Evolution of content — the Concise Communication J. Clin. Invest. (IF 12.784) Pub Date : 2017-11-01 Gordon F. Tomaselli
A central goal of the Editorial group at Johns Hopkins is to accelerate the transmission of cutting-edge biomedical science. There is often a tension between the timeliness of publication and the completeness of a story. We are interested in stories that are complete, and even if brief, a part of the message should be definitive. The definition of definitive is often in the eye of the beholder (i.e., editors and reviewers) and the mandate of the publication venue. We will maintain a rigorous standard for publication in the JCI but do wish to solicit brief, elegant, and captivating reports — memorable scientific short stories.In this spirit, we have reconfigured the Brief Report category and renamed it Concise Communication, with the goal of publishing brief but complete pieces of science. The Concise Communication has a 4,000-word limit, with up to four display items (combinations of figures and tables) and may include a supplement. The final format of the Concise Communication is: Abstract, Introduction, combined Results and Discussion, followed by Methods. The Methods section may be entirely online, but for clinical studies, the study approval information must be reported in the main text. The supplements for Concise Communications will not have a length or word limit. The change from the Brief Report to Concise Communication format will occur with the November 2017 edition of the JCI, therefore, any submitted Brief Reports published after this date will appear in the Concise Communication format.Another goal of our Board is to make submission to the JCI easier for authors. In order to streamline the submission process, we are allowing for more flexibility in the format of original science that comes to the JCI. We know that our authors have a number of venue choices for publishing their work, and liberalizing the format will allow authors to avoid having to change their manuscript for submission to the JCI. Revisions to align with the JCI’s format will only be required of manuscripts that are considered for publication. We seek the timely publication of discoveries in basic and clinical biomedical science that will advance the practice of medicine. We look forward to the opportunity to evaluate your work.FootnotesReference information: J Clin Invest. 2017;127(11):3915. https://doi.org/10.1172/JCI97531.
A conversation with Michael Hall J. Clin. Invest. (IF 12.784) Pub Date : 2017-11-01 Ushma S. Neill
Excerpt: The control of cell growth was once thought to be passive when there were cellular building blocks in nutrients; a cell would grow and ultimately divide. But I’m joined today by Dr. Michael Hall (Figure 1) from the University of Basel in Switzerland who upended this simple assumption and, instead,...
Cannabis in fat: high hopes to treat obesity J. Clin. Invest. (IF 12.784) Pub Date : 2017-10-16 Melody N. Hawkins; Tamas L. Horvath
Cannabinoid receptor type-1 (CB1) is known to have a substantial impact on the regulation of energy metabolism via central and peripheral mechanisms. In this issue of the JCI, Ruiz de Azua and colleagues provide important insights into the regulation of adipocyte physiology by CB1. Mice with adipocyte-specific deletion of the CB1-encoding gene had an overall improved metabolic profile in addition to reduced body weight and total adiposity. These changes were associated with an increase in sympathetic tone of the adipose tissue and expansion of activated macrophages, both of which occurred prior to changes in body weight, lending support to a causal relationship between loss of CB1 in adipocytes and systemic metabolic changes. This work identifies adipocyte CB1s as a potential novel peripheral target for affecting systemic metabolism with diminished CNS effects.
Young endothelial cells revive aging blood J. Clin. Invest. (IF 12.784) Pub Date : 2017-10-16 Vivian Y. Chang; Christina M. Termini; John P. Chute
The hematopoietic system declines with age, resulting in decreased hematopoietic stem cell (HSC) self-renewal capacity, myeloid skewing, and immune cell depletion. Aging of the hematopoietic system is associated with an increased incidence of myeloid malignancies and a decline in adaptive immunity. Therefore, strategies to rejuvenate the hematopoietic system have important clinical implications. In this issue of the JCI, Poulos and colleagues demonstrate that infusions of bone marrow (BM) endothelial cells (ECs) from young mice promoted HSC self-renewal and restored immune cell content in aged mice. Additionally, delivery of young BM ECs along with HSCs following total body irradiation improved HSC engraftment and enhanced survival. These results suggest an important role for BM endothelial cells (ECs) in regulating hematopoietic aging and support further research to identify the rejuvenating factors elaborated by BM ECs that restore HSC function and the immune repertoire in aged mice.
Mutations in the netrin-1 gene cause congenital mirror movements J. Clin. Invest. (IF 12.784) Pub Date : 2017-09-25 Aurélie Méneret; Elizabeth A. Franz; Oriane Trouillard; Thomas C. Oliver; Yvrick Zagar; Stephen P. Robertson; Quentin Welniarz; R.J. MacKinlay Gardner; Cécile Gallea; Myriam Srour; Christel Depienne; Christine L. Jasoni; Caroline Dubacq; Florence Riant; Jean-Charles Lamy; Marie-Pierre Morel; Raphael Guérois; Jessica Andreani; Coralie Fouquet; Mohamed Doulazmi; Marie Vidailhet; Guy A. Rouleau; Alexis Brice; Alain Chédotal; Isabelle Dusart; Emmanuel Roze; David Markie
Netrin-1 is a secreted protein that was first identified 20 years ago as an axon guidance molecule that regulates midline crossing in the CNS. It plays critical roles in various tissues throughout development and is implicated in tumorigenesis and inflammation in adulthood. Despite extensive studies, no inherited human disease has been directly associated with mutations in NTN1, the gene coding for netrin-1. Here, we have identified 3 mutations in exon 7 of NTN1 in 2 unrelated families and 1 sporadic case with isolated congenital mirror movements (CMM), a disorder characterized by involuntary movements of one hand that mirror intentional movements of the opposite hand. Given the diverse roles of netrin-1, the absence of manifestations other than CMM in NTN1 mutation carriers was unexpected. Using multimodal approaches, we discovered that the anatomy of the corticospinal tract (CST) is abnormal in patients with NTN1-mutant CMM. When expressed in HEK293 or stable HeLa cells, the 3 mutated netrin-1 proteins were almost exclusively detected in the intracellular compartment, contrary to WT netrin-1, which is detected in both intracellular and extracellular compartments. Since netrin-1 is a diffusible extracellular cue, the pathophysiology likely involves its loss of function and subsequent disruption of axon guidance, resulting in abnormal decussation of the CST.
Neural precursor cell–secreted TGF-β2 redirects inflammatory monocyte-derived cells in CNS autoimmunity J. Clin. Invest. (IF 12.784) Pub Date : 2017-09-25 Donatella De Feo; Arianna Merlini; Elena Brambilla; Linda Ottoboni; Cecilia Laterza; Ramesh Menon; Sundararajan Srinivasan; Cinthia Farina; Jose Manuel Garcia Manteiga; Erica Butti; Marco Bacigaluppi; Giancarlo Comi; Melanie Greter; Gianvito Martino
In multiple sclerosis, the pathological interaction between autoreactive Th cells and mononuclear phagocytes in the CNS drives initiation and maintenance of chronic neuroinflammation. Here, we found that intrathecal transplantation of neural stem/precursor cells (NPCs) in mice with experimental autoimmune encephalomyelitis (EAE) impairs the accumulation of inflammatory monocyte-derived cells (MCs) in the CNS, leading to improved clinical outcome. Secretion of IL-23, IL-1, and TNF-α, the cytokines required for terminal differentiation of Th cells, decreased in the CNS of NPC-treated mice, consequently inhibiting the induction of GM-CSF–producing pathogenic Th cells. In vivo and in vitro transcriptome analyses showed that NPC-secreted factors inhibit MC differentiation and activation, favoring the switch toward an antiinflammatory phenotype. Tgfb2–/– NPCs transplanted into EAE mice were ineffective in impairing MC accumulation within the CNS and failed to drive clinical improvement. Moreover, intrathecal delivery of TGF-β2 during the effector phase of EAE ameliorated disease severity. Taken together, these observations identify TGF-β2 as the crucial mediator of NPC immunomodulation. This study provides evidence that intrathecally transplanted NPCs interfere with the CNS-restricted inflammation of EAE by reprogramming infiltrating MCs into antiinflammatory myeloid cells via secretion of TGF-β2.
Uromodulin p.Cys147Trp mutation drives kidney disease by activating ER stress and apoptosis J. Clin. Invest. (IF 12.784) Pub Date : 2017-10-09 Bryce G. Johnson; Lan T. Dang; Graham Marsh; Allie M. Roach; Zebulon G. Levine; Anthony Monti; Deepak Reyon; Lionel Feigenbaum; Jeremy S. Duffield
Uromodulin-associated kidney disease (UAKD) is caused by mutations in the uromodulin (UMOD) gene that result in a misfolded form of UMOD protein, which is normally secreted by nephrons. In UAKD patients, mutant UMOD is poorly secreted and accumulates in the ER of distal kidney epithelium, but its role in disease progression is largely unknown. Here, we modeled UMOD accumulation in mice by expressing the murine equivalent of the human UMOD p.Cys148Trp point mutation (UmodC147W/+ mice). Like affected humans, these UmodC147W/+ mice developed spontaneous and progressive kidney disease with organ failure over 24 weeks. Analysis of diseased kidneys and purified UMOD-producing cells revealed early activation of the PKR-like ER kinase/activating transcription factor 4 (PERK/ATF4) ER stress pathway, innate immune mediators, and increased apoptotic signaling, including caspase-3 activation. Unexpectedly, we also detected autophagy deficiency. Human cells expressing UMOD p.Cys147Trp recapitulated the findings in UmodC147W/+ mice, and autophagy activation with mTOR inhibitors stimulated the intracellular removal of aggregated mutant UMOD. Human cells producing mutant UMOD were susceptible to TNF-α– and TRAIL-mediated apoptosis due to increased expression of the ER stress mediator tribbles-3. Blocking TNF-α in vivo with the soluble recombinant fusion protein TNFR:Fc slowed disease progression in UmodC147W/+ mice by reducing active caspase-3, thereby preventing tubule cell death and loss of epithelial function. These findings reveal a targetable mechanism for disease processes involved in UAKD.
Commensal Propionibacterium strain UF1 mitigates intestinal inflammation via Th17 cell regulation J. Clin. Invest. (IF 12.784) Pub Date : 2017-09-25 Natacha Colliou; Yong Ge; Bikash Sahay; Minghao Gong; Mojgan Zadeh; Jennifer L. Owen; Josef Neu; William G. Farmerie; Francis Alonzo III; Ken Liu; Dean P. Jones; Shuzhao Li; Mansour Mohamadzadeh
Consumption of human breast milk (HBM) attenuates the incidence of necrotizing enterocolitis (NEC), which remains a leading and intractable cause of mortality in preterm infants. Here, we report that this diminution correlates with alterations in the gut microbiota, particularly enrichment of Propionibacterium species. Transfaunation of microbiota from HBM-fed preterm infants or a newly identified and cultured Propionibacterium strain, P. UF1, to germfree mice conferred protection against pathogen infection and correlated with profound increases in intestinal Th17 cells. The induction of Th17 cells was dependent on bacterial dihydrolipoamide acetyltransferase (DlaT), a major protein expressed on the P. UF1 surface layer (S-layer). Binding of P. UF1 to its cognate receptor, SIGNR1, on dendritic cells resulted in the regulation of intestinal phagocytes. Importantly, transfer of P. UF1 profoundly mitigated induced NEC-like injury in neonatal mice. Together, these results mechanistically elucidate the protective effects of HBM and P. UF1–induced immunoregulation, which safeguard against proinflammatory diseases, including NEC.
Mast cell hyperactivity underpins the development of oxygen-induced retinopathy J. Clin. Invest. (IF 12.784) Pub Date : 2017-10-09 Kenshiro Matsuda; Noriko Okamoto; Masatoshi Kondo; Peter D. Arkwright; Kaoru Karasawa; Saori Ishizaka; Shinichi Yokota; Akira Matsuda; Kyungsook Jung; Kumiko Oida; Yosuke Amagai; Hyosun Jang; Eiichiro Noda; Ryota Kakinuma; Koujirou Yasui; Uiko Kaku; Yasuo Mori; Nobuyuki Onai; Toshiaki Ohteki; Akane Tanaka; Hiroshi Matsuda
Mast cells are classically thought to play an important role in protection against helminth infections and in the induction of allergic diseases; however, recent studies indicate that these cells also contribute to neovascularization, which is critical for tissue remodeling, chronic inflammation, and carcinogenesis. Here, we demonstrate that mast cells are essential for sprouting angiogenesis in a murine model of oxygen-induced retinopathy (OIR). Although mouse strains lacking mast cells did not exhibit retinal neovascularization following hypoxia, these mice developed OIR following infusion of mast cells or after injection of mast cell tryptase (MCT). Relative hypoxia stimulated mast cell degranulation via transient receptor potential ankyrin 1. Subsequent surges in MCT stimulated retinal endothelial cells to produce monocyte chemotactic protein-1 (MCP1) and angiogenic factors, leading to sprouting angiogenesis. Mast cell stabilizers as well as specific tryptase and MCP1 inhibitors prevented the development of OIR in WT mice. Preterm infants with early retinopathy of prematurity had markedly higher plasma MCT levels than age-matched infants without disease, suggesting mast cells contribute to human disease. Together, these results suggest therapies that suppress mast cell activity should be further explored as a potential option for preventing eye diseases and subsequent blindness induced by neovascularization.
mTORC1 loss impairs epidermal adhesion via TGF-β/Rho kinase activation J. Clin. Invest. (IF 12.784) Pub Date : 2017-09-25 Kaushal Asrani; Akshay Sood; Alba Torres; Dan Georgess; Pornima Phatak; Harsimar Kaur; Amber Dubin; C. Conover Talbot Jr.; Loubna Elhelu; Andrew J. Ewald; Bo Xiao; Paul Worley; Tamara L. Lotan
Despite its central position in oncogenic intracellular signaling networks, the role of mTORC1 in epithelial development has not been studied extensively in vivo. Here, we have used the epidermis as a model system to elucidate the cellular effects and signaling feedback sequelae of mTORC1 loss of function in epithelial tissue. In mice with conditional epidermal loss of the mTORC1 components Rheb or Rptor, mTORC1 loss of function unexpectedly resulted in a profound skin barrier defect with epidermal abrasions, blistering, and early postnatal lethality, due to a thinned epidermis with decreased desmosomal protein expression and incomplete biochemical differentiation. In mice with mTORC1 loss of function, we found that Rho kinase (ROCK) signaling was constitutively activated, resulting in increased cytoskeletal tension and impaired cell-cell adhesion. Inhibition or silencing of ROCK1 was sufficient to rescue keratinocyte adhesion and biochemical differentiation in these mice. mTORC1 loss of function also resulted in marked feedback upregulation of upstream TGF-β signaling, triggering ROCK activity and its downstream effects on desmosomal gene expression. These findings elucidate a role for mTORC1 in the regulation of epithelial barrier formation, cytoskeletal tension, and cell adhesion, underscoring the complexity of signaling feedback following mTORC1 inhibition.
Enterobacteria secrete an inhibitor of Pseudomonas virulence during clinical bacteriuria J. Clin. Invest. (IF 12.784) Pub Date : 2017-09-25 Shannon I. Ohlemacher; Daryl E. Giblin; D. André d’Avignon; Ann E. Stapleton; Barbara W. Trautner; Jeffrey P. Henderson
Escherichia coli and other Enterobacteriaceae are among the most common pathogens of the human urinary tract. Among the genetic gains of function associated with urinary E. coli isolates is the Yersinia high pathogenicity island (HPI), which directs the biosynthesis of yersiniabactin (Ybt), a virulence-associated metallophore. Using a metabolomics approach, we found that E. coli and other Enterobacteriaceae expressing the Yersinia HPI also secrete escherichelin, a second metallophore whose chemical structure matches a known synthetic inhibitor of the virulence-associated pyochelin siderophore system in Pseudomonas aeruginosa. We detected escherichelin during clinical E. coli urinary tract infection (UTI) and experimental human colonization with a commensal, potentially probiotic E. coli bacteriuria strain. Escherichelin production by colonizing enterobacteria may help human hosts resist opportunistic infections by Pseudomonas and other pyochelin-expressing bacteria. This siderophore-based mechanism of microbial antagonism may be one of many elements contributing to the protective effects of the human microbiome. Future UTI-preventive probiotic strains may benefit by retaining the escherichelin biosynthetic capacity of the Yersinia HPI while eliminating the Ybt biosynthetic capacity.
Clinically resolved psoriatic lesions contain psoriasis-specific IL-17–producing αβ T cell clones J. Clin. Invest. (IF 12.784) Pub Date : 2017-09-25 Tiago R. Matos; John T. O’Malley; Elizabeth L. Lowry; David Hamm; Ilan R. Kirsch; Harlan S. Robins; Thomas S. Kupper; James G. Krueger; Rachael A. Clark
In psoriasis, an IL-17–mediated inflammatory skin disease, skin lesions resolve with therapy, but often recur in the same locations when therapy is discontinued. We propose that residual T cell populations in resolved psoriatic lesions represent the pathogenic T cells of origin in this disease. Utilizing high-throughput screening (HTS) of the T cell receptor (TCR) and immunostaining, we found that clinically resolved psoriatic lesions contained oligoclonal populations of T cells that produced IL-17A in both resolved and active psoriatic lesions. Putative pathogenic clones preferentially utilized particular Vβ and Vα subfamilies. We identified 15 TCRβ and 4 TCRα antigen receptor sequences shared between psoriasis patients and not observed in healthy controls or other inflammatory skin conditions. To address the relative roles of αβ versus γδ T cells in psoriasis, we carried out TCR/δ HTS. These studies demonstrated that the majority of T cells in psoriasis and healthy skin are αβ T cells. γδ T cells made up 1% of T cells in active psoriasis, less than 1% in resolved psoriatic lesions, and less than 2% in healthy skin. All of the 70 most frequent putative pathogenic T cell clones were αβ T cells. In summary, IL-17–producing αβ T cell clones with psoriasis-specific antigen receptors exist in clinically resolved psoriatic skin lesions. These cells likely represent the disease-initiating pathogenic T cells in psoriasis, suggesting that lasting control of this disease will require suppression of these resident T cell populations.
