Investigational Drug Steering Committee Team Science Meeting 11 Jan, 2013 11 Jan, 2013 This work was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under contract Livermore National Laboratory under contract DE ‐ AC52 ‐ 07NA27344. Lawrence Livermore National Security, LLC
Is a multi ‐ sponsor FFRDC, managed by NNSA Our role… • Provide enduring focus on issues in national security • Leverage multidisciplinary capabilities Laser Sciences & Isotopic Sciences (National Ignition Facility) — High Performance Computing — Analytical and Measurement Sciences Analytical and Measurement Sciences — Material Sciences — Advanced Engineering, Instrumentation & Diagnostics — Biosciences — 2 Lawrence Livermore National Laboratory
3 1073 18 633 Lawrence Livermore National Laboratory 551
Multidisciplinary teams including bioscientists engineers computational Multidisciplinary teams including bioscientists, engineers, computational scientists, physicists, chemists . . . Working at the interface of engineering, materials, chemical and g g g, , biological sciences Detection & diagnostics – detection and surveillance platforms, fit ‐ for ‐ purpose arrays… High precision measurement/Instrumentation — Accelerator Mass Spectrometry, single molecule spectroscopy, microfabrication & S i l l l i f b i i & engineering Computational biology Computational biology —Massively parallel computing resources and Massively parallel computing resources and biocomputing expertise Expertise in medical devices, assay development, genomics, biological Expertise in medical devices, assay development, genomics, biological /chemical threats, and countermeasures Lawrence Livermore National Laboratory 4
The original mission was to investigate the effects of ionizing radiation on humans Focus on goal driven research, developing technology that is coupled to solving problems of national significance in health and the environment 1970 ’ s 1990 ’ s 2000 ’ s 1980 ’ s High FISH Human Genome Automated Cell Radiation Performance Performance Chromosome Chromosome Project Project S Sorting ti Eff Effects Simulations Painting 5 Lawrence Livermore National Laboratory
Now: 15 years Our goal: 5 years Target Lead Preclinical discovery Lead optimization Phase 0 generation generation development development validation Pathway BSL/3 Testing Characterization AMS Microdosing 3D Organ Culture Rapid sample prep & biomarker C Computational t ti l measurement t Prediction lipid functionalization Apolipoprotein NLP’s for Delivery, Imaging & NLP s for Delivery, Imaging & Functional Studies Structural Characterization Lawrence Livermore National Laboratory 6 Lawrence Livermore National Laboratory 6
Computational Analysis and Simulation Computational Analysis and Simulation DNA Protein Protein/enzyme Protein sequence sequence structure function and regulation Homology T oter based A Promo Molecular T protein Sequence A simulations structure Annotation C prediction A Q G age T T Messa Y A C C Expt. data R G integration T Network Organism g Pathway y analysis simulations simulations Metabolic pathways Bacteria Bacterial communities Multi ‐ protein & regulatory networks & l t t k and cells d ll & & multicellular organisms l i ll l i machines
HPC is Being Used to Design Affinity Reagents for HPC is Being Used to Design Affinity Reagents for Use in Detection Assays and Therapeutics Use in Detection Assays and Therapeutics Use in Detection Assays and Therapeutics Use in Detection Assays and Therapeutics Utilizes DNA signature and protein structural d i l data to identify target sites. More robust detection Longer shelf life Longer shelf ‐ life Better treatments Protein structure information may allow developing synthetic ligands as interventions developing synthetic ligands as interventions or detectors. Lawrence Livermore National Laboratory
Developing Advanced Methods for Structural Developing Advanced Methods for Structural Characterization with XFELs to improve Models Characterization with XFELs to improve Models Fixed-target support Fixed-target support Why? Why? LCLS detector LCLS detector •Allows 2D crystallography • Membrane proteins in a native environment! •Reduced sample consumption •Reduced sample consumption • 100s µg vs 10s to 100s mg LCLS beam •Room temperature protein structures! Apply sample • Possibly more biologically relevant relevant Thorough characterization of mechanical damage pathways and 3D crystallography implications for structure results from determination determination proteins involved in putative virulence pathways to atomic resolution Lawrence Livermore National Laboratory
