Author Archives: Blue Sky Science

Undermining a cornerstone of medical research – examining a biased commentary on animal studies

Medical sociologist, Pandora Pound, and epidemiologist, Michael Bracken, recently wrote an opinion piece entitled “Is animal research sufficiently evidence based to be a cornerstone of biomedical research?” for the British Medical Journal. The article was chosen as the editor’s choice, leading to an editorial by the editor in chief, Fiona Godlee.

BMJ Pound and Bracken

Pound and Bracken criticise the poor quality and reporting of many animal studies, asserting that this is leading to ineffective drugs going on to clinical trials before failing.

Pound and Bracken make some suggestions for improvement, concluding:

In addition to intensifying the systematic review effort, providing training in experimental design and adhering to higher standards of research conduct and reporting, prospective registration of preclinical studies, and the public deposition of (both positive and negative) findings would be steps in the right direction. Greater public accountability might be provided by including lay people in some of the processes of preclinical research such as ethical review bodies and setting research priorities. However, if animal researchers continue to fail to conduct rigorous studies and synthesise and report them accurately, and if research conducted on animals continues to be unable to reasonably predict what can be expected in humans, the public’s continuing endorsement and funding of preclinical animal research seems misplaced.”

While some aspects of the article are reasonable, the overall impression the reader is left with is that animal research doesn’t work and can’t work in its current form. Their bias is obvious to those who are familiar with the arguments of those who argue against animal research. When they’re not incorrectly conflating basic science* with animal research (most basic biomedical research does not involve animals, e.g. human genetic research), Pound and Bracken argue that “lack of translation” is (apparently) not just from poor research practises, but also due to fundamental differences between humans and other animals, writing:

Even if the research was conducted faultlessly, animal models might still have limited success in predicting human responses to drugs and disease because of inherent inter-species differences in molecular and metabolic pathways.”

However, the bulk of the supporting literature they present to support this statement is – unlike most of the claims made in their commentary – not in the form of peer reviewed scientific research papers or meta-analyses but rather commentaries and books written by (other) opponents of animal research, including a certain Dr Greek whose misleading claims we have discussed several times on this blog (most recently here). For a commentary that sets great store by its evidence-based credentials this is, to say the least, disappointing.

Indeed, in their 2004 publication on whose anniversary this commentary was published, Pound, Bracken and their co-authors found that in all 5 cases where a therapy appeared to be successful in pre-clinical animal studies but later failed in human studies, more rigorous meta-analysis of the pooled pre-clinical animal studies showed that the treatment was not in fact successful in them, and that for one therapy (thrombolysis for stroke) such rigorous analysis would have enabled a serious side effect observed in clinical trials to be identified in the pre-clinical animal studies. In short, their own work shows that animal studies can predict the human outcome when their results are analyzed properly..

Other investigators who have examined failed therapies in cancer, ALS and stroke, have come to the same conclusion that too many therapies in some areas of research have failed in clinical trials not because of species differences, but because they never actually succeeded in animal studies, with most of the apparent successes being false-positive results due to flaws in experimental design and biases in reporting and publication. The authors all agree on a number of steps that need to be taken to avoid false-positive results being taken through to clinical trials, including better study design, requirement for independent replication of results in several animal models of the condition in question, publication of negative results (where the candidate therapy doesn’t work), meta-analyses of animal studies before beginning human trials.

An excellent analysis of animal models of stroke by van der Worp et al (2010) covers many of these issues, but also advises that to avoid false negative results in the clinical trials – where poor trial design leads to the erroneous conclusion that a therapy doesn’t work when in fact it does – human trials should match as closely as possible the conditions e.g. time to drug administration, dose, type of injury) of the successful animal studies.

The “rapid responses” to Pound and Bracken’s piece shows that many scientists who specialize in translating research from bench to bedside are alert to the flaws in their analysis.

To quote the response by Andrew Whitelaw and Marianne Thoresen, Professors of Neonatal Neuroscience at the University of Bristol:

The reader was left with impression that there were no examples in recent years of animal research leading directly to major advances in human health.

Three life-saving treatments in neonatal medicine would never have been given ethical approval for clinical trial if there had not been high quality animal models showing efficacy.

Rather than unselectively condemning the whole of biomedical animal research, we suggest that a more critical approach by funding bodies and journal editors could reduce bad research while supporting the good.

They ought to know, as basic and applied research in animals was crucial to the development of techniques that use cooling and xenon gas to protect babies from brain damage following oxygen starvation during birth.

