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THE NEW GERM THEORY OF DISEASE: WATER POWER

Wednesday, December 15th, 2010
The evidence for evolutionary control of the harmfulness of diarrheal pathogens is at a more advanced state than the evidence for vector-borne pathogens. Evolutionary considerations suggest that provisioning of clean water supplies should cause an evolutionary reduction in the harmfulness of diarrheal pathogens. Indeed, much of the evidence that waterborne transmission causes evolutionary increases in harmfulness comes from studies in which the provisioning of clean water supplies was associated with a replacement of harmful diarrheal pathogens with similar but milder pathogens. The most harmful agents of bacterial dysentery, for example, were replaced like clockwork by milder species in country after country as water supplies were purified. These studies indicate that the same trends would occur in poorer countries if sufficient investment was made in cleaning up water supplies. Does this change occur on a finer level within particular species of pathogens? If so, would the time period be sufficiently short to allow this evolutionary change to be incorporated into a control strategy? In theory such changes could be stronger and more rapid; the more similar bacteria are, the greater the intensity of competition between them, particularly because the cross-reactive immune response becomes stronger as pathogens become more similar.
One can imagine some large-scale experiments that could resolve the issue. For example, one could release a diarrheal pathogen like the agent of cholera, Vibrio cholerae, in one country with a poor water supply and in another country with a protected water supply and then follow the evolutionary trajectory in each over the next decade to see whether V. cholerae evolved reduced harmfulness in the region with the protected water supply. Obviously the ethical problems with such an experiment would make its rejection a no-brainer for a funding agency. The next best thing would be to see whether a natural version of this experiment had occurred and could be analyzed to find out if the predicted changes had taken place. In January 1991 such a natural experiment occurred. Cholera arrived in Peru and quickly spread throughout Central and South America, to countries with both good and poor water quality. Although this arrival caused and is still causing great difficulties for the inhabitants of Latin America, it created an opportunity to assess whether a disease organism like the agent of cholera could become rapidly more benign in response to transmission in an area with clean water supplies.
V. cholerae is particularly amenable to such study largely because its inherent harmfulness is quantifiable by measuring its toxigenicity, the amount of toxin it produces under carefully controlled growth conditions. The specific onset of the epidemic allows for the assessment of whether any evolutionary reduction in V. cholerae’s toxigenicity could occur in a time period comparable to that over which other kinds of interventions might provide beneficial effects. Specifically, if the toxigenicity of V. cholerae declined in areas with relatively safe water supplies but not in countries with unsafe water supplies during the 1990s, evolutionary control of virulence through improvement of water quality would occur over a time period comparable to the best of the alternative options, such as vaccination programs or interventions to reduce the frequency of infection. Since 1996 my colleagues in Latin America have sent strains Vibrio cholerae to our lab at Amherst to test this idea.
The key experiments were done in 1998 and 1999 largely through the hard work of two of my students, Alissa and Jill Saunders, a pair of identical twins whose effervescence and ail-American charm made stepping into the lab during this period eerily like stepping into a commercial for Doublemint gum. They led a crew that tested about one hundred strains sent in from Chile, Peru, and Guatemala. The particular prediction was that the toxigenicity of strains isolated from Chile, where water supplies are relatively safe, should have declined during the 1990s; the toxigenicity of strains from Peru and Guatemala should not have declined as much, if at all, because water supplies in these countries have been less free of fecal contamination. The strains isolated from Chile in 1991 were variable in their toxigenicity; but strains with high toxigenicity were absent from collections made just a few years later. Not so in Peru and Guatemala, where a broad range of toxigenicity persisted throughout the decade. The corresponding difference in the incidence of cholera in Chile was particularly dramatic. In 1994 only one case of cholera was reported in Chile. In neighboring Peru twenty-five thousand were reported.
The entire set of findings on diarrheal diseases offers strong support for the idea that the diarrheal disease problem as a whole could be greatly ameliorated by an intervention that gives people what they would prefer to have anyhow. All else being equal, people prefer water that is not contaminated with fecal material. As is the case with mosquito-proof housing, people do not have to know about the long-term evolutionary benefits of the intervention, nor do they have to be forced to accept something they are averse to. They need only be offered ready access to uncontaminated water that is as aesthetically pleasing as the contaminated water.
The evidence from Latin America also lends support to the idea that the evolution of antibiotic resistance can be controlled by controlling the evolution of pathogen harmfulness. If increased harmfulness favors increased antibiotic usage, which in turn favors increased antibiotic resistance, then one should find the more harmful lineages within a region to be more resistant to antibiotics. The Guatemalan strains provide the best test of this idea because they vary widely in toxigenicity and because the antibiotic usage pattern is known. Trimethoprimsulfamethoxazole was the drug of choice in Guatemala during the 1990s. In accordance with the theoretical predictions, the resistance to this drug was significantly correlated with harmfulness. By causing evolution toward benignity through the provisioning of safe water, one should be able to reverse the process, thereby favoring reduced antibiotic resistance as well. The data set as a whole is therefore encouraging with regard to the possibilities of controlling the evolution of both harmfulness and antibiotic resistance through water purification.
These ideas can be similarly applied to the other factors that allow transmission from immobile hosts. Mosquito-proofing of housing, for example, should favor not only reduced virulence of malaria but also reduced antimalarial drug resistance. Similarly, according to the logic presented in chapter 1, reductions in attendant-borne transmission in hospitals should favor the evolution of reduced harmfulness and reduced antibiotic resistance among the pathogens acquired in hospitals.
