Medical research in the news

Epilepsy in vitro

Researchers at Newcastle University have observed spontaneous epileptic activity in brain tissue removed from patients during surgery as part of their treatment.

Thanks to this breakthrough, they have discovered why traditional drugs which target chemical release from nerve cells are ineffective in almost a third of patients: the signals which send these patients’ brains haywire are electrical rather than chemical. Although brain disorders are notoriously difficult to mimic in the lab, this sort of insight could only be obtained by looking at real patients, rather than animal ‘models’. Now scientists have high hopes that they will be able to find effective drugs to help such patients – of whom there are an estimated 45 million worldwide – so that they will no longer have to resort to surgery.

‘Until now we have only been able to mimic epilepsy using experimental animal models but this can never give you a true picture of what is actually going on inside the human brain in epilepsy’
– Dr Mark Cunningham, Institute of Neuroscience, Newcastle University.

Reference: ScienceDaily.com, 1st December 2009

Clinical trials in a dish

‘It feels like we’re on the cusp of a revolution. This is a breakthrough – to take human cells and use them to make the tissue involved in the disease’
– Dr. George Daley, Associate Director of the Stem Cell Institute at Children’s Hospital Boston and Co- Chairman of Ipierian’s scientific advisory board.

Scientists have taken skin cells from a patient with a rare heart disorder and turned them into heart cells.
The skin cells, which are obviously much safer & easier to extract than heart cells, are specially treated so that they become stem cells – the cells which eventually give rise to all the cells in the body. These are then ‘reprogrammed’ in the lab so that they turn into heart cells with the same problem seen in the patient. Thus scientists have an endless, safe & ethically obtained supply of defective human cells. They can be used to study the basic biology of the disease, and perhaps most promisingly of all, to design and test new drugs.

Around the world, skin cells have also been turned into muscles, nerves, kidney, liver & other organs from patients with devastating genetic diseases. John Walker, CEO of Ipierian, a company which develops & uses these cells to discover treatments, believes that using human cells instead of animals will not only give more accurate results, but could also cut the time taken to get drugs to patients by years.

Reference: Forbes Magazine, 5th October 2009

A whole (human) system

Leeds-based Kirkstall has developed an advanced commercially available cell culture system which links human cells from different organs of the body together to form a ‘quasi vivo’ mimic of the human body.

Drugs can be added to the ‘body’ and the complex interactions between the different ‘organs’ observed. For example, the liver is crucial to drug metabolism, and the effect of the drugs’ metabolites on a variety of organs can be determined simultaneously. The result is a more accurate – and economical – model of what will happen in people, and they are currently working hard to validate it.

Kirkstall believes that barriers to the adoption of sophisticated human biology-based techniques are regulatory rather than technological, as regulatory agencies have simply grown accustomed to relying on animal test data.

US company, Hurel (Human-relevant) has developed a system designed to achieve similar results, and spoke at our Speed & Safety in Drug Discovery conference at the Royal Society in 2008 (see their presentation at www.drugtestingconference.com). By eliminating the time, money and potential inaccuracies associated with animal testing, Hurel estimates their test could shave $100 million off the roughly $1 billion cost of developing a new drug.

Reference: outsourcing-pharma.com, 20th October 2009

Toxichip

A 3 year project, called Toxichip, is being funded by the European Union to develop two types of biochip: one using bacteria engineered to change colour in the presence of dangerous chemicals in the environment, and one for the toxic assessment of chemicals using cultured human cells. The latter chip will find use, not only in evaluating chemicals for environmental risk, but also in looking at drug safety. The chip will allow cellular responses to drugs (or chemicals) to be assessed in combination, which is important as many patients need to take more than one drug at a time, and people may be exposed to many agents simultaneously in the environment. By incorporating microfluidic, electronic and computer technologies, the aim is to produce chips that can be used quickly, simply and cheaply to assess the risks posed by new drugs or chemicals more accurately than animal tests.