Dr Thomas Wood, is more succinct:

[T]he overriding message of the article is somewhat confusing – demanding that we optimise and streamline animal research is very different from suggesting that it is useless, but both of these ideas are presented side-by-side.”

Prof Malcolm Macleod, a neurologist at the University of Edinburgh, and a frequent critic of poor design in some animal studies, agrees with many of Pound and Bracken’s criticisms, but in a more balanced manner, noting:

When conducted to the highest standards, animal research can indeed inform the development of human medicines. Given that there are many diseases for which we do now have treatments, it is perhaps self evident that the diseases which remain are more challenging, probably requiring research that is done to a higher standard – there is less signal, and more noise.”

Professor Macleod is one of Europe’s leading experts on the development of therapies for stroke, and is one of the leaders of the EuroHYP-1 trial of therapeutic hypothermia in adult patients with acute ischaemic stroke, a trial he advocated after undertaking a rigorous meta-analysis of studies on this therapy in animal models of ischaemic stroke.

Dr Charles M Pearman discussed how basic science makes up the building blocks that lead to human medicine:

Much clinical research is performed by standing on the shoulders of giants. A phase III drug trial comparing two antihypertensives will have much greater direct impact on clinical decision making than any individual animal model based basic science study. However, hundreds or thousands of such “low impact” works are needed to develop the drugs in questions. The authors reference Wooding et al. who themselves acknowledge this and conclude that clinically motivated basic biomedical research should be encouraged.

Basic biomedical research may try and may fail. Without it, however, there will be no successes to base clinical triumphs upon.

There have been many other comments, Prof Fernando Martins do Vale discusses why some of Pound and Bracken’s criticisms may not have much of an impact on results. Prof Robert Perlman argues that evolutionary differences between species can inform animal research. And Dr Vanitha A J explains that much cancer research has been effectively translated from animals to humans, noting in particular recent progress in cancer immunotherapy.

Another, separate, but strong response to Pound and Bracken’s paper was from Dr Liz Harley at Understanding Animal Research. Harley notes that many of the criticisms made in the original opinion piece are already being addressed by the industry. The UK Government’s delivery plan, “Working to Reduce the Use of Animals in Scientific Research”, explicitly mentioned the problems of poor experimental design and outlined several initiatives aimed to improve current practices. While Pound and Bracken call for a lay person to sit on ethical review bodies, they fail to note this is standard practice in the UK, while US regulations demand a lay person unaffiliated with the university stand on their Institutional Animal Care and Use Committees. Clearly Pound and Bracket do not do their homework sufficiently.

We finish with a quote from Prof Martins do Vale:

But the existence of bias and errors does not invalidate Science; on the contrary, as Karl Popper said, the awareness of errors is the first step for their correction and scientific progress.”

Pound and Bracken’s article opens up some important questions, but their biased interpretation risks throwing out the baby with the bathwater as they use flaws in experimental design to try and argue for a fundamental flaw in animal research. Their attempts to use legitimate concerns over experimental design to attack animal research are in fact a dangerous distraction from ongoing efforts to address problems that affect all areas of biomedical research (and indeed any areas of research where scientists have looked for them) from the most fundamental in vitro molecular biology studies right through to clinical trails.

Speaking of Research

* Confusion over what is meant by basic research is a theme throughout Pound and Bracken’s piece, it’s notable that many of the examples of “basic” research they mention are in fact applied or translational research, and that they focus on a paper on translation of basic research published by Contopoulos-Ioannidis et al. in 2003, a paper whose serious flaws in both design and conclusion we have discussed previously.

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.

Kicking off a new era for neuroprosthetics, or just the warm-up?

Tonight, if everything goes according to plan, a young person will stand up in front of a global audience numbering in the hundreds of millions, walk a few paces, and kick a football.  This by itself may not seem remarkable, after all this is the opening ceremony of the World Cup, but for the Miguel Nicolelis and the more than 100 scientists on the Walk Again project – and the millions watching from around the world – this will mark the triumph of hope and dedication against adversity, for the young person in question is paraplegic.

Image: Miguel Nicolelis

Image: Miguel Nicolelis

The exoskeleton that is being used in this demonstration is a formidable technological achievement, collecting nerve signals from non-invasive EEG electrodes placed on the scalp of the operator, and converts these into commands for the exoskeleton, while sensors on the operators feet detect when they make contact with the ground and send a signal to a vibrating device sewn into the forearm of the wearer’s shirt. This feedback, which has never been incorporated into an exoskeleton before, allows the operator to control the motion of the exoskeleton more precisely. While this is not the first EEG controlled exoskeleton to be tested by paraplegic individuals, videos released by the Walk Again suggest that it has allows for far quicker and more fluent movement than existing models.

