

    In 2011, 6-year-old Nicholas Volker became the first child to be saved by the new technology. He had undergone a hundred surgeries, including the removal of his colon, as doctors tried to identify his mysterious bowel disease. Genomic sequencing uncovered a genetic mutation that could be treated with a bone marrow transplant consisting of cells from umbilical cord blood.

    “Knowing more of the basic genetics that makes up an individual has allowed us to diagnose far more genetic diseases,” said Dr. Barbara Pober, a medical geneticist at the Frank H. Netter, M.D. School of Medicine at Quinnipiac University in North Haven, Conn.

    Once a diagnosis has been made, doctors can now use gene sequencing to determine treatment for some diseases. For instance, breast cancer patients can be tested to see how they will respond to the drug Herceptin. HIV patients can be tested to determine their response to the drug abacavir. And those on the widely used blood thinner warfarin can be tested to determine the most effective dose, according to the NIH.

    The field of pharmacogenetics, still in its infancy, enables doctors to use a patient’s genetic information to figure out which cancer drugs the patient will best respond to before treatment even starts.

    The U.S. Food and Drug Administration now includes genetic information on labeling for more than 100 drugs, up from just four 10 years ago, Green said.

    The goal of developing new drugs to target diseases with genetic roots, however, will take much longer to realize.

    Although the NIH states that there are roughly 350 biotechnological products currently being tested in clinical trials, new drugs take a decade or more to develop. Not only that, the knowledge gained from the Human Genome Project has actually made the field of genetic medicine even more complex. Scientists are finding that many diseases are triggered by interaction involving multiple gene variants, making it difficult to design a treatment that targets all the culprits in a particular illness.

    And the complexities don’t end there.

    Not long ago, scientists discovered that so-called “junk” DNA, which makes up 98 percent of the genome, is not junk at all but serves critical regulatory functions.

    What’s more, about 10 percent of the human genome still hasn’t been sequenced and can’t be sequenced by existing technology, Green added. “There are parts of the genome we didn’t know existed back when the genome was completed,” he said.

    More information

    For more on developments over the past 10 years, visit the Human Genome Projectwebsite.

    SOURCES: Eric Green, M.D., Ph.D., director, National Human Genome Research Institute, Bethesda, Md.; Barbara Pober, M.D., professor, medical sciences, Frank H. Netter, M.D., School of Medicine, Quinnipiac University, North Haven, Conn.; Eric Schadt, Ph.D., professor and chairman, department of genetics and genomic sciences, Mount Sinai Icahn School of Medicine, New York City

    Last Updated: April 12, 2013

    Health News Copyright © 2013 HealthDay. All rights reserved.


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    Reporter: Aviva Lev-Ari, PhD, RN

    Centers of Excellence in Genomic Sciences (CEGS): NHGRI to Fund New Center (CEGS) on the Brain: Mental Disorders and the Nervous System

    April 16, 2013

    NEW YORK (GenomeWeb News) – The National Human Genome Research Institute plans to fund new Centers of Excellence in Genomic Sciences, or CEGS, to create interdisciplinary teams that pursue innovative genome-based approaches to address biomedical problems and to understanding the basis of biological systems.

    NHGRI, along with support from the National Institute of Mental Health, expects to provide up to $2 million per year for each of the new CEGS it funds, and plans to award up to four new awards each year.

    Although these CEGS may pursue a wide range of research objectives, NIMH will support the program because it wants to fund research using novel genomic approaches that can accelerate the understanding of the genetic basis of mental disorders and the nervous systemNHGRI said on Friday.

    The CEGS program was created to use the new knowledge and technologies that resulted from the Human Genome Project and subsequent genomics research to develop new tools, methods, and concepts that apply to human biology and disease.
    CEGS grantees are expected to be innovative, to focus on a critical issue in genomic science, to use multiple investigators working under one leader, to work toward a specific outcome, and to tackle challenging aspects of problems that may have impeded previous research efforts.

    Further, they are supposed to bolster the pool of professional scientists and engineers who are trained in genomics through offering educational programs, and they are expected to address the shortage of scientists from underrepresented minority communities by developing recruiting programs that encourage minority community members to become independent genomics investigators.

    The technologies and methods the CEGS investigators develop should be applicable to a wide range of cell types and organisms, and they should be scalable and expandable so they may apply to other model systems, according to NHGRI’s funding opportunity announcement.

    Recent CEGS centers include

    • Caltech’s Center for In Toto Genomic Analysis of Vertebrate Development;
    • Harvard University’s Center for Transcriptional Consequences of Human Genetic Variation;
    • Johns Hopkins University’s Center for the Epigenetics of Common Human Disease;
    • Stanford University’s Center for the Genomic Basis of Vertebrate Diversity;
    • Arizona State University’s Microscale Life Sciences Center;
    • Medical College of Wisconsin, Milwaukee’s Center of Excellence in Genomics Science;
    • The University of North Carolina at Chapel Hill‘s CISGen center;
    • The Broad Institute’s Center for Cell Circuits;
    • Yale University’s Center for the Analysis of Human Genome Using Integrated Technologies; and
    • Dana-Farber Cancer Institute‘s Center for Genomic Analysis of Network Perturbations in Human Disease.


    Center for In Toto Genomic Analysis of Vertebrate Development

    P50 HG004071
    Marianne Bronner-Fraser
    California Institute of Technology, Pasadena, Calif.

    This Center of Excellence in Genomic Science (CEGS) assembles a multidisciplinary group of investigators to develop innovative technologies with the goal of imaging and mutating every developmentally important vertebrate gene. Novel “in toto imaging” tools make it possible to use a systems-based approach for analysis of gene function in developing vertebrate embryos in real time and space. These tools can digitize in vivo data in a systematic, high-throughput, and quantitative fashion. Combining in toto imaging with novel gene traps permits a means to rapidly screen for developmentally relevant expression patterns, followed by the ability to immediately mutagenize genes of interest. Initially, key technologies will be developed and tested in the zebrafish embryo due to its transparency and the ability to obtain rapid feedback. Once validated, these techniques will be applied to an amniote, the avian embryo, due to several advantages including accessibility and similarity to human embryogenesis. Finally, to monitor alterations in gene expression in normal and mutant embryos, we will develop new techniques for in situ hybridization that permit simultaneous analysis of multiple marker genes in a sensitive and potentially quantitative manner. Our goal is to combine real time analysis of gene expression on a genome-wide scale coupled with the ability to mutate genes of interest and examine global alterations in gene expression as a result of gene loss. Much of the value will come from the development of new and broadly applicable technologies. In contrast to a typical technology development grant, however, there will be experimental fruit emerging from at least two vertebrate systems (zebrafish and avian). The following aims will be pursued: Specific Aim 1: Real-time “in toto” image analysis of reporter gene expression; Specific Aim 2: Comprehensive spatiotemporal analysis of gene function of the developing vertebrate embryo using the FlipTrap approach for gene trapping; Specific Aim 3: Design of quantitative, multiplexed ‘hybridization chain reaction’ (HCR) amplifiers for in vivo imaging with active background suppression; Specific Aim 4: Data analysis and integration of data sets to produce a “digital” fish and a “digital” bird. The technologies and the resulting atlases will be made broadly available via electronic publication.

    Center Web Site: California Institute of Technology Center of Excellence in Genomic Science

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    Causal Transcriptional Consequences of Human Genetic Variation

    P50 HG005550
    George M. Church
    Harvard University, Cambridge, Mass.

    The Center for Transcriptional Consequences of Human Genetic Variation (CTCHGV) will develop innovative and powerful genetic engineering methods and use them to identify genetic variations that causally control gene transcription levels. Genome Wide Association Studies (GWAS) find many variations associated with disease and other phenotypes, but the variations that may actually cause these conditions are hard to identify because nearby variations in the same haplotype blocks consistently co-occur with them in human populations, so that specifically causative ones cannot be distinguished. About 95% of GWAS variations are not in gene coding regions, and many of these presumably associate with altered gene expression levels. CTCHGV will identify the variations that directly control gene expression by engineering precise combinations of changes to gene regulatory regions that break down the haplotype blocks, allowing each variations’ effect on gene expression to be discerned independently of the others. To perform this analysis, CTCHGV will extract ~100kbps gene regulatory regions from human cell samples, create precise variations in them in E. coli, and re-introduce the altered regions back into human cells, using zinc finger nucleases (ZFNs) to efficiently induce recombination. CTCHGV will target 1000 genes for this analysis (Aim 1), and will use human induced Pluripotent Stem cells (iPS) to study the effects of variations in diverse human cell types (Aim 2). To explore the effects of variations in complex human tissues, CTCHGV will develop methods of measuring gene expression at transcriptome-wide levels in many single cells, including in situ in structured tissues (Aim 3). Finally, CTCHGV will develop novel advanced technologies that integrate DNA sequencing and synthesis to construct thousands of large DNA constructs from oligonucleotides, that enable very precise targeting and highly efficient performance of ZFNs, and that enable cells to be sorted on the basis of morphology as well as fluorescence and labeling (Aim 4). CTCHGV will also develop direct oligo-mediated engineering of human cells, and create “marked allele” iPS that will enable easy ascertainment of complete exon distributions for many pairs of gene alleles in many cell types.

    Center Web Site: Center for Causal Transcriptional Consequences of Human Genetic Variation (CTCHGV)

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    Center for the Epigenetics of Common Human Disease

    P50 HG003233
    Andrew P. Feinberg
    Johns Hopkins University, Baltimore
    (co-funded by National Institute of Mental Health)

    Epigenetics, the study of non-DNA sequence-related heredity, is at the epicenter of modern medicine because it can help to explain the relationship between an individual’s genetic background, the environment, aging, and disease. The Center for the Epigenetics of Common Human Disease was created in 2004 to begin to develop the interface between epigenetics and epidemiologic-based phenotype studies, recognizing that epigenetics requires new ways of thinking about disease. We created a highly interdisciplinary group of faculty and trainees, including molecular biologists, biostatisticians, epidemiologists, and clinical investigators. We developed novel approaches to genome-wide DNA methylation (DNAm) analysis, allele-specific expression, and new statistical epigenetic tools. Using these tools, we discovered that most variable DNAm is in neither CpG islands nor promoters, but in what we term “CpG island shores,” regions of lower CpG density up to several kb from islands, and we have found altered DNAm in these regions in cancer, depression and autism. In the renewal period, we will develop the novel field of epigenetic epidemiology, the relationship between epigenetic variation, genetic variation, environment and phenotype. We will continue to pioneer genome-wide epigenetic technology that is cost effective for large scale analysis of population-based samples, applying our knowledge from the current period to second-generation sequencing for epigenetic measurement, including DNAm and allele-specific methylation. We will continue to pioneer new statistical approaches for quantitative and binary DNAm assessment in populations, including an Epigenetic Barcode. We will develop Foundational Epigenetic Epidemiology, examining: time-dependence, heritability and environmental relationship of epigenetic marks; heritability in MZ and DZ twins; and develop an epigenetic transmission disequilibrium test. We will then pioneer Etiologic Epigenetic Epidemiology, by integrating novel genome-wide methylation scans (GWMs) with existing Genome-Wide Association Study (GWAS) and epidemiologic phenotype data, a design we term Genome-Wide Integrated Susceptibility (GWIS), focusing on bipolar disorder, aging, and autism as paradigms for epigenetic studies of family-based samples, longitudinal analyses, and parent-of-origin effects, respectively. This work will be critical to realizing the full value of previous genetic and phenotypic studies, by developing and applying molecular and statistical tools necessary to integrate DNA sequence with epigenetic and environmental causes of disease.

