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Pro-Test: standing up for science
Pro-Test: Standing Up For Science
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Keyword(s): breakthrough of the year

15/02/11

Permalink 10:27:27 pm, by Tom, 731 words, 17432 views   English (UK)
Categories: News

A fish named Hope.

If you have watched TV in the past week or two, you may have seen the excellent ads produced by the British Heart Foundation (BHF) as part of a major fundraising drive to support their new Mending Broken Hearts campaign.

The Mending Broken Hearts campaign is a major new multidisciplinary initiative which seeks to harness the power of regenerative medicine to better treat, and one day cure, heart failure. If you want to learn more about this work, the BHF website has information on the science behind the initiative, and why their scientists are studying zebrafish.

It is an ambitious and fascinating project, and an excellent example of how the differences between species can be as valuable to medical advancement as the similarities.

But that’s not all that is striking about this campaign.

This is a fundraising campaign by a major medical research charity that not only acknowledges the importance of animal research, but places it centre stage. Little more than a decade ago that would have been unthinkable.

When I first started my career in science in the late 1990’s public support for animal research in the UK was considerably lower than it is now, and few scientists willing to discuss their work in public or counter the misleading propaganda of animal rights activists. Animal rights extremists appeared to be able to harass, intimidate and coerce at will, using tactics such as hate mail, vandalism, arson, grave robbing and violence to force several animal breeders to close, and even contributing to a decision by Cambridge University to abandon plans to construct a new primate laboratory in 2004. As the 21st century dawned the future of biomedical research in the UK looked very bleak.

But behind the scenes things were changing. The tireless efforts of research advocacy groups including RDS and the Coalition for Medical Progress (now merged to form Understanding Animal Research ), Sense about Science, and Seriously Ill for Medical Research, who spoke up for animal research and countered the distortions spread by animal research, and the bravery of individuals including the Oxford neuroscientist Professor Colin Blakemore and patient activist Andrew Blake, who continued to speak out in support of animal research despite threats against themselves and their families, began to yield dividends. As time went on more and more scientists were persuaded to discuss the role of animal research in their work in more detail when talking to journalists, rather than referring obliquely to “laboratory studies”, and by the middle of the decade opinion polls indicated that public support for the use of animals in medical research had increased dramatically. Politicians also began to wake up to the threat posed to science in the UK by animal rights extremism, and the danger that other unrepresentative minorities might adopt the tactics of animal rights extremists to foist their views on the rest of society: Something had to be done. A series of laws were passed to prevent intimidation and harassment being used as campaign tools, while for the first time sufficient resources were made available to police units to counter domestic extremism.

The tide finally turned in the spring of 2006 when hundreds of citizens, scientists, students in Oxford joined together under the banner of Pro-Test to march in support the construction of a new animal research laboratory. Responding to threats by animal rights extremists, and inspired by the example set by Laurie Pycroft, the marchers showed that they would not be silenced and would not be intimidated. That rally, and the widespread coverage it received in national and international news media, released a pent-up wave of support from animal research that almost instantly changed the tenor of the debate on animal research in the UK. The new Oxford laboratory was completed in 2008.

Now five years later many of the animal rights extremists whose terror campaigns made the lives of so many people a misery are behind bars, and scientists are more willing than ever before to talk about the contribution of animal research to medical progress.

So the zebrafish are not just an example of the promise of 21st century medicine, but show us that if scientists and supporters of science stand together we can defeat extremism, we can counter the lies and distortions spread by animal rights campaigns, and we can secure the future of scientific medicine. That's a lot of hope for such a small fish.

Paul Browne

31/08/10

Permalink 08:36:28 pm, by Tom, 669 words, 2839 views   English (UK)
Categories: Information

Heart failure breakthrough: animal research paved the way!

Heart failure, where the heart is unable to maintain a sufficient blood flow to supply the body’s needs, is a leading cause of death, especially among the over 65’s. Half of all chronic heart failure patients die within four years of diagnosis. It can have a number of causes, for example damage to heart tissue after a heart attack, and leads to a variety of problems in patients. Fatigue and muscle weakness are common as the muscles receive insufficient oxygen, and because waste products cannot be removed from tissues quickly enough fluid can build up in the lungs and other parts of the body, often the legs and abdomen. The extra strain placed on the heart as it tries to maintain adequate blood pressure can lead to further damage to the heart and ultimately cardiac arrest.

