Tag Archives: animal research

Spinal cord stimulation restores monkey’s ability to move paralysed hand

Today scientists at the Newcastle University Movement Laboratory announced that they have succeeded in restoring the ability to grasp and pull a lever with a paralysed hand using spinal cord stimulation. In a study undertaken in macaque monkeys they demonstrated for the first time that it is possible to restore voluntary movement in upper limb paralysis and tetraplegia, where there has been damage to the upper regions of the spinal cord that blocks the nerve pathways which pass messages to the muscles from the brain.

Macaque monkeys were key to Newcastle University paralysis breakthrough. Image: Understanding Animal Research

Macaque monkeys were key to Newcastle University paralysis breakthrough. Image: Understanding Animal Research

At this point some of you are probably thinking ‘Wait a minute, didn’t you just write about spinal stimulation being used to restore voluntary movement in paralysed human patients, why is this news?’ Well, it’s news because while both techniques use electrical stimulation they use it in very different ways, and will benefit paralysis patients in different ways.

In the study we discussed earlier this month Professor V. Reggie Edgerton and colleagues restored voluntary movement to the legs of 4 paraplegic men by using epidural stimulation to excite spinal nerve networks below the injury in a diffuse way. The method exploits the fact that spinal nerve networks are to some degree, “smart.” If certain sensory information is provided, for example pressure on a foot, the activated spinal cord can recognize this information and respond by generating a specific pattern of muscle activity, without requiring input from the brain. This activity can be enhanced with repetition and training, and also takes advantage of the fact that often even in spinal injuries that appear to be complete not all the nerve connections through the area of damage are broken, so once the network below the injury is activated these remaining nerve connections can be exploited to achieve conscious control over movement. However, epidural stimulation may not restore voluntary movement in spinal patients with most complete injuries, and it is not clear that the degree of voluntary control restored will be enough to allow all the patients treated so far to walk unaided.

Intraspinal microstimulation, the technique pioneered by the Newcastle University team led by Dr Andrew Jackson and Dr Jonas Zimmermann is very different. Rather than stimulating the spinal cord in a diffuse manner to increase activity in a non-specific way, it works by transmitting signals from the brain to specific spinal nerve circuits below the injury, in order to activate particular muscle groups (1). Working with macaque monkeys, they recorded the activity of individual nerve cells in the premotor cortex of the brain using a microwire array (similar to the brain machine interfaces used to control robot arms),  processed those signals in the computer, and then used the output from the computer to stimulate specific motor neuron circuits in the spinal cord via an implanted microelectrode array that in turn control the movement of the hand.

Closing the loop: By recording neural activity in the brain and then using this to generate a stimulation pattern in the spinal cord, Newcastle scientists were able to restore voluntary movement in a temporarily paralysed macaque. Image: Zimmerman, J.B. and Jackson A. Frontiers in Neuroscience (2014).

Closing the loop: By recording neural activity in the brain and then using this to generate a stimulation pattern in the spinal cord, Newcastle scientists were able to restore voluntary movement in a temporarily paralysed macaque. Image: Zimmerman, J.B. and Jackson A. Frontiers in Neuroscience (2014).

Intraspinal microstimulation does involve more invasive surgery than epidural stimulation, but opens up the possibility of new treatments within the next few years which could help stroke victims and upper spinal cord injuries to regain some movement in their arms and hands. Intraspinal microstimulation may also benefit patients whose lower spinal injuries are too complete for epidural stimulation to enable them to walk, and provide them with a much finer degree of control over movement that could mean the difference between being able to move their legs and being able to walk fluidly.

To conduct this study, published today in the journal Frontiers in Neuroscience, the team first trained macaque monkeys to grasp and pull a spring-loaded handle in order to obtain a treat such as a piece of dried fruit or yoghurt. The monkeys were then temporarily paralysed, using a drug that wore off after about two hours. During that time the monkey had no movement in their hand and was unable to grasp, even though most of the brain was functioning normally. But when the stimulation circuit was switched on the monkey was able to control its own arm and pull the handle.

This is an advance that rests on decades of basic research to understand the pathways within the nervous system and applied research to develop the technology required to restore function, undertaken by thousands of scientists around the world. The microwire array used to record single neuron activity in the brain was developed through studies in macaques by the Newcastle team in 2007, while more recently they undertook a series of studies which examined different patterns of microarray electrostimulation of motor neurons in the upper spinal cord to identify those that could restore voluntary movement.

Commenting on their research Dr Zimmermann  noted that:

“Animal studies such as ours are necessary to demonstrate the feasibility and safety of procedures before they can be tried in human patients, to minimise risk and maximise chance of successful outcomes.”

The next stage will be to further develop the technology to eventually have a small implant for use in patients that can then form the link between the brain and the muscles, and Dr Jackson is optimistic that this technology will be available to patients within a few years

“Much of the technology we used for this is already being used separately in patients today, and has been proven to work. We just needed to bring it all together.

“I think within five years we could have an implant which is ready for people. And what is exciting about this technology is that it would not just be useful for people with spinal injuries but also people who have suffered from a stroke and have impaired movement due to that. There are some technical challenges which we have to overcome, as there is with any new technology, but we are making good progress.”

It’s tempting to think of intraspinal microstimulation and epidural stimulation as competing techniques, but this would be a mistake as it very likely that both will be used, separately or together, depending on the nature of an individual patient’s injury. The greatest benefits for patients may be achieved when these neurostimulation techniques are combined with other approaches such as regenerative medicine/cell therapy and active rehabilitation. In 2012 Jackson and Zimmerman published a review of neural interfaces in restoring movement which examined the evidence from both animal and clinical studies, which highlighted a process known as Hebbian plasticity which can be summarised as “cells that fire together wire together”. Evidence is mounting that stimulation of the spinal cord below the site of injury does not only bypass lost nerve pathways or awaken dormant neural networks, but actually promotes the development of connections between nerves on each side of the damaged area to create new pathways along which signals can be passed from the brain to muscles in the arms or legs.