 

A late substitution

What many viewers may not know is that the use of EEG (Electroencephalography) was not part of Miguel Nicolelis’ original plan, as late as spring 2013 he was planning to use an alternative technology, implanted microelectrode grids within the cerebral cortex of the operator. Unfortunately about a year ago it became clear that the implant technology he was developing would not be ready for use in humans in time to meet the deadline of the opening ceremony of the 2014 FIFA World Cup, so the team had to fall back on the more established technique of EEG.

Is this an issue? Well, to understand this you first have to know a little about the two approaches.

EEG is a very mature technology. Its development dates back to 1875 when Richard Caton observed electrical impulses on the surface of the brains of rabbits and monkeys. In 1912 Vladimir Pravdich-Neminsky published the first EEG in dogs, and in 1924 the first EEG in human subjects was recorded by Hans Berger. It has the advantage that it doesn’t require surgery, but also serious disadvantages. The main disadvantage is that it records the combined signals from millions of neurons across wide areas of the cortex simultaneously, and this makes it difficult to separate out the signal from the noise. By contrast microclectrode implants record the individual signals from just a few neurons.

A common analogy is that EEG records the sound made by the whole orchestra, whereas microelectrode implants record individual instruments.  The result is that EEG can only be used to give relatively simple commands “move leg forward” “back” “stop” “kick” and requires a great deal of concentration by the operator. It is unlikely that the performance cam be improved upon very much. By contrast the microelectrode implants, while requiring invasive surgery, have the potential to enable much finer control over movement.

A pioneer of brain implant technology

There is no doubt that for over a decade Miguel Nicolelis and his colleagues at the Duke University Center for Neuroengineering have been among a very select group of scientists at the forefront of brain implant research, demonstrating that implanted electrodes could be used to control a simple robotic arm in rats in 1999 and in monkeys in 2000 (1). In 2012 Nicolelis highlighted the importance of animal studies to progress in the field in an article for Scientific American:

The project builds on nearly two decades of pioneering work on brain-machine interfaces at Duke—research that itself grew out of studies dating back to the 1960s, when scientists first attempted to tap into animal brains to see if a neural signal could be fed into a computer and thereby prompt a command to initiate motion in a mechanical device. Back in 1990 and throughout the first decade of this century, my Duke colleagues and I pioneered a method through which the brains of both rats and monkeys could be implanted with hundreds of hair-thin and flexible sensors, known as microwires. Over the past two decades we have shown that, once implanted, the flexible electrical prongs can detect minute electrical signals, or action potentials, generated by hundreds of individual neurons distributed throughout the animals’ frontal and parietal cortices—the regions that define a vast brain circuit responsible for the generation of voluntary movements.”

In 2008 the Duke University team showed that microelectrode arrays implanted in the cortex could be used record the neuron activity that controls the actions of leg muscles (2), and that this could be used to control the movements of robotic legs.

It was this that spurred Nicolelis to try to develop a mind-controlled exoskeleton that would be demonstrated at the World Cup opening ceremony.

Brain Machine Interfaces – from monkeys to humans.

So, if brain implant technology to control an exoskeleton wasn’t ready for 2014, when will it be ready?

The answer is probably very soon, as this approach has already been demonstrated successfully in humans.

In 2008 we discussed how Andy Schwartz and colleagues at the University of Pittsburgh had succeeded in developing a brain-machine interface system where microelectrode arrays implanted in the motor cortex of macaque monkeys allowed them to control the movement of a robotic arm with a degree of dexterity that surprised even the scientists conducting the study.

Then in 2012 we reported that Jan Scheuermann, quadraplegic for over a decade due to a spinal  degenerative disease, was able to feed herself with the help of two intracortical microelectrode arrays developed by the University of Pittsburgh team.

 

What happens now?

Tonight’s demonstration will mark the culmination of an extraordinary year-long effort by scientists and patients, but it also marks the public debut of a revolution in brain machine interface technology that has been gathering pace over the past decade, largely unnoticed by the mass media.

Miguel Nicolelis has come in for some heavy criticism for the cost of the Walk Again project, and for raising hopes too high, but the criticism is largely unfair. His team set themselves an extraordinarily ambitions target, and that they have fallen a little short is understandable. Once they have recovered from their exertions they will no doubt set to integrating the exoskeleton technology that they have developed with the implant technology that they are developing back in the lab at Duke University.