    Center Web Site: Center of Excellence in Genomic Science at Johns Hopkins

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    Genomic Basis of Vertebrate Diversity

    P50 HG002568
    David M. Kingsley
    Stanford University, Stanford, Calif.

    The long-term goal of this project is to understand the genomic mechanisms that generate phenotypic diversity in vertebrates. Rapid progress in genomics has provided nearly complete sequences for several organisms. Comparative analysis suggests many fundamental pathways and gene networks are conserved between organisms. And yet, the morphology, physiology, and behavior of different species are obviously and profoundly different. What are the mechanisms that generate these key differences? Are unique traits controlled by few or many genetic changes? What kinds of changes? Are there particular genes and mechanisms that are used repeatedly when organisms adapt to new environments? Can better understanding of these mechanisms help explain dramatic differences in disease susceptibility that also exist between groups? The Stanford CEGS will use an innovative combination of approaches in fish, mice, and humans to identify the molecular basis of major phenotypic change in natural populations of vertebrates. Specific aims include: 1) cross stickleback fish and develop a genome wide map of the chromosomes, genes, and mutations that control a broad range of new morphological, physiological, and behavioral traits in natural environments; 2) test which population genetic measures provide the most reliable “signatures of selection” surrounding genes that are known to have served as the basis of parallel adaptive change in many different natural populations around the world; 3) assemble the stickleback proto Y chromosome and test whether either sex or autosomal rearrangements play an important role in generating phenotypic diversity, or are enriched in genomic regions that control phenotypic change; 4) test whether particular genes and mechanisms are used repeatedly to control phenotypic change in many different vertebrates. Preliminary data suggests that mechanisms identified as the basis of adaptive change in natural fish populations may be broadly predictive of adaptive mechanisms across a surprisingly large range of animals, including humans. Genetic regions hypothesized to be under selection in humans will be compared to genetic regions under selection in fish. Regions predicted to play an important role in natural human variation and disease susceptibility will be modeled in mice, generating new model systems for confirming functional variants predicted from human population genetics and comparative genomics.

    Center Web Site: Stanford Genome Evolution Center

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    Microscale Life Sciences Center

    P50 HG002360
    Deirdre R. Meldrum
    Arizona State University, Tempe

    Increasingly, it is becoming apparent that understanding, predicting, and diagnosing disease states is confounded by the inherent heterogeneity of in situ cell populations. This variation in cell fate can be dramatic, for instance, one cell living while an adjacent cell dies. Thus, in order to understand fundamental pathways involved in disease states, it is necessary to link preexisting cell state to cell fate in the disease process at the individual cell level.

    The Microscale Life Sciences Center (MLSC) at the University of Washington is focused on solving this problem, by developing cutting-edge microscale technology for high throughput genomic-level and multi-parameter single-cell analysis, and applying that technology to fundamental problems of biology and health. Our vision is to address pathways to disease states directly at the individual cell level, at increasing levels of complexity that progressively move to an in vivo understanding of disease. We propose to apply MLSC technological innovations to questions that focus on the balance between cell proliferation and cell death. The top three killers in the United States, cancer, heart disease and stroke, all involve an imbalance in this cellular decision-making process. Because of intrinsic cellular heterogeneity in the live/die decision, this fundamental cellular biology problem is an example of one for which analysis of individual cells is essential for developing the link between genomics, cell function, and disease. The specific systems to be studied are proinflammatory cell death (pyroptosis) in a mouse macrophage model, and neoplastic progression in the Barrett’s Esophagus (BE) precancerous model. In each case, diagnostic signatures for specific cell states will be determined by measuring both physiological (cell cycle, ploidy, respiration rate, membrane potential) and genomic (gene expression profiles by single-cell proteomics, qRT-PCR and transcriptomics; LOH by LATE-PCR) parameters. These will then be correlated with cell fate via the same sets of measurements after a challenge is administered, for instance, a cell death stimulus for pyroptosis or a predisposing risk factor challenge (acid reflux) for BE. Ultimately, time series will be taken to map out the pathways that underlie the live/die decision.

    Finally, this information will be used as a platform to define cell-cell interactions at the single-cell level, to move information on disease pathways towards greater in vivo relevance. New technology will be developed and integrated into the existing MLSC Living Cell Analysis cassette system to support these ambitious biological goals including 1) automated systems for cell placement, off-chip device interconnects, and high throughput data analysis with user friendly interfaces; 2) new optical and electronic sensors based on a new detection platform, new dyes and nanowires; and 3) new micromodules for single-cell qRT-PCR, LATE-PCR for LOH including single-cell pyrosequencing, on-chip single-cell proteomics, and single-cell transcriptomics using barcoded nanobeads.

    Collaborating InstitutionsFred Hutchison Cancer Research Center, Brandeis University, University of Washington.

    Center Web Site: Microscale Life Sciences Center

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    Wisconsin Center of Excellence in Genomics Science

    P50 HG004952
    Michael Olivier
    Medical College of Wisconsin, Milwaukee

    The successful completion of the human genome and model organism sequences has ushered in a new era in biological research, with attention now focused on understanding the way in which genome sequence information is expressed and controlled. The focus of this proposed Wisconsin Center of Excellence in Genomics Science is to facilitate understanding of the complex and integrated regulatory mechanisms affecting gene transcription by developing novel technology for the comprehensive characterization and quantitative analysis of proteins interacting with DNA. This new technology will help provide for a genome-wide functional interpretation of the underlying mechanisms by which gene transcriptional regulation is altered during biological processes, development, disease, and in response to physiological, pharmacological, or environmental stressors. The development of chromatin immunoprecipitation approaches has allowed identification of the specific DNA sequences bound by proteins of interest. We propose to reverse this strategy and develop an entirely novel technology that will use oligonucleotide capture to pull down DNA sequences of interest, and mass spectrometry to identify and characterize the proteins and protein complexes bound and associated with particular DNA regions. This new approach will create an invaluable tool for deciphering the critical control processes regulating an essential biological function. The proposed interdisciplinary and multi-institutional Center of Excellence in Genomics Science combines specific expertise at the Medical College of Wisconsin, the University of Wisconsin Madison, and Marquette University. Technological developments in four specific areas will be pursued to develop this new approach: (1) cross-linking of proteins to DNA and fragmentation of chromatin; (2) capture of the protein-DNA complexes in a DNA sequence-specific manner; (3) mass spectrometry analysis to identify and quantify bound proteins; and (4) informatics to develop tools enabling the global analysis of the relationship between changes in protein-DNA interactions and gene expression. The Center will use carefully selected biological systems to develop and test the technology in an integrated genome-wide analysis platform that includes efficient data management and analysis tools. As part of the Center mission, we will combine our technology development efforts with an interdisciplinary training program for students and fellows designed to train qualified scientists experienced in cutting-edge genomics technology. Data, technology, and software will be widely disseminated by multiple mechanisms including licensing and commercialization activities.

    Collaborating InstitutionsUniversity of Wisconsin-Madison, Marquette University

    Center Web Site: Wisconsin Center of Excellence in Genomic Science

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    P50 MH090338
    Fernando Pardo-Manuel de Villena
    University of North Carolina, Chapel Hill

    p>In this application, we propose a highly ambitious yet realistically attainable goal: to align existing expertise at UNC-Chapel Hill into a CEGS called CISGen. The overarching purpose of CISGen is to develop as a resource and to exploit the utility of the murine Collaborative Cross (CC) mouse model of the heterogeneous human population to delineate genetic and environmental determinants of complex phenotypes drawn from psychiatry, which are among the most intractable set of problems in all of biomedicine. Psychiatric disorders present a paradox – the associated morbidity, mortality, and costs are enormous and yet, despite over a century of scientific study, there are few hard facts about the etiology of the core diseases. Although our GWAS meta- analyses are in progress, early results suggest that strong and replicable findings may be elusive. Therefore, our proposal provides a complementary approach to the study of fundamental psychiatric phenotypes.

    We propose a particularly challenging definition of success – we will identify high probability etiological models (which can be realistically complex) and then prove the predictive capacity of these models by generating novel strains of mice predicted to be at very high risk for the phenotype. Once validated, these high confidence models can then be tested in subsequent human studies – we do not propose human extension studies in CISGen but this is achievable for the investigators and their colleagues. Data collected in CISGen would be a valuable resource to the wider scientific community and could be applied to a large set of biological problems and these data can rapidly add to the knowledge base for any new genomewide association study (GWAS) finding. Delivery of sophisticated and user-friendly databases are a key component of CISGen.

    Accomplishing this overarching goal requires an exceptional diversity of scientific expertise – psychiatry, human genetics, mouse behavior, mouse genetics, statistical genetics, computational biology, and systems biology. Experts in these disciplines are deeply involved in CISGen and are committed to the projects described herein. Successful integration of these diverse fields is non-trivial; however, all scientists on this application have had extensive interactions over the past five years, already know how to work together, and have a working knowledge of their colleagues’ expertise. UNC-Chapel Hill has an intense commitment to inter- disciplinary genomics research and provides a fertile backdrop for 21st century projects like CISGen.

    Collaborating InstitutionsThe Jackson Laboratory, North Carolina State University, University of Texas at Arlington

    Center Web Site: Center for Integrated Systems Genomics at UNC (CISGen)

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    Center for Cell Circuits

    P50 HG006193
    Aviv Regev
    The Broad Institute, Inc., Cambridge, Mass.