Reference: RTÉ News 30th November 2009

Superior human tissue

In another example of innovative UK companies rising to the challenge of developing human biology-based tests, University of Oxford spin-out Zyoxel is using bioreactor technology to grow human tissues in environments closer to those the cells experience in the body.

‘Recent research has shown our technology can be used to culture more realistic cancer tissue for testing, offering a powerful new tool for cancer drug discovery programmes’
– Prof Cui, University of Oxford & Zyoxel technology co-inventor.

This boosts test accuracy, cuts drug development times & potentially slashes costs by at least 10%. As Zyoxel CEO Dr Tim Hart estimates that failure to detect toxicity early in drug development costs the industry about £5 billion each year, the impact could be huge.

The company’s advances have not gone unnoticed as far afield as China, where a company keen to have such technology on-board has invested £1million to help fund test development.

Reference: Oxford Mail, 19th July 2009

Cancers catalogued

Scientists have unlocked the entire genetic code of two of the most common cancers – skin and lung –identifying 90% of the mutations in two human cancer cell lines. Not only will these ‘mutational signature’ maps pave the way for blood tests to spot tumours far earlier, they will also yield new drug targets, says the Wellcome Trust team.
‘This is a landmark moment in cancer research. From this moment on, this is going to be our expectation for what we want to know about individual cancers – it resets our ambitions for cancer’ – Professor Michael Stratton FRS, Wellcome Trust and Institute of Cancer Research.

Reference: TheScientist.com, 16th December 2009

Blood donor to VaxDesign "immune system in a test tube" research programme benefits from early cancer detection

A member of the public who donated blood to biotech company VaxDesign as part of their programme developing in vitro immune systems has discovered that he had leukaemia much earlier than would ever have been picked up by conventional tests. Scientists at the company recognised abnormalities in his blood sample and flagged this up with his doctor. After discussions between the researchers & the donor's doctor, tests were identified that could help pinpoint what was the matter - although it took a further month for conventional tests to identify the same changes that VaxDesign's technology had shown up. It would probably have taken another seven years before the problems the gentleman had were diagnosed conventionally.

VaxDesign's "immune system in a test tube" technology is currently being used for vaccine and immune-modulating drug testing, and can also be employed to predict how any individual will respond to a new drug or vaccine, advancing the goal of personalised medicine. It's hoped that VaxDesign's technology will now also lead to vast improvements in diagnostics, being far more sensitive as well as faster and cheaper.

After the diagnosis, the grateful donor asked if he could make a testimonial about what the technology did for him, which you can view here: http://www.youtube.com/watch?v=1wNWv_a-upc

Virtual humans a step closer

Dr Peter Kohl, a researcher at Oxford University, where Professor Denis Noble pioneered the virtual heart (see our film, Safer Medicines) is driving research into the use of computer models to improve heart surgery. His team aims to use heart scans combined with modelling to investigate surgical options before the patient is operated on, to ensure they receive the best treatment first time. His research is part of an international drive to model the human body known as the Virtual Physiological Human initiative.

Meanwhile, the US Food and Drug Administration, the world’s largest drug regulator, has entered into a partnership with Entelos, a company which specialises in modeling patients and even whole clinical trials. Their advanced computer simulations, which they liken to ‘flight simulators’ for predicting how a drug will react, will be used to focus particularly on risks associated with the heart, to try to improve the safety of drugs released onto the market. It is believed that had the Entelos system been available at the time, the Vioxx painkiller tragedy, where tens of thousands of patients died of heart attacks and strokes, could have been avoided.

James Karis, CEO of Entelos remarked:

‘Currently, it is a trial and error process to try and predict clinical response, but given the high failure rate [of investigational drugs], clearly it doesn’t work very well.’

References:
BBC News online 12th January 2009,
Outsourcing-pharma.com, 23rd Decemeber 2008,
Pharmalot.com, 12th Decemeber 2008.

Test to prevent another Northwick Park

Using a mixture of human immune cells, scientists have developed a test that replicates the devastating side effects seen in six young volunteers who almost died while testing a new drug that had been shown to be safe at 500 times the dose in monkeys. The test is already being used by drug companies working on other drugs that may interfere with the human immune system.