In heart failure the rate at which the heart beats is often increased, and group of scientists led by Karl Svedberg and Michael Komajda set up the SHIfT study, to evaluate whether a drug called Ivabradine, which lowers the heart rate, could reduce risk of death or hospitalization in a group of patients who had heart failure accompanied by an elevated resting heart rate. Significantly fewer patients taking Ivabradine in addition to their existing treatments required hospital admission during the course of the study, compared to a control group who were given a placebo in addition to their existing treatment. The most striking outcome was that Ivabradine cut the risk of death by 26%.

So what is Ivabradine, and where does it come from?

Ivabradine slows the heart rate by inhibiting an electrical current known as the If current* which is a major regulator of the activity of the sinoatrial node – better known as the pacemaker. Inhibiting the If current slows the generation of the electrical impulses by the sinoatrial node that trigger heart contraction, and therefore slows the heart rate itself. Ivabradine, then known as S16257, was first developed in the early 1990’s when it was found to be able to block the If current in-vitro in sinoatrial node tissue from rabbits and guinea pigs, and slowed the generation of electrical impulses in a manner that was safer than other bradycardic drugs (1). Ivabradine was then evaluated in live rats and dogs, where it safely reduced the heart rate, and moreover did so without reducing the blood pressure (2,3). While beta-blockers such as Propranolol can reduce the heart rate they also lower the blood pressure – indeed they are used to treat hypertension - and hence are not suitable for many patients, so the development of a drug that could reduce heart rate without affecting blood pressure was very welcome.

Following the successful animal studies Ivabradine entered human clinical trials and in 2005 was approved for the treatment of angina pectoris. In angina pectoris the heart muscle receives too little oxygen, a problem exacerbated by a fast heart beat that increases the need for oxygen, so lowering of the heart rate by Ivabradine reduced oxygen demand and prevents angina attacks. The success of Ivabradine in the treatment of angina pectoris in turn led to its evaluation in heart failure.

The successful outcome of SHIfT study is a major boost to the development of better treatment regimes for heart failure, and if it is confirmed by further clinical trials will improve and prolong the lives of many heart failure patients.

* Hence the name of the SHIfT study - Systolic Heart failure treatment with the If inhibitor ivabradine Trial

Paul Browne

1) Thollon C. et al. "Electrophysiological effects of S 16257, a novel sino-atrial node modulator, on rabbit and guinea-pig cardiac preparations: comparison with UL-FS 49." Br J Pharmacol. Volume 112(1), Pages 37-42 (1994) PubMedCentral:PMC1910295

2) Gardiner S.M. et al. "Acute and chronic cardiac and regional haemodynamic effects of the novel bradycardic agent, S16257, in conscious rats." Br J Pharmacol. Volume 115(4):579-586 (1995) PubMedCentral:PMC1908496

3) Simon L. et al. "Coronary and hemodynamic effects of S 16257, a new bradycardic agent, in resting and exercising conscious dogs." J Pharmacol Exp Ther. Volume 275(2), Pages 659-666 (1995) PubMed:7473152

11/04/10

Permalink 12:26:59 am, by Tom, 721 words, 3821 views   English (UK)
Categories: News

Pro-Test for Science have success in LA

Read more about Pro-Test for Science

On a beautiful sunny day in Los Angeles, Pro-Test for Science (A US side project of Pro-Test) organisers arrived at the junction of Le Conte and Westwood, on the edge of the UCLA campus, with armfuls of placards in support of animal research. Within ten minutes every placard had found a new owner as hundreds of scientists, students and members of the public showed up to support the cause. Those gathering chatted together, sharing their reasons for attending the rally.

Marchers Gather

Those participating were not limited to the UCLA community. Faculty from University of Southern California, California Institute of Technology, and California State University - Los Angeles, all came out to demonstrate their support for lifesaving medical research using animals. Soon the chants began to ring out - "Penicillin? ANIMAL RESEARCH! Insulin? ANIMAL RESEARCH! Vaccines? ANIMAL RESEARCH! Anaesthetics? ANIMAL RESEARCH!" A short while later, when the crowd had swelled further, the rally set off towards the center of the UCLA campus.