    Systematic reconstruction of genetic and molecular circuits in mammalian cells remains a significant, largescale and unsolved challenge in genomics. The urgency to address it is underscored by the sizeable number of GWAS-derived disease genes whose functions remain largely obscure, limiting our progress towards biological understanding and therapeutic intervention. Recent advances in probing and manipulating cellular circuits on a genomic scale open the way for the development of a systematic method for circuit reconstruction. Here, we propose a Center for Cell Circuits to develop the reagents, technologies, algorithms, protocols and strategies needed to reconstruct molecular circuits. Our preliminary studies chart an initial path towards a universal strategy, which we will fully implement by developing a broad and integrated experimental and computational toolkit. We will develop methods for comprehensive profiling, genetic perturbations and mesoscale monitoring of diverse circuit layers (Aim 1). In parallel, we will develop a computational framework to analyze profiles, derive provisional models, use them to determine targets for perturbation and monitoring, and evaluate, refine and validate circuits based on those experiments (Aim 2). We will develop, test and refine this strategy in the context of two distinct and complementary mammalian circuits. First, we will produce an integrated, multi-layer circuit of the transcriptional response to pathogens in dendritic cells (Aim 3) as an example of an acute environmental response. Second, we will reconstruct the circuit of chromatin factors and non-coding RNAs that control chromatin organization and gene expression in mouse embryonic stem cells (Aim 4) as an example of the circuitry underlying stable cell states. These detailed datasets and models will reveal general principles of circuit organization, provide a resource for scientists in these two important fields, and allow computational biologists to test and develop algorithms. We will broadly disseminate our tools and methods to the community, enabling researchers to dissect any cell circuit of interest at unprecedented detail. Our work will open the way for reconstructing cellular circuits in human disease and individuals, to improve the accuracy of both diagnosis and treatment.

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    Analysis of Human Genome Using Integrated Technologies

    P50 HG002357
    Michael P. Snyder
    Yale University, New Haven, Conn.

    We propose to establish a center to build genomic DNA arrays and develop novel technologies that will use these arrays for the large-scale functional analysis of the human genome. 0.3-1.4 kb fragments of nonrepetitive DNA from each of chromosomes 22, 21, 20, 19,7, 17, and perhaps the X chromosome will be prepared by PCR and attached to microscope slides. The arrays will be used to develop technologies for the large-scale mapping of 1) Transcribed sequences. 2) Binding sites of chromosomal proteins. 3) Origins of replication. 4) Genetic mutation and variation. A web-accessible database will be constructed to house the information generated in this study; data from other studies will also be integrated into the database. The arrays and technologies will be made available throughout both the Yale University and the larger scientific community. They will be integrated into our training programs for postdoctoral fellows, graduate students and undergraduates at Yale. We expect these procedures to be applicable to the analysis of the entire human genome and the genomes of many other organisms.

    Center Web Site: Yale University Center for Excellence in Genomic Science

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    Genomic Analysis of the Genotype-Phenotype Map

    P50 HG002790
    Simon Tavaré
    University of Southern California, Los Angeles

    Our Center, which started in 2003, focused on implications of haplotype structure in the human genome. Since that time, there have been extraordinary advances in genomics: Genome-wide association studies using single nucleotide polymorphisms and copy number variants are now commonplace, and we are rapidly moving towards whole-genome sequence data for large samples of individuals. Our Center has undergone similar dramatic changes. While the underlying theme remains the same — making sense of genetic variation — our focus is now explicitly on how we can use the heterogeneous data produced by modern genomics technologies to achieve such an understanding. The overall goal of our proposal is to develop an intellectual framework, together with computational and statistical analysis tools, for illuminating the path from genotype to phenotype, and for predicting the latter from the former. We will address three broad questions related to this problem: 1) How do we infer mechanisms by which genetic variation leads to changes in phenotype? 2) How do we improve the design, understanding and interpretation of association studies by exploiting prior information? 3) How do we identify general principles about the genotype-phenotype map? We will approach these questions through a series of interrelated projects that combine computational and experimental methods, explored in Arabidopsis, Drosophila and human, and involve a wide range of researchers including molecular biologists, population geneticists, genetic epidemiologists, statisticians, computer scientists, and mathematicians.

    Collaborating InstitutionsUniversity of Utah

    Center Web Site: The USC Center of Excellence in Genomic Science

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    Genomic Analysis of Network Perturbations in Human Disease

    P50 HG004233
    Marc Vidal
    Dana-Farber Cancer Institute, Boston

    Genetic differences between individuals can greatly influence their susceptibility to disease. The information originating from the Human Genome Project (HGP), including the genome sequence and its annotation, together with projects such as the HapMap and the Human Cancer Genome Project (HCGP) have greatly accelerated our ability to find genetic variants and associate genes with a wide range of human diseases. Despite these advances, linking individual genes and their variations to disease remains a daunting challenge. Even where a causal variant has been identified, the biological insight that must precede a strategy for therapeutic intervention has generally been slow in coming. The primary reason for this is that the phenotypic effects of functional sequence variants are mediated by a dynamic network of gene products and metabolites, which exhibit emergent properties that cannot be understood one gene at a time. Our central hypothesis is that both human genetic variations and pathogens such as viruses influence local and global properties of networks to induce “disease states.” Therefore, we propose a general approach to understanding cellular networks based on environmental and genetic perturbations of network structure and readout of the effects using interactome mapping, proteomic analysis, and transcriptional profiling. We have chosen a defined model system with a variety of disease outcomes: viral infection. We will explore the concept that one must understand changes in complex cellular networks to fully understand the link between genotype, environment, and phenotype. We will integrate observations from network-level perturbations caused by particular viruses together with genome-wide human variation datasets for related human diseases with the goal of developing general principles for data integration and network prediction, instantiation of these in open-source software tools, and development of testable hypotheses that can be used to assess the value of our methods. Our plans to achieve these goals are summarized in the following specific aims: 1. Profile all viral-host protein-protein interactions for a group of viruses with related biological properties. 2. Profile the perturbations that viral proteins induce on the transcriptome of their host cells. 3. Combine the resulting interaction and perturbation data to derive cellular network-based models. 4. Use the developed models to interpret genome-wide genetic variations observed in human disease, 5. Integrate the bioinformatics resources developed by the various CCSG members within a Bioinformatics Core for data management and dissemination. 6. Building on existing education and outreach programs, we plan to develop a genomic and network centered educational program, with particular emphasis on providing access for underrepresented minorities to internships, workshop and scientific meetings.

    Center Web SiteCenter for Cancer Systems Biology (CCSB) Center of Excellence in Genomic Science

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    What is the Future for Genomics in Clinical Medicine?

    What is the Future for Genomics in Clinical Medicine?

    Author and Curator: Larry H Bernstein, MD, FCAP



    This is the last in a series of articles looking at the past and future of the genome revolution.  It is a revolution indeed that has had a beginning with the first phase discovery leading to the Watson-Crick model, the second phase leading to the completion of the Human Genome Project, a third phase in elaboration of ENCODE.  But we are entering a fourth phase, not so designated, except that it leads to designing a path to the patient clinical experience.
    What is most remarkable on this journey, which has little to show in treatment results at this time, is that the boundary between metabolism and genomics is breaking down.  The reality is that we are a magnificent “magical” experience in evolutionary time, functioning in a bioenvironment, put rogether like a truly complex machine, and with interacting parts.  What are those parts – organelles, a genetic message that may be constrained and it may be modified based on chemical structure, feedback, crosstalk, and signaling pathways.  This brings in diet as a source of essential nutrients, exercise as a method for delay of structural loss (not in excess), stress oxidation, repair mechanisms, and an entirely unexpected impact of this knowledge on pharmacotherapy.  I illustrate this with some very new observations.

    Gutenberg Redone

    The first is a recent talk on how genomic medicine has constructed a novel version of the “printing press”, that led us out of the dark ages.


    In our series The Creative Destruction of Medicine, I’m trying to get into critical aspects of how we can Schumpeter or reboot the future of healthcare by leveraging the big innovations that are occurring in the digital world, including digital medicine.

    We have this big thing about evidence-based medicine and, of course, the sanctimonious randomized, placebo-controlled clinical trial. Well, that’s great if one can do that, but often we’re talking about needing thousands, if not tens of thousands, of patients for these types of clinical trials. And things are changing so fast with respect to medicine and, for example, genomically guided interventions that it’s going to become increasingly difficult to justify these very large clinical trials.

    For example, there was a drug trial for melanoma and the mutation of BRAF, which is the gene that is found in about 60% of people with malignant melanoma. When that trial was done, there was a placebo control, and there was a big ethical charge asking whether it is justifiable to have a body count. This was a matched drug for the biology underpinning metastatic melanoma, which is essentially a fatal condition within 1 year, and researchers were giving some individuals a placebo.

    The next observation is a progression of what he have already learned. The genome has a role is cellular regulation that we could not have dreamed of 25 years ago, or less. The role is far more than just the translation of a message from DNA to RNA to construction of proteins, lipoproteins, cellular and organelle structures, and more than a regulation of glycosidic and glycolytic pathways, and under the influence of endocrine and apocrine interactions. Despite what we have learned, the strength of inter-molecular interactions, strong and weak chemical bonds, essential for 3-D folding, we know little about the importance of trace metals that have key roles in catalysis and because of their orbital structures, are essential for organic-inorganic interplay. This will not be coming soon because we know almost nothing about the intracellular, interstitial, and intrvesicular distributions and how they affect the metabolic – truly metabolic events.

    I shall however, use some new information that gives real cause for joy.

    Reprogramming Alters Cells’ Fate

    Kathy Liszewski
    Gordon Conference  Report: June 21, 2012;32(11)
    New and emerging strategies were showcased at Gordon Conference’s recent “Reprogramming Cell Fate” meeting. For example, cutting-edge studies described how only a handful of key transcription factors were needed to entirely reprogram cells.
    M. Azim Surani, Ph.D., Marshall-Walton professor at the Gurdon Institute, University of Cambridge, U.K., is examining cellular reprogramming in a mouse model. Epiblast stem cells are derived from the early-stage embryonic stage after implantation of blastocysts, about six days into development, and retain the potential to undergo reversion to embryonic stem cells (ESCs) or to PGCs.”  They report two critical steps both of which are needed for exploring epigenetic reprogramming.  “Although there are two X chromosomes in females, the inactivation of one is necessary for cell differentiation. Only after epigenetic reprogramming of the X chromosome can pluripotency be acquired. Pluripotent stem cells can generate any fetal or adult cell type but are not capable of developing into a complete organism.”
    The second read-out is the activation of Oct4, a key transcription factor involved in ESC development. The expression of Oct4 in epiSCs requires its proximal enhancer.  Dr. Surani said that their cell-based system demonstrates how a systematic analysis can be performed to analyze how other key genes contribute to the many-faceted events involved in reprogramming the germline.
    Reprogramming Expressway
    A number of other recent studies have shown the importance of Oct4 for self-renewal of undifferentiated ESCs. It is sufficient to induce pluripotency in neural tissues and somatic cells, among others. The expression of Oct4 must be tightly regulated to control cellular differentiation. But, Oct4 is much more than a simple regulator of pluripotency, according to Hans R. Schöler, Ph.D., professor in the department of cell and developmental biology at the Max Planck Institute for Molecular Biomedicine.
    Oct4 has a critical role in committing pluripotent cells into the somatic cellular pathway. When embryonic stem cells overexpress Oct4, they undergo rapid differentiation and then lose their ability for pluripotency. Other studies have shown that Oct4 expression in somatic cells reprograms them for transformation into a particular germ cell layer and also gives rise to induced pluripotent stem cells (iPSCs) under specific culture conditions.
    Oct4 is the gatekeeper into and out of the reprogramming expressway. By modifying experimental conditions, Oct4 plus additional factors can induce formation of iPSCs, epiblast stem cells, neural cells, or cardiac cells. Dr. Schöler suggests that Oct4 a potentially key factor not only for inducing iPSCs but also for transdifferention.  “Therapeutic applications might eventually focus less on pluripotency and more on multipotency, especially if one can dedifferentiate cells within the same lineage. Although fibroblasts are from a different germ layer, we recently showed that adding a cocktail of transcription factors induces mouse fibroblasts to directly acquire a neural stem cell identity.
    Stem cell diagram illustrates a human fetus st...

