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Inscription by William H. Welch
No full textWilliam H. Welch. Public health in theory and practice. New Haven, 1925
This book from Markus Library Special Collection is inscribed by Dr. Welch and dedicated to Simon Flexnerhttps://digitalcommons.rockefeller.edu/jem-the-beginnings/1036/thumbnail.jp
William H. Welch As a Young Boy
No full textWilliam H. Welch as a young boy, circa 1858
Courtesy of Medical Archives of The Johns Hopkins Medical Institution In the middle of the last century, the New England towns, and none more so than this beautiful town of Norfolk, afforded the best which this country could offer in the way of heredity and environment for the up building of that strength of character, that soundness of mind and of body, those moral and intellectual ideals which have been in the past (whatever the future may have in store for us), the determining forces in the development and prosperity of our country and happy they whose lot was here cast. Our life\u27s as children centered around the family, the church, the Sunday school, the walks to the cemetery on Sunday afternoon, the school, the village green, our games, our picnics in the old spring lot, our birthday parties. I was led to believe by my father, and I do not dispute it, that I owed every thing in my start in life to my attendance at the Misses Nettleton\u27s school, and I am sure that it was an excellent school of its kind.
The Norfolk of those and later days bore no resemblance to the “Main Street” depicted so realistically in that most depressing book by Sinclair, in these beautiful surroundings there resulted a life and work of sincere grace. - Welch WH. Remarks at the unveiling of a tablet in memory of Miss Isabella Eldridge in the Congregational Church, Norfolk, Conn. Litchfield County Leader, July 1, 1921https://digitalcommons.rockefeller.edu/jem-the-beginnings/1003/thumbnail.jp
Louis Schmidt\u27s Drawing
No full textLouis Schmidt\u27s drawing for the menu of the farewell dinner given for Simon Flexner when he left the University of Pennsylvania for the Rockefeller Institute, 1903https://digitalcommons.rockefeller.edu/jem-the-beginnings/1027/thumbnail.jp
Simon Flexner in His Office, ca.1930
No full textSimon Flexner, ca.1930
Courtesy of the Rockefeller Archive Center
When Simon Flexner retired in 1935 as the first director of The Rockefeller Institute for Medical Research, his colleagues wanted to organize a testimonial in his honor. But Flexner, in keeping with his characteristic reserve, politely declined. He had been the director for thirty-three years, during which time the Institute had grown from a handful of scientists working in rented quarters to a world-renowned research center. As he passed through its gates for the last time, he left behind on its library shelves, the most durable and eloquent tribute to his career: one hundred bound volumes containing the reports of the scientists whose research he had guided, encourage, and nurtured.https://digitalcommons.rockefeller.edu/jem-the-beginnings/1037/thumbnail.jp
NOGGIN Transport in a Model Human Epiblast
Get PDFUsing self-organizing human models of gastrulation, the Brivanlou/Siggia labs previously showed that (i) BMP4 initiates the cascade of events leading to gastrulation; (ii) BMP4 signal-reception is restricted to the basolateral domain; and (iii) in a human-specific manner, BMP4 directly induces the expression of NOGGIN. In this work, I interrogate the interplay of the morphogen/inhibitor pair BMP4/NOGGIN within our model of the polarized human embryonic disc. Here, I report the surprising discovery that in human epiblasts, NOGGIN and BMP4 were selectively secreted into opposite sides of the polarized epithelium, effectively segregating the ligand and its inhibitor into distinct extracellular spaces. Moreover, utilizing a microfluidic flow chamber, I unambiguously demonstrated the long-distance diffusion of NOGGIN through the extracellular medium at the apical side as well as the short-distance diffusion of BMP4 over few direct neighbors. Surprisingly, I further demonstrate that apically-applied NOGGIN can inhibit basally-applied BMP4 across a tight hESC epithelium, which points to mechanisms of trans-epithelial transport. And finally, I trace the transcytosis route of apical NOGGIN through the endosomal system. Overall, I highlight a complex mechanism where apically-secreted NOGGIN diffuses over long distance in the apical compartment; NOGGIN is then internalized, transcytosed, and trafficked to the basal-lateral surface close to the subcellular locus where BMP receptors are located. This apical-to-basal transcytosis was indispensable for NOGGIN inhibition. Taken together, the segregation of activator/inhibitor into distinct extracellular spaces challenges classical views of morphogen movement. This discovery challenges current dogma which assumes that the morphogen activator and inhibitor diffuse in the same compartment. I propose that the transport of morphogen inhibitors regulates the spatial availability of morphogens during embryogenesis. My study shed light on an important and unexpected level of regulation for the transport of morphogen inhibitors whose role in spatially restricting the spread of morphogen signaling ultimately shapes the embryonic body plan
Chemical Tools for Exploring Metabolite Interactions with Nuclear Receptors and Beyond
