Monthly Archives: December 2010

Merry Christmas and Happy New Year

From all of us on the SR Committee:

Cheers

SR Committee

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, which safely -though relatively modestly conpared to other new therapies – reduced the number of relapses, while slowing progression of disability more that current disease modifying drugs in a Phase III clinical trial. This is good 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.

Rats are crucial to many areas of MS research. Image courtesy of Understanding Animal Research.

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.

Paul Browne

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

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.

Prof. Michael Hengartner, Prof. Dieter Imboden and Prof. Stefan Treue sign the declaration

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:

“Over the last 100 years biomedical research has contributed substantially to our understanding of biological processes and thus to an increase in life expectancy and improvement in the quality of life of humans and animals. However, the list of challenges and new opportunities remains long.

Without research using animals, it will not be possible to overcome the social and humanitarian challenges posed by these problems. Despite new and refined alternative methods, animal experiments will remain essential in the foreseeable future for biomedical research.”

The Declaration makes clear that:

“Biomedical research in particular cannot be separated into ‘basic’ and ‘applied’ research; it is a continuum stretching from studies of fundamental physiological processes to an understanding of the principles of disease and the development of therapies.”

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:

Biomedical scientists in Germany perceive a separate crisis — increasing legislative restrictions that make it more difficult to carry out animal experiments. Hearing little to the contrary from researchers themselves, the public tends to assume that animal experiments are an unnecessary evil, so politicians respond with more restrictions.”

That problem was a major motivation for the Basel Declaration — drafted and signed at a meeting in Basel, Switzerland, last week (see page 742). Its signatories pledge to engage in open debate with the public about their work on animal experiments, to stress the high ethical standards to which they adhere and to explain why they have to do it. They intend, for example, to visit local schools or to mention that their research used animals when speaking to the press about new results.”

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.

Allyson J. Bennett, Ph.D*. and Paul Browne, Ph.D.

Speaking of Research

*The views expressed on this blog post are mine alone and do not necessarily reflect the views of my employer, Wake Forest University Health Sciences.

 

The Voices of Reason Ring Through

In the days since the announcement that I had received a letter containing heinous death threats and razor blades from animal rights extremists opposed to my research, the voices of sanity and reason have started to be heard. From scientific and professional societies to non-scientists across the country, there is a strong support for the notion that biomedical research involving animals contributes irreplaceably to advancements in human and animal health and that because the use of animals in this research is responsible and humane, it is also justifiable and ethical. Many of these messages show particular support for our repudiation of these threats and our unwavering intention to continue the work that we feel morally obliged to conduct despite them.

In particular, scientific and professional societies have stepped up to voice their support for humane and responsible animal use in biomedical research and to condemn, in the clearest manner possible, the threats made by animal rights extremists against researchers.

The American Society of Primatologists, the nation’s leading scientific group dedicated to the study of “nonhuman primates, including their biology, care, and conservation” took the lead in a resolution posted to their website.

The American Society of Primatologists condemns these terrorist actions. Terrorism does not, and will not, contribute to the betterment of animal welfare. Nor does it contribute to civil dialogue and thoughtful consideration of the role of responsible, humanely-conducted and ethical animal-based research in contributing to scientific and medical advances.

The American Society of Primatologists calls upon groups and individuals concerned with animal welfare to join in universal and public condemnation of all terrorist activities directed at members of the scientific community.

The American Medical Veterinary Association is comprised of more than 80,000 member veterinarians who are dedicated to advancing the science and art of animal, human and public health. They reasserted their position in a recent press release, also posted on their website.

Animals play a central and essential role in research, testing and education for continued improvement in the health and welfare of human beings and other animals. … The use of animals used in research, testing and education is a privilege carrying with it unique professional, scientific and moral obligations.

…  America has no room for terrorist activities that threaten not only that discourse but the lives of our scientists and their families. We condemn all acts of violence, vandalism and intimidation directed toward individuals and facilities engaged in the ethical use of animals for research.

This position is paralleled by the American Association for Laboratory Animal Science (AALAS) who, in a statement on their website, affirms their commitment to preserving laboratory animal welfare in the context of humane research aimed at conquering human disease.

“Acts of terrorism do not result in improvements in animal welfare. Progress comes only from thoughtful discussion and scientific assessment of alternative methods that refine the animal research process–efforts that AALAS itself fosters through educational and scientific programs. Terrorism in the name of “animal rights” jeopardizes the lives of people and animals–in the present by the violence itself, and in the future by hindering the progress of ethical animal-based research designed to find cures and treatments for diseases that affect humans and animals. The AALAS membership extends heartfelt support to our scientific colleagues and their families who have been affected by threats and acts of violence.”

