NIH Director Research Articles

Mis‐translation as a potential, new mechanism of adaption and stress response

A central tenet of biology is the accurate flow of information from nucleic acids to proteins through the genetic code. It is commonly believed that translation deviating from the genetic code is to be avoided at all times in cells. We have discovered that in contrary, mammalian cells can deliberately reprogram the genetic code with the amino acid methionine upon innate immune activation and chemically triggered oxidative stress. Reprogramming the genetic code with methionine occurs through aminoacylation of non‐methionyl‐tRNAs with methionine in unstressed cells, and is further inducible upon regulated production of the reactive oxygen species (ROS) in the cell. We also found that tRNA misacylation with methionine occurs in all three kingdoms of life, and is highly regulated under cell growth conditions. We propose that mis‐translation via regulated tRNA misacylation is a common mechanism for environmental adaption and for stress response in cells. We are exploring and testing hypotheses on the regulatory mechanism, the biological effects and function of mis‐translation with methionine. The results and conceptual understanding obtained here shall help establish mis‐translation as a new mechanism of stress response in biology.Supported by NIH Director's Pioneer Award (DP1GM105386).

Careers beyond the bench ‐ an overview

Individuals trained in biomedical research follow many career paths, extending well beyond the traditional path of conducting research in academia. A recent report from a working group of the Advisory Committee to the NIH Director tasked with examining the future of the biomedical research workforce in the US (http://acd.od.nih.gov/bwf.htm) showed that fewer than 50% of US‐trained individuals who hold a PhD in biomedical research pursue a research or teaching career in academia. Many conduct research in industry or government settings, while others take positions in science‐related non‐research occupations. Careers paths in science policy and scientific editing will be discussed as examples of such occupations.

Emerging Subspecialties in Neurology: Global health

Global health is the study, research, and practice that places a priority on improving health and achieving equity in health for all people worldwide.1 In contrast to the public health concerns of a particular country or region, global health looks at populations irrespective of borders. One of the key elements in advancing the field of global health was the establishment of the WHO in 1948. Since its inception, the WHO has helped coordinate global efforts toward eradication of diseases such as smallpox and polio as well as elimination of onchocerciasis. It now assumes responsibility for the International Classification of Diseases. More recently, the field of global health has received considerable attention from world leaders, philanthropists, and academics. In 2009, President Obama introduced his Global Health Initiative that proposed spending $63 billion over 6 years to support global health programs specifically targeting areas such as HIV/AIDS, malaria, tuberculosis, nutrition, and reproductive health. On his first day of work as NIH Director, Francis Collins announced global health as one of his 5 themes of “exceptional opportunity” that would receive special priority during his tenure.2 The Fogarty International Center is a branch of the NIH that helps to support global health research for US and foreign researchers, often in resource-limited settings. The research initiatives encompass a diverse range of disciplines within the field of medicine.

