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  • Microtissues in 4D to Improve Drug Toxicity Risk Assessment

    Contains 1 Component(s) Recorded On: 02/07/2018

    Our results demonstrate the potential to use sophisticated imaging and machine learning analysis techniques to interrogate increasingly complex cellular systems such as microtissues to assess and mitigate for toxicity risk in preclinical drug discovery.

    Drug discovery and development is often halted or delayed due to toxicological risks associated with the candidate drug and in particular those associated with cardiac toxicity. Cellular models that enable early and accurate assessment of compound liability are required.  We have developed a suite of 384-well based 3D spheroid based multicellular model systems and applied novel kinetic imaging and analytical approaches to better assess compound toicity risk early in drug discovery.  Cardiac microtissues utilised tri-cultures of human primary, IPS cell derived and primary cells to better represent cardiac tissue structure and functional activity. Characterisation of these model systems show physiologically relevant responses. Cardiac microtissues had a spontaneous beat rate of 62 ± 24 beats/minute (mean ± SD) and the microtissues maintained synchronized contraction transients following stimulation at 1, 2 and 3 Hz. To study and quantify changes in cardiac contractility we developed a bespoke fast frame-rate widefield image acquisition methodology coupled with optical flow image analysis and Wavelet decomposition.  Structural cardiotoxicity was assessed using cytotoxicity and live cell high-throughput confocal microscopy, combined with analysis of endoplasmic reticulum integrity and mitochondrial membrane potential from all-in-focus images.  Validation against a panel of in vivo clinical and pre-clinical compounds that represented diverse mechanisms of toxic effect showed improved sensitivity and specificity over 2D model systems.  73% of internal compounds stopped due to changes in cardiac pathology between first GLP dose and FTiH (2001-2014) were detected using this live cell imaging and cytotoxicity approach for structural cardiotoxicity with functional cardiotoxicants identified at 91% sensitivity and 80% specificity.  These developed models and imaging-based screening systems are in use at a scale enabling full dose-response testing of compounds to enable effective decisions to be made early in a drug project lifecycle.  Our results demonstrate the potential to use sophisticated imaging and machine learning analysis techniques to interrogate increasingly complex cellular systems such as microtissues to assess and mitigate for toxicity risk in preclinical drug discovery.

    James Pilling

    AstraZeneca

    James Pilling is an Associate Principal Scientist within the Global High Content Biology Group in AstraZeneca. James joined AstraZeneca in 2004 and has worked with applying novel technologies and approaches to Drug Discovery processes across various therapeutic areas. The remit of the High Content Biology Group is to develop and deploy high content phenotypic assays, mechanistic profiling and high content imaging platforms across AstraZeneca. James holds an MSc in Biochemistry and Biological Chemistry from Nottingham University and a BPS Diploma in Pharmacology. Current research interests include the development and application of Precise Genome Editing technologies to aid Target Identification and the use of advanced 2D and 3D cellular models for the prediction of drug safety and efficacy.

  • Chemical and genomic identification of globin regulators that induce fetal hemoglobin reactivation

    Contains 1 Component(s) Recorded On: 02/07/2018

    We identified multiple druggable components of lipid metabolism, nuclear receptor pathways and transcription/chromatin regulatory pathways that modulate HBgamma mRNA using our automated, cell-based chemical genetic screening platform. Through characterization of these regulators, we have demonstrated that CRISPR targeting of different protein domains of components of the globin regulatory network can have profoundly different effects on globin gene expression patterns.

