Download emergent properties and determinism in infectious diseases

EMERGENT PROPERTIES AND
DETERMINISM IN INFECTIOUS DISEASES
Arturo Casadevall
Albert Einstein College of Medicine
Bronx, NY
SOME QUESTIONS?
• DO HOST-MICROBE INTERACTIONS MANIFEST EMERGENT
PROPERTIES? IF YES, WHAT DOES THAT MEAN?
• IS VIRULENCE A CHAOTIC, STOCHASTIC AND/OR
DETERMINISTIC SYSTEM?
• ASSUMING THAT VIRULENCE IS CHAOTIC, STOCHASTIC OR
DETERMINISTIC, DOES THE DESIGNATION APPLY TO ALL
HOST-MICROBE INTERACTIONS?
• CAN VIRULENCE BE PREDICTED?
SOME DEFINITIONS
• CHAOTIC SYSTEM (MANY DEFINITIONS – ALL
INADEQUATE) – LETS JUST SAY A SYSTEM WHERE THE
OUTCOME IS HIGHLY DEPENDENT ON THE INITIAL
CONDITIONS
• DETERMINISTIC SYSTEM IS A SYSTEM IN WHICH NO
RANDOMNESS IS INVOLVED IN THE DEVELOPMENT OF
FUTURE STATES OF THE SYSTEM
• STOCHASTIC SYSTEM (RANDOM PROCESS) IS A SYSTEM
WHERE THE OUTCOME IS DETERMINED BY A COLLECTION
OF RANDOM VARIABLES
STANDARD REDUCTIONIST APPROCHES HAVE
CREATED THE MICROBIOLOGICAL ARCHIPELAGO
BACTERIOLOGY
MYCOBACTERIA
PARASITOLOGY
MYCOLOGY
PRION
VIROLOGY
DIRTY SECRETS FROM THE
MICROBIOLOGICAL ARCHIPELAGO
• EACH HOST-MICROBE INTERACTION IS UNIQUE
• EVEN WITHIN A MICROBIAL SPECIES STRAINS GIVE
DIFFERENT RESULTS (CAN’T EXTRAPOLATE FROM STRAIN-TO-STRAIN)
• ALL INTRACELLULAR PATHOGENIC STRATEGIES ARE
DIFFERENT (Salmonella ≠ Cryptococcus ≠ Histoplasma)
• THERE ARE NO SUCH THINGS AS MODEL ORGANISMS
(HOW THERE BE MODELS WHEN EACH IS DIFFERENT?)
• UNIQUENESS EXTENDS TO THE IMMUNE RESPONSE
• IN A SITUATION WHERE UNIQUENESS REIGNS ONE
MUST STRIVE TO FIND PATTERNS
DARWIN LOOKED FOR PATTERNS
1859
•
•
•
•
•
ALL THOUGHT
FEW EXPERIMENTS
ALL DESCRIPTIVE
NO MECHANISM
NOT PUBLISHABLE 2012
BRINGING THINKING BACK INTO BIOLOGY
HUBBLE DEEP FIELD
THE GREAT COSMOLOGY
REVOLUTION – ONGOING
• OBSERVATION ONLY
• DESCRIPTIVE
• PURE THOUGHT
• NO EXPERIMENTS
WATSON & CRICK 1953
• A MODEL
• DESCRIPTIVE
• A SYNTHESIS OF MANY
TYPES OF DATA
SPECIAL & GENERAL
RELATIVITY 1905, 1916
• PURE THOUGHT
• DESCRIPTIVE
• NO EXPERIMENTS
• INSPIRED BY KANT
VIRULENCE IS AN ‘EMERGENT PROPERTY’
DEFINITION OF EMERGENT PROPERTY:
any unique property that "emerges" when component objects are
joined together in constraining relations to "construct" a higher-level
aggregate object, a novel property that unpredictably comes from a
combination of two simpler constituents
COMPONENTS
HOST + MICROBE
NOVELTY
VIRULENCE → PATHOGENICITY → DISEASE
MUTUALISM
COMMENSALISM
DEATH OF EITHER PARTY
THE FOUR OUTCOMES OF HOSTMICROBE INTERACTIONS
SYMBIOSIS AND
MUTUALISM
HEALTH
DISEASE
EFFECTIVE IMMUNE
RESPONSES
↑↑ ↑↓
↓↑ ↓↓
HOST
MICROBE
HOST
MICROBE
INFECTIOUS DISEASES
HOST
HOST
MICROBE
MICROBE
DEAD END HOST INFECTIONS
AUTOIMMUNITY
DAMAGE-RESPONSE FRAMEWORK
BASIC TENETS (OBVIOUS AND INCONTROVERTIBLE)
1. TWO ENTITIES
HOST
MICROBE
MOLECULE
VIRUS
PROKARYOTE
EUKARYOTE
Dr. Liise-anne Pirofski
PROFESSOR
CHIEF, ID DIVISION
INTERACTION
2. RELEVANT OUTCOME = HOST DAMAGE
DAMAGE
ALBERT EINSTEIN/MONTEFIORE
?
