̽��ֱ�� of Cambridge - malaria

AI 'scientist' finds that toothpaste ingredient may help fight drug-resistant malaria

cjb250 — Thu, 18 Jan 2018 10:00:15 +0000

When a mosquito infected with malaria parasites bites someone, it transfers the parasites into their bloodstream via its saliva. These parasites work their way into the liver, where they mature and reproduce. After a few days, the parasites leave the liver and hijack red blood cells, where they continue to multiply, spreading around the body and causing symptoms, including potentially life-threatening complications.

Malaria kills over half a million people each year, predominantly in Africa and south-east Asia. While a number of medicines are used to treat the disease, malaria parasites are growing increasingly resistant to these drugs, raising the spectre of untreatable malaria in the future.

Now, in a study published today in the journal Scientific Reports, a team of researchers employed the Robot Scientist ‘Eve’ in a high-throughput screen and discovered that triclosan, an ingredient found in many toothpastes, may help the fight against drug-resistance.

When used in toothpaste, triclosan prevents the build-up of plaque bacteria by inhibiting the action of an enzyme known as enoyl reductase (ENR), which is involved in the production of fatty acids.

Scientists have known for some time that triclosan also inhibits the growth in culture of the malaria parasite Plasmodium during the blood-stage, and assumed that this was because it was targeting ENR, which is found in the liver. However, subsequent work showed that improving triclosan’s ability to target ENR had no effect on parasite growth in the blood.

Working with ‘Eve’, the research team discovered that in fact, triclosan affects parasite growth by specifically inhibiting an entirely different enzyme of the malaria parasite, called DHFR. DHFR is the target of a well-established antimalarial drug, pyrimethamine; however, resistance to the drug among malaria parasites is common, particularly in Africa. ̽��ֱ��Cambridge team showed that triclosan was able to target and act on this enzyme even in pyrimethamine-resistant parasites.

“Drug-resistant malaria is becoming an increasingly significant threat in Africa and south-east Asia, and our medicine chest of effective treatments is slowly depleting,” says Professor Steve Oliver from the Cambridge Systems Biology Centre and the Department of Biochemistry at the ̽��ֱ�� of Cambridge. “ ̽��ֱ��search for new medicines is becoming increasingly urgent.”

Because triclosan inhibits both ENR and DHFR, the researchers say it may be possible to target the parasite at both the liver stage and the later blood stage.

Lead author Dr Elizabeth Bilsland, now an assistant professor at the ̽��ֱ�� of Campinas, Brazil, adds: “ ̽��ֱ��discovery by our robot ‘colleague’ Eve that triclosan is effective against malaria targets offers hope that we may be able to use it to develop a new drug. We know it is a safe compound, and its ability to target two points in the malaria parasite’s lifecycle means the parasite will find it difficult to evolve resistance.”

Robot scientist Eve was developed by a team of scientists at the Universities of Manchester, Aberystwyth, and Cambridge to automate – and hence speed up – the drug discovery process by automatically developing and testing hypotheses to explain observations, run experiments using laboratory robotics, interpret the results to amend their hypotheses, and then repeat the cycle, automating high-throughput hypothesis-led research.

Professor Ross King from the Manchester Institute of Biotechnology at the ̽��ֱ�� of Manchester, who led the development of Eve, says: “Artificial intelligence and machine learning enables us to create automated scientists that do not just take a ‘brute force’ approach, but rather take an intelligent approach to science. This could greatly speed up the drug discovery progress and potentially reap huge rewards.”

̽��ֱ��research was supported by the Biotechnology & Biological Sciences Research Council, the European Commission, the Gates Foundation and FAPESP (São Paulo Research Foundation).

Reference
Bilsland, E et al. Plasmodium dihydrofolate reductase is a second enzyme target for the antimalarial action of triclosan. Scientific Reports; 18 Jan 2018; DOI: 10.1038/s41598-018-19549-x

An ingredient commonly found in toothpaste could be employed as an anti-malarial drug against strains of malaria parasite that have grown resistant to one of the currently-used drugs. This discovery, led by researchers at the ̽��ֱ�� of Cambridge, was aided by Eve, an artificially-intelligent ‘robot scientist’.

