Parasites’ Achilles heel

Using supercomputers and the latest gene sequencing technology, Professor Robin Gasser’s research group from The University of Melbourne’s Veterinary School is working hard to decode the genomes of a number of devastating parasites, in order to find new ways of controlling them.

The researchers, who call themselves molecular parasitologists, employ the power of supercomputers to piece together the DNA and RNA of parasites into genomes, and compare them with other organisms. Once a parasite genome is assembled, it can be mined for useful and practical information.

The group began by working on the genome of a devastating sheep parasite, the barber’s pole worm (Haemonchus contortus), and have already developed, and are testing, a new treatment for it.

“We are completing a number of other parasite genomes at present,” Professor Gasser (left) says.

“Two years ago we were just dreaming of this. It wouldn’t have entered my mind to sequence a whole genome. Now we are doing it. The quantum leap in using supercomputers is really the ability to handle huge amounts of data quickly.”

Hundreds of millions of humans and animals worldwide, particularly in developing countries, are seriously affected by a broad range of destructive parasitic worms. The parasites have devastating, long-term impacts on human health and welfare, but in spite of this, they are seriously neglected in terms of funding for fundamental research and R&D of drugs, vaccines and diagnostics. Of ~ $2.5 billion spent globally in 2007 on R&D of ‘neglected’ diseases, 80 per cent was spent on HIV/AIDS, malaria and tuberculosis, and less than one per cent on parasitic worms.

Using a raft of new technologies to unlock the genomes of these neglected pathogens will lead to entirely new ways of controlling them and will have substantial outcomes through the development of new drugs, vaccines and/or diagnostic tests. At the same time, a vast body of knowledge of the biology and evolution of these complex organisms will be acquired.

In their work, Professor Gasser’s group used Bruce, the SGI Altix x86 cluster supercomputer at the VLSCI, to compare the barber’s pole worm’s DNA and RNA with that of other organisms in order to track down genes essential for growth, development, reproduction and survival.

Although these genes had not been detected in this worm before, they were able to be targeted by referring to what is already known about the genetics of related organisms such as the free-living roundworm, Caenorhabditis elegans, the fruit or vinegar fly, Drosophila, yeast and mice.

In fact, the researchers were looking for specific enzymes in critical biological and metabolic pathways. Chemicals that act selectively to inhibit these enzymes were already known. Members of Professor Gasser’s group not only found the enzymes for which they were searching, but they matched them to inhibitors. What’s more, they were able to use their information to design new inhibitors with improved and specific properties which act upon worms.

But that’s only part of the story. For the group has now moved on from projects involving single genes, to exploring whole genomes. “In general, we know very, very little about the genomics and genetics of parasites,” Professor Gasser says.

Initially, researchers employed microarray technology to determine the genes which are active at different stages of the life cycle of a parasite. Then they sequenced this entire spectrum of active genes – in the case of the barber’s pole worm, maybe 15,000 to 20,000 of them – using “next -generation” technology.

The sequencing of a whole genome, however, is much more complicated than simply assembling these active genes. A genome includes a lot of genetic material, which does not seem to play any part in coding proteins at all. This is sometimes called “junk DNA”. Some of it is involved with gene regulation; some of it is structural, and we have no idea of the role of much of it. Reconstructing the genome, including the junk DNA, is a bit like putting Humpty Dumpty back together again – a job for a supercomputer, indeed.

Much of the work so far has been undertaken together with expertise and facilities available at the Beijing Genomics Institute (BGI) in Shenzhen, near Hong Kong, and California Institute of Technology (Caltech). In addition, the group is undertaking a series of projects in collaboration with other researchers around the world. Great progress has been made in sequencing the genomes of several well-known but neglected parasites of humans, including waterborne pathogens. “By cracking these, we are putting in place the genomic infrastructure to support fundamental studies which can often lead to applied outcomes, such as drugs, vaccines and diagnostic tests,” says Professor Gasser.

The work is being undertaken in collaboration with experts around the world, including Professors Huanming Yang and Jun Wang at BGI – Shenzhen in China; Erich Schwarz and Paul Sternberg at Caltech, USA and C. Titus Brown at Michigan State University, USA.

http://research.vet.unimelb.edu.au/gasserlab/index.html