Administration of low doses (/100 th (/ the anticipated therapeutic dose) to healthy volunteers Many benefits including : Reduced animal testing Reduced drug synthesis Early assessment of l f efficacy/safety Difficult without extremely sensitive Difficult without extremely sensitive methods of analysis Lawrence Livermore National Laboratory 10
Type of mass spectrometer that T f t t th t analyzes ions at very high energies through use of a linear acceleration stage g 0.0007 Volunteer 1 – selected data V l 1 l d d Run 2a 0.0006 Run 2b Measures isotope ratios n (ng/ml) Run 2c 0.0005 Run 3a sma concentration Run 3b 0.0004 Analysis of attomole quantities Run 3c of chemical or biological entities 0.0003 in µg mg sized samples with in µg ‐ mg sized samples with Plas 0.0002 0 0002 high precision 0.0001 Directly determines drug safety Directly determines drug safety 0.0000 4 8 12 16 20 24 & relevance in humans Time (hours) -0.0001 11 Lawrence Livermore National Laboratory
Microfluidic chip Piezoelectric transducer LE channel LE gel electrode sample channel TE gel electrode TE l l t d TE channel gel electrode focusing of fluorescein focusing of fluorescein edges edges Maxim Shusteff, LLNL 12 Lawrence Livermore National Laboratory
Passive Lateral flow array assay Next generation device uses simple microfluidics Blood Blood Blood Blood Blood Blood for smart phone based diagnostics for smart phone ‐ based diagnostics serum serum serum serum serum serum serum serum serum Antibody Array A A Antibody Array ib d A ib d A Cancer Cancer Cancer Cancer Cancer Cancer Antibody Array Antibody Array sample sample sample sample sample sample Antigen Antigen Antigen Antigen Antigen Antigen Conjugate Pad Conjugate Pad Conjugate Pad Conjugate Pad Wicking block Wicking block Wicking block Wicking block Porous Membrane Porous Membrane Porous Membrane Porous Membrane containing antibody- containing antibody- containing antibody containing antibody - - reporter complex reporter complex reporter complex reporter complex 8 ” 8 ” 4 ” 1 ug, 100 ng, 10 ng. 1 ng Hand ‐ held detector for array ‐ based assays 13 Lawrence Livermore National Laboratory
1st Principal Component for the 4 Biomarkers 25000 25000 Metastatic 20000 15000 10000 5000 Early onset 0 -5000 Controls -10000 10000 -15000 0 50 100 150 200 4 biomarkers for breast cancer / n = 40 people per group 4 biomarkers for breast cancer / n = 40 people per group Rao, R., et al., (In preparation) Passive-flow breast cancer screens capable of discriminating between normal from metastatic breast cancer in serum. Lawrence Livermore National Laboratory
5,964 microbial species • 3,368 viral species i l i • 2,223 bacterial species • 136 fungi 387,156 total probes l b • Probes are 50 ‐ 65 bases long • Unique regions from viral and bacterial sequences used • >15 ‐ 50 probes per each sequence A Microbial Detection Array (MDA) for Viral and Bacterial Detection. Enabled by Bioinformatics Gardner SN, Jaing CJ, McLoughlin KS, Slezak TR. BMC Genomics 2010, 11: 668doi:10.1186/1471 ‐ 2164 ‐ 11 ‐ 668, published Nov 25, 2010. http://www.biomedcentral.com/1471 ‐ 2164/11/668 . • Expertise in DNA signatures and biostatistics More than 20 collaborations with academia, government More than 20 collaborations with academia, government agency and pharmaceutical companies agency and pharmaceutical companies d h d h ti ti l l i i • Large Cluster computing used Multiple licensing discussions underway. Multiple licensing discussions underway. Lawrence Livermore National Laboratory
Non-Hodgkin ’ s lymphoma Non Hodgkin s lymphoma, malignancy of bone marrow-derived cells which results in unregulated replication and expansion of these p p cells in lymphoid tissue and beyond. Drs. Ralph Greene and Mingyi Chen; Postdoc Joe Tellez Analyze viruses and/or bacteria in control lymphoid tissues, indolent lymphomas and aggressive lymphomas Identify unique groups of commensal and pathogenic microbial species that might y q g p p g p g be associated with each sample group Compare the relative abundances of microbial families between normal vs indolent vs progressive lymphomas to determine whether higher abundance of certain p g y p g microbes in tissues correlates with lymphomas and the progression of lymphomas. Dr. Crystal Jaing, LLNL Lawrence Livermore National Laboratory
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