    Red blood cell disorders like Sickle Cell Disease (SCD) and beta-thalassemias are caused by alterations within the gene for the hemoglobin beta (HBbeta) subunit. A fetal ortholog of HBbeta, hemoglobin gamma (HBgamma) can reverse disease-related pathophysiology in these disorders by also forming complexes with the required hemoglobin alpha subunit. Because beta-like globin expression is developmentally regulated, with a reduction in the fetal ortholog (gamma) occurring shortly after birth concomitantly with an increase in the adult ortholog (beta), it has been postulated that maintaining expression of the anti-sickling gamma ortholog may be of therapeutic benefit in children and adults. Previously, inhibitors of chromatin modifying enzyme G9a/GLP (G9a-i) have been shown to upregulate HBgamma expression relative to HBbeta expression and therefore G9a/GLP has been proposed as a reasonable molecular target for maintenance of the anti-sickling HBgamma ortholog.  However, we have uncovered limitations to G9a-i as a therapeutic strategy to reactivate HBgamma and therefore set out to identify novel modulators and targets of HBgamma expression using both chemical probe and CRISPR-based genetic screening strategies.  We identified multiple druggable components of lipid metabolism, nuclear receptor pathways and transcription/chromatin regulatory pathways that modulate HBgamma mRNA using our automated, cell-based chemical genetic screening platform. Through characterization of these regulators, we have demonstrated that CRISPR targeting of different protein domains of components of the globin regulatory network can have profoundly different effects on globin gene expression patterns.  More specifically, modulation of key domains of chromatin writers, readers and erasers results in markedly different globin expression profiles that informs small molecule discovery against these novel targets. Additionally, we are utilizing a newly developed in vitro SCD cellular model to investigate how these globin gene regulators impact SCD pathophysiology.

    Pete Rahl

    Fulcrum Therapeutics

    More information coming!

  • The Open Targets Cell Line Epigenome Project: Determining the Biological Relevance of Cellular Assay Models through Epigenetic Analysis

    Contains 1 Component(s) Recorded On: 02/07/2018

    The data and tools we have generated provide an impactful framework enabling biologists to select the most appropriate, predictive cellular model for their research and to better establish optimal assay critical paths for translating target biology & compound pharmacology to the clinic. In this presentation we will demonstrate how we have used this approach to quantify the impact of 2D vs. 3D culture in cellular models of liver drug toxicity; identify the most relevant immune cell models of inflammatory response and validate immortalised cell surrogates for genome wide gene editing studies.

    The Open Targets Cell Line Epigenome Project addresses the challenge of selecting appropriate cellular models for target validation and drug screening that exhibit sufficient relevance to pathways and phenotypes associated with a particular disease or biology. The implementation of more complex, disease relevant models through use of 3D culture, tissue slices and primary cells is improving the predictive power of in vitro assays. However, due to limitations in cell and tissue supply, scalability, assay reproducibility and amenability to genetic manipulation, there often remains a need to utilise transformed cell lines, particularly for higher throughput cellular screens and gene editing studies. Currently cell lines are often chosen for these purposes based on historical usage, even if they are a poor substitute for that cell type or tissue. To address the gap in data driven cell line and model selection, we have developed a novel systematic approach to determine biological relevance through the generation and analysis of transcriptomic and epigenomic data. Epigenomic and transcriptomic profiles (RNA/ChIP/ATAC-seq) from common immortalised cell models have been generated and integrated with publicly available reference data from primary cells. Statistical methods have been developed to score cells based on distance / similarity at the global genome level or more specific gene sets, signaling pathways or genomic loci of interest. The data and tools we have generated provide an impactful framework enabling biologists to select the most appropriate, predictive cellular model for their research and to better establish optimal assay critical paths for translating target biology & compound pharmacology to the clinic. In this presentation we will demonstrate how we have used this approach to quantify the impact of 2D vs. 3D culture in cellular models of liver drug toxicity; identify the most relevant immune cell models of inflammatory response and validate immortalised cell surrogates for genome wide gene editing studies.

    Rebecca Randle

    Screening Profiling & Mechanistic Biology, GlaxoSmithKline

    Following a PhD at Imperial College London focusing on expression of P-glycoprotein and the development of multidrug resistance in cancer, I established a career in the pharmaceutical industry with positions at UCB-Celltech (Cambridge, UK) and GlaxoSmithKine (Stevenage, UK). I have a strong background in cell biology, phenotypic screening and a deep interest in epigenetics. I currently work within GSK’s Screening Profiling and Mechanistic Biology Department (within Platform Technology and Science) as a cell biologist and program leader. My role involves leadership of GSK early drug discovery programs and external collaborative projects such as the Cell Line Epigenome Project, an Open Targets project in collaboration with EMBL-EBI and the Wellcome Trust Sanger Institute. 

  • The use of DNA Encoded Library Technology to identify hits for less tractable targets

    Contains 1 Component(s) Recorded On: 02/07/2018

    DEL technology has been adopted by many organisations including AstraZeneca. In partnership with X-Chem we have screened over 40 targets using this screening paradigm. In this presentation I will describe the principles of the DEL platform, and how AstraZeneca has applied this platform as part of our integrated hit discovery strategy, providing examples of the identification of hit series for less tractable targets, and the use of the DEL platform to identify novel binding sites on target proteins.