Today we congratulate Andrew Jackson and Jonas Zimmermann – and the Wellcome Trust who funded their work – on their outstanding accomplishment, but we also remember that it is not happening in isolation. The true importance of the therapy published today that it is part of a neuroscience-driven revolution that will in a few years time begin to transform the lives of many thousands of people with spinal injury.  We may not be there yet, but the destination is at last in sight.

Paul Browne

  1. Zimmermann J.B. and Jackson A.”Closed-loop control of spinal cord stimulation to restore hand function after paralysis” Frontiers in Neuroscience, Published Online 19 May 2014.

Addendum 21st May 2014: Interesting to note the comment by the animal rights group the BUAV that “Claiming, as do some apologists for animal research, that this news is worthwhile because the electrical stimulation in the monkeys ‘was used differently’ is desperate, and overlooks the importance of human-based studies and the contribution they have made.” which only shows that their ignorance (or willingness to lie about) this subject. The BUAV article also includes the usual outlandish claims about the monkeys used in this study being terrified, deprived of food and water etc. completely missing the point that this study required the active alert participation of the monkeys, so they needed to be relaxed and cooperative throughout it.

All surgery was accompanied by appropriate anesthesia and pain relief so that the monkeys would not suffer, and the monkeys used in this study were trained over a period of time through positive-reinforcement to gradually accustom them to the test apparatus used so that it caused them no distress. The monkey’s access to water was not limited, and their access to food in the study was only restricted for a few hours so that they were not too full to be interested in the food reward. While there is no doubt that this was an invasive procedure (just as the procedure will be for human patients) the BUAV’s comments completely misrepresented it.

To learn more about the role of animal research in advancing human and veterinary medicine, and the threat posed to this progress by the animal rights lobby, follow us on Facebook or Twitter.

 

Paralysis breakthrough – electrical stimulation enables four paraplegic men to voluntarily move their legs

This weeks issue of the neuroscience journal Brain carries an unusual image; against a background of nerve activity traces a man lies on the ground, and as you scan down the images he lifts his right leg off the ground. For most people this might just be a simple warm-up exercise, but for Kent Stephenson it was little short of a miracle, because he has suffered complete paralysis after suffering a mid-thoracic spinal cord injury. Speaking about his experience Kent noted that “Everything’s impossible until somebody does it”, and this is a breakthrough that is possible due to animal research.

Brain_cover image

Kent was one of four patients participating in a pilot study of epidural electrical stimulation sponsored by the Christopher and Dana Reeve foundation, which is overseen by an international team comprising of Claudia Angeli and Susan J. Harkema of the University of Louisville, Yury Gerasimenko of the St. Petersburg’s Pavlov Institute and UCLA, led by V. Reggie Edgerton of UCLA.

Before the implantation of an epidural stimulator all four participants were unable to move their lower extremities, and two had also lost all sensation below the injury. This continues a study published in the Lancet in 2011 that evaluated the effects of epidural stimulation in the first participant, Rob Summers, was able to stand again thanks to electrical stimulation, which also improved his general health and quality of life by improving bladder and sexual function, and thermoregulatory activity.

The key findings reported in an open-access article “Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans” in Brain (and discussed in detail on the Christopher and Dana Reeve Foundation website) detail the impact of epidural stimulation in all four participants, including new tests conducted on Rob Summers. Surprisingly the 3 new participants were able to perform voluntary leg movements immediately following the implantation and activation of the stimulator, and the researchers to speculate that some pathways may be intact post-injury and therefore able to facilitate voluntary movements. For a pilot study this is extraordinarily encouraging, as it shows that many paraplegic patients, even those who are diagnosed as having complete motor and sensory injuries can benefit from this technique. V. Reggie Edgerton, who led this project remarked:

“This is a wake-up call for how we see motor complete spinal cord injury, We don’t have to necessarily rely on regrowth of nerves in order to regain function. The fact that we’ve observed this in four out of four people suggests that this is actually a common phenomenon in those diagnosed with complete paralysis.”

There should be no doubt that this is a medical advance that depended on animal research, indeed in a guest article on this blog in 2009 Professor Edgerton noted following the publication of a key Nature Neuroscience paper on epidural electrical stimulation in rats that led to this clinical trial:

It has been characterized as a major breakthrough in facilitating the level of recovery of locomotion following a severe spinal cord injury. This in itself implies that these findings were the result of a single experiment with rats. But the reality is that these experiments were based on 100s of other experiments by not only my laboratory, but many other scientists. All of the previous animal experiments relevant to our understanding of the control of movement, involving many different species ranging at least from fish to humans, have contributed to the evolution of the concepts that underly our most recent publication. This full range of animal species is essential for the continuing progress toward the development of interventions to recover all of those functions that are lost, following a severe spinal cord injury. Our particular publication only addressed the recovery of locomotion, but there are other severe functional losses such as bladder and bowel control and hand function among others that are in need of breakthroughs. It is certain that the concepts which led to the Nature Neuroscience publication would not have evolved at any time in the near future without these gradual and incremental experiments which formed the scientific basis of these concepts. There is no way that these concepts and the experimental results could have been predicted by any non-animal mechanism, for example, computer modeling.

In these videos from Professor Edgerton we see how years of careful animal research underpinned the development of this therapy.

Animal studies continue to be crucial to Professor Edgerton’s work, for example the use of rats in the evaluation of a new multi-electrode array for improving spinal cord epidural stimulation in order to enable more complete restoration of function. The success reported in Brain this week is only just the beginning!

So when you hear animal rights activists claiming that animal research is an outdated science remember these four young men who can move again, and the hundreds of scientists whose decades of careful studies in animal models of spinal cord injury made this breakthrough possible.

