Evolution of antibiotic resistance

breed [ antibiotics antibiotic ]
breed [ bacterias bacteria ]

bacterias-own [
  variation
  age
  my-target-patch
]

patches-own [
  my-bacteria
]

globals [
  antibiotic-flow-rate
  fever-factor?
  #-minutes
  #-hours
  #-days
  bacteria-counts
  given-doses
  wiped-out?
  tick-entered ; each antibiotics entering time
]

;;;;;;;;; initial setup procedures ;;;;;;;;;

to setup
  clear-all

  set-default-shape bacterias "bacteria"

  set fever-factor? false
  set antibiotic-flow-rate 0.8
  set #-hours 0
  set #-days 0
  set #-minutes 0
  set given-doses 0
  set wiped-out? false

  ask patches [
    set pcolor white
    set my-bacteria nobody
  ]

  setup-initial-bacteria

  reset-ticks
end 

to setup-initial-bacteria
  let which-variations (list 3 4 5 6) ; four types of bacteria
  let #init-of-each-variation (list init#-3pores init#-4pores init#-5pores init#-6pores)
  (foreach #init-of-each-variation which-variations [ [n v] -> make-bacteria n v ])

  update-bacteria-counts
end 

to make-bacteria [ number-of-bacteria which-variation ]
  create-bacterias number-of-bacteria [
    let this-bacteria self
    set variation which-variation
    set shape (word "bacteria-holes-" variation)
    set my-target-patch one-of patches with [ my-bacteria = nobody ]
    move-to my-target-patch
    ask my-target-patch [ set my-bacteria this-bacteria ]
    set age (reproduce-every * 60) ; initial bacteria are aged enough to be reproductive
    set size 1
    set color variation-color variation
  ]
end 

;;;;;;;;;;;;;;;;;;;;;; runtime procedures ;;;;;;;;;;;;;;;;;;;;;;

to go
  reproduce-bacteria-into-available-space
  let count-of-bacteria count bacterias
  ask bacterias [
    move-bacteria  ; do age ++
    natural-death-bacteria
  ]
  move-antibiotics
  antibiotics-remove ; half of antibiotic molecules are removed at every half-life
  dose-admin
  update-bacteria-counts
  tick
  update-time
end 

to dose-admin
  if not any? bacterias with [ not wiped-out? ] [
    set wiped-out? true
  ]
  auto-dose
end 

to update-bacteria-counts
  ; count each type of bacteria. used for output plots.
  let cnt [ 0 0 0 0 ]
  ask bacterias [
    let i variation - 3
    set cnt replace-item i cnt (item i cnt + 1)
  ]
  set bacteria-counts cnt
end 

to update-time
  ; one tick = 1 minute in simulated time
  set #-minutes ticks
  set #-hours floor (ticks / 60)
  set #-days (floor (#-hours / 2.4) / 10)
end 

;;;;;;;;;;;;;;;;;;; antibiotic procedures ;;;;;;;;;;;;;;;;;;;

to auto-dose
  if give-dose? [
    dose-enter dosage
    set given-doses given-doses + 1
    set tick-entered ticks
  ]
end 

to-report give-dose?
  report
    ticks mod (dose-every * 60) = 0 and
    not wiped-out? and (
      (auto-dose? = "yes, skip no doses")
    )
end 

to dose-enter [ amount ]
  create-antibiotics amount[
    set shape "molecule"
    set size 1
    set color red
    setxy random-xcor random-ycor ; an antibiotic molecule is assigned to a random position.
  ]
end 

to move-antibiotics
  ask antibiotics [
    forward antibiotic-flow-rate
    check-antibiotic-interaction

    set heading random-float 360 ; freely change its direction as it moves around the space.
  ]
end 

to check-antibiotic-interaction
  let this-molecule self
  if any? bacterias-here [
    ask one-of bacterias-here [
      if kill-this-bacteria? [
        ask this-molecule [ die ]
        bacteria-death
      ]
    ]
    die
  ]
end 

to antibiotics-remove ; every half-life
  if (ticks - tick-entered) mod (half-life * 60) = 0 [
    let count-of-antibiotics count antibiotics
    ask n-of (0.5 * count-of-antibiotics) antibiotics [ die ]
  ]
end 