Finally, leading scientific societies have spoken up as well. The Society for Neuroscience, , the world’s leading organization of scientists dedicated to exploration of the brain and its diseases,  released a statement on this matter.

The Society stands united with Dr. Jentsch, the members of his team, and all researchers who use animal models to advance scientific discovery, and SfN is committed to promoting public awareness of the vital role of animals in research and supporting all scientists that come under attack.

 

The American Physiological Society, which represents more than 10,000 members devoted to fostering education, scientific research, and dissemination of information in the physiological sciences, posted a policy statement to their website supporting, in the broadest manner, researchers under attack and the value of the work that they do.

…[M]any scientists … have been harassed or threatened because they work with animals. Research involving animals plays an essential role in efforts to discover causes, preventions, treatments, and cures for disease. Knowledge obtained through research with animals has saved many lives and improved the quality of life for millions of people and animals. Scientists recognize that they have ethical duties both to relieve suffering through research as well as to provide humane care for research animals. Moreover, the use of animals in research is subject to strict regulatory oversight.

The American Physiological Society condemns extremist actions against researchers in the strongest possible terms: It is thuggery, pure and simple. Harassment, threats, and violence contribute nothing to the betterment of animal welfare, nor do they promote dialogue or thoughtful consideration of serious issues.

Additionally, I have received countless emails and phone calls from individuals around the country who have felt the sting of mental illness in their own lives, or in the lives of those they love. Not surprisingly, I have also been the recipient of emails encouraging me to stop conducting animal research, but those missives are outnumbered more than 10-to-1 by expressions of appreciation and gratitude for biomedical researchers. People from all walks of life have chimed in, expressing their personal and unwavering belief that animal use in medical research is justifiable and ethical.

A science educator from the upper mid-west:

Thank you for sticking up for all those hard working folks who do science each and every day… not to get rich… but because they love people, they love animals, and they are deeply  committed to their mission to make this world a better place.

A university undergraduate student from the Pacific northwest:

I write to express my support for your research and to note that I greatly respect your decision not to be dissuaded by terrorist tactics.  The benefits of your research into chemical dependence and schizophrenia are and will continue to be considerable, and the use of animal subjects in this case is, in my  opinion, amply justified.  You have my continuing support and the support of many other informed individuals.

A Los Angeles local:

Thank you for your research into addiction and cognitive changes in schizophrenia.  And a special thanks for not being bowed by extremist Animal Rights people.  It’s the people like you who are working so hard to help us.

Years ago, I read an article in the LA Times about a lab … that was burned to the ground by these dangerous individuals.  That lab lost over 10 years of research into Osteoarthritis…

Flash forward a decade and I was diagnosed with a chronic illness, rheumatoid arthritis.  Nothing like getting a chronic illness of your own to realize how important research is to the patient.

A bio-technology researcher from the mid-Atlantic:

All of us in science are working to improve the lives of all, and to relieve suffering wherever we can.  The fact that our work is now used as an indictment against us by vigilante thugs is inexcusable.  Thanks for your courage in standing up to their threats, always shrouded in the cowardice of anonymity, while you try to lead your life in public without compromising your ideals and scientific goals.  Good luck to you and to your collaborators.

Many of these sentiments were summarized in a recent editorial written by the incredible undergraduate students who manage UCLA’s campus newspaper, the Daily Bruin:

The idea of such misguided activists destroying the lives of world-class researchers through their tasteless, violent tactics is atrocious.

These attacks should create concern for the community at large, because the implications are far-reaching. Medical breakthroughs occur in large part as a result of the valuable research that scientists perform.

Mailing blades to a researcher and continuing threats on his life endangers future progress and is a threat to every UCLA student, faculty member and researcher.

Intimidation and death threats should never be the solution, no matter how bad an action may seem to somebody. What ever happened to dialogue?

These statements indicate that scientists and non-scientists alike often stand strong in support of biomedical research and understand that there are circumstances where the use of animal models is justifiable. These messages further expose just how much damage to their own credibility animal rights extremists cause when they continue to use fists, razors and hate speech to push their agenda.

My colleagues, trainees and I extend our most heart-felt thanks to all that have reached out to offer support, as well as to those who quietly support research and researchers around the world. The attacks by animal rights activists are insidious and discouraging, but the voices of encouragement, coupled to our knowledge that the work is ethical and responsible, ensure that we will continue pursuing solutions for the problems of human and animal health that biomedical investigation can address. Our experience underscores the notion that vocal support for research and researchers ensures overwhelming support and appreciation, and we call on others to join us in our effort.