Paul Browne

To learn more about the role of animal research in advancing human and veterinary medicine, and the threat posed to this progress by the animal rights lobby, follow us on Facebook or Twitter.

Pictures in need of accurate words: University of Florida animal photos

Pictures of a cat spay clinic misrepresented as a laboratory horror shop circulated the internet recently to support appeals to “end animal testing.” Speaking of Research wrote about it here “Fact into fiction: Why context matters with animal images,” noting the importance of understanding the facts and context for photographs.

This picture was used to misrepresent animal research

This picture was used to misrepresent animal research

In the cat spay clinic case, the photos were from a newspaper article. We have written previously about images of laboratory animals that have made their way to the internet via leaks, undercover operations, and open records release. In all cases, several points remain true. Images are powerful. Providing accurate information about the images is important. It is also true that there are important differences between the sources and ways that images are obtained. Those obtained via infiltrations and undercover operations may be from manipulated situations, or  small fractions of hours of recording, in both cases providing a deliberately misrepresentative view. Photos obtained from institutions via open records release can also be used to misrepresent laboratory animals’ care and treatment and can be the centerpiece in “shock” campaigns. Their value is obvious from even a quick survey of high profile attacks on research, as we’ve written about previously (here, here, here). As in the case of the spay clinic images, conflating veterinary and clinical care with scientific research is also common and further serves to confuse the issues.

Can the laboratory animal research community do a better job of providing context for images of animals?  Yes.

Knowing what the images show and why matters, particularly to people who would like to engage in serious and thoughtful consideration to inform their point of view and judgments. In absence of context and facts, the audience is left without key knowledge and an opportunity to educate is missed. Yet all too often the opportunity is missed and the images remain in public view without comment or context from those who could provide a better understanding of what the photographs show.

In reviewing laboratory animal photographs that appear on animal rights sites, it is obvious that there are generally two types: those from activities directly related to the scientific project and those related to veterinary care or housing and husbandry. In terms of providing context and information, the two differ with respect to their source and which personnel may best explain the content of the photographs.

What does the image depictSome images may be of actual scientific research activities. These may be of animals engaging in an activity directly related to the science question under study. For example, the images may illustrate how animals perform a cognitive or memory task, how they navigate a maze, or how a particular measurement is obtained. The Max Planck Institute for Biological Cybernetics website provides an example of this, with description and photographs of rhesus monkeys and cognitive neuroscience research. Another type of image directly related to the scientific project may be of a surgery or procedure. An example of this is found in pictures of a surgery involved in cat sound localization research (photos here, video here). In each case, it is not particularly challenging to provide additional information and context because the activities are typically also explained in the protocols, grants, and scientific papers about the study.

Images of clinical veterinary care, husbandry, and housing appear frequently in activist campaigns and public view. For example, pictures of routine physical examinations, health tests, unexpected injuries unrelated to scientific procedures, or photos of animals in their normal housing, have all appeared via various sources. Many times– perhaps more often than not– the activity depicted in the images would not be obvious to a lay audience because it remains unexplained.

A common image – tuberculosis skin test

One of the best examples of misunderstood images is found in pictures of an anesthetized macaque monkey with a needle injecting something in its eyelid. The picture circulates the internet with various captions opposing “animal testing.”   What does this picture show?

tb imageIt is a skin test, commonly used in human and nonhuman primates, for early detection of tuberculosis. A small amount of tuberculin (non-harmful) is injected just under the skin. In almost all cases, the primate does not have tuberculosis and the skin remains normal. If the primate—human or not—does have a reaction to the test, indicated by redness and some swelling, it provides evidence of possible tuberculosis infection. That person, or monkey, then receives additional testing and preventive measures for treatment and to avoid infecting and harming others.

Tuberculosis testing is routinely performed as a health procedure in humans who work in hospitals, schools, with children and with others who may be vulnerable. In settings where nonhuman primates are housed, tuberculosis testing is often routinely performed with all human personnel and with the other animals. Why? Because tuberculosis is a rare disease, but one that can be a threat to the animals’ health and thus, precautions are necessary to ensure their health. The difference between human and monkey tb testing is that for humans, the injection is given without pain relief or anesthesia, via a needle inserted into the forearm.

Aside from the momentary discomfort of the injection, the test is painless and without irritating after-effects. In monkeys, the injection is typically given while the animal is anesthetized and is placed just under the skin of the upper eyelid. Why the difference? It is a simple reason—the key to the test is looking for redness or slight swelling. In monkeys, the forearm is fur-covered and it would be very difficult to detect a reaction in an unobtrusive way.

University of Florida monkey pictures

Not surprisingly, the monkey tb test photo is one that seems to appear in an ongoing campaign against the University of Florida. In response to several years of attacks on their animal research programs, public universities in Florida are pursuing new action to shield personal information about their personnel from public disclosure.   We’ve written previously about an ongoing campaign of violent threats, harassment, and protest by local activists (here, here, here).

In parallel to other campaigns, photographs are a centerpiece of the current attacks on animal research. As reported by Beatrice Dupuy in the Independent Alligator:

“Disturbing pictures of primates being examined by researchers are featured on the organization’s website along with posters with quotes like “stop the holocaust inside UF, free the monkeys.” After a three year lawsuit, the organization, formerly named Negotiation is Over, obtained UF’s public veterinary records last April. The researchers named in public records were the first ones to be targeted by animal rights activists, said Janine Sikes, a UF spokeswoman.”

What are these “disturbing pictures of primates being examined by researchers”?

