Antony Dodd: Manipulating malaria by changing the clocks
Professor Antony Dodd, image courtesy of Antony Dodd
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Speaking of food security and climate change, in our Bread and Fishes episode at the end of last year we spoke with Dr Hannah Rees about how circadian rhythms affect wheat crops, and how she’s effectively giving wheat jet lag to create a more future-proof plant.
Now we all know about the molecular biology of circadian rhythms, I want to continue the conversation about how we can influence these daily cycles to improve our lives. Professor Antony Dodd is a plant scientist at the John Innes Centre who is interested in clock genes not only in humans and mammals, but across the tree of life, from plants to fungi to bacteria.
One of the organisms Antony has been studying is one you might not think of when it comes to day and night cycles, but it turns out understanding its circadian rhythms may help us save millions of human lives. And that’s because the organism in question is Plasmodium falciparum, otherwise known as malaria.
Sally: I love a bit of pure biology. I love researching things for the sake of it. But also there's a lot of applications for the study of circadian clocks. I want to bring up two. So firstly, malaria. Malaria is a single cell eukaryotic parasite. How does that respond to day and night? Does it care what time of day it is?
Antony: Malaria is caused by a parasite called Plasmodium that infects your blood and it has a very distinct life cycle that involves a phase in the liver and a phase in the red blood cells. And these specific stages of the life cycle appear to be aligned with the 24h cycle in the human or mammalian host.
Antony: So, one hypothesis is that the synchronisation of the malaria parasites to a 24h cycle enables them to all be at the same stage in their life cycle at each point, which enables them to overwhelm the host immune system. Whereas if only a few of them were in the blood stage at any point in time, it would be less likely that they would not be attacked by the host immune system.
Sally: So it's like at the start of a spy film where they're all like, "Let's synchronise our watches to 0800h."
Antony: Right, exactly. And then by doing that, it gives them greater infectious power. Well, one of the questions that's open at the moment that's quite interesting is exactly what the malaria parasites are aligning their daily rhythm to.
Antony: And there's been some thinking that it might involve the timekeeping hormone in the blood which is called melatonin. But there's emerging evidence that it actually could also relate to the feeding-fasting cycle that we undergo over a 24h period. And there's some really beautiful work from the University of Edinburgh that has shown that perhaps rather than the malaria 24h cycle aligning with the cycles of light and dark that their human host is exposed to, which is communicated through the blood hormone melatonin, instead it might relate to the feeding-fasting cycle.
Antony: I think it's not entirely clear why that might be at the moment and whether the alignment with the feeding-fasting cycle itself is what provides an advantage for the malaria parasites, or whether they just use that information as a proxy for something else.
Antony: We know that the parasites seem to be able to perceive a variety of cues, but a thing to remember is that perhaps if we can break this perception of the host 24h cycle by the parasites, it might make it easier to treat malaria.
Sally: Well, this is exactly what I'm thinking. Can we weaken malaria by having a midnight snack?
Antony: That's possible. Disruption of the host's circadian rhythm in some way could weaken malaria. There's a study that was conducted in Brazil a number of years ago that suggested that supplying quite large doses of the hormone melatonin to mice that have been infected with malaria could enable the immune system to overcome the parasite more effectively, but I think that used quite high doses of melatonin that are not really representative of what happens in nature.
Antony: So there's some really exciting thinking around this at the moment that we might be able to harness our knowledge of circadian rhythms in both mammals and in the parasites to make it easier to treat the infection.
Sally: Yeah, especially with drug resistant malaria, we need everything we can get.
Sally: The other kind of translational aspect I wanted to chat about was pesticides and glyphosate, so Roundup to you or me with a garden. It works better or works worse at certain times of day? It's a poison, doesn't it just poison it regardless?
Antony: Circadian rhythms do quite a lot of different things in plants. They control their growth rates, they control photosynthesis, they control how they use their carbohydrates.
Antony: However, they also affect how plants respond to their environments. And there were a number of reports that were published in the 1980s; they'd used field studies and they sprayed plants with various pesticides and they found that the effectiveness of those pesticides varied according to the time of day.
Antony: And I noticed this some years ago and was talking to some people that work at a company called Syngenta, who develop agrochemicals. And we had the idea that the biological clock might affect how plants could respond to pesticides based on these older field studies that are being conducted. So we decided to test this.
Antony: And we decided to test this general idea using what is the world's most commonly used herbicide that's used a lot in agriculture, that's called glyphosate, which works by interfering with a particular biochemical pathway that's only found in plants, which is why it is non-toxic to other organisms. And we developed a set of experiments whereby the glyphosate could be applied in the lab under very controlled conditions to Arabidopsis plants at different times of day.
Antony: And then we measured how well the plants grew after treatments with glyphosate at different times of day. What we found was that there was variation across the day in how sensitive the plants were to glyphosate, so that when they received a glyphosate treatment first thing in the morning it was much more effective than when the treatment was applied at other times of day.
Antony: We think this might be because of the way that glyphosate interferes with the ability of the plant to produce a hormone called auxin, because it affects the production of certain amino acids that are required for auxin production. And during that study, the other thing we found was that the effective dose of the herbicide that was needed varied according to the time of day.
Antony: So it might be possible to tune the concentration of a herbicide or other agrochemical according to the time of day so that less could be used, which would cost farmers less and result in less of the agrochemicals entering the environment.
Antony: This was a kind of new insight, but it has interesting conceptual parallels to the way that certain pharmacological drugs have varying effectiveness depending on the time that they're applied. You know, certain hospital drugs if they're given at certain times of day are more effective than at other times of day. And in our study we found that something very similar in principle was occurring in plants whereby the time of day that glyphosate was applied led to a variation in the response to glyphosate.
Antony: We only tested glyphosate but you could imagine that because plants have so many different metabolites and proteins that have a 24h cycle in their expression, that the targets of other types of chemicals that are applied to plants during farming might also have time-of-day sensitivity. So it opens a whole area of science which might help us to reduce the cost of agricultural processes and reduce the impact of agriculture on the environment as well.
