Outsmart Ebola Together

Outsmart Ebola Together – a collaboration project using idle computers to search for compounds to cure Ebola

The World Community Grid, a volunteer computing platform developed by IBM that uses the idle computer time of internet-connected computers to perform research calculations, has teamed up with the Scripps Research Institute to help find chemical compounds to fight Ebola Virus Disease.

The aim of this collaboration project called ‘Outsmart Ebola Together’ is to find drugs with high binding affinity with certain of the Ebola virus’ proteins, which can then block the crucial steps in the life cycle of the virus. Currently two targets have been identified: a surface protein used by the virus to infect human cells, and "transformer" proteins which change shape to carry out different functions.

Deadly pathogen

The Ebola virus is a member of the filovirus or Filoviridae family and is shaped like a long, flexible filament. This filament can attach itself to cells and penetrate the cells. The virus then uses the host cell’s mechanisms to replicate itself after which numerous copies of the virus are then released to further infect nearby cells. The result of this repeat infection and replication results in clotting of the blood, leakage from blood vessels, inflammation, organ failure and shock. Infection only occurs by contact with an infected person’s bodily fluids or the body of patient who died from the disease. The virus cannot be transmitted through the air or water. Other members of the filovirus family are Marburg, Sudan and Reston viruses, which are all very virulent and deadly pathogens. These four viruses all have caused outbreaks in 2014 in Africa and Asia (animals only). The Ebola virus has infected over 15,000 people and killed at least 7,500 in West Africa (data of WHO), representing a case-fatality rate of 36%. 

Therapeutic agents under consideration

Currently there are no treatments or vaccines available, but numerous research projects are ongoing, esp. since the 2014 outbreak. This has been confirmed by Marco Cavalari, head of Anti-infectives and Vaccines at the European Medicines Agency (EMA). The EMA has reviewed several potential treatments for Ebola in order to have an overview of data from these treatment and to support decisions on potential emergency use for individual patients. However, they found that evidence for safety and efficacy of the included treatments (which were selected as they have direct virus activity) was not yet sufficient to draw any conclusions.  The therapeutic agents considered by the EMA were three nucleos(t)ide polymerase inhibitors (BCX4430, Brincidofovir and Favipiravir), two oligonucleotide based products (TKM-100802 and AVI-7537), a cocktail of monoclonal antibodies (ZMapp) and polyclonal immunoglobelins derived from immunized horses (Anti-Ebola F(ab’)₂ fragments). These potential treatments are all based on newly developed compounds or compounds currently registered for treatment of other viruses. The WHO has confirmed that two vaccines are in safety trials for use in Ebola affected countries.

Millions of candidate drug molecules

The Outsmart Ebola Together project of the World Community Grid and the Scripps Research Institute however uses a different approach as it is screening the structures of millions of known candidate drug molecules (ligands) against the atomic structure of the target Ebola virus molecule (targets). This screening by using computers, called in-silico screening, uses specific software developed by the Olson Laboratory at the Scripps Research Institute. The target and ligand are evaluated with regard to binding affinity between the molecules. Such screening is traditionally done in a laboratory using test tubes and actual chemicals which have to synthesized first is sufficient quantity, a very laborious and costly business. The screening can however also be done by using software in which the structures of the target and ligands are analyzed and will result in the binding affinity value. The Scripps Research Institute has already solved the structures of the  critical target proteins of the virus and converted these to molecular images. Two of these targets have been identified for inclusion in the Outsmart Ebola Together collaboration project.

Transformer protein

The first target is a surface protein on the Ebola virus that is responsible for injection of new human cells. This target protein is similar for Ebola, Marburg, Reston and Sudan viruses so it could potentially lead to a drug effective against any of these viruses. The second target is a so called shape-shifting ‘transformer’ protein of the Ebola virus, which adopts different forms at different times of the virus lifecycle to achieve different functions.