The photographs <warning: link to AR site> are of macaque monkeys that appear to be receiving routine veterinary care or are simply in fairly standard housing. While the activists claim these photos are evidence of maltreatment at the hands of researchers, they likely are mostly of routine veterinary procedures. For example, two appear to be of an anesthetized macaque monkey receiving a tattoo, another two of an anesthetized monkey receiving a tuberculosis test, while others show the reddened skin that rhesus macaques exhibit normally in the wild and captivity. One photo depicts what looks like a stillborn infant macaque. Without context or confirmation, it isn’t surprising that the photographs can be interpreted in many ways.

UF’s spokesperson says: “The university wants to be very open and honest about its research,” … “It wants to stop these personal attacks against our researchers.”

One place to begin is to provide straightforward and accurate context for the images of laboratory animals that have been released. While those with experience in laboratory care of nonhuman primates can view the images and be reasonably certain that they are mostly of clinical veterinary care, it is only the UF veterinary, animal care program, and scientific personnel that can provide accurate information. Other universities have done exactly that when faced with the same situation. In “An Open Letter to the Laboratory Animal Veterinary Community and Research Institution Administration”   we wrote:

“While scientists can address questions about the scientific side of animal research, we need the laboratory animal care and veterinary staff to provide their expertise in service of addressing public questions about clinical care and husbandry.  If they do not, it will be no surprise if the public view of animal research is disproportionately colored by the relatively rare adverse events and the misrepresentations of animal rights activists. Many believe that it is possible—and perhaps acceptable—to ignore this part of reality in order to focus on more immediate demands for time, energy, and resources. Consider, however, that a fundamental part of the AWA, accreditation, regulation, and professional obligation is actually to ensure communication with the public that supports animal research.  Thus, it is our entire community who share a primary obligation to engage in the dialogue that surrounds us.”

We have consistently condemned the extremists who have targeted UF scientists and others with outrageous harassment. Tactics designed to elicit fear and terror do not have a place in democratic society and do nothing to promote fair and civil dialogue about complex issues.

At the same time, we believe and have written often, that the scientific and laboratory animal community, including scientists, veterinarians, and institutional officials should consider that better education and explanation are key to building public dialogue and understanding of research. Furthermore, as highlighted in this case and others, releasing photographs, records, and other materials without providing context serves no one well. Providing straightforward explanation of the veterinary practices, housing, husbandry, and care of laboratory animals not only gives context to photographs, but also should not be that hard to do.

Allyson J. Bennett

More information and resources:

Raising the bar: What makes an effective public response in the face of animal rights campaigns:  http://speakingofresearch.com/2013/02/20/raising-the-bar-what-makes-an-effective-public-response-in-the-face-of-animal-rights-campaigns/

Time for a change in strategies? http://speakingofresearch.com/2013/06/24/time-for-a-change/

A detailed response to a PETA video accusing a primate lab of mistreatment:  http://speakingofresearch.com/2008/07/04/peta-out-with-the-new-in-with-the-old/

Speaking of Research media briefing (pdf):  Background Briefing on Animal Research in the US

To learn more about the role of animal research in advancing human and veterinary medicine, and the threat posed to this progress by the animal rights lobby, follow us on Facebook or Twitter.

How to help girls with Rett syndrome, and strike a blow against extremism!

Today we have a guest post by Dr Nicoletta Landsberger, Associate Professor at the University of Insubria and Principle Investigator at the San Raffaele Rett Research Center. The San Raffaele Rett Research Center is supported by the Pro Rett Ricerce (proRett), a small but energetic Italian patient organization that funds research in Italy and abroad to find a cure for the neurodevelopmental disorder Rett syndrome, which affects about 1 in 10,000 girls. 

A fortnight ago Dr Landsberger was forced to cancel a fundraising event – which included a raffle – for proRett due to the threat of disruption from animal rights extremists. Our friends in Pro-Test Italia wrote an open letter to Italian prime minister Matteo Renzi about this attack on medical progress, and bought 200 tickets for the raffle (worth 400 Euros).

Regular readers of this blog will be well aware of the recent increase in animal rights extremism in Italy, but the campaign against a charity that seeks to find effective therapies for a disease that devastates many thousands young lives around the world marks a new low. We need to support our friends in Italy, to support the children who suffer from Rett syndrome, and to send a strong message to animal rights extremists that their intimidation and bullying will not be tolerated. We are not asking you to march in the streets, or to sign a petition, or even to write a letter, we are asking you to do something a lot simpler; we are asking you to make a donation to proRett.

Please take a few minutes to give proRett what you can via their PayPal account, even a small donation will help (The PayPal account is in Italian, but essentially identical to the English language version. United States is Stati Unita in Italian, and United Kingdom is Regno Unito. If you are unsure of anything just use Google Translate).

Imagine Anna, a wonderful eight months girl sitting in her high chair and turning the pages of a book while watching it. Imagine Anna’s mother showing you other pictures of her daughter, smiling to her siblings or grasping objects. Everything seems normal, but then, few months later, the pictures are different. Anna is not smiling anymore, the expression of her face is different, the brightness has disappeared and in many pictures Anna has protruding jaws. Anna’s mother tells me “this is when I realized that something was changing…. At that time Anna’s progress stopped, the ability to hold the book and turn its pages was lost, overcome by continuous stereotyped hand-wringing movements. Rett syndrome and its regression phase were taking Anna away, locking her in her body for good”.

Anna is now 16, she is wheel chair bound, unable to talk and to play; like most girls affected by Rett syndrome she suffers from seizures, hypotonia, constipation, scoliosis, osteopenia, and breathing irregularities. Like most girls affected (over 90%) by typical Rett syndrome she carries a mutation in the X-linked MECP2 gene.

Today, almost 30 years after Rett syndrome was internationally recognized as a unique disorder mainly affecting girls, we know that it is a rare genetic disease, and that because of its prevalence (roughly 1:10.000 born girls) can be considered one of the most frequent causes of intellectual disability in females worldwide.