The marchers begin to walk towards the center of the UCLA

The mood was one of excitement and passion. Those participating exchanged ideas for public outreach in the future - sharing the best of ways of explaining to the public the clear connection between animal research and medical benefits. The rally continued to snake along Westwood and up towards Wilson Plaza.
Those at the front were unable to see the back of the rally!

As the rally turned into Wilson Plaza, passing the top of Bruin Walk, hundreds of students turned their heads towards the march, many shouting words of encouragement or joining in the rally.

Eventually the tail end of the rally reached the destination (some time after the front end due to the length), and Tom Holder brought the crowd together for a picture perfect moment of solidarity before shouting "What do we need?". "Animal Research" replied the hundreds of voices in unison.

David Jentsch at the Pro-Test rally 2010

Holder then introduced the first speaker, Prof. David Jentsch - founder of Pro-Test for Science and member of the Speaking of Research committee - who took the microphone to rapturous applause. David spoke of the progress of Pro-Test for Science, and the struggle against animal rights extremists in UCLA. He took the time to thank each of the individuals who had made the 2010 rally possible eliciting a cheer from the crowd as each name was called. Jentsch then passed over to Tom Holder, founder of Speaking of Research.

Tom Holder at the Pro-Test for Science Rally

Holder thanked the crowd, insisting that UCLA were winning in their battle against extremists. However he warned the crowd against complacency - saying that public outreach was the only way to win this battle in the long run. Holder also announced the success of the Pro-Test Petition, which had gained 11,621 signatures over the previous year (including Nobel Prize Laureates, and every chancellor in the UC system, including UC President Mark Yudof). He finished by announcing the presentation of the signatures to Dr. Kevin Quinn, Dr. Michael Steinmetz.

Dr. Quinn, the Chief of Behavioural Science and Intergrative Neuroscience at the National Institute of Mental Health (NIMH), accepted one copy of the petition on behalf of NIMH. Quinn spoke of the important role that animal research has in our understanding of Mental Health problems:

"Animal research conducted in a humane, ethical and responsible manner is absolutely critical … to understand, treat and cure mental disorders"

Dr. Michael Steinmetz, program director of the National Eye Institute, talked of the medical breakthroughs in vision. He spoke particularly of Leber's congenital amaurosis, a form of blindess which affects thousands of people across the United States. Through research in mice and then dogs (Briards), scientists found a way of inserting a gene into the eye through a virus, which could corect the problem.

"The National Eye Institute supports strongly the use of appropriate animal models in research, not just for the big clinical advances but for the many, many years of basic science that it takes to discover the underlying biological principles"

Jentsch then returned to the stage to introduce UC Executive Vice-Chancellor, Scott Waugh. Waugh offered his continued support to researchers at UCLA, mentioning that the Pro-Test for Science movement has played an important role in bolstering support for research. He congratulated Jentsch and Ringach for organizing the February pabel debate, explaining that "violence, threats and other criminal activity are never a viable alternative to dialogue".

Jentsch and Holder finished the rally by talking of the importance of continued education and outreach.

07/02/10

Permalink 09:31:17 pm, by Tom, 1420 words, 3264 views   English (UK)
Categories: Information

Pompe disease – a starring role for animal research

The new Harrison Ford film, Extraordinary Measures, hitting UK cinemas from 26 February, is a fictionalised account of the development of a treatment for Pompe disease, a rare genetic disorder. Pompe disease (glycogen storage disease type 2, acid maltase deficiency) is an enzyme deficiency with devastating effects – progressive muscle weakness and, in the severe infantile form, gross enlargement of the heart. Until fairly recently, the infantile form of the disease was invariably fatal within the first year of life. Now, however an effective treatment is in place.

While the increased awareness that the film’s fictional account brings is very welcome, the real story of how that treatment came about is a fascinating one (1) and laboratory animals play a starring role. The long road to a treatment started in 1932 with the first observation of the disease by Dr JC Pompe, after whom it is named. Pompe described accumulation of glycogen in muscle tissue, which was a puzzle, as the enzymes involved in the usual metabolism of glucose and glycogen were all present and correct. The solution to this puzzle had to wait until Christian de Duve’s 1974 Nobel Prize-winning discovery of lysosomes in 1955. These cellular compartments or organelles are the ‘recycling units’ of animal cells. They have an acid environment and their own specific set of enzymes for breaking down cellular components.