‘We have made significant progress in designing new in vitro tests that hopefully will avoid the consequences that occurred with TGN1412 (the Northwick Park Hospital drug); indeed such tests could prevent harmful drugs of this type even reaching the animal testing stage’ – Dr Stephen Poole, National Institute for Biological Standards and Control

Reference: British Medical Journal 337:a3061, 18th December 2008.

Stem cell breakthrough

‘The animal models are pretty useless, to be honest’

– Professor Clive Svendsen, University of Wisconsin- Madison, USA

Spinal Muscular Atrophy (SMA) is a devastating condition that kills nerve cells controlling muscles, causing paralysis and death, usually by the age of two. American scientists have now been able to recreate nerve cells affected in the same way, using skin cells from an affected child. The skin cells were ‘reprogrammed’ to turn into stem cells and then prompted to become nerve cells, meaning that a limitless supply of these cells will now be available for study.

Professor Svendsen explains: ‘Now you can replay the human disease over and over in the dish and ask what are the very early steps that began the process.’

The cells have already been used to test two potential treatments, and should be available for large scale drug screening within a couple of years. According to Professor Chris Mason, a leading stem cell researcher at University College London, these cells will ‘play a major role in future drug discovery.’

Reference: Nature, 22nd December 2008.

New drugs more likely to harm than help

‘Drug disasters are literally built into the current system of drug testing and approvals in the United States’ – Donald Light, Professor of comparative health policy at the University of Medicine and Dentistry of New Jersey

Professor Light’s study shows that whilst one in seven new drugs is superior to existing treatments, two in every seven result in serious side effects. Thus new drugs are twice as likely to harm some patients as to provide them with benefits superior to existing drugs. Professor Light believes this is partly due to the fact that drugs are approved based on superiority to a placebo, rather than to existing drugs. Another reason is that clinical trials are too short and use volunteers who are not representative of the populations who will actually use the medicines.

The European Commission has estimated that across the EU, adverse drug reactions cost 197,000 lives and €79 billion each year. Hopefully this situation will be improved by new EU regulations mandating enhanced monitoring of drugs for side effects after they have been marketed.

References:
American Sociological Association press release, 3rd August 2008,
Outsourcing-pharma.com, 15th December 2008.

Drugs double risk of death

A large study of newer treatments for schizophrenia, autism and dementia, such as Risperdal, Zyprexa and Seroquel, has found the drugs double the risk of death from sudden heart failure in patients over the age of 30. Previous research showed that three out of four new drugs tested were no more effective than their older and much less expensive predecessors for treating schizophrenia, and no better than placebos for dementia-related psychosis.

A study funded by the Alzheimer’s Research Trust reveals that up to 23,500 dementia patients are being killed by the drugs each year. A report from the allparty parliamentary group on dementia stated last year that almost three quarters of those taking the drugs were given them inappropriately – at a cost of more than £60 million a year.

References: New York Times, 14th January 2009,
The Times, 9th January 2009.

New study blames animal tests for thalidomide

‘The rapid and fatal approval of thalidomide at that time ultimately was a consequence of the sole use of thalidomide-insensitive species in animal toxicity tests.’

Fifty years after the thalidomide tragedy, a new paper was published in December that reveals why rats and mice are resistant to the terrible effects of thalidomide in humans.

This knowledge could help scientists to make thalidomide safer for those who depend on it today for conditions including leprosy and multiple myeloma. The supreme irony of thalidomide is that while the tragedy prompted worldwide regulations demanding animal tests for drug safety, those same animal tests would still fail to alert us to the hazard of thalidomide even today.

Reference: Molecular Pharmaceutics, 1st December 2008.

Resistance to HIV

By studying people who have been exposed to HIV and yet do not go on to develop AIDS, scientists have discovered what makes these lucky few resistant. Using genetic techniques on blood samples, they found that such people have cells that produce more of a particular protein. When cells from patients with AIDS were stimulated in the laboratory to produce more of the same protein, they too were much more successful at killing virus-infected cells. It’s hoped that this discovery will lead to vaccines that could stimulate everybody’s immune systems to behave in the same way.

