Cover Story - 'This is the Future'
IAH’s Martin Shirley is leading the way to mapping the Eimeria genome and developing an even better understanding of coccidiosis in poultry
Shirley and Tomley: ‘By sequencing Eimeria DNA, or unraveling its genetic code, we can open up the parasite…and come up with thousands of potential targets for control.’
For the moment, coccidiosis can
Dr. Martin Shirley has just put in another long day at his lab in Compton, England, where the world-renowned coccidiologist serves as principal scientist for the Institute of Animal Health’s division of molecular biology.
After stopping home to squeeze in some house painting and taking a long walk through the quiet countryside, he’s ready to unwind at a pub in his hometown of Wantage — a quaint 17th century village some 50 miles northwest of London.
Sipping on a frothy pint of his favorite beer, he enthusiastically discusses his latest accomplishment: Converting more than 7,500 songs from his personal CD collection to the MP3 format and cataloging them by artist and genre on his home PC, which is wired to a state-of-the-art sound system.
“And I just found a new program that will allow me to transfer all the old stuff I have on vinyl to MP3 while eliminating all the pops and scratches,” he says, clearly embracing the new technology. “So when I’m all done, I’ll have everything from Dylan, Sam & Dave and the Stones to Beethoven, Mozart and Verdi completely catalogued. Every song will be only a mouse click away.”
The following day, when he returns to
his lab at IAH, Shirley is all business.
He’s still working at his PC, only this
time he’s labeling and cataloging the
DNA of Eimeria parasites, not the vintage
recordings of Led Zeppelin or
“This is the future of coccidiosis management in poultry,” he says confidently.
“In human medicine, if you look at the number of drugs available for controlling diseases, we can effectively hit about 470 biological targets. That sounds like a lot, but not when you consider that our bodies produce something like 30,000 to 40,000 gene products. We still have a long way to go. That’s one of the attractions of the human genome project. Scientists are opening up the whole genome, so potentially, we can find and then tackle every gene that’s linked to a particular disease situation.
“The same is true for Eimeria in poultry,” he adds. “By sequencing Eimeria DNA, or unraveling its genetic code, we can open up the parasite for public display, look at it, dissect it and come up with maybe thousands of potential targets for control in the future.”
Shirley notes that Eimeria parasites are
“complicated” organisms with perhaps
up to 10,000 gene products or, put
another way, 10,000 targets for either
direct chemotherapeutic or biological
“At the moment, we have a small portfolio of coccidiosis drugs and vaccines that, while very effective, probably target no more than a half dozen biological targets, perhaps 10 at the most.
Coccidiosis Control: How Good Can It Get?
It could be argued that the poultry
industry is already achieving good or at
least adequate control of coccidiosis
with current drugs and vaccines. Still,
Shirley sees plenty of room for improvement.
“That’s one of the reasons we’re
sequencing the DNA of Eimeria,” he
continues. “For all the progress we’ve
made against coccidiosis in poultry, we
really know nothing about the finer
points of the biology of Eimeria parasites.
For example, almost nothing is
known about metabolic pathways, the
mechanisms by which the parasite
damages the host or of the molecules
that stimulate protective immunity (i.e.,
how and why vaccines such as
Coccivac and Paracox are so effective).
All of this information is contained in
the genome sequence.”
Shirley says his research team at IAH is concerned primarily with molecular aspects of the Eimeria genome, as well as the genetics of the parasites.
“Without doubt, the most exciting spin-off from our work has been our recent success in securing the funding of a genome sequencing project for Eimeria tenella, which causes cecal coccidiosis in chickens,” he says. “This is a fantastic outcome for the coccidiosis community worldwide, as E. tenella has become the first protozoan of global veterinary importance to be sequenced on a large scale.”
In March 2002, Shirley, IAH colleague
Dr. Fiona Tomley and Drs. Bart Barrell
and Al Ivens from the Sanger Institute,
Cambridge, were awarded a grant of
£750,000 (US$1.2 million) from the UK’s
Biological and Biotechnological Science
Research Council to determine the DNA
sequence for the world reference
Houghton strain of E. tenella.