CD56bright NK cells exhibit potent antitumor responses following IL-15 priming J. Clin. Invest. (IF 12.784) Pub Date : 2017-10-03 Julia A. Wagner; Maximillian Rosario; Rizwan Romee; Melissa M. Berrien-Elliott; Stephanie E. Schneider; Jeffrey W. Leong; Ryan P. Sullivan; Brea A. Jewell; Michelle Becker-Hapak; Timothy Schappe; Sara Abdel-Latif; Aaron R. Ireland; Devika Jaishankar; Justin A. King; Ravi Vij; Dennis Clement; Jodie Goodridge; Karl-Johan Malmberg; Hing C. Wong; Todd A. Fehniger
NK cells, lymphocytes of the innate immune system, are important for defense against infectious pathogens and cancer. Classically, the CD56dim NK cell subset is thought to mediate antitumor responses, whereas the CD56bright subset is involved in immunomodulation. Here, we challenge this paradigm by demonstrating that brief priming with IL-15 markedly enhanced the antitumor response of CD56bright NK cells. Priming improved multiple CD56bright cell functions: degranulation, cytotoxicity, and cytokine production. Primed CD56bright cells from leukemia patients demonstrated enhanced responses to autologous blasts in vitro, and primed CD56bright cells controlled leukemia cells in vivo in a murine xenograft model. Primed CD56bright cells from multiple myeloma (MM) patients displayed superior responses to autologous myeloma targets, and furthermore, CD56bright NK cells from MM patients primed with the IL-15 receptor agonist ALT-803 in vivo displayed enhanced ex vivo functional responses to MM targets. Effector mechanisms contributing to IL-15–based priming included improved cytotoxic protein expression, target cell conjugation, and LFA-1–, CD2-, and NKG2D-dependent activation of NK cells. Finally, IL-15 robustly stimulated the PI3K/Akt/mTOR and MEK/ERK pathways in CD56bright compared with CD56dim NK cells, and blockade of these pathways attenuated antitumor responses. These findings identify CD56bright NK cells as potent antitumor effectors that warrant further investigation as a cancer immunotherapy.
Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling J. Clin. Invest. (IF 12.784) Pub Date : 2017-10-03 Samir Softic; Manoj K. Gupta; Guo-Xiao Wang; Shiho Fujisaka; Brian T. O’Neill; Tata Nageswara Rao; Jennifer Willoughby; Carole Harbison; Kevin Fitzgerald; Olga Ilkayeva; Christopher B. Newgard; David E. Cohen; C. Ronald Kahn
Overconsumption of high-fat diet (HFD) and sugar-sweetened beverages are risk factors for developing obesity, insulin resistance, and fatty liver disease. Here we have dissected mechanisms underlying this association using mice fed either chow or HFD with or without fructose- or glucose-supplemented water. In chow-fed mice, there was no major physiological difference between fructose and glucose supplementation. On the other hand, mice on HFD supplemented with fructose developed more pronounced obesity, glucose intolerance, and hepatomegaly as compared to glucose-supplemented HFD mice, despite similar caloric intake. Fructose and glucose supplementation also had distinct effects on expression of the lipogenic transcription factors ChREBP and SREBP1c. While both sugars increased ChREBP-β, fructose supplementation uniquely increased SREBP1c and downstream fatty acid synthesis genes, resulting in reduced liver insulin signaling. In contrast, glucose enhanced total ChREBP expression and triglyceride synthesis but was associated with improved hepatic insulin signaling. Metabolomic and RNA sequence analysis confirmed dichotomous effects of fructose and glucose supplementation on liver metabolism in spite of inducing similar hepatic lipid accumulation. Ketohexokinase, the first enzyme of fructose metabolism, was increased in fructose-fed mice and in obese humans with steatohepatitis. Knockdown of ketohexokinase in liver improved hepatic steatosis and glucose tolerance in fructose-supplemented mice. Thus, fructose is a component of dietary sugar that is distinctively associated with poor metabolic outcomes, whereas increased glucose intake may be protective.
CAMKIIγ suppresses an efferocytosis pathway in macrophages and promotes atherosclerotic plaque necrosis J. Clin. Invest. (IF 12.784) Pub Date : 2017-10-03 Amanda C. Doran; Lale Ozcan; Bishuang Cai; Ze Zheng; Gabrielle Fredman; Christina C. Rymond; Bernhard Dorweiler; Judith C. Sluimer; Joanne Hsieh; George Kuriakose; Alan R. Tall; Ira Tabas
Atherosclerosis is the underlying etiology of cardiovascular disease, the leading cause of death worldwide. Atherosclerosis is a heterogeneous disease in which only a small fraction of lesions lead to heart attack, stroke, or sudden cardiac death. A distinct type of plaque containing large necrotic cores with thin fibrous caps often precipitates these acute events. Here, we show that Ca2+/calmodulin-dependent protein kinase γ (CaMKIIγ) in macrophages plays a major role in the development of necrotic, thin-capped plaques. Macrophages in necrotic and symptomatic atherosclerotic plaques in humans as well as advanced atherosclerotic lesions in mice demonstrated activation of CaMKII. Western diet–fed LDL receptor–deficient (Ldlr–/–) mice with myeloid-specific deletion of CaMKII had smaller necrotic cores with concomitantly thicker collagen caps. These lesions demonstrated evidence of enhanced efferocytosis, which was associated with increased expression of the macrophage efferocytosis receptor MerTK. Mechanistic studies revealed that CaMKIIγ-deficient macrophages and atherosclerotic lesions lacking myeloid CaMKIIγ had increased expression of the transcription factor ATF6. We determined that ATF6 induces liver X receptor-α (LXRα), an Mertk-inducing transcription factor, and that increased MerTK expression and efferocytosis in CaMKIIγ-deficient macrophages is dependent on LXRα. These findings identify a macrophage CaMKIIγ/ATF6/LXRα/MerTK pathway as a key factor in the development of necrotic atherosclerotic plaques.
Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond–like features J. Clin. Invest. (IF 12.784) Pub Date : 2017-10-03 Raphael Carapito; Martina Konantz; Catherine Paillard; Zhichao Miao; Angélique Pichot; Magalie S. Leduc; Yaping Yang; Katie L. Bergstrom; Donald H. Mahoney; Deborah L. Shardy; Ghada Alsaleh; Lydie Naegely; Aline Kolmer; Nicodème Paul; Antoine Hanauer; Véronique Rolli; Joëlle S. Müller; Elisa Alghisi; Loïc Sauteur; Cécile Macquin; Aurore Morlon; Consuelo Sebastia Sancho; Patrizia Amati-Bonneau; Vincent Procaccio; Anne-Laure Mosca-Boidron; Nathalie Marle; Naël Osmani; Olivier Lefebvre; Jacky G. Goetz; Sule Unal; Nurten A. Akarsu; Mirjana Radosavljevic; Marie-Pierre Chenard; Fanny Rialland; Audrey Grain; Marie-Christine Béné; Marion Eveillard; Marie Vincent; Julien Guy; Laurence Faivre; Christel Thauvin-Robinet; Julien Thevenon; Kasiani Myers; Mark D. Fleming; Akiko Shimamura; Elodie Bottollier-Lemallaz; Eric Westhof; Claudia Lengerke; Bertrand Isidor; Seiamak Bahram
Shwachman-Diamond syndrome (SDS) (OMIM #260400) is a rare inherited bone marrow failure syndrome (IBMFS) that is primarily characterized by neutropenia and exocrine pancreatic insufficiency. Seventy-five to ninety percent of patients have compound heterozygous loss-of-function mutations in the Shwachman-Bodian-Diamond syndrome (sbds) gene. Using trio whole-exome sequencing (WES) in an sbds-negative SDS family and candidate gene sequencing in additional SBDS-negative SDS cases or molecularly undiagnosed IBMFS cases, we identified 3 independent patients, each of whom carried a de novo missense variant in srp54 (encoding signal recognition particle 54 kDa). These 3 patients shared congenital neutropenia linked with various other SDS phenotypes. 3D protein modeling revealed that the 3 variants affect highly conserved amino acids within the GTPase domain of the protein that are critical for GTP and receptor binding. Indeed, we observed that the GTPase activity of the mutated proteins was impaired. The level of SRP54 mRNA in the bone marrow was 3.6-fold lower in patients with SRP54-mutations than in healthy controls. Profound reductions in neutrophil counts and chemotaxis as well as a diminished exocrine pancreas size in a SRP54-knockdown zebrafish model faithfully recapitulated the human phenotype. In conclusion, autosomal dominant mutations in SRP54, a key member of the cotranslation protein-targeting pathway, lead to syndromic neutropenia with a Shwachman-Diamond–like phenotype.
Proprotein convertase furin regulates osteocalcin and bone endocrine function J. Clin. Invest. (IF 12.784) Pub Date : 2017-10-03 Omar Al Rifai; Jacqueline Chow; Julie Lacombe; Catherine Julien; Denis Faubert; Delia Susan-Resiga; Rachid Essalmani; John W.M. Creemers; Nabil G. Seidah; Mathieu Ferron
Osteocalcin (OCN) is an osteoblast-derived hormone that increases energy expenditure, insulin sensitivity, insulin secretion, and glucose tolerance. The cDNA sequence of OCN predicts that, like many other peptide hormones, OCN is first synthesized as a prohormone (pro-OCN). The importance of pro-OCN maturation in regulating OCN and the identity of the endopeptidase responsible for pro-OCN cleavage in osteoblasts are still unknown. Here, we show that the proprotein convertase furin is responsible for pro-OCN maturation in vitro and in vivo. Using pharmacological and genetic experiments, we also determined that furin-mediated pro-OCN cleavage occurred independently of its γ-carboxylation, a posttranslational modification that is known to hamper OCN endocrine action. However, because pro-OCN is not efficiently decarboxylated and activated during bone resorption, inactivation of furin in osteoblasts in mice resulted in decreased circulating levels of undercarboxylated OCN, impaired glucose tolerance, and reduced energy expenditure. Furthermore, we show that Furin deletion in osteoblasts reduced appetite, a function not modulated by OCN, thus suggesting that osteoblasts may secrete additional hormones that regulate different aspects of energy metabolism. Accordingly, the metabolic defects of the mice lacking furin in osteoblasts became more apparent under pair-feeding conditions. These findings identify furin as an important regulator of bone endocrine function.
Olfactory receptor 544 reduces adiposity by steering fuel preference toward fats J. Clin. Invest. (IF 12.784) Pub Date : 2017-10-09 Chunyan Wu; Su Hyeon Hwang; Yaoyao Jia; Joobong Choi; Yeon-Ji Kim; Dahee Choi; Duleepa Pathiraja; In-Geol Choi; Seung-Hoi Koo; Sung-Joon Lee
Olfactory receptors (ORs) are present in tissues outside the olfactory system; however, the function of these receptors remains relatively unknown. Here, we determined that olfactory receptor 544 (Olfr544) is highly expressed in the liver and adipose tissue of mice and regulates cellular energy metabolism and obesity. Azelaic acid (AzA), an Olfr544 ligand, specifically induced PKA-dependent lipolysis in adipocytes and promoted fatty acid oxidation (FAO) and ketogenesis in liver, thus shifting the fuel preference to fats. After 6 weeks of administration, mice fed a high-fat diet (HFD) exhibited a marked reduction in adiposity. AzA treatment induced expression of PPAR-α and genes required for FAO in the liver and induced the expression of PPAR-γ coactivator 1-α (Ppargc1a) and uncoupling protein-1 (Ucp1) genes in brown adipose tissue (BAT). Moreover, treatment with AzA increased insulin sensitivity and ketone body levels. This led to a reduction in the respiratory quotient and an increase in the FAO rate, as indicated by indirect calorimetry. AzA treatment had similar antiobesogenic effects in HFD-fed ob/ob mice. Importantly, AzA-associated metabolic changes were completely abrogated in HFD-fed Olfr544–/– mice. To our knowledge, this is the first report to show that Olfr544 orchestrates the metabolic interplay between the liver and adipose tissue, mobilizing stored fats from adipose tissue and shifting the fuel preference to fats in the liver and BAT.
Caspase-11–mediated endothelial pyroptosis underlies endotoxemia-induced lung injury J. Clin. Invest. (IF 12.784) Pub Date : 2017-10-09 Kwong Tai Cheng; Shiqin Xiong; Zhiming Ye; Zhigang Hong; Anke Di; Kit Man Tsang; Xiaopei Gao; Shejuan An; Manish Mittal; Stephen M. Vogel; Edward A. Miao; Jalees Rehman; Asrar B. Malik
Acute lung injury is a leading cause of death in bacterial sepsis due to the wholesale destruction of the lung endothelial barrier, which results in protein-rich lung edema, influx of proinflammatory leukocytes, and intractable hypoxemia. Pyroptosis is a form of programmed lytic cell death that is triggered by inflammatory caspases, but little is known about its role in EC death and acute lung injury. Here, we show that systemic exposure to the bacterial endotoxin lipopolysaccharide (LPS) causes severe endothelial pyroptosis that is mediated by the inflammatory caspases, human caspases 4/5 in human ECs, or the murine homolog caspase-11 in mice in vivo. In caspase-11–deficient mice, BM transplantation with WT hematopoietic cells did not abrogate endotoxemia-induced acute lung injury, indicating a central role for nonhematopoietic caspase-11 in endotoxemia. Additionally, conditional deletion of caspase-11 in ECs reduced endotoxemia-induced lung edema, neutrophil accumulation, and death. These results establish the requisite role of endothelial pyroptosis in endotoxemic tissue injury and suggest that endothelial inflammatory caspases are an important therapeutic target for acute lung injury.
Circulating osteocrin stimulates bone growth by limiting C-type natriuretic peptide clearance J. Clin. Invest. (IF 12.784) Pub Date : 2017-10-09 Yugo Kanai; Akihiro Yasoda; Keita P. Mori; Haruko Watanabe-Takano; Chiaki Nagai-Okatani; Yui Yamashita; Keisho Hirota; Yohei Ueda; Ichiro Yamauchi; Eri Kondo; Shigeki Yamanaka; Yoriko Sakane; Kazumasa Nakao; Toshihito Fujii; Hideki Yokoi; Naoto Minamino; Masashi Mukoyama; Naoki Mochizuki; Nobuya Inagaki
Although peptides are safe and useful as therapeutics, they are often easily degraded or metabolized. Dampening the clearance system for peptide ligands is a promising strategy for increasing the efficacy of peptide therapies. Natriuretic peptide receptor B (NPR-B) and its naturally occurring ligand, C-type natriuretic peptide (CNP), are potent stimulators of endochondral bone growth, and activating the CNP/NPR-B system is expected to be a powerful strategy for treating impaired skeletal growth. CNP is cleared by natriuretic peptide clearance receptor (NPR-C); therefore, we investigated the effect of reducing the rate of CNP clearance on skeletal growth by limiting the interaction between CNP and NPR-C. Specifically, we generated transgenic mice with increased circulating levels of osteocrin (OSTN) protein, a natural NPR-C ligand without natriuretic activity, and observed a dose-dependent skeletal overgrowth phenotype in these animals. Skeletal overgrowth in OSTN-transgenic mice was diminished in either CNP- or NPR-C–depleted backgrounds, confirming that CNP and NPR-C are indispensable for the bone growth–stimulating effect of OSTN. Interestingly, double-transgenic mice of CNP and OSTN had even higher levels of circulating CNP and additional increases in bone length, as compared with mice with elevated CNP alone. Together, these results support OSTN administration as an adjuvant agent for CNP therapy and provide a potential therapeutic approach for diseases with impaired skeletal growth.
Adipocyte cannabinoid receptor CB1 regulates energy homeostasis and alternatively activated macrophages J. Clin. Invest. (IF 12.784) Pub Date : 2017-10-16 Inigo Ruiz de Azua; Giacomo Mancini; Raj Kamal Srivastava; Alejandro Aparisi Rey; Pierre Cardinal; Laura Tedesco; Cristina Maria Zingaretti; Antonia Sassmann; Carmelo Quarta; Claudia Schwitter; Andrea Conrad; Nina Wettschureck; V. Kiran Vemuri; Alexandros Makriyannis; Jens Hartwig; Maria Mendez-Lago; Laura Bindila; Krisztina Monory; Antonio Giordano; Saverio Cinti; Giovanni Marsicano; Stefan Offermanns; Enzo Nisoli; Uberto Pagotto; Daniela Cota; Beat Lutz
Dysregulated adipocyte physiology leads to imbalanced energy storage, obesity, and associated diseases, imposing a costly burden on current health care. Cannabinoid receptor type-1 (CB1) plays a crucial role in controlling energy metabolism through central and peripheral mechanisms. In this work, adipocyte-specific inducible deletion of the CB1 gene (Ati-CB1–KO) was sufficient to protect adult mice from diet-induced obesity and associated metabolic alterations and to reverse the phenotype in already obese mice. Compared with controls, Ati-CB1–KO mice showed decreased body weight, reduced total adiposity, improved insulin sensitivity, enhanced energy expenditure, and fat depot–specific cellular remodeling toward lowered energy storage capacity and browning of white adipocytes. These changes were associated with an increase in alternatively activated macrophages concomitant with enhanced sympathetic tone in adipose tissue. Remarkably, these alterations preceded the appearance of differences in body weight, highlighting the causal relation between the loss of CB1 and the triggering of metabolic reprogramming in adipose tissues. Finally, the lean phenotype of Ati-CB1–KO mice and the increase in alternatively activated macrophages in adipose tissue were also present at thermoneutral conditions. Our data provide compelling evidence for a crosstalk among adipocytes, immune cells, and the sympathetic nervous system (SNS), wherein CB1 plays a key regulatory role.
Endothelial transplantation rejuvenates aged hematopoietic stem cell function J. Clin. Invest. (IF 12.784) Pub Date : 2017-10-16 Michael G. Poulos; Pradeep Ramalingam; Michael C. Gutkin; Pierre Llanos; Katherine Gilleran; Sina Y. Rabbany; Jason M. Butler
Age-related changes in the hematopoietic compartment are primarily attributed to cell-intrinsic alterations in hematopoietic stem cells (HSCs); however, the contribution of the aged microenvironment has not been adequately evaluated. Understanding the role of the bone marrow (BM) microenvironment in supporting HSC function may prove to be beneficial in treating age-related functional hematopoietic decline. Here, we determined that aging of endothelial cells (ECs), a critical component of the BM microenvironment, was sufficient to drive hematopoietic aging phenotypes in young HSCs. We used an ex vivo hematopoietic stem and progenitor cell/EC (HSPC/EC) coculture system as well as in vivo EC infusions following myelosuppressive injury in mice to demonstrate that aged ECs impair the repopulating activity of young HSCs and impart a myeloid bias. Conversely, young ECs restored the repopulating capacity of aged HSCs but were unable to reverse the intrinsic myeloid bias. Infusion of young, HSC-supportive BM ECs enhanced hematopoietic recovery following myelosuppressive injury and restored endogenous HSC function in aged mice. Coinfusion of young ECs augmented aged HSC engraftment and enhanced overall survival in lethally irradiated mice by mitigating damage to the BM vascular microenvironment. These data lay the groundwork for the exploration of EC therapies that can serve as adjuvant modalities to enhance HSC engraftment and accelerate hematopoietic recovery in the elderly population following myelosuppressive regimens.
