J CRAIG VENTER INSTITUTE
4120 CAPRICORN LANE, LA JOLLA, CA 92037 www.jcvi.org

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Organizations Filed Purposes: JCVI IS ADVANCING THE SCIENCE OF GENOMICS THROUGH BOLD INNOVATIONS. OUR MISSION IS TO UNDERSTAND MOREABOUT THE BIOLOGICAL WORLD, AND TO DEVELOP UNIQUE INSIGHTS AND ANSWERSABOUT DISEASE, HEALTH, AND THE ENVIRONMENT FOR THE BENEFIT OF ALL.

DEPARTMENT OF HEALTH AND HUMAN SERVICES (DHHS)DURING 2019, JCVI HAD MULTIPLE ACTIVE RESEARCH GRANTS AND CONTRACTS FROM AGENCIES WITHIN THE DHHS. AMONG THESE WAS JCVI'S LARGEST FUNDED RESEARCH PROGRAM, A 5-YEAR U54 GRANT FROM THE NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES (NIAID/NIH) TO SERVE AS A DESIGNATED GENOME CENTER FOR INFECTIOUS DISEASES (GCID). THE GCID PROGRAM SCOPE INCLUDES ANALYSIS OF VIRAL, BACTERIAL, AND PARASITE PATHOGENS. THE BACTERIAL AND PARASITE PROGRAMS HAVE A PARTICULAR EMPHASES ON ANTIMICROBIAL RESISTANCE. THE BACTERIAL PROGRAM IS FOCUSED ON THE EVOLUTION AND TRANSMISSION OF CARBAPENEM-RESISTANT ENTEROBACTERIACEAE AND OTHER GRAM-NEGATIVE BACTERIA. ALL GENOME SEQUENCE DATA PRODUCED WITH GCID FUNDING IS RAPIDLY DEPOSITED IN PUBLIC REPOSITORIES TO PROMOTE THE WIDEST POSSIBLE USE AMONG RESEARCH SCIENTISTS. JCVI IS THE PRIMARY LEAD OF A LARGE 5-YEAR COLLABORATIVE NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES (NCATS/NIH) U01 GRANT WITH THE GOAL TO DEVELOP, VALIDATE AND DISSEMINATE A COMPUTATIONAL INFRASTRUCTURE FOR UNBIASED ANALYSIS OF CYTOMETRY DATA FOR BOTH DIAGNOSTIC AND DISCOVERY APPLICATIONS THAT COULD HELP OVERCOME THE CURRENT LIMITATIONS OF MANUAL ANALYSIS AND PROVIDE FOR MORE EFFICIENT, OBJECTIVE, ACCURATE, AND REPRODUCIBLE ANALYSIS OF CYTOMETRY DATA. FLOW CYTOMETRY ANALYSIS IS WIDELY USED IN TRANSLATIONAL RESEARCH LAB TO EXPLORE THE MECHANISMS OF NORMAL AND ABNORMAL BIOLOGICAL PROCESSES AND IN THE CLINICAL DIAGNOSTIC LAB FOR THE IDENTIFICATION AND CLASSIFICATION OF BLOOD-BORNE MALIGNANCIES. HOWEVER, THE CURRENT PRACTICE FOR CYTOMETRY DATA ANALYSIS RELIES ON SUBJECTIVE AND AD HOC "MANUAL GATING". THE PROJECT TEAM OF JCVI, THE UNIVERSITY OF CALIFORNIA, SAN DIEGO (UCSD), THE UNIVERSITY OF CALIFORNIA, IRVINE (UCI), AND STANFORD UNIVERSITY COLLABORATED TO CONTINUE IMPROVING THE ACCESSIBILITY, FUNCTIONALITY, AND USABILITY OF THE PROPOSED INFRASTRUCTURE. THE PROJECT TEAMS ASSEMBLED MULTIPLE FLOW CYTOMETRY DATASETS FROM IMPORTANT BIOMEDICAL PROJECTS CONDUCTED BY TRANSLATIONAL RESEARCHERS AT UC IRVINE AND FROM THE CLINICAL DIAGNOSTICS LAB AT UCSD. THE JCVI TEAM PROCESSED AND ANALYZED THE DATASETS USING THE COMPUTATIONAL INFRASTRUCTURE AND VALIDATED THE ANALYSIS