;;;;;;;;;;;;;;;;;;; bacteria  procedures ;;;;;;;;;;;;;;;;;;;;

to bacteria-death
  let this-bacteria self
  if is-patch-set? my-target-patch [
    ask my-target-patch [
      set my-bacteria nobody
    ]
  ]
  die
end 

to natural-death-bacteria
  if random-float 1 < bacteria-death-prob [
    bacteria-death
  ]
end 

to move-bacteria
  let my-distance-to-my-patch-center distance my-target-patch
  let speed-scalar 0.15 ; scales the speed of motion of the bacteria
  if my-distance-to-my-patch-center > 0.2 [
    set heading towards my-target-patch
    forward 0.1 * speed-scalar
    set age 0
  ]
  set age age + 1
end 

to reproduce-bacteria-into-available-space
  let count-of-bacteria count bacterias
  let all-bacteria-that-can-reproduce bacterias with [ can-reproduce? count-of-bacteria ]
  let this-fever-factor 1

  if reproduce? [
    ask all-bacteria-that-can-reproduce [
      let available-patches neighbors with [ my-bacteria = nobody ]
      let this-bacteria self
      if any? available-patches [
        hatch 1 [
          set my-target-patch one-of available-patches
          ask my-target-patch [ set my-bacteria this-bacteria ]

          let new_variation variation
          if random-float 1 < mutation_p [ ; mutate offspring variation: +1 or -1
            ifelse random-float 1 < 0.5[
              set new_variation variation - 1 ; mutation decreasing susceptibility
            ]
            [
              set new_variation variation + 1 ; mutation increasing susceptibility
            ]
            ; if new number of holes excedes the min or max number of holes,
            ; keep its original value (i.e., no mutation occurs).
            if new_variation >= 3 and new_variation <= 6 [
              set variation new_variation
              set color variation-color variation
              set shape (word "bacteria-holes-" variation)
            ]
          ]
        ]
      ]
    ]
  ]
end 

;;;;;;;;;;;;;;;;;;;;;;; reporters ;;;;;;;;;;;;;;;;;;;;;;;;

to-report kill-this-bacteria?
  ; variations go from 3 to 6, for the number of holes in the membrane,
  ; so the odds of getting into the bacteria are 30%, 40%, 50% and 60%
  report random 100 < (variation * 10)
end 

to-report can-reproduce? [ total-bacteria-count ]
  let result false
  let this-fever-factor 1
  ; total-bacteria-count is used to simulate a slower growth rate for bacteria as their numbers increase in the body
  ; due to an immune system response of raising the temperature of the body as more an more bacteria above a certain
  ; threshold are detected in the body
  if total-bacteria-count > 50 and fever-factor? [
    set this-fever-factor (1 + 2 * ((total-bacteria-count - 50) / 75))
  ]
  if age >= (reproduce-every * 60 * this-fever-factor) [
    if not any? other bacterias in-radius 0.75 and my-target-patch = patch-here [
      set result true
    ]
  ]
  report result
end 

;;;;;;;;;;;;;;;; visualization procedures ;;;;;;;;;;;;;;;;

to-report variation-color [ which-variation ]
  report item (which-variation - 3) [ violet green brown red orange ]
end 

;;;;;;;;;;;;;;;;; plotting procedures ;;;;;;;;;;;;;;;;;;;;;

to make-variation-pens [ plot-pen-mode ]
  foreach [ 3 4 5 6 ] [ v ->
    create-temporary-plot-pen (word v)
    set-plot-pen-mode plot-pen-mode ; bar mode
    set-plot-pen-color variation-color v
  ]
end