    Stem cell diagram illustrates a human fetus stem cell and possible uses on the circulatory, nervous, and immune systems. (Photo credit: Wikipedia)

    English: Embryonic Stem Cells. (A) shows hESCs...

    English: Embryonic Stem Cells. (A) shows hESCs. (B) shows neurons derived from hESCs. (Photo credit: Wikipedia)

    Transforming growth factor beta (TGF-β) is a s...

    Transforming growth factor beta (TGF-β) is a secreted protein that controls proliferation, cellular differentiation, and other functions in most cells. http://en.wikipedia.org/wiki/TGFbeta (Photo credit: Wikipedia)

    Pioneer Transcription Factors

    Pioneer transcription factors take the lead in facilitating cellular reprogramming and responses to environmental cues. Multicellular organisms consist of functionally distinct cellular types produced by differential activation of gene expression. They seek out and bind specific regulatory sequences in DNA. Even though DNA is coated with and condensed into a thick fiber of chromatin. The pioneer factor, discovered by Prof. KS Zaret at UPenn SOM in 1996, he says, endows the competence for gene activity, being among the first transcription factors to engage and pry open the target sites in chromatin.
    FoxA factors, expressed in the foregut endoderm of the mouse,are necessary for induction of the liver program. They found that nearly one-third of the DNA sites bound by FoxA in the adult liver occur near silent genes

    A Nontranscriptional Role for HIF-1α as a Direct Inhibitor of DNA Replication

    ME Hubbi, K Shitiz, DM Gilkes, S Rey,….GL Semenza. Johns Hopkins University SOM
    Sci. Signal 2013; 6(262) 10pgs. [DOI: 10.1126/scisignal.2003417]   http:dx.doi.org/10.1126/scisignal.2003417

    http://SciSignal.com/A Nontranscriptional Role for HIF-1α as a Direct Inhibitor of DNA Replication/

    Many of the cellular responses to reduced O2 availability are mediated through the transcriptional activity of hypoxia-inducible factor 1 (HIF-1). We report a role for the isolated HIF-1α subunit as an inhibitor of DNA replication, and this role was independent of HIF-1β and transcriptional regulation. In response to hypoxia, HIF-1α bound to Cdc6, a protein that is essential for loading of the mini-chromosome maintenance (MCM) complex (which has DNA helicase activity) onto DNA, and promoted the interaction between Cdc6 and the MCM complex. The binding of HIF-1α to the complex decreased phosphorylation and activation of the MCM complex by the kinase Cdc7. As a result, HIF-1α inhibited firing of replication origins, decreased DNA replication, and induced cell cycle arrest in various cell types. To whom correspondence should be addressed. E-mail: gsemenza@jhmi.edu
    Citation: M. E. Hubbi, Kshitiz, D. M. Gilkes, S. Rey, C. C. Wong, W. Luo, D.-H. Kim, C. V. Dang, A. Levchenko, G. L. Semenza, A Nontranscriptional Role for HIF-1α as a Direct Inhibitor of DNA Replication. Sci. Signal. 6, ra10 (2013).

    Identification of a Candidate Therapeutic Autophagy-inducing Peptide

    Nature 2013;494(7436).    http://nature.com/Identification_of_a_candidate_therapeutic_autophagy-inducing_peptide/   http://www.ncbi.nlm.nih.gov/pubmed/23364696

    Beth Levine and colleagues have constructed a cell-permeable peptide derived from part of an autophagy protein called beclin 1. This peptide is a potent inducer of autophagy in mammalian cells and in vivo in mice and was effective in the clearance of several viruses including chikungunya virus, West Nile virus and HIV-1.

    Could this small autophagy-inducing peptide may be effective in the prevention and treatment of human diseases?

    PR-Set7 Is a Nucleosome-Specific Methyltransferase that Modifies Lysine 20 of

    Histone H4 and Is Associated with Silent Chromatin

    K Nishioka, JC Rice, K Sarma, H Erdjument-Bromage, …, D Reinberg.   Molecular Cell, Vol. 9, 1201–1213, June, 2002, Copyright 2002 by Cell Press   http://www.cell.com/molecular-cell/abstract/S1097-2765(02)00548-8

    http://www.sciencedirect.com/science/article/pii/S1097276502005488           http://www.ncbi.nlm.nih.gov/pubmed/12086618

    We have purified a human histone H4 lysine 20methyl-transferase and cloned the encoding gene, PR/SET07. A mutation in Drosophila pr-set7 is lethal: second in-star larval death coincides with the loss of H4 lysine 20 methylation, indicating a fundamental role for PR-Set7 in development. Transcriptionally competent regions lack H4 lysine 20 methylation, but the modification coincided with condensed chromosomal regions polytene chromosomes, including chromocenter euchromatic arms. The Drosophila male X chromosome, which is hyperacetylated at H4 lysine 16, has significantly decreased levels of lysine 20 methylation compared to that of females. In vitro, methylation of lysine 20 and acetylation of lysine 16 on the H4 tail are competitive. Taken together, these results support the hypothesis that methylation of H4 lysine 20 maintains silent chromatin, in part, by precluding neighboring acetylation on the H4 tail.

    Next-Generation Sequencing vs. Microarrays

    Shawn C. Baker, Ph.D., CSO of BlueSEQ
    GEN Feb 2013
    With recent advancements and a radical decline in sequencing costs, the popularity of next generation sequencing (NGS) has skyrocketed. As costs become less prohibitive and methods become simpler and more widespread, researchers are choosing NGS over microarrays for more of their genomic applications. The immense number of journal articles citing NGS technologies it looks like NGS is no longer just for the early adopters. Once thought of as cost prohibitive and technically out of reach, NGS has become a mainstream option for many laboratories, allowing researchers to generate more complete and scientifically accurate data than previously possible with microarrays.

    Gene Expression

    Researchers have been eager to use NGS for gene expression experiments for a detailed look at the transcriptome. Arrays suffer from fundamental ‘design bias’ —they only return results from those regions for which probes have been designed. The various RNA-Seq methods cover all aspects of the transcriptome without any a priori knowledge of it, allowing for the analysis of such things as novel transcripts, splice junctions and noncoding RNAs. Despite NGS advancements, expression arrays are still cheaper and easier when processing large numbers of samples (e.g., hundreds to thousands).
    While NGS unquestionably provides a more complete picture of the methylome, whole genome methods are still quite expensive. To reduce costs and increase throughput, some researchers are using targeted methods, which only look at a portion of the methylome. Because details of exactly how methylation impacts the genome and transcriptome are still being investigated, many researchers find a combination of NGS for discovery and microarrays for rapid profiling.


    They are interested in ease of use, consistent results, and regulatory approval, which microarrays offer. With NGS, there’s always the possibility of revealing something new and unexpected. Clinicians aren’t prepared for the extra information NGS offers. But the power and potential cost savings of NGS-based diagnostics is alluring, leading to their cautious adoption for certain tests such as non-invasive prenatal testing.
    Perhaps the application that has made the least progress in transitioning to NGS is cytogenetics. Researchers and clinicians, who are used to using older technologies such as karyotyping, are just now starting to embrace microarrays. NGS has the potential to offer even higher resolution and a more comprehensive view of the genome, but it currently comes at a substantially higher price due to the greater sequencing depth. While dropping prices and maturing technology are causing NGS to make headway in becoming the technology of choice for a wide range of applications, the transition away from microarrays is a long and varied one. Different applications have different requirements, so researchers need to carefully weigh their options when making the choice to switch to a new technology or platform. Regardless of which technology they choose, genomic researchers have never had more options.

    Sequencing Hones In on Targets

    Greg Crowther, Ph.D.

    GEN Feb 2013

    Cliff Han, PhD, team leader at the Joint Genome Institute in the Los Alamo National Lab, was one of a number of scientists who made presentations regarding target enrichment at the “Sequencing, Finishing, and Analysis in the Future” (SFAF) conference in Santa Fe, which was co-sponsored by the Los Alamos National Laboratory and DOE Joint Genome Institute. One of the main challenges is that of target enrichment: the selective sequencing of genomic or transcriptomic regions. The polymerase chain reaction (PCR) can be considered the original target-enrichment technique and continues to be useful in contexts such as genome finishing. “One target set is the unique gaps—the gaps in the unique sequence regions. Another is to enrich the repetitive sequences…ribosomal RNA regions, which together are about 5 kb or 6 kb.” The unique-sequence gaps targeted for PCR with 40-nucleotide primers complementary to sequences adjacent to the gaps, did not yield the several-hundred-fold enrichment expected based on previously published work. “We got a maximum of 70-fold enrichment and generally in the dozens of fold of enrichment,” noted Dr. Han.

    “We enrich the genome, put the enriched fragments onto the Pacific Biosciences sequencer, and sequence the repeats,” continued Dr. Han. “In many parts of the sequence there will be a unique sequence anchored at one or both ends of it, and that will help us to link these scaffolds together.” This work, while promising, will remain unpublished for now, as the Joint Genome Institute has shifted its resources to other projects.
    At the SFAF conference Dr. Jones focused on going beyond basic target enrichment and described new tools for more efficient NGS research. “Hybridization methods are flexible and have multiple stop-start sites, and you can capture very large sizes, but they require library prep,” said Jennifer Carter Jones, Ph.D., a genomics field applications scientist at Agilent. “With PCR-based methods, you have to design PCR primers and you’re doing multiplexed PCR, so it’s limited in the size that you can target. But the workflow is quick because there’s no library preparation; you’re just doing PCR.” She discussed Agilent’s recently acquired HaloPlex technology, a hybrid system that includes both a hybridization step and a PCR step. Because no library preparation is required, sequencing results can be obtained in about six hours, making it suitable for clinical uses. However, the hybridization step allows capture of targets of up to 5 megabases—longer than purely PCR-based methods can deliver. The Agilent talk also provided details on the applications of SureSelect, the company’s hybridization technology, to Methyl-Seq and RNA-Seq research. With this technology, 120-mer baits hybridize to targets, then are pulled down with streptavidin-coated magnetic beads.
    These are selections from the SFAF conference, which is expected to be a boost to work on the microbiome, and lead to infectious disease therapeutic approaches.