    Over the last decade there has been increasing application of DNA Encoded Library (DEL) technology to complement traditional high throughput screening for hit discovery.  DNA Encoded Libraries consist of hundreds of millions of molecules synthesised on a DNA tag, such that the structure of the small molecule is genetically encoded by the sequence of the tagged DNA.  These libraries are tested against molecular targets in an affinity based selection method.  Through the use of such libraries it is possible to test huge numbers of small molecules without incurring the costs of creating a traditional small molecule library and without the automation infrastructure requirements to house and test such compounds.   It is the rapid advancement in Next Generation Sequencing technologies that has enabled the creation of this screening paradigm, the ability to mine screening data in depth and has reduced the costs of screening.   DEL technology has been adopted by many organisations including AstraZeneca.  In partnership with X-Chem we have screened over 40 targets using this screening paradigm.  In this presentation I will describe the principles of the DEL platform, and how AstraZeneca has applied this platform as part of our integrated hit discovery strategy, providing examples of the identification of hit series for less tractable targets, and the use of the DEL platform to identify novel binding sites on target proteins.

    Stephen Rees

    AstraZeneca

    In March 2017 Steve was appointed as Vice-President of the Discovery Biology department at AstraZeneca with global accountability for protein and cellular reagent generation and assay development, functional genomics and chemical biology. Prior to this Steve led the Screening Sciences and Sample Management department and successfully implemented strategies for hit identification, compound profiling, sample management and open innovation. Steve has led multiple international collaborations and has authored >60 scientific papers. Steve is currently Chair of the European Laboratory Research and Innovation group (ELRIG), has served as Chair of the SLAS Europe Council, and is a member of the Scientific Advisory Board for Axol Biosciences, LifeArc and the Centre for Membrane Protein and Receptor research at the Universities of Nottingham and Birmingham.

  • CROP-seq: Pooled CRISPR screening with single-cell transcriptome readout – a high-throughput method for dissecting gene-regulatory mechanisms

    Contains 1 Component(s) Recorded On: 02/07/2018

    We are exploring combinations with alternative functions, such as CRISPR inhibition, activation and targeted epigenetic modifications. I will further provide insights into further technical improvements such as higher gRNA detection rates and demonstrate CROP-seq compatibility with single cell sequencing platforms capable of further upscaling screens. Given the increasing throughput of single-cell transcriptomics and the advent of single-cell multi-omics technology (reviewed in: Bock et al. 2016 Trends in Biotechnology), CROP-seq has the potential to provide comprehensive characterization of large CRISPR libraries and constitutes a powerful method for dissecting cellular regulation at scale.

    CRISPR-based genetic screens are accelerating biological discovery, but current methods have inherent limitations. Widely used pooled screens work well for mechanisms that affect cell survival and proliferation, and can be extended by sortable marker proteins. However, they are restricted to measuring the distribution of guide RNAs before and after applying a selective challenge, and do not provide any detailed phenotypic information. Since the actual cellular responses are not measured, the interpretation and validation of screening hits is generally work-intensive and prone to false positive results. Arrayed CRISPR screens, in which only one gene is targeted at a time, allow for more comprehensive molecular readouts, but at much lower throughput. We have recently developed a third and complementary screening paradigm, single-cell CRISPR screens, based on the idea that gRNAs and their induced cellular responses are already compartmentalized within single cells. We combined pooled CRISPR screening with single-cell RNA sequencing into a broadly applicable workflow, directly linking guide RNA expression to transcriptome responses in thousands of individual cells (Datlinger et al. 2017 Nature Methods). Our method for CRISPR droplet sequencing (CROP-seq) enables pooled CRISPR screens for entire gene signatures that can be derived directly from the data. Due to its single-cell resolution, CROP-seq can localize the effect of perturbations in complex tissues and cellular differentiation hierarchies, and can work efficiently on scarce material. Furthermore, CROP-seq is compatible with virtually all current methods for single-cell RNA-seq and established strategies for pooled library cloning.