RESULTS USING FOLLOW-UP STUDIES. THE COMPUTATIONAL ANALYSES OF THESE DATASETS HAVE IDENTIFIED NOVEL CELL SUBSETS FROM HUMAN LEUKOCYTES FOR INDEPENDENT ASTHMA RESEARCH PROJECTS BEING CONDUCTED AT PEDIATRICS OF UC IRVINE. THE ANALYSES HAVE ALSO IDENTIFIED A NOVEL COMBINATION OF CELL SURFACE MARKERS FOR PRECISION DIAGNOSIS OF THE CHRONIC LYMPHOCYTIC LEUKEMIA BASED ON THE CLINICAL FLOW CYTOMETRY DATA PROVIDED BY UCSD. THE RESULTS AND FINDINGS HAVE BEEN PUBLISHED ON PEER-REVIEWED JOURNALS OR REPORTED AT SCIENTIFIC CONFERENCES. THE PROJECT TEAM HAVE ALSO BEEN TRAINING THE TRANSLATIONAL RESEARCHERS OF UCI PEDIATRICS AND HEMATOPATHOLOGISTS OF UCSD PATHOLOGY FOR USING THE ADVANCED DATA ANALYTICS TOOLS ON THE COMPUTATIONAL INFRASTRUCTURE THROUGH IN-PERSON SITE VISITS AND WEBEX MEETINGS.ANTIBIOTIC RESISTANCE IS ONE OF THE BIGGEST PUBLIC HEALTH PROBLEMS OF OUR TIME. JCVI IN COLLABORATION WITH NORTHEASTERN UNIVERSITY HAVE DEVELOPED NEW METHODS TO GROW AND EXPLOIT PREVIOUSLY UNCHARACTERIZED MICROBES. JCVI HAS DEVELOPED A TRANSCRIPTION-BASED PLATFORM THAT BIOINFORMATICALLY PREDICTS WHETHER NEW POTENTIAL COMPOUNDS ARE EXPRESSING ANTIBIOTIC PROPERTIES WITH NOVEL MECHANISMS OF ACTION. PROMISING COMPOUNDS ARE VALIDATED AND BECOME LEAD ANTIMICROBIAL COMPOUNDS FOR FURTHER STUDY. JCVI, IN COLLABORATION WITH NORTHROP GRUMMAN (THROUGH SEPTEMBER 14, 2019) AND THE UNIVERSITY OF CHICAGO (SINCE SEPTEMBER 15, 2019), SERVES AS THE MAIN DEVELOPER OF THE VIRAL PATHOGEN RESOURCE (WWW.VIPRBRC.ORG) AND THE INFLUENZA RESEARCH DATABASE (WWW.FLUDB.ORG). THESE RESOURCES SERVE AS FREE PUBLIC PORTALS TO A WIDE RANGE OF INFORMATION, DATA, AND ANALYTICAL TOOLS FOR INTERPRETING VIRAL GENOMES IN THE CONTEXT OF DISEASE. OVER 3000 RESEARCHERS THROUGHOUT THE WORLD USE THESE RESOURCES EVERY WEEK. SEVERAL ADDITIONAL DHHS GRANTS AT JCVI ARE RELATED TO HUMAN MICROBIOME STUDIES. THE MICROBIOME IS THE COLLECTION OF MICROBES THAT LIVE IN AND ON THE HUMAN BODY; THESE SPECIES HAVE RECEIVED CONSIDERABLE ATTENTION IN RECENT YEARS BECAUSE A NEW APPRECIATION OF THE COMPLEX ROLES THAT THEY PLAY IN HEALTH AND DISEASE. SOME OF THESE STUDIES ARE AIMED AT BASIC CHARACTERIZATION OF THE COMPOSITION AND ACTIVITY OF THE MICROBIOME, WHILE OTHERS SEEK TO UNDERSTAND THE CONTRIBUTION OF THE MICROBIOME TO THE DEVELOPMENT OF VARIOUS DISEASES INCLUDING ALCOHOLIC HEPATITIS, TYPE 1 DIABETES, DENTAL CARIES, DIARRHEA, AND ESOPHAGEAL CANCER, AMONG OTHERS. IN COLLABORATION WITH THE SANFORD BURNHAM PREBYS INSTITUTE, THE JCVI IS DEVELOPING METHODS TO IDENTIFY NEW DRUGS THAT SPECIFICALLY TARGET AN ENZYME IN THE MALARIA PARASITE THAT WE KNOW IS ESSENTIAL FOR THE GROWTH OF THE