If a suitable candidate drug molecule, based on a high binding affinity with the Ebola virus protein, has been selected, this can then be tested in the lab. Additional trials will then be necessary to optimize the compound and find a suitable formulation of a drug product. All results from the Outsmart Ebola Together project are shared so that other scientists around the world can use this data as well in their own research to find a cure Ebola. The Scripps Research Institute in La Jolla, California, USA is a non-profit research institution which is on the forefront of such ‘open source’ research in the biosciences. 

On 30 December, the project had already ‘run’ for 132 years, 155 days and 16 hrs, generating 193,870,193 points and returned 491,434 results. This is only 1% of the project. You can help the researchers by donating your computing power to this project. Anyone with a computer, smartphone or tablet can donate their unused computing powder to scientists by installing an application on these devices which runs when they are not using the full capacity of their computer. By connecting all these computers, the World Community Grid is essentially a virtual supercomputer, using its computational power for humanitarian research. Other projects include the Clean Energy Project and the FightAIDS@home project.

Solution to resistance - a lesson in chirality

Jørn Bolstad Christensen, a chemist from the University of Copenhagen has obtained a patent for a drug that can make previously multidrug-resistant bacteria once again responsive to antibiotics. Christensen, together with doctors Jette Kristiansen from the University of South Denmark and Oliver Hendricks from the King Christian X’s Hospital for Rheumatic Diseases in Gråsten, Denmark, discovered that Thioridazin, an antipsychotic drug, was able to kill bacteria without any noticeably harmful effects upon humans.

Thioridazin, who’s chemical name is 10-{2-[(RS)-1-Methylpiperidin-2-yl]ethyl}-2-methylsulfanyl phenothiazine was registered as an antipsychotic drug and used in the treatment of schizophrenia and psychosis, but has also been reported to have antibacterial properties. Due to the many side effects and cardiotoxicity, the drug Thioridazin has been withdrawn from many countries and is no longer used for treatment of schizophrenia and psychosis. The Thioridazine as included in the antiphychotic drug is a so called ‘racemic mixture’, the combination of 50% (S)-thioridazine and 50% (R)-thioridazine. The (S) and (R) indicate the two enantiomers or ‘mirror images’ of each other. Dr Ruben Thanacoody, a physician at the Royal Infirmary Edinburgh, discovered that it was the R-Thioridazine which was responsible for most of the anti-psychotic activity, but that both R- and S-thioridazine were capable of inhibiting bacterial growth. This was further substantiated by the study from Christensen. Hence the idea was born to isolate the separate S-thioridazine and use this as an antimicrobial agent.

(S)-Thioridazine’s own antibacterial properties are not that spectacular, but other researchers from the University of Southern Denmark revealed what the actual effects of Thioridazine on the gene expression and cell wall composition of a drug-resistant bacteria called Methicillin-Resistant Staphylococcus aureus were. Thioridazine acts by blocking the efflux pump of bacteria, which is responsible to pumping any unwanted chemicals out of the bacterial cell. So if another antibacterial agent is given, due to the lack of ‘outflowing’ opportunities , the concentration of the other antibacterial agent within the bacterial cell increases. Jørn Bolstad Christensen has put this idea into practice and obtained said patent to pair (S-)Thioridazine and other antibacterial agents.

If this drug (currently called JEK 47) will become available in Europe, depends on the interest of investors in this substance. “I would rather donate this discovery to an NGO able to use this substance in poor countries that suffer from drug-resistance problems than watch it collect dust in the industrialised world. So, I hope that an investor comes along to develop this ground-breaking substance,” concludes Bolstad Christensen.

Direct to Consumer Genetic Testing (DTC-GT) and the physician’s role

Direct-to-consumer (DTC) genetic testing is a type of genetic test that is accessible directly to the consumer without having to go through a health care professional.  In clinical practice, the health care professionals are the ones requesting for genetic testing and obtain informed consent of the patient. However, for some genetic tests, consumers can obtain such a test themselves. They only have to collect a sample of their saliva in the provided test tube and send it to the DTC-GT company where the laboratory will analyze their DNA. There are a variety of DTC tests, including testing for breast cancer alleles to mutations linked to cystic fibrosis. Although the companies who develop and sell the DTC-GTs promote these tests with slogans like ‘to empower you with genetic insights to help motivate you to improve your health’, it is not expected that consumers themselves can correctly interpret the complex results. In genetic testing, the results are usually expresses as ‘risks’ to certain diseases or disorders and not a simple ‘yes or no’ outcome. In addition, these GT should be fully validated so as not to provide false-positive or false-negative results.