Editorial introductions

Editorial introductions

Toni S Shippenberg

Toni Shippenberg was both a distinguished scientist and a pillar of the NIDA IRP community, having devoted two decades of her life pursuing neuroscience addiction research on behalf of NIDA's mission. She was seen as an influential leader—both nationally and internationally—in the opiate and psychostimulant research areas, and was one of the crown jewels of the IRP. Dr Shippenberg received her BS in Neuroscience from Colgate University in 1979 and earned a PhD in pharmacology in 1985 from the Baylor College of Medicine. She subsequently undertook post-doctoral work at the Max Planck Institute of Psychiatry in Martinsried, Germany, where she would work for 7 years in the field of neuropharmacology, gradually taking on greater leadership roles culminating in the position of Chief of the Drug Abuse Research Unit for the Institute in Munich. In 1992, she joined NIDA in the Preclinical Pharmacology Laboratory as a Senior Staff Fellow and later went on to a Tenure Track position, obtaining tenure in 2001 as a Senior Investigator and Chief of the Integrative Neuroscience Section of the Behavioral Neuroscience Research Branch. In 2010, she was appointed as Chief of the newly created Integrative Neuroscience Research Branch before formally stepping down from that position earlier this year due to illness. Toni's contributions to the fields of neuroscience and neuropharmacology over the years were outstanding and are reflected by the high esteem she was held in by colleagues within NIH as well as throughout the United States and abroad. For many years, she held influential positions within the neuroscience community by serving as Reviewing Editor for the Journal of Neuroscience and on the Editorial Boards of Neuropsychopharmacology and Molecular and Cellular Pharmacology. In addition, she served as a reviewer for dozens of extramural and intramural grants, participated on numerous advisory boards, and maintained a myriad of extramural collaborations. Her contributions to the field did not go unnoticed, as the NIH Director appointed her to the prestigious Senior Biomedical Research Service (SBRS) in 2005, a designation allotted to only 500 of the most outstanding scientists within the United States Public Health Service (PHS). In addition, in 2004, she was appointed as an Honorary Professor by the University of Queensland in Australia and also held appointments of Adjunct Associate Professor at the University of Maryland Medical School and Research Associate Professor at Georgetown University Medical Center. Dr Shippenberg was the recipient of numerous awards over the years, including the NIDA/NIH Women Scientist Achievement Award in 2009, a J. William Fulbright Senior Specialist Award in 2008, an Australian Federation Fellow award in 2006, and the NIDA Director's Scientific Merit Award in 1994, 1995, and 1998. Not only was Toni a distinguished neuroscientist, but she was also an exemplary mentor and citizen within the NIH and NIDA communities. Her mentees consistently moved on to successful independent scientific careers at leading institutions around the world, and her fellows invariably lauded her for her availability, knowledge, support, and generosity. Her mentorship abilities were recognized in 2005 when she won an NIH Outstanding Mentor of the Year Award. Furthermore, Toni was extremely generous with her time through service on the NIDA Animal Care and Use Committee, the IRP Promotions and Tenure Committee, and the NIDA Postdoctoral Advisory Committee, not to mention memberships on a host of additional NIH committees. On a personal note, Toni's positive energy, sense of humor, and warm personality will be missed as much as her science. She will be remembered both as a wonderful person and for her contributions to addiction neuroscience.

New infrastructure to support clinical translational research at the US National Institutes of Health: role of the NIH Clinical Center

The development of new drugs and devices is expensive with long timelines and high rate of failure. The director of NIH is concerned with these issues and has made reengineering the translational sciences a top priority [1]. One outcome of the planning has been the creation of a new NIH National Center for Advancing Translational Sciences (NCATS) [2]. NCATS has three major goals: reengineering translational sciences, creating a network of clinical and translational science awardees (CTSAs) at 60 academic institutions in the US and supporting research on rare diseases and therapeutics. Recent novel approaches to technology development under NCATS leadership include designing new “organ chips” and use of induced pluripotent stem cells (iPS cells) to screen for drug toxicity. Another project is the 1000 genomes project which estimated that human genomes typically contain about 100 genuine loss of function variants with about 20 genes completely inactivated but without obvious disease consequence. In some cases the loss of function variants are associated but with protection from disease thereby providing new targets for drug discovery [3]. Another effort to reengineer drug discovery is a drug repurposing project that has resulted in partnerships with 8 pharmaceutical companies who recently announced 58 compounds available for repurposing studies [4]. The Office of Rare Diseases Research has moved into NCATS and is working to establish partnerships throughout the world for the study of rare diseases. The Office of Rare Diseases Research continues to work on the development of novel treatment strategies. The NIH Clinical Center, the largest hospital in the world totally dedicated to clinical research, will work closely with NCATS. A new vision for the NIH Clinical Center will be “to open its doors” to outside investigators through new partnerships between extramural scientists and investigators in the NIH intramural program. These partnerships will include access to the special technical resources at the Clinical Center, access to the clinical research training programs including the NIH curriculum for clinical research training, courses designed to demystify medicine for PhDs, as well as a sabbatical in clinical research management. In addition, the Clinical Center will make available new tools it has developed for protocol management and information technology (see http://www.cc.nih.gov/ for review of the Clinical Center programs). The many approaches NIH is implementing to improve translational research will be monitored closely for success.