Rett syndrome is a pediatric neurological disorder with a delayed onset of symptoms and has to be clinically diagnosed relying on specific criteria. Girls affected by typical Rett Syndrome are born apparently healthy after a normal pregnancy and uneventful delivery and appear to develop normally usually throughout the first 6-18 months of life. Then their neurological development appears to arrest and, as the syndrome progresses, a regression phase occurs that leads to a documented loss of early acquired developmental skills, such as purposeful hand use, learned single words/babble and motor skills. During the regression phase, patients develop gait abnormalities and almost continuous stereotypic hand wringing, washing, clapping, and mouthing movements that constitute the hallmark of the disease. Many other severe clinical features are associated with typical Rett syndrome, including breathing abnormalities, seizures, hypotonia and weak posture, scoliosis, weight loss, bruxism, underdeveloped feet, severe constipation and cardiac abnormalities. Rett syndrome patients often live into adulthood, even though a slight increase in the mortality rate is observed, which is often caused by sudden deaths, probably triggered by breathing dysfunctions and cardiac alterations. There are no effective therapies available to slow or stop the disease, only treatments to help manage symptoms.

Genetic analyses show that most cases are caused by a mutation in the X-linked MECP2 gene, and many different missense mutations and deletions have been identified within the MECP2 gene of girls with Rett syndrome that prevent the protein from functioning correctly. The formal genetic proof of the involvement of the MECP2 gene in Rett syndrome is further provided by a number of diverse mouse models carrying different MECP2 alterations, which display the same symptoms observed in human patients (for more information see this recent open-access review by David Katz and colleagues) . These animals that fully recapitulate the disease have permitted us to demonstrate that the neurons have a constellation of minor defects, but that no degeneration is occurring, and that our brain need MECP2 at all times. Whenever the gene gets inactivated the disease appears.

Genetically modified mice have made crucial contributions to our understanding of Rett syndrome. Image courtesy of Understanding Animal Research.

Genetically modified mice have made crucial contributions to our understanding of Rett syndrome. Image courtesy of Understanding Animal Research.

Rett syndrome is mainly a neuronal disease, and obviously the amount of research we can do with the girls’ brains is limited. Because of this a range of mouse models of the disease have been instrumental for the study of the pathology. Furthermore, the same mice have permitted scientists to find the first molecular pathways that appear altered in the disease leading to test some therapeutic molecules in mice. Translational research leads to a clinical trial; and this is the case here, for example a clinical trial of IGF1 therapy is currently under way. Importantly, in 2007, Professor Adrian Bird and colleagues at the University of Edinburgh demonstrated in a mouse model that it is in principle possible to reverse Rett syndrome, and that MECP2-related disorders can be treated even at late stages of disease progression. However, the functional role(s) of MECP2 and their relevance to different aspects of development and neurological function are not fully understood, and different mutations in the MECP2 have varying effects on these roles, which any treatments will have to account for. Research indicates that too much MECP2 expression can be damaging, so scientists will need to find a way to express just the right amount of MECP2, in just the areas it is required. The clinical community has decided that no drug can be given to Rett syndrome girls without having first been tested in two different laboratories and on at least two diverse mice models of the disease. Nevertheless, this research is very promising, and not just for those with Rett syndrome and their families, as the insights gained through developing therapies for Rett syndrome are likely to be applicable to therapeutic strategies for a wide range of neurodevelopmental disorders. Studies in mouse models of Rett syndrome have a crucial role to play in this ongoing work.

proRETT is an association founded in 2004 by parents of children born with Rett syndrome, who began their activity by raising funds for the US based Rett Syndrome Research Foundation (now the International Rett Syndrome Foundation). proRett now supports the work of top Rett researchers in Italy, the UK and USA. I am a professor of molecular biology who has worked on MECP2 since I was a post-doctoral fellow in the team of the late Dr Alan P Wolffe at the National Institute of Child Health and Human Development.

In 2005 I met with proRETT to launch a collaboration in order to accelerate the scientific interest in the disease in Italy and abroad, and over the next few years   we worked together to organize two international scientific meetings (e.g. the European Working Group on Rett Syndrome) and attracted the interest of several Italian researcher to the disease. In 2010 proRETT felt the necessity to support more research in Italy and decided to open a laboratory – the San Raffaele Rett Research Center  – at the prestigious San Raffaele Scientific Institute in Milan. The laboratory, which I lead, employs 2 post-doctoral scientists, 3 PhD students and an undergraduate student. Further a second laboratory employing 8 scientists, supervised by myself and Danish researcher Dr. Charlotte Kilstrup-Nielsen, and fully dedicated to Rett syndrome is located at the University of Insubria in Busto Arsizio. As I outlined earlier, our research, as well as that of many other laboratories in the world, is interested in defining the molecular pathways that get deregulated because of a dysfunctional MECP2.  We are also examining the role of the gene during early development and outside of the brain itself. Eventually we hope to develop some novel protocols of gene therapy that can reverse Rett syndrome.

The Rett syndrome research team at the University of Insubria in Busto Arsizio

The Rett syndrome research team at the University of Insubria in Busto Arsizio

Because one of the two labs supported by proRETT is in Busto Arsizio and in Busto Arsizio there is a strong female volleyball team – Unendo Yamamay – almost one year ago we decided to organize a match of the Yamamay team dedicated to proRETT. The idea was for a female team to support research on a disease that affects girls, with both volleyball and research in the same town. The team were keen to help and the event was scheduled to be held on Saturday 15th March 2014. That evening we would have been the guests of Yamamay, and we were going to hold a raffle to raise money for research.