And that technology is increasingly impressive, more advanced implant systems that allow monkeys to simultaneously control two virtual arms, microelectrode arrays that allow signals from almost 2,000 individual neurons to be recorded simultaneously (3) (in contrast the already very capable BrainGate implant system used by the University of Pittsburgh team records from less than 100 individual neurons) potentially allowing for much more subtle and delicate control, and interfaces that will allow sensory information from prosthetics to be transmitted directly into the brain. We will certainly be hearing from Miguel Nicolelis and his colleagues at Duke – and their colleagues and competitors around the world - again very soon.

So tonight, as you watch the opening ceremony, remember this; for Brain Machine Interface technology as much as for the World Cup itself, this is just the warm up!

Paul Browne

p.s. And of course BMI controlled robotic exoskeletons are just one promising technology under development to help paralysed people, stem cell therapy, epidural stimulation and intraspinal microstimulation have all delivered impressive results in recent studies.

1) Wessberg J, Stambaugh CR, Kralik JD, Beck PD, Laubach M, Chapin JK, Kim J, Biggs SJ, Srinivasan MA, Nicolelis MA. “Real-time prediction of hand trajectory by ensembles of cortical neurons in primates.” Nature. 2000 Nov 16;408(6810):361-5.

2) Fitzsimmons NA, Lebedev MA, Peikon ID, Nicolelis MA. “Extracting kinematic parameters for monkey bipedal walking from cortical neuronal ensemble activity.” Front Integr Neurosci. 2009 Mar 9;3:3. doi: 10.3389/neuro.07.003.2009. eCollection 2009.

3) Schwarz DA, Lebedev MA, Hanson TL, Dimitrov DF, Lehew G, Meloy J, Rajangam S, Subramanian V, Ifft PJ, Li Z, Ramakrishnan A, Tate A, Zhuang KZ, Nicolelis MA.”Chronic, wireless recordings of large-scale brain activity in freely moving rhesus monkeys.” Nat Methods. 2014 Jun;11(6):670-6. doi: 10.1038/nmeth.2936.

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.

The BUAV – Spies, Lies and Videotapes

For the second time this year the British Union for the Abolition of Vivisection (BUAV) infiltrated an animal research facility and sent footage to a British tabloid. For a second time this year, the BUAV has shown us nothing the public could not find out for themselves. No unnecessary suffering. No misbegotten science.

Let us also make a quick distinction between whistleblowing and infiltration. Whistleblowing is a standard lab policy in all UK labs whereby anyone who sees anything they find concerning (particularly relating to animal welfare) can – and should – report it to one of a number of different people up the chain of leadership. Infiltration is a tactic of sending someone into a lab with the express intention of filming as much as they can to create the most dramatic short video possible. Those involved are often double paid by both the organisation they infiltrate and the animal rights group who sent them there. Importantly, infiltrators are actively trying to find shocking video moments. Furthermore, whereas whistleblowers should report animal welfare issues quickly, infiltrators will tend to sit on any animal welfare issues they see until they have finished working at an institution – leading to unnecessary animal suffering.

Cambridge University research into Huntington’s and Batten disease
Last weekend, the Mirror on Sunday ran a story alleging sheep were “being left to suffer in pain and misery for pointless experiments” at Cambridge University following a BUAV infiltration. It should be noted that we have given examples before of the Daily Mirror playing fast and loose with the truth of animal research. Thankfully the Mirror on Sunday provided more balance than its Daily sister-publication usually does by including the perspective of both a patient and a scientist.

The BUAV took hours and hours of footage provided by their undercover infiltrator and edited it down to 4 mins 21 of the “worst” footage. In it we see several sheep exhibiting the symptoms of Batten’s disease. The BUAV also make several allegations about animal welfare, none of which seem to be corroborated by their video footage.

sheep

We see sheep, group housed in large hay-covered pens, clearly well cared for, and behaving calmly when examined by scientists and veterinarians. It is a mark of the BUAV’s duplicity that they make a great play on the term “crush cage”, when in fact these cages (known as squeeze chutes in the US) are widely used by farmers to hold an animal still to minimise the risk of injury to both the animal and the operator while work – veterinary care or routine husbandry – on the animal is performed. It is worth considering that the UK eats around 1 million sheep and lambs per month.