Editorial introductions

Current Opinion in Neurology was launched in 1988. It is one of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of neurology is divided into 14 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Journal's Editors and Section Editors for this issue. SECTION EDITORS Jean-Marc LégerJean-Marc LégerDr Léger started his career in neurology at the University Hospital Pitié-Salpêtrière and University Pierre et Marie Curie (Paris VI), France, in 1980, where he trained in general neurology and clinical neurophysiology. He was then nominated as full-time senior neurologist in 1987 in the Department of Neurology, University Hospital Pitié-Salpêtrière, and received his post-graduate degree (Habilitation à diriger des Recherches) from University Paris VI in 1991. He is currently coordinator, together with Dr Eymard, of the National Referral Center for rare neuromuscular diseases, that was built up in the Department of Neurology of University Hospital Pitié-Salpêtrière in 2004. Dr Léger's clinical and research interests are in the field of peripheral neuropathy and in particular chronic immune-mediated neuropathy. He has authored and co-authored more than 150 articles in peer-reviewed journals, and contributed more than 30 chapters to books on neurology, mainly in the field of diagnostic features and therapeutic trials in vasculitic neuropathy, chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy and paraproteinaemic neuropathies. He served as Editor-in-Chief of the Revue Neurologique for 8 years and as member of the Editorial Board of Brain for 5 years, and is currently member of the Board of the European Journal of Neurology and Associate Editor of the Journal of the Peripheral Nervous System. Dr Léger is currently President of the Société Française de Neurologie, in which he served as Secretary General for 8 years. He serves as officer of the Management Committee of the European Federation of Neurological Societies (EFNS) and as chairman of the Training and Education Committee of the EFNS. He is also member of the Board of the Peripheral Nerve Society and will organize its biennal meeting in Saint-Malo, France, in July 2013. He is Corresponding Fellow of the American Academy of Neurology, and Corresponding Member of the American Neurological Association. He was elected as Corresponding Member of the Académie Nationale de Médecine, France, in 2009. Tom RandoTom RandoThomas Rando is Professor of Neurology and Neurological Sciences at the Stanford University School of Medicine, USA. He received his A.B. degree in biochemistry from Harvard College and he received his MD and PhD (cell and developmental biology) degrees from Harvard University, USA. He completed his clinical training in neurology at the University of California San Francisco, USA, and he completed his postdoctoral training in the Department of Molecular Pharmacology at Stanford University where he was a Howard Hughes Physician Postdoctoral Scholar. Dr Rando's laboratory has been focused on the role of tissue-specific stem cells in muscle homeostasis and repair, as well as on the mechanisms by which those cells fail to sustain muscle either in the setting of muscular dystrophies, or during the process of age-related muscle atrophy (sarcopenia). Groundbreaking work from his laboratory showed that the age-related decline in stem cell function is due primarily to influences of the aged environmental, rather than to intrinsic aging of stem cells themselves. In addition, his laboratory focuses on the pathogenesis and treatment of the muscular dystrophies, with particular emphasis on cell and gene therapy. Dr Rando is Chief of Neurology at the VA Palo Alto Health Care System, USA, where he is Director of the Rehabilitation Research & Development Center of Excellence whose focus is the emerging field of regenerative medicine, particularly in neuromuscular disorders. He is also Director of the Glenn Laboratories for the Biology of Aging at the Stanford University School of Medicine. Dr Rando has received numerous awards and has been recognized by academic and professional societies for his work. He is a past recipient of a Junior Faculty Research Award from the American Academy of Neurology, and in 2007 he was honored to deliver the F.L. McNaughton Lecture at the Montreal Neurological Institute. He received a Paul Beeson Physician Faculty Scholar in Aging from the American Federation for Aging Research, an Ellison Medical Foundation Senior Scholar Award, and a “Breakthroughs in Gerontology” (BIG) Award from the American Federation for Aging Research. In 2005 he received an NIH Director's Pioneer Award for his work at the interface between stem cell biology and the biology of aging.