Unfortunately, once the event was announced last month, the trouble started. It began when the Busto Arsizio branch of the large Italian animal rights group the Lega Anti Vivisesione published decontextualised images of dead mice (seems familiar – SR)not belonging to my lab on their facebook page and claimed that our activities were unscientific  in order to stir up anger amongst their supporters against our lab (you can read more details about this in Italian here). They then tried to start a boycott of Unendo Yamamay and started a mass  e-mailing campaign, writing on social networks and to the proRETT and Unendo Yamamay. At the end of this nightmare, and because the local police headquarters was not confident about keeping the event safe from disruption by violent animal rights extremists, we had to give up. The match went ahead but proRETT were no longer guests, with Unendo Yamamay issuing a statement expressing their extreme regret at the events leading to the cancellation that had “caused serious harm to persons engaged daily in medical research against this terrible disease”.

Organizers had hoped to sell 6 thousand tickets for the lottery in aid of Rett syndrome research

Organizers had hoped to sell 6 thousand tickets for the lottery in aid of Rett syndrome research

The cancellation was felt as a tragedy by the parents, who, obviously, felt themselves even more alone than before. Because of that we decided to hold the raffle in our university in Busto Arsizio on Friday evening the in order to raise some money for proRETT, where we were joined by some parents and girls with Rett syndrome, as well as several journalists, and the president of Pro-Test Italia, who chose to show solidarity by attending. In the end we raised almost 6,000 euros from the raffle, less than we had initially hoped, but enough to show us and the parents of girls with Rett syndrome that there are still good people who are prepared to stand up for vital research.

We need to make sure this never happens in Italy again. This fight goes beyond Rett girls but is in the name of the progress of biomedical science in Italy and in the world; it is in the name of a future with less suffering. We would like the parents of Rett girls  and researchers dedicated to curing this disease to not feel alone, so we ask you to join good people in Italy and across the world to show your support for our girls, and your contempt for animal rights extremism, by making a small donation to proRETT.

Thank you.

Nicoletta Landsberger

To learn more about the role of animal research in advancing human and veterinary medicine, and the threat posed to this progress by the animal rights lobby, follow us on Facebook or Twitter.

Understanding addiction: NIDA article highlights contribution of animal research

Professor David Jentsch is a highly respected UCLA neuroscientist who specialises in the study of addiction, one of the most widespread and serious medical problems in our society today. Sadly, by devoting his career to finding out how to better treat a condition that ruins – and all too often ends – many millions of lives in the USA and around the world every year, David has found himself, his colleagues, and his friends and neighbors under attack from animal rights extremists whose tactics have ranged from harassment, stalking and intimidation, to arson and violence.

Did this extremist campaign persuade David to abandon his research?

No chance!

In 2009 David responded to the extremist campaign against him and his colleagues by helping to found Pro-Test for Science to campaign for science and against animal rights extremism at UCLA, and has been a key contributor to Speaking of Research, writing articles on the role of animal studies in the development of new therapies for addiction, what his studies on rodents and vervet monkeys involve, and how addiction research can help us to understand obesity.

Vervet monkeys involved in David Jentsch's research program live in outdoor social groups to ensure optimal welfare

Vervet monkeys involved in David Jentsch’s research program live in outdoor social groups to ensure optimal welfare

This week the NIH’s National institute on Drug Abuse (NIDA) has published an excellent article on David’s ongoing research entitled  “Methamphetamine Alters Brain Structures, Impairs Mental Flexibility”, which highlights the importance of non-human primate research in identifying how addiction alters the brain and why some individuals are more prone to develop damaging methamphetamine dependency than others. You can read the article in full here.

Human chronic methamphetamine users have been shown to differ from nonusers in the same ways that the post-exposure monkeys differed from their pre-exposure selves. The researchers’ use of monkeys as study subjects enabled them to address a question that human studies cannot: Did the drug cause those differences, or were they present before the individuals initiated use of the drug? The study results strongly suggest that the drug is significantly, if not wholly, responsible”

This knowledge of how drug use disrupts brain function will be crucial to development effective clinical interventions for methamphetamine addiction, and the huge scale and devastating impact of methamphetamine use makes it clear that such interventions are desperately needed, as David highlights in the article’s conclusion.

Methamphetamine dependence is currently a problem with no good medical treatments, when you say a disease like methamphetamine dependence is costly, it’s not just costing money, but lives, productivity, happiness, and joy. Its impact bleeds through families and society.”

At a time when animal rights activists in many countries are pushing to ban addiction research involving animals, the NIDA article on the work of David and his colleagues shows why this work is so valuable, and just what would be lost if animal rights extremists are allowed to have their way.

Speaking of Research

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Saving Life on Earth

recent petition asks 22 scientists, myself included, to “justify your science claims.”  So far it has collected slightly over 14,000 signatures. It was organized by a group called For Life on Earth (FLOE) which bases its opposition to the use of animals in medical research based on the writings of Dr. Ray Greek.
 
How do I justify my science?  
 
It is a strange question.  To start my science is no different from the one conducted by my colleagues  — whether a geologist or a physicist.  There is only one science. It is the one based on the notion that we can postulate how some aspect of nature works, make our ideas specific enough to generate testable predictions, and use experimental methods to put those hypothesis to the test. Concepts that are refuted by the data go into the pile of rejected ideas, those that survive are pursued further and, in some occasions, after many years, and with much community effort, they are refined to the point that the account for such a vast amount experimental outcomes that we refer to them as theories.  This scientific method has proven itself over and over again over centuries and has led to the many technological advancements you enjoy today.  Science is the crown jewel of human intellect and reason.
 
The questions life scientists ask differ form those working in other fields.  We are interested in seeking fundamental knowledge about the nature and behavior of living systems.  How do cells work?  How do they communicate with each other? How do they develop and differentiate into different tissues and organs?  How do they die and why?  In my subfield of neuroscience we ask question related to how neurons work together to allow us to store and retrieve memories, plan and generate movements, visually recognize objects, make decisions, and so on.  These are all questions scientists not only find intellectually interesting, but there is wide consensus that such fundamental knowledge is critical to enhance the health, lengthen life, and reduce the cost of illness and disability in both humans and non-human animals. 
 
