Medical research in the news
Heart drug blunder revisited
An article in the prestigious science journal Nature discussed the now discredited use of anti-arrhythmia drugs after heart attacks. These drugs were supposed to save lives by reducing irregular heart beats.
Subsequent reviews of the outcomes for patients who had received these drugs, compared with those who had not, caused consternation when it was discovered that the drugs more than doubled the risk of death or heart attack:
‘Everyone was so confident that if you quieted the extra heartbeats, the patients would do better, but people died.’ Dr Harlan Krumholtz, Yale University.
‘It is not easy to think of a greater medical error, since the practice of therapeutic bleeding, than the use of antiarrhythmic drugs in patients after myocardial infarction.’ Robert Temple, director of the Office of Medical Policy at the US Food and Drug Administration (Clinical Measurement in Drug Evaluation, 1995).
The author reminded readers that the use of the drugs:
‘depends principally on tradition, on an unproven expectation that antiarrhythmic effects are likely to be beneficial for potentially lethal arrhythmias as well as for less malignant conditions, and on extrapolation from animal experiments.’ (Chamberlain, Heart 1998; 80: 408).
Reference: Nature 452, April 2008: 510.
 Adverse drug reactions cost NHS £2bn
Compass, a London-based thinktank, has revised the latest estimates for the cost of adverse drug reactions dramatically upwards.
According to Health Minister Dawn Primarolo, 6.5% of hospital admissions (well over a million) are as a result of bad reactions to prescription drugs. When the cost of caring for
patients who become ill whilst already in hospital as a result of drugs they are prescribed is factored in, Compass estimates that the cost to the NHS is £2billion.
With the NHS coming under ever increasing pressure to provide expensive drugs to patients, it is imperative that the burden of adverse drug reactions be reduced. Part of the solution would be to introduce more personalised medicine (making use of genetic and other testing techniques to check whether a drug is suitable for a patient). Also, to ensure that only drugs with the best safety profiles are marketed, more extensive clinical trials need to be carried out, preceded by the most human-relevant laboratory tests.
Reference: the Guardian, 3rd April 2008.
Every cloud has a silver lining?
Researchers writing in the journal Science have found, using test tube-based experiments, that unexpected uses for drugs may be identified by comparing the side effects they cause with those of other, unrelated drugs. This finding makes it even more important that accurate information about the side effects patients experience is collected and analysed.
Reference: Science, 321: 263, July 2008
 Mice are not men
A study published in the prestigious journal, the Proceedings of the National Academy of Sciences, in May has found that although humans and mice share about 85% of their genes, 22% of genes known to be essential in humans are not at all essential in mice. This casts serious doubt over the relevance of using mice to find out the roles of genes in humans.
Another study published in the Proceedings of the National Academy of Sciences (PNAS) in July showed that a gene which promotes colon cancer growth in mice has the opposite effect in human colon cancer cells. So a drug designed to suppress this gene or its protein product - based on its function in mice - might actually speed the growth of colon cancers in people.
References: PNAS 105:6987 and 105:9697
 Virtual children
‘We now have a tool which allows complex clinical scenarios to be explored in the safety of a computer.’ Professor Amin Rostami
Testing medicines in children has always been difficult as they cannot give consent to participate in trials and parents are, naturally, wary of exposing their children to unknown risks. However, thanks to a computer model developed by Sheffield-based company Simcyp, it should now be much easier to calculate safe doses. This development could not have come at a better time after a new EU regulation demanding that medicines destined for children must now have been tested especially for them. This makes sense as it is now acknowledged that children cannot simply be treated as scaled-down adults:
‘In particular, children under two years old are the most physiologically different to adults, so it can be too simplistic to scale back from adult values when determining appropriate doses for children, as currently happens.’ Amin Rostami, Professor of Systems Pharmacology at the University of Sheffield and director of research and development at Simcyp.
Reference: The Times, July 28 2008.
 Animal pain research criticized
‘In my research, animal models don’t represent human patients sufficiently well, and that’s a problem that extends across pain research as a whole. New and highly sophisticated brain-imaging technology is providing vital insights that animal research has failed to produce. I would like to see far greater uptake of these and other human-relevant approaches to pain research to help us develop the effective treatments that patients so desperately need.‘
Professor Qasim Aziz, Barts and the London School of Medicine and Dentistry.
A report in the journal Neuroimage has criticised the use of animals in pain research.
