Anti-malarials from seaweed: a tale of two pathogens, and one very nifty chemical.

This morning I went to a seminar given by Prof. Julia Kubanek from the University of British Columbia, entitled "Antifungal chemical cues in marine algae and their future in drug discovery".

It was excellent. It was excellent because it told a story, and an unlikely story at that.

In the coral reefs off Fiji, there lives a red seaweed named Callophycus serratus. Not only is it very pretty, but it's also fairly rare, with its geographic distribution limited to the South Pacific Ocean.

But it wasn't the prettiness or rarity of C. serratus that interested Julia and her team, who were investigating antimicrobial defence compounds produced by organisms in coral reefs. What caught their attention was its cleanliness. The fronds of the algae were free from bacterial biofilms, slime moulds and other microbial disease agents, including Lindra thalassia, a common ascomycete fungal pathogen of sea grass. C. serratus clearly had a few tricks up its sleeve when it came to evading infection, and the researchers wanted to learn these tricks.

Callophycus serratus [source]

They discovered that the seaweed was producing a family of antimicrobial chemicals called bromophycolides, which accumulate around wounds on the surface of the algae, acting as a 'chemical band-aid' to prevent invasion of the wound site by microbial pathogens such as L. thalassia. Of these, Bromophycolide A appeared to be the most abundant in the algal tissue, and the most potent in its activity against L. thalassia.

[source]

Needless to say, as an agricultural pathologist I wondered what the effects of these bromophycolides on fungal crop pathogens might be. As it turns out, they weren't particularly impressive; while Bromophycolide A did inhibit the growth of the wheat leaf blotch pathogen Septoria tritici, it took very high doses of the chemical to do so. Results from the other two crop pathogens tested were equally unimpressive, and I slumped back in my chair, disappointed at these findings, and that my own beloved wheat pathogen Fusarium  hadn't been investigated.

But this is where the story takes a sudden turn, a twist that had me shake off my grumps and sit back up in my seat. Because while the effects of bromophycolides on fungal plant pathogens were yawn worthy, their effects on human pathogens, namely the malarial parasite Plasmodium falcifarum, had me wide awake.

Despite having been isolated from a marine plant species, due to its role in defence against a marine plant fungus, Bromophycolide A is able to kill a P. falcifarum, a human red blood cell parasite completely unrelated to its natural target, even when applied to infected blood samples at micromolar levels. The researchers found that it does this in the same way that conventional quinine based anti-malarial drugs do:

In order to replicate, P. falcifarum invades a red blood cell, and sets up camp, consuming the cell's haemoglobin to give it energy for replication. The problem is that the core of the haemoglobin molecule, haem, is toxic to the parasite, so they bundle it up into a crystal structure called hemozoin, where it can do no harm. Both conventional quinine based anti-malarial drugs and bromophycolides prevent the formation of hemozoin, exposing the parasite to toxic haem. The difference is that while some malarial parasites have evolved mechanisms to pump the quinine compounds out of the blood cell, they have no such strategy for avoiding the effects of bromophycolides.

While Bromophycolide A seems a promising new candidate for anti-malarial drug development, there are a few obstacles still to be crossed. These include the challenge of synthesising the drug from scratch, in order for it to be mass produced, and finding a way to prevent it being metabolised (broken down) by the mammalian body before it has chance to kill off the malarial parasite. Even so, with resistance to existing anti-malarial drugs developing and spreading with alarming speed and frequency, these obstacles are ones worth crossing.

I don't know what made Julia and her team think to look at the effects of an anti-fungal marine plant compound on a terrestrial mammalian parasite. It's likely that the mechanism by which bromophycolide A limits P. falcifarum growth is completely different to the way it prevents infection of C. serrata  by marine fungi, making its limiting effects on the growth of both pathogens all the more improbable and amazing. As a young scientist who also looks at plant defence mechanisms against disease, I find this story inspirational and encouraging, and a reminder to think outside the box. It's also a reminder of the wealth and value of marine ecoysystems, and the ways in which their protection may benefit our own species.

GM goes Green: aphid repelling wheat could reduce the need for pesticides

This summer, field trials of genetically modified (GM) wheat will be held at Rothamsted Agricultural Research Station, where I happen to be doing my PhD. I'm not involved in the field trials in any way, and do not work directly with the scientists who have developed the GM wheat. However, I find the research incredibly exciting, both in terms of the underlying science and the possible implications for sustainable agriculture.

So, the science bit.