MNK1/2 inhibition limits oncogenicity and metastasis of KIT-mutant melanoma J. Clin. Invest. (IF 12.784) Pub Date : 2017-10-16 Yao Zhan; Jun Guo; William Yang; Christophe Goncalves; Tomasz Rzymski; Agnieszka Dreas; Eliza Żyłkiewicz; Maciej Mikulski; Krzysztof Brzózka; Aniela Golas; Yan Kong; Meng Ma; Fan Huang; Bonnie Huor; Qianyu Guo; Sabrina Daniela da Silva; Jose Torres; Yutian Cai; Ivan Topisirovic; Jie Su; Krikor Bijian; Moulay A. Alaoui-Jamali; Sidong Huang; Fabrice Journe; Ghanem E. Ghanem; Wilson H. Miller Jr.; Sonia V. del Rincón
Melanoma can be stratified into unique subtypes based on distinct pathologies. The acral/mucosal melanoma subtype is characterized by aberrant and constitutive activation of the proto-oncogene receptor tyrosine kinase C-KIT, which drives tumorigenesis. Treatment of these melanoma patients with C-KIT inhibitors has proven challenging, prompting us to investigate the downstream effectors of the C-KIT receptor. We determined that C-KIT stimulates MAP kinase–interacting serine/threonine kinases 1 and 2 (MNK1/2), which phosphorylate eukaryotic translation initiation factor 4E (eIF4E) and render it oncogenic. Depletion of MNK1/2 in melanoma cells with oncogenic C-KIT inhibited cell migration and mRNA translation of the transcriptional repressor SNAI1 and the cell cycle gene CCNE1. This suggested that blocking MNK1/2 activity may inhibit tumor progression, at least in part, by blocking translation initiation of mRNAs encoding cell migration proteins. Moreover, we developed an MNK1/2 inhibitor (SEL201), and found that SEL201-treated KIT-mutant melanoma cells had lower oncogenicity and reduced metastatic ability. Clinically, tumors from melanoma patients harboring KIT mutations displayed a marked increase in MNK1 and phospho-eIF4E. Thus, our studies indicate that blocking MNK1/2 exerts potent antimelanoma effects and support blocking MNK1/2 as a potential strategy to treat patients positive for KIT mutations.
Hdac3 regulates lymphovenous and lymphatic valve formation J. Clin. Invest. (IF 12.784) Pub Date : 2017-10-16 Harish P. Janardhan; Zachary J. Milstone; Masahiro Shin; Nathan D. Lawson; John F. Keaney Jr.; Chinmay M. Trivedi
Lymphedema, the most common lymphatic anomaly, involves defective lymphatic valve development; yet the epigenetic modifiers underlying lymphatic valve morphogenesis remain elusive. Here, we showed that during mouse development, the histone-modifying enzyme histone deacetylase 3 (Hdac3) regulates the formation of both lymphovenous valves, which maintain the separation of the blood and lymphatic vascular systems, and the lymphatic valves. Endothelium-specific ablation of Hdac3 in mice led to blood-filled lymphatic vessels, edema, defective lymphovenous valve morphogenesis, improper lymphatic drainage, defective lymphatic valve maturation, and complete lethality. Hdac3-deficient lymphovenous valves and lymphatic vessels exhibited reduced expression of the transcription factor Gata2 and its target genes. In response to oscillatory shear stress, the transcription factors Tal1, Gata2, and Ets1/2 physically interacted with and recruited Hdac3 to the evolutionarily conserved E-box–GATA–ETS composite element of a Gata2 intragenic enhancer. In turn, Hdac3 recruited histone acetyltransferase Ep300 to form an enhanceosome complex that promoted Gata2 expression. Together, these results identify Hdac3 as a key epigenetic modifier that maintains blood-lymph separation and integrates both extrinsic forces and intrinsic cues to regulate lymphatic valve development.
mTORC1 stimulates phosphatidylcholine synthesis to promote triglyceride secretion J. Clin. Invest. (IF 12.784) Pub Date : 2017-10-16 William J. Quinn III; Min Wan; Swapnil V. Shewale; Rebecca Gelfer; Daniel J. Rader; Morris J. Birnbaum; Paul M. Titchenell
Liver triacylglycerol (TAG) synthesis and secretion are closely linked to nutrient availability. After a meal, hepatic TAG formation from fatty acids is decreased, largely due to a reduction in circulating free fatty acids (FFA). Despite the postprandial decrease in FFA-driven esterification and oxidation, VLDL-TAG secretion is maintained to support peripheral lipid delivery and metabolism. The regulatory mechanisms underlying the postprandial control of VLDL-TAG secretion remain unclear. Here, we demonstrated that the mTOR complex 1 (mTORC1) is essential for this sustained VLDL-TAG secretion and lipid homeostasis. In murine models, the absence of hepatic mTORC1 reduced circulating TAG, despite hepatosteatosis, while activation of mTORC1 depleted liver TAG stores. Additionally, mTORC1 promoted TAG secretion by regulating phosphocholine cytidylyltransferase α (CCTα), the rate-limiting enzyme involved in the synthesis of phosphatidylcholine (PC). Increasing PC synthesis in mice lacking mTORC1 rescued hepatosteatosis and restored TAG secretion. These data identify mTORC1 as a major regulator of phospholipid biosynthesis and subsequent VLDL-TAG secretion, leading to increased postprandial TAG secretion.
iNKT cells require TSC1 for terminal maturation and effector lineage fate decisions J. Clin. Invest. (IF 12.784) Pub Date : 2017-11-01 Jinhong Wu; Jialong Yang; Kai Yang; Hongxia Wang; Balachandra Gorentla; Jinwook Shin; Yurong Qiu; Loretta G. Que; W. Michael Foster; Zhenwei Xia; Hongbo Chi; Xiao-Ping Zhong
Original citation: J Clin Invest. 2014;124(4):1685–1698. https://doi.org/10.1172/JCI69780Citation for this expression of concern: J Clin Invest. 2017;127(11):4216. https://doi.org/10.1172/JCI98066An investigative committee at Duke University recently reported that a research technician in the animal pulmonary physiology laboratory fabricated and/or falsified flexiVent data reported in Figure 3A of this paper. The Editorial Board is issuing this Expression of Concern to alert readers to these problems. The Editors have requested that the experiments in question be repeated by the authors and resubmitted to the Journal. We will inform our readers of the outcome after the data have been evaluated.FootnotesSee the related article at iNKT cells require TSC1 for terminal maturation and effector lineage fate decisions.
The public good of science for health J. Clin. Invest. (IF 12.784) Pub Date : 2017-10-02 Linda P. Fried
April 22, 2017, was the date of the 132nd annual meeting of the Association of American Physicians (AAP). April 22nd was also the date of the March for Science, which was held in 600 cities globally. AAP was a formal sponsor of the march, with 84% of its members endorsing it. Apart from the march, the trisociety AAP-ASCI and American Physician Scientists Association (APSA) meeting offered its usual evidence of why the March for Science is relevant: that science both represents some of the best of the human condition — of curiosity, knowledge, and exploration of the meaning of being human — and is a basis for securing a better future. The premise that science will serve better health futures goes back to the founding of the AAP in 1885. Established “for the advancement of scientific and practical medicine,” it was formed and led by the — then — young Turks, who were forceful leaders in bringing science to medicine in the US. Their expectation was that scientifically based medicine would transform the physician’s ability to improve the health of patients. We now can look back on the results: more than 130 years of advances in science have been critical to the US and to the world, creating dramatic improvements in health, well-being, life expectancy, and prosperity. One summary metric demonstrates an increase in life expectancy by over 30 years in the last 100 years (1), largely due to the scientific contributions of public health and medicine, improved education,and poverty alleviation. Further, Robert Solow’s Nobel Prize–winning attribution is that over half of all economic growth in the US since World War II is due to technological progress and our underlying investments in education, basic science, research and development, and infrastructure (2). At the same time, improved health status of the US, and of all nations, is fundamental to our productivity as well as our well-being and longevity. I have had the opportunity to review the archives of the AAP and find that it offers a history of the roots and the trajectory of these achievements in terms of the US origins of medical and public health science and then the evolution of medical science in particular. I would like to reflect on this trajectory and accomplishments and suggest how I think this offers a lens to both understand the impact of science on health and the impact of health on well-being and our future and suggest a redefined status for science for health as a public good. AAP was organized in 1885 to be a society of “American physicians and pathologists” — initially limited to 100 members — who would meet annually to discuss subjects of “general interest for the advancement of scientific and practical medicine” (Table 1). Table 1 AAP: First Council, 1885 The first council of AAP included seven physicians from the east coast, Chicago, and Montreal, including several who were at the forefront of the move to make science the basis for advancing medicine. The members are listed in Table 1. Two in the table, Doctors William Osler and William Henry Welch, are preeminent figures in medicine and science. Figure 1 shows a photo of William Osler, who became AAP president in 1895, while he was writing The Principles and Practice of Medicine. Osler was the creator of the medical residency, bedside rounds, and clinical clerkships and was the author of “Aequanimitas.” He was one of the “fab four” who started the Johns Hopkins School of Medicine, the first US medical school committed to science as the foundation to medicine. Figure 2 shows a photo of the AAP president’s gavel. It is made from the wood from Dr. Osler’s birthplace in Bond Head, Canada. Figure 1 Osler at work on his textbook. Figure 2 Gavel. The other member from the first AAP council meeting who I would like to particularly honor is William Henry Welch (Figure 3), the impresario of US scientific medicine who started the Johns Hopkins School of Medicine, recruited all of its initial faculty, and served as founding dean from 1893 to 1898 — with the goal of creating the first scientifically based school of medicine in the US. Welch was president of AAP in 1901. He subsequently served as founding dean of the first school of public health, at Johns Hopkins, from 1916 to 1926. In fact, Welch proposed that a school of public health be developed at the same time as the school of medicine, but that ultimately happened sequentially. Welch also served over his career as the founding editor of the Journal of Experimental Medicine and president or chairman of 19 major scientific organizations, including the American Medical Association (AMA), the American Association for the Advancement of Science (AAAS), the National Academy of Science (NAS), and the National Research Council as well as AAP. Figure 3 William Henry Welch. Image credit: US National Library of Medicine. The founders’ vision for AAP was to foster discourse and advances in understanding through an annual meeting that would span the full breadth of physician-led science and to generate exchange across disciplines and between science and practice. There were to be original communications and demonstrations of gross and microscopic preparations and of apparati and instruments. After the first meetings, they immediately decided to “issue a volume of transactions each year” — since discontinued — and also decided that social events that would foster a community of medical scientists were important, and they created the annual dinner AAP still holds. The first two AAP meetings give us insight into where medical science was at the onset of AAP. The first meeting had a debate: “Does the present state of knowledge justify a clinical and pathological correlation of rheumatism, gout, diabetes and chronic Bright’s disease?” Other presentations included “Certain elements found in the blood of malarial fever” and “Demonstration of bacterial cultures from a case of mycotic endocarditis in man, and of specimens showing the experimental production of the disease in rabbits” — the first mention of animal models. It is amazing that these scientific discoveries were occurring less than 40 years after Virchow first set out to create a cellular theory of human biology. In 1887, the second AAP meeting had 2 debates, one of clinical interest (“Antipyretic therapy and its use in the treatment of typhoid fever”) and one of pathological interest (“Embolic infarctions”) plus a presentation of “Cases of sewer gas poisoning.” The meetings typically spanned pathophysiologic investigations, bacteriology, and evidence on the environmental causes of disease. After only two meetings, in October 1887, they had their first debate of the council about how narrow or broad the society should be. Council approved the following motion: “Dr. Miles should be informed of the large number of papers on cardiac subjects, and that it be suggested to him that it would be advisable to choose some other subject for discussion.” The following year, 1888, in response to this request, the meeting ranged in topics from “Geographical distribution of typhoid in the US” to “Management of typhoid convalescence” to the “Demonstration by Dr. Welch of a series of microscopical specimens of the thyroid gland” to “Photographs of bacteria” to one cardiac topic: “Disturbances of heart rhythm with reference to their causation and their value in diagnosis.” This discussion continues to this day: how to learn from the most cutting edge of clinically relevant sciences in ways that honor key advances in science and also support cross-fertilization and synergies across fields. The 2017 meeting sought to tackle this 130-year-old discussion in a new way: the trisociety planning committee selected three themes (see Table 2) and invited speakers to represent the spectrum of physician-led science within each theme. Our goal here is to represent the phenomenal breadth of our members’ science, but also to do more of what the founders were intending: both the cross-fertilization across fields and linking the discrete parts of the full cycle of science to foster appreciation of the interconnectivity between sciences and propel translation to impact. Table 2 2017 trisociety meeting themes Figure 4 presents a conceptual expression of our goals to represent the full cycle of translation, which entails discovery at every level of the progression of science. Physician-led science for health (a) begins with the challenge of the clinical problem, (b) develops evidence as to its import and prevalence, and (c) establishes standardized characterization of the clinical problem and clinical and population-based evidence as to etiology and consequences. From this base, discovery involves hypothesis development, elucidation of question, and evaluation (3, 4) of causes in populations and the laboratory (5). Ultimately, interventions can be developed from each stage to improve the clinical problem being addressed. Figure 4 Ultimately, interventions can be developed at each level to improve the clinical problem being addressed. The archives of the scientific advances reported and discussed by AAP members since its inception show many of the same topics we considered at this 2017 meeting and illuminate the dramatic progression of science over more than 130 years. For instance, Table 3 displays some examples of original communications on brain science presented at AAP meetings in its initial years. Table 4 shows some of the initial presentations on approaches to measuring and displaying clinical characteristics circa 1900. Table 5 displays a range of examples of talks on infectious disease at AAP meetings from 1885 to 1914, while Table 6 displays examples of the early work on vaccines. Table 3 AAP Brain science, circa 1900 Table 4 Visualizing medicine Table 5 Infectious diseases at AAP meetings Table 6 Vaccines Susser and Stein, in 2009, offered a broad summary of the generational progression of science since Welch, conceived as eras and conceptually displayed in graphical form in Figure 5 and ref. 6. These eras very much align with AAP’s trajectory of science at its meetings. Further, the trajectory of health improvement in the US in the last 100 years resulted from these scientific advances along with improvements in living conditions, education, and poverty. The dramatic improvements in our population’s health is something that we sometimes take for granted, even while we constantly push forward to make the next advance that is needed. Just to tip our hat to those advances, we can compare measures of health status in 1900 to those in 2000: (a) In 1900, the top 3 causes of death were infectious diseases; by the mid-20th century it was chronic diseases (3). (b) From 1920 to 1940, the US saw dramatic declines in tuberculosis and typhoid fever, and in 1949, smallpox disappeared from the US; polio vaccines, implemented shortly after, led to eradication of polio in the US (4, 5). (c) Due to vaccines, it is estimated that 103 million cases of smallpox, polio, measles, rubella, mumps, hepatitis A, and diphtheria have been prevented in the US since 1924 — including 24 million in the last decade (7). (d) The advent of the antibiotic era in the mid-20th century was a component of the tremendous advances in pharmaceutical therapies. By 1950, more than half the drugs in common medical use had been unknown ten years before (4). (e) At the same time, population-based and laboratory evidence showed us that a substantial proportion of major chronic diseases are preventable. This includes 50% of cardiovascular disease (CVD) and 30% to 50% of cancers (8). Prevention is accomplished through environmental or lifestyle changes or early detection and treatment of risk factors. By 2000, interventions had resulted in a decline in age-adjusted CVD mortality rates to one-third of their 1960s baseline; half of this decline was due to effective prevention and half to treatment (9). (f) US life expectancy rose from 47 to 68 over 50 years and to 79 years over 100 years (1). Figure 5 Progression of US science for medicine and public health. Conceptually displayed summary of the generational progression of science since Welch (6). Reviewing data like these, and many more, it is clear that science has transformed the health of our nation — the dream of 130-plus years ago has borne fruit. This evidence that science can really improve health provides a basis for changing the conversation in the public sphere to one of understanding both health and the science that enables it as “public goods.” To explore this, let’s start with the arguments used by economists through the concept of “public bads,” which is applied to global health challenges. “Public bads” is a formal economic term for circumstances that are seriously negative for people and society and that are “nonexcludable,” meaning that everyone is at risk (10). Generally, pandemics, HIV, and other contagious diseases or drug-resistant microbial strains are readily recognized as “public bads,” along with poor food quality, and food and water insecurity. We also now know that societies that are ill are less productive. If we look at diseases endemic outside the US, such as malaria, the “public bad” impact is clear: from 1965 to 1990, more than one-third of the countries with intensive malaria had negative economic growth, compared to an average rate of economic growth of 2.3% in countries without malaria (11). Our recognition of ill health as a “public bad” has recently extended — as our evidence as to modifiability has grown — to other global exposures that affect health and that require collective action to protect people, including curtailing tobacco smoking and the serious impact on health of both air pollution and global warming. Thus far, these discussions have occurred in a global context. And yet the US has many of its own “public bads” in terms of ill health and its causes. Among many in the news in the last year is the recognition of serious causes of ill health from water pollution from industrial run-off or corroded pipes. (Notably, the relation of drinking water to disease was first introduced in AAP in 1892 in a presentation on the “Bacteriological study of drinking water.”) The fact that this most recent evidence has not led to renewed commitment to strengthening environmental science and action to protect against these “public bads” suggests that our public and decision makers don’t know enough about the modifiability of health or the highly cost-effective benefits of prevention. Or perhaps they do not see a public responsibility to resolve these “public bads.” It is the latter that takes me from the concept of ”public bads” to its companion concept, “public goods.” Most goods are private — in the sense that consumption can be withheld until a payment is made for them and once consumed, they cannot be consumed again. In contrast, we implicitly understand that health is a public good and that health meets the economists’ definition of “public goods” as goods that are useful for the public generally, exist in the public domain, and where the benefit is shared at the societal level. Further, consumption by one individual does not reduce the amount available to be consumed by another individual, and individuals cannot be effectively excluded from use (Table 7). Examples generally cited as public goods are national parks, public transport, and clean air. The public good nature of health can now be advanced because of the evidence that health is modifiable. That science gives us the knowledge of how to improve health forms the argument for societal investment in science for health. This has rarely, if at all, been articulated in this context. We can do this now because of a century of compelling evidence that health and longevity can be improved, that improvements are based on scientific knowledge, and, together, they propel the well-being of society. Table 7 Principles of public goods Based on this rationale, I think that we would do well to now apply the concept of global public goods for global health to our own US-focused articulation of why science for health matters as well as to health itself. There are two parts to health as a public good. First, scientific knowledge itself is a public good. The cost of sharing knowledge with everyone is zero or relatively modest, and your knowing something does not limit my ability to know it. Plus, knowledge has important public properties of decreasing disparities and strengthening society. Of course, knowledge also has significant private properties, since it is produced by individual researchers and teams and can be withheld and thus made “excludable”; further, researchers want to be adequately rewarded for their efforts and to have adequate investment for innovations in R&D products. For these reasons, it is thought that policies should foster both private and public goods for the health economy (11). Second, the health that results from scientific knowledge is a public good. As I cited before, public bads undermine a society’s productivity and well-being. Because communicable diseases are not exclusive to one person or group versus another and if you get it that doesn’t mean I won’t, communicable disease control is most readily recognized as a public good: once achieved, it benefits all people, both poor and rich and future as well as present generations. Additionally, one person’s “consumption” — let’s say preventive measures or treatment — is often necessary for another to benefit in the case of infectious diseases. We now know this is also true in the case of social contagion, such as for obesity (12) or even for our collective health care costs (13). To achieve prevention or treatment requires collective investment in the knowledge and then investment in the provision of the solutions. An outstanding example of this presented at this 2017 trisociety meeting is the new approaches to pandemic preparedness (14). One other critical aspect