PARASITE. MALARIA, A PARASITIC DISEASE TRANSMITTED BY MOSQUITOES, IS STILL A MAJOR THREAT TO PUBLIC HEALTH AND ECONOMIC DEVELOPMENT IN THE TROPICAL AND SUB-TROPICAL REGIONS OF THE GLOBE, AS WELL AS TO TRAVELERS TO THESE AREAS FROM THE DEVELOPED WORLD. CONTINUAL DEVELOPMENT OF NEW DRUGS AND VACCINES IS ESSENTIAL TO ENSURE THAT MALARIA CONTROL IS MAINTAINED TO PREVENT UNNECESSARY ILLNESS AND LOSS OF LIFE. THIS PROJECT HAS SHOWN THAT ONE PARTICULAR CHEMICAL THAT BLOCKS THIS ENZYME CAN KILL MALARIA PARASITES IN THE LABORATORY. THIS COLLABORATION IS NOW DEVELOPING A LABORATORY TEST THAT WE CAN USE TO SCREEN THOUSANDS OF CHEMICALS TO FIND THOSE THAT ARE MORE EFFECTIVE AT KILLING MALARIA PARASITES THAN THE FIRST CHEMICAL. THE INSTITUTE ALSO PARTICIPATES IN THE H3AFRICA PROGRAM VIA A COLLABORATION THE UNIVERSITY OF CAPE TOWN, SOUTH AFRICA, TO TRAIN COLLABORATORS IN HUMAN MICROBIOME ANALYSIS. THE PROGRAM IS SPONSORED BY THE NIH COMMON FUND TO BRING TECHNOLOGICAL RESOURCES AND TRAINING IN A CAPITAL INVESTMENT-INTENSIVE FIELD (GENOMICS) TO THE AFRICAN CONTINENT VIA COLLABORATIONS WITH US SCIENTISTS WITH EXPERTISE IN THIS FIELD.

JCVI IS THE RECIPIENT OF A LARGE COLLABORATIVE ASSISTANCE AWARD FROM THE US DEPARTMENT OF ENERGY. AWARDED TO THE VALUE OF $10.7M, THE JCVI AND ITS COLLABORATORS, COLORADO STATE UNIVERSITY, VANDERBILT UNIVERSITY AND THE UNIVERSITY OF CALIFORNIA, SAN DIEGO, SEEK TO LEVERAGE SIGNIFICANT RECENT ADVANCES IN DIATOM GENOME ENGINEERING AND METABOLIC MODELING; INCLUDING THE ABILITY TO INTRODUCE CHROMOSOME-LIKE EXPRESSION PLATFORMS, WHICH SUBSTANTIALLY ADVANCE POSSIBILITIES FOR HIGH-THROUGHPUT GENERATION AND SCREENING OF GENETICALLY ENGINEERED DIATOMS. RESEARCH PROPOSED HERE WILL RESULT IN DRAMATIC IMPROVEMENTS IN THE PREDICATIVE CAPACITY OF EXISTING GENOME SCALE METABOLIC MODELS OF DIATOM METABOLISM. FOR THE FIRST TIME ON A LARGE SCALE, FLUXOMICS, WHICH IS COMPOUND SPECIFIC INCORPORATION OF AN ISOTOPICALLY-LABELED FEEDSTOCK, WILL BE USED TO PROVIDE BETTER FIRST STEP CONSTRAINTS ON CO2 ASSIMILATION OF IN DIATOMS. STATE-OF-THE-ART HIGH THROUGHPUT IN VITRO EXAMINATIONS OF NEARLY ALL 200 DIATOM TRANSCRIPTION FACTORS WILL BE CONDUCTED TO BETTER UNDERSTAND REGULATORY ARCHITECTURE UNDERLYING DIATOM METABOLISM AS WELL AS SERVE AS A SOURCE FOR NEW TOOLS FOR GENOME ENGINEERING. TAKEN TOGETHER, RESEARCH PROPOSED HERE WILL ADDRESS CURRENTLY LIMITING BOTTLENECKS THROUGH FOSTERING STATE-OF-THE-ART INTEGRATION OF GENOME-SCALE MODELING WITH GENOME ENGINEERING TO OPTIMIZE ENERGY AND METABOLTE FLUX THROUGH SUBCELLULAR COMPARTMENTS TO PROMOTE EFFICIENT PRODUCTION OF HIGH VALUE AND FUEL-RELATED METABOLITES.