    Since the original publication, we continued to develop CROP-seq with a particular focus on in vivo screens in Cas9 mice. We are exploring combinations with alternative functions, such as CRISPR inhibition, activation and targeted epigenetic modifications. I will further provide insights into further technical improvements such as higher gRNA detection rates and demonstrate CROP-seq compatibility with single cell sequencing platforms capable of further upscaling screens. Given the increasing throughput of single-cell transcriptomics and the advent of single-cell multi-omics technology (reviewed in: Bock et al. 2016 Trends in Biotechnology), CROP-seq has the potential to provide comprehensive characterization of large CRISPR libraries and constitutes a powerful method for dissecting cellular regulation at scale.

    Andre Rendeiro

    CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences

    More information coming!


  • Precision Enabled: Discovery of Gene Networks and New Drug Targets in Metastatic Melanoma with Single Cell Sequencing

    Contains 1 Component(s) Recorded On: 02/07/2018

    Despite the buzz regarding cloud facilitated data integration, notification, and tracking, LIMS and electronic laboratory notebooks have failed to deliver for multi-omics. Instead, current solutions are open source or have the user-friendliness of an electronic medical records system -- raising the activation energy and time required to install, to collaborate, and ultimately to produce insight. Herein, we describe a workflow-based collaboration and communication approach and its use in a coordinating the analysis of single cell gene expression from 19 melanoma metastases.

    Despite the buzz regarding cloud facilitated data integration, notification, and tracking, LIMS and electronic laboratory notebooks have failed to deliver for multi-omics.  Instead, current solutions are open source or have the user-friendliness of an electronic medical records system -- raising the activation energy and time required to install, to collaborate, and ultimately to produce insight.   Herein, we describe a workflow-based collaboration and communication approach and its use in a coordinating the analysis of single cell gene expression from 19 melanoma metastases. We show that each metastatic tissue is unique to each patient, but identify a rare subpopulation present in each tumor which shares the same gene expression pattern.  Thus, we identify two new drug targets shared between patients, and uncover the gene expression pattern of the immune response, particularly exhausted CD8+ T cells within each metastatic tissue could be reversed.  Thus, we show how single cell phenotyping and gene expression experiment execution may be coordinated and executed to reveal both tumor and immune response drug targets and gene expression networks.  We extend this work to compare the tumor gene expression patterns to the published literature and drug trials, and show that drug repurposing may be an effective strategy for melanoma.

    Michael Stadnisky

    FlowJo, LLC

    Michael Stadnisky, Ph.D. is the CEO of FlowJo, LLC, the leading single cell flow cytometry and sequencing informatics company.  Mike recently led his team to bring a new gene expression analysis platform to scientists in under 9 months in collaboration with Illumina.  He is an author of 4 patents, was a finalist for the 2014 International Society for the Advancement of Cytometry President’s Award. 

  • DIY integration of a Hamamatsu FDSS to a High-Throughput Screening System; a problem solving and design-for-manufacture exercise, and supporting case for the value of in-house prototyping ability

    Contains 1 Component(s) Recorded On: 02/07/2018

    A perception exists in the life sciences field that the creation, implementation, integration, modification and maintenance of instrumentation are tasks exclusively to be outsourced to dedicated vendors. At the National Center for Advancing Translational Sciences (NCATS) we believe that readily available solutions can be quick and cost-effective, but if the science or the scientist dictates a new tool that doesn’t yet exist, the ability to quickly design and produce real, usable instruments can tremendously accelerate progress.

    A perception exists in the life sciences field that the creation, implementation, integration, modification and maintenance of instrumentation are tasks exclusively to be outsourced to dedicated vendors. At the National Center for Advancing Translational Sciences (NCATS) we believe that readily available solutions can be quick and cost-effective, but if the science or the scientist dictates a new tool that doesn’t yet exist, the ability to quickly design and produce real, usable instruments can tremendously accelerate progress. This value is proven by our in-house integration of a Hamamatsu FDSS7000EX Functional Drug Screening System to an existing single-arm High Throughput Robotic Platform, and further integration of an Ion Field Tip Charger plasma pin tool cleaning system to that FDSS. This project demonstrates that the process of problem solving is of enormous importance to the outcome. Good design involves engineering, but not exclusively so; time spent at the very beginning to “consider what bears consideration” is always time well spent, and it’s often the least expensive time billed to the project. “A designer is an emerging synthesis of artist, inventor, mechanic, objective economist and evolutionary strategist” – R. Buckminster Fuller This quote encapsulates the concept that problem solving for life sciences is an open-ended, inquisitive process in which diverse disciplines spanning engineering and sociology must be given consideration, equally.