While this may be disturbing, the reality of Batten’s disease in humans, and its effects on a patient’s loved ones, are far, far crueller.

The University of Cambridge has strongly defended this research, pointing out that:

The researchers have been testing a sheep model of Huntington’s Disease developed by collaborators in New Zealand and Australia and studying a line of sheep that carries a natural mutation for Batten’s Disease.

Whilst every attempt is made to keep distress to a minimum, the very nature of these diseases means that the animals will show symptoms related to damage of the nervous system similar to those seen in humans.

A treatment that could slow the disease process once it has started would be a major advance, but the ideal treatment would prevent the onset of symptoms.”

MSD testing and developing vaccines for pets
In March, the Sunday Express (another tabloid not known for its science journalism…to put it mildly) ran a story purporting to show “horrific photographs and video footage showing puppies panicking as they were injected with needles before being dissected” that had been taken by “a brave undercover investigator who worked at the centre for eight months” while “also working with the BUAV throughout that time”. The research at MSD Animal Health was for testing and developing veterinary vaccines. This time the BUAV edited eight months recording into six minutes of footage that showed …. nothing. No, not nothing, it showed researchers and lab technicians conducting research with animal welfare heavy on the list of priorities. The animals were healthy, well socialised, group housed and cared for by researchers who stroked and chatted to the animals.

The video did include the dissection of a dead animal. This doesn’t look nice. Dissection rarely does. However, let us remember that the animal had been humanely killed and its welfare was not influenced by the science being carried out after it died.

Who are the BUAV?
The activities of animal rights groups cost money – the BUAV spent well in excess of £1.3 million in 2013 (and almost £2 million in 2012). With fierce competition between the numerous large national animal rights groups in the UK addressing the animal research issue (including BUAV, Animal Aid, NAVS, PETA UK and HSI), the public donations tend to go to the one with the biggest campaigns and resulting media stories (see our post on structure and motivations of animal rights groups).

The BUAV spend around 10% of their £1.7m (2013; $2.9m) – £2.0m (2011/12; $3.4m) income on investigations. Half of this is on staffing, and half is on “Other Costs”. Given the sums involved it is not unreasonable to assume that the BUAV has lab technicians it has placed in labs on its payroll (note the Sunday Express described the infiltrator at MSD as “working ” with the BUAV). These are not casual whistleblowers, but people who are working at animal research facilities with the express intention of creating horrifying videotapes.

BUAV infiltration Finances

From BUAV accounts 2011-13

One has to wonder how many BUAV infiltrators are in labs around the UK. Moreover, one wonders, how many BUAV infiltration videos were never publicised due to the lack of shocking footage (even after clever editing)? Then again, if the last two videos are the best (or worst, depending on your perspective) that the BUAV produce Each of the above infiltrations involved hundreds of hours of footage being taken of which 5 minutes was considered dramatic enough for watching. Even those five minutes lack any real substance.

To the BUAV – Prove it!
To the BUAV we ask you for the openness and transparency you accuse the research community of lacking. Show us the rest of the footage. Show us the hours and hours of footage that never made it onto your final mix tapes.
Will we find hours of shocking footage? Or will we find hours and hours of individuals working hard, caring for animals, and conducting research in a manner which provided high standards of animal welfare. It’s for you to prove.

Speaking of Research

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.

More dishonesty about animal research from the Daily Mirror

Today the British tabloid newspaper the Daily Mirror published a truly execrable piece of animal rights propaganda dressed up as journalism, in an article attacking neuroscience research undertaken using cats at University College London. The article mischaracterized the two research projects, which were published in the Journal of Neurophysiology in 2012 and 2013,   from start to finish, and as you can see below included a litany of basic errors (or were they deliberate lies?). This is not the first time that the Mirror has got its story very, very wrong.

It’s interesting to see the source of the images of cats used in the report, as they tell you something about what is going on here.

The first image may seem familiar to some readers, as it is an image that PETA have used in a campaign against hearing research at the University of Wisconsin-Madison It is a campaign marked by a mixture of clever publicity and a willingness to distort and misrepresent the facts, and of course two independent investigations refuted PETA’s allegations.

The second image, also from PETA, shows a connector to a 10×10 silicon micro-electrode array first developed at the University of Utah in the late 1990′s, which later formed a key part of  the Braingate system. In 2012 the Braingate system enabled a woman named Jan Scheuermann, quadraplegic for over a decade due to a spinal  degenerative disease, to feed herself using a brain-machine interface that monitored her motor neuron activity and allowed her to manipulate a robotic arm and hand.