Aphids (greenfly) are an important pest of crops. They cause direct damage by feeding from the plant, and also transmit plant viruses. The main method of controlling aphids is to spray crops with insecticides. Unfortunately, these insecticides often kill other insects, including natural enemies of aphids such as ladybirds and parasitoid wasps (they lay their eggs inside live aphids - think bodysnatchers). Overuse of insecticides is also increasing the numbers of resistant aphids, in the same way that overuse of antibiotics selects for resistant strains of infectious bacteria in humans.

When in danger, aphids produce an alarm chemical called (E)-β-farnesene (EBF), which repels other aphids. Some plants, such as mint, also produce this chemical, cleverly keeping aphids at bay.

Scientists at Rothamsted have genetically engineered wheat to synthesise EBF. Laboratory tests have shown that the EBF emitting wheat not only repels aphids, but also attracts their natural insect enemies. This could provide a means of controlling aphids on wheat without the need for heavy pesticide sprays, working with the aphids' natural enemies, rather than against them.

With a 70% increase in global food demand predicted by 2050, and increased concern over the effects of pesticides, herbicides and fertilisers on the environment, you might think that a field trial to test the effectiveness of this GM wheat under farm conditions would be welcomed. However, a number of concerns have been raised about the field trials, both by anti GM campaigners and the general public. I've tried to address some of them below.

The first that I came across was put forward by my Mum, an avid gardener and allotment keeper.

She asked me,  "Where will all the aphids go?"

Since this is a small scale field trial on the Rothamsted Farm site (eight 6m x 6m plots), it is very unlikely that any displaced aphids would manage to leave the farm or damage the crops of other farmers. The trial's own Q&A page suggests that the aphids might move to wild grasses, where they would be eaten by predators such as ladybirds and parasitoid wasp larvae. The field trial will be used to evaluate what effect the GM wheat might have on these insect communities.

If the EBF emitting wheat were ever to become a commercially available crop, then farmers could potentially use a "push-pull" method - planting an attractive crop around the wheat to 'pull in' the aphids repelled by the EBF. This could limit any potential damage of neighbouring wheat crops by the repelled aphids.

A concern raised about GM crops in general, rather than this trial in particular, is what effect do they have on the environment?

As previously outlined, a possible outcome from this research is the reduced need for pesticides to control aphids. I personally believe that the benefit to the environment gained from this would far outweigh any risks. However, in order to assess any possible risks, such as persistence of the modified genetic material in the environment, and unforeseen effects on insect communities, further research is required, which is why a farm scale field trial is so important.

This small scale field trial itself is unlikely to cause environemntal impacts beyond the trial site. It has been approved by the Advisory Commitee on Releases to the Environment (ACRE), who have advised a number of measures which will further limit any health or environmental impacts.

Another general concern about GM crops is that the GM seed market is monopolised by multinational agrochemical companies whose primary aim is to make money.

This is where this research really is special. It was funded entirely by the Government's Biotechnology and Biological Sciences Research Council, with no sponsorship from agrochemical companies. All results from the trial will be freely available and the idea has not and will not be patented. The researchers also make it very clear on their Q&A page that what they're testing is not a finished commercial product, and that as scientists they are simply looking for evidence that their technology works.

In addition to these general concerns, anti-GM campaign groups have also voiced objections to this particular field trial. They warn that the GM wheat contains a synthetic cow gene.

In order for the wheat to synthesise EBF, two genes were synthesised and put into the wheat. Niether were taken directly from other organisms. The first is most similar to the gene in mint responsible for synthesis of EBF. The second is a gene found in many organisms, including plants such as maize and tomato. The version of the gene synthesised by the scientists happens to be most similar to the version found in cows, but is also very similar to that found in plants. Therefore to refer to the gene as a "cow gene" is a little misleading.  As already said, the wheat being tested in the field trials is not a finished commercial product and the researchers have stated that "alternative [genes] would need to be used in a commercial variety that is able to produce (E)-β-farnesene" suggesting that the 'cow-y' version of the gene might not be used at all.

This also goes for objections that the GM wheat contains an antibiotic gene and a herbicide tolerance gene.

Both these genes were merely used to aid the insertion of the EBF synthesis genes into the wheat, and to check that the insertion of these genes had been successful. The antibiotic resistance gene is very unlikely to be transferred to infectious bacteria, and the herbicide tolerance gene is not being used to allow blanket spraying of the crop with herbicides, nor is it likely to confer herbicide resistance to wild grass species or nearby wheats, as wheat is self pollenating and the pollen is not easily wind dispersed.

Campaign groups also warn that the aphid repellent effects will wear off.

