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BiodefenseBiodefense / Human / Human Threats and Mass Threats and Mass
Spectrometry Spectrometry ApplicationsApplicationsGerman German HenostrozaHenostroza MDMD
Division of Infectious Diseases and Division of Infectious Diseases and International MedicineInternational Medicine
ColeraColeraGram negative bacteria causes Gram negative bacteria causes
severe watery diarrhea.severe watery diarrhea.Severe dehydration.Severe dehydration.Incubation period 24 hoursIncubation period 24 hoursJanuary 1991 to September January 1991 to September
1994 1994 -- Outbreak in Outbreak in South South AmericaAmerica, apparently initiated , apparently initiated when a ship discharged ballast when a ship discharged ballast water. Beginning in water. Beginning in PeruPeru there there were 1.04 million identified were 1.04 million identified cases and almost 10,000 deaths.cases and almost 10,000 deaths.
Plague : The Black DeathPlague : The Black Death
SmallpoxSmallpoxErradicatedErradicated ; 05/1980; 05/1980
Last case Birmingham , England after Last case Birmingham , England after which all isolates were sent to reference which all isolates were sent to reference labs for destruction.labs for destruction.
In 2003 Smallpox scabs found in Civil In 2003 Smallpox scabs found in Civil War Medicine book in Santa Fe, New War Medicine book in Santa Fe, New Mexico, no cases reported.Mexico, no cases reported.
? used as biological weapon in French ? used as biological weapon in French and Indian wars, American and Indian wars, American Revolutionary war and perhaps World Revolutionary war and perhaps World War II (research).War II (research).
Incubation period 10 days , if severe Incubation period 10 days , if severe disease death may happen in 3disease death may happen in 3--5 days.5 days.
Vaccine available but hypothesized that Vaccine available but hypothesized that virus might be genetically modified for virus might be genetically modified for use as use as bioweaponbioweapon..
DETECTION OF BIOATTACK OR OUTBREAK
RELEASE
PROGRESSION
SYNDROME Disease SURVEILLANCEBioSense ProMed
PATHOGEN in AIR PATHOGEN in PEOPLEBioWatch
Human:
Bug:
DETECTION OF BIOATTACK OR OUTBREAK
RELEASE
PROGRESSION
SYNDROME Disease SURVEILLANCEBioSense ProMed
PATHOGEN in AIR PATHOGEN in PEOPLE
PRE-SYMPTOMATIC HOST-BASED DETECTION
Advantages of HostAdvantages of Host--BasedBasedPrePre--Symptomatic DetectionSymptomatic Detection
Treat to PreventTreat to Prevent
Containment of OutbreakContainment of Outbreak
Triage Based on DiagnosisTriage Based on Diagnosis
Solution to AGENT X ProblemSolution to AGENT X Problem
DUAL USE TECHNOLOGYDUAL USE TECHNOLOGY
Biosignature Pattern Recognition in Human DiseasesHost-based Presymptomatic Detection of Events
Genes
Environment
Age
Sex
Serum/Cell components
State of Health
Center for Innovations in Medicine
Doc In Box: BioSignatures
prognosis
treatment strategy
diagnosis
PresymptomaticDiagnosis
clinical validation
drugs/vaccines
ILL
NOT ILLILL
NOT ILL
Signal
Signal
DiagnosticDevice
Center for Innovations in Medicine
Upper Respiratory DiseaseUpper Respiratory DiseaseIncubation PeriodsIncubation Periods
RhinovirusesRhinoviruses
InfluenzaInfluenza
ParainfluenzaParainfluenza
Respiratory Respiratory SyncytialSyncytial Virus (RSV)Virus (RSV)
PertussisPertussis
AdenovirusAdenovirus
EpsteinEpstein--Barr virus (EBV)Barr virus (EBV)
I I I I I I I I I I I I I I I I I I I I I I I I I I I 1 5 10 15 20 Days
4-6 Weeks
5-8 Days
7-10 Days
7 Days
4 Days
1-4 Days
5 Days
Sources: http://www.emedicine.com/med/topic2339.htmhttp://virus.stanford.edu/adeno/adeno.htmlhttp://www.cdc.gov/flu/professionals/diagnosis/
Goal:Goal:Characterize the pathogen and/or host cell proteome, Characterize the pathogen and/or host cell proteome,
identifying proteins associated with biology of identifying proteins associated with biology of microbes, mechanisms of microbial pathogenesis, microbes, mechanisms of microbial pathogenesis, and host response to infection.and host response to infection.