Drug-resistant malaria is becoming an increasingly significant threat in Africa and south-east Asia, and our medicine chest of effective treatments is slowly depleting

Steve Oliver

Photo-Mix (Pixabay)

Toothpaste

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Reducing number of infectious malaria parasites in donated blood could help prevent transmission during transfusion

cjb250 — Thu, 21 Apr 2016 22:30:45 +0000

Malaria is a blood-borne disease caused by the malaria parasite – in west Africa, this is mainly Plasmodium falciparum. ̽��ֱ��parasite is mainly transmitted to humans through mosquito bites. In sub-Saharan Africa, malaria infection is endemic and a substantial proportion of the population carries the parasite, even when individuals do not show any symptoms. Only a few blood centres screen donor blood of the parasite and hence there is a high risk of malaria transmission through transfusion.

Because of resource limitations, the most common red blood cell product transfused is whole blood. A half of all blood donors in Ghana carry detectable levels of malaria parasites in the blood and as many as one in four (between 14-28%) of blood recipients become infected.

̽��ֱ��Mirasol pathogen reduction technology system, developed by the US-based Japanese company Terumo BCT, has been developed to treat whole blood using ultraviolet light energy and riboflavin (vitamin B2) to reduce the parasite load and to inactivate white blood cells. It has been shown to reduce P. falciparum load in vitro and to maintain adequate blood quality during 21 days of cold storage.

In a study published today in ̽��ֱ��Lancet and funded by Terumo BCT, researchers report the results of the African Investigation of the Mirasol System (AIMS) trial, which explored whether the use of blood treated with Mirasol would prevent the transmission of malaria to patients with anaemia being supported with whole blood transfusion.

“In developing countries, blood supplies are often contaminated and blood banking systems cannot afford the newest technologies for detecting blood-borne pathogens,” explains Professor Jean-Pierre Allain from the Department of Haematology at the ̽��ֱ�� of Cambridge. “Technologies aimed at reducing the levels of parasites or infectious agents in the blood could benefit individual patients and also health-care systems.”

̽��ֱ��trial involved 214 patients, 107 of whom received Mirasol-treated blood, the remainder of whom received the normal blood products. Overall, 65 patients who previously were free of detectable parasites were transfused with blood retrospectively found to contain parasites – 28 of these blood products had been treated with Mirasol, 37 were untreated.

̽��ֱ��incidence of transfusion-transmitted malaria was significantly lower for those patients who received the treated blood (one out of 28 patients, or 4%) compared to the untreated group (eight out of 37 patients, or 22%).

At the same time, the safety profile did not differ for patients receiving treated or untreated whole blood units. ̽��ֱ��treated whole blood group had fewer allergic reactions to the transfusion (5% vs 8%) and fewer overall reactions (8% vs 13%), possibly because of the technology also inactivates white blood cells including immune cells.

̽��ֱ��researchers recognise that the overall number of transmissions was small, reducing the power of the study, but believe it still provides a clear indication that the Mirasol system could make a dramatic difference to the number of cases of malaria transmission via blood transfusion.

“This could be a real game-changer for blood safety in sub-Saharan African,” adds Dr Shirley Owusu-Ofori from the Transfusion Medicine Unit, Komfo Anokye Teaching Hospital, Kumasi, Ghana. “Reduced transfusion-transmissions of infectious agents means a more stable blood supply, reduced costs for the treatment of preventable infections, and direct benefits to women and children who are especially vulnerable to malaria.”

Reference
Allain, JP et al. Effect of Plasmodium inactivation in whole blood on the incidence of blood transfusion-transmitted malaria in endemic regions: the African Investigation of the Mirasol System (AIMS) randomised controlled trial. Lancet; 23 April 2016; DOI 10.1016/S0140-6736(16)00581-X

Declaration of interests
Jean-Pierre Allain, Alex Owusu-Ofori and Shirley Owusu-Ofori have received grants from Terumo BCT. Susanne Marschner is an employee of Terumo BCT. Raymond Goodrich is an employee of Terumo BCT and owns patents assigned to Terumo BCT. Sonny Michael Assennato declares no competing interests. Terumo BCT did not interfere with the basic design of the study, nor in the conducting of the trial or the interpretation of the data.