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THE NEW GERM THEORY OF DISEASE: WATER POWERThe evidence for evolutionary control of the harmfulness of diarrheal pathogens is at a more advanced state than the evidence for vector-borne pathogens. Evolutionary considerations suggest that provisioning of clean water supplies should cause an evolutionary reduction in the harmfulness of diarrheal pathogens. Indeed, much of the evidence that waterborne transmission causes evolutionary increases in harmfulness comes from studies in which the provisioning of clean water supplies was associated with a replacement of harmful diarrheal pathogens with similar but milder pathogens. The most harmful agents of bacterial dysentery, for example, were replaced like clockwork by milder species in country after country as water supplies were purified. These studies indicate that the same trends would occur in poorer countries if sufficient investment was made in cleaning up water supplies. Does this change occur on a finer level within particular species of pathogens? If so, would the time period be sufficiently short to allow this evolutionary change to be incorporated into a control strategy? In theory such changes could be stronger and more rapid; the more similar bacteria are, the greater the intensity of competition between them, particularly because the cross-reactive immune response becomes stronger as pathogens become more similar.One can imagine some large-scale experiments that could resolve the issue. For example, one could release a diarrheal pathogen like the agent of cholera, Vibrio cholerae, in one country with a poor water supply and in another country with a protected water supply and then follow the evolutionary trajectory in each over the next decade to see whether V. cholerae evolved reduced harmfulness in the region with the protected water supply. Obviously the ethical problems with such an experiment would make its rejection a no-brainer for a funding agency. The next best thing would be to see whether a natural version of this experiment had occurred and could be analyzed to find out if the predicted changes had taken place. In January 1991 such a natural experiment occurred. Cholera arrived in Peru and quickly spread throughout Central and South America, to countries with both good and poor water quality. Although this arrival caused and is still causing great difficulties for the inhabitants of Latin America, it created an opportunity to assess whether a disease organism like the agent of cholera could become rapidly more benign in response to transmission in an area with clean water supplies.V. cholerae is particularly amenable to such study largely because its inherent harmfulness is quantifiable by measuring its toxigenicity, the amount of toxin it produces under carefully controlled growth conditions. The specific onset of the epidemic allows for the assessment of whether any evolutionary reduction in V. cholerae’s toxigenicity could occur in a time period comparable to that over which other kinds of interventions might provide beneficial effects. Specifically, if the toxigenicity of V. cholerae declined in areas with relatively safe water supplies but not in countries with unsafe water supplies during the 1990s, evolutionary control of virulence through improvement of water quality would occur over a time period comparable to the best of the alternative options, such as vaccination programs or interventions to reduce the frequency of infection. Since 1996 my colleagues in Latin America have sent strains Vibrio cholerae to our lab at Amherst to test this idea.The key experiments were done in 1998 and 1999 largely through the hard work of two of my students, Alissa and Jill Saunders, a pair of identical twins whose effervescence and ail-American charm made stepping into the lab during this period eerily like stepping into a commercial for Doublemint gum. They led a crew that tested about one hundred strains sent in from Chile, Peru, and Guatemala. The particular prediction was that the toxigenicity of strains isolated from Chile, where water supplies are relatively safe, should have declined during the 1990s; the toxigenicity of strains from Peru and Guatemala should not have declined as much, if at all, because water supplies in these countries have been less free of fecal contamination. The strains isolated from Chile in 1991 were variable in their toxigenicity; but strains with high toxigenicity were absent from collections made just a few years later. Not so in Peru and Guatemala, where a broad range of toxigenicity persisted throughout the decade. The corresponding difference in the incidence of cholera in Chile was particularly dramatic. In 1994 only one case of cholera was reported in Chile. In neighboring Peru twenty-five thousand were reported.The entire set of findings on diarrheal diseases offers strong support for the idea that the diarrheal disease problem as a whole could be greatly ameliorated by an intervention that gives people what they would prefer to have anyhow. All else being equal, people prefer water that is not contaminated with fecal material. As is the case with mosquito-proof housing, people do not have to know about the long-term evolutionary benefits of the intervention, nor do they have to be forced to accept something they are averse to. They need only be offered ready access to uncontaminated water that is as aesthetically pleasing as the contaminated water.The evidence from Latin America also lends support to the idea that the evolution of antibiotic resistance can be controlled by controlling the evolution of pathogen harmfulness. If increased harmfulness favors increased antibiotic usage, which in turn favors increased antibiotic resistance, then one should find the more harmful lineages within a region to be more resistant to antibiotics. The Guatemalan strains provide the best test of this idea because they vary widely in toxigenicity and because the antibiotic usage pattern is known. Trimethoprimsulfamethoxazole was the drug of choice in Guatemala during the 1990s. In accordance with the theoretical predictions, the resistance to this drug was significantly correlated with harmfulness. By causing evolution toward benignity through the provisioning of safe water, one should be able to reverse the process, thereby favoring reduced antibiotic resistance as well. The data set as a whole is therefore encouraging with regard to the possibilities of controlling the evolution of both harmfulness and antibiotic resistance through water purification.These ideas can be similarly applied to the other factors that allow transmission from immobile hosts. Mosquito-proofing of housing, for example, should favor not only reduced virulence of malaria but also reduced antimalarial drug resistance. Similarly, according to the logic presented in chapter 1, reductions in attendant-borne transmission in hospitals should favor the evolution of reduced harmfulness and reduced antibiotic resistance among the pathogens acquired in hospitals.*59\225\2*

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