of public goods is that the production and provision of these goods are often not remunerated sufficiently for the market to find it worthwhile to invest. Often, there are no natural commercial incentives to produce these goods in a market economy. Therefore, underprovision is likely for public goods without any strong special interest support (15). This is the basis for what Adam Smith argued in 1802: he recognized the existence of certain goods which he thought “may be in the highest degree advantageous to a great society, but are, however, of such a nature that the profits could never repay the expense to an individual or small number of individuals, and which it therefore cannot be expected that any individual or small number of individuals should erect” (16). But, as was articulated at the 2017 trisociety meeting, public and private sectors need to enact this together. We now know that investing in health for all — as a public good — has a high return on investment (ROI) for society. The prevention and containment of infectious or communicable diseases are classic cases of public goods and high returns. For example, it is estimated that devoting an additional $100 million to HIV vaccine research and development is valued to generate returns 6-fold as high (14). The ROI is at least as high from decreasing air pollution (17). Another recent example is the Human Genome Project, conducted from 1988 to 2003 and costing 0.005% of the US GDP spread out over 15 years, or $3.6 billion. Even before we see the health effects realized to the extent we anticipate (18, 19), it is estimated that the Genome Project had an ROI over 14,000% in terms of economic output per federal dollar invested since 1988 and 310,000 jobs (20). Beyond this, US health science investment is a global public good for our interdependent world, helping people everywhere benefit from, as Speth said, “the accumulated stock of global knowledge” (21). Collective action for the creation of public goods — by both the public and private sectors together — underpins each of these. The health of our population would greatly benefit from our societal investment in both improving health itself and in the science for health, recognizing that both are public goods: for the knowledge production by science is a value and translates into value for individuals and the productivity of society and high ROI for health. Further, the nonexcludability and nonrivalrousness of health for all of us (if you get healthy, it doesn’t deprive me of the opportunity for health), exemplifies a public good. Societal policy that sees health and its foundational science as public goods is essential to ensure that benefits are available to all and to create the most health for the resources required. If science for health and health itself are understood to be public goods, then it is to our collective benefit to secure these. Further, pure public goods that are inseparable and inclusive can only be provided by public means. Adam Smith said it best here as well: “Increasingly, we will need to be explicit about how governments and markets should work together to provide the range of goods fundamental to people’s well-being” (22). The evidence is that we need to include health investments in that public good expectation. Implicit in this is the social compact involved. One dimension of that social compact is with us, the scientists themselves: that scientific results that were created as public goods are made fully available to the public — nonexcludable and nonrivalrous. The March for Science that was held today, April 22, 2017, advocates that the value and need for ongoing investment in science — and its basis for sound policy — needs to be valued by our political leadership and by the public itself. In past decades, commitment to public goods is thought to have receded, in part from higher valuation of market forces and patent rights; this has contributed to our lack of preparedness or effective response to many of the health crises we have seen domestically and globally (11). Overall, as has been said by Sean Pool as of 2011, “The US has not kept up. Our national investments in research and development as a percentage of discretionary public spending have fallen from a 17% high (1962) to 9% today, with the biggest decline in civilian research and development” (23). Actually, all the evidence indicates that we need more science for health at this critical time. We are on the cusp of many breakthroughs in longstanding as well as emerging areas. At the same time, many new health needs and opportunities are emerging — starting with the evidence that the health status of the US has fallen substantially relative to peer nations in the last two decades and now stands at the bottom of our peer nations according to a report of the National Academy of Medicine (NAM)/National Research Council (NRC) (24, 25). The themes of today’s trisociety meeting include some of the urgent and emerging issues for our health. These needs extend much further, from the health impact of poisoned water in the US to the health and disease challenges of older age in an aging society to antimicrobial resistance and many more. Further, new issues stand on longstanding problems: the US stroke belt was originally in the northeast, then moved to the southeast as the northeast became healthier. Since 1940, the highest stroke mortality rates have been, and remain, in the southeast US (26). This same area is also a hot spot in the US opioid addiction belt, for obesity, and a region of high cancer mortality hot spots. One could argue that leadership by members of the AAP and by the organization itself may be more important than ever and that the investment in science for solutions is critical. This takes us back to the March for Science today across the US and the AAP membership’s stance — by 84% of members — that the organization should formally endorse the march. Some say that AAP is a “pure science” organization and should not offer opinions on anything outside the conduct of the science itself, and others say that this is not something AAP has done. Interestingly, at least to me, I reviewed the history of the AAP to ask myself this question. I found that, since its inception, the AAP has spoken out, albeit intermittently, as an organization on issues of science, policy, and practice for the public good in areas of its mission: that objective science and evidence are essential foundations for improving health and health care. In his 1978 AAP presidential address, Kurt Isselbacher said that “I look forward to the time when the Association includes in its responsibilities a new role — involvement in the shaping of science and health policy, for there can be little doubt that what happens in the powerful corridors of Congress is as important to our future as what happens in our lecture halls and our laboratories.” The AAP’s endorsement of the March for Science is in line with his wish and with the evidence. In a fitting conclusion to this year’s AAP meeting, I am pleased to announce that the 2016–2017 council has just completed substantial work leading to a 21st Century Statement of the mission of the AAP (Table 8). Perhaps the evidence of a public goods framework of science for health, united with the modern understanding of public and private collective commitments required to meet our responsibilities for health, could now be translated into a 21st century social compact — addressing the essential and sustained basis for societal investment in science and in health. The AAP’s sponsorship of the March for Science is consistent with this vision. Table 8 AAP mission statement Footnotes Reference information: J Clin Invest. 2017;127(10):3561–3567. https://doi.org/10.1172/JCI96941. This article is adapted from a presentation at the 2017 AAP/ASCI/APSA Joint Meeting, April 22, 2017, in Chicago, Illinois, USA. References National Institute on Aging and World Health Organization. Global health and aging. Bethesda, Maryland, USA: National Institute on Aging; 2011. Available at: http://www.who.int/ageing/publications/global_health.pdf Accessed August 18, 2017. Solow RM. 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Vitalizing physician-scientists: it’s time to overcome our imagination fatigue J. Clin. Invest. (IF 12.784) Pub Date : 2017-10-02 Vivian G. Cheung
I know it’s a little late in the day for it, but I want to start with breakfast. It was a Sunday in May 1990, final exam week of my first year in medical school. I was thoroughly tired of exams. Filling out another answer sheet with a number 2 pencil was the last thing I wanted to do. So I was thrilled to see the flyer on my desk for a breakfast seminar. Free breakfast and a lecture by Dr. Robert Mahley. I went for the breakfast, but was nourished more by Dr. Mahley’s project, a population study of lipid metabolism in Turkey. Afterwards, I don’t know what possessed me, but I walked up to him and told him that in college I had studied lipid metabolism in elephant seals with Dr. Donald Puppione. Could I join his team and go to Turkey to take part in this research? I remember the look on his face: who is this? But instead of laughing at my naiveté or doubting my ability, he took me on. That breakfast was the first step in my journey as a physician-scientist. Along the way, Dr. Mahley sent me to UT Southwestern, where I met Dr. Helen Hobbs. Since then, the two of them have supported every step of my career, including some challenging times, such as when I suddenly lost my husband, to discoveries that were exciting but very much counter to prevailing ideas. No matter how trivial or how difficult a problem, they were there to listen and advise. Through doubts, fears, and excitement, they were there. I am certain that without them, I would not be standing here today. In those days, they knew, as I did not, that I was a future physician-scientist at risk. I might have become discouraged, or distracted, and quit research. But today, as a Council member, and this year, as President of the ASCI, I have spent considerable time thinking about the existential risks of physician-scientists. Like many physicians working in academic centers, I was startled to learn how few of us there are: we make up less than 2% of US medical doctors (1). This number is based on a rather liberal definition of physicians doing research, in which research is not necessarily a major component of one’s effort. An increasing number of medical schools have abbreviated the basic science courses in their curricula. Perhaps more important, physician-scientists have virtually disappeared from the teaching arena of direct patient care. Today, practical nuances, such as documentation and charge capture, have displaced curiosity and understanding of patient presentations and disease pathophysiology. In response, many physician-scientists have retreated to the comfort zones of our laboratories; few of us have proactively stepped up to interact with students and residents in clinical settings. With decreasing emphasis on basic science and having so few role models, how can we expect young people to want to become physician-scientists? Often, the brightest students most interested in science are those who are admitted to medical school. However, on the long path from medical school through residency, they often do not have any meaningful contact with role models, so even the most brilliant students cannot sustain that interest. In this climate, how can we expect physicians to play a key role in finding the root cause of disease? Who will bring the next infectious outbreak to the bench? Opportunities to develop treatments for nearly 5,000 diseases with known genetic causes will be deferred or lost. Even if we can provide accessible health care to everyone in our country, patients will still suffer from dementia, ALS, and many diseases of which we have little understanding. We cannot deemphasize research. Of course, this is not a new problem. The term “endangered species” was used by Dr. James Wyngaarden to describe physician-scientists in the late 1970s (2). Since then, Drs. David Ginsburg, Robert Lefkowitz, Stuart Orkin, Leon Rosenberg, Andrew Schafer, and many others have discussed the declining number of physicians in research. But what is new is our imagination fatigue. As I talk to colleagues, junior and senior, about physician-scientists, I have a growing sense that we are accepting the status quo rather than striving to promote the phenomenal science that we should bring to our patients. Often I hear that “the days of the triple threat are over” or that “today, one can no longer take care of patients and do research.” Many even say that it is not possible for an individual researcher to make major contributions, but rather that only teams can bring substantive advances. I am not diminishing the importance of collaborations. Of course major discoveries are the culmination of many advances. But is it true that medicine and science have gotten so much harder? I don’t think so. Instead, I suspect that we have simply accepted that it is much harder, only because we have been hearing that pessimistic refrain for so long. What we need to do is to imagine what is possible. It is not that medicine or science has gotten harder, but rather the bureaucracy has gotten in the way, and the value system has changed. We accept the mounting administrative burden and rewards for medical procedures, rather than academic contributions. Others including Dr. Holly Smith have pointed out the unusual and complex arrangement in which medical education and research take place alongside the health care system. Research, education, and patient care have different goals. To evaluate their success with the same criteria can lead to the sense that individuals cannot participate in all three missions. Nevertheless, our Society has maintained an illustrious roster of physician-scientists for over 100 years; it is our responsibility to ensure its vitality. Let’s remember what we saw in our mentors who inspired us to become physician-scientists.We cannot sit and accept the stacks of reports on declining funding and the decreasing numbers of young physicians going into research. Instead, we have to fix them. The time is now. I think we all know what this “ideal situation” should look like. We do not need another study or report. We need to find practical and actionable solutions. Today is the eve of the March for Science taking place in Washington, DC, and in cities around the world, including Chicago. We can take steps in our own march for science, starting right here. Let me share some steps, large and small, that I hope we can take together. First, let me start with the boldest one: What if we have an independent fund to support young physician-scientists, especially at the transition from training to independence? Dr. Holly Smith referred to this period as “neonatal care.” He said, “In the biogenesis of a physician-scientist, one of the most neglected stages is that of the precarious transition into independence. This phase shift from training, which implies dependence, to independence as a scientist requires careful consideration and support” (3). So, let’s imagine a fund aimed to address this period of vulnerability. It will be coupled with mentoring, including strong commitment from advisors to help their trainees transition to independence. Sustained support should encourage our trainees to take on riskier and more challenging problems. The funding will be generous, but the bar will also be held high. This is a dream that several colleagues and I share; we are still discussing details. In the audience, if you are sitting on $1 billion, please talk to me. And for the rest, stay tuned and be a voice for funds for young investigators. We will need all of your support for this major step forward in our march. Second, deans, department chairs, and division chiefs: fellows and young faculty have put their careers and therefore the future of biomedicine in your hands. The beginning of a career is the most difficult. Your encouragement of faculty can turn their worries into productive action. The intellectually stimulating culture and research support that you provide prompt a willingness to take on difficult clinical cases and challenging research questions. Research is accompanied by failures; your departments’ supportive environment can reassure our younger colleagues that each failed experiment is one step closer to a key finding. Most important, faculty pay close attention to how you judge them — whether it is by the amount of grant dollars, the number of clinical procedures, or the time spent to solve difficult cases and understand basic mechanisms. How you reward and/or compensate your faculty goes far beyond those individuals; it sets the value system for our community. Even though we do not know exactly what fosters breakthroughs, we do know from academic pedigrees that excellence, curiosity, and creativity are contagious. Environments that demand critical thinking and true progress rather than incremental advances are important. Today, there is much uncertainty in funding for research and health care. In these times, an instinct may be to retreat to safer problems and use more conservative approaches, but these have long-term negative effects on science and medicine. Your leadership is critical at this juncture. Perhaps we can leverage this challenging time to encourage transformative changes on longstanding issues such as length of training, salary and compensation, as well as board and recertification requirements. Adversity does not have to hinder progress; we look to you for guidance and plans that invest in our futures. Third, what can we do as the ASCI? We need to lead by examining the meaning of “honor” and “excellence” in selecting new members. It is easy for us to reward individuals by looking at discernible results, such as impact factors and grant dollars, rather than evaluating the process or the bravery in taking on difficult problems or spending time to understand a fundamental process that has no clear trajectory to disease treatments. We can either encourage a whole generation of physician-scientists who are good at scoring As or reward those who are committed to groundbreaking discoveries. The criteria we use in what Dr. Goldstein referred to as “mid-career checkups” (4) influence the composition of this room and the atmosphere of academic medicine. The Joint Meeting should be where everyone wants to come to hear the latest discoveries and meet the newest inductees — and not just a rite of passage. So let’s lead by carefully defining the meaning of “honor” in this honor society. I just listed some big cultural changes that we have to make; there are also smaller steps that each of us can take, starting today. Notice the students and fellows in this room, talk to them, show interest in their research and career plans, tell them to stay in touch, and check in with them from time to time. We like to say we offer a wonderful network. Demonstrate that by reaching out to our colleagues and young trainees. Make sure our fellows and junior faculty have protected time and support for research. And if we notice they don’t, intervene for them, and don’t accept the less-than-ideal situation; help them to imagine and achieve the best. Give to funds such as the Seldin~Smith Award or the Medical Fellows Fund that allow the ASCI to support young investigators. We need your financial support. We will be a good steward of your contributions. There is a table outside with information on ASCI programs that need your support; I hope you will stop by and make a contribution. Come to the annual meeting regularly and encourage your colleagues to do the same — it’s a great time to catch up with friends, meet with mentors, and mentor the next generation. We cannot be a single voice for physician-scientists unless we act together. Consider the annual meeting a step in your march for science. A single march is not enough, nor is coming to the meeting only in the year of your induction. Thank our hard-working staff and our Council members for their service. Every march needs good organizers. I, personally, have valued receiving their advice and expertise during my presidential year. Fellows and students: your steps are the most difficult. Your responsibility is to work hard and excel. Like many others, I am going to tell you to follow your passion and remain curious. A question or a finding may be very cool at first sight, but for it to take root requires time and hard work. So start by finding an interesting topic, and then learn everything about it by reading, doing experiments, and talking to experts; in Dr. Michael Brown’s words, “be totally consumed by it” (5). Your strongest voice is showing excellence in what you do. Pick a reasonable set of things to do, and give it your all. Don’t be afraid to pursue hard problems, and don’t settle for anything less than excellence. This persistence will enable you to make discoveries that improve patients’ lives. You will find that these pursuits are intellectually gratifying and outright enjoyable. I hope everyone in this room will refuse to accept the status quo, commit to doing something, and support each other’s efforts. We have to rekindle the same level of excitement that was present for those who started the ASCI in 1908. Fundamental research by ASCI members led to the development of drugs to treat heart diseases, stomach ulcers, and immune deficiencies. Later today, you will hear from three colleagues whose basic studies led to drugs for diabetes that benefited many millions of patients. It’s just the most recent evidence that our work is essential to America and the world. Finally, let us be the generation that reverses the decline in the number of physician-scientists. We have to shed our imagination fatigue and take concerted actions together. I am confident that we can achieve this most important goal. Let’s march together; I count on each and every one of you to take bold steps to support physician-scientists. Acknowledgments I had the privilege of working with colleagues and friends who care deeply about physician-scientists. I wish to express my gratitude for their ideas, suggestions, and unwavering support. The enthusiasm and dedication of Mukesh Jain, Brian Kobilka, Robert Lefkowitz, Paul J. (PJ) Utz, and Tachi Yamada have motivated me to focus on building support for physician-scientists. I must also thank Victor Dzau, Kenneth (Kurt) Fischbeck, Frederick Ognibene, Marschall Runge, Holly Smith, and Andrew Schafer for their mentoring and advice. I thank Melanie Daub for many conversations and ideas on how we can improve support for trainees. Special thanks to members of my lab, in particular, Alan Bruzel, Colleen McGarry, and Isabel Wang, who sustain me by sharing their excitement and commitment to research. I dedicate this address to the memory of my husband, Richard S. Spielman, who taught me to “always be on the lookout for the presence of wonder” (6). Footnotes Reference information: J Clin Invest. 2017;127(10):3568–3570. https://doi.org/10.1172/JCI96939. This article is adapted from a presentation at the 2017 AAP/ASCI/APSA Joint Meeting, April 22, 2017, in Chicago, Illinois, USA. References NIH. NIH Physician-Scientist Workforce Report, 2014. NIH Website. https://acd.od.nih.gov/documents/reports/PSW_Report_ACD_06042014.pdf Accessed August 17, 2017. Wyngaarden JB. The clinical investigator as an endangered species. N Engl J Med. 1979;301(23):1254–1259.View this article via: PubMed CrossRef Google Scholar Smith LH. Training of physician-scientists assessment of career outcomes. An address delivered at: Howard Hughes Medical Institute. 1995. Goldstein JL. On the origin and prevention of PAIDS (Paralyzed Academic Investigator’s Disease Syndrome). J Clin Invest. 1986;78(3):848–854.View this article via: JCI PubMed CrossRef Google Scholar Brown MS. November 7, 2014. How to win a Nobel Prize [Video file]. Retrieved from: https://www.youtube.com/watch?v=MdarocitY6k Accessed August 17, 2017. Attributed to EB White.