It is therefore not strange that consumers who have bought a DTC-GT then consult their physician for her/him to interpret the results. This provides the primary-health care physicians with quite a few dilemmas. First of all they themselves should be able to understand the type of test performed, the presented outcome and any possible consequences for the patient, which is not usual for non-geneticists. Secondly, they have to make sure the test results are valid and might have to order additional tests though the regular health care system. Thirdly, if the results indicate a high risk for a certain disease but possibly also for other diseases, is the physician obliged to report this to the patient who might not wanted to know this. So DTC-GT also put a burden on the physicians who have the moral obligation to inform patients, to treat them and to protect patient confidentiality.

As the prices of these DTC-GTs are expected to drop (DNA test are currently available for $99), physicians can expect an increase in patients who not only googled their symptoms, but might have gone an extra step and requested genetic testing. Canadian researcher Gillian Bartlett of the Department of Family Medicine of the McGill University in Montreal therefore urgently asks to develop best practice recommendations and identify the ethical, legal and social implications of DTC-GT.

The FDA has recently requested that several companies refrain from providing direct to consumer tests with health-related results, as they have not approved these tests yet.

 

 

 

Pharming for fish oil: Camelina plants produce omega-3 fatty acids

Scientists in the UK have genetically modified the Camelina plant to produce components of fish oils beneficial for cardiovascular health. Omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are traditionally sourced from fish, but can also be made in our bodies from another omega-3 acid called alpha-linolenic acid (ALA), found in nuts and vegetable oil. Although the richest source of the omega-3 fatty acids is fish, they themselves get the acids from their diet of smaller fishes that have eaten algae. These algae can synthesize the EPA and DHA. To obtain the EPA and DHA for human consumption, every year around a million tonnes of oil is extracted from ground up fish.

An alternative and more sustainable source of EPA and DHA has now been created by Noemi Ruiz-Lopez, Richard Haslam and Jonathan Napier from Rothamsted Resarch in the UK in the form of genetically modified Camelina sative plants. These plants, of the Brassicaceae family and usually called ‘false flax’, are already rich in ALA but have been ‘boosted’ by inserting seven genes of marine algea and other photosynthetic marine organisms into their genome. The seeds of this modified plant can be extracted and purified and the resulting oil can contain up to 12% EPA and 14% DHA. In addition to these health-beneficial fatty acids, the researchers have developed the plants in such a way that they do not contain undesirable intermediate (shorter) fatty acids. These ‘green factories’ could partially replace the current need for fish oil.

Imaga © rothamsted research

Overview of Measle Outbreak in 2013

The following confirmed cases of Measles have been reported worldwide in 2013:

• Australia (Queensland): 51, as reported by Queensland Health
• USA: 159 up to August 2013, as reported by the CDC
• UK: over 800 cases in the Swansea area, as reported by the NHS
• The Netherlands: 2,543 cases, as reported by RIVM
• Canada (Alberta); 42 cases, as reported by Alberta Health Services

Other notable outbreaks occurred in Indonesia (6,300 confirmed cases), Germany (1,520 cases), Turkey (7,132 cases) and Pakistan (over 30,000).
Most of these cases were in unvaccinated (82%) or incompletely vaccinated (13%) people.

In addition to the current measle outbreak, in Germany two cases of subacute sclerosing panencephalitis (SSPE), a rare, late complication of measles have been reported in 2013. SSPE occurs in general about seven years after having a measles infection. The CDC reports that it SSPE concerns a "progressive deterioration of behavior and intellect, followed by ataxia (awkwardness), myoclonic seizures, and eventually death." There is currently no cure for SSPE or measles, but both can be prevented by vaccination.