̽��ֱ�� of Cambridge - schistosomiasis

New tool in the fight against tropical diseases

gm349 — Wed, 27 Feb 2013 01:01:00 +0000

A novel tool exploits baker’s yeast to expedite the development of new drugs to fight multiple tropical diseases, including malaria, schistosomiasis, and African sleeping sickness. ̽��ֱ��unique screening method uses yeasts which have been genetically engineered to express parasite and human proteins to identify chemical compounds that target disease-causing parasites but do not affect their human hosts.

Parasitic diseases affect millions of people annually, often in the most deprived parts of the world. Every year, malaria alone infects over 200 million people, killing an estimated 655,000 individuals, mostly under the age of five. Unfortunately, our ability to treat malaria, which is caused by Plasmodium parasites, has been compromised by the emergence of parasites that are resistant to the most commonly used drugs. There is also a pressing need for new treatments targeting other parasitic diseases, which have historically been neglected.

Currently, drug-screening methods for these diseases use live, whole parasites. However, this method has several limitations. First, it may be extremely difficult or impossible to grow the parasite, or at least one of its life cycle stages, outside of an animal host. (For example, the parasite Plasmodium vivax, responsible for the majority of cases of malaria in South America and South-East Asia, cannot be continuously cultivated in laboratory conditions.) Second, the current methods give no insight into how the compound interacts with the parasite or the toxicity of the compound to humans.

In an effort to develop new drugs to fight parasitic diseases, scientists from the ̽��ֱ�� of Cambridge have collaborated with computer scientists at Manchester ̽��ֱ�� to create a cheaper and more efficient anti-parasitic drug-screening method. ̽��ֱ��clever screening method identifies chemical compounds which target the enzymes from parasites but not those from their human hosts, thus enabling the early elimination of compounds with potential side effects.

Professor Steve Oliver, from the Cambridge Systems Biology Centre and Department of Biochemistry at the ̽��ֱ�� of Cambridge, said: “Our screening method provides a faster and cheaper approach that complements the use of whole parasites for screening. This means that fewer experiments involving the parasites themselves, often in infected animals, need to be carried out.”

̽��ֱ��new method uses genetically engineered baker’s yeast, which either expresses important parasite proteins or their human counterparts. ̽��ֱ��different yeast cells are labelled with fluorescent proteins to monitor the growth of the individual yeast strains while they grow in competition with one another. High-throughput is provided by growing three to four different yeast strains together in the presence of each candidate compound. This approach also provides high sensitivity (since drug-sensitive yeasts will lose out to drug-resistant strains in the competition for nutrients), reduces costs, and is highly reproducible.

̽��ֱ��scientists can then identify the chemical compounds that inhibit the growth of the yeast strains carrying parasite-drug targets, but fail to inhibit the corresponding human protein (thus excluding compounds that would cause side-effects for humans taking the drugs). ̽��ֱ��compounds can then be explored for further development into anti-parasitic drugs.

In order to demonstrate the effectiveness of their screening tool, the scientists tested it on Trypanosoma brucei, the parasite that causes African sleeping sickness. By using the engineered yeasts to screen for chemicals that would be effective against this parasite, they identified potential compounds and tested them on live parasites cultivated in the lab. Of the 36 compounds tested, 60 per cent were able to kill or severely inhibit the growth of the parasites (under standard lab conditions).

Dr Elizabeth Bilsland, the lead author of the paper from the ̽��ֱ�� of Cambridge, said: “This study is only a beginning. It demonstrates that we can engineer a model organism, yeast, to mimic a disease organism and exploit this technology to perform low-cost, fully-automated drug screens to select and optimise drug candidates as well as identify and validate novel drug targets.”

“In the future, we hope to engineer entire pathways from pathogens into yeast and also to construct yeast strains that mimic diseased states of human cells.”

̽��ֱ��research, which was funded by the Biotechnology and Biological Sciences Research Council (BBSRC), was published today, 27 February, in the journal Open Biology.

Screening method created to expedite the development of new drugs in the fight against tropical diseases such as malaria and African sleeping sickness.

Our screening method provides a faster and cheaper approach that complements the use of whole parasites for screening.

Steve Oliver

Harry J. Moss

Different yeast cells are labelled with fluorescent proteins to monitor the growth of the individual yeast strains

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Robot scientist becomes first machine to discover new scientific knowledge

bjb42 — Thu, 02 Apr 2009 00:00:00 +0000

̽��ֱ��robot, called Adam, is a computer system that fully automates the scientific process. ̽��ֱ��work, which was funded by the Biotechnology and Biological Sciences Research Council (BBSRC) was published today, 03 April 2009, in the journal Science.