Refs: The Scientist, NewsBlog 4th Dec 08, Migueles et al, Immunity 29 (6): 1009, 4th Dec 08.

Cancer genetic blueprint revealed

Scientists have decoded the complete DNA of a cancer patient and traced her disease to its genetic roots.

Dr Francis Collins, former director of the US National Human Genome Research Institute, called the study a ‘true landmark in cancer research.’ He said:

‘In the past, cancer researchers have been ‘looking under the lamp-post’ to find the causes of malignancy - but now the team from Washington University has lit up the whole street.

This achievement ushers in a new era of comprehensive understanding of the fundamental nature of cancer, and offers great promise for the development of powerful new approaches to diagnosis, prevention and treatment.’

Reference: BBC News online, 6th November 2008.

Call to study humans, not mice

‘Mice are lousy models for clinical studies’

– Professor Mark Davis, Director of the Stanford Institute for Immunity, Transplantation and Infection, California.

Prof Davis calls for a national or even international effort to collect information from human blood and tissue samples. He says:

‘We can’t depend on the mouse for all the answers, because in some cases it’s not giving us the right answers. But think about what we can do with people. People come to hospitals, get vaccinations, give blood and tissue samples for routine lab tests and clinical trials. We’re not learning nearly as much as we could from these samples. We seem to be in a state of denial, where there is so much invested in the mouse model that it seems almost unthinkable to look elsewhere.’

Reference: Immunity 29: 835, 19th December 2008.

Personalised Medicine Blood test for lung cancer treatments

Lung cancer still kills 30,000 people every year in the UK alone. By looking at patients’ blood, scientists have discovered that they can predict which patients are most likely to be resistant to treatment. This could help doctors to decide what sort of treatment a patient needs early on, help monitor progress and perhaps select patients for particular clinical trials.

Reference: BBC News online, 31st December 2008.

Test for Tamoxifen resistance

‘Previously our understanding of why this occurred could be compared with trying to fix a broken car without knowing how the engine worked’ – Dr Jason Carroll, Cambridge Research Institute

Research has previously shown that only women with certain genetic features will respond to anti-breast cancer drug Herceptin, and this finding has now been extended to another important treatment, tamoxifen. By studying tissues donated by cancer patients, scientists in Cambridge have discovered that they can predict the quarter of patients whose tumours will become resistant to tamoxifen, meaning that those patients can be treated with a more suitable drug from the start. The new test, which should be available within five years, stands to benefit thousands of women. Meanwhile, understanding how some tumours become resistant to drugs could help researchers to develop new anti-cancer treatments.

References: BBC News online, 13th November 2008;
New York Times, 29th December 2008.

Childhood brain tumour clue

‘We think this important finding will be vital in guiding our future research’ –Dr Lesley Walker, Cancer Research UK

The genetic root of an aggressive form of childhood brain cancer, pilocytic astrocytoma, has been uncovered by another group of Cambridge scientists who conducted genetic scans of patients’ brain tumours. It should now be possible to tailor treatments to patients more accurately, as scientists now have a way of differentiating between certain types of cancer. Also, because researchers know what genetic fault triggers the development tumour development, they can begin to construct treatments designed to specifically target the cause of the tumour.

Reference: BBC News online, 1st November 2008.

Personalising brain tumour treatment

‘This is a hugely important development for the patients in terms of morale’ – Dr Willie Stewart, head of Institute of Neurological Sciences

Doctors from Glasgow’s Southern General Hospital have identified a way of profiling patients’ tumours in order to identify who would benefit most from radiotherapy, and who from chemotherapy. The researchers have discovered that tumours have different molecular ‘signatures’ or profiles that identify them as being more responsive to one treatment. This discovery means that many patients will be spared unnecessary side effects, and receive the most effective treatment as early as possible. More centres plan to offer the same tailored service soon.

Reference: BBC News online, 6th November 2008.

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