SYSTEMS MICROBIOLOGY

SCOTT MITCHELL, JENNIFER MITCHELL, NEELA ZALMAY

What is it? And what are it’s implications for Applied Microbiology?

1. What is Systems Microbiology?

2. A brief history

3. Tools of the trade

4. Practical Applications -A case study in medicine and healthcare

5. Understanding the environment, evolution, and ecology

6. Conclusion: Limitations and the future of systems microbiology

PRESENTATION OUTLINE

1. WHAT IS SYSTEMS MICROBIOLOGY?

“…the study of the dynamic interactions of more than one component in a microbiological system in order to understand and predict the behaviour of the system as a whole.”

-Systems Microbiology: Current Topics and Applications, 2012

SO… WHAT THE HECK DOES THAT MEAN?

Systems Approach: how components influence each other within the whole

Stepping back and examining all the parts

- how do they influence each other?

Create models that are used to make predictions

A systems approach can be applied to pretty much anything.

A SYSTEMS APPROACH TO… NATURE

Animals Plants Air quality Water quality Human activity Weather patterns

A SYSTEMS APPROACH TO… SOCIETY

Individuals Organizations Political parties Lobby groups Social structures

A SYSTEMS APPROACH TO WHAT MARK WE’RE GOING TO GET

How well each of us present

How well-organized the PowerPoint is

Suitability and scope of the chosen materials (?)

How well the other groups do

Too many analogies

SYSTEMS APPROACH: A WAY TO SOLVE PROBLEMS

Minimizing unintentional consequences

Example: Cane toad in Australia- invasive species Introduced to control Cane

beetle population 100 200 million No natural predators

SO… WHAT IS SYSTEMS MICROBIOLOGY?

Applied microbiology: a method of problem solving Interaction of genes, proteins, other molecules, cell

organelles, and the environment Individual microorganisms, metabolisms, surrounding

environment, trapped pathogens

WHY DO A SYSTEMS APPROACH TO MICROBIOLOGY?

Microbes are ideal for a systems approach:

Microbes are abundant and found everywhere

Easy to manipulate Small Genomes High Impact on environment,

biosphere, health, agriculture, energy production

Biofilm- problem solving

2. HISTORY OF SYSTEMS MICROBIOLOGY

Not a new concept, but a relatively new field of study

Systems approach to biology ~ 50 years old

Influenced by recently developed and emerging fields

3. TOOLS OF THE TRADE

TECHNOLOGY EXPLOSION

Transcriptomics- study the total set or subset of RNA molecules in a cell or community (mRNA, tRNA, rRNA, non coding)

Proteomics- large scale study of protein function and structure

Metabolomics- characterization of metabolites

Obtaining quantitative measurements from a single cellDevelopments in sequencing- next generation platforms, reducing cost and time

High throughput parallel sequencing Previously only molecular biology methods (very

laborious!)

RELEVANT TECHNOLOGIES AND TECHNIQUES

High-throughput methods to sequence cDNA.

Information about RNA content Expression of different alleles Gene fusions Post-transcriptional mutations Study of certain diseases

(cancer) Direct information about gene

regulation

TRANSCRIPTOMICS & RNA-SEQ

Combination of new technologies and old ideas

High-throughput sequencing methods

Transcriptomics.

Characterizes RNA transcribed from a genome

More dynamic, direct access to gene regulation, protein information.

Not a new idea- many old methods to determine cDNA sequences (Sanger sequencing)

RNA-SEQ:

Efficient method for gene discovery

Finding both coding and noncoding genes

Gives the ‘whole picture’ (captures genome-wide transcription and splicing)

What is it? How does it apply to a systems approach?

METAGENOMICS Characterizes DNA content of communities Can study microbes in natural habitats “Microbial fingerprint” for different ecosystems

(determined by microbial capabilities)

4. SYSTEMS MICROBIOLOGY- APPLICATIONS OVERVIEW

Too complex and far-reaching to be limited to a single discipline

Many applications across a broad range of fields

Contributions from microbiologists, computer scientists, control theorists, biostatisticians, and others

Powerful new tools: agricultural, medical, industrial & environmental innovations

SYSTEMS BIOLOGY OF PERSISTENT INFECTION: A CASE STUDY

Major problem: infections that evolve over the course of prolonged, persistent interactions between host and pathogen

More difficult to predict impact of interventions on persistent infections (as opposed to acute infections)

Why? Infectious diseases: equilibrium

between host and a pathogen Determined by network of

interactions Ranging from molecular to cellular,

to whole organism and population levels

HOW CAN SYSTEMS MICROBIOLOGY HELP?• Experimental approaches applied to each of these levels results in a pool of information, cannot be integrated across scales and systems