Lessons in leadership and the impact of trainee leaders J. Clin. Invest. (IF 12.784) Pub Date : 2017-10-02 Alexander J. Adami
Introduction I am certain I do not need to explain to this audience the importance of the physician-scientist to the advancement of the science of human health and disease. I am equally certain that I do not need to explain that the pathway to becoming a physician-scientist is far from easy or straightforward. Indeed, I imagine many of you have felt, as I have, that this at-times tortuous journey is like a marathon swim, where pausing for breath or even slowing down seemingly invites drowning. However, I am not here to deliver a somber message on the challenges we face, nor am I here to wax philosophic on the virtues (of which there are many) of a career combining medicine and scientific discovery. Instead, I hope to leave with you some concrete lessons I have learned during my time with the American Physician Scientists Association (APSA) and to share my thoughts on the importance of leadership and involvement as a physician-scientist trainee. Lessons not taught in medical school When I first became a member of APSA, I thought of this association as I suspect many trainees think of their field’s society: an interesting group to which I had an obligation to belong, but one unlikely to yield more than a line on a CV. What I did not anticipate were the lessons that being a part of APSA taught me, and I assure you that advancing to the presidency is not required to learn these lessons for yourself. The first skill APSA taught me was simple: how to lead. It may surprise some of you to learn that I had never held a single leadership position prior to medical school. I was never one for clubs, for sports teams, or for honor societies. I came to APSA with a very blank slate. Initially, beginning as a member and, soon thereafter, Vice-Chair of the Public-Relations Committee, I learned to manage projects with input from my fellow leaders across the country, how to coordinate efforts between multiple committees, and how to organize and run a team. I believe I am safe in stating that these are not skills many medical or graduate schools teach, yet all of us will use these skills throughout our careers. If you become the principal investigator of your own laboratory, you will be managing a team. If you someday run all or part of a multicenter clinical study, you will be coordinating between actors on a stage which may span the continent or even the globe. Learning and practicing some of these skills as a trainee, when mistakes are far more forgiving, will position you well for the future. I suspect many of you are already grumbling at the suggestion of adding more to your plate, with the constant drone of your medical school and research mentors lecturing you about staying focused on your work. Here too, however, the acts of leadership and service impart invaluable skills for our future careers, and this is the second lesson APSA taught me: time and priority management. All of us, no matter the career path we choose, will have to juggle many responsibilities and wear many hats, sometimes simultaneously. Whether navigating research and clinical duties, moving between research and teaching, enjoying a fulfilling family life and launching a career, or a combination of everything and more, it is important to learn how to balance demands. Don’t believe me? Just think back to any one of the “work-life balance” panels you have been to in your trainee careers (and if you have not yet seen one — trust me — you will). These panels are ubiquitous at scientific meetings, because balancing competing demands is one of the hardest things you will have to do. Serving as an officer in APSA honed my ability to strike a balance between priorities. I can assure you, nothing could have forced me to solidify my ability to manage multiple competing priorities faster than running a national association while trying to survive inpatient surgery, OB/GYN, and medicine clerkships as a third-year medical student. But, you need not be that crazy (and I would recommend wholeheartedly that you do not attempt to do so) to learn these valuable lessons. Join an APSA committee and take on a small project. If you find yourself ready for more, apply to become a committee chair or member-at-large. Challenge yourself, and you will grow stronger with each summit surmounted. If you are not one for national service, APSA is not the only place to acquire these skills. Closer to home, give back to your institution by serving as a student leader. Every medical school has a veritable forest of committees and working groups that are striving to improve the education and research environment of the institution. If your institution is redesigning its curriculum (as seems to be in vogue these days), lend your voice to the redesign. If you are interested in student government, stand for an elected position. Even small experiences while you are a trainee help you learn to manage your time effectively and to succeed in many arenas at once, and you will be helping your school and fellow trainees at the same time. This is not to say you should throw yourself into leadership or society service with reckless abandon. Your job as a trainee is first and foremost to be a good trainee. Do well in medical school classes and clerkships, build a solid foundation of research training, and publish your good work for the benefit of human health and the advancement of human knowledge. However, take this opportunity to stretch your boundaries while it is “safer” to do so. As a junior faculty member — or even a clinical or postdoctoral fellow — scrambling to do research while seeing patients or teaching, no one is going to give you the option to put one demand aside to focus on the other, nor will they be forgiving if you master one but fail to achieve in another. APSA taught me how to juggle competing demands efficiently and, more importantly, how to effectively set priorities, so what needed to get done did. I believe my experiences will serve me well in the next stages of my career, and I am confident they would do the same for you. The third thing APSA taught me is more intangible but immensely satisfying: how to mentor. I am certain that all of us have encountered absolutely fantastic mentors who have been critical to the success of their trainees. Many of the presentations from distinguished physician-scientists at the Association of American Physicians (AAP)/American Society for Clinical Investigation (ASCI)/APSA Joint Meeting include homage to the mentors who helped those now-successful investigators get to where they are. I am certain, too, that all of us have encountered mentors who were decidedly less than stellar. As trainees, many of us will have some exposure to mentoring even before we graduate, such as overseeing undergraduates in the laboratory, but I found national service to APSA, as well as my own institutional service as a member of UConn’s Medical Dental Student Government, to be particularly important training grounds for my own mentorship skills. This was not a skill that came naturally — I found my way as a mentor through being a leader. While being a good mentor is not synonymous with being a good leader, and vice versa, I think my leadership team would agree that the greatest achievements of my presidential term came, not by way of my personal skills and energy, but by harnessing the skills and energy of the team working with me. As I watch many of those individuals move on to senior positions within APSA or the next stage of their training, such as residency, I am humbled to think that my efforts might have had a positive impact on their training. Indeed, the most personally gratifying moments of my presidency were those in which I saw how my encouragement, mentorship, and advice helped members of my leadership team grow and strengthen themselves. Remarkable as it may turn out to be, the greatest legacy you will leave as a physician-scientist is likely not to be your own science. Rather, it is likely to be the science of those you train and mentor and, by extension, the science of all those they too come to mentor. This is not a skill you can gain from a book, a symposium, or a two-day workshop. It comes from doing and experiencing — something that is granted through holding a leadership role. The impact of determined trainees Lest you be left with the impression that extracurricular involvement and leadership produces little else than personal growth, let me assure you that this could not be further from the truth. Whether you lead nationally or at your own institution, the efforts of trainee leaders have had, and continue to have, an enormous impact on the training and future of physician-scientists. To illustrate this, please indulge my brief sojourn into the historic; as the tenth president to lead APSA (Table 1), I am particularly proud of the accomplishments of my predecessors and the teams they led. Each of the following achievements were driven by trainees, individuals much like many of you, and have made a lasting impact far beyond the scope of APSA. Table 1 Presidents of the APSA, 2004–2017 I suspect few statements will more strongly unite medical students of all stripes, including physician-scientist trainees, than this one: the US Medical Licensing Exam (USMLE) is a big deal. We all must pass its several steps, and like it or not, our scores are major factors in where we end up after medical school. Some of you may know that the USMLE undergoes review to ensure it is meeting the needs of students and institutions. One such review, beginning in January of 2004 (1), was aimed at determining whether to combine Step 1 and Step 2 Clinical Knowledge of the USMLE into one exam administered during the clinical phase of training. Naturally, there were many strong opinions on the subject from governing bodies, schools of medicine, and trainees themselves. For dual-degree trainees, many of whom complete the clinical years of medical school following graduate school, being required to have total mastery of the basic sciences so many years after the fact was a daunting proposition. For all medical students, the prospect of a single, fate-determining exam was enough to send those predisposed straight into supraventricular tachycardia. APSA’s policy committee, recognizing a need for a strong student voice in the process, surveyed the entire US medical student population, in part through the Institutional Representatives (IRs) of APSA. APSA then shared the responses of over seven thousand US medical students (2) with the USMLE review committee, and while we certainly cannot claim to be the sole determinant of the decision to maintain separate exams (3), APSA’s voice was definitely influential. A program near and dear to the hearts of all dual-degree trainees is the Ruth L. Kirschstein National Research Service Award F30 Predoctoral Fellowship of the NIH. Many younger trainees may not realize this, but until recently, the number of NIH institutes that supported one unified F30 mechanism could be counted on less than two hands (4). APSA members had long expressed frustration that many large institutes, including the National Cancer Institute, did not support this fellowship, leaving applicants to join the larger pool of predoctoral candidates applying for the F31, a mechanism often poorly suited to a dual-degree training plan. APSA’s trainee leaders recognized this unmet need and again took the pulse of the trainee community, gathering data and assembling a strong argument. APSA leaders presented the NIH with a clear indication — straight from the mouths of trainees — of the importance of the F30 for all dual-degree trainees. While APSA again cannot claim to be the sole driver of this decision, it is no coincidence that many previously recalcitrant institutes began supporting the F30 after APSA delivered its findings to NIH leadership (5). A further historical achievement, and one which APSA has continued throughout its existence, has been our representation at the highest levels of discussions and deliberations regarding the future of physician-scientists. I could devote dozens of presidential addresses (as have many past ASCI and AAP presidents) to the plight of the physician-scientist as an “endangered species” (6). However, instead of directing you to the woes of the profession, I seek to show you the ways in which APSA has worked to combat them. Many of you have likely heard of the Physician-Scientist Initiative, originally spearheaded by the Association of Professors of Medicine, but how many of you were aware that APSA’s founder, Freddy Nguyen, was a participant in the initial phases of this initiative (7)? Or that APSA leaders have regularly joined meetings focusing on physician-scientist training, such as those of the National Association of MD-PhD Programs and the Alliance for Academic Internal Medicine (AAIM)? Our voices have always been valued at these discussions, and as trainee leaders we can play a direct and concrete role in shaping how physician-scientists are trained and supported in this country. Taking the measure of a year of successes Of course, achievements of APSA trainee leaders are not merely found in the dusty pages of more distant history. No presidential address would be complete without pausing to exalt the many accomplishments the president oversaw during the past year. My greatest contribution to this year of many achievements was to assemble an outstanding leadership team (Figure 1) who truly did all of the work and deserve all of the accolades. Each of these successes, like the historical ones I outlined above, are examples of how trainee leaders have made an impact on the association and the broader community of physician-scientist trainees. Figure 1 Members of the 2016–2017 APSA Leadership Team. Some of the members of the 2016–2017 APSA Board of Directors and Executive Council at the 2016 Leadership Retreat in Atlanta, Georgia, USA. From left to right, clockwise: Alexander J. Adami, Mariam Bonyadi-Camacho, Hanna Erickson, Kofi Mensah, Krishan Chhiba, Tim Kennell, Daniel DelloStritto, Brandon Fox, Travis Hull, Karen Doersch, Abhik Banerjee, Eric Schauberger, Audra Iness, and Dania Daye. This year was one of many milestones. APSA saw over 1,500 dues-paying members, a considerable achievement for a society less than 15 years old. Our Annual Meeting, held as part of the AAP/ASCI/APSA Joint Meeting, attracted more than 360 physician-scientist trainees, a record number. We held five successful regional meetings across the country and have several dozen thriving local APSA chapters at institutions nationwide, all of which are doing important work for physician-scientist trainees at their own institutions. While chasing numbers may seem egotistical, they are important. Not only does reaching more trainees help APSA more accurately assess the needs and desires of future physician-scientists, but doing so gives the association more clout with stakeholders, strengthening arguments we make on your behalf and enabling us to truly represent your concerns to those whose efforts may influence your training path and eventual careers. As a unified community, our voice is one to which leaders of the scientific and medical communities truly do listen. Speaking of stakeholders, APSA leaders were very active this year in representing you to key decision makers and drivers of policy changes. In July and December of 2016, APSA’s senior leadership participated in the final two workshops on the physician-scientist convened by Francis Collins, director of the NIH. In February 2017, APSA represented trainees at the Research Pathway Directors Meeting of the AAIM, giving voice to your needs and concerns as directors of physician-scientist training programs sought to strengthen and expand them. It may be tempting to dismiss such meetings as mere generators of white papers, but the topics discussed are already having an impact. New NIH initiatives discussed during these meetings, including a K99/R00 career development award tailored to physician-scientists, are already appearing (8), and other proposals in the pipeline will soon be outlined in a formal publication by the organizers of the NIH workshops (refer to ref. 9, which was published after the initial text of this address was prepared). This year was also one of great data for APSA. APSA’s first publication, exploring the career intentions of physician-scientist trainees, is nearing publication as I pen this speech (refer to ref. 10, which was published as this address was prepared for printing), representing the culmination of many years of data collection, analysis, and diligent work by a talented team of trainee leaders. Among other things, this manuscript represents perhaps the first comprehensive effort to compare MD-PhD trainees with MD trainees who express interest in research careers. The data presented therein will hopefully help guide schools of medicine as they offer programs to help MD trainees launch their careers as physician-scientists. This summer, APSA will present a project exploring the clinical continuity strategies of MD-PhD programs at the National MD-PhD Association Meeting in Washington, DC. It may surprise you to know that no one has ever examined how different programs provide clinical continuity, or if they do at all, during the graduate school phase of training. It was the suggestion of an APSA leader, an IR in fact, that launched this project, and the interest we have received from directors of MD-PhD programs has been intense. With these and more efforts soon to be revealed, APSA is contributing more than just an opinion and a viewpoint, important as those may be: we are contributing concrete data which may be used to influence training and training outcomes. Earlier in the training pipeline, APSA’s Undergraduate Mentorship Program continues to grow, with over 150 mentor-mentee pairs assembled. This program is both an example of how working with APSA can build your mentorship skills as a medical student and how APSA can meaningfully strengthen the pipeline of physician-scientists. Schools of medicine and large institutional stakeholders, such as the NIH, can apply their efforts to medical students, residents, and fellows, but few are as well-placed to help more interested undergraduates prepare for this career path as those who were, just a short time ago, undergraduates themselves. My immediate predecessor, Daniel DelloStritto, delineated the virtues and relevance of scientific societies in his own presidential address (11). I may be biased, but I firmly believe the successes of this year, and many more I do not have time to address, are proof positive of the importance of societies, particularly APSA, to the physician-scientist community. The accomplishments of this year and of all the years since APSA’s founding are all the more remarkable because they were not driven by faculty, administrators, or funding agencies: they were driven by trainees. APSA is greater than the sum of its parts, and it is the efforts of trainees just like you or me who make everything that we do possible. Conclusion I am now approaching my seventh year in APSA, and it has been my great privilege and distinct honor to serve and represent the trainee community. Far more meaningful than any fleeting glory has been working alongside and getting to know many extraordinary trainees from across the country, individuals whose efforts were critical to the accomplishments I have mentioned in this address. As I pass stewardship of the society to the next generation of trainee leaders, I am more confident than ever that APSA will flourish and continue to advance its mission of supporting aspiring physician-scientists. Our country, and the whole of humanity, needs a strong pipeline of physician-scientists to continue to make advances in our understanding of human health and disease, and I look forward to watching APSA play an important part in strengthening that pipeline. To all trainees who may not yet be APSA members or may not be taking on leadership roles within APSA or at their own institutions, I encourage you to get involved to whatever degree you are able. To all who are leaders now, I congratulate you and wish you the very best. Your efforts will play an important part in strengthening the future of the physician-scientist and in ensuring that the greatest advances in the science of human health are not behind us but are yet to come. Acknowledgments The author was supported in part during his training, including this presidential term, by a fellowship from the National Heart, Lung, and Blood Institute (F30 HL-126324). The author thanks Audra Iness, Jillian Liu, and Freddy Nguyen for their review and thoughtful comments on this address. Footnotes Conflict of interest: The author has declared that no conflict of interest exists. Reference information: J Clin Invest. 2017;127(10):3571–3574. https://doi.org/10.1172/JCI97039. This article is adapted from a presentation at the 2017 AAP/ASCI/APSA Joint Meeting, April 22, 2017, in Chicago, Illinois, USA. References United States Medical Licensing Examination. United States Medical Licensing Examination. The Comprehensive Review, CRU Updates – August 2007. USMLE Website. http://www.usmle.org/cru/updates/2007-08.html Published August 15, 2007. Accessed August 22, 2017. Schauberger E, Nguyen F. Medical Student Attitudes and Perceptions on the USMLE Review. American Physician Scientists Association. http://www.freddynguyen.org/2008/medical-student-attitudes-and-perceptions-usmle-review Accessed September 7, 2017. Scoles PV. Comprehensive review of the USMLE. Adv Physiol Educ. 2008;32(2):109–110.View this article via: PubMed CrossRef Google Scholar NIH. PA-10-107: Ruth L. Kirschstein National Research Service Awards for Individual Predoctoral MD/PhD and Other Dual Doctoral Degree Fellows (Parent F30). NIH Website. https://grants.nih.gov/grants/guide/pa-files/PA-10-107.html Accessed August 22, 2017. NIH. PA-11-110: Ruth L. Kirschstein National Research Service Awards for Individual Predoctoral MD/PhD and Other Dual Doctoral Degree Fellows (Parent F30). NIH Website. https://grants.nih.gov/grants/guide/pa-files/PA-11-110.html Accessed August 22, 2017. Wyngaarden JB. The clinical investigator as an endangered species. N Engl J Med. 1979;301(23):1254–1259.View this article via: PubMed CrossRef Google Scholar Nguyen FT. The birth of the American Physician Scientists Association — the next generation of Young Turks. J Clin Invest. 2008;118(4):1237–1240.View this article via: JCI PubMed CrossRef Google Scholar NIH. PAR-17-329: NIAID Physician-Scientist Pathway to Independence Award (K99/R00). NIH Website. https://grants.nih.gov/grants/guide/pa-files/PAR-17-329.html Accessed August 22, 2017. Hall AK, Mills SL, Lund PK. Clinician-investigator training and the need to pilot new approaches to recruiting and retaining this workforce [published online ahead of print August 1, 2017]. Acad Med. https://doi.org/10.1097/ACM.0000000000001859. View this article via: CrossRef Google Scholar Kwan JM, et al. Exploring intentions of physician-scientist trainees: factors influencing MD and MD/PhD interest in research careers. BMC Med Educ. 2017;17(1):115. View this article via: PubMed CrossRef Google Scholar DelloStritto DJ. Why societies? 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Introduction of Laurie H. Glimcher, MD J. Clin. Invest. (IF 12.784) Pub Date : 2017-10-02 Carl F. Nathan
Laurie H. Glimcher personifies the qualities honored by the George M. Kober Medal. A renowned immunologist who has taken on a series of leadership positions in medical education, research, and clinical care, she has played a key role in the rapidly advancing field of immunotherapy and in the lives and careers of scientists who are driving the field forward. Dr. Glimcher (Figure 1), who became President and CEO of Dana-Farber Cancer Institute in Boston late last year, had an early exposure to the demands and rewards of a medical career; her father, Melvin Glimcher, was a prominent orthopedic surgeon at Massachusetts General Hospital and Boston Children’s Hospital. Over the course of a 40-year career, she has been, in many ways, a pioneer, not only as a scientist but as a model of professional achievement for women in science and academic medicine. Figure 1 Laurie H. Glimcher, winner of the 2017 Association of American Physicians George M. Kober Medal. Image credit: Alexey Levchenko. Dr. Glimcher graduated from Radcliffe College and earned her medical degree from Harvard Medical School in 1976, followed by internship and residencies at Mass. General and Brigham and Women’s Hospital. Her medical school studies sparked a fascination with the immune system and autoimmune disease. From 1979 to 1982, she conducted immunology research at the National Institutes of Health in the lab of the late William Paul, work that would later result in the discovery of the transcription factors XBP1 and T-bet, which play a role in immune system development and activation. It was during these early years that she also began raising a family. Dr. Glimcher joined the Harvard T.H. Chan School of Public Health in 1984, and she was the Irene Heinz Given Professor of Immunology from 1991to 2011. As a professor of medicine at Harvard Medical School, she directed one of the world’s leading academic immunology programs. Having devoted her career primarily to laboratory research, Dr. Glimcher decided to broaden her efforts. In 2012, she joined Weill Cornell Medical College as Dean and Professor of Medicine — becoming the first woman to serve as dean at the medical school — and Provost for Medical Affairs at Cornell University. There, she took steps to help women achieve work-life balance, setting up a daycare center and a grant program for postdoctoral fellows who are primary caregivers, and establishing an award program for excellence in mentoring women. Her determination to do big things is captured in a comment she made after being named Dana-Farber’s President: “If you don’t aim high, you’re never going to make major discoveries.” As Dr. Glimcher has demonstrated, that passion can have as powerful an impact in the laboratory as in the culture of science and medicine itself. Footnotes Reference information: J Clin Invest. 2017;127(10):3575. https://doi.org/10.1172/JCI97404. This article is adapted from a presentation at the 2017 AAP/ASCI/APSA Joint Meeting, April 22, 2017, in Chicago, Illinois, USA.