A technique for reducing the number of infectious malaria parasites in whole blood could significantly reduce the number of cases of transmission of malaria through blood transfusion, according to a collaboration between researchers in Cambridge, UK, and Kumasi, Ghana.

This could be a real game-changer for blood safety in sub-Saharan African

Shirley Owusu-Ofori

Wellcome Images

Blood transfusion bags

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Artificially-intelligent Robot Scientist ‘Eve’ could boost search for new drugs

cjb250 — Wed, 04 Feb 2015 00:00:01 +0000

Robot scientists are a natural extension of the trend of increased involvement of automation in science. They can automatically develop and test hypotheses to explain observations, run experiments using laboratory robotics, interpret the results to amend their hypotheses, and then repeat the cycle, automating high-throughput hypothesis-led research. Robot scientists are also well suited to recording scientific knowledge: as the experiments are conceived and executed automatically by computer, it is possible to completely capture and digitally curate all aspects of the scientific process.

In 2009, Adam, a robot scientist developed by researchers at the Universities of Aberystwyth and Cambridge, became the first machine to independently discover new scientific knowledge. ̽��ֱ��same team has now developed Eve, based at the ̽��ֱ�� of Manchester, whose purpose is to speed up the drug discovery process and make it more economical. In the study published today, they describe how the robot can help identify promising new drug candidates for malaria and neglected tropical diseases such as African sleeping sickness and Chagas’ disease.

“Neglected tropical diseases are a scourge of humanity, infecting hundreds of millions of people, and killing millions of people every year,” says Professor Steve Oliver from the Cambridge Systems Biology Centre and the Department of Biochemistry at the ̽��ֱ�� of Cambridge. “We know what causes these diseases and that we can, in theory, attack the parasites that cause them using small molecule drugs. But the cost and speed of drug discovery and the economic return make them unattractive to the pharmaceutical industry.

“Eve exploits its artificial intelligence to learn from early successes in her screens and select compounds that have a high probability of being active against the chosen drug target. A smart screening system, based on genetically engineered yeast, is used. This allows Eve to exclude compounds that are toxic to cells and select those that block the action of the parasite protein while leaving any equivalent human protein unscathed. This reduces the costs, uncertainty, and time involved in drug screening, and has the potential to improve the lives of millions of people worldwide.”

Eve is designed to automate early-stage drug design. First, she systematically tests each member from a large set of compounds in the standard brute-force way of conventional mass screening. ̽��ֱ��compounds are screened against assays (tests) designed to be automatically engineered, and can be generated much faster and more cheaply than the bespoke assays that are currently standard. This enables more types of assay to be applied, more efficient use of screening facilities to be made, and thereby increases the probability of a discovery within a given budget.

Eve’s robotic system is capable of screening over 10,000 compounds per day. However, while simple to automate, mass screening is still relatively slow and wasteful of resources as every compound in the library is tested. It is also unintelligent, as it makes no use of what is learnt during screening.

To improve this process, Eve selects at random a subset of the library to find compounds that pass the first assay; any ‘hits’ are re-tested multiple times to reduce the probability of false positives. Taking this set of confirmed hits, Eve uses statistics and machine learning to predict new structures that might score better against the assays. Although she currently does not have the ability to synthesise such compounds, future versions of the robot could potentially incorporate this feature.

Professor Ross King, from the Manchester Institute of Biotechnology at the ̽��ֱ�� of Manchester, says: “Every industry now benefits from automation and science is no exception. Bringing in machine learning to make this process intelligent – rather than just a ‘brute force’ approach – could greatly speed up scientific progress and potentially reap huge rewards.”

To test the viability of the approach, the researchers developed assays targeting key molecules from parasites responsible for diseases such as malaria, Chagas’ disease and schistosomiasis and tested against these a library of approximately 1,500 clinically approved compounds. Through this, Eve showed that a compound that has previously been investigated as an anti-cancer drug inhibits a key molecule known as DHFR in the malaria parasite. Drugs that inhibit this molecule are currently routinely used to protect against malaria, and are given to over a million children; however, the emergence of strains of parasites resistant to existing drugs means that the search for new drugs is becoming increasingly more urgent.