    We have finished a breathtaking ride through the genomic universe in several sessions.  This has been a thorough review of genomic structure and function in cellular regulation.  The items that have been discussed and can be studied in detail include:

    1.  the classical model of the DNA structure
    2. the role of ubiquitinylation in managing cellular function and in autophagy, mitophagy, macrophagy, and protein degradation
    3. the nature of the tight folding of the chromatin in the nucleus
    4. intramolecular bonds and short distance hydrophobic and hydrophilic interactions
    5. trace metals in molecular structure
    6. nuclear to membrane interactions
    7. the importance of the Human Genome Project followed by Encode
    8. the Fractal nature of chromosome structure
    9. the oligomeric formation of short sequences and single nucletide polymorphisms (SNPs)and the potential to identify drug targets
    10. Enzymatic components of gene regulation (ligase, kinases, phosphatases)
    11. Methods of computational analysis in genomics
    12. Methods of sequencing that have become more accurate and are dropping in cost
    13. Chromatin remodeling
    14. Triplex and quadruplex models not possible to construct at the time of Watson-Crick
    15. sequencing errors
    16. propagation of errors
    17. oxidative stress and its expected and unintended effects
    18. origins of cardiovascular disease
    19. starvation and effect on protein loss
    20. ribosomal damage and repair
    21. mitochondrial damage and repair
    22. miscoding and mutational changes
    23. personalized medicine
    24. Genomics to the clinics
    25. Pharmacotherapy horizons
    26. driver mutations
    27. induced pluripotential embryonic stem cell (iPSCs)
    28. The association of key targets with disease
    29. The real possibility of moving genomic information to the bedside
    30. Requirements for the next generation of electronic health record to enable item 29

    Other Related articles on this Open Access Online Scientific Journal, include the following:

    https://pharmaceuticalintelligence.com/2013/01/14/oogonial-stem-cells-purified-a-view-towards-the-future-of-reproductive-biology/   SSaha

    https://pharmaceuticalintelligence.com/2012/10/22/blood-vessel-generating-stem-cells-discovered/ RSaxena

    https://pharmaceuticalintelligence.com/2012/08/22/a-possible-light-by-stem-cell-therapy-in-painful-dark-of-osteoarthritis-kartogenin-a-small-molecule-differentiates-stem-cells-to-chondrocyte-healthy-cartilage-cells/   ASarkar and RSaxena

    https://pharmaceuticalintelligence.com/2012/08/07/human-embryonic-pluripotent-stem-cells-and-healing-post-myocardial-infarction/    LHB

    https://pharmaceuticalintelligence.com/2013/02/03/genome-wide-detection-of-single-nucleotide-and-copy-number-variation-of-a-single-human-cell/  SJWilliams

    https://pharmaceuticalintelligence.com/2013/01/09/gene-therapy-into-healthy-heart-muscle-reprogramming-scar-tissue-in-damaged-hearts/ ALev-Ari

    https://pharmaceuticalintelligence.com/2013/01/03/differentiation-therapy-epigenetics-tackles-solid-tumors/  SJWilliams

    https://pharmaceuticalintelligence.com/2012/12/09/naotech-therapy-for-breast-cancer/  TBarliya

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    CRACKING THE CODE OF HUMAN LIFE: Milestones along the Way – Part IIA

    Curator: Larry H Bernstein, MD, FCAP

    Introduction and purpose

    This material goes beyond the Initiation Phase of Molecular Biology, Part I.

    Part II reviews the Human Genome Project and the decade beyond.

    In a three part series:
    Part IIA.  CRACKING THE CODE OF HUMAN LIFE: Milestones along the Way
    Part IIB.  CRACKING THE CODE OF HUMAN LIFE: The Birth of BioInformatics & Computational Genomics
    Part IIC.  CRACKING THE CODE OF HUMAN LIFE: Recent Advances in Genomic Analysis and Disease

    Part III will conclude with Ubiquitin, it’s Role in Signaling and Regulatory Control.
    Part I reviewed the huge expansion of the biological research enterprise after the Second World War. It concentrated on the

    • discovery of cellular structures,
    • metabolic function, and
    • creation of a new science of Molecular Biology.

    Part II follows the race to delineation of the Human Genome, discovery methods and fundamental genomic patterns that are ancient in both animal and plant speciation. But it explores both the complexity and the systems view of the architecture that underlies and understanding of the genome.

    These articles review a web-like connectivity between inter-connected scientific discoveries, as significant findings have led to novel hypotheses and many expectations over the last 75 years. This largely post WWII revolution has driven our understanding of biological and medical processes at an exponential pace owing to successive discoveries of

    • chemical structure,
    • the basic building blocks of DNA  and proteins,
    • nucleotide and protein-protein interactions,
    • protein folding, allostericity,
    • genomic structure,
    • DNA replication,
    • nuclear polyribosome interaction, and
    • metabolic control.

    In addition, the emergence of methods for

    • copying,
    • removal,
    • insertion,
    • improvements in structural analysis
    • developments in applied mathematics that have transformed the research framework.

    Part IIA:


    Milestones along the Way

    A NOVA interview with Francis Collins (NHGRI) (FC), J. Craig Venter (CELERA)(JCV), and Eric Lander (EL).
    RK: For the past ten years, scientists all over the world have been painstakingly trying to read the tiny instructions buried inside our DNA. And now, finally, the “Human Genome” has been decoded.
    EL: The genome is a storybook that’s been edited for a couple billion years.
    The following will address the odd similarity of genes between man and yeast

    EL: In the nucleus of your cell the DNA molecule resides that is about 10 angstroms wide curled up, but the amount of curling is limited by the negative charges that repel one another, but there are folds upon folds. If the DNA is stretched the length of the DNA would be thousands of feet.
    EL: We have known for 2000 years that your kids look a lot like you. Well it’s because you must pass them instructions that give them the eyes, the hair color, and the nose shape they have. RK: Cracking the code of those minuscule differences in DNA that influence health and illness is what the Human Genome Project is all about. Since 1990, scientists all over the world have been involved in the effort to read all three billion As, Ts, Gs, and Cs of human DNA.  It took 10 years to find the one genetic mistake that causes cystic fibrosis. Another 10 years to find the gene for Huntington’s disease. Fifteen years to find one of the genes that increase the risk for breast cancer. One letter at a time, painfully slowly…     And then came the revolution. In the last ten years the entire process has been computerized. The computations can do a thousand every second and that has made all the difference. EL: This is basically a parts list with a lot of parts. If you take an airplane, a Boeing 777, I think it has like 100,000 parts. If I gave you a parts list for the Boeing 777 in one sense you’d know 100,000 components, screws and wires and rudders and things like that.  But you wouldn’t know how to put it together, or why it flies. We now have a parts list, and that’s not enough to understand why it flies.

    The Human Genome

    The Human Genome (Photo credit: dullhunk)

    A Quest For Clarity

    Tracy Vence is a senior editor of Genome Technology
    Tracy Vence @GenomeTechMag
    Projects supported by the US National Institutes of Health will have produced 68,000 total human genomes — around 18,000 of those whole human genomes — through the end of this year, National Human Genome Research Institute estimates indicate. And in his book, The Creative Destruction of Medicine, the Scripps Research Institute’s Eric Topol projects that 1 million human genomes will have been sequenced by 2013 and 5 million by 2014.
    Daniel MacArthur, a group leader in Massachusetts General Hospital’s Analytic and Translational Genetics Unit estimates that “From a capacity perspective … millions of genomes are not that far off. If you look at the rate that we’re scaling, we can certainly achieve that.”    The prospect of so many genomes has brought clinical interpretation into focus. But there is an important distinction to be made between the interpretation of an apparently healthy person’s genome and that of an individual who is already affected by a disease.
    In an April Science Translational Medicine paper, Johns Hopkins University School of Medicine‘s Nicholas Roberts and his colleagues reported that personal genome sequences for healthy monozygotic twin pairs are not predictive of significant risk for 24 different diseases in those individuals. The researchers concluded that whole-genome sequencing was not likely to be clinically useful. Ambiguities have clouded even the most targeted interpretation efforts.

    • Technological challenges,
    • meager sample sizes,
    • a need for increased,
    • fail-safe automation and most important
    • a lack of community-wide standards for the task.

    have hampered researchers’ attempts to reliably interpret the clinical significance of genomic variation.

    How signals from the cell surface affect transcription of genes in the nucleus.

    James Darnell, Jr., MD, Astor Professor, Rockefeller
    After graduation from Washington University School of Medicine he worked with Francois Jacob at the Pasteur Institute in Paris and served as Vice President for Academic Affairs at Rockefeller in 1990-91. He is the coauthor with S.E. Luria of General Virology and the founding author with Harvey Lodish and David Baltimore of Molecular Cell Biology, now in its sixth edition. His book RNA, Life’s Indispensable Molecule was published in July 2011 by Cold Spring Harbor Laboratory Press. A member of the National Academy of Sciences since 1973, recipient of  numerous awards, including the 2003 National Medal of Science, the 2002 Albert Lasker Award.
    Using interferon as a model cytokine, the Darnell group discovered that cell transcription was quickly changed by binding of cytokines to the cell surface. The bound interferon led to the tyrosine phosphorylation of latent cytoplasmic proteins now called STATs (signal transducers and activators of transcription) that dimerize by

    • reciprocal phosphotyrosine-SH2 interchange.
    • accumulate in the nucleus,
    • bind DNA and drive transcription.

    This pathway has proved to be of wide importance with seven STATs now known in mammals that take part in a wide variety of developmental and homeostatic events in all multicellular animals. Crystallographic analysis defined functional domains in the STATs, and current attention is focused on two areas:

    • how the STATs complete their cycle of  activation and inactivation, which requires regulated tyrosine dephosphorylation; and how
    • persistent activation of STAT3 that occurs in a high proportion of many human cancers contributes to blocking apoptosis in cancer cells.

    Current efforts are devoted to inhibiting STAT3 with modified peptides that can enter cells.

    Cell cycle regulation and the cellular response to genotoxic stress

    Stephen J Elledge, PhD, Gregor Mendel Professor of Genetics and Medicine, Investigator, Howard Hughes Medical Institute, Harvard Medical School
    As a postdoctoral fellow at Stanford working on eukaryotic homologous recombination, he serendipitously found a family of genes known as ribonucleotide reductases. He subsequently showed that

    • these genes are activated by DNA damage and
    • could serve as tools to help scientists dissect the signaling pathways
    • through which cells sense and respond to DNA damage and replication stress.