Starting out as a physician-scientist: the crucial first step on the ladder to success J. Clin. Invest. (IF 12.784) Pub Date : 2017-10-02 Joseph L. Goldstein
Many of you in the audience are just beginning your careers as physician-scientists. And most of you, I suspect, are struggling with the question of how can I do something worthwhile in biomedical research. The answer to your struggles may be found in a provocative sculpture created by the contemporary African American artist Martin Puryear (Figure 1). Figure 1 Ladder for Booker T. Washington. Martin Puryear. 1966. Wood (ash and maple). 36 × 1.9 feet (narrowing at top to 3 inches). Collection of the Modern Art Museum of Fort Worth. Gift of Ruth Carter Stevenson, by Exchange. Puryear’s sculpture is a tall wooden ladder (36 feet high) suspended by invisible wires, enabling it to float from the ceiling of the atrium of the Museum of Modern Art in Fort Worth. Puryear constructed the ladder from a single oak tree. The bottom rung is 2 feet wide, and the top rung is 1 inch wide. There are 100 rungs, most of which are at the top and not visible in the photograph. The narrowing of the ladder towards the top creates a distorted visual perspective that evokes an illusionary goal that is unattainable. It is easy to get both feet on the first rung of the ladder, but it is an almost impossible struggle to reach the top. Opportunity narrows at the very highest reaches. Puryear created this work to symbolize the struggles of Booker T. Washington, who was the dominant African American figure in the U.S. in the early 1900s. Booker T. Washington was born into slavery in 1856, was freed at age 9, and by age 25 had established the Tuskegee Institute in Alabama as a trade school for African Americans. His autobiography, Up from Slavery, is still read today, more than 100 years after it was written. Harvard University conferred an honorary degree on Washington in 1896 when he was only 40 years of age. Puryear’s ladder can be thought of as a universal metaphor for everyone who struggles to do something worthwhile. But there’s another way to think about the ladder that may be more relevant to beginning physician-scientists (Figure 2). If we turn the Booker T. Washington ladder upside down, the difficult challenge is not at the top, but at the bottom — getting your little toe on the first rung. Here the ladder symbolizes the struggles of physician-scientists like Barry J. Marshall, who made the totally unexpected discovery that peptic ulcers are caused not by stress, but by a bacterial Helicobacter infection that can be cured with antibiotics. Marshall got his first toe on the ladder by doing a bold experiment in 1985 that opened a new field, but virtually no one recognized the significance of his work when it was first published in the Medical Journal of Australia — not one of your high-profile journals! Figure 2 Ladder for physician-scientists. Puryear’s Ladder has been turned upside down. Illustration by Nancy Heard; reproduced with permission of the artist. The Barry J. Marshalls of the world who do truly original research have the first 94 rungs of the upside-down ladder all to themselves for many years until reaching the 95th rung — the 5th rung from the top — where there’s now room for other scientists to jump on the bandwagon and join in on the fun and excitement of a new venture. This is the tipping point when a new field of science or medicine explodes with widening opportunities and becomes widely recognized as important. So what is the best way for a young physician-scientist to get his or her little toe on the first rung of the upside-down ladder? The key is to choose the right mentor. You don’t want a mentor who counts papers, who is focused on impact, or who seeks press conferences. What you want is a mentor who can teach you how to ask the right question. Asking and framing the right question — one that is original, interesting, and experimentally tractable — is the hardest thing to do in science. In my view, the biggest mistake that beginning scientists make is to follow the crowd, which means you will be asking the next incremental question — not a bold one. To the beginning physician-scientists in the audience, I wish you all good luck and success in selecting a mentor who can teach you how to ask the right question. Remember, you can’t choose your parents, but you can choose your mentors. Footnotes Reference information: J Clin Invest. 2017;127(10):3576. https://doi.org/10.1172/JCI97405. Remarks at the Presentation of the 2017 Donald Seldin~Holly Smith Award for Pioneering Research during the annual meeting of the American Society for Clinical Investigation and Association of American Physicians, Chicago, IL, April 22, 2017.
CNS inflammation and neurodegeneration J. Clin. Invest. (IF 12.784) Pub Date : 2017-09-05 Tanuja Chitnis; Howard L. Weiner
There is an increasing recognition that inflammation plays a critical role in neurodegenerative diseases of the CNS, including Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, and the prototypic neuroinflammatory disease multiple sclerosis (MS). Differential immune responses involving the adaptive versus the innate immune system are observed at various stages of neurodegenerative diseases, and may not only drive disease processes but could serve as therapeutic targets. Ongoing investigations into the specific inflammatory mechanisms that play roles in disease causation and progression have revealed lessons about inflammation-driven neurodegeneration that can be applied to other neurodegenerative diseases. An increasing number of immunotherapeutic strategies that have been successful in MS are now being applied to other neurodegenerative diseases. Some approaches suppress CNS immune mechanisms, while others harness the immune system to clear deleterious products and cells. This Review focuses on the mechanisms by which inflammation, mediated either by the peripheral immune response or by endogenous CNS immune mechanisms, can affect CNS neurodegeneration.
Genome editing of human embryos: to edit or not to edit, that is the question J. Clin. Invest. (IF 12.784) Pub Date : 2017-08-28 Srinivasan Chandrasegaran; C. Korin Bullen; Dana Carroll
Excerpt: The powerful tools of genome editing are rapidly making their way toward the clinic. Zinc-finger nucleases, TALENs, and CRISPR-Cas have all been used in conjunction with somatic cell therapies, and in vivo approaches are being tested. Both excitement and concern have been elicited by the prospects for gene editing in...
Mice deficient for ERAD machinery component Sel1L develop central diabetes insipidus J. Clin. Invest. (IF 12.784) Pub Date : 2017-09-18 Daniel G. Bichet; Yoann Lussier
Deficiency of the antidiuretic hormone arginine vasopressin (AVP) underlies diabetes insipidus, which is characterized by the excretion of abnormally large volumes of dilute urine and persistent thirst. In this issue of the JCI, Shi et al. report that Sel1L-Hrd1 ER–associated degradation (ERAD) is responsible for the clearance of misfolded pro–arginine vasopressin (proAVP) in the ER. Additionally, mice with Sel1L deficiency, either globally or specifically within AVP-expressing neurons, developed central diabetes insipidus. The results of this study demonstrate a role for ERAD in neuroendocrine cells and serve as a clinical example of the effect of misfolded ER proteins retrotranslocated through the membrane into the cytosol, where they are polyubiquitinated, extracted from the ER membrane, and degraded by the proteasome. Moreover, proAVP misfolding in hereditary central diabetes insipidus likely shares common physiopathological mechanisms with proinsulin misfolding in hereditary diabetes mellitus of youth.
All TIEd up: mechanisms of Schlemm’s canal maintenance J. Clin. Invest. (IF 12.784) Pub Date : 2017-09-18 Jeremiah Bernier-Latmani; Tatiana V. Petrova
Glaucoma is a leading cause of blindness, with an estimated world-wide prevalence of 3.5% in members of the population older than 40 years of age. Elevated intraocular pressure as the result of abnormal resistance to aqueous humor drainage is a major contributing, and the only preventable, factor in glaucoma development. Schlemm’s canal (SC), a lymphatic-like vessel encircling the anterior portion of the eye, plays a key role in promoting aqueous humor outflow and maintenance of normal intraocular pressure. The risk of developing glaucoma increases with age; therefore, understanding mechanisms of SC maintenance and how aging affects SC function are of special importance, both for prevention and novel treatment approaches to glaucoma. Using a compelling array of genetic models, Kim et al. report in this issue of the JCI that continuous angiopoietin/TIE2 signaling is required for maintaining SC identity and integrity during adulthood and show that its age-related changes can be rescued by a TIE2 agonistic antibody.
Dysfunction of the MDM2/p53 axis is linked to premature aging J. Clin. Invest. (IF 12.784) Pub Date : 2017-08-28 Davor Lessel; Danyi Wu; Carlos Trujillo; Thomas Ramezani; Ivana Lessel; Mohammad K. Alwasiyah; Bidisha Saha; Fuki M. Hisama; Katrin Rading; Ingrid Goebel; Petra Schütz; Günter Speit; Josef Högel; Holger Thiele; Gudrun Nürnberg; Peter Nürnberg; Matthias Hammerschmidt; Yan Zhu; David R. Tong; Chen Katz; George M. Martin; Junko Oshima; Carol Prives; Christian Kubisch
The tumor suppressor p53, a master regulator of the cellular response to stress, is tightly regulated by the E3 ubiquitin ligase MDM2 via an autoregulatory feedback loop. In addition to its well-established role in tumorigenesis, p53 has also been associated with aging in mice. Several mouse models with aberrantly increased p53 activity display signs of premature aging. However, the relationship between dysfunction of the MDM2/p53 axis and human aging remains elusive. Here, we have identified an antiterminating homozygous germline mutation in MDM2 in a patient affected by a segmental progeroid syndrome. We show that this mutation abrogates MDM2 activity, thereby resulting in enhanced levels and stability of p53. Analysis of the patient’s primary cells, genome-edited cells, and in vitro and in vivo analyses confirmed the MDM2 mutation’s aberrant regulation of p53 activity. Functional data from a zebrafish model further demonstrated that mutant Mdm2 was unable to rescue a p53-induced apoptotic phenotype. Altogether, our findings indicate that mutant MDM2 is a likely driver of the observed segmental form of progeria.
Proteasome activity regulates CD8+ T lymphocyte metabolism and fate specification J. Clin. Invest. (IF 12.784) Pub Date : 2017-08-28 Christella E. Widjaja; Jocelyn G. Olvera; Patrick J. Metz; Anthony T. Phan; Jeffrey N. Savas; Gerjan de Bruin; Yves Leestemaker; Celia R. Berkers; Annemieke de Jong; Bogdan I. Florea; Kathleen Fisch; Justine Lopez; Stephanie H. Kim; Daniel A. Garcia; Stephen Searles; Jack D. Bui; Aaron N. Chang; John R. Yates III; Ananda W. Goldrath; Hermen S. Overkleeft; Huib Ovaa; John T. Chang
During an immune response, CD8+ T lymphocytes can undergo asymmetric division, giving rise to daughter cells that exhibit distinct tendencies to adopt terminal effector and memory cell fates. Here we show that “pre-effector” and “pre-memory” cells resulting from the first CD8+ T cell division in vivo exhibited low and high rates of endogenous proteasome activity, respectively. Pharmacologic reduction of proteasome activity in CD8+ T cells early during differentiation resulted in acquisition of terminal effector cell characteristics, whereas enhancement of proteasome activity conferred attributes of memory lymphocytes. Transcriptomic and proteomic analyses revealed that modulating proteasome activity in CD8+ T cells affected cellular metabolism. These metabolic changes were mediated, in part, through differential expression of Myc, a transcription factor that controls glycolysis and metabolic reprogramming. Taken together, these results demonstrate that proteasome activity is an important regulator of CD8+ T cell fate and raise the possibility that increasing proteasome activity may be a useful therapeutic strategy to enhance the generation of memory lymphocytes.
Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche J. Clin. Invest. (IF 12.784) Pub Date : 2017-08-28 Ioannis Mitroulis; Lan-Sun Chen; Rashim Pal Singh; Ioannis Kourtzelis; Matina Economopoulou; Tetsuhiro Kajikawa; Maria Troullinaki; Athanasios Ziogas; Klara Ruppova; Kavita Hosur; Tomoki Maekawa; Baomei Wang; Pallavi Subramanian; Torsten Tonn; Panayotis Verginis; Malte von Bonin; Manja Wobus; Martin Bornhäuser; Tatyana Grinenko; Marianna Di Scala; Andres Hidalgo; Ben Wielockx; George Hajishengallis; Triantafyllos Chavakis
Hematopoietic stem cells (HSCs) remain mostly quiescent under steady-state conditions but switch to a proliferative state following hematopoietic stress, e.g., bone marrow (BM) injury, transplantation, or systemic infection and inflammation. The homeostatic balance between quiescence, self-renewal, and differentiation of HSCs is strongly dependent on their interactions with cells that constitute a specialized microanatomical environment in the BM known as the HSC niche. Here, we identified the secreted extracellular matrix protein Del-1 as a component and regulator of the HSC niche. Specifically, we found that Del-1 was expressed by several cellular components of the HSC niche, including arteriolar endothelial cells, CXCL12-abundant reticular (CAR) cells, and cells of the osteoblastic lineage. Del-1 promoted critical functions of the HSC niche, as it regulated long-term HSC (LT-HSC) proliferation and differentiation toward the myeloid lineage. Del-1 deficiency in mice resulted in reduced LT-HSC proliferation and infringed preferentially upon myelopoiesis under both steady-state and stressful conditions, such as hematopoietic cell transplantation and G-CSF– or inflammation-induced stress myelopoiesis. Del-1–induced HSC proliferation and myeloid lineage commitment were mediated by β3 integrin on hematopoietic progenitors. This hitherto unknown Del-1 function in the HSC niche represents a juxtacrine homeostatic adaptation of the hematopoietic system in stress myelopoiesis.
ER phospholipid composition modulates lipogenesis during feeding and in obesity J. Clin. Invest. (IF 12.784) Pub Date : 2017-08-28 Xin Rong; Bo Wang; Elisa N.D. Palladino; Thomas Q. de Aguiar Vallim; David A. Ford; Peter Tontonoz
Sterol regulatory element–binding protein 1c (SREBP-1c) is a central regulator of lipogenesis whose activity is controlled by proteolytic cleavage. The metabolic factors that affect its processing are incompletely understood. Here, we show that dynamic changes in the acyl chain composition of ER phospholipids affect SREBP-1c maturation in physiology and disease. The abundance of polyunsaturated phosphatidylcholine in liver ER is selectively increased in response to feeding and in the setting of obesity-linked insulin resistance. Exogenous delivery of polyunsaturated phosphatidylcholine to ER accelerated SREBP-1c processing through a mechanism that required an intact SREBP cleavage–activating protein (SCAP) pathway. Furthermore, induction of the phospholipid-remodeling enzyme LPCAT3 in response to liver X receptor (LXR) activation promoted SREBP-1c processing by driving the incorporation of polyunsaturated fatty acids into ER. Conversely, LPCAT3 deficiency increased membrane saturation, reduced nuclear SREBP-1c abundance, and blunted the lipogenic response to feeding, LXR agonist treatment, or obesity-linked insulin resistance. Desaturation of the ER membrane may serve as an auxiliary signal of the fed state that promotes lipid synthesis in response to nutrient availability.