    Eric Wallgren

    National Institutes of Health - National Center For Advancing Translational Sciences

    Eric Wallgren is an art school graduate who grew up in a house with a small machine shop in the basement.  He has worked as a mechanical and industrial designer and prototyper,  primarily in life sciences instrumentation, photovoltaic/renewable energy and powersports for about twenty years, before which he received an informal mechanical education while working as a bicycle mechanic.  In addition to his position as Instrumentation Lead at NCATS he also is owner/driver/crew  of Area 51 Racing, competing in the SCCA P2 class, and proprietor of MMW Engineering a small machine and fabrication shop.

  • Targeting the DCN1-UBC12 Protein-Protein Interaction in the Neddylation Activation Complex

    Contains 1 Component(s) Recorded On: 02/07/2018

    The Cullin-RING E3 ubiquitin ligases (CRLs) regulate homeostasis of approximately 20% of cellular proteins and their activation require neddylation of their cullin subunit. Cullin neddylation is modulated by a scaffolding DCN protein through interactions with both the cullin protein and an E2 enzyme such as UBC12. Here we report the discovery of high-affinity, cell-permeable small molecule inhibitors of the DCN1-UBC12 interaction.

    The Cullin-RING E3 ubiquitin ligases (CRLs) regulate homeostasis of approximately 20% of cellular proteins and their activation require neddylation of their cullin subunit. Cullin neddylation is modulated by a scaffolding DCN protein through interactions with both the cullin protein and an E2 enzyme such as UBC12. Here we report the discovery of high-affinity, cell-permeable small molecule inhibitors of the DCN1-UBC12 interaction. Using these small-molecule inhibitors as chemical probes, we have made a surprising discovery that the DCN1-UBC12 protein-protein interaction is much more important for the neddylation of cullin 3 over other cullin family members. Treatment of cells of different tissue types with these potent DCN1 inhibitors selectively convert cellular cullin 3 into a unneddylated inactive form with no or minimum effects on other cullin members. Our data firmly establish a previously unrecognized specific role of the DCN1-UBC12 interaction for cellular neddylation of cullin 3. Our compounds represent the first-in-class of selective inhibitors of a specific cullin member, and are excellent probe compounds to investigate the role of the cullin 3 ligase in biological processes and human diseases. We will also discuss their potential therapeutic applications.

    Shaomeng Wang

    University of Michigan

    Dr. Wang received his B.S. in Chemistry from Peking University and his Ph.D. in Chemistry from Case Western Reserve University. Dr. Wang did his postdoctoral training in drug design at the National Cancer Institute, NIH between1992-1996.  Wang is currently the Warner-Lambert/Parke-Davis Professor in Medicine i.  Dr. Wang serves as the Co-Director of the Molecular Therapeutics Program at the University of Michigan Comprehensive Cancer Center and is the Director of the Cancer Drug Discovery Program at the University of Michigan. Dr. Wang is the Editor-in-Chief for Journal of Medicinal Chemistry, a premier international journal in medicinal chemistry and drug discovery by the American Chemical Society.  Dr. Wang has published more than 270 papers in peer-reviewed scientific journals and 100+ meeting abstracts, and is an inventor on more than 48  patents and patent applications. In addition to his academic role, Dr Wang is a co-founder for several biotech companies.

  • CRISPR-Mediated Tagging of Endogenous Proteins with a Luminescent Peptide

    Contains 1 Component(s) Recorded On: 02/07/2018

    The effects of synthetic compounds on signaling pathways are often evaluated using overexpressed genetic reporters. It is now possible with CRISPR/Cas9 to better preserve native biology by appending reporters directly onto the endogenous genes. For this purpose, we introduced the HiBiT peptide (11 amino acids) as a small reporter tag capable of producing bright and quantitative luminescence through complementation (KD = 700 pM) with an 18 kDa subunit derived from NanoLuc (LgBiT).