    At Baylor College of Medicine he made a second major breakthrough with the discovery of the cyclin-dependent kinase 2 gene (Cdk2), which

    • controls the G1-to-S cell cycle transition,
    • an entry checkpoint for the cell proliferation cycle and
    • a critical regulatory step in tumorigenesis.

    From there, using a novel “two-hybrid” cloning method he developed, Elledge and Wade Harper, PhD, proceeded to

    • isolate several members of the Cdk2-inhibitory family.

    Their discoveries included the p21 and p57 genes, mutations in the latter (responsible for Beckwith-Wiedemann syndrome), characterized by somatic overgrowth and increased cancer risk. Elledge is also recognized for his work in understanding

    • proteome remodeling through ubiquitin-mediated proteolysis.
    • they identified F-box proteins that regulate protein degradation in the cell by
    1. binding to specific target protein sequences and then
    2. marking them with ubiquitin for destruction by the cell’s proteasome machinery.

    This breakthrough resulted in

    • the elucidation of the cullin ubiquitin ligase family,
    • which controls regulated protein stability in eukaryotes.

    nature10774-f5.2  nature10774-f3.2   ubiquitin structures  Rn1  Rn2

    Elledge’s recent research has focused on the cellular mechanisms underlying DNA damage detection and cancer using genetic technologies. In collaboration with Cold Spring Harbor Laboratory researcher Gregory Hannon, PhD, Elledge has generated complete human and mouse short hairpin RNA (shRNA) libraries for genome-wide loss-of-function studies. Their efforts have led to

    • the identification of a number of tumor suppressor proteins
    • genes upon which cancer cells uniquely depend for survival.

    This work led to the development of the “non-oncogene addiction” concept. This is noted as follows:

    • proteome remodeling through ubiquitin-mediated proteolysis
    • F-box proteins regulate protein degradation in the cell by binding to specific target protein sequences
    • and then marking them with ubiquitin for destruction by the cell’s proteasome machinery
    • elucidation of the cullin ubiquitin ligase family, which controls regulated protein stability in eukaryotes

    Playing the dual roles of inventor and investigator, Elledge developed original techniques to define

    • what drives the cell cycle and
    • how cells respond to DNA damage.

    By using these tools, he and his colleagues have identified multiple genes involved in cell-cycle regulation.

    Elledge’s work has earned him many awards, including a 2001 Paul Marks Prize for Cancer Research and a 2003 election to the National Academy of Sciences. In his Inaugural Article (1), published in this issue of PNAS, Elledge and his colleagues describe the function of Fbw7, a protein involved in controlling cell proliferation (see below). Elledge studied the error-prone DNA repair mechanism in E-Coli (Escherichia coli) called SOS mutagenesis for his PhD thesis at MIT. His work identified  and described

    • the regulation of a group of enzymes now known as error-prone polymerases,
    • the first members of which were the umuCD genes in E. coli.

    It was then that he developed a new cloning tool. Elledge invented a technique that allowed him to approach future cloning problems of this type with great rapidity. With the new technique, “you could make large libraries in lambda that behave like plasmids. We called them `phasmid’ vectors, like plasmid and phage together”. The phasmid cloning method was an early cornerstone for molecular biology research.

    Elledge began working on homologous recombination in postdoctoral fellowship at Stanford University, an important niche in the field of eukaryotic genetics. Working with the yeast genome, Elledge searched for rec A, a gene that allows DNA to recombine homologously. Although he never located rec A, he discovered a family of genes known as ribonucleotide reductases (RNRs), which are involved in DNA production. Rec A and RNRs share the same last 4 amino acids, which caused an antibody crossreaction in one of Elledge’s experiments. Initially disappointed with the false positives in his hunt for rec A, Elledge was later delighted with his luck. He found that

    • RNRs are turned  on by DNA damage, and
    • these genes are regulated by the cell cycle.

    Prior to leaving Stanford, Elledge attended a talk at the University of California, San Francisco, by Paul Nurse, a leader in cell-cycle research who would later win the 2001 Nobel Prize in medicine. Nurse described his success in isolating the homolog of a key human cell-cycle kinase gene, Cdc2, by using a mutant strain of yeast (8). Although Nurse’s methods were primitive, Elledge was struck by the message he carried: that

    • cell-cycle regulation was functionally conserved, and
    • many human genes could be isolated by looking for complimentary genes in yeast.

    Elledge then took advantage of his past successes in building phasmid vectors to build a versatile human cDNA library that could be expressed in yeast. After setting up a laboratory at Baylor, he introduced this library into yeast, screening for complimentary cell-cycle genes.  He quickly identified the same Cdc2 gene isolated by Nurse. However, Elledge also discovered a related gene known as Cdk2. Elledge subsequently found that

    • Cdk2 controlled the G1 to S cell-cycle transition, a step that often goes awry in cancer. These results were published in the EMBO Journal in 1991.

    He then continued to use

    • RNRs to perform genetic screens to
    • identify genes involved in sensing and responding to DNA damage.

    He subsequently worked out the

    • signal transduction pathways in both yeast and humans that recognize damaged DNA and replication problems.

    These “checkpoint” pathways are central to the

    • prevention of genomic instability and a key to understanding tumorigenesis.

    This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected on April 29, 2003.

    Defective cardiovascular development and elevated cyclin E and Notch proteins in mice lacking the Fbw7 F-box protein.

    Tetzlaff MT, Yu W, Li M, Zhang P, Finegold M, Mahon K , Harper JW, Schwartz RJ, and SJ Elledge. PNAS 2004; 101(10): 3338-3345. cgi doi 10.1073.  pnas.0307875101

    The mammalian F-box protein Fbw7 and its Caenorhabditis elegans counterpart Sel-10 have been implicated in

    • the ubiquitin-mediated turnover of cyclin E
    • as well as the Notch Lin-12 family of transcriptional activators. Both unregulated
    1. Notch and cyclin E
    2. promote tumorigenesis, and
    3. inactivate mutations in human

    Fbw7 studies suggest that it may be a tumor suppressor. To generate an in vivo system to assess the consequences of such unregulated signaling, we generated mice deficient for Fbw7.  Fbw7-null mice die around 10.5 days post coitus because of a combination of deficiencies in hematopoietic and vascular development and heart chamber mutations. The absence of Fbw7 results in elevated levels of cyclin E, concurrent with inappropriate DNA replication in placental giant trophoblast cells. Moreover, the levels of both Notch 1 and Notch 4 intracellular domains were elevated, leading to stimulation of downstream transcriptional pathways involving Hes1, Herp1, and Herp2. These data suggest essential functions for Fbw7 in controlling cyclin E and Notch signaling pathways in the mouse.

    Science as an Adventure


    Prof. Avram Hershko – Science as an Adventure
    Prof. Avram Hershko shared the 2004 Nobel Prize in Chemistry with Aaron Ciechanover and Irwin Rose for “for the discovery of ubiquitin-mediated protein degradation.”


    Gene Switches

    Nipam Patel is a professor in the Departments of Molecular and Cell Biology and Integrative Biology at UC Berkeley and runs a research laboratory that studies the role, during embryonic development, of homeotic genes (the genetic switches described in this feature). “Ghost in Your Genes” focuses on epigenetic “switches” that turn genes “on” or “off.” But not all switches are epigenetic; some are genetic. That is, other genes within the chromosome turn genes on or off. In an animal’s embryonic stage, these gene switches play a predominant role in laying out the animal’s basic body plan and perform other early functions;

    • the epigenome begins to take over during the later stages of embryogenesis.

    Beginning as a fertilized single egg that egg becomes many different kinds of cells.  Altogether, multicellular organisms like humans have thousands of differentiated cells. Each is optimized for use in the brain, the liver, the skin, and so on. Remarkably, the DNA inside all these cells is exactly the same. What makes the cells differ from one another is that different genes in that DNA are either turned on or off in each type of cell.

    Take a typical cell, such as a red blood cell. Each gene within that cell has a coding region that encodes the information used to make a particular protein. (Hemoglobin shuttles oxygen to the tissues and carbon dioxide back out to the lungs—or gills, if you’re a fish.) But another region of the gene, called “regulatory DNA,” determines whether and when the gene will be expressed, or turned on, in a particular kind of cell. This precise transcribing of genes is handled by proteins known as transcription factors, which bind to the regulatory DNA, thereby generating instructions for the coding region.

    One important class of transcription factors is encoded by the so called homeotic, or Hox, genes. Found in all animals, Hox genes act to “regionalize” the body along the embryo’s anterior-to-posterior (head-to-tail) axis. In a fruit fly, for example, Hox genes lay out the various main body segments—the head, thorax, and abdomen. Amazingly, all animals, from fruit flies to mice to people, rely on the same basic Hox-gene complex. Using different-colored antibody stains, we can see exactly where and to what degree Hox genes are expressed. Each Hox gene is expressed in a specific region along the anterior-to-posterior axis of the embryo.

    A fly’s body has three main divisions: head, thorax, and abdomen. We’ll focus on the thorax, which itself has three main segments. In a normal adult fly, the second thoracic segment features a pair of wings, while the third thoracic segment has a pair of small, balloon-shaped structures called halteres. A modified second wing, the haltere serves as a flight stabilizer. In order for the pair of wings and the pair of halteres (as well as all other parts of the fly) to develop properly, the fly’s suite of

    • Hox genes must be expressed in a precise way and at precise times.

    During development, the fly’s two wings grow from a structure in the larva known as the wing imaginal disk. (An imago is an insect in its final, adult state.) The haltere grows from the larval haltere imaginal disk. Remember the Ubx Hox gene? Using staining again, we can detect the gene product of Ubx. This reveals that

    • the Ubx gene is naturally “off” in the wing disk—
    • and is “on” in the haltere disk.
    • Now you’ll see what happens when the Ubx gene—just one of a large number of Hox genes—is turned off in the haltere disk. What if a genetic mutation caused the Ubx gene to be turned off, during the larval stage, in the third thoracic segment, the segment that normally produces the haltere? Instead of a pair of halteres, the fly has a second set of wings. With the switch of that single Hox gene, Ubx, from on to off, the third thoracic segment becomes an additional second thoracic segment and the pair of halteres became a second pair of wings. This illustrates the remarkable ability of transcription factors like Ubx to control patterning as well as cell type during development.


    A. Data Suggests “Gene” Redefinition

    As part of a huge collaborative effort called ENCODE (Encyclopedia of DNA Elements), a research team led by Cold Spring Harbor Laboratory (CSHL) Professor Thomas Gingeras, PhD, publishes a genome-wide analysis of RNA messages, called transcripts, produced within human cells.
    Their analysis—one component of a massive release of research results by ENCODE teams from 32 institutes in 5 countries, with 30 papers appearing in 3 different high-level scientific journals—shows that three-quarters of the genome is capable of being transcribed.  This indicates that nearly all of our genome is dynamic and active.  It stands in marked contrast to consensus views prior to ENCODE’s comprehensive research efforts, which suggested that

    • only the small protein-encoding fraction of the genome was transcribed.

