Transcript Evolution and public policy

Evolution and policy: outline
• Antibiotic use in agriculture: risk to human
health?
• Insecticide resistance
• Genetically modified crops: risks and
outcomes
• Public health cost:benefit analysis –
tuberculosis
Applying evolution: risks of
antibiotic use in agriculture
Uses of antibiotics
Estimates of US non-therapeutic
(nt) antibiotic usage (lbs / year)
Class
Description
Antibiotics
nt use
I
No substitute exists
Vancomycin
Erythromycin
600,000
II
Used by humans,
but alternatives
penicillin, bacitracin
tetracyclin
12.9 x 106
III
Not currently used
by humans
11 x 106
Effect of farm antibiotics on
humans?
• Levy (1976) fed farm chickens tetracycline
at low levels (“sub-therapeutic”)
• Monitored gut bacteria: saw resistance
• Monitored farm staff:
Do food-borne anti-biotic resistant
bacteria occur?
• Case I: Denmark 1998. Salmonella. 25
patients, 2 died. 2 were nurses infected
by patients. Source: Danish pigs.
• Resistant to ampicillin, chloramphenicol,
streptomycin, *tetracycline, *sulfonamides
( * = used as food supplements).
• Also, partially resistant to fluoroquinolones
(eg cipro)
Case 2:
• Antibiotic resistance in Minnesota
• Fluoroquinolones licensed for use in poultry in 1995
(therapeutic only).
• Campylobacter: bacterial gastroenteritis. Treated with
erythromycin, cipro.
• 1992: 1.3% of human infections resistant to cipro
Case 3: removal of antibiotic from
farm use
• Denmark: used avoparcin as growth promoter until
1995.
• Avoparcin: similar in fucntion to vancomycin
• 1995: vancomycin-resistance Enterococci 72.7% in
Denmark
• 2000: 5.8%
Applying evolution: studying insecticide
resistance in mosquitoes, fruit flies
• DDT: discovered 1939, extensive use in
WW II (3 million pounds / year), resistance
by 1945
• Quite successful in malaria control
– Sri Lanka: 1 million cases 1955, 24 in 1961
• 1972, anti-malaria program dead
• Agricultural use: 1986 100 million pounds
of insecticide used in US; 13% of crop lost
Genetic basis for insecticide
resistance
• Mosquitoes: organic phosphate resistance due to
duplicated gene; dominant mutation. Cost of resistance
• Fruit flies: resistant to almost all pesticides at a single
locus (p450); dominant. No detected cost of resistance
“Natural insecticides”: Bacillus
thuringiensis (Bt)
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Invade insect gut
toxins open holes
Insect dies – bacteria reproduce
Bt used as insecticide 1958; first
resistance 1989
Nature of Bt toxicity
Strain
toxins
*kurstaki HD1 CryIA(a), Cry1A(b), CryIA(c), CryIIA, CryIIB
kurstaki HD-73 CryIA(c)
aizawai
CryIA(a), CryIA(b), CryIC, CryID
israelensis
CryIVA, CryIVB, CryIVC, CryIVD, CytA
• most commonly used strain
Mode of resistance to Bt?
• Reduced binding of toxin - recessive
• Other modes remain unknown – but
dominant (F1 test)
• Cross-resistance:
• Cost of resistance?
Applying evolution: evaluating the
risk of genetically modified crops
1997: first commercial use of Bt-modified
corn and cotton
Plants produce Cry1A protein
Strategy to maintain resistance
• Dosage:
• Refuge:
• Rationale:
Assumptions behind control
strategies?
Concerns
Escape of transgenes?
• Many crops have wild or weedy relatives
Evolution and public health:
treating tuberculosis
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Mycobacterium tuberculosis
aerosol droplets
20-24 hours per division
waxy coating
lump of bacteria - tubercle
daughter cells may split off to colonize
elsewhere
tb prevention and treatment
• 1890: test developed.