This doesn't surprise me. While one might hope that solutions to agricultural problems such as drought and salinity could perhaps be permanent, no scientist would assume this of a control strategy, GM or not, against living threats to crops, such as insect pests and diseases. This is because these life forms are constantly evolving new mechanisms to sidestep plant resistance, often faster than the plants can evolve new resistance strategies. The struggle between plant and pest can be seen as an evolutionary arms race, and pests that can sidestep plant defences will have a selective advantage over those that can't. This is one area where GM technology could be very beneficial; conventionally breeding a resistance trait into a commercially viable, high yielding wheat line can take many years, by which time the pest or pathogen may have already become immune to this trait. Insertion of a resistance trait into a plant using genetic modification is relatively quick in comparison, and more than one gene can be 'stacked' to give resistance to a wider range of crop pests.

On a pedantic note, the loss of responsiveness of the aphids to EBF was not shown on wheat, but rather on Arabidopsis, a little cress plant used to model crop plants the same way we use mice to model humans when studying disease. The species of aphid used was also different to the one which most commonly invades wheat. The aphids were reared on EBF emitting Arabidopsis, in the absence of natural enemies which are attracted to EBF. In order to assess whether this would indeed happen, on EBF emitting wheat, under farm conditions, in the presence of natural enemies which would be a danger to any EBF habituated aphids, a field trial is needed.

A final argument (last one I promise!) is that non-GM approaches have been effective in protecting crops  from pests/parasites, so we don't need GM.

GM freeze presents an impressive list of these non-GM breakthroughs. However, some of them, just like EBF emitting wheat, are still in the research stage. Others have led to resistance to one particular pest or pathogen, but there could be a potential cost in terms of resistance to others. However, my intention here is not to pick at the pitfalls of any of these case studies. Several of them are also funded by the BBSRC, indicating that it is willing to fund research into both GM and non-GM avenues of crop protection. This is because our best chance of protecting crops against pests, limiting chemical inputs and meeting the global demand for food production does not lie in an "either/or" approach, but rather in "both/and". It has long been agreed by agricultural scientists and farmers that the best strategy for controlling pests and diseases of crops is an Integrated Pest Management (IPM) approach, rather than focusing on one aspect of control. In my opinion the best IPM approach would use all the ecological and scientific tools available, including GM.

Science Communication

This is a slimmed down version of an old post from my other blog, since I'm moving Science related posts to this blog, leaving my old blog free for non science related ramblings.

My PhD has been an interesting ride so far - I'm working on a wheat ear fungus called Fusarium culmorum, but modelling the infection in a little cress type plant called Arabidopsis which is also susceptible to Fusarium infection in its floral tissue. Arabidopsis has a quicker life cycle than wheat, and is easier to study at the genetic level.

I spent the first 5 months trying to get the fungus to successfully infect Arabidopsis floral tissue. I tried many things, from lowering the temperature to infecting the plants earlier to giving the fungus special nutrients to help it grow, with varying degrees of success.

I got lots of helpful comments from friends and family; "well then surely you've cured the disease if your plants are already resistant?" which made me realise that I maybe wasn't communicating my research very well. This irritated me, because Science Communication is something that I'm very passionate about and would maybe like a career in some day, and I felt I had failed if I couldn't get my own mother to understand the point of my research, and that the cress plant was just a 'model' - it's wheat that we're trying to protect against Fusarium.

The problem is, not all Science is equal(ly interesting) in the eye of the lay person. This became very clear at the student symposium in March - an event when all the PhD students at Rothamsted Research made posters and gave presentations to showcase their projects. Topics ranged from control strategies against invasive ladybirds, to whether sick bees have altered learning capability, to the epigenetics of defence priming against Pseudomonas to....oh sorry, did I loose you at bees and ladybirds?

And herein lies the problem - some research areas just seem more lay person friendly. Nearly everyone with some level of interest in ecology will know that honey bee populations are declining, and that a foreign ladybird named the harlequin is eating our natives. And even if they don't, a simple explanatory sentence, such as the previous one, will suffice as a basic introduction. And people generally like honey bees and ladybirds. Fungal diseases of wheat are, on the other hand, an acquired taste - very acquired in fact, since Fusarium produces deadly toxins. The fact that fungal diseases are the leading cause of yield loss in wheat, and that wheat is one of the most widespread and important food crops in the world, should get people pricking their ears - but without the degree of anthropomorphism assigned to bees, butterflies, ladybirds and dare I say it, even aphids - it's a tough topic to get people interested in.

I don't mean to imply that entomologists (those who study insects) have it easy. Yes, perhaps I am a little jealous - mostly though I'm just dancing around my own head looking for ways to communicate my research, and its importance, to the general public. Until then, I'll stick to judging primary school competitions and telling people about stuff I don't personally work on - no one said I had to communicate MY science, right?