    The effects of synthetic compounds on signaling pathways are often evaluated using overexpressed genetic reporters.  It is now possible with CRISPR/Cas9 to better preserve native biology by appending reporters directly onto the endogenous genes.  For this purpose, we introduced the HiBiT peptide (11 amino acids) as a small reporter tag capable of producing bright and quantitative luminescence through complementation (KD = 700 pM) with an 18 kDa subunit derived from NanoLuc (LgBiT).  The small size of HiBiT minimally alters protein structure, while the luminescent assay provides sensitive analysis at very low expression levels.  Using CRISPR/Cas9, we demonstrated that HiBiT can be rapidly and efficiently integrated into the genome to serve as a quantitative tag for endogenous proteins.  Without requiring clonal isolation of the edited cells, we were able to determine changes in abundance of the hypoxia inducible factor 1A (HIF1α) and several of its downstream transcriptional targets in response to various stimuli.  In combination with fluorescent antibodies, we further used energy transfer from HiBiT to directly correlate HIF1α levels with the hydroxyproline modification that mediates its degradation.  These assay methods allowed dynamics in protein abundance and covalent modifications to be assessed within 24-48 hours of introducing synthetic oligonucleotides together with Cas9 into the cells, thus circumventing the prerequisite for molecular cloning.

    Keith Wood

    PROMEGA CORPORATION

    Keith Wood is Head of Research, Advanced Technologies and Senior Research Fellow at Promega Corporation. Widely regarded for his work in bioluminescence, he currently leads a cross‐disciplinary team focused on long‐range innovation in biochemical and cellular research.  His current research centers on the development of bioanalytical capabilities, including novel bioluminescent chemistries, intracellular detection technologies, and efficient isolation methods for protein and drug complexes.  He has authored over 64 journal articles and book chapters and is an inventor for 164 issued and 124 pending U.S. and foreign patents.  Keith received his Ph.D. in Biochemistry at University of California‐San Diego, where he also performed post‐doctoral research before joining Promega in 1990.

  • Raman spectroscopy of isogenic breast cancer cells derived from organ-specific metastases reveals distinct biochemical signatures

    Contains 1 Component(s) Recorded On: 02/07/2018

    Objective characterization of the biomolecular divergences of metastatic lesions, which distinguish them from the primary tumor, remains challenging but is crucial for better understanding of organ-specific adaptations that regulate metastatic progression. Using an orthotopic xenograft model, we have isolated isogenic metastatic human breast cancer cells directly from organ explants that show phenotypic differences from the primary tumor cell line.

    Objective characterization of the biomolecular divergences of metastatic lesions, which distinguish them from the primary tumor, remains challenging but is crucial for better understanding of organ-specific adaptations that regulate metastatic progression. Using an orthotopic xenograft model, we have isolated isogenic metastatic human breast cancer cells directly from organ explants that show phenotypic differences from the primary tumor cell line. Leveraging label-free Raman spectroscopic measurements on these isogenic metastatic breast cancer cells from the brain, spine, lung and liver, we designed decision algorithms to enable accurate differentiation without requiring staining or human interpretation. The Raman spectroscopy-based decision models show significant diagnostic power in resolving these isogenic cell lines by analyzing the nucleic acid, protein, lipid and metabolite content. The latter differences were validated through metabolomic analyses that revealed tissue of origin distinctions between the cell lines. Our findings provide evidence that metastatic spread generates tissue-specific adaptations at the molecular level within cancer cells, and open the door for use of Raman spectroscopy to define organ-specific smart chemotherapeutic approaches.

    Chi Zhang

    Johns Hopkins University

    Mr. Chi Zhang is a Ph.D candidate in Mechanical Engineering, Johns Hopkins University. His current research efforts in Dr. Ishan Barman’s lab are directed towards application of Raman spectroscopy and multivariate data analysis to develop novel quantitative approaches for addressing unmet needs in the biochemical study of cancers. He recent mainly focuses on breast cancer cell biochemical and biomechanical variances diagnosis during metastasis by using Raman spectroscopy and machine learning techniques. He also works on kidney stone identification and otitis media effusion analysis. He has published five papers in journals such as Analytical chemistry and Accounts of Chemical Research. He has been awarded the Whiting School Doctoral Fellowship and Mechanical Engineering Departmental Fellowship by Johns Hopkins University.