Discover targets for potential candidates for the next Discover targets for potential candidates for the next generation of vaccines, therapeutics, and generation of vaccines, therapeutics, and diagnostics.diagnostics.
Proteomic Technology DevelopmentProteomic Technology Development
Albert Einstein College of MedicineAlbert Einstein College of MedicinePI: PI: Ruth Ruth AngelettiAngelettiPathogens:Pathogens: ToxoplasmaToxoplasma gondiigondii, Cryptosporidium , Cryptosporidium
parvumparvum
Myriad Genetics, IncMyriad Genetics, IncPI: PI: Jerry Jerry LanchburyLanchburyPathogens:Pathogens: Bacillus Bacillus anthracisanthracis, , YersiniaYersinia pestispestis, ,
FrancisellaFrancisella tularensistularensis, , vacciniavaccinia, , variolavariola
The Scripps Research InstituteThe Scripps Research InstitutePI:PI: Peter KuhnPeter KuhnPathogens:Pathogens: SARSSARS--CoVCoV
University of MichiganUniversity of MichiganPI:PI: Phillip HannaPhillip HannaPathogen:Pathogen: Bacillus Bacillus anthracisanthracis
Harvard Medical SchoolHarvard Medical SchoolPI: PI: Joshua Joshua LaBaerLaBaerPathogens: Pathogens: Bacillus Bacillus anthracisanthracis, , VibrioVibrio choleraecholerae
CaprionCaprion Pharmaceuticals, Inc Pharmaceuticals, Inc PI: PI: Eustache Eustache ParamithiotisParamithiotisPathogen: Pathogen: BrucellaBrucella abortusabortus
Pacific Northwest National LaboratoryPacific Northwest National LaboratoryPI:PI: Richard SmithRichard SmithPathogens: Pathogens: OrthopoxOrthopox ((vacciniavaccinia and and
monkeypoxmonkeypox),), Salmonella Salmonella typhimuriumtyphimurium andandSalmonella Salmonella typhityphi
Administrative Resource CenterAdministrative Resource CenterPI:PI: Margaret MooreMargaret Moore
www.niaid.nih.gov/dmid/genomes/prc/default.htm
Overall SummaryOverall Summary--May 2006May 2006
Proteins Identified:Proteins Identified:
6 structures solved for SARS6 structures solved for SARS--CoVCoV; 282 human proteins that interact with ; 282 human proteins that interact with Y.Y.pestispestis(60), (60), B.B. anthracisanthracis(50), and vaccinia(172) proteins; 176 novel proteins (50), and vaccinia(172) proteins; 176 novel proteins identified from identified from B. B. abortusabortus, and 360 from , and 360 from T. T. gondiigondii..
Genes Identified:Genes Identified:
493 differentially expressed 493 differentially expressed murinemurine macrophage genes found upon infection macrophage genes found upon infection with anthraxwith anthrax
Reagents GeneratedReagents Generated
2983 2983 V. V. choleraecholerae Gateway entry clones made and deposited in an NIAID Gateway entry clones made and deposited in an NIAID repository for use by the communityrepository for use by the community
Progress AchievedProgress Achieved ––May 2006May 2006
Proteins IdentifiedProteins Identified
360 membrane and 360 membrane and cytoskeletalcytoskeletal proteins identified in proteins identified in T. T. gondiigondii
176 outer membrane proteins associated with virulence identified176 outer membrane proteins associated with virulence identified in in B. B. abortusabortus
282 human proteins found to interact with 282 human proteins found to interact with vacciniavaccinia (172), (172), B. B. anthracisanthracis (50), and (50), and Y.Y.pestispestis(60) proteins(60) proteins
6 SARS6 SARS--CoVCoV structures solvedstructures solved
2121/2343 proteins identified in virulent/2121/2343 proteins identified in virulent/avirulentavirulent S. S. typhimuriumtyphimurium
263 early response and 329 late response proteins identified in 263 early response and 329 late response proteins identified in murinemurine macrophages macrophages infected with anthraxinfected with anthrax
Average annual healthcare Average annual healthcare expenditures by age, 2005expenditures by age, 2005
$0
$500
$1,000
$1,500
$2,000
$2,500
$3,000
$3,500
$4,000
$4,500
All ages Under25
25-34 35-44 45-54 55-64 65+ 65-74 75+
Age
Source: U.S. Bureau of Labor Statistics, U.S. Department of Labor. Consumer Expenditures in 2005. Report 998, Feb 2007.