Infection with M. tuberculosis also determined by how interactions at one level affect interactions occurring at another level

Complex interactions: Systems Microbiology’s specialty

Combines mathematical modeling and simulation to complement traditional empirical and experimental approaches to biomedical research

OVERVIEW OF TUBERCULOSIS

• Mycobacterium tuberculosis

• Carried to host through air

• One third of the world’s population is

infected with M. tuberculosis

• A new infection occurs at a rate of about one per second

Pathogenesis•Latent tuberculosis – 90%

• Active infections – 10%

DOES SO IN TWO WAYS:

1) Creates computational and mathematical models to pin point the key network interactions & suggest their functional properties

Predicts future experiments

2) Develops a common language that creates links between models mirroring different scales involved in the process of infection

• Example – designing new antimicrobial drug

WHAT GUIDES US THROUGH THIS HOST-PATHOGEN INTEGRATED RELATIONSHIP?

From a human health perspective:

• at host population levels, we aim to predict the epidemiological effects

• we aim to predict the outcome of the disease at the individual level

Therefore, the interplay between these two is very important

MODELS USED

At the population level:

• SIR (susceptible-infected-recovered) model

At the Individual level:

• effect of Heterogeneities

• biological heterogeneity

Other approaches:

• considering the genetic variations in pathogen population

- original strains of M. Tuberculosis being displaced by “aggressive” strains

• Immune system perspective

5. FURTHER APPLICATIONS: ENVIRONMENT, EVOLUTION & ECOLOGY

Not just about single cells or a population

Looking at: Environment Ecology Drug resistance Designer microbes

COMMUNITIES V.S. INDIVIDUALS

Studying interactions between microbes in natural habitats

“Inventories” of microbial capabilities in different types of ecosystems

9 types of ecosystems studied:

-Studying what microorganisms ‘do,’ not what they ‘are’

ENVIRONMENTAL APPLICATIONS

all microbial interactions must be considered

Example: Microbes of the North Sea Response to increased acidity Overall increase in genes that

would help cells to maintain constant pH

BUT WHY IS THIS USEFUL?

Can be used as an early warning system

Microbes are very in tune with their environment

Ecosystem’s “first responders” Monitoring changes in

microorganisms- detecting ecological stresses earlier

WEATHER PATTERNS

Could microbes cause weather patterns?

Bacteria found throughout the atmosphere

Basic question: why do clouds produce precipitation when they do?

Certain bacteria carry a gene for ice formation

Systems Microbiology: helping scientists identify new, novel genes

Climate Change

Gene expression in R. sphaeroides in presence of greenhouse gases

MICROBIOLOGICAL EVOLUTION- DRUG RESISTANCE

Co-evolution, phage-co-evolution, host-pathogen, environment, resources

Synergistic drugs- promoting development of multidrug resistance?

Staphylococcus aureus- tested with three drug pairs

Synergistic combination: resistant cells selected

DYNAMIC ADAPTATION

Bacteria can adapt to rapidly changing conditions (reversible)

Resource fluctuations, habitat complexity and diversity Microorganisms in complex and dynamic environments-

more pathway redundancy Tradeoff: coping ability and efficiency. More energy input required

DYNAMIC ADAPTATION: EXAMPLE

Bacillus subtilis Cells in less rich media: grow faster in starvation media Cells in richer media: growth, enzyme synthesis and

sporulation delayed in starvation media ‘Memory' of previous conditions

ECOLOGY

Photosynthesis insights into processes that

support life on the planet Rhodobacter sphaeroides:

previously undiscovered genes required for photosynthesis

Agriculture Diseases for livestock ‘live’ pesticides

FURTHER APPLICATIONS: DESIGNER MICROBES

Microbial cell factories Introducing new metabolic

pathways to host organisms Testing viability and

productivity Production of desired product

CAN SYSTEMS MICROBIOLOGY HELP SAVE THE PLANET?

Bioremediation Biocontrol Phytostimulation Biofertilization

Cleaning up contaminated soils, reducing pathogens, disease, fungicide usage

Increasing nitrogen reuptake, reducing water pollution

6. LIMITATIONS OF SYSTEMS MICROBIOLOGY

Technical bottlenecks DNA sequencing

difficulties Poor infrastructure and

coordination Lack of ability to visualize

presence and activity of proteins

SYSTEMS MICROBIOLOGY: PUTTING THE JIGSAW TOGETHER

Integrating knowledge, research, and technology

Discovering new genes and new possibilities

Understanding the world around us, one microbe at a time

QUESTIONS?