Mosquitos, Jesuits, &
Botanical Expeditions:
The Cinchona Tree &
the Fight Against
Malaria
A story in 3 chapters
Chapter 1:
The Problem
• Intermittent fever
• pioneer shakes
• febris acuta → “ague”
• mal aria
http://www.hidrosam.com.br
Impact of malaria
2023
 In 20th Century, malaria
accounted for ca. 10% of
global deaths
 263 million documented
cases in ~85 countries
 608,000 deaths
 May have contributed to
 76% under age 5
 down >50% from 2000
 ~94% in Africa
 >50% & in 6 countries
 Nigeria
 Ethiopia
 D.R. Congo  Mozambique
 Uganda
WHO annual Malaria report:
https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2024
fall of Roman Empire!
The causal organism:
Plasmodium
 Genus of parasitic,
single-celled eukaryotes
 Over 200 known species
 5 species cause malaria
in humans
 P. falciparum ~50-99%
 Discovered as cause of
malaria in 1880
 Nobel Prize 1907
 Charles Laveran
Transmitted by…
Vector: Anopheles mosquitoes
 Not discovered until 1898! → 1902 Nobel Prize for Ronald Ross
Malaria Life
Cycle
 2 hosts
 9 stages
 Synchrony
Diagnosing malaria
Symptoms of
Malaria
 Headache
 Paroxysm
 Cyclical occurrence of
sudden cold, shivering, and
fever with sweating
 Occur every 24–72 hours
depending on species of
parasite
 Joint pain
 Nausea
 Hemolytic anemia
 Convulsions
http://www.malwest.gr/en-us/malaria/informationforhealthcareprofessionals/clinicalmanifestations.aspx
Symptoms of
Malaria
 These symptoms often
mask paroxysms!
Severe or complicated
malaria
(vs. “uncomplicated” malaria)
 Caused by P. falciparum
 Normal symptoms, plus…
 Enlarged spleen and liver
 Anemia
 Hypoglycemia
 Renal failure
 Blackwater fever
 Encephalopathy
Paroxysm
Malaria today
Malaria historically
US: 1947 - 15000 cases,
1950 - 2000
1951 - gone
1870
Malaria in Ohio 2000-2009
282 cases
Global distribution of Anopheles
But: https://www.cdc.gov/han/2023/han00494.html
How can malaria be controlled?
1. Avoidance
 screens
 air
conditioning
 bed nets
How can malaria be controlled?
1. Avoidance
2. Vector (mosquito)
elimination
•
sterile mosquitoes
How can malaria be controlled?
1. Avoidance
2. Vector (mosquito)
elimination
3. Treatment
Historic treatments
 limb blood-letting,
emesis, amputation,
and skull operations
Chapter 2
The Cure:
Cinchona &
quinine
Collections from the Ruiz & Pavón
Expedition, Peru (1778-1816)
•
Real Jardín Botánico de Madrid
Cinchona - the
plant
 Genus of ca. 25 spp.
 Rubiaceae
 coffee family
 shrubs or trees
 tropical South America
 Andes mountains
 many contain active
alkaloids
An abbreviated
history of quinine
 Harvest not
sustainable
Vallée de San Juan del Oro by J. Denis in Histoire naturelle des quinquinas
An abbreviated
history of quinine
 Clements Markham
 recognized global
need for quinine
 organized a Cinchona
collecting expedition
 1860: exported > 450
seedlings & cuttings
 Richard Spruce
 1861: exported ~500,
463 arrived in India
 by 1866, 244,000!
An abbreviated
history of quinine
 Charles Ledger (self-appointed)
 1864 – smuggled 16 pounds of
Cinchona seeds out of Bolivia
 Contained 8-15%
quinine!
 Soon, plantations in…
 India
 Indonesia
 Ceylon
 East Africa
 Jamaica
 etc.
Administration of quinine
 tonic water: 83mg/L
 malaria: 2100mg/day
“The gin and tonic has
saved more Englishmen’s
lives, and minds, than all
the doctors in the Empire.”
- Winston Churchill
The problem with quinine
 “Cinchonism”
 tinnitus
 nausea
 blurred vision
 vertigo
 headache
 flushing
 sweating
 irregular heartbeat
Chapter 3:
The Arms Race
vs.
Chemistry
Biology
Quinine
 Widely used since the 17th Century
 First reported case of resistance – 1910
 Quinine remains the ’silver bullet’ cure
for difficult cases
 Today, most quinine ends up in tonic
water…
The evolution of pharmaceuticals
1. Discovery
— ethnobotany
2. Molecular
modification →
Atabrine
(quinacrine)
 Developed in 1931
 Bayer Dye Co.
 Used in World War II
 Side effects
→ MUCH less severe than
quinine
 yellow skin
 toxic psychosis
Chloroquine
 Developed in 1934
 Bayer Dye Co.
 considered too toxic
 Re-developed by US Army in 1947
 Side effects
 similar to quinine, but much less
severe
 resistance appeared in 1957
and spread rapidly
Quinine substitutes
= atabrine
= “Lariam” developed by the
Walter Reed Army Institute of
Research. Approved in 1989
The resistance problem
malariasite.com
New malaria drugs needed
 Artemisia annua (Asteraceae)
 wormwood - “Qing Hao”
 Tu Youyou
 1971
 Traditional Chinese
treatment for fever,
described by
Ge Hong (340 AD)
 Nobel Prize, 2015
Artemisia annua
Artemisinin
 Ethiopia switched from…
 Standard treatment – 36%
 Artemisinin ~ 100%
 …then: resistance & molecular modification
Artemether
Artesunate
The evolution of pharmaceuticals
1. Discovery
2. Molecular
modification
Artemether
+
Artesunate
+
3. Combination
therapies
Amodiaquine
Camoquin
Lumefantrine
Coartem
Modern anti-malarials
 drug combinations
Proguanil hydrochloride
+
Artemether
+
Artesunate
+
Atovaquone
Amodiaquine
Malarone
Camoquin
Lumefantrine
Coartem
Malaria vaccine
 RTS,S = ”Mosquirix”
 Large-scale trial in Ghana, Kenya, and Malawi
 1 million children – deaths reduced by 13%,
hospitalizations with severe malaria cut by 22%
 Production slow
 $10/dose – 3 doses by age 2, followed by a 4th
 Production slow
 R21
 Endorsed by WHO in late 2023
 Early trials show 77% efficacy
 $2–4/dose
 100s of millions of doses
expected by mid-2024
Malaria