It’s worth noting that valuable to advancing medical science as the implants used in the UW-Madison and University of Utah research are, they were not used in the UCL research  that the Daily Mirror is attacking, but when has the Mirror ever let the facts (or truth) stand in the way of a good image*?

UCL has issued a statement on the use of cats in research, which concludes by saying:

Despite advances in non-animal methods it is still essential to use animals where no viable alternatives exist – for both the clinical science which directly informs medical treatments, as well as the basic science which, by advancing understanding of biological processes, is an important precursor to it. The earlier work carried out on cats provided an excellent understanding of how the visual system works. As a result, it is no longer necessary to use cats as the model for this type of work which is why it has been discontinued.

So here goes, a run through of what is  – hopefully – one of the worst pieces of yellow journalism that you’ll see this year.

cat story mirror

* The Mirror has a long history of distorting research to advance animal rights propaganda. In the late 1980′s they made false allegations against Professor Colin Blakemore of the University of Oxford, and were eventually forced to print a retraction.

Speaking of Research

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.

Ebola virus vaccine developed to protect wild gorillas and chimpanzees

The current Ebola virus outbreak in Guinea, Sierra Leone and Liberia is a stark reminder on the need for effective therapies and vaccines for this disease, which has claimed the lives of thousands of people in West Africa in a series of outbreaks since the 1970’s.

It is not just the human inhabitants of West Africa who are threatened by the Ebola virus. Over the past few decades thousands of endangered gorillas and chimpanzees in the wild have been killed in devastating outbreaks, including over 5,000 gorillas in just one outbreak in Northern Congo in 2002—2003.

A new report (1) by scientists at the University of Cambridge and New Iberia Research Center illustrates “high conservation potential” of vaccines for endangered wild primates devastated by viral disease. The paper published today in the prestigious scientific journal PNAS shows that candidate vaccines which despite very promising preclinical results never complete the expensive licensing process for human use – can be co-opted for use in populations of highly endangered species such as gorillas and chimpanzees.

The study was supported by an unusual constellation of organizations, including the Universities of Cambridge and Louisiana, the conservation charity Apes Incorporated, the US Army Medical Research Institute of Infectious Diseases and the biotech company Integrated BioTherapeutics Inc.  The work was conducted at the US’s New Iberia Research Center in Louisiana, one of the research facilities that houses chimpanzees who are not owned by the National Institutes of Health.

This is the first time that a conservation-specific vaccine trial has been undertaken on captive chimpanzees, and proves that a vaccine against Ebola virus is both safe and capable of producing a robust immune response in chimpanzees.

The research team, led by Dr Peter Walsh of the University of Cambridge, administered captive chimpanzees with a new virus-like particle (VLP) vaccine being developed by the biotech company Integrated Biotherapeutics for use on humans. While they did not challenge the vaccinated animals directly with Ebola, researchers tested whether antibodies harvested from the chimpanzees’ blood could protect mice against the deadly virus. They also monitored the chimpanzees in case the vaccine produced health complications.

Results showed that the vaccine is safe in chimpanzees. The vaccinated chimpanzees developed robust immune responses, with virus-specific antibodies detected as early as 2 to 4 weeks after the first vaccination in some animals and within 2 weeks of the second vaccination in all animals.

The antibody transfer study is not the only evidence that this vaccine will work. In 2007 a key paper (2) published in The Journal of Infectious Diseases by Dr Kelly Warfield of the US Army Medical Research Institute of Infectious Diseases – who was also first author on today’s PNAS paper – demonstrated that the VLP vaccine used to vaccinate chimpanzees provides rhesus macaques with very robust protection against the Ebola virus. The 2007 paper also highlights earlier studies in mice and guinea pigs that allowed the refining and evaluation of VLP vaccines against challenge with filoviruses such as Ebola and Marburg, work that underpinned the development of this vaccine.

Transmission electron micrograph of Ebola virus. Courtesy of the Centers for Disease Control and Prevention

Transmission electron micrograph of Ebola virus. Courtesy of the Centers for Disease Control and Prevention

Next steps:  Testing in captive apes prior to field trials

The authors of today’s paper note that these VLP vaccines currently require multiple administrations to reach “full potency”, but could prove the difference between survival and extinction for species that are highly endangered or immunologically fragile but also easy to vaccinate.

Peter Walsh stressed the need to test this vaccine on captive ape populations prior to field trials.