• 1921: vaccine developed
• key antibiotics: streptomycin (1944); PAS
(1946); isoniazid (1952); ethambutol
(1963), rifampin (1966)
• early signs of resistance: multi-drug
therapy
Mechanisms of action
Isoniazid: Inhibits mycolic acid synthesis
PAS: active at low pH
Rifampin: inhibits RNA polymerase
ethambutal: disrupts metabolism
Problems in tb treatment
• Mass of bacteria difficult to penetrate:
• Slow growing
Good news for treatment
• Most anti-tuberculin drugs are used only
for this purpose
– Most show little cross-resistance
– Exception: rifampin
• Mycobacterium tuberculosis is not
exposed to most gut bacteria
Why is multi-drug resistance a
major problem?
• Some natural resistance
• Not a problem in all locations
– Africa:
– Western Europe and US:
– Russia:
– Peru:
TB treatment in 1990s
• World Health Organization: DOTS
• Direct Observed Treatment, Short-course
• Premise: eliminate resistance by ensuring that patients
always take medication
• Effectiveness: excellent
• Cost: low
($10 / patient in India)
Unless: Peru.
Paul Farmer
Cost:benefit analysis
• Treating tb with DOTS: cheap
• Testing for drug resistance: expensive and slow
• Procedure: use all four drugs.
• Failure?
• Treat drug-resistant? Yes: 2+ years, very
expensive ($2200 in India)
• Treat 1 MDR patient or 200 non-MDR
Study questions
1.
2.
3.
Explain the potential risks and benefits of using antiviral
drugs to treat farm animals. In your view, when would this be
appropriate?
What sorts of antibiotics should be prohibited from nontherapeutic uses on animals (if any), and why? Explain the
relative risks of different classes.
You are studying populations of fruit flies in Africa that are
susceptible to an insecticide. A dominant mutation to the
p450 promoter arises, resulting in resistance in that fly.
Graph the frequency of the p450 mutant allele over time.
Ignore drift and gene flow.
Study questions
4.
You are studying populations of cotton bollworms on
transgenic bt-producing cotton. A recessive mutation arises
that confers resistance to the bt protein in the cotton. Graph
the frequency of the resistance allele in the population over
time. Ignore drift and gene flow.
5. Explain how migration and random mating with susceptible
insects might slow the evolution of resistance to transgenic
Bt crops.
–
From an evolutionary point of view, would it be wise to
introduce a two-toxin transgenic crop plant in areas where
one of the two toxins was already present? Why or why not?
–
Explain how the cost of resistance would alter the risks and
benefits of halting multi-drug treatment of TB when the TB
was resistant to one of the drugs.
References
Avise, J. C. 2004. The hope, hype, and reality of genetic
engineering. Oxford.
Bates, S.L. et al. 2005. Insect resistance management in GM crops:
past, present, and future. Nature biotechnology 23:57-62.
Daborn, P. J. et al. 2002. A single p450 allele associated with
insecticide resistance in Drosophila. Science 297:2253-2256.
Ellstrand, N. C. 2003. Dangerous liasons? When cultivated plants
mate with their wild relatives. John Hopkins: Baltimore.
Gillespie, S. H. 2002. Evolution of drug resistance in
Mycobacterium tuberculosis: clinical and molecular
perspectives. Antimicrobial agents and chemotherapy 46:267274.
Molbak, K. et al. 1999. An outbreak of multidrug-resistant,
quinolone-resistant Salmonella enterica serotype Typhimurium
DT104. New England Journal of Medicine 341:1420Palumbi, S. R. 2001. The evolution explosion: how humans cause
rapid evolutionary change. Norton: New York.
Reichman, L. B. and Tanne, J. H. 2002. Timebomb: the global
epidemic of multi-drug-resistant tuberculosis. McGraw-Hill: New
York.
References
Smith, K. E. et al. 1999. Quinolone-resistant Campylobacgter
jejuni infections in Minnesota, 1992-1998. New England Journal
of Medicine. 340:1525-1532.
Tabashink, B. E. 1994. Evolution of resistance to Bacillus
thuringensis. Annual review of entomology 39:47-79.
Wedel, S. D. et al. 2005. Antimicrobial-drug susceptibility of
human and animal Salmonella Typhimurium, Minnesota, 19972003. Emerging infectious diseases 11:1899-1906.