Total Population vs. 65+ Population, 1950Total Population vs. 65+ Population, 1950--20502050
0
100,000,000
200,000,000
300,000,000
400,000,000
500,000,000
U.S
. Pop
ulat
ion
(n)
1950
1960
1970
1980
1990
2000
2004
2005
2010
2020
2030
2040
2050
All ages65 years and over
Source: U.S. Bureau of the Census, multiple Census years.
20.7% of the total population in 2050 is estimated to be over 65 years old.
*Only 8.1% of the total population in 1950 was over 65 years old.
What are the Costs of Medicine?What are the Costs of Medicine?
$2.26T/Year*Drugs
DiagnosticsCare
Source: Centers for Medicare & Medicaid Services, Office of the Actuary, 2007. Healthcare spending projections are based on the 2005 version of the National Healthcare Expenditure data released by the CMS in January 2007. Borger C, et al. “Health spending projections through 2015: changes on the horizon.” Health Affairs. March/April 2006; 25(2): 61-73.
*Estimated health expenditures for 2007
The Cost of PostThe Cost of Post--symptomatic Medicinesymptomatic Medicine
~$2 Trillion in Direct Medical Costs per Year
Patient Care88%
Drugs10%
Diagnostics2%
Two Options to Solve HC CrisisTwo Options to Solve HC Crisis
REDUCE CARE PROVIDEDREDUCE CARE PROVIDED
oror
TRANSITION TO PRETRANSITION TO PRE--SYMPTOMATIC SYMPTOMATIC DIAGNOSIS AND PREVENTATIVE DIAGNOSIS AND PREVENTATIVE MEDICINEMEDICINE
1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 2010 2015 2020 2025 2030 2035 2040
Time
Risk
BioRevolution
Natural Pathogens
AntibioticResistance
DecisionDriven Δ
Valley of theShadow ofDeath
GenomeSequencing
DNA Shuffling
Chemical GeneSynthesis
Reverse Viral Genetics
RNAi
RecombinantDNA
Changing Spectrum of Changing Spectrum of BioThreatBioThreat RiskRisk
TuberculosisTuberculosis
Exposure to Infectiouspatients
No infection (70%)
Infection (30%)
Early progression (5%)
Containment (95%)
Late progression (5%)
Continued containment (90%)
Nonimmunologicdefenses
Immunologicdefenses
Immunologicdefenses
Diagrammatic representation of the consequences of exposure to M. tuberculosis. The percentages shown are derived from epidemiologic data in persons without recognized immune response
•Three important steps:
•Phagosome formation
•Granuloma formation
•Failure of containment
TB Pathogenesis in a “Nutshell”
• Recruitment of cells induced by CC and CXC production.
•TNF-α dominant CC. Produced by infected macrophages and induced production of other CC and CXC.
• Subsequent recruitment of cells and production of IFN-γ
Cytokine / Chemokine Storm
0.0 5.0k 10.0k 15.0k 20.0k
0
1000
2000
3000
4000
5000
6000
Nor
mal
ized
Rel
ativ
e In
tens
ities
m/z
Control TB TB/HIV
13.80k 13.85k 13.90k 13.95k
0
200
m/z
11.2k 11.4k 11.6k 11.8k 12.0k
0
m/z
4.92k 4.95k 4.97k 5.00k0
1000
m/z
11.2k 11.4k 11.6k 11.8k 12.0k
0
Nor
mal
ized
Rel
ativ
e In
tens
ities
m/z
Control TB TB/HIV
13.80k 13.85k 13.90k 13.95k
0
200
Nor
mal
ized
Rel
ativ
e In
tens
ities
m/z
Control TB TB/HIV
4.92k 4.95k 4.97k 5.00k0
1000
Nor
mal
ized
Rel
ativ
e In
tens
ities
m/z
Control TB TB/HIV
2007
3312
3953
4051
4151
4208
4465
4787
7764
8125
8125
8601
8931
928711
52511
68112
45013
879
0
5000
10000
15000
20000
25000
30000
35000
40000
45000ControlTBTB/HIV
m/z
Nor
mal
ized
Rel
ativ
e In
tens
ities
MDS
MDS - Control Vs. TB
Medicine: Art to ScienceMedicine: Art to ScienceSir William Osler 1892
“If it were not for the great variability among individuals, medicine might be a science, not an art”
Because of our new ability to measure variability among individuals, medicine now can become a science rather than an art.
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