From the Editors’ Desk: Why NCATS Should Read this Issue of JGIM

From the Editors’ Desk: Why NCATS Should Read this Issue of JGIM

NIH director retracts congratulatory email

NIH director retracts congratulatory email

Race Disparity in Grants: Oversight at Home

NIH Director Francis Collins has promised to lead the NIH in identifying the cause(s) of and redressing the recently reported disparity in NIH funding associated with race (“Weaving a richer tapestry in biomedical science,” L. A. Tabak and F. S. Collins, Policy Forum, 19 August, p. [940][1]; “Race, ethnicity, and NIH research awards,” D. K. Ginther et al. , Reports, 19 August, p. [1015][2]). The limited public discussion on the possible underlying factors has focused on the NIH review process. Although this is an obvious place to continue the investigation, the explanation may lie elsewhere. Investigators in the National Cancer Institute have reported that a major responsible factor cited by unfunded and underfunded minority investigators was “barriers at the home institution” ([ 1 ][3]). These included “inadequate research infrastructure, training, and development,” “barriers to development as independent investigators,” “inadequate mentoring,” and “lack of institutional support.” Although the report focused on barriers to NIH funding for minority investigators pursuing primarily cancer health disparities research, many of the identified obstacles apply to biomedical research funding in general. To address these issues, Director Collins must be prepared to extend NIH policies to providing better oversight of the manner in which minority investigators are treated in their home institutions. For example, although NIH requires the writing of minority recruitment plans by its grantee institutions, it currently neither evaluates how nor even whether such plans are implemented. NIH also does not require outcome measures for whether minority scientists are fairly supported and promoted for successful research careers. Such stark omissions in NIH funding policies could certainly perpetuate or engender unfair racially biased attitudes and practices that would not have been uncovered by Ginther et al. 's study. 1. [↵][4]1. V. L. Shavers 2. et al ., J. Natl. Med. Assoc. 97, 1063 (2005). [OpenUrl][5][PubMed][6] [1]: /lookup/doi/10.1126/science.1211704 [2]: pending:yes [3]: #ref-1 [4]: #xref-ref-1-1 View reference 1 in text [5]: {openurl}?query=rft.jtitle%253DJournal%2Bof%2Bthe%2BNational%2BMedical%2BAssociation%26rft.stitle%253DJ%2BNatl%2BMed%2BAssoc%26rft.aulast%253DShavers%26rft.auinit1%253DV.%2BL.%26rft.volume%253D97%26rft.issue%253D8%26rft.spage%253D1063%26rft.epage%253D1077%26rft.atitle%253DBarriers%2Bto%2Bracial%252Fethnic%2Bminority%2Bapplication%2Band%2Bcompetition%2Bfor%2BNIH%2Bresearch%2Bfunding.%26rft_id%253Dinfo%253Apmid%252F16173321%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [6]: /lookup/external-ref?access_num=16173321&link_type=MED&atom=%2Fsci%2F334%2F6058%2F901.atom

News from NIH: using basic behavioral science to develop better behavioral interventions

It is widely recognized that increasing the availability and use of proven medical and behavioral therapies is essential to improving the public health. While Translation II research, aimed at promoting the adoption of evidence-based treatments within practice or public health settings, is gaining recognition as an important avenue for preventing and treating disease, Translation I research—the development of new treatments for disease based on basic science discoveries—is also a priority. NIH director Francis Collins highlighted the importance of translating basic research findings into new treatments by including it as one of NIH's five priority areas for future research [1], and NIH's preeminent role in promoting the “translation of biomedical research into safe and effective clinical applications” has recently been affirmed with the creation of a National Center for Advancing Translational Sciences [2]. Given NIH's emphasis on “bench to bedside” or Translation I research, is there a “place at the table” for behavioral scientists interested in developing new and potentially more effective behavioral interventions to improve health outcomes? How can NIH facilitate Translation I behavioral science—the translation of basic behavioral science discoveries into new ways to prevent and treat disease? In this column I highlight several NIH activities and initiatives intended to promote the development of the field of Translation I behavioral science.