DURING 2019, JCVI HAD MULTIPLE ACTIVE RESEARCH AWARDS FROM THE DEPARTMENT OF DEFENSE (DOD). THESE AWARDS FOCUS ON THE UNDERSTANDING OF POLYMICROBIAL INFECTIONS IN WOUNDS, THE DEVELOPMENT OF SYNTHETIC GENOMIC TECHNOLOGIES FOR MANIPULATION OF CHROMOSOMES AND GENOMES AND FOR THE DEVELOPMENT OF SAFE METHODS FOR DNA ISOLATION AND ANALYSIS FROM BIOTHREAT AGENTS. FUNDED BY THE DEFENSE ADVANCED RESEARCH PROJECTS AGENCY (DARPA) BIOLOGICAL ROBUSTNESS IN COMPLEX SETTINGS (BRICS) PHASE II PROGRAM, THE JCVI IS USING INNOVATIVE RESEARCH APPROACHES TO DEVELOP A MICROBIOME FORENSIC MICROBIAL SYSTEM (FMS) THAT WILL DETECT WHETHER AND WHEN AN OBJECT ENCOUNTERED A PARTICULAR ENVIRONMENT. IN ADDITION, THE FMS SHOULD CONTAIN A SAFETY MECHANISM THAT WILL ENSURE ITS REMOVAL FROM THE ENVIRONMENT FOR CONTAINMENT. THIS FMS WILL ULTIMATELY ALLOW FOR BROAD RANGE FORENSIC APPLICATIONS OF SYNTHETIC MICROBIOMES THAT INCLUDE, BUT ARE NOT LIMITED TO, GEOSOURCING, TRACKING, AND CRIME SCENE INVESTIGATIONS. THE JCVI IS PROVIDING LONGITUDINAL DNA METHYLATION PROFILING, LONGITUDINAL HISTONE MODIFICATION PROFILING AND LONGITUDINAL METABOLOME PROFILING ON MULTIPLE SAMPLES IN COLLABORATION WITH DARPA FOR THE SELECTING ELITE-PERFORMERS WITH LONGITUDINAL EPIGENOMIC CHARCTERIZATION AND TRACKING (SELECT) PROJECT.WOUND MICROBIOME PROJECT - CHRONIC WOUNDS ARE WOUNDS THAT FAIL TO HEAL AFTER 3 MONTHS UNDER STANDARD OF CARE WOUND MANAGEMENT. THE GOAL OF THIS DOD STUDY IS TO GAIN A BETTER UNDERSTANDING OF THE DIFFERENT CLASSES OF MICROBES THAT COULD BE PRESENT IN HUMAN CHRONIC WOUNDS (I.E. THE WOUND MICROBIOME), AND ASK WHETHER SPECIFIC MICROBES OR MICROBIAL COMMUNITIES ARE ASSOCIATED WITH NON-HEALING WOUNDS. NEXT GENERATION SEQUENCING WILL BE USED TO IDENTIFY AND CATALOG THE MICROBIAL SPECIES OF BACTERIA, FUNGI, AND VIRUSES THAT ARE PRESENT IN CHRONIC WOUND SPECIMENS. COMPUTATIONAL AND BIOINFORMATICS ANALYSES OF THE MICROBIAL COMMUNITY DNA SEQUENCES WILL BE CARRIED OUT TO CHARACTERIZE THE PRESENCE ANY PATHOGENIC, VIRULENCE, AND ANTIMICROBIAL RESISTANCE-RELATED GENES AND PATHWAYS. THE EVENTUAL GOAL IS TO IDENTIFY ANY PATHOGENIC SPECIES OR FEATURES THAT ARE ASSOCIATED WITH NON-HEALING WOUNDS, AND COULD BE USED AS DIAGNOSTIC AND TREATMENT TARGETS OF CHRONIC WOUNDS. SYNTHETIC ENGINEERING OF BACTERIOPHAGE FOR TREATMENT OF WOUND INFECTIONS ANTIMICROBIAL RESISTANCE IN BACTERIAL PATHOGENS IS STEADILY INCREASING AND RECOGNIZED AS ONE OF THE GREATEST THREATS TO GLOBAL PUBLIC HEALTH. SHORTLY AFTER THE BEGINNING OF THE WARS IN AFGHANISTAN AND IRAQ, THE MILITARY HEALTH SYSTEM EXPERIENCED A MAJOR INCREASE IN WOUND AND HEALTHCARE-ASSOCIATED INFECTIONS CAUSED BY MULTIDRUG RESISTANT ORGANISMS (MDROS) WITH EXTREMELY LIMITED TREATMENT