̽��ֱ��scientists designed Adam to carry out each stage of the scientific process automatically without the need for further human intervention. ̽��ֱ��robot has discovered simple but new scientific knowledge about the genomics of the baker's yeast Saccharomyces cerevisiae, an organism that scientists use to model more complex life systems. ̽��ֱ��researchers have used separate manual experiments to confirm that Adam's hypotheses were both novel and correct.

Stephen Oliver, one of the co-authors on the paper and Professor of Systems Biology and Biochemistry at the ̽��ֱ�� of Cambridge, said: " ̽��ֱ��novel thing is that Adam is able to formulate hypotheses on its own and test them. In this project, a machine has discovered new scientific knowledge.

"As we start to consider living systems in a holistic manner, the complexity of such systems means that it will become increasingly difficult for scientists to formulate hypotheses unaided. Thus it will be necessary for human and robot scientists to work together to achieve the goals of biological research.

"It is not the management and analysis of complex data that is the big deal about Adam, it is the ability of the machine to reason with those data and make proposals about how a living thing works."

Prof Ross King, who led the research at Aberystwyth ̽��ֱ��, said: "Ultimately we hope to have teams of human and robot scientists working together in laboratories. Because biological organisms are so complex it is important that the details of biological experiments are recorded in great detail. This is difficult and irksome for human scientists, but easy for Robot Scientists."

Using artificial intelligence, Adam hypothesised that certain genes in baker's yeast code for specific enzymes which catalyse biochemical reactions in yeast. ̽��ֱ��robot then devised experiments to test these predictions, ran the experiments using laboratory robotics, interpreted the results and repeated the cycle.

Adam is a still a prototype, but Prof King's team believe that their next robot, Eve, holds great promise for scientists searching for new drugs to combat diseases such as malaria and schistosomiasis, an infection caused by a type of parasitic worm in the tropics.

Prof King continued: "If science was more efficient it would be better placed to help solve society's problems. One way to make science more efficient is through automation. Automation was the driving force behind much of the 19th and 20th century progress, and this is likely to continue."

Professor Oliver of Wolfson College and his post-doc Pnar Pir participated in the construction of the logical model of yeast metabolism that formed Adam's background knowledge. They also designed the basic experimental format in terms of media, growth conditions, etc., and analysed Adam's hypotheses to figure out why human scientists failed to connect those genes to the orphan enzymes.

̽��ֱ��image and video were kindly provided by Aberystwyth ̽��ֱ��.

Scientists from the ̽��ֱ�� of Cambridge and Aberystwyth ̽��ֱ�� have created a "robot scientist" which the researchers believe is the first machine to have independently discovered new scientific knowledge.

It is not the management and analysis of complex data that is the big deal about Adam, it is the ability of the machine to reason with those data and make proposals about how a living thing works.

Stephen Oliver

Roger Schultz from Flickr

Rusty C3PO

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Parasites: the master manipulators

tdk25 — Sat, 01 Sep 2007 00:00:00 +0000

̽��ֱ��human race used to have a consensus attitude towards the organisms that we call parasites. They were simply pests, causative agents of disease that warranted nothing else other than extermination. As soon as new life-cycles were described in the literature, the race began to find a way of interrupting transmission and end the misery. ̽��ֱ��literature is therefore full of examples of control programmes for just about every parasite that has ever been identified. Some, such as the programme against the guinea worm, Dracunculus medinensis, have been so successful that complete eradication is now on the World Health Organization’s agenda.

As we wave goodbye to the guinea worm, it will be time to re-visit the hit-list, and to see how far we’ve progressed. In doing so, we are likely to observe that not much has changed. In fact, the guinea worm is the only parasitic infection that has ever been described and then systematically eradicated. There are even signs that the parasitic fauna of the planet is flourishing – recent estimates put the toll of malaria at between 300 and 660 million cases a year, and there are still hundreds of millions of people infected by each of several parasitic worm species. This group includes the trematode parasite Schistosoma mansoni – a blood fluke that infects approximately 200 million people in the tropics and sub-tropics, and which has been the focus of research efforts at the ̽��ֱ�� of Cambridge Department of Pathology for the past 30 years.

Fighting the fluke

Theodor Bilharz formally described schistosome parasites in 1851, at which point the centimetre-long, red-blood-cell-eating worm joined the most-wanted list. Like every other parasitic infection, S. mansoni was viewed with fear and loathing – and with good reason. Infection occurs through contact with free-living larvae in freshwater, with rapid penetration of intact human skin. ̽��ֱ��adults live in the mesenteric veins between the liver and gut. Females produce eggs that become trapped in the liver, promoting an inflammatory response that eventually leads to a form of hepatic fibrosis and portal hypertension. About half the eggs pass through the gut wall, each puncture causing a small amount of blood to be lost. As the worm burden increases with repeated exposure, so the number of eggs in both the liver and gut increases, leading to ever more severe disease.