The report’s authors encouraged scientists to make better use of the latest technologies, such as MRI scanning, in ethically conducted studies in people who actually suffer from the pain they are trying to treat. The role of human tissues grown in the lab was also emphasised.
Pain research experts from leading institutes across the UK made these recommendations at a workshop organised by Focus on Alternatives, a coalition of notfor- profit organisations promoting non-animal research, including the UK Human Tissue bank and chaired by the Dr Hadwen Trust.
Reference: NeuroImage 42:467.
Animal studies contribute very little to human healthcare
A review of the contribution of animal-based studies has failed to find significant agreement between the results seen in animals and in humans. The author examined an extensive list of published research, including experiments conducted on chimpanzees, and found that they were generally very poor at predicting human outcomes and contributed little to the development of successful human treatments.
Reference: Knight, Reviews on Recent Clinical Trials, 2008; 3(2): 89.
Animal tests miss liver poisons
Scientists have reviewed the ability of animal tests to predict which drugs will harm patients’ livers and found that they miss dangerous chemicals around half of the time.
Perhaps surprisingly, non-rodents (such as pigs or monkeys) predicted human toxicity in many cases only 19% of the time, which is even less often than rodents (such as mice or rats), which can correlate as poorly as 46% of the time! These astonishing figures go some way towards explaining why 92% of drugs fail in human trials, despite undergoing extensive animal tests.
The pharmaceutical researchers who wrote the report, Species Concordance for Liver Injury, are part of an initiative known as the Safety Intelligence Program. They are currently trying to understand why the animal tests translated so poorly to humans; hopefully they will now look at human biology-based methods for predicting liver toxicity as a means of improving this abysmal track record.
Reference: Nature Reviews Drug Discovery 7:719, September 2008.
 Brain Bank appeals for donors
The Parkinson's Disease Society Tissue Bank, at Imperial College London opened five years ago to provide a vital resource to any researcher wishing to study Parkinson's Disease. The bank has since received more than 250 brains. However, perhaps unsurprisingly, the majority of donors have been patients with Parkinson's Disease, leaving a shortfall of only 17 ’control’ brains, which can be used for comparisons between the brains of sufferers and non-sufferers of this debilitating disease.
"Alzheimer's, Parkinson's and other neurodegenerative diseases occur in humans and it is in human tissue that we will find the answers to these diseases." Dr. John Xuereb, Director, Cambridge Brain Bank Laboratory (BBC Radio Cambridgeshire, 2002).
For more information on becoming a donor, contact the UK Parkinson's Disease Society Tissue Bank: 0207 594 9732, pdbank@imperial.ac.uk or visit www.parkinsons.org.uk
Read the whole article from the Times, 30th August 2008
VaxDesign CorporationVaxDesign builds "clinical trial in a test-tube" for vaccines
There is an urgent need for technologies that can mimic the human immune system, as time and again animal tests have shown that they are simply not up to the job. An excellent article in Time magazine on 27th March, showed how the answer has now arrived in the shape of a human-relevant, fast test that can be performed entirely by robots, developed by a Florida company called VaxDesign (www.vaxdesign.com).
According to William Warren, president, CEO and co-founder of VaxDesign:
"We know animal models do not translate to human responses...Animal models of treatments for HIV to psoriasis and flu are not representative of human responses" (TechJournal South, 2nd October 2007).
The scientists at VaxDesign saw this urgent need for something that was more relevant to people and the MIMIC (Modular IMmune In vitro Constructs) system was born.
MIMIC uses plastic dishes with almost 100 wells in which cells from different human blood samples are grown. This means that you can effectively test the impact of a new vaccine on hundreds of humans, safely and rapidly, before a single volunteer has to be exposed! Scientists at the company are confident that this revolutionary technology therefore offers benefits that animal tests can never hope to provide. Michael Rivard, vice president of corporate development at VaxDesign says that:
"The information you get from this type of test is far and beyond what you'd get out of a mouse study, both because it's humans and because you can see the effect across a spectrum of genotypes (different genetic make-ups)." (quoted in Time magazine, 27th March)
In March, the International AIDS Vaccine Initiative bestowed its first ever Innovation Award on VaxDesign. Their approach is supported by Wayne Koff, senior vice president of research and development at the International AIDS Vaccine Initiative, who commented:
"In the end, you can only extrapolate so much from a monkey model." (quoted in Time magazine, 27th March)
More funding for AIDS vaccine research in monkeys despite record of total failure
Meanwhile, many AIDS vaccine researchers (and their funders) appear determined to keep their heads buried in the sand. In the wake of several high profile vaccine failures, some of which actually increased the risk of infection with HIV, doubts about our ability to produce a vaccine have resurfaced:
"Despite hundreds and hundreds of millions of dollars, the reality in 2008 is that an HIV vaccine clearly remains beyond our grasp." Prof Warner C. Greene, University of California, San Francisco (quoted in The Baltimore Sun, 26th March).