OPTIONS. FUNDED THROUGH THE US MEDICAL RESEARCH ACQUISITION ACTIVITY, THE JCVI IN COLLABORATION WITH THE MILITARY AND THE WALTER REED ARMY INSTITITUTE OF RESEARCH, IS COLLABORATING WITH THE GOAL TO DESIGN, BUILD, TEST AND CHARACTERIZE NOVEL ENGINEERED BACTERIOPHAGE BIOLOGICS SPECIFICALLY TARGETING MDROS FOR USE AS NOVEL THERAPEUTICS FOR TREATING AND PREVENTING COMBAT WOUND INFECTIONS USING PIONEERING TECHNOLOGY DEVELOPED AT JCVI. THIS OBJECTIVE WILL BE ACCOMPLISHED THROUGH EXPERIMENTS FOCUSED ON PRODUCING SYNTHETICALLY ENGINEERED PHAGE WITH AN ENHANCED HOST RANGE SUFFICIENT TO COVER CURRENT AND FUTURE CIRCULATING MDR STRAINS OF S. AUREUS AND K. PNEUMONIAE COMMONLY FOUND IN THE MILITARY HEALTH SYSTEM, INCLUDING METHICILLIN-RESISTANT S. AUREUS AND CARBAPENEM-RESISTANT K. PNEUMONIAE STRAINS. CANDIDATE ENGINEERED THERAPEUTIC PHAGE CHASSIS WILL BE PRODUCED, CHARACTERIZED AND TESTED IN MOUSE WOUND INFECTION MODELS BY RESEARCHERS AT WRAIR AS A PRELUDE TO FUTURE HUMAN USE. IT IS ANTICIPATED THAT WE WILL DEVELOP ONE OR MORE PHAGE CHASSIS CAPABLE OF SPECIFICALLY TARGETING AND KILLING EACH PATHOGEN BOTH IN VITRO AND IN VIVO."FUNDED BY THE DEFENSE THREAT REDUCTION AGENCY (DTRA), THE JCVI IS INVESTIGATING AN ASPECT OF THE WELL-RECOGNIZED PUBLIC HEALTH THREAT OF ANTIBIOTIC DRUG RESISTANCE IN PATHOGENIC BACTERIA. IN ADDITION TO STANDARD BACTERIAL RESISTANCE TO ANTIBIOTICS, INFECTION CAUSING BACTERIA ARE ABLE TO ASSUME A METABOLIC STATE THAT MAKES THE BACTERIA HIGHLY TOLERANT OF MASSIVE DOSES OF ANTIBIOTICS. THIS STATE IS TERMED THE PERSISTER STATE AND ACCOUNTS FOR ANTIBIOTIC FAILURE IN PATIENTS BEING TREATED FOR INFECTIONS AND FOR THE REEMERGENCE OF AN INFECTION AFTER AN APPARENT CLEARING OF THE DISEASE BY ANTIBIOTIC TREATMENT. JCVI IS INVESTIGATING THE GENETIC/GENOMIC INFRASTRUCTURE OF THE PERSISTER STATE IN THE PUBLIC HEALTH AND BIOTHREAT BACTERIAL PATHOGEN BURKHOLDERIA PSEUDOMALLEI USING BOTH GENOME BASED TECHNOLOGIES AND TRADITIONAL MICROBIOLOGY APPROACHES WITH THE ULTIMATE GOAL OF FINDING WAYS TO ELIMINATE EVEN BACTERIA IN THE PERSISTER STATE FROM PATIENTS WITH BACTERIAL INFECTIONS. JCVI, FUNDED THROUGH THE DARPA BIOLOGICAL CONTROL PROGRAM IS APPLYING THE LESSONS LEARNED FROM MINIMIZING AND REORGANIZING A BACTERIAL GENOME TO REMODEL THE GENOME OF AN INDUSTRIALLY USEFUL, VASTLY MORE COMPLICATED EUKARYOTIC YEAST, CALLED KLUYVEROMYCES MARXIANUS. IN USING A SINGLE K. MARXIANUS CHROMOSOME AS A PLATFORM, JCVI IS DEVELOPING A GENERALIZED SET OF ALGORITHMS FOR MINIMIZATION AND DEFRAGMENTING THE GENES INTO FUNCTIONAL MODULES THAT COULD BE APPLIED TO ALL SMALL GENOME EUKARYOTES, SUCH AS YEASTS, EUKARYOTIC ALGAE, AND PARASITES.

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