“Despite extensive efforts, no one has been able to find a new antimalarial that targets DHFR and is able to pass clinical trials,” adds Professor King. “Eve’s discovery could be even more significant than just demonstrating a new approach to drug discovery.”

̽��ֱ��research was supported by the Biotechnology & Biological Sciences Research Council and the European Commission.

Reference
Williams, K. and Bilsland, E. et al. Cheaper faster drug development validated by the repositioning of drugs against neglected tropical diseases. Interface; 4 Feb 2015.

Eve, an artificially-intelligent ‘robot scientist’ could make drug discovery faster and much cheaper, say researchers writing in the Royal Society journal Interface. ̽��ֱ��team has demonstrated the success of the approach as Eve discovered that a compound shown to have anti-cancer properties might also be used in the fight against malaria.

[Eve's artificial intelligence] reduces the costs, uncertainty, and time involved in drug screening, and has the potential to improve the lives of millions of people worldwide

Steve Oliver

̽��ֱ�� of Manchester

Eve, the Robot Scientist

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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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Finding malaria's weak spot

admin — Wed, 06 Feb 2013 09:06:33 +0000

After over a decade of research into malaria, biologists Dr Teresa Tiffert and Dr Virgilio Lew at the Department of Physiology, Development and Neuroscience found their efforts to observe a key stage of the infection cycle severely hindered by the limits of available technology. An innovative collaboration with physicist Dr Pietro Cicuta at the Cavendish Laboratory and bio-imaging specialist Professor Clemens Kaminski in the Department of Chemical Engineering and Biotechnology is now yielding new insights into this devastating disease.

Under attack

Malaria is caused by parasites transmitted to humans through the bites of infected mosquitoes. According to the World Malaria Report 2011, there were about 216 million cases of malaria causing an estimated 655,000 deaths in 2010. Tiffert and Lew established their malaria laboratory in Cambridge in 1999 to investigate the most deadly form of the parasite, Plasmodium falciparum. Becoming increasingly resistant to available drugs, this species in particular is a growing public health concern.

Their current focus is a mysterious step in the life cycle of P. falciparum occurring inside the infected human’s bloodstream. ̽��ֱ��parasites, at this stage called merozoites, attach to and enter red blood cells (RBCs) to develop and multiply. After two days, the new merozoites are released and infect neighbouring RBCs. Over several days, this process amplifies the number of parasitised RBCs and causes severe and potentially lethal symptoms in humans.

“A huge amount of research has been devoted to understanding the RBC penetration process,” said Tiffert. “ ̽��ֱ��focus of many vaccine efforts is the molecules on the surfaces of both parasite and red cell that are instrumental in recognition and penetration. Our collaboration with Clemens developed new imaging approaches to investigate what happens in the cells after invasion. But the pre-invasion stage, when a merozoite first contacts a cell targeted for invasion, remained a profound mystery. Our research indicates that this stage is absolutely critical in determining the proportion of cells that will be infected in an individual.”

For invasion to occur, the tip of the merozoite has to be aligned perpendicularly to the RBC membrane. Tiffert and Lew are focusing on how this alignment comes about, which has proved a formidable technical challenge. “ ̽��ֱ��merozoites are only in the bloodstream for less than two minutes, where they are vulnerable to attack by the host’s immune system, before entering a RBC. To investigate what is going on we need to record lots of pre-invasion and penetration sequences at high speed, using high magnification and variable focusing in three dimensions. And the real challenge is to have the microscope on the right settings and to be recording at exactly the time when an infected cell has burst and released merozoites – something that is impossible to predict,” said Tiffert.

Techniques used by previous investigators have produced few useful recordings of this process occurring in culture, but from these an astonishing picture is emerging. “ ̽��ֱ��contact of the merozoite with the RBC elicits vigorous shape changes in the cell, not seen in any other context,” said Lew. “It seems clear that this helps the merozoite orientate itself correctly for penetration, because all movement stops as soon as this happens. ̽��ֱ��parasite is somehow getting the RBC to help it invade.”