De Duve was carrying out ‘blue skies’ research, with no thought of direct medical application. However, as so often in research, a breakthrough in our basic understanding of biology led to medical applications. In this case, de Duve’s colleague Henri Hers realised that the deficiency of a lysosomal enzyme (alpha glucosidase) for the breakdown of glycogen would explain the symptoms of Pompe disease. This proved to be the case, and Hers established the principle of lysosomal storage diseases, of which around 40 have now been described, in 1965. Before moving on, let us note the role of laboratory animals in this breakthrough. I wrote to Professor de Duve and asked what part the use of animals had played in his work and he replied that “We would not have been able to make the discoveries we made without an extensive use of laboratory animals.”(2) - a statement confirmed by his Nobel Prize lecture.

Having discovered the basis of Pompe disease, the next milestone was to develop a treatment. This proved to be very difficult, largely due to the lack of animal models. A recurring refrain from the animal rights lobby is that if the humane use of animals in medical research was banned, scientists would soon find other ways to ensure medical progress. That comforting belief is belied by the series of attempts, some of them pretty desperate, to treat terminally ill children over the next 25 years. None of them worked.

The next great leap forward came from The Netherlands in 1990 and relied on the use of laboratory mice. Enzyme replacement therapy (ERT) had long been suggested as a potential treatment for lysosomal storage diseases but had never succeeded. In the case of Pompe disease, where large amounts of enzyme were needed in the muscle, introduced enzyme was simply soaked up by the liver. Two Dutch scientists, Arnold Reuser and Ans van der Ploeg, had the idea that phosphorylated enzyme would be taken via by the mannose-6-phosphate receptors in lysosomes, allowing the enzyme to be targeted.

However the supply of phosphorylated enzyme was small – nowhere near enough to treat a sick child. How could efficacy be demonstrated, in the absence of an animal model? In an ingenious experiment (3), they used specific monoclonal antibodies to demonstrate that when bovine phosphorylated alpha glucosidase was introduced to mice, it was taken up by heart and skeletal muscle lysosomes and caused a significant increase in enzyme activity – a 43% increase in skeletal muscle and 70% in the heart. An increase that, if repeated in humans, would result in the level of enzyme found in the healthy population. With characteristic understatement, van der Ploeg et al concluded "...we think that the original idea of enzyme replacement therapy for treatment of lysosomal storage diseases deserves new attention." At last, thanks to this ground-breaking work, a treatment for Pompe disease was a real possibility.

Now that there had been ‘proof of principle’ all that was needed was for a pharmaceutical company to spend millions of dollars in developing a treatment. Understandably perhaps, given the rarity of the disease and the inability to demonstrate actual efficacy, there was no immediate rush. Fortunately, at this point two animal models became available that allowed scientists to demonstrate that not only did the phosphorylated alpha glucosidase make its way to the lysosomes, it also had a beneficial effect.

From 1998 onwards, transgenic mice with Pompe disease, developed in Rotterdam and elsewhere, were used to demonstrated the efficacy of alpha-glucosidase enzyme. At the same time the potential of ERT was also illustrated, more dramatically perhaps, by YT Chen at Duke University, using quail. The quail had the same enzyme deficiency as found in humans, resulting in muscle weakness. After injection with the enzyme, they recovered to the extent of one subject actually flying around the lab (4). The evidence was therefore now pretty convincing – it was time for human trials.

The big problem was in producing enough enzyme for humans, even for babies. This required substantial industry investment. Two rival approaches were tried. A Dutch company, Pharming, produced the enzyme in the milk of transgenic animals for use in a trial led by Ans van der Ploeg, whose PhD research had led to the original breakthrough. The transgenic animal used was the rabbit, on the grounds that a human alpha-glucosidase-producing line could be established quite quickly. This work was used in a successful clinical trial, the results of which were published in The Lancet in July 2000 (5).

Another trail was carried out by YT Chen, using enzyme produced via Chinese Hamster Ovary (CHO) cell culture, by Synpac, a Taiwan-based company. This trial was also successful.

