̽��ֱ�� of Cambridge - Cambridge Systems Biology Centre

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

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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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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Single component biology is past; bioengineering has begun

bjb42 — Wed, 01 Oct 2008 15:36:26 +0000

̽��ֱ�� ̽��ֱ�� of Cambridge has become increasingly aware of the major importance of recent advances at the interface between the life sciences, physical sciences and engineering. A key challenge is to assist the evolution of the established reductionist ‘molecular’ view of biology into a more quantitative, data-rich and predictive science, with an holistic and integrative understanding of its principles.

Research activities are crossing disciplines in efforts to address complex biological systems and provide technical solutions to current and emerging global concerns. Researchers are using new tools in predictive biology and synthetic biology for bio-product design – seeking to go beyond the analysis of enzymes, metabolic networks and cells to consider functionality and delivery as intimately linked elements of the design process. Developments in Cambridge are breaking new ground in biomechanics, tissue engineering and biomimetics: from strategies for restoring function to the damaged nervous system, to next-generation medical implants that interact therapeutically with the body, to the development of mechanically robust bone-like materials for engineering purposes.

̽��ֱ��need to integrate expertise in multidisciplinary research environments is well recognised in Cambridge, and 2008 sees the launch of two new research complexes. ̽��ֱ��Centre for the Physics of Medicine at the West Cambridge Site brings together researchers from the medical, biological and physical sciences to solve problems in healthcare and cell biology; and the Laboratory for Regenerative Medicine at the Cambridge Biomedical Campus provides a link between stem cell biologists, tissue engineers and clinicians for translating fundamental stem cell research to clinical benefits.

Systems biology also describes a multi-component approach, combining theoretical modelling with real data about the interaction between genes and their products. Arising from this is the need to interpret large datasets of complex biological information. ̽��ֱ��recently launched Cambridge Systems Biology Centre is enabling research groups from different disciplines to interact closely and develop a long-lasting multidisciplinary research environment.

Professor Nigel Slater, from the Department of Chemical Engineering and Biotechnology, describes how the influx of ideas and principles from non-biological disciplines is shaping a new biology.

Research activities are crossing disciplines in efforts to address complex biological systems and provide technical solutions to current and emerging global concerns.

Amy Loves Yah from Flickr

Bio Lab

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