HOST RESPONSE
3. DAMAGE CAN COME FROM HOST, MICROBE OR BOTH
Casadevall & Pirofski, Infect Immun 1999
Infect Immun 2000
Nature Micro Rev. 2003
A DEFINITION IS AN ACCOUNT (logos)
THAT SIGNIFIES THE ESSENCE, Aristotle
‘PATHOGEN’
PATHOGENICITY
VIRULENCE
A MICROBE CAPABLE OF
CAUSING HOST DAMAGE
THE CAPACITY OF A MICROBE TO
CAUSE DAMAGE IN A HOST
THE RELATIVE CAPACITY OF A
MICROBE TO CAUSE DAMAGE IN A HOST
Infect Immun 1999
VIRULENCE
VIRULENCE IS A MICROBIAL PROPERTY THAT IS EXPRESSED ONLY IN A SUSCEPTIBLE HOST
VIRULENCE = f(HOST IMMUNITY)
J. Infect Dis. 2001
…AND IF VIRULENCE IS THE
RELATIVE CAPACITY OF A MICROBE
TO CAUSE DAMAGE IN A HOST…THEN
DAMAGE
DAMAGE = f(HOST IMMUNITY)
NATURE MICRO REVIEWS 2003
IMMUNE RESPONSE
BASIC RELATIONSHIP FOR ‘DAMAGE-RESPONSE
FRAMEWORK’
Casadevall & Pirofski, Nature Micro Rev. 2003
↓↑ ↓↓
DISEASE THRESHOLD
HOST MICROBE
HOST MICROBE
DISEASE THRESHOLD
↑↑ ↑↓
HOST MICROBE
WEAK
WEAK
HOST RESPONSE
HOST RESPONSE
HOST MICROBE
STRONG
STRONG
THE INTELLECTUAL DIVIDE
MICROBIOLOGY
VIROLOGY
VACCINOLOGY
IMMUNOLOGY
AGE
300
110
220
110
FOCUS
MICROBE-CENTRIC HOST-CENTRIC
HOST-CENTRIC
ORIGIN
NATURAL
PHILOSOPHY
PLANT
AND CELL
MEDICINE
BIOLOGY
VACCINOLOGY
VARIABLE
MICROBE
MICROBE
MICROBE & HOST
HOST
DISPOSITION
STALWART
FOCUSED
NONCONFORMISTS
TRENDY, RIOT
PRONE
RELIGION
PARTISAN
EXCLUSIVE
UTILITARIAN
UNIVERSALIST
HOST-CENTRIC
Biron C & Casadevall A, mBio 2010
EXAMPLES OF EMERGENT PROPERTIES
FISH SCHOOL
SURFACE TENSION
SAND DUNES
BIRD FLOCKS
C. NEOFORMANS CAPSULE AND MELANIN ARE MOST
IMPORTANT VIRULENCE FACTORS
POLYSACCHARIDE CAPSULE
~26%
~14%
MELANIN IN CELL WALL
IS INFORMATION GATHERED WITH CRYPTOCOCCUS NEOFORMANS PREDICTIVE
FOR THE VIRULENCE OF OTHER CRYPTOCOCCAL SPECIES?