We need to be pragmatic about saving these animals now before they are wiped out forever, and vaccination could be a turning point. But park managers are adamant – and rightly so at this stage – that all vaccines are tested on captive apes before deployment in the wild. This means access to captive chimpanzees for vaccine trials.”

The ability to test new vaccines for conservation purposes relies on research access to captive chimpanzees, but this access is now under threat just as the recognition of its necessity is increasing in the conservation community.

The US Fish and Wildlife Service is now considering regulations that would end all biomedical testing on captive chimpanzees over the next few years – the US being the only developed country to allow such research. The study’s authors believe that the US should establish a “humanely housed” captive chimpanzee population dedicated solely to conservation research.  The US already has research facilities with humane housing, including social groups, complex enclosures, expert behavioral management to provide enrichment, cognitive engagement, excellent clinical care and chimpanzees trained for cooperative clinical procedures. Thus, it is possible that the need for conservation research could be met by existing populations or centers.

Peter Walsh suggests that, by ending captive research in an effort to pay back an “ethical debt” to captive chimpanzees, the US Government is poised to “renege on an even larger debt to wild chimpanzees” at risk from viruses transmitted by tourists and researchers – as safety testing on captive chimpanzees is required before vaccines can be used in the wild.

“There is a large pool of experimental vaccines that show excellent safety and immunity profiles in primate trails but are never licensed for human use, we’ve demonstrated that it’s feasible for very modestly funded ape conservationists to adapt these orphan vaccines into conservation tools, but the ability to trial vaccines on captive chimps is vital. Ours is the first conservation-related vaccine trial on captive chimpanzees – and it may be the last.

“Although Congress specifically instructed the National Institutes of Health (NIH) to consider the conservation value of captive chimpanzee research, no findings on its possible impact were presented (in the 2011 Institute of Medicine report – SR). If the biomedical laboratories that have the facilities and inclination to conduct controlled vaccine trials ‘liquidate’ (by which he means retire to sanctuaries – SR) their chimpanzee populations, there will be nowhere left to do conservation-related trials.”

Consideration of the work, its continuation, and implications for wild chimpanzees poses challenging ethical questions, particularly in light of recent changes in US chimpanzee research.  They are questions worth serious discussion not only to inform the future of the vaccine research and conservation efforts, but also because they highlight some of the core issues in decision-making about nonhuman animal research.  Primary among the philosophical and pragmatic questions is whether it is ethical to subordinate the interests of individual animals to those of the species, or of other species.  Should some captive chimpanzees be subjected to invasive, infectious disease research in order to potentially benefit wild apes—not only chimpanzees, but also the gorillas who are most threatened by Ebola?  Another set of questions surround which chimpanzees should be used in this research.  Should it be chimpanzees housed in research facilities in the US who are now to be retired to sanctuaries?  Chimpanzees privately owned by research facilities in the US?  Zoo chimpanzees in Europe who are not intended to breed?

While none of these questions are new, progress in Ebola vaccine development and testing puts into sharp relief the kinds of serious ethical challenges that should engage both the scientific community and the broad public.  The questions are not, as the quote from Peter Walsh suggests, relevant only in the US, they are—like many issues in conservation—global.  The results of scientific study and medical progress are not limited to the country in which the research is performed and in this case, it is the global community that has interests in protecting highly endangered African ape populations.

Ethical consideration of conservation goals vs individual ape’s interests

Invasive research with chimpanzees is permitted in a number of countries, including both the US and the UK, when the goal of the research is to benefit the species itself.  At the heart of this justification is priority of the interests of the species, rather than the interests of the individual animal. Subordinating the individual ape’s interests to those of his own species is generally consistent with conservation and environmental ethics, where the basic overarching goal is protection of natural resources, balance, and preservation of endangered species.

By contrast, the basic position of those arguing for personhood for great apes, or for animal rights, is to protect the interests of the individual. From the latter perspective, using captive chimpanzees to develop and test a vaccine for a disease that they do not have and that is unlikely to pose a threat to them, would be ethically prohibited.

It is the conservationist position that appears compatible with performing infectious disease and invasive research with captive animals in order to potentially protect highly endangered wild populations from a disease that greatly affects their survival and future.  Whether the species’ interests should outweigh the individual’s as ethical justification for the research and testing is not the only question, however.  We might also ask which individuals should serve in the research?  Should these be laboratory chimpanzees?  Those living in zoos?  Sanctuaries?  The research was conducted in the US, but just as well could be conducted in the UK or other countries with appropriate scientific resources and expertise.