Regards

David Jentsch

A Very British Story

It is rare in the US that anything about the benefits of animal research makes the national newspapers. In the UK such stories do appear more often, and have contributed greatly to the general change in opinion surrounding the animal research issue. Saturday, December 4th, provided a wonderful example in The Guardian newspaper (a British national paper).

Experience: I’m proud I worked in an animal testing lab

It was a surprise to me that I ended up working in an animal testing facility. I’ve been a vegetarian most of my life and I wanted to be a teacher when I was younger. Animal testing wasn’t something I saw in my future.

I’ve always cared deeply about animals. My parents stopped eating meat because they disliked the way animals were farmed and slaughtered, and I felt the same way. Then I met my partner at university and when we graduated, he started working as a toxicologist, testing drugs that might potentially go on to be used for humans.

I was interested in his field of work; the more he told me, the more I understood and believed in it. My partner qualified for a Home Office licence, so he learned to handle animals in the right way and cause the least amount of trauma possible.

When a job came up, I applied. They checked me out thoroughly to make sure I had no affiliations with antivivisectionist groups. I started in a technical role away from the animal facility, preparing doses and equipment for clinical tests on humans.

After a few months, I asked to see where the animals were kept. In the back of my mind I saw the grainy black and white pictures of cats and monkeys in agony that appear on antivivisectionist stands. I was curious but reluctant, particularly to see the dogs. It was so hard to think of them in that environment. But they were bright-eyed and pleased to see us. They were kept in a different building from the rats, rabbits and mice, so the barking didn’t disturb them. The animals were behind strengthened glass, not unlike you see in a pet shop. Everything was clean and they all seemed content.

You couldn’t walk the dogs outside because it would interfere with the research, but there were play areas with toys. The husbandry staff talked to the animals and petted them. Seeing them reinforced my opinion that I was doing the right thing for the right reasons.

After a few years, I moved to my partner’s department, assisting research scientists with paperwork. It was like any other company, once the doors were shut and you’d passed security. People socialised, just like any other workplace.

I was fairly comfortable telling close friends where I worked, although initially I told only people I thought would be sympathetic. As time went on, I became indignant about having to be defensive and got more relaxed about who I told. People sometimes pulled faces but often they just wanted to clarify what was involved. Many people think cosmetics are still tested on animals, so they’d assume we squirted perfume into rabbits’ eyes.

I had to be more careful with people I didn’t know well. My partner and I had cover stories. Most people did, for self-protection. You wouldn’t call it a secret identity, but we gave people ideas that weren’t exactly accurate. We kept it general and vague. I’d say I was an administrator. I was quite adept at sidestepping the conversation to avoid getting too deep into telling lies. I didn’t get any thrill out of being secretive.

Our employer was happy to do as much as possible to protect us. An arrangement with the DVLA let us register our cars at another address so the plates couldn’t be used to trace where we lived. Protesters often followed or photographed cars. A group of people rolled up every week to protest – security sometimes knew when to expect them and circulated advance warnings. They’d stand outside the gates shouting “Murderer!” and lie down to prevent people’s cars coming out.

I stopped worrying about them – they were more of an inconvenience. It was sometimes scary wondering what they’d do, but they didn’t throw bricks at our cars, they usually just shouted abuse. In some ways, they won simply by making us paranoid. I’d be much more fearful outside work, but I got used to it.

Having a bunch of people so set against you can make you become more determined. I thought: “You might not agree, but I’m doing the right thing.” I was proud of my contribution, helping to test out potentially life-saving drugs.

Leaving was never about the work or the company – I moved away for family reasons. I work in administration now. It’s a relief not having to hesitate or look around before saying what I do, but I was proud to work there and I’m always looking for that same sense of satisfaction.

It is honest, heartfelt stories like this which help change the minds of ordinary people who had not previously considered the role of animals in research, but hear only the shock stories from groups like PETA.

There is, of course, only one flaw with the story. The author has chosen to remain anonymous, which may serve to perpetuate the idea that speaking out in favour of research will lead to them being targeted. This is not the case. Animal rights activists target a very, very small minority of researchers – this is usually on how prolific their research is (and how easily it can be misconstrued) and irrelevant of how outspoken they are about their research. In fact, those who are more pro-actively vocal about the benefits of their research are often left alone as a “hard” target by animal rights activists who prefer to simply scare a researcher into providing them with a successful “I quit” story.

It is up to people, like the author, to speak up, through all avenues available, to explain the benefits of animal research; there are many misconceptions about testing – it is up to researchers to face these misunderstandings head on.

Cheers

Tom