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Archives for: December 2010
11:31:05 am, by Tom, 857 words, 2085 views
The Basel Declaration: Standing up for Medical Progress
Top European scientists have pledged to engage in more public dialogue, openness, and education about animal research. Concerned about threats to the future of medical research, the scientists met recently and drafted a declaration that affirms commitment to responsible research and animal welfare and calls for increased effort to facilitate public understanding of the essential role that animal studies play in contributing to scientific and medical progress. The call for “trust, transparency, and communication on animal research” was adopted by the first Basel conference “Research at a Crossroads” November 29th. The Declaration can be found here, along with an invitation to sign up to it.
The Declaration underscores the importance of a wide range of animal research, from basic research that seeks to understand fundamental biological processes, to applied research that seeks to turn such knowledge into new medical treatments, and the critical ongoing need for this work:
The Declaration makes clear that:
A Nature report on the meeting and an accompanying editorial highlight the crucial considerations underlying the scientists’ call for action, including not only the actions of extremists, but also the broad consequences of failing to build understanding of animal research:
Such efforts have already yielded dividends; the Nature report notes how a determined effort over the past decade by scientists in the United Kingdom to inform the public about the reality of animal research resulted in greatly increased support for it.
Speaking of Research applauds this effort and joins in urging others not only to sign on to the declaration, but also to act on the pledge to continue to increase efforts in outreach, education, and engagement.
In fact, there are many groups and sources for information and conversation to which scientists can turn to for advice on outreach. They include advocacy groups and collaborative networks such as Understanding Animal Research, Americans for Medical Progress, States United for Biomedical Research, and the Foundation for Biomedical Research. They also include scientific societies such as the American Physiological Society, Society for Neuroscience, American Association of Laboratory Animal Science, and the Federation of American Societies for Experimental Biology. Many academic institutions have actively built outreach and education programs that offer good models for others.
Speaking of Research also offers information, tools and support for those who choose to contribute to public discussion of animal research. There are many resources and avenues to support individuals who want to learn more and identify a range of effective ways to contribute to the public discussion of animal research.
Before we finish we’d like to draw your attention to an excellent example of the importance of basic animal research, Christina Agapakis writes on the Oscillator blog about a fascinating study which used gene therapy to restore vision in blind mice. This news comes only a few weeks after scientists in Germany reported that they had used a vision chip containing 1,500 light-sensitive elements to partially restore sight in patients who were blind due to damage to the light-sensitive cells in their eyes. In an open access paper published in Proceedings of the Royal Society B, the team who carried out this important clinical study highlight the importance of in vivo studies in rats, cats, and pigs, and in vitro studies using isolated chicken retinas, in establishing both the theoretical basis for this study, and subsequently in determining the safety of the implant they developed. These advances in vision research suggest that devices available to help blind people see in the 21st century will soon eclipse those that Star Trek predicted for the 24th century!
This is of course exactly the kind of groundbreaking biomedical research that the Basel declaration seeks to defend.
11:26:30 am, by Tom, 993 words, 1559 views
From the bench and the bedside; how animal research is taming Multiple Sclerosis
Multiple sclerosis (MS) is one of the most common diseases of the central nervous system – the brain and spinal cord - affecting about one person in every thousand in the USA. It is an inflammatory condition, where the immune system attacks the myelin sheath that surrounds the axons of nerve cells. Myelin is a fatty material that insulates nerves, acting much like the covering of an electric wire and allowing the nerve to transmit its impulses rapidly. It is the speed and efficiency with which these impulses are conducted that permits smooth, rapid and co-ordinated movements to be performed with little conscious effort. Loss of myelin interrupts these impulses, and the nerve cells themselves are also damaged and eventually die.
The consequences for people with MS can be devastating, and MS is associated with a wide variety of symptoms, including muscle weakness, spasms, ataxia, problems with speech and vision, acute and chronic pain, and fatigue. MS is a very variable disorder, and the rate at which it progresses varies considerably from one patient to another, but a defining characteristic of it is the lesions that are visible by MRI where the myelin has come under attack. The relapses, attacks of worsening neurological function that are often found in MS, are closely associated appearance of new lesions in the CNS, although not all new lesions cause a relapse.