The use of chimpanzees in US biomedical research has received a great deal of attention in the past several years, with the frequent assertion that it is one of only two countries that continue chimpanzee research.  What is actually true is that the US has maintained chimpanzees in research facilities that serve the global scientific community. Foreign scientists, including the British researcher involved in the Ebola vaccine study and Canadian scientists, conduct research in US research centers with chimpanzees.  Following the recent National Institutes of Health decision to move away from the small amount of invasive and infectious disease research involving chimpanzees and retire almost all of its research chimpanzees, it is now far less clear that the US differs substantially from other countries with respect to being the location where Ebola vaccine research should occur.

Given the nature of the justification for the work, there appears to be no legal reason that it would be opposed in the UK or other countries that allow for invasive studies meant to benefit the species. The real threat is that if chimpanzees are not available in research facilities it will be impossible to test vaccines to protect wild apes against deadly diseases, even where regulations permit such research.

So the primary obstacle to performing this work in the UK or elsewhere in the EU might be the absence of laboratory chimpanzees; however, like many countries, the UK does hold captive chimpanzees in other types of facilities. The justification for the work appears to fall within current use of European zoo chimpanzees for research to improve the health of the individual or the species, a recent example being research on heart disease in Zoo ape populations. In addition while the EU Directive on animals in scientific research forbids the use of apes in biomedical research, this ban does not cover “veterinary clinical trials required for the marketing authorisation of a veterinary medicinal product” which would cover vaccines against Ebola or other infectious diseases.

The inherent weighting of species’ interests over the individual’s interests for the Ebola vaccine work is  consistent with the ethical justification often offered for keeping endangered species captive in zoological parks in order to serve conservation goals.  These goals are thought to be served in two ways in zoos: First, by allowing animals to reproduce in carefully managed breeding schemes where decision-making is driven by the goal of maintaining genetic diversity.  In this way, populations of endangered animals are continued within protected environments to guard against the species becoming extinct should the wild population disappear.  The interests of the individual animals may be served by the management practices, but the individual’s welfare is not the primary consideration. Thus, individuals may be removed from stable social groups to move to other zoos and form new breeding pairs, other individuals may not have the opportunity to reproduce.  Surplus males may be castrated, or may live in all-male social groups.  The recent controversy over the killing of a young male giraffe in a Danish zoo provided a vivid example of subordinating an individual animal’s interests to those of the group, species, or zoo.

A second justification offered for zoos is that they provide opportunities for public education that in turn can increase public support for conservation in the wild. The first goal could be served by keeping animals in situations without public display, in sanctuary or private park settings. Thus, it is this second goal that is the primary justification for public zoos. Given that the primary ethical justification for maintaining captive apes in zoos is related to conservation, the idea of considering these animals within the pool of eligible research subjects for vaccine development and testing to serve conservation goals is not unreasonable.

Consideration of the work by Peter Walsh, Kelly Warfield and colleagues, its next steps, and implications for wild chimpanzees poses challenging ethical questions.  The choice to develop and test a vaccine may harm individual animals, but benefit some of their species and other apes, in this case gorillas (and potentially also humans if the threat from Ebola grows). Some will argue that it is wrong to use individual animals in work that does not benefit them directly, though benefit to others has long been considered an adequate justification for clinical trials in humans. Here, ruling out benefits to others as a justification for research would eliminate the possibility of a vaccine that could save highly endangered wild populations.

Questions about which animals serve in research and where the work is undertaken clearly merit serious consideration that takes into account global responsibilities and the recent changes in US chimpanzee research.  Today’s announcement demonstrates that making choices about animal research is complex, with harms not only in action, but also inaction.  The work should stimulate serious, thoughtful discussion not only within the scientific, conservation, and animal protection communities, but also among policy makers and the wider public.

Paul Browne, PhD and Allyson J. Bennett, PhD

  1. Warfield KL, Goetzmann JE, Biggins JE, Kasda MB, Unfer RC, Vu H, Aman MJ, Olinger GG, Walsh PD “Vaccinating captive chimpanzees to save wild chimpanzees” PNAS 2014 Published online 26 May 2014. http://www.pnas.org/cgi/content/short/1316902111
  2. Warfield KL, Swenson DL, Olinger GG, Kalina WV, Aman MJ, Bavari S. “Ebola virus-like particle-based vaccine protects nonhuman primates against lethal Ebola virus challenge.” J Infect Dis. 2007 Nov 15;196 Suppl 2:S430-7. PMID: 17940980

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.

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.

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.