A collaborative approach

Cicuta, a ̽��ֱ�� Lecturer involved in the ̽��ֱ��’s Physics of Medicine Initiative – which is bringing together researchers working at the interface of physical sciences, life sciences and clinical sciences – met the trio by chance three years ago. He realised he could use his background in fundamental physics to pioneer a new approach to understanding malaria. “It’s been a gradual move for me to apply what I’ve learnt in physics to biology,” he said. “From the physics point of view, RBC membranes are a material. This material is very soft and undergoes deformations and fluctuations, and I was interested in understanding the mechanics involved during infection with malaria.”

Drawing on his expertise in the development of experimental techniques, Cicuta collaborated with Tiffert, Lew and Kaminski to pioneer a completely automated imaging system that pushes the boundaries of live cell imaging, enabling individual RBCs and merozoites to be observed throughout the process of infection. ̽��ֱ��research was funded by the Biotechnology and Biological Sciences Research Council and the Engineering and Physical Sciences Research Council.

“This microscope can not only run by itself for days, it can perform all the tasks that a human would otherwise be doing. It can refocus, it can find infected cells and zoom in, and when it detects a release of parasites it can change its imaging modality by going into a high frame-rate acquisition. And when the release has finished it can search around in the culture to find another cell to monitor automatically,” said Cicuta. “We also want to integrate a technique called an optical trap, which uses a laser beam to grab cells and move them around, so we can deliver the parasites to the cells ourselves and see how they invade.”

“So far, we’ve been able to gather over 50 videos of infections, which my PhD student Alex Crick has processed to show very clearly that the RBCs undergo large changes in shape when the merozoites touch them. We’ve also seen very strange shape changes just before the parasites come out of the cells, and we want to see whether this has a bearing on the parasites’ ability to infect subsequent cells.”

During the development of the microscope, the team discovered variability in the way the infected RBCs behave before they burst. “It’s important to know that there isn’t just one story. ̽��ֱ��only way to find this out is to look at many cells, which this system allows,” said Lew. “It’s a new level of data that allows us to get experimentally significant results, and better understand the diversity of the merozoites,” Cicuta added.

Used in conjunction with other tools such as fluorescent indicators and molecular biological tools, the new technology will allow Tiffert and Lew to test their hypotheses about the pre-invasion stage of the disease. They hope to determine the critical steps, which could provide clues as to how to stop an infection. “This microscope is an extraordinary new tool that has potential for use across a huge field of biological problems involving cellular interactions,” explained Lew.

“It may provide a route to designing effective antimalarial drugs, reducing invasive efficiency and decreasing mortality,” said Tiffert. “ ̽��ֱ��automation we have achieved with this microscope will also be very important for future testing of malaria drugs and vaccines,” added Cicuta.

A visionary initiative

“ ̽��ֱ��Physics of Medicine Initiative has been essential to our work,” said Cicuta. ̽��ֱ�� ̽��ֱ�� formally established the Initiative in December 2008 through the opening of a new purpose-built research facility adjacent to the Cavendish Laboratory, funded by the ̽��ֱ�� and ̽��ֱ��Wolfson Foundation. ̽��ֱ��goal is to break down traditional barriers that have tended to limit interactions between researchers in the physical and biomedical sciences.

“I met my collaborators through a Physics of Medicine symposium, and the new building is the only place in the ̽��ֱ�� where this type of research can be done,” added Cicuta. “It’s set up for safe handling of hazardous biological organisms like P. falciparum, and also has the facilities to design hardware for our advanced microscopes. This work is exciting because it’s interdisciplinary. By applying physics to the knowledge biologists have been developing for many years, we can make very fast progress.”

For more information, please contact Jacqueline Garget at the ̽��ֱ�� of Cambridge Office of External Affairs and Communications

A ground-breaking imaging system to track malarial infection of blood cells in real time has been created by a collaboration catalysed by the ̽��ֱ��’s Physics of Medicine Initiative.

Finding Malaria's Weak Spot

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