Until about 20 years ago there were no treatments available that could prevent relapses or slow the progression of MS – known as disease modifying treatments - but thanks to the efforts of scientists working around the word this situation has begun to change. A number of effective disease modifying treatments are now available, the most recent to receive FDA approval is Fingolimod (known as FTY720 during its development), a drug whose immunosuppressant properties in reducing transplant rejection and as a treatment for MS were evaluated in a range of animal models during its development.
These drugs may soon be joined by another. A couple of years ago I wrote about the crucial role of studies in mice, rats, and dogs in the development of a new disease modifying treatment called Laquinimod, and last week the manufacturers of laquinimod announced that it had performed well in a phase III clinical trial, safely reducing the number of relapses and slowing progression of disability. This is excellent news, and one more step towards turning MS form being an incurable disease to being a manageable disease.
One reason I say manageable rather than curable is that while these treatments are effective in reducing the number of relapses for many patients they do not work for all patients and all forms of MS (particularly for primary progressive MS), and can sometimes have serious side effects that prevent patients from continuing treatment. That is why scientists are continuing to study the biological mechanisms in MS, a disease whose origin is still not fully understood, though clinical and animal research indicates that both genetic and environmental factors play a role, their ultimate goal is to develop treatments that can stop relapses altogether.
Another reason for not referring to disease modifying treatments as “cures” is that they do not directly repair the damaged myelin sheath at the lesions. Spontaneous repair of the damaged myelin sheath in MS lesions does happen and plays an important role in limiting neurological damage, but until now the molecular basis of myelin regeneration by cells called oligodentrocytes, in the central nervous system (CNS) has been poorly understood. The Guardian reports on how scientists at the University of Cambridge have discovered how to promote remyelination in MS lesions by activating a population of stem cells in the CNS called oligodentrocyte precursor cells (1).
The team led by Professor Robin Franklin generated a comprehensive transcriptional profile of 22,000 genes during the separate stages of spontaneous remyelination that follow focal toxin-induced demyelination in the rat CNS, and found that the level of retinoid acid receptor RXR-gamma expression was increased during remyelination. Cells of the oligodendrocyte lineage expressed RXR-gamma in rat tissues that were undergoing remyelination, in both active lesions and in older remyelinated lesions. By examining post-mortem brain samples from MS patients, they were able to show that RXR-gamma expression was also elevated in oligodendrocyte precursor cells at the active lesion sites, supporting a general role for RXR-gamma in remyelination. Interesting as these findings were they did not demonstrate that RXR-gamma is actually required for remyelination, so they next performed studies to determine whether blocking the function of RXR-gamma would prevent remyelination.
Knockdown of RXR-gamma by RNA interference or RXR-specific antagonists severely inhibited the differentiation of oligodendrocyte precursor cells into mature oligodendrocytes in culture. In mice that lacked RXR-gamma, adult oligodendrocyte precursor cells efficiently repopulated lesions after demyelination, but showed delayed differentiation into mature oligodendrocytes. The next question was whether increasing the activity of RXR-gamma would speed up remyelination. Administration of the RXR agonist 9-cis-retinoic acid to demyelinated mouse cerebellar slice cultures and then to aged rats in vivo after focal demyelination caused an increase in remyelinated axons. Focal toxin-induced demyelination was used to produce the lesions, rather than an immunity mediated model of demyelination such as experimental autoimmune encephalomyelitis, in order to determine that the increased remyelination was due to promotion of oligodendrocyte differentiation rather than to the anti-inflammatory effects of 9-cis retinoic acid.
The results indicate that RXR-gamma plays an important role in endogenous oligodendrocyte precursor cell differentiation and remyelination, and might be a pharmacological target for regenerative therapy in MS. The discovery that 9-cis-retinoic acid, a compound already in limited clinical use, can be used to stimulate myelin regeneration raises the possibility that within the next decade treatments that repair the neurological damage in MS will begin to enter clinical trials.
For people with MS these scientific and clinical advances are a great source of hope for a better future.
1) Huang J.K. et al. “Retinoid X receptor gamma signalling accelerates CNS remyelination” Nature Neuroscience Published Online 05 December 2010 DOI: 10.1038/nn.2702
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