Get PDFThe identification and functional characterization of specific metabolite–protein interactions remains a major challenge in chemical biology and drug development. The functionalization of native metabolites and synthetic small molecules with bio-orthogonal detection tags (alkyne, azide, and others) has afforded chemical reporters for the biochemical analysis of metabolically labelled proteins, whereas functionalization with photo-crosslinkers enables non-covalent metabolite–protein interactions to be captured. While we and many others have employed this approach to different metabolites and synthetic ligands, the installation of bio-orthogonal detection tags and photo-crosslinkers to more complex and diverse small molecules can be challenging and limiting. In this regard, activity-based protein profiling (ABPP) using active site–directed probes in combination with small molecule competition studies allows the discovery of potential substrates and inhibitors of selective enzyme families. Moreover, the development of proteome-wide labelling of select amino acid (cysteine and lysine) has revealed new sites in proteins for function modulation. However, some key protein classes and specific ligand-binding domains have been inaccessible by these methods. New activity-based probes and targeted chemical reporters of specific protein families are thus needed to characterize their endogenous and exogenous ligands for fundamental biology and drug discovery. In this thesis, we describe two projects aimed at developing chemical probes to assist in small molecule target engagement and target deconvolution studies. In Chapter 1, we provide an overview of the origin and evolution of ABPP and related chemical reporter–based chemical proteomics methods. We also summarise recent developments in label-free methods that work with underivatized molecules. In Chapter 2, we describe the development of a ligand-directed probe (alk-GW9662) for a subset of nuclear receptors (NRs). NRs are a family of ligand-activated transcription factors that regulate diverse physiological processes in animals and are key targets for therapeutic development. Recent studies implicated NRs in host–microbiota interactions and suggested that various microbiota-derived metabolites may serve as ligands for NRs. We demonstrate alk-GW9662\u27s utility to assess target engagement of candidate ligands of peroxisome proliferator–activated receptor (PPAR) γ. We also explore repurposing alk-GW9662. We profile its target proteins using chemical proteomics and demonstrate that the probe can be used in target engagement study of other proteins. Overall, our results suggest that alk-GW9662 may be useful for target engagement analysis of candidate PPAR ligands and offer a starting scaffold in developing probes for other proteins. In Chapter 3, we describe efforts towards the combined use of proteolysis-targeting chimeras (PROTACs) and chemical proteomics in target deconvolution studies. We describe the design and synthesis of PROTACs that recruit putative E3 ligases. Overall, the projects described herein underline the utility of chemical tools such as ligand-directed probes and PROTACs in target engagement and target deconvolution studies
Characterizing Inflammatory Mechanisms in Hidradenitis Suppurativa
Get PDFHidradenitis suppurativa (HS) is an inflammatory skin disease manifesting in painful nodules and abscesses, and malodorous draining tunnels in more advanced disease. Effective treatment options remain limited, with Tumor Necrosis Factor inhibitor adalimumab remaining the only approved biologic despite its limited efficacy. The development of novel therapeutics is impeded by our lack of understanding of disease pathogenesis and an absence of standardized approaches to study HS. In this thesis, we establish a translational approach to characterize HS by examining nonlesional, perilesional and lesional HS skin in comparison to site-matched control skin from healthy volunteers. We demonstrate that relatively healthy-appearing perilesional skin (2cm away from the target nodule) has the same inflammatory profile as the visibly inflamed lesional skin (target nodule) and is marked by an increase of Th17 and neutrophil-related signatures. Given that inflammation in HS extends beyond visible nodules to perilesional skin, we asked if dermal inflammation also contributes to disease pathogenesis. Dermal tunnels, also known as tracts or sinuses, are structures unique to HS and have been considered an end-stage feature of the disease. By examining biopsies of dermal tunnels, we show that tunnels recapitulate features of the overlying epidermis and are associated with increased infiltration of T cells, dendritic cells and neutrophils, formation of neutrophil extracellular traps, and increased production of epithelium-derived inflammatory cytokines. Our work demonstrates that dermal tunnels are active contributors to the inflammatory burden of HS. To address whether tunnels are associated with a unique HS subtype, we assessed serum biomarkers in HS compared to healthy controls. Patients with tunnels had higher levels of IL-17 regulated neutrophil gelatinase-associated lipocalin (LCN2), and serum level of this biomarker correlated with clinical severity. These data demonstrate that HS tunnels are associated with a unique inflammatory profile in the skin and blood, suggesting a novel HS endotype. Data from our clinical trial of brodalumab, a human anti-IL-17 receptor A (IL-17RA) monoclonal antibody, provides the first molecular characterization of IL-17 pathway blockade in HS. We demonstrate that treatment with brodalumab reduces several pathogenic inflammatory axes in HS skin and serum. We also establish that perilesional skin provides a more robust assessment of treatment response. To further support