Galleria mellonella alternative host system for C. neoformans that
allows one to explore the virulence of non-thermotolerant fungi
Mylonakis et al. Infect Immun. 2005 Jul;73(7):3842-5
RELATIVE VIRULENCE OF THREE CRYPTOCOCCAL SPECIES IN GALLERIA
C. neoformans
C. amylolentus
CAPSULE +
C. podzolicus
CAPSULE +
CAPSULE -
MELANIN +
MELANIN -
PHOSPHOLIPASE +
UREASE +
BOTTOM LINE: CONSISTENT WITH THE CONCEPT OF EMERGENCE THE PRESENCE OF
VIRULENCE FACTORS WAS NOT PREDICTIVE FOR VIRULENCE
Garcia Solache, M, Bergman A, (UNPUBLISHED)
IS VIRULENCE A CHAOTIC SYSTEM?
CHAOTIC SYSTEMS
1. MUST BE SENSITIVE TO THE INITIAL CONDITIONS
2. TOPOLOGICALLY MIXING
3. ORBITS MUST BE DENSE
CHAOS THEORY
1972 Lecture: Predictability: Does the Flap of a Butterfly's
Wings in Brazil Set Off a Tornado in Texas?"
• ACCIDENTAL DISCOVERY OF CHAOS IN 1961
• TRUNCATING NUMBERS TO BY 0.001 CHANGED RESULT
• CONCLUDED THAT PERFECT WEATHER PREDICTION WAS ‘FANTASY’
Edward Lorenz
1917-2008
CHAOTIC SYSTEMS
CHAOTIC SYSTEM
•
•
•
•
HARD TO DEFINE PRECISELY MATHEMATICALLY
VERY SENSITIVE TO INITIAL CONDITIONS
CHAOS ≠ RANDOM
DETERMINISTIC
OUR SYSTEM
• GALLERIA
• C. NEOFORMANS (5 X 104/LARVA)
• SIX EXPERIMENTS WITH 40 LARVA/GROUP
AUTOCORRELATION ANALYSIS
where M(t) is the concatenated time series of the six survival experiments,
defined as death events per period of time (t) and Ac(t) is the total accumulated
number of deaths at time t
IS VIRULENCE A CHAOTIC SYSTEM?
MONICA GARCIA-SOLACHE
VIRULENCE AND CHAOS
• WE HAVE A DEVELOPED AN APPROACH TO
STUDYING CHAOS IN VIRULENCE
• WE FOUND NO SIGNATURES OF CHAOS
• VIRULENCE BEHAVED AS A DETERMINISTIC SYSTEM
CAVEAT: ONE HOST-MICROBE INTERACTION, ONE
INNOCULUM, ONE OUTCOME (DEATH).
WOULD NOT GENERALIZE AT THIS TIME
SOME ANSWERS
• DO HOST-MICROBE INTERACTIONS MANIFEST EMERGENT
PROPERTIES?
yes…but some prediction may be possible
• IS VIRULENCE A CHAOTIC, STOCHASTIC AND/OR
DETERMINISTIC SYSTEM?
No chaotic behavior observed in one system
• ASSUMING THAT VIRULENCE IS CHAOTIC OR
DETERMINISTIC, DOES THE DESIGNATION APPLY TO ALL
HOST-MICROBE INTERACTIONS?
Unknown
• CAN VIRULENCE BE PREDICTED?
Unknown – determinism may be impossible but probabilistic predictive
models may be possible
SOME FINAL THOUGHTS
• DETERMINING WHETHER INDIVIDUAL HOST-MICROBE
SYSTEMS ARE DETERMINISTIC, CHAOTIC, OR STOCHASTIC IS A
FUNDAMENTAL QUESTION THAT NEEDS TO BE ADDRESSED
• SUCCESS IN CONTROLLING CERTAIN DISEASES, DEVELOPING
THERAPIES AND VACCINES MAY DEPEND ON WHETHER THE
SYSTEM IN QUESTION IS DETERMINISTIC, CHAOTIC OR
STOCHASTIC
• WE NEED TO DEVELOP NEW TOOLS TO APPROACH THESE
QUESTIONS IN MICROBIAL PATHOGENESIS BECAUSE THE
APPROACHES USED IN OTHER SYSTEMS ARE NOT EASILY
APPLICABLE
• WE NEED TO THINK MORE!