RACE AND FEDERAL GRANTS

BLACK SCIENTISTS are less likely to receive NIH funding than their white colleagues, according to an NIH-commissioned study published in Science (DOI: 10.1126/science.1196783 ). The study shows that black scientists were 10% less likely than white scientists to receive NIH funding in the years 2000–06, even after controlling for such factors as former training grants, publication record, and institutional affiliation. The study also looked at grant success rates for other minority scientists and found no statistically significant differences between them and white scientists when comparing only those who are U.S. citizens. “The problem has been there all along. Now we know about it,” says NIH Director Francis S. Collins , who admits that he and other agency brass are troubled by the study’s findings. “I am committed to making sure we don’t miss out on this opportunity to change the current situation for the better.” Collins says NIH will examine potential causes for the skewed ...

Prognostic Immune Markers in Non–Small Cell Lung Cancer

Tumor-associated immune responses have polarized effects in regulating tumor growth. Although a clear association has been shown between the tumor immune response and clinical outcome in colorectal and ovarian cancers, the role of immune markers for stratifying prognosis in non-small cell lung cancer (NSCLC) is less defined. Herein, we review the prognostic significance of published immune markers in the tumor microenvironment and peripheral blood of NSCLC patients. To identify prognostic immune genes, we reviewed all published gene-profiling studies in NSCLC and delineated the significance of immune genes by doing subanalysis on the microarray database of the NIH Director's Challenge study. This first comprehensive review of prognostic immune markers provides a foundation for further investigating immune responses in NSCLC.

Fetal Hepatic Sirt1, a Histone H3 Deacetylase, Is Decreased in a Nonhuman Primate Model of Maternal Obesity.

Sirt1 is a known and highly conserved NAD+-dependent protein deacetylase and an important regulator of metabolism, senescence, cancer and longevity. We have previously reported in our nonhuman primate model of maternal obesity that fetal hepatic acetylation levels of histone H3 lysine 14 (H3K14ac) are increased with in utero maternal high fat diet (HFD) exposure compared with control diet, and that increased H3K14ac is accompanied by diminished histone deacetylase (HDAC) activity. However, the identity of the HDAC(s) mediating increased fetal H3K14ac had eluded us. We hypothesized that Sirt1 might in fact retain histone deacetylase in addition to protein deacetylase activity, and thereby modulate fetal epigenomic alterations in our model. Employing QPCR, Western blot and IP analyses from extracts of fetal liver under conditions of high fat or control diet exposure in utero, we observed that fetal hepatic Sirt1 transcription and translation is significantly reduced in offspring of high fat diet fed dams (p<0.001). In order to analyze Sirt1 activity, we transfected human wildtype and dominant negative mutant (H363Y) Sirt1 cDNA into Cos-1 cells. Sirt1 activity, as measured by a chromogenic protein and HDAC assay (BioMol), was greatly increased in the over-expressed recombinant Sirt1 Cos-1 cell line (p<0.001), while Sirt1 activity in cell lysates transfected with the dominant negative Sirt1 was inhibited (p<0.01). Resveratrol, a Sirt1 agonist, further increased Sirt1 protein and histone in vitro deacetylase activity in Cos-1 cells. Finally, to clearly delineate Sirt1-mediated histone deacetylation of H3K14ac, MOLDTI-TOF mass spectrometry with constructed histone peptides as substrate. Both the human recombinant Sirt1 and transfected Cos-1 cell lysate significantly and specifically the histone peptide deacetylation on mass spec. Taken together, these findings are consistent with fetal hepatic Sirt1 functioning as both a protein and histone deacetylase, with altered expression and activity following exposure to maternal HFD. The implications of these findings are to suggest that Sirt1 may function as a highly conserved regulator of metabolism and longevity, which is reprogrammable in fetal life. This research was supported by NIH Director New Innovator Pioneer Award DP2120OD001500-01 to K.A.T. and NICHD March of Dimes Reproductive Scientist Development Program to K.A.T. (poster)