HS stratification in the context of therapeutic antagonism, we demonstrate that patients with high expression of LCN2 in skin and IL-17A in serum had a superior molecular response in the skin as measured by a greater decrease of known inflammatory mediators of HS. Furthermore, we validate that dermal tunnels are therapeutically targetable, exhibiting decrease of tunnel wall and lumen diameter, as well as a decrease in clinical drainage. Taken together, this work provides novel insight into HS pathogenesis. Given the equally high inflammation present in lesional and perilesional HS skin, our data suggests there is a large field of inflammation beyond visible lesions. HS can be subdivided into unique subtypes, potentially introducing the concept of disease endotypes in this highly heterogeneous disease. This has direct applicability towards stratification of patients who may be better responders in the context of targeted therapy in HS
A Role for ACSBG1 in Obesity-Accelerated Breast
Get PDFOverweight and obesity affect more than 70% of American adults and are major risk factors for the development of comorbidities, including cancer. Breast cancer is the most commonly diagnosed malignancy in American women: 1 in 8 women will develop breast cancer in their lifetimes, and more than 40,000 women die from breast cancer each year. Obesity is associated with increased incidence and worse prognosis in breast cancer, including aggressive triple-negative breast cancer, which has a particularly poor prognosis with few treatment options. The goal of this thesis was to elucidate the mechanisms by which obesity promotes breast cancer progression. To that end, we used an orthotopic model of triple-negative murine mammary carcinoma in a diet-induced model of obesity. We found that obesity significantly accelerated tumor growth, which was due to increased proliferation. Upon performing whole-tissue RNA sequencing of tumors isolated from lean or obese animals, we found that many of the transcriptional programs differentially regulated in obesity were immune-related. Since tumors are cellularly heterogeneous and contain tumor-associated cell types, such as immune cells, adipocytes, endothelial cells, and fibroblasts, we devised a fluorescence-based approach to specifically isolate cancer cells prior to analysis. To achieve this, we produced a stable-mCherry expressing breast cancer cell line and utilized fluorescence-activated cell sorting to isolate cancer cells from heterogeneous tumor tissue. RNA sequencing of this pure cancer cell population identified the acyl-CoA synthetase, Acsbg1, as robustly upregulated in cancer cells isolated from tumors in obese compared to lean animals. Overexpression of Acsbg1 in tumor cells further enhanced tumor growth in an obesity-specific manner, which required intact creatine transport. Inhibition of acyl-CoA synthetase activity, on the other hand, significantly attenuated tumor growth in obese animals. This led us to hypothesize that Acsbg1 may reprogram the breast cancer cell metabolome. We performed targeted metabolomic analysis on tumors from lean and obese animals and identified a role for Acsbg1 in promoting mitochondrial ATP production, which was confirmed with plate-based respirometry. We used untargeted lipidomic analysis to identify the lipid substrate and products of Acsbg1 activity and found that phospholipids containing 20:4 and 22:4 side chains were more abundant in Acsbg1-overexpressing tumors in obesity. The most common 20:4 and 22:4 lipid species are arachidonic and adrenic acid, respectively. Since arachidonic and adrenic acid are products of sequential steps of linoleic acid metabolism, an essential fatty acid, this suggests a role for dietary lipids in the pathogenesis of obesity-driven breast cancer progression. These findings further suggest that Acsbg1 supports obesity-related tumor progression through both catabolic ATP generation and anabolic processes to build biomass. Finally, we analyzed a dataset of human tumor gene expression and found that Acsbg1 levels are associated with worse tumor grade and with aggressive, basal-like cancers in overweight and obese individuals. Overall, these studies identified an undescribed, obesityspecific role for Acsbg1 in promoting tumor progression and provide the foundation for further studies investigating Acsbg1 and acyl-coA synthetase activity as a possible target for therapeutic intervention in breast cancer and other obesity-driven cancer types
William H. Welch on the Porch of William Wickham Welch\u27s Home
No full textWilliam H. Welch on the porch of William Wickham Welch\u27s home, circa 1870s
Courtesy the Norfolk Historical Museum
From left to right: Frederic Walcott, his brother-in-law; William H. Welch; Emily Sedwick Welch, his stepmother; William Wickham Welch, his father; and Emeline Walcott, his sister. Seated are the Walcott children.
After receiving the A.B. degree from Yale University in 1870, William H. Welch helped to organize a new school in Norwich, NY and taught there for an academic year. German and Cicero were among the courses he taught. At the end of the school term, he decided to follow family tradition and become a physician. He returned to Norfolk and served as an apprentice to his father.https://digitalcommons.rockefeller.edu/jem-the-beginnings/1005/thumbnail.jp
Introduction to the First Volume of JEM
No full textPapers and addresses by William Henry Welch, vol.3. Introduction to the first volume of The Journal of Experimental Medicine. Baltimore, 1920
Full texthttps://digitalcommons.rockefeller.edu/jem-the-beginnings/1012/thumbnail.jp