Mice expressing KrasG12D in hematopoietic multipotent progenitor cells develop neonatal myeloid leukemia J. Clin. Invest. (IF 12.784) Pub Date : 2017-08-28 Stefan P. Tarnawsky; Rebecca J. Chan; Mervin C. Yoder
Juvenile myelomonocytic leukemia (JMML) is a pediatric myeloproliferative neoplasm that bears distinct characteristics associated with abnormal fetal development. JMML has been extensively modeled in mice expressing the oncogenic KrasG12D mutation. However, these models have struggled to recapitulate the defining features of JMML due to in utero lethality, nonhematopoietic expression, and the pervasive emergence of T cell acute lymphoblastic leukemia. Here, we have developed a model of JMML using mice that express KrasG12D in multipotent progenitor cells (Flt3Cre+ KrasG12D mice). These mice express KrasG12D in utero, are born at normal Mendelian ratios, develop hepatosplenomegaly, anemia, and thrombocytopenia, and succumb to a rapidly progressing and fully penetrant neonatal myeloid disease. Mutant mice have altered hematopoietic stem and progenitor cell populations in the BM and spleen that are hypersensitive to granulocyte macrophage–CSF due to hyperactive RAS/ERK signaling. Biased differentiation in these progenitors results in an expansion of neutrophils and DCs and a concomitant decrease in T lymphocytes. Flt3Cre+ KrasG12D fetal liver hematopoietic progenitors give rise to a myeloid disease upon transplantation. In summary, we describe a KrasG12D mouse model that reproducibly develops JMML-like disease. This model will prove useful for preclinical drug studies and for elucidating the developmental origins of pediatric neoplasms.
Haploinsufficiency for DNA methyltransferase 3A predisposes hematopoietic cells to myeloid malignancies J. Clin. Invest. (IF 12.784) Pub Date : 2017-09-05 Christopher B. Cole; David A. Russler-Germain; Shamika Ketkar; Angela M. Verdoni; Amanda M. Smith; Celia V. Bangert; Nichole M. Helton; Mindy Guo; Jeffery M. Klco; Shelly O’Laughlin; Catrina Fronick; Robert Fulton; Gue Su Chang; Allegra A. Petti; Christopher A. Miller; Timothy J. Ley
The gene that encodes de novo DNA methyltransferase 3A (DNMT3A) is frequently mutated in acute myeloid leukemia genomes. Point mutations at position R882 have been shown to cause a dominant negative loss of DNMT3A methylation activity, but 15% of DNMT3A mutations are predicted to produce truncated proteins that could either have dominant negative activities or cause loss of function and haploinsufficiency. Here, we demonstrate that 3 of these mutants produce truncated, inactive proteins that do not dimerize with WT DNMT3A, strongly supporting the haploinsufficiency hypothesis. We therefore evaluated hematopoiesis in mice heterozygous for a constitutive null Dnmt3a mutation. With no other manipulations, Dnmt3a+/– mice developed myeloid skewing over time, and their hematopoietic stem/progenitor cells exhibited a long-term competitive transplantation advantage. Dnmt3a+/– mice also spontaneously developed transplantable myeloid malignancies after a long latent period, and 3 of 12 tumors tested had cooperating mutations in the Ras/MAPK pathway. The residual Dnmt3a allele was neither mutated nor downregulated in these tumors. The bone marrow cells of Dnmt3a+/– mice had a subtle but statistically significant DNA hypomethylation phenotype that was not associated with gene dysregulation. These data demonstrate that haploinsufficiency for Dnmt3a alters hematopoiesis and predisposes mice (and probably humans) to myeloid malignancies by a mechanism that is not yet clear.
Fibroblast-specific inhibition of TGF-β1 signaling attenuates lung and tumor fibrosis J. Clin. Invest. (IF 12.784) Pub Date : 2017-09-05 Ying Wei; Thomas J. Kim; David H. Peng; Dana Duan; Don L. Gibbons; Mitsuo Yamauchi; Julia R. Jackson; Claude J. Le Saux; Cheresa Calhoun; Jay Peters; Rik Derynck; Bradley J. Backes; Harold A. Chapman
TGF-β1 signaling is a critical driver of collagen accumulation and fibrotic disease but also a vital suppressor of inflammation and epithelial cell proliferation. The nature of this multifunctional cytokine has limited the development of global TGF-β1 signaling inhibitors as therapeutic agents. We conducted phenotypic screens for small molecules that inhibit TGF-β1–induced epithelial-mesenchymal transition without immediate TGF-β1 receptor (TβR) kinase inhibition. We identified trihydroxyphenolic compounds as potent blockers of TGF-β1 responses (IC50 ~50 nM), Snail1 expression, and collagen deposition in vivo in models of pulmonary fibrosis and collagen-dependent lung cancer metastasis. Remarkably, the functional effects of trihydroxyphenolics required the presence of active lysyl oxidase–like 2 (LOXL2), thereby limiting effects to fibroblasts or cancer cells, the major LOXL2 producers. Mechanistic studies revealed that trihydroxyphenolics induce auto-oxidation of a LOXL2/3–specific lysine (K731) in a time-dependent reaction that irreversibly inhibits LOXL2 and converts the trihydrophenolic to a previously undescribed metabolite that directly inhibits TβRI kinase. Combined inhibition of LOXL2 and TβRI activities by trihydrophenolics resulted in potent blockade of pathological collagen accumulation in vivo without the toxicities associated with global inhibitors. These findings elucidate a therapeutic approach to attenuate fibrosis and the disease-promoting effects of tissue stiffness by specifically targeting TβRI kinase in LOXL2-expressing cells.
Pericyte-targeting prodrug overcomes tumor resistance to vascular disrupting agents J. Clin. Invest. (IF 12.784) Pub Date : 2017-08-28 Minfeng Chen; Xueping Lei; Changzheng Shi; Maohua Huang; Xiaobo Li; Baojian Wu; Zhengqiu Li; Weili Han; Bin Du; Jianyang Hu; Qiulin Nie; Weiqian Mai; Nan Ma; Nanhui Xu; Xinyi Zhang; Chunlin Fan; Aihua Hong; Minghan Xia; Liangping Luo; Ande Ma; Hongsheng Li; Qiang Yu; Heru Chen; Dongmei Zhang; Wencai Ye
Blood vessels in the tumor periphery have high pericyte coverage and are resistant to vascular disrupting agents (VDAs). VDA treatment resistance leads to a viable peripheral tumor rim that contributes to treatment failure and disease recurrence. Here, we provide evidence to support a hypothesis that shifting the target of VDAs from tumor vessel endothelial cells to pericytes disrupts tumor peripheral vessels and the viable rim, circumventing VDA treatment resistance. Through chemical engineering, we developed Z-GP-DAVLBH (from the tubulin-binding VDA desacetylvinblastine monohydrazide [DAVLBH]) as a prodrug that can be selectively activated by fibroblast activation protein α (FAPα) in tumor pericytes. Z-GP-DAVLBH selectively destroys the cytoskeleton of FAPα-expressing tumor pericytes, disrupting blood vessels both within the core and around the periphery of tumors. As a result, Z-GP-DAVLBH treatment eradicated the otherwise VDA-resistant tumor rim and led to complete regression of tumors in multiple lines of xenografts without producing the drug-related toxicity that is associated with similar doses of DAVLBH. This study demonstrates that targeting tumor pericytes with an FAPα-activated VDA prodrug represents a potential vascular disruption strategy in overcoming tumor resistance to VDA treatments.
miR-146a modulates autoreactive Th17 cell differentiation and regulates organ-specific autoimmunity J. Clin. Invest. (IF 12.784) Pub Date : 2017-09-05 Bo Li; Xi Wang; In Young Choi; Yu-Chen Wang; Siyuan Liu; Alexander T. Pham; Heesung Moon; Drake J. Smith; Dinesh S. Rao; Mark P. Boldin; Lili Yang
Autoreactive CD4 T cells that differentiate into pathogenic Th17 cells can trigger autoimmune diseases. Therefore, investigating the regulatory network that modulates Th17 differentiation may yield important therapeutic insights. miR-146a has emerged as a critical modulator of immune reactions, but its role in regulating autoreactive Th17 cells and organ-specific autoimmunity remains largely unknown. Here, we have reported that miR-146a–deficient mice developed more severe experimental autoimmune encephalomyelitis (EAE), an animal model of human multiple sclerosis (MS). We bred miR-146a–deficient mice with 2D2 T cell receptor–Tg mice to generate 2D2 CD4 T cells that are deficient in miR-146a and specific for myelin oligodendrocyte glycoprotein (MOG), an autoantigen in the EAE model. miR-146a–deficient 2D2 T cells induced more severe EAE and were more prone to differentiate into Th17 cells. Microarray analysis revealed enhancements in IL-6– and IL-21–induced Th17 differentiation pathways in these T cells. Further study showed that miR-146a inhibited the production of autocrine IL-6 and IL-21 in 2D2 T cells, which in turn reduced their Th17 differentiation. Thus, our study identifies miR-146a as an important molecular brake that blocks the autocrine IL-6– and IL-21–induced Th17 differentiation pathways in autoreactive CD4 T cells, highlighting its potential as a therapeutic target for treating autoimmune diseases.
mTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagy J. Clin. Invest. (IF 12.784) Pub Date : 2017-09-05 Rosa Bartolomeo; Laura Cinque; Chiara De Leonibus; Alison Forrester; Anna Chiara Salzano; Jlenia Monfregola; Emanuela De Gennaro; Edoardo Nusco; Isabella Azario; Carmela Lanzara; Marta Serafini; Beth Levine; Andrea Ballabio; Carmine Settembre
The mammalian target of rapamycin complex 1 (mTORC1) kinase promotes cell growth by activating biosynthetic pathways and suppressing catabolic pathways, particularly that of macroautophagy. A prerequisite for mTORC1 activation is its translocation to the lysosomal surface. Deregulation of mTORC1 has been associated with the pathogenesis of several diseases, but its role in skeletal disorders is largely unknown. Here, we show that enhanced mTORC1 signaling arrests bone growth in lysosomal storage disorders (LSDs). We found that lysosomal dysfunction induces a constitutive lysosomal association and consequent activation of mTORC1 in chondrocytes, the cells devoted to bone elongation. mTORC1 hyperphosphorylates the protein UV radiation resistance–associated gene (UVRAG), reducing the activity of the associated Beclin 1–Vps34 complex and thereby inhibiting phosphoinositide production. Limiting phosphoinositide production leads to a blockage of the autophagy flux in LSD chondrocytes. As a consequence, LSD chondrocytes fail to properly secrete collagens, the main components of the cartilage extracellular matrix. In mouse models of LSD, normalization of mTORC1 signaling or stimulation of the Beclin 1–Vps34–UVRAG complex rescued the autophagy flux, restored collagen levels in cartilage, and ameliorated the bone phenotype. Taken together, these data unveil a role for mTORC1 and autophagy in the pathogenesis of skeletal disorders and suggest potential therapeutic approaches for the treatment of LSDs.
Deficiency in Kelch protein Klhl31 causes congenital myopathy in mice J. Clin. Invest. (IF 12.784) Pub Date : 2017-09-05 James B. Papizan; Glynnis A. Garry; Svetlana Brezprozvannaya; John R. McAnally; Rhonda Bassel-Duby; Ning Liu; Eric N. Olson
Maintenance of muscle structure and function depends on the precise organization of contractile proteins into sarcomeres and coupling of the contractile apparatus to the sarcoplasmic reticulum (SR), which serves as the reservoir for calcium required for contraction. Several members of the Kelch superfamily of proteins, which modulate protein stability as substrate-specific adaptors for ubiquitination, have been implicated in sarcomere formation. The Kelch protein Klhl31 is expressed in a muscle-specific manner under control of the transcription factor MEF2. To explore its functions in vivo, we created a mouse model of Klhl31 loss of function using the CRISPR-Cas9 system. Mice lacking Klhl31 exhibited stunted postnatal skeletal muscle growth, centronuclear myopathy, central cores, Z-disc streaming, and SR dilation. We used proteomics to identify several candidate Klhl31 substrates, including Filamin-C (FlnC). In the Klhl31-knockout mice, FlnC protein levels were highly upregulated with no change in transcription, and we further demonstrated that Klhl31 targets FlnC for ubiquitination and degradation. These findings highlight a role for Klhl31 in the maintenance of skeletal muscle structure and provide insight into the mechanisms underlying congenital myopathies.
RNA-binding protein ZFP36L1 maintains posttranscriptional regulation of bile acid metabolism J. Clin. Invest. (IF 12.784) Pub Date : 2017-09-11 Elizabeth J. Tarling; Bethan L. Clifford; Joan Cheng; Pauline Morand; Angela Cheng; Ellen Lester; Tamer Sallam; Martin Turner; Thomas Q. de Aguiar Vallim
Bile acids function not only as detergents that facilitate lipid absorption but also as signaling molecules that activate the nuclear receptor farnesoid X receptor (FXR). FXR agonists are currently being evaluated as therapeutic agents for a number of hepatic diseases due to their lipid-lowering and antiinflammatory properties. FXR is also essential for maintaining bile acid homeostasis and prevents the accumulation of bile acids. Elevated bile acids activate FXR, which in turn switches off bile acid synthesis by reducing the mRNA levels of bile acid synthesis genes, including cholesterol 7α-hydroxylase (Cyp7a1). Here, we show that FXR activation triggers a rapid posttranscriptional mechanism to degrade Cyp7a1 mRNA. We identified the RNA-binding protein Zfp36l1 as an FXR target gene and determined that gain and loss of function of ZFP36L1 reciprocally regulate Cyp7a1 mRNA and bile acid levels in vivo. Moreover, we found that mice lacking hepatic ZFP36L1 were protected from diet-induced obesity and steatosis. The reduced adiposity and antisteatotic effects observed in ZFP36L1-deficient mice were accompanied by impaired lipid absorption that was consistent with altered bile acid metabolism. Thus, the ZFP36L1-dependent regulation of bile acid metabolism is an important metabolic contributor to obesity and hepatosteatosis.
Syntaphilin controls a mitochondrial rheostat for proliferation-motility decisions in cancer J. Clin. Invest. (IF 12.784) Pub Date : 2017-09-11 M. Cecilia Caino; Jae Ho Seo; Yuan Wang; Dayana B. Rivadeneira; Dmitry I. Gabrilovich; Eui Tae Kim; Ashani T. Weeraratna; Lucia R. Languino; Dario C. Altieri
Tumors adapt to an unfavorable microenvironment by controlling the balance between cell proliferation and cell motility, but the regulators of this process are largely unknown. Here, we show that an alternatively spliced isoform of syntaphilin (SNPH), a cytoskeletal regulator of mitochondrial movements in neurons, is directed to mitochondria of tumor cells. Mitochondrial SNPH buffers oxidative stress and maintains complex II–dependent bioenergetics, sustaining local tumor growth while restricting mitochondrial redistribution to the cortical cytoskeleton and tumor cell motility. Conversely, introduction of stress stimuli to the microenvironment, including hypoxia, acutely lowered SNPH levels, resulting in bioenergetics defects and increased superoxide production. In turn, this suppressed tumor cell proliferation but increased tumor cell invasion via greater mitochondrial trafficking to the cortical cytoskeleton. Loss of SNPH or expression of an SNPH mutant lacking the mitochondrial localization sequence resulted in increased metastatic dissemination in xenograft or syngeneic tumor models in vivo. Accordingly, tumor cells that acquired the ability to metastasize in vivo constitutively downregulated SNPH and exhibited higher oxidative stress, reduced cell proliferation, and increased cell motility. Therefore, SNPH is a stress-regulated mitochondrial switch of the cell proliferation-motility balance in cancer, and its pathway may represent a therapeutic target.
Fibroblast-specific TGF-β–Smad2/3 signaling underlies cardiac fibrosis J. Clin. Invest. (IF 12.784) Pub Date : 2017-09-11 Hadi Khalil; Onur Kanisicak; Vikram Prasad; Robert N. Correll; Xing Fu; Tobias Schips; Ronald J. Vagnozzi; Ruijie Liu; Thanh Huynh; Se-Jin Lee; Jason Karch; Jeffery D. Molkentin
The master cytokine TGF-β mediates tissue fibrosis associated with inflammation and tissue injury. TGF-β induces fibroblast activation and differentiation into myofibroblasts that secrete extracellular matrix proteins. Canonical TGF-β signaling mobilizes Smad2 and Smad3 transcription factors that control fibrosis by promoting gene expression. However, the importance of TGF-β–Smad2/3 signaling in fibroblast-mediated cardiac fibrosis has not been directly evaluated in vivo. Here, we examined pressure overload–induced cardiac fibrosis in fibroblast- and myofibroblast-specific inducible Cre-expressing mouse lines with selective deletion of the TGF-β receptors Tgfbr1/2, Smad2, or Smad3. Fibroblast-specific deletion of Tgfbr1/2 or Smad3, but not Smad2, markedly reduced the pressure overload–induced fibrotic response as well as fibrosis mediated by a heart-specific, latency-resistant TGF-β mutant transgene. Interestingly, cardiac fibroblast–specific deletion of Tgfbr1/2, but not Smad2/3, attenuated the cardiac hypertrophic response to pressure overload stimulation. Mechanistically, loss of Smad2/3 from tissue-resident fibroblasts attenuated injury-induced cellular expansion within the heart and the expression of fibrosis-mediating genes. Deletion of Smad2/3 or Tgfbr1/2 from cardiac fibroblasts similarly inhibited the gene program for fibrosis and extracellular matrix remodeling, although deletion of Tgfbr1/2 uniquely altered expression of an array of regulatory genes involved in cardiomyocyte homeostasis and disease compensation. These findings implicate TGF-β–Smad2/3 signaling in activated tissue-resident cardiac fibroblasts as principal mediators of the fibrotic response.