Early attempts at large-scale control of schistosome infections relied on crude drugs and environmental modification, with success in some areas, but in most places the parasite persisted. Although treatment (praziquantel) is available, re-infection occurs rapidly, especially in children. ̽��ֱ��lack of effective, non-toxic medicine, and the success of vaccination programmes against bacterial diseases, led to the emergence of renewed research efforts aimed at understanding the biology of the worm and its relationship with the human host.

But, despite promises of an anti-schistosome vaccine ‘within five years’ for the past 20 years or so, there is still no vaccine available, because we don’t yet understand the biology of the schistosome worm. Like a fractal puzzle, as we peer more closely we see even greater complexity.

Keeping things quiet

Such is the intimate relationship between host and parasite that we can use the study of schistosome parasites to understand how humans work. One of the key questions that has kept scientists busy is how schistosomes manage to evade the immune response for extended periods. It has been estimated that adult worms live for up to 10 years in their human host. To make this possible, the worms have evolved several mechanisms for diverting, blocking and repressing the immune response. ̽��ֱ��adult worms coat themselves in host proteins to appear invisible to the immune system. They induce the host to produce ineffective immune responses and they manipulate host cells to produce molecules that signal a general downregulation of the host’s response. This essentially produces a drowsy immune response with impaired vision against a camouflaged target – perfect conditions for the parasite to thrive and reproduce

Recent studies in Cambridge in the laboratory of Professor David Dunne have demonstrated the magnitude of this repressive effect by treating people who are already infected with the parasite and measuring their immune responses before and after taking praziquantel. Responses that are thought to be effective against the parasite often increase several fold after drug treatment, and this ‘boosting’ of the host’s ability to respond appears to help prevent re-infection in the future. Recently, the scientists also reported that the ability to respond after treatment is genetically restricted – an observation that has important implications for the development of any therapy or vaccine that relies on increasing the magnitude of the immune response for its protective effect.

Medical benefits

Although a vaccine is not yet in sight, recent discoveries have raised an interesting conundrum: rather than simply being agents of disease, it appears that parasitic infections, including schistosome worms, may bring medical benefits. Scientists in Cambridge are leading the field in efforts to find out just what is going on.

As more knowledge of the host–parasite relationship is gained, it is becoming increasingly clear that parasitic infections are not necessarily pests that need to be eradicated. Nobody used to have any sympathy for leeches or maggots, but both creatures are now used in medical settings: leeches to clear blood from congested tissues after surgery, and maggots to liquefy dead tissue and kill harmful bacteria in infected wounds. ̽��ֱ��same thing is now happening to parasites, as it emerges that their influence on the immune system can benefit both host and parasite.

In the Department of Pathology, a clear example of this win–win scenario was demonstrated when researchers in Professor Anne Cooke’s group prevented type 1 diabetes from developing in mice by injecting them with antigens of schistosome parasites. This is likely to be due to the same skewing and downregulation of the host immune response described above.

It seems that by diverting and subverting the immune response, schistosome parasites may prevent the immune system from over-reacting to other proteins. One hypothesis gaining popularity is that, when parasites are removed, the immune response finds new targets, either in harmless allergens (leading to allergy), or in the host itself (leading to autoimmune diseases such as type 1 diabetes).

With such tantalising evidence, it may be time to look at the parasite hit-list with fresh eyes, and ask: can we exploit the intimate relationship parasites have with humans at the same time as reducing their tremendous burden on affected populations?

̽��ֱ��Matangini Project

̽��ֱ��Matangini Project was created by Dr Mark Booth, in the Schistosomiasis Research Group at the Department of Pathology, to raise funds for community projects in Kenya and Uganda. ̽��ֱ��aim in 2007 is to raise £5000 to bring safe water to thousands of school children in areas of Kenya affected alternately by drought and water-borne infections such as schistosomiasis.

Cambridge Infectious Disease Initiative

̽��ֱ�� ̽��ֱ�� of Cambridge is currently developing a major Infectious Disease Initiative, with the aim of increasing the ̽��ֱ��’s contribution to reducing the global impact of infectious diseases. By building new partnerships based on core strengths, the vision is to establish the ̽��ֱ�� as a leading international centre for infectious disease teaching and research.

For further information, please contact the Co-ordinator Dr Gill Rands (gfr21@cam.ac.uk).

For more information, please contact the author Dr Mark Booth (mb350@cam.ac.uk) at the Department of Pathology (www.path.cam.ac.uk/~schisto).

̽��ֱ��common view has been that parasitic infections cause disease and must be eliminated. But can we live without them?

As more knowledge of the host–parasite relationship is gained, it is becoming increasingly clear that parasitic infections are not necessarily pests that need to be eradicated.

Max0rz from Flickr

Flatworm

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