Unfortunately, at this point in time, our methods do not allow to pursue cellular and molecular-level questions non-invasively in human subjects, and this is why part of the work requires the use of animals in research. Accordingly, a recent poll by the journal Nature revealed that nearly 92% of scientists agree with the statement “animal research is essential to the advancement of biomedical science.” 
 
Any reasonable person would agree a mechanic would be in a better position to fix a car if s/he actually knows the role each part plays, how they fit together, and what can happen if one of them fails.  Similarly, any reasonable person must agree that we would be in a better position to develop therapies and cures if we knew exactly how living organisms work in health, and what happens to our cells and other organs in disease. 
 
In contrast, the petition attempts to refute this self-evident truth, arguing that some recent scientific results explain why animal research has no value whatsoever for human health:
 
As the history of landmark scientific advances clearly documents, the scientific breakthroughs are often produced by the dedicated work of enlightened individuals, such as Darwin who brought us the Theory of Evolution, Einstein who gave us the Theory of Relativity and Kenner, Lister and Semmelweis who all contributed to the Germ Theory of Disease.  Science has more recently delivered the Trans-Species Modeling Theory (TSMT)[1], which demonstrates how current understanding of evolutionary biology and complexity explain decades of practical examples, the results of which oppose using animal experiments to try and predict human responses in medical research and the safety testing of new human medicines.
So what exactly is this Trans-Species Modeling Theory that the petitioners list as a scientific achievement of comparable in significance to Evolution, Relativity and Germ Theory?   
 
I invite you to look it up. If you search for “Trans-Species Modeling Theory” in Pubmed you will find the term not mentioned even once. If you look up the article cited by the petition in Google Scholar you will see it was authored by animal rights activists Dr. Ray Greek and Lawrence Hansen and cited a total of 5 times, not once in peered-review scientific articles. All citations are from web sites, including one from the petition itself (which, I have to say, appears written by Dr. Greek himself.)
 
We are also directed by FLOE to read what is supposed to be Dr. Greek’s seminal work — a book entitled “Animal models in light of evolution”. The book has been cited a total of 42 times. Not impressive. Even less when you consider 28 are self-citations from Dr. Greek himself; 5 come from animal rights activists who have been Greek’s co-authors; and the rest is from a handful of other authors, including myself which speak about the book in not very positive terms.
The FLOE web site shows Greek's book next to Darwin's "On the Origin of Species."  One if science, they other is not.  Can you tell which one is which?

The FLOE web-site shows Greek’s book next to Darwin’s “On the Origin of Species.” Works of comparable significance?  I don’t think so.

Let it be clear that contrary to what the petition says, science did not deliver Trans-Species Modeling Theory — a couple of animal rights activists did.  And it is not a theory of anything, but merely an opinion. To list Trans-Species Modeling Theory in the same sentence as Evolution and Relativity is a cruel joke on science.  At least, whoever wrote the petition, had the decency to spare us the pain of seeing the names of animal rights cranks listed among those of Darwin and Einstein.  
 
There is another reveling passage in the petition.  It refers to the use of animals in basic research as using them to gain “knowledge for knowledge sake,”  as if somehow such knowledge had no consequence whatsoever to the improvement of human health.  Such statement illustrates the ignorance of the petitioners about how science works.  When we talk about applied science, what is applied is knowledge.  You can even find this fact embedded in the opening words of the mission of the NIH, which is “to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability.”
 
Lastly, the central question the petition tries to isolate and eager to debate is meaningless. Animals are used in medical research by formulating a hypothesis about a disease of interest, trying to recreate the disease in animal subjects, studying the basic mechanisms involved, and developing new methods to interfere or stop the development of the disease in humans.  When any one such attempt fails, it is a grave mistake to see it as a failure of science or as a general failure of the use of animals in research. It is simply a sign we failed to correctly capture all the relevant processes that take place in the human condition. Such failures are an integral part of the scientific process, as they narrow the space of possible solutions and will lead you to the accurate model.  Medical history has shown time and again that such process can, over the objections of animal rights activists, lead to a fruitful completion and save millions of human and animal lives.  
The work is justified because it saves lives on Earth.
Note: for other valid points see David Gorski’s response.

Gary Francione: “I don’t believe in vaccinations”

We previously discussed the anti-vaccination stance of a member of the animal rights group “Progress for Science”.  The fact that this individual prefers oregano oil, ginger, garlic, and other herbs over vaccines did not come as a surprise.  We have already noted the strong similarities between the arguments espoused by the anti-vaccination and animal rights groups.  But you may be asking yourself — just how prevalent is the view among animal rights activists? It turns out the position can be traced all the way up to prominent academics, such a Professor Gary Francione:

Yes, you heard right (play it again if in doubt) — Rutgers Law Professor Gary Francione does not believe in vaccinations. He is not alone.  The exuberant applause he receives comes from animal rights supporters in the audience, and you can easily judge there are no shortage of them.

How could this be? You would think that any reasonable person who looks at the data ought to conclude that childhood vaccinations do in fact work and that, without any shred of doubt whatsoever, they save thousands and thousands of human (and animal) lives each year.

Take a look at the incidence of measles and diphtheria over the last decades, for example, and notice how the numbers drop precipitously as vaccines for these illnesses were introduced. You can find similar graphs for many other common diseases.

vaccines

If Professor Francione had any children he would not vaccinate them.  What about those who have children?  Does he truly understand what would happen if the public were to follow his recommendation?  The data say that millions would die each year.

It is shocking that a respected scholar offers a view that is nothing short of a pubic health hazard. It is mind-boggling that anyone who calls himself compassionate would put the lives of so many children at risk.  What kind of meaningful ethical discussion can one possibly have with those who blatantly reject scientific facts and deny past contributions of the work to human health?