    The vast amount of data generated with advanced technologies by Gingeras’ group and others in the ENCODE project changes the prevailing understanding of what defines a gene. The current outstanding question concerns

    • the nature and range of those functions.  It is thought that these
    • “non-coding” RNA transcripts act something like components of a giant, complex switchboard, controlling a network of  many events in the cell by
    1. regulating the processes of
    2. replication,
    3. transcription
    4. and translation

    – that is, the copying of DNA and the making of proteins is based on information carried by messenger RNAs.  With the understanding that so much of our DNA can be transcribed into RNA comes the realization that there is much less space between what we previously thought of as genes, Gingeras points out.

    The full ENCODE Consortium data sets can be freely accessed through

    • the ENCODE project portal as well as at the University of California at Santa Cruz genome browser,
    • the National Center for Biotechnology Information, and
    • the European Bioinformatics Institute.

    Topic threads that run through several different papers can be explored via the ENCODE microsite page at http://Nature.com/encode.    Date: September 5, 2012   Source: Cold Spring Harbor Laboratory

    1000 Genomes Project Team Reports on Variation Patterns

    (from Phase I Data) October 31, 2012 GenomeWeb

    In a study appearing online today in Nature, members of the 1000 Genomes Project Consortium presented an integrated haplotype map representing the genomic variation present in more than 1,000 individuals from 14 human populations.  Using data on 1,092 individuals tested by

    • low-coverage whole-genome sequencing,
    • deep exome sequencing, and/or
    • dense genotyping,

    the team looked at the nature and extent of the rare and common variation present in the genomes of individuals within these populations. In addition to population-specific differences in common variant profiles, for example, the researchers found distinct rare variant patterns within populations from different parts of the world — information that is expected to be important in interpreting future disease studies. They also encountered a surprising number of the variants that are expected to impact gene function, such as

    • non-synonymous changes,
    • loss-of-function variants, and, in some cases,
    • potentially damaging mutations.

    ENCODE was designed to pick up where the Human Genome Project left off.
    Although that massive effort revealed the blue­print of human biology, it quickly became clear that the instruction manual for reading the blueprint was sketchy at best. Researchers could identify in its 3 billion letters many of the regions that code for proteins, but they make up little more than 1% of the genome, contained in around 20,000 genes. ENCODE, which started in 2003, is a massive data-collection effort designed to catalogue the

    • ‘functional’ DNA sequences,
    • learn when and in which cells they are active and
    • trace their effects on how the genome is
    1. packaged,
    2. regulated and
    3. read.

    After an initial pilot phase, ENCODE scientists started applying their methods to the entire genome in 2007. That phase came to a close with the publication of 30 papers, in Nature, Genome Research and Genome Biology. The consortium has assigned some sort of function to roughly 80% of the genome, including

    • more than 70,000 ‘promoter’ regions — the sites, just upstream of genes, where proteins bind to control gene expression —
    • and nearly 400,000 ‘enhancer’ regions that regulate expression of  distant genes (see page 57)1. But the job is far from done.

    Junk DNA? What Junk DNA?

    New data reveals that at least 80% of the human genome encodes elements that have some sort of biological function. [© Gernot Krautberger – Fotolia.com] Far from containing vast amounts of junk DNA between its protein-coding genes, at least 80% of the human genome encodes elements that have some sort of biological function, according to newly released data from the Encyclopedia of DNA Elements (Encode) project, a five-year initiative that aims to delineate all functional elements within human DNA. The massive international project, data from which are published in 30 different papers in Nature, Genome Research, Genome Biology, the Journal of Biological Chemistry, Science, and Cell, has identified four million gene switches, effectively

    • regulatory regions in the genome where
    • proteins interact with the DNA to control gene expression.

    Overall, the Encode data define regulatory switches that are scattered all over the three billion nucleotides of the genome. In fact, the data suggests,

    • the regions that lie between gene-coding sequences contain a wealth of previously unrecognized functional elements,Including
    • nonprotein-coding RNA transcribed sequences,
    • transcription factor binding sites,
    • chromatin structural elements, and
    • DNA methylation sites.

    The combined results suggest that 95% of the genome lies within 8 kb of a DNA-protein interaction, and 99% lies within 1.7 kb of at least one of the biochemical events, the researchers say. Importantly, given the complex three-dimensional nature of DNA, it’s also apparent that

    • a regulatory element for one gene may be located quite some ‘linear’ distance from the gene itself.

    “The information processing and the intelligence of the genome reside in the regulatory elements,” explains Jim Kent, director of the University of California, Santa Cruz Genome Browser project and head of the Encode Data Coordination Center. “With this project, we probably went from understanding less than 5% to now around 75% of them.”
    The ENCODE results also identified SNPs within regulatory regions that are associated with a range of diseases, providing new insights into the roles that

    • noncoding DNA plays in disease development.

    “As much as nine out of 10 times, disease-linked genetic variants are not in protein-coding regions,” comments Mike Pazin, Encode program director at the National Human Genome Research Institute.  “Far from being junk DNA, this regulatory DNA clearly makes important contributions to human disease.”

    Other Related Articles on this Open Access Online Scientific Journal, include the following: 

    Big Data in Genomic Medicine LHB


    BRCA1 a tumour suppressor in breast and ovarian cancer – functions in transcription, ubiquitination and DNA repair S Saha

    Computational Genomics Center: New Unification of Computational Technologies at Stanford A Lev-Ari

    Personalized medicine gearing up to tackle cancer ritu saxena

    Differentiation Therapy – Epigenetics Tackles Solid Tumors sj Williams

    Mechanism involved in Breast Cancer Cell Growth: Function in Early Detection & Treatment A Lev-Ari

    The Molecular pathology of Breast Cancer Progression tilde barliya`

    Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1 (pharmaceuticalintelligence.com) A Lev-Ari


    LEADERS in Genome Sequencing of Genetic Mutations for Therapeutic Drug Selection in Cancer Personalized Treatment: Part 2 A Lev-Ari

    Personalized Medicine: An Institute Profile – Coriell Institute for Medical Research: Part 3 A Lev-Ari

    Harnessing Personalized Medicine for Cancer Management, Prospects of Prevention and Cure: Opinions of Cancer Scientific Leaders @ http://pharmaceuticalintelligence.com ALA
    http://pharmaceuticalintelligence.com/2013/01/13/7000/Harnessing Personalized Medicine for Cancer Management, Prospects of Prevention and Cure: Opinions of Cancer Scientific Leaders/

    GSK for Personalized Medicine using Cancer Drugs needs Alacris systems biology model to determine the in silico effect of the inhibitor in its “virtual clinical trial” A Lev-Ari

    Recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes in serous endometrial tumors S Saha

    Personalized medicine-based cure for cancer might not be far away ritu saxena

    Human Variome Project: encyclopedic catalog of sequence variants indexed to the human genome sequence A Lev-Ari

    Prostate Cancer Cells: Histone Deacetylase Inhibitors Induce Epithelial-to-Mesenchymal Transition sjwilliams

    Inspiration From Dr. Maureen Cronin’s Achievements in Applying Genomic Sequencing to Cancer Diagnostics A Lev-Ari

    The “Cancer establishments” examined by James Watson, co-discoverer of DNA w/Crick, 4/1953 A Lev-Ari

    Directions for genomics in personalized medicine lhb

    How mobile elements in “Junk” DNA promote cancer. Part 1: Transposon-mediated tumorigenesis. SJwilliams

    Mitochondria: More than just the “powerhouse of the cell” eritu saxena

    Mitochondrial fission and fusion: potential therapeutic targets? Ritu saxena

    Mitochondrial mutation analysis might be “1-step” away ritu saxena

    mRNA interference with cancer expression lhb

    Expanding the Genetic Alphabet and linking the genome to the metabolome LHB

    Breast Cancer, drug resistance, and biopharmaceutical targets lhb

    Breast Cancer: Genomic profiling to predict Survival: Combination of Histopathology and Gene Expression Analysis A Lev-Ari

    Gastric Cancer: Whole-genome reconstruction and mutational signatures A Lev-Ari

    Ubiquinin-Proteosome pathway, autophagy, the mitochondrion, proteolysis and cell apoptosis lhb

    Genomic Analysis: FLUIDIGM Technology in the Life Science and Agricultural Biotechnology A Lev-Ari

    Reveals from ENCODE project will invite high synergistic collaborations to discover specific targets A. Sarkar


    ENCODE: the key to unlocking the secrets of complex genetic diseases R. Saxena


    Impact of evolutionary selection on functional regions: The imprint of evolutionary selection on ENCODE regulatory elements is manifested between species and within human populations s Saha


    ENCODE Findings as Consortium A Lev-Ari


    Genomics Orientations for Personalized Medicine SJH, ALA, LHB


    2013 Genomics: The Era Beyond the Sequencing of the Human Genome: Francis Collins, Craig Venter, Eric Lander, et al.


     Related Articles

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    Nation’s BiobanksAcademic institutions, Research institutes and Hospitals – vary by Collections Size, Types of Specimens and Applications: Regulations are Needed

    Reporter: Aviva Lev-Ari, PhD, RN

    On this Open Access Online Scientific Journal a series of posts address the Gemonic Research Establishment

    Personalized Medicine: An Institute Profile – Coriell Institute for Medical Research: Part 3


    Cancer Diagnostics by Genomic Sequencing: ‘No’ to Sequencing Patient’s DNA, ‘No’ to Sequencing Patient’s Tumor, ‘Yes’ to focus on Gene Mutation Aberration & Analysis of Gene Abnormalities

    How to Tailor Cancer Therapy to the particular Genetics of a patient’s Cancer

    THIS IS A SERIES OF FOUR POINTS OF VIEW IN SUPPORT OF the Paradigm Shift in Human Genomics

    ‘No’ to Sequencing Patient’s DNA, ‘No’ to Sequencing Patient’s Tumor, ‘Yes’ to focus on Gene Mutation Aberration & Analysis of Gene Abnormalities

    PRESENTED in the following FOUR PARTS. Recommended to be read in its entirety for completeness and arrival to the End Point of Present and Future Frontier of Research in Genomics

    Part 1:

    Research Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine


    Part 2:

    LEADERS in the Competitive Space of Genome Sequencing of Genetic Mutations for Therapeutic Drug Selection in Cancer Personalized Treatment


    Part 3:

    Personalized Medicine: An Institute Profile – Coriell Institute for Medical Research


    Part 4:

    The Consumer Market for Personal DNA Sequencing


    We present the State of Affairs of Nation’s BioBank Industry
    Characterizing Biobank Organizations in the U.S.: Results from a National Survey