“Our previous work has shown that the genome of E. tenella comprises about 60 million base pairs of DNA contained within 14 chromosomes,” says Shirley, who expects to wrap up the project by June 2004. “This amount of DNA may give rise to around 8,000 to 10,000 different proteins. But at present, literally only a small handful of these proteins have been identified and only very few of the genes responsible have been characterized.”
When the project is finished in June 2004, Shirley’s team will have assembled a genetic blueprint for E. tenella and revealed 90% of the parasite’s encoded proteins. All the data generated by the project is being posted on the Internet and available to the public. Shirley says the data will allow current and future coccidiologists to identify new targets for vaccination and chemotherapy.
“The data will yield a much greater
understanding of how Eimeria parasites
go about their lifestyle — for example,
how they cause disease, find the correct
parts of the gut in which to develop,
get into the host cells, reproduce themselves,
cause the host to develop
immune responses, and a myriad of
other biological features,” Shirley
“In addition, the data will allow the biology of Eimeria parasites to be compared with that of close relatives, such as Plasmodium (the malarial parasites), Cryptosporidium, Neospora and Toxoplasma. If one of these parasites invades in a particular way, for example, you can be sure that Eimeria probably invades the host cell in a similar way. In the research community, there’s a lot of mixing and matching between these different organisms.”
The sequencing initiative under way at the IAH and the Sanger Institute was provided with many letters of support from international scientists and veterinarians working on coccidial parasites and coccidiosis. Shirley says the funding of the work by the BBSRC represents a major push for veterinary science. “To date, the genomes of very few pathogens of purely veterinary importance have been sequenced, and none remotely as big as E. tenella” he says.
But Shirley and his colleagues at IAH and Sanger are not going at this alone. The UK scientists are also collaborating with sequencing efforts by Dr. Arthur Gruber in São Paolo, Brazil, and Dr. Wan Kiew Lian at the Universiti Kebangsaan, Malaysia.
“Arthur is doing some great research that dovetails in to the big sequencing initiative and Wan has been awarded a grant from the Malaysian government to derive the complete sequence of chromosomes 1 and 2 (each of 1 million base pairs of DNA),” Shirley says.
“These chromosomes will be sequenced in their entirety to capture all genes and, most interestingly, chromosome 2 is linked to the trait of precocious development that characterizes the attenuated parasites used in Schering-Plough Animal Health’s Paracox, the current attenuated vaccine.”
Why Target Eimeria?
Eimeria is the most economically significant family of parasites for poultry and intensively
reared livestock, according to Dr. Martin Shirley of IAH.
“Coccidiosis has most impact in the intensive poultry industry, where all 35 billion chickens raised annually are likely to become infected,” he says. “Despite routine prophylaxis with anticoccidial drugs, coccidiosis costs the UK poultry industry alone around £40 million ($64 million) a year, which is equivalent to 4.5% of the revenue from sales of live broilers.”
Subclinical coccidiosis is commonplace because the efficacy of drugs is severely compromised by drug-resistant parasites, Shirley says. In the EU, coccidiosis is also considered a “severe welfare problem” causing malabsorption, weight loss, diarrhea, hemorrhaging, anemia and death.
“Eimeria tenella is one of the most common and pathogenic species that infect the domestic chicken and the disease of cecal coccidiosis is one of the most highly visible aspects of coccidiosis in poultry,” he says. “Coccidiosis control is complex and it seems clear that sustainable control will rely increasingly on vaccination, either alone or in combination with drugs.”
But don’t expect coccidiosis to be eradicated any time soon.
“Eimeria is fantastically suited for survival and replication, especially in circumstances — warmth, moisture, high bird density — provided so wonderfully by the poultry industry,” Shirley says. “For example, the oocysts have a transmission stage that is extremely robust and tough. In fact, in the laboratory, we can incubate these in bleach and the parasites still survive very well.”
“The parasite itself is a bit like a Russian doll, with four discrete genomes inside it,” he adds. “Once the Eimeria parasite gets into the host, it really kicks in with a large range of genomes.”
Solving the Eimeria Puzzle
Scientists use one of four letters — A,
C, G or T — to identify each DNA molecule
within a chromosome. These letters
occur in pairs (A with T and C with
G) and, in total, the 14 chromosomes in
the Eimeria organism contain about 60
million such pairs of DNA.
Source: CocciForum Issue No.6, Schering-Plough Animal Health.