BERG, NEUREITER RECEIVE ACS HONOR

THE AMERICAN Chemical Society presented its 2011 Public Service Award to Jeremy M. Berg, a chemist who runs a $2 billion-per-year research institute at the National Institutes of Health, and Norman P. Neureiter, the first science and technology adviser at the State Department, at an April 13 ceremony on Capitol Hill. The award honors the scientists for their vision and leadership in science and engineering policy. “I am very pleased that ACS is recognizing two scientists who have dedicated their talents to public service,” ACS President Nancy B. Jackson said in a statement. Berg, director of NIH’s National Institute of General Medical Sciences, “is an effective advocate for basic research who has worked to increase the visibility of chemistry at NIH,” Jackson said. He has also focused his efforts on training and motivating the next generation of scientists and increasing the diversity of the biomedical workforce. Berg plans to leave NIH at the end ...

Abstract 4747: Twist1-induced invadopodia formation promotes tumor metastasis

Abstract Tumor cells acquire the ability to degrade basement membrane and extracellular matrix (ECM), thus allowing them to invade and metastasize to distant organs. The molecular triggers for ECM degradation and invasion are largely unknown. The Twist1 transcription factor plays key roles in tumor metastasis and is known to induce Epithelial-Mesenchymal Transition (EMT). In addition to Twist1, a number of studies show that other EMT-inducing transcription factors, including Snail1/Snail2 and ZEB1/ZEB2, are also important players in tumor metastasis. One question unanswered is what are the specific cellular functions and transcriptional targets of individual EMT-inducing transcription factors required for EMT and tumor metastasis. Here we report a novel function of Twist1 in promoting extracellular matrix degradation by inducing the formation of invadopodia. Invadopodia are specialized actin-based membrane protrusions that degrade ECM via clustering of proteases. Invadopodia contain a F-actin core and actin regulatory proteins, such as cortactin, the unique adaptor proteins Tks4 and Tks5 in clustering components of invadopodia, and a large number of proteases for matrix degradation. Twist1 induces PDGFRα expression, which in turn activates Src kinase in various breast tumor cells. Phosphorylation of multiple invadopodia components by Src kinase promotes invadopodia assembly and matrix degradation. We show that Twist1 and PDGFRα are central mediators of invadopodia formation and ECM degradation in response to various EMT-inducing signals, including TGFβ and Snail1. Induction of PDGFRα and invadopodia is essential for Twist1 to promote invadopodia formation, local tumor invasion, and distant metastasis in vivo. Consistent with PDGFRα being a direct transcriptional target of Twist1, expression of Twist1 and PDGFRα is highly correlated and associated with poor survival in breast cancer patients. Together, our study demonstrates that invadopodia-mediated matrix degradation is a key function of Twist1 in promoting tumor metastasis. Furthermore, it reveals that matrix degradation and loss of cell adhesion are regulated by different EMT-inducing transcription factors. This explains why multiple factors need to be activated coordinately to promote carcinoma cells to undergo EMT and invade. We also identify PDGFRα as a direct transcriptional target of Twist1 in promoting invadopodia formation and tumor metastasis, therefore suggesting that PDGFRs might be potential targets for anti-metastasis therapies. Grant acknowledgements: NIH Director's New Innovator Award (DP2 OD002420-01), Kimmel Scholar Award, and California Breast Cancer Research Program(12IB-0065) to J.Y. a DOD Breast Cancer Pre-doctoral fellowship to M.A.E, a DOD Breast Cancer Era of Hope Postdoctoral Fellowship to E.D., Susan G. Komen Foundation grant FAS0703850 to J.K. and L.O. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4747. doi:10.1158/1538-7445.AM2011-4747

Is Drug Development Too Slow? NIH to the Rescue!

Is Drug Development Too Slow? NIH to the Rescue!

NIH director wins bid for translational medicine centre

New nexus will bridge basic and clinical research to improve health.

Translation under one roof

NIH director Francis Collins has cleared a major hurdle to one of his highest priorities—creating a center to consolidate translational research programs scattered around the institutes. Some academics worry about competition for resources in an era of funding austerity.

Saving the National Children's Study

Saving the National Children's Study