What follows next is a slightly convoluted story. The short version is that a third company, Genzyme, with an existing enzyme replacement therapy for Gaucher disease, bought out both Pharming and Synpac. In the end, they didn’t use either of the enzymes produced by these companies but developed their own, in-house CHO product, now marketed as Myozyme. This was a difficult decision – how could they decide which of the competing products should be invested in to produce a commercial treatment? The answer was what Genzyme called “The mother of all experiments” which compared the different products in transgenic Pompe mice. The result led to the availability of the treatment we have today.

However, the eventual production system is a technicality that need not concern today’s patients. Their concern is that an untreatable, terminal illness is now treatable. If you go and see Extraordinary Measures do bear in mind the starring role that doesn’t appear in the cast list – that of the mice and quail that made this treatment possible.

Kevin O’Donnell

Edinburgh

1. http://pompestory.blogspot.com
2. Letter from Christian de Duve to Kevin O’Donnell, 4 March 1997
3. Intravenous Administration of Phosphorylated Acid Alpha-Glucosidase Leads to Uptake of Enzyme in Heart and Skeletal Muscle of Mice http://www.jci.org/articles/view/115025
4. Clinical and metabolic correction of pompe disease by enzyme therapy in acid maltase-deficient quail http://www.jci.org/articles/view/1722/pdf
5. Recombinant human alpha-glucosidase from rabbit milk in Pompe patients http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02533-2/fulltext#article_upsell (free registration required)

Biographical note.

I should declare an interest. I am a professional scientist, however my involvement with Pompe disease dates from the diagnosis of our first child, Calum, with infantile Pompe disease in 1993. At that time the disease was still untreatable and Calum died at 8 months of age. Following that I had the great privilege of participating in an international community of patients and scientists that championed the development of a treatment for Pompe disease. They don’t appear in the cast list of the film either, or the book on which it is based The Cure by Geeta Anand. This prompted me to write the real story down – I think it’s a better story than either rthe book or the film though not, sadly, as well written. Your comments welcome at http://pompestory.blogspot.com You can find out more about Pompe disease from the following sites:

International Pompe Association www.worldpompe.org
Acid Maltase Deficiency Association www.amda-pompe.org
UK Pompe Group www.pompe.org.uk
Genzyme www.pompe.com

25/12/08

Permalink 12:26:33 am, by Tom, 412 words, 1848 views   English (UK)
Categories: Information

Looking back, looking forward

As 2008 comes to a close it's a good opportunity to look back on the year, and what a year it's been. Support for animal research at Oxford remains high and in November the University announced that work on the construction of the new biomedical facility has been completed. This new facility, which prompted angry and sometimes violent opposition from animal rights campaigners but also unprecedented demonstrations of public support from scientists, students and ordinary members of the public, will enable Oxford scientists to build on an excellent record that sees work of many of its medical researchers rated as either world-leading or internationally excellent.

We're also excited to see that the prestigious research journal Science has named reprogramming cells as its "Breakthrough of the year" (1), and notes that:

"The feat rests on a genetic trick, first developed in mice and described 2 years ago, in which scientists wipe out a cell's developmental "memory," causing it to return to its pristine embryonic state and then regrow into something else. In 2008, researchers achieved another milestone in cell reprogramming. In an elegant study in live mice, they prompted cells to make the leap directly from one mature cell into another--flouting the usual rule that development of cells is a one-way street. These and other advances in tweaking cells to assume new identities add up to make the now flourishing field of cellular reprogramming Science's Breakthrough of the Year."

We are delighted to see that this exciting work, which we have discussed on a couple of occasions of occasions on our science blog and more recently on the blog of our sister organization Speaking of Research, recognized in this way. Another interesting technique we reported on, the use of advanced GFP technology to track embryonic development was one of 10 runners up, ranging from the detection of planets outside our solar system to calculating the forces that bind sub atomic particles, chosen by Science. We all know that animal research is held in high regard by the scientific community, but the decision made by Science is further proof if any were needed that it is held in the highest regard.

With new members and continuing support from students at Oxford and beyond we will strive to build on our successes and make 2009 another year to remember. We wish all our supporters a very Merry Christmas and a peaceful and prosperous New Year!

Regards

Paul Browne

1) Vogel G. "Breathrough of the year: reprogramming cells" Science Volume 322 (5909), pages 1766 1767 (2008) DOI: 10.1126/science.322.5909.1766

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