This has led to calls on some sides to focus resources on proven strategies to help prevent the spread of infection and provide drugs to those who need them.
“I think we should pull the plug on vaccine research. Do we have any other enterprise that has been studied for 25 years and for which we’ve spent billions of dollars where we have no results?” Michael Weinstein, President of the AIDS Healthcare Foundation (quoted in The Washington Post, 26th March).
Clearly the focus needs to be on patients and human biology-based research, rather than on attempting to improve animal "models" and tests.
"When it comes to testing HIV vaccines, only humans will do." Alison Tonks, British Medical Journal, 2007;334;1346.
A poll conducted by the Independent has revealed that most leading AIDS researchers are deeply pessimistic about the prospects for developing a truly effective vaccine within 10 - 20 years (if ever). Moreover, Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases (NIAID) told the Independent that:
"We've learnt a few important things [from the clinical trial]. We've learnt that one of the animal models, the SHIV [an artificial virus meant to mimic the human virus but capable of infecting monkeys] model, really doesn't predict very well at all. At least we now know that you can get a situation where it looks like you are protecting against SHIV and you're not protecting at all in the human model – that's important." (the Independent, 24th April)
Yet despite accepting that the major animal model for AIDS is not predictive for humans, and significant doubts about the ability of tests in animals to ever produce a successful vaccine, the US NIAID has vowed to continue to fund and promote much more basic research… in animals.
"We will not discontinue research, period. Not only will we not decrease it, we will in fact try to increase it." Dr. Anthony S. Fauci, director of the NIAID (quoted in The Baltimore Sun, 26th March).
This is particularly alarming given that about a third of the NIAID's £1.45 billion budget goes on HIV vaccine research. Let's hope that the other agencies rethink their strategy along the lines of the International AIDS Vaccine Initiative, which is supporting VaxDesign's human immune system in a test-tube, and whose senior vice president of research and development asserted:
"[getting from small animal studies to monkeys] takes a lot of time, and, with HIV, we don't have a lot of time. We asked the question is there a way to do it faster and take it to humans more quickly?" (quoted in Time magazine, 27th March)
US Government Agencies move to replace animal tests
Following the revolutionary US National Research Council report published last June (http://safermedicines.org/reports/toxicitytesting.shtml), three agencies — the Environmental Protection Agency, the National Toxicology Program and the National Institutes of Health — have outlined a collaboration to replace animal tests with faster, cheaper and more human-relevant methods, using many of the technologies that are already available (published in top journal Science, 15th February 2008).
Almost 3,000 environmental chemicals are now being screened in over 50 cell-based tests. The results will then be compared with information already gleaned from humans and past animal tests. A highly encouraging study has already put over 1,400 chemicals through a battery of 13 cell-based tests. Unsurprisingly, they found differences between the way in which human and animal cells reacted: 'A striking finding from the current study is the lack of similarity in the patterns of compound activity in cells derived from the same tissue but from different species' (NIH scientists Menghang Xia & colleagues, Environmental Health Perspectives, March 2008). Surely this illustrates how important it is to focus on using human cells as it is humans that must be mimicked.
Discussing this ground-breaking venture, Dr. Francis Collins, who led the publicly funded project to sequence the human genome and is now the Director of the National Human Genome Research Institute, told reporters at an American Association for the Advancement of Science conference: 'We are not rats and we are not even other primates… After all, ultimately what you are looking for is, does this compound do damage to cells? Can we, instead of looking at a whole animal, look at cells from different organs?'
He was backed up by another eminent scientist, Dr Christopher Austin, Director of the National Institutes of Health Chemical Genomics Center, who explained that 'Traditional animal testing is expensive, time-consuming, uses a lot of animals and from a scientific perspective the results do not necessarily translate to humans.'
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