    Gail E Henderson, R Jean Cadigan, Teresa P Edwards, Ian Conlon, Anders G Nelson, James P Evans, Arlene M Davis, Catherine Zimmer and Bryan J Weiner

    Abstract (provisional)


    Effective translational biomedical research hinges on the operation of “biobanks,” repositories which assemble, store, and manage collections of human specimens and related data. Some are established intentionally to address particular research needs; many, however, have arisen opportunistically, in a variety of settings and with a variety of expectations regarding their functions and longevity. Despite their rising prominence, little is known about how biobanks are organized and function beyond simple classification systems (“government, academia, industry”). Methods: In 2012, we conducted the first national survey of biobanks in the U.S., collecting information on their origins, specimen collections, organizational structures, and market contexts and sustainability. From a list of 636 biobanks assembled through a multi-faceted search strategy, representatives from 456 U.S. biobanks were successfully recruited for a 30 minute online survey (72% response rate). Both closed and open-ended responses were analyzed using descriptive statistics. Results: While nearly two-thirds of biobanks were established within the last decade, 17% have been in existence for over 20 years. Fifty-three percent listed research on a particular disease as the most important reason for establishment; 29% listed research generally. Other reasons included response to a grant or gift, and intent to centralize, integrate, or harmonize existing research structures. Biobank collections are extraordinarily diverse in number and types of specimens and in sources (often multiple) from which they are obtained, including from individuals, clinics/hospitals, public health programs, and research studies. Forty-four percent of biobanks store pediatric specimens, and 36% include post-mortem specimens. Most biobanks are affiliated in one or multiple ways with other entities: 88% are part of at least one or more larger organizations (67% of these are academic, 23% hospitals, 13% research institutes). The majority of biobanks seem to fill a particular “niche” within a larger organization or research area; a minority are concerned about competition for services, although many are worried about underutilization of specimens and long term funding. Conclusions: Effective utilization of biobank collections and effective policies to govern their use will require understanding the immense diversity found in organizational features, including the very different history and primary goals that many biobanks have.

    The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.


    US Sees Boom in Diverse Range of Biobanks, But Regulations are Lacking

    January 25, 2013

    NEW YORK (GenomeWeb News) – The past decade has seen a dramatic rise in the number and diversity of biobanks in the US, from academic institutions to research institutes and hospitals, and any efforts at creating regulations or governing rules for them will require more than a ‘one-size-fits-all’ approach, according to a new survey.

    Funded by the National Human Genome Research Institute and published today in BioMed Central‘s Genome Medicinethe survey found that nearly two-thirds of the nation’s biobanks were launched over the past decade, and they are an “extraordinarily diverse” group, from the size of their collections to the types of specimens they harbor to their fields of study and applications.

    The study’s lead author, Gail Henderson, professor and chair of the Department of Social Medicine at the University of North Carolina at Chapel Hill, told GenomeWeb Daily News this week that the “rise of genomics and large-scale gene-environment studies” have led biobanks to “play an increasingly important role in biomedical research.”

    “Many articles discuss the ways they are changing the research enterprise – but they have never been systematically studied,” and there is little empirical data or details “on how they are run or on the policies and practices they have to manage their work,” Henderson said.

    Although it is difficult to determine the exact number of biobanks operating in the US, by hunting through a range of sources the UNC-based research team was able to create a list of nearly 800 banks. Their online survey generated responses from 456 biobanks, and the team found that 59 percent of these were established after 2001.

    Nearly 50 percent of these banks said that the main biomolecule that they store is DNA, 11 percent said RNA, 7 percent said protein, 20 percent said they do not store biomolecules, and 9 percent said ‘other’.

    In total, these banks may house from tens of millions to over 50 million samples, the researchers found, and 53 percent of these specimens were stored to support research on particular diseases or disease types. By far, the largest portion of these is being used for cancer research, which is followed by biospecimens stored for neurological diseases like Alzheimer’s and HIV/AIDS.

    As for the types of biological specimens these repositories store, 77 percent said they hold serum/plasma, 69 percent store solid tissues, 55 percent store whole blood, and 49 percent house peripheral blood cells or bone marrow. Around 7 percent of the biobanks store pathological body fluids, and around two or three percent have hair and toenail samples.

    The rise of genome-focused research after the completion of the sequencing of the human genome a decade ago appears as if it may be a key driver in the biobank explosion. Since then, biobanks have been created to facilitate research generally, rather than to support studies of single diseases or to focus on one area of human biology.

    “While there are likely multiple explanations for these results, it is possible that the changing landscape of genomic technology has facilitated a broadening of scope in research pursuits, so that biobanks are not as likely to limit their work to one disease,” the authors stated in the paper.

    The expansion and use of new biobanks likely is “all about genomic information,” Henderson told GWDN.

    “When we talk about specimens, and look at the numbers and kinds of specimens that people are saving, and the fact that the majority of our banks are cancer banks, and cancer research is fundamentally about DNA,” it is hard not to come to the conclusion that much of this growth is about genomics, she said.

    Henderson also said the survey uncovered a “huge diversity” in the types of biobanks in the US.

    “They get established for a variety of reasons, some accidental, some intentional, and they vary in size, in when they were established, how formal they are as organizations, what kind of specimens they hold, and where those specimens come from,” she said.

    Biobanks also are diverse in their structural affiliations, although nearly 90 percent are embedded within other institutions, and nearly 80 percent of those embedded banks are located within academic institutions. Hospitals house around a quarter of these biobanks, and around 15 percent are part of a research institute.

    While they house the samples that are helping to fuel genomics and molecular research, biobanks also can bring up ethical and policy questions that have caught the eye of policy-watchers at NHGRI.

    Several issues that have been flagged by the institute’s Ethical, Legal, and Social Implications Research program are stirred up by the expansion of biobanks, such as questions about policies governing data sharing and security, privacy and the identifiability of genomic information, how and when to return research results and incidental findings, how governance structures function at genomic repositories, and informed consent issues caused by the multiple uses for samples by genome researchers.

    “Given the diversity in biobank organizational characteristics, it is likely that management and governance policies will have to be tailored to fit the particular context. One size will not fit all,” Henderson said.

    For example, she said, the biobanks in the survey showed a range of policies regarding who may access the data, with some enabling only the researchers who run the repository to access it, and others providing nearly universal access with no applicants denied.

    There currently are few or no specific guidelines and laws that specifically govern biobanks and biorepositories, she explained.

    A list of voluntary best practices for biospecimen resources published by the National Cancer Institute is probably the best available guidelines for biobanks to follow, Henderson explained, but there is not enough specificity in those or other rules or guidelines to apply them to the range of biobanks that are out there now.

    “It’s not as is if there are no federal regulations that affect biobanks,” she said. “Certainly, human subject regulations do, and material transfer agreements and commercialization [rules] fall under certain federal regulatory guidance, but none are specific to biobanks.”

    In some ways, she said, the biobanking and biorepository boom has created a “Wild West” landscape that will require further study, Henderson said. She and her fellow investigators now plan to begin to tack their research aims toward the ethical and regulatory issues that the proliferation of and multiple new uses for biobanks have brought about.

    Matt Jones is a staff reporter for GenomeWeb Daily News. He covers public policy, legislation, and funding issues that affect researchers in the genomics field, as well as the operations of research institutes. E-mail him here or follow GWDN’s headlines at@DailyNewsGW.

    ACMG Issues Guidelines on Sequencing for Dx, Screening Purposes

    March 29, 2012

    By a GenomeWeb staff reporter

    NEW YORK (GenomeWeb News) – The American College of Medical Genetics last night released a policy statement and guidelines for the use of genomic sequencing for diagnostic genetic screening applications.

    The guidelines cover how clinical whole-genome and whole-exome sequencing should be applied, distinguishing between cases where the technology is applied to diagnose a specific condition and when it is used as a screening purpose on asymptomatic individuals. It also asserted that the guidelines are applicable to sequencing for clinical purposes, not research.

    In a statement, ACMG said that it recognizes that “genomic sequencing approaches can be of great value in the clinical evaluation of individuals with suspected germ-line genetic disorders,” and there are already “instances in which genomic sequencing approaches can and should contribute to clinical care.”

    The organization also distinguished between returning results directly associated with the patient’s phenotype or clinical condition and secondary findings or results generated from screening asymptomatic individuals.

    For secondary findings, or returning results to asymptomatic individuals, “it is critical that the standards for what is reportable be high to avoid burdening the health care system and consumers with what could be very large numbers of false positive results,” it wrote. By contrast, “a lower threshold for reporting is appropriate” for returning “diagnostic results that are clearly related to a patient’s phenotype or clinical condition.”

    ACMG said whole-genome or whole-exome sequencing should be considered as a diagnostic test for individuals when the phenotype or family history data strongly implicate a genetic etiology, but the disorder is unknown and a specific genetic test is not available; when a patient presents with a defined genetic disorder with a high degree of genetic heterogeneity, making multiple single-gene tests less practical; when a patient has a likely genetic disorder, but available tests have failed at diagnosing the disorder; and when a fetus has a likely genetic disorder, but available tests have failed to diagnose it.

    Prior to testing, ACMG recommends patients and families receive genetic counseling and be informed about the expected outcomes, likelihood of finding incidental results, and what types of results will be returned. Labs performing the tests should have clear policies related to disclosing secondary findings, and patients should also have the option of not receiving certain results.

    Additionally, patients should be informed if a laboratory’s institutional review board has approved a protocol that allows variants of unknown significance to be used for further research, and patients should consent to this use of their data.

    The test itself, and every component of it, including the bioinformatics and interpretation, should be performed in a lab directed by a board-certified individual with broad medical genetics and genomics training, ACMG said.

    Regarding what results it recommends returning, ACMG said that test results could include variants known to be associated with the patient’s condition; novel variants whose “genetic, biological, and pathological features” indicate that they are likely involved with the patient’s phenotype; and secondary findings not associated with the patient’s condition, but that are known to be associated with a phenotype.

    ACMG has different recommendations for whole-genome or whole-exome sequencing done not for diagnostic purposes, but as a screen of asymptomatic individuals. In these instances, it stresses that the threshold for determining which results should be returned should be “significantly higher” than when the technology is used for a specific diagnostic purpose.

    Additionally, it said that individuals should be informed of the “virtual certainty of finding variants of unknown significance.”

    While many in the field assume that everyone will eventually have their genomes sequenced at birth, the ACMG’s current position is that sequencing should not be used as a first-tier approach for newborn screening. Whole-genome or whole-exome sequencing should also not be used as a method for prenatal screening, it wrote.

    However, whole-genome or whole-exome sequencing could be considered for preconception carrier screening to “focus on genetic variants known to be associated with significant phenotypes in homozygous or hemizygous progeny,” ACMG said.

    ACMG acknowledged that the field is rapidly evolving and said that its recommendations would likely be revised over time.

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