Puzzles and Parasites

By Alison Cranage, Science Writer at the Sanger Institute

Sheep flocks in the UK are affected by gastrointestinal worms, such as Haemonchus contortus. Image credit: Scott Payne from Pixabay

Haemonchus contortus is not a spell from Harry Potter’s world, but a gastrointestinal parasitic worm that infects sheep and goats. It feeds on the blood of its host, giving it its characteristic “barber’s pole” name, and causes significant economic and animal health burdens on farmers worldwide. In the UK alone, gastrointestinal worms including Haemonchus cost the sheep industry over £80 million per year.

The worm is one of many species of parasitic worms called helminths. Helminths infect both plants and animals, including humans; over 1.5 billion people, mainly in lower- and middle-income countries, are infected with at least one species of parasitic worm. Infection can cause various diseases, from elephantiasis – a condition in which limbs become grossly enlarged – to river blindness, as well as contributing to developmental delay, social stigmatisation and the cycle of poverty.

H. contortus is increasingly recognised as a model parasite for understanding the response to drug treatment and vaccine research, and is one of the few species of helminth that is experimentally tractable – it is possible to culture the larval stages from eggs in the laboratory, the larvae can be cryopreserved, and it can be manipulated by selectively mating worms with particular phenotypical and genetic traits.

Barber's Pole worm - Haemonchus contortus. Image Credit: Kingdom of Saudi Arabia, Madinah, Veterinary Clinic in Agriculture Department, Wikimedia Commons
Barber’s Pole worm – Haemonchus contortus. Image Credit: Kingdom of Saudi Arabia, Madinah, Veterinary Clinic in Agriculture Department, Wikimedia Commons

Although it is one of the few helminth species for which a vaccine is available, the primary way to control helminths like Haemonchus is large scale treatment with drugs called anthelmintics. However, just like a whole range of pathogens across the globe, drug resistance is a serious problem. Worldwide, resistance to veterinary drugs is huge, and in some places, treatment options are running out.

Dr Stephen Doyle, in the Sanger Institute’s Parasites and Microbes Programme, has just been awarded a new UKRI Future Leaders Fellowship to use genomic approaches at population to single cell resolution to understand how H. contortus evolves in response to drug treatments. Stephen hopes his work will lead to a better understanding of not just H. contortus but a number of helminth species including those that infect humans, and how we can better treat and manage these parasites into the future.

Helminth genomes

Dr Stephen Doyle

Stephen and his collaborators from the Parasite Genomics group at Sanger, University of Glasgow, University of Calgary, and the Moredun Research Institute have been working on the H. contortus genome, amongst others, for several years. Determining the sequence has relied on some of the big advances in technology.

“Sequencing the Haemonchus contortus genome has been a decade long project,” said Stephen. “It’s a really genetically diverse species, which has made resolving its genome sequence challenging. Because the worm is relatively small, we’ve had to pool thousands of individual worms to get enough DNA to sequence the genome. We have been fortunate to utilise new technologies as they have become available at Sanger, together with local expertise in manual genome finishing. Now, we’ve produced a high quality reference genome in chromosome scale pieces – the first amongst an important group of animal and human helminth species.”

The genome sequence is available via WormBase ParaSite, and a research paper will be published soon.

Haemonchus is relatively closely related to the model nematode Caenorhabditis elegans. C. elegans was the first multicellular organism to have its genome sequenced back in 1998 – a landmark moment in biology that was led by John Sulston. While they are both worms, C. elegans is a very different creature to H. contortus. It is a free-living nematode, and it isn’t a parasite. The function of a huge number of genes in both species remains unknown.

“The use of genomics is really revolutionising our understanding of helminth biology. I’ve got a unique opportunity to push this understanding forward with our research,” said Stephen.

“A real challenge is to define the function of the parasite’s genes. By sequencing the genetic information in single parasite cells, during different life stages, I hope we’ll be able to provide a big step forward towards doing that,” he says. “In regard to drug resistance, our work has shown that it’s easy to be misled by the genetics of this parasite by just looking at individual candidate genes. We’ve shown that taking a genome-wide approach, we can exclude most of the noise and really focus in on what’s important.”

The Moredun Research Institute

Stephen is working with the Moredun Research Institute in Scotland, an organisation focused on infectious diseases of livestock.

“I feel very fortunate to continue existing collaborations with the Moredun Research Institute. Their expertise in large animal handling allows us to perform genetic crosses between genetically and phenotypically different strains of the parasite. The real advantage of this is that we can control and monitor the genetics of the parasites, in their hosts, over time,” said Stephen. “This is extremely difficult to do in the field, and can’t be done with human parasites, and so it will be exciting to see how this work evolves in this system in which we do have some control.”

“There are only a few drugs that can treat these infections, and given the increasing prevalence of drug resistance, we need to be able to manage them to ensure they remain effective. By using genomic surveillance in this controlled system, we will be able to track how drug resistance evolves, as well as improve our ability to diagnose and monitor infections.”

Broad applications

“I’m really excited by the broad applications of this research,” said Stephen. Whilst his work focuses on H. contortus, it will be relevant to related species, with similar life-cycles, such as the soil transmitted helminths that infect humans. Some of these species are studied by others in the Parasites and Microbes department at the Sanger Institute.

“The UKRI fellowship also gives us the opportunity to develop some resources that will benefit everyone working on these parasites,” he says. “We’ve been publishing all of our data, the genomes, and functional data, into publicly available databases as soon as possible.”

“I’m a big advocate for open access. I think doing science in bubbles doesn’t work.”

From Melbourne to Sanger

Stephen is originally from Australia, and studied for a PhD in human molecular genetics in Melbourne before moving to work on parasites. “I’ve always been interested in solving puzzles. I’m a naturally curious person,” he says. “So science fits well.”

Stephen’s first postdoctoral position was studying a human filarial nematode that causes river blindness predominantly in West Africa, and how genetic variation in these worms changes in response to drug treatment. “We undertook a genome-wide scan in parasite populations in Ghana and Cameroon that show a sub-optimal response to drug treatment, and identified discrete regions of the genome linked with this response,” he says.

Stephen joined the Sanger Institute in 2015 to work on a BBSCR-funded consortium project to build genetic resources to understand drug resistance in parasitic worms. He says, “My new work extends and builds on that. It’s a bigger picture approach to understanding parasite evolution more broadly.”

“Already a lot of my research and results are being utilised, and so I get a lot of satisfaction from that. Our genomics work and resources only are one piece of the puzzle, however I believe we can have a real positive impact toward understanding and managing these parasites.”