Already, her lab’s work is complementing that of other leading Candida researchers around the world, and they are starting to identify how Candida parapsilosis forms hard-to-shift “biofilms” on medical devices.
Professor Butler is no stranger to the inner workings of fungi, having spent the start of her career looking at how cells grow in Saccharomyces cerevisiae, also known as brewer’s or baker’s yeast. Based in the former Biochemistry Department in Merville House (now NovaUCD), in the 1990s she examined elements of the “cell cycle” in the model organism, but sensed that Ireland lacked the facilities to keep up with the international pace of the field.
“At the time what I felt was happening - and this was with Saccharomyces in particular - was that the research was moving into a very high throughput mode, and it just wasn’t really possible to do that in Ireland then, you would need an awful lot of money,” recalls Butler, who is now associate professor of genetics at UCD School of Biomolecular & Biomedical Science. “So I decided to try and find an area that was more fundable. Saccharomyces was a model organism, but I was looking for something that was more health related.”
That decision led her towards Candida, a genus of fungus that includes both harmless and diseasecausing species. They can be particularly stubborn infections to treat, because their cell structure is broadly similar to human cells, explains Professor Butler. “Any drugs to treat them will work against you as well as against them, so the drugs all have side effects,” she says. “And they all have cell walls, so they are hard to treat.”
Professor Geraldine Butler in the UCD Conway Institute, University College Dublin
One species, Candida parapsilosis, caught her attention, because it poses a particularly insidious hazard in clinical environments. “The problem with Candida parapsilosis is that it is spread. It’s on the hands of most healthcare workers whereas other [disease-causing Candida species] are not,” she explains. “The big problem is that the species grows on any indwelling medical device and with premature babies that tends to mean feeding tubes.”
Once the organism gets into catheters and feeding tubes, it forms biofilms that are hard to shift. And if the fungus manages to invade the patient’s bloodstream, the mortality rate can be up to 40 per cent, notes Professor Butler. “It’s a particular problem in premature babies, but noone knows why,” she says. “And it’s known as an emerging pathogen because it is becoming more and more prevalent.”
Her lab started to investigate Candida parapsilosis by surveying parts of its genome – working out its whole genetic sequence was not practical in 2003. And as the project developed, Butler formed links with industry through the Wellcome Trust Sanger Institute, and other collaborators, including the Fungal Genome Initiative at MIT and Harvard. “I started presenting the work at conferences and people started to realise what was happening and it grew really fast,” she recalls.
A milestone in the field was the publication earlier this year – with Butler as first author – of a paper in the prestigious journal Nature that identified important gene sequences in disease-causing Candida species. The study, which involved 21 institutions over around five years, compared genome sequences from six species, three of which cause human disease, and found the harmful ones were better endowed with genes for “stickiness”.
“There were more copies in the pathogenic ones of gene families that are involved in adhesion and the cell wall than were in the non-pathogenic ones. So basically they have more genes that allow them to become pathogens,” explains Professor Butler. “In some cases the gene families just weren’t present in the non-pathogenic ones, or there might have been one, but 15 or 16 more in the pathogenic ones.”
The extra “stickiness” factor in the diseasecausing Candida species could help explain why problematic organisms like Candida parapsilosis form biofilms on plastic surfaces, and why they are so invasive in humans.
“When they stick, they tend to stick both to plastic and to human cells so it’s the same proteins that are involved, and we are looking at that,” says Professor Butler, whose eight-strong research team at UCD is funded through Science Foundation Ireland, the Health Research Board and IRCSET.
“We are really concentrating on Candida parapsilosis and trying to figure out what controls the biofilms in that species and compare it to Candida albicans. They are actually surprisingly different, more different than we expected. So we are trying to find out about the pathways that control the biofilm development.”
Teasing out the pathways involved in controlling that stickiness in the fungus could help identify ways of breaking the chain using more effective pharmaceutical drugs, cleaning agents or anti-stick coatings for the inside of catheters to stop the fungi setting up camp.
“That’s a long term goal,” says Butler. “The assumption is that if you understand how they stick then you can stop them sticking. But it’s never very simple. There’s never just one protein for a start, there are always lots of them.”
To date, Butler’s group has been growing Candida parapsilosis on squares of the plastic from which feeding tubes and catheters are made, but they are now starting to collaborate with researchers in Wisconsin on how the fungus grows within such tubes and invades a host.
Meanwhile Butler is also trying to shed light on some mysteries about the reproductive traits of Candida species. In particular, Candida parapsilosis appears to be asexual, as its genetic machinery for mating seem to be degenerate. “What has been noticed in the last few years is that pathogens, and particularly fungal pathogens, seem to suppress mating when they infect humans. So it seems to be an advantage to them not to mate,” she says.