Herpes simplex virus-1 evasion of CD8+ T cell accumulation contributes to viral encephalitis J. Clin. Invest. (IF 12.784) Pub Date : 2017-09-11 Naoto Koyanagi; Takahiko Imai; Keiko Shindo; Ayuko Sato; Wataru Fujii; Takeshi Ichinohe; Naoki Takemura; Shigeru Kakuta; Satoshi Uematsu; Hiroshi Kiyono; Yuhei Maruzuru; Jun Arii; Akihisa Kato; Yasushi Kawaguchi
Herpes simplex virus–1 (HSV-1) is the most common cause of sporadic viral encephalitis, which can be lethal or result in severe neurological defects even with antiviral therapy. While HSV-1 causes encephalitis in spite of HSV-1–specific humoral and cellular immunity, the mechanism by which HSV-1 evades the immune system in the central nervous system (CNS) remains unknown. Here we describe a strategy by which HSV-1 avoids immune targeting in the CNS. The HSV-1 UL13 kinase promotes evasion of HSV-1–specific CD8+ T cell accumulation in infection sites by downregulating expression of the CD8+ T cell attractant chemokine CXCL9 in the CNS of infected mice, leading to increased HSV-1 mortality due to encephalitis. Direct injection of CXCL9 into the CNS infection site enhanced HSV-1–specific CD8+ T cell accumulation, leading to marked improvements in the survival of infected mice. This previously uncharacterized strategy for HSV-1 evasion of CD8+ T cell accumulation in the CNS has important implications for understanding the pathogenesis and clinical treatment of HSV-1 encephalitis.
NF-κB regulates GDF-15 to suppress macrophage surveillance during early tumor development J. Clin. Invest. (IF 12.784) Pub Date : 2017-09-11 Nivedita M. Ratnam; Jennifer M. Peterson; Erin E. Talbert; Katherine J. Ladner; Priyani V. Rajasekera; Carl R. Schmidt; Mary E. Dillhoff; Benjamin J. Swanson; Ericka Haverick; Raleigh D. Kladney; Terence M. Williams; Gustavo W. Leone; David J. Wang; Denis C. Guttridge
Macrophages are attracted to developing tumors and can participate in immune surveillance to eliminate neoplastic cells. In response, neoplastic cells utilize NF-κB to suppress this killing activity, but the mechanisms underlying their self-protection remain unclear. Here, we report that this dynamic interaction between tumor cells and macrophages is integrally linked by a soluble factor identified as growth and differentiation factor 15 (GDF-15). In vitro, tumor-derived GDF-15 signals in macrophages to suppress their proapoptotic activity by inhibiting TNF and nitric oxide (NO) production. In vivo, depletion of GDF-15 in Ras-driven tumor xenografts and in an orthotopic model of pancreatic cancer delayed tumor development. This delay correlated with increased infiltrating antitumor macrophages. Further, production of GDF-15 is directly regulated by NF-κB, and the colocalization of activated NF-κB and GDF-15 in epithelial ducts of human pancreatic adenocarcinoma supports the importance of this observation. Mechanistically, we found that GDF-15 suppresses macrophage activity by inhibiting TGF-β–activated kinase (TAK1) signaling to NF-κB, thereby blocking synthesis of TNF and NO. Based on these results, we propose that the NF-κB/GDF-15 regulatory axis is important for tumor cells in evading macrophage immune surveillance during the early stages of tumorigenesis.
Neutrophil FcγRIIA promotes IgG-mediated glomerular neutrophil capture via Abl/Src kinases J. Clin. Invest. (IF 12.784) Pub Date : 2017-09-11 Hiroshi Nishi; Kazuhiro Furuhashi; Xavier Cullere; Gurpanna Saggu; Mark J. Miller; Yunfeng Chen; Florencia Rosetti; Samantha L. Hamilton; Lihua Yang; Spencer P. Pittman; Jiexi Liao; Jan M. Herter; Jeffrey C. Berry; Daniel J. DeAngelo; Cheng Zhu; George C. Tsokos; Tanya N. Mayadas
The kidney glomerular capillaries are frequent sites of immune complex deposition and subsequent neutrophil accumulation in post-infectious and rapidly progressive glomerulonephritis. However, the mechanisms of neutrophil recruitment remain enigmatic, and there is no targeted therapeutic to avert this proximal event in glomerular inflammation. The uniquely human activating Fc receptor FcγRIIA promotes glomerular neutrophil accumulation and damage in anti–glomerular basement membrane–induced (anti-GBM–induced) glomerulonephritis when expressed on murine neutrophils. Here, we found that neutrophils are directly captured by immobilized IgG antibodies under physiological flow conditions in vitro through FcγRIIA-dependent, Abl/Src tyrosine kinase–mediated F-actin polymerization. Biophysical measurements showed that the lifetime of FcγRIIA-IgG bonds increased under mechanical force in an F-actin–dependent manner, which could enable the capture of neutrophils under physiological flow. Kidney intravital microscopy revealed that circulating neutrophils, which were similar in diameter to glomerular capillaries, abruptly arrested following anti-GBM antibody deposition via neutrophil FcγRIIA and Abl/Src kinases. Accordingly, inhibition of Abl/Src with bosutinib reduced FcγRIIA-mediated glomerular neutrophil accumulation and renal injury in experimental, crescentic anti-GBM nephritis. These data identify a pathway of neutrophil recruitment within glomerular capillaries following IgG deposition that may be targeted by bosutinib to avert glomerular injury.
No evidence of HIV replication in children on antiretroviral therapy J. Clin. Invest. (IF 12.784) Pub Date : 2017-09-11 Gert U. Van Zyl; Mary Grace Katusiime; Ann Wiegand; William R. McManus; Michael J. Bale; Elias K. Halvas; Brian Luke; Valerie F. Boltz; Jonathan Spindler; Barbara Laughton; Susan Engelbrecht; John M. Coffin; Mark F. Cotton; Wei Shao; John W. Mellors; Mary F. Kearney
It remains controversial whether current antiretroviral therapy (ART) fully suppresses the cycles of HIV replication and viral evolution in vivo. If replication persists in sanctuary sites such as the lymph nodes, a high priority should be placed on improving ART regimes to target these sites. To investigate the question of ongoing viral replication on current ART regimens, we analyzed HIV populations in longitudinal samples from 10 HIV-1–infected children who initiated ART when viral diversity was low. Eight children started ART at less than ten months of age and showed suppression of plasma viremia for seven to nine years. Two children had uncontrolled viremia for fifteen and thirty months, respectively, before viremia suppression, and served as positive controls for HIV replication and evolution. These latter 2 children showed clear evidence of virus evolution, whereas multiple methods of analysis bore no evidence of virus evolution in any of the 8 children with viremia suppression on ART. Phylogenetic trees simulated with the recently reported evolutionary rate of HIV-1 on ART of 6 × 10–4 substitutions/site/month bore no resemblance to the observed data. Taken together, these data refute the concept that ongoing HIV replication is common with ART and is the major barrier to curing HIV-1 infection.
Age-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling J. Clin. Invest. (IF 12.784) Pub Date : 2017-09-18 Chunhua Dai; Yan Hang; Alena Shostak; Greg Poffenberger; Nathaniel Hart; Nripesh Prasad; Neil Phillips; Shawn E. Levy; Dale L. Greiner; Leonard D. Shultz; Rita Bottino; Seung K. Kim; Alvin C. Powers
Inadequate pancreatic β cell function underlies type 1 and type 2 diabetes mellitus. Strategies to expand functional cells have focused on discovering and controlling mechanisms that limit the proliferation of human β cells. Here, we developed an engraftment strategy to examine age-associated human islet cell replication competence and reveal mechanisms underlying age-dependent decline of β cell proliferation in human islets. We found that exendin-4 (Ex-4), an agonist of the glucagon-like peptide 1 receptor (GLP-1R), stimulates human β cell proliferation in juvenile but not adult islets. This age-dependent responsiveness does not reflect loss of GLP-1R signaling in adult islets, since Ex-4 treatment stimulated insulin secretion by both juvenile and adult human β cells. We show that the mitogenic effect of Ex-4 requires calcineurin/nuclear factor of activated T cells (NFAT) signaling. In juvenile islets, Ex-4 induced expression of calcineurin/NFAT signaling components as well as target genes for proliferation-promoting factors, including NFATC1, FOXM1, and CCNA1. By contrast, expression of these factors in adult islet β cells was not affected by Ex-4 exposure. These studies reveal age-dependent signaling mechanisms regulating human β cell proliferation, and identify elements that could be adapted for therapeutic expansion of human β cells.
Gα13 ablation reprograms myofibers to oxidative phenotype and enhances whole-body metabolism J. Clin. Invest. (IF 12.784) Pub Date : 2017-09-18 Ja Hyun Koo; Tae Hyun Kim; Shi-Young Park; Min Sung Joo; Chang Yeob Han; Cheol Soo Choi; Sang Geon Kim
Skeletal muscle is a key organ in energy homeostasis owing to its high requirement for nutrients. Heterotrimeric G proteins converge signals from cell-surface receptors to potentiate or blunt responses against environmental changes. Here, we show that muscle-specific ablation of Gα13 in mice promotes reprogramming of myofibers to the oxidative type, with resultant increases in mitochondrial biogenesis and cellular respiration. Mechanistically, Gα13 and its downstream effector RhoA suppressed nuclear factor of activated T cells 1 (NFATc1), a chief regulator of myofiber conversion, by increasing Rho-associated kinase 2–mediated (Rock2-mediated) phosphorylation at Ser243. Ser243 phosphorylation of NFATc1 was reduced after exercise, but was higher in obese animals. Consequently, Gα13 ablation in muscles enhanced whole-body energy metabolism and increased insulin sensitivity, thus affording protection from diet-induced obesity and hepatic steatosis. Our results define Gα13 as a switch regulator of myofiber reprogramming, implying that modulations of Gα13 and its downstream effectors in skeletal muscle are a potential therapeutic approach to treating metabolic diseases.
Increased intracellular proteolysis reduces disease severity in an ER stress–associated dwarfism J. Clin. Invest. (IF 12.784) Pub Date : 2017-09-18 Lorna A. Mullan; Ewa J. Mularczyk; Louise H. Kung; Mitra Forouhan; Jordan M.A. Wragg; Royston Goodacre; John F. Bateman; Eileithyia Swanton; Michael D. Briggs; Raymond P. Boot-Handford
The short-limbed dwarfism metaphyseal chondrodysplasia type Schmid (MCDS) is linked to mutations in type X collagen, which increase ER stress by inducing misfolding of the mutant protein and subsequently disrupting hypertrophic chondrocyte differentiation. Here, we show that carbamazepine (CBZ), an autophagy-stimulating drug that is clinically approved for the treatment of seizures and bipolar disease, reduced the ER stress induced by 4 different MCDS-causing mutant forms of collagen X in human cell culture. Depending on the nature of the mutation, CBZ application stimulated proteolysis of misfolded collagen X by either autophagy or proteasomal degradation, thereby reducing intracellular accumulation of mutant collagen. In MCDS mice expressing the Col10a1.pN617K mutation, CBZ reduced the MCDS-associated expansion of the growth plate hypertrophic zone, attenuated enhanced expression of ER stress markers such as Bip and Atf4, increased bone growth, and reduced skeletal dysplasia. CBZ produced these beneficial effects by reducing the MCDS-associated abnormalities in hypertrophic chondrocyte differentiation. Stimulation of intracellular proteolysis using CBZ treatment may therefore be a clinically viable way of treating the ER stress–associated dwarfism MCDS.
Expression of Piwi protein MIWI2 defines a distinct population of multiciliated cells J. Clin. Invest. (IF 12.784) Pub Date : 2017-09-18 Gregory A. Wasserman; Aleksander D. Szymaniak; Anne C. Hinds; Kazuko Yamamoto; Hirofumi Kamata; Nicole M.S. Smith; Kristie L. Hilliard; Claudia Carrieri; Adam T. Labadorf; Lee J. Quinton; Xingbin Ai; Xaralabos Varelas; Felicia Chen; Joseph P. Mizgerd; Alan Fine; Dónal O’Carroll; Matthew R. Jones
P-element–induced wimpy testes (Piwi) proteins are known for suppressing retrotransposon activation in the mammalian germline. However, whether Piwi protein or Piwi-dependent functions occur in the mammalian soma is unclear. Contrary to germline-restricted expression, we observed that Piwi-like Miwi2 mRNA is indeed expressed in epithelial cells of the lung in adult mice and that it is induced during pneumonia. Further investigation revealed that MIWI2 protein localized to the cytoplasm of a discrete population of multiciliated airway epithelial cells. Isolation and next-generation sequencing of MIWI2-positive multiciliated cells revealed that they are phenotypically distinct from neighboring MIWI2-negative multiciliated cells. Mice lacking MIWI2 exhibited an altered balance of airway epithelial cells, demonstrating fewer multiciliated cells and an increase in club cells. During pneumococcal pneumonia, Miwi2-deficient mice exhibited increased expression of inflammatory mediators and increased immune cell recruitment, leading to enhanced bacterial clearance. Taken together, our data delineate MIWI2-dependent functions outside of the germline and demonstrate the presence of distinct subsets of airway multiciliated cells that can be discriminated by MIWI2 expression. By demonstrating roles for MIWI2 in airway cell identity and pulmonary innate immunity, these studies elucidate unanticipated physiological functions for Piwi proteins in somatic tissues.
Impaired angiopoietin/Tie2 signaling compromises Schlemm’s canal integrity and induces glaucoma J. Clin. Invest. (IF 12.784) Pub Date : 2017-09-18 Jaeryung Kim; Dae-Young Park; Hosung Bae; Do Young Park; Dongkyu Kim; Choong-kun Lee; Sukhyun Song; Tae-Young Chung; Dong Hui Lim; Yoshiaki Kubota; Young-Kwon Hong; Yulong He; Hellmut G. Augustin; Guillermo Oliver; Gou Young Koh
Primary open-angle glaucoma (POAG) is often caused by elevated intraocular pressure (IOP), which arises due to increased resistance to aqueous humor outflow (AHO). Aqueous humor flows through Schlemm’s canal (SC), a lymphatic-like vessel encircling the cornea, and via intercellular spaces of ciliary muscle cells. However, the mechanisms underlying increased AHO resistance are poorly understood. Here, we demonstrate that signaling between angiopoietin (Angpt) and the Angpt receptor Tie2, which is critical for SC formation, is also indispensable for maintaining SC integrity during adulthood. Deletion of Angpt1/Angpt2 or Tie2 in adult mice severely impaired SC integrity and transcytosis, leading to elevated IOP, retinal neuron damage, and impairment of retinal ganglion cell function, all hallmarks of POAG in humans. We found that SC integrity is maintained by interconnected and coordinated functions of Angpt-Tie2 signaling, AHO, and Prox1 activity. These functions diminish in the SC during aging, leading to impaired integrity and transcytosis. Intriguingly, Tie2 reactivation using a Tie2 agonistic antibody rescued the POAG phenotype in Angpt1/Angpt2-deficient mice and rejuvenated the SC in aged mice. These results indicate that the Angpt-Tie2 system is essential for SC integrity. The impairment of this system underlies POAG-associated pathogenesis, supporting the possibility that Tie2 agonists could be a therapeutic option for glaucoma.
ER-associated degradation is required for vasopressin prohormone processing and systemic water homeostasis J. Clin. Invest. (IF 12.784) Pub Date : 2017-09-18 Guojun Shi; Diane Somlo; Geun Hyang Kim; Cristina Prescianotto-Baschong; Shengyi Sun; Nicole Beuret; Qiaoming Long; Jonas Rutishauser; Peter Arvan; Martin Spiess; Ling Qi
Peptide hormones are crucial regulators of many aspects of human physiology. Mutations that alter these signaling peptides are associated with physiological imbalances that underlie diseases. However, the conformational maturation of peptide hormone precursors (prohormones) in the ER remains largely unexplored. Here, we report that conformational maturation of proAVP, the precursor for the antidiuretic hormone arginine-vasopressin, within the ER requires the ER-associated degradation (ERAD) activity of the Sel1L-Hrd1 protein complex. Serum hyperosmolality induces expression of both ERAD components and proAVP in AVP-producing neurons. Mice with global or AVP neuron–specific ablation of Se1L-Hrd1 ERAD progressively developed polyuria and polydipsia, characteristics of diabetes insipidus. Mechanistically, we found that ERAD deficiency causes marked ER retention and aggregation of a large proportion of all proAVP protein. Further, we show that proAVP is an endogenous substrate of Sel1L-Hrd1 ERAD. The inability to clear misfolded proAVP with highly reactive cysteine thiols in the absence of Sel1L-Hrd1 ERAD causes proAVP to accumulate and participate in inappropriate intermolecular disulfide–bonded aggregates, promoted by the enzymatic activity of protein disulfide isomerase (PDI). This study highlights a pathway linking ERAD to prohormone conformational maturation in neuroendocrine cells, expanding the role of ERAD in providing a conducive ER environment for nascent proteins to reach proper conformation.
CXCL11-dependent induction of FOXP3-negative regulatory T cells suppresses autoimmune encephalomyelitis J. Clin. Invest. (IF 12.784) Pub Date : 2017-08-28 Yaniv Zohar; Gizi Wildbaum; Rostislav Novak; Andrew L. Salzman; Marcus Thelen; Ronen Alon; Yiftah Barsheshet; Christopher L. Karp; Nathan Karin
Original citation: J Clin Invest. 2014;124(5):2009–2022. https://doi.org/10.1172/JCI71951 Citation for this expression of concern: J Clin Invest. 2017;127(10):3913. https://doi.org/10.1172/JCI97015 The Editors recently became aware that some of the flow cytometry plots in this article were duplicated and used to represent different samples. Specifically, in Figure 5C, the flow cytometry plots of IFN-γ– and IL-17–stained cells from IgG1- and CXCL10-Ig–treated animals are from the same sample. In addition, in Figure 7A, the spinal cord samples from the PBS- and IgG1-treated animals are the same; the spleen samples from the CXCL11-Ig– and IgG1–treated animals are the same; and the lymph node samples for the PBS- and IgG1-treated animals are the same. The authors were unable to provide the original data for these figures. The Journal subsequently requested an institutional investigation by the Technion – Israel Institute of Technology, which was recently completed. The investigative committee concluded that identical data were presented twice in the publication and that the raw data were not archived for the amount of time required by Technion. The authors have stated that the errors were unintentional. The Editorial Board is issuing this Expression of Concern to alert readers to the problems identified in Figures 5C and 7A. The Editors have requested that the experiments in question be repeated by the authors and resubmitted to the Journal. We will inform our readers of the outcome after the data have been evaluated. Footnotes See the related article at CXCL11-dependent induction of FOXP3-negative regulatory T cells suppresses autoimmune encephalomyelitis.
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