One must also recognize there is something ludicrous about the entire situation.  On one hand, many animal rights activists deny the benefits of animal research.  On the other, they work extremely hard to argue they should be entitled to the benefits of the very same work they oppose.

Thus, we see hear Professor Francione say he does not believe in vaccinations (and other pharmaceuticals?) and but elsewhere he writes —

[…] Those who object to animal use for [animal research], however, have no control as individuals over government regulations or corporate policies concerning animals. To say that they cannot consistently criticize the actions of government or industry while they derive benefits from these actions, over which they have no control, is absurd as a matter of logic. (Francione 1995, 181).

No, it is not absurd. While it is true he may not have control over government actions or policies he does have control over his healthcare and that of his family.  In fact, he exemplified for us how he would exercise that control by not vaccinating his children.

Consider the following analogy. Suppose you are a social activist who forcefully opposes child and forced labor practices.  You discover that a particular US company manufactures its products overseas under deplorable labor conditions. Would you still buy form such a company or boycott its products? Is there any way in which you can say that you morally oppose forced labor but argue you are nevertheless entitled to benefit from the cheap prices the company has to offer? If you were to buy from such a company can you be surprised if someone called you a called a hypocrite?  After all, would be supporting, financing and perpetuating a practice you consider immoral and advocate against.  It makes sense to argue the same applies to animal research.

Many animal rights activists may respond the analogy is not adequate because, in the case of refusing healthcare derived from animal research, the outcome may include death, instead of the more mundane consequence of not purchasing the latest smart phone.  This would be a curious argument coming from those who fail to acknowledge the benefits of the research in the first place. Nevertheless, in objecting in such a way they would be making our case — animal research saves lives.  Herein lies the moral dilemma opponents of research who refuse to confront even when it is their own lives that are saved by the work of biomedical researchers.

To learn more about the role of animal research in advancing human and veterinary medicine, and the threat posed to this progress by the animal rights lobby, follow us on Facebook at: https://www.facebook.com/SpeakingofResearch

From clinic to mouse to clinic: New HIV gene therapy shows promise!

Yesterday a team of University of Pennsylvania researchers – led by Dr Pablo Tebas, Professor Carl June, and Dr Bruce Levine – announced the successful conclusion of a clinical trial to evaluate the safety of a new gene therapy technique for treating HIV. It is a result that may eventually allow millions of HIV positive people to control the infection without having to take daily medication.

Two technicians in Penn Medicine's Clinical Cell and Vaccine Production Facility hold up a bag of modified T cells. Image: Penn Medicine

Two technicians in Penn Medicine’s Clinical Cell and Vaccine Production Facility hold up a bag of modified T cells. Image: Penn Medicine

Their study, published in the New England Journal of Medicine, involved taking a sample of T-cells from 12 patients and then using an adenoviral vector to introduce into these cells an enzyme known as a zinc-finger nuclease (ZFN) that has been targeted to the CCR5 receptor gene so that it introduces a mutation called CCR5-delta-32.  They then expanded the number of T-cells in vitro until they had billions of the transformed T-cells ready for transplant back into the patients.

Most HIV strains need to bind to CCR5 to infect T-cells, and the CCR5-delta-32 mutation prevents this binding and subsequent infection, as was dramatically demonstrated in the case of the “Berlin patient”, so the Pennsylvania team are hoping that their method will enable long-term control of HIV infection in patients, so that they may no longer need to take anti-retroviral medication.

An important part of the development of this therapy was its evaluation in vivo in an animal model of HIV infection. To do this they turned to mice rather than the more usual SIV/macaque model, as the sequence of the CCR5 gene at the site targeted by ZFN in macaques is not conserved with humans and would require the design and assembly of a distinct ZFN binding set for testing in SIV infection. Mice don’t normally become infected with HIV, but by using NOG mice that have been genetically modified so that their own immune system do not develop and then transplanting human immune cells into the mice they were able to produce mice with “humanized” immune systems that could be used to evaluate the ability of their ZFN modified T-cells to block HIV infection. In a paper published in the journal Nature Biotechnology in 2008, the team led by Carl June reported that the transformed human T-cells could successfully engraft and proliferate when transplanted into the NOG mice, and protect against subsequent HIV infection.

To our knowledge, genome editing that is sufficiently robust to support therapy in an animal model has not been shown previously. The ZFN-guided genomic editing was highly specific and well tolerated, as revealed by examination of the stability, growth and engraftment characteristics of the genome-modified sub-population even in the absence of selection…We also observed a threefold enrichment of the ZFN-modified primary human CD4+ T cells and protection from viremia in a NOG mouse model of active HIV-1 infection. As predicted for a genetically determined trait, the ZFN-modified cells demonstrated stable and heritable resistance in progeny cells to HIV-1 infection both in vitro and in vivo. These results demonstrate that ZFN-mediated genome editing can be used to reproduce a CCR5 null genotype in primary human cells.”

Following this they also undertook more extensive regulatory studies in mice to demonstrate that there were no toxicities associated with the ZFIN transformation of the T-cells.

While the clinical trial announced yesterday focused on the safety of the technique, the authors also reported that HIV RNA became undetectable in one of four patients who could be evaluated, and that the blood level of HIV DNA decreased in most patients, which bodes well for future trials when larger quantities of ZFN-modified cells will be transplanted.

This is not the first time that the pioneering work of Bruce Levine and Carl June has caught our attention, they are the same researchers who have hit the headlines with an innovative “Chimeric Antibody Receptor” gene therapy for leukemia that is part of the cancer immunotherapy revolution now underway. Their latest breakthrough is another indication of how gene therapy is becoming an important part of 21st century medicine.

Paul Browne

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