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Lecture 5: Exponential Growth Part 1

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Our initial thought experiment

  • carbon (sugar, for example)
  • nitrogen (ammonia, glutamate, ...)
  • several salts (CaCl2, MgCl2, …)

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Our initial thought experiment

Liquid broth

?

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+

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Growth

etc . . .

etc . . .

Process not perfect

evolution

Why should we study exponential growth if it is likely not the state of most cells in the wild?

Highly repeatable and quantitative laboratory phenotype!

Capability of exponential growth essential for expanding into new territory, creating multicellular structures, etc.

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What is our goal studying exponential growth this week?

Understand dynamics: how does population size evolve in time?

How do cells regulate their genes and physiology to achieve this state of growth?

Define quantitative parameters of growth dynamics

 

  • First we’ll discuss methods to measure microbial growth
  • Then we’ll characterize the data quantitatively

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How do we measure microbial growth?

1. Colony counting

Gel with nutrient mixture

Liquid nutrient mixture with growing cells

  1. Grow microbes in liquid nutrient mixture (called a “medium”)
  2. At regular time intervals, spread a small volume of liquid culture on a plate containing nutrients
  3. Count colonies formed (“colony-forming units”/”CFUs”)
  4. Colonies formed is proportional to cell density

Early growth > few colonies formed

Late growth > many colonies formed

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How do we measure microbial growth?

2. Turbidity

Low turbidity > few cells

High turbidity > many cells

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How do we measure microbial growth?

2. Turbidity

How to measure turbidity

shine light through sample

light detector

measure transmitted intensity

Light attenuation ~proportional to biomass density

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How do we measure microbial growth?

2. Turbidity

How to measure turbidity

shine light through sample

detector

measure transmitted intensity

Light attenuation ~proportional to biomass density

 

 

attenuation or absorbance, measured

path length, set by measurement container

extinction coefficient, property of the growing cells/biomass (assumed to be constant)

concentration/density of biomass

 

 

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How do we measure microbial growth?

3. Microscopy

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Methods for measuring growth

Method

Pro

Con

Colony counting

-can estimate cell number/density

-can directly observe decline in viable cell number during death phase

-cannot measure biomass

-takes many plates and much time to county colonies

Turbidity

-quick/easy

-sensitive to biomass

-not sensitive to cell number

Microscope

-can observe differences in cell shape/length/morphology

-with time-lapse, can observe cell-to-cell heterogeneity

-specialized equipment

-limited to the number of cells in fields of view

-generally limited to single-cell layer growth

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Let’s take a look

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Let’s take a look

1 cell

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Let’s take a look

2 cells

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Let’s take a look

2 cells

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Let’s take a look

5 cells

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Let’s take a look

13 cells

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Let’s take a look

31 cells

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Let’s take a look

108 cells

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Let’s take a look

316 cells!

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Let’s take a look

586 cells!!

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What’s this?

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What’s this?

↓ This looks like a line! ↓

 

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How can we describe bacterial growth in time?

↓ This looks like a line! ↓

 

 

 

 

 

 

 

 

 

The cells grow exponentially!

 

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Some notes on exponential growth

↓ This looks like a line! ↓

 

 

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What is a simple model for exponential growth?

  •  

If there’s only 1 cell that can divide, the population’s rate of increase should be small.

If there’s tons of cells that can divide, the rate of increase should be big!

The simplest equation then is one where the rate of population growth is proportional to the population size.

A differential equation!!

 

constant

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How do we solve this equation?

 

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Important notes on exponential growth

  •  

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What must happen to synthesize new cells?

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A very simplified molecular picture

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A very simplified molecular picture

Within our exponential growth model, somehow all of this complexity is subsumed under one parameter, the doubling time!

We’ve seen that to build a new cell, the parent cells must incorporate carbon, nitrogen, phosphorous.

How can we determine what biochemical processes determine the doubling time?

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How do we start understanding growth?

We carefully control what resources bacteria are given to make new cells and observe how this impacts growth.

Investigate the physiological state of the cell under these different conditions

A very powerful tool here is that we have identified a single, quantitative parameter we can measure: the doubling time!

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Laboratory growth conditions

“Rich medium” / ”Broth”

“Defined medium”

“Minimal medium”

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Laboratory growth conditions

“Rich medium” / ”Broth”

Common: LB (Lysogeny Broth)

  • Yeast extract
  • Tryptone (milk protein)
  • NaCl

Some rich media get pretty wild!!

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Laboratory growth conditions

“Defined medium”

Liquid made of water and purified chemicals.

We know the precise concentration of every single component.

Always contains

  • Carbon source (often sugar like glucose or glycerol; sometimes organic acid like acetate or citrate)
  • Nitrogen source (ammonia or amino acid e.g. glutamate)
  • Phosphate source (potassium phosphate)
  • Salts
    • Iron, magnesium, calcium, etc
  • Above components differ across species
  • A defined medium where if any ingredient is removed cells can’t grow is often called a “minimal medium”

Defined media allow precise control of the bacterial growth environment

  • Allows for highly repeatable experimental results!
  • Isolates metabolic processes

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Laboratory growth conditions

“Defined/minimal media”

Common minimal medium:

M9 medium (most E. coli experiments, for example)

  • Glucose (usually; sometimes glycerol or other)
  • MgSO4
  • CaCl2
  • Na2HPO4
  • KH2PO4
  • NaCl
  • NH4Cl
  • water

Often people (including me) will say something like bacteria “growing on glucose”; this refers to cells growing in a minimal medium with glucose as a carbon source.

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How does growth rate depend on the available nutrients?

Intuitively, the exponential growth rate should depend on the concentration of nutrients, no?

What’s my response to any question like that in this class (and in general)?

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Basic experiment

  1. Make minimal medium
  2. Grow bacteria
  3. Measure doubling time as a function of
    • Nutrient content/”quality”
    • Nutrient concentration

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What determines doubling time?

 

 

  • above a certain concentration, per capita growth rate is constant
  • depends on “quality” of carbon source������
  • Michaelis-Menten dependence of growth on concentration!

 

 

 

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What determines doubling time?

 

 

 

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What determines doubling time?

Exponential growth rate strongly dependent on nutrient conditions

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Next time: What aspect of cell physiology determines these growth rates?�

A large fraction of the cell mass is protein.

Proteins are synthesized by ribosomes.

We will see that to grow faster, cells dedicate more of their available biosmass to ribosomes.

We will find quantitative relationships between the fraction of cell mass that is in ribosomes and the per capita growth rate.