Category Archives: Science News

Israel provides animal research statistics for 2013

The Israeli newspaper, Haaretz, has reported on the 2013 animal testing statistics, which were recently released by the Health Ministry’s Council for Experimentation of Animals.

The total numbers rose 6% to 299,144 animals, of which 86% were mice or rats. This total is still much lower than the peak of over 340,000 animals were used in 2007. Rodent use has increased since 2010, from 81% of the total up to 86%, with an increase in genetically modified rodents likely to be influencing this rise.

Animals used in research in Israel 2010-13

Click to Enlarge

Non-rodent species have declined since 2010, with dogs and cats falling to 0, and primate use falling by almost a third, from 33 down to 25.

Dogs cats monkeys used in Israel

Most research, 80%, is conducted at universities and research institutes, while only 10% were carried out by biotechnology and pharmaceutical companies. Cosmetic testing is illegal in Israel, as is the sale and import of cosmetics and cleaning materials tested on animals.

Like the UK, and several other EU countries (e.g. Denmark, Germany, Switzerland), the Israeli Government publishes a breakdown, by species, of the number of animals involved in experiments every year. This proactive publication of the stats is a step in the right direction for openness in animal research.

On July 10th 2014 (Thursday), the UK Home Office will publish the 2013 statistics for animal research in England, Scotland and Wales (Northern Ireland publishes it statistics separately, though its numbers are very small by comparison). We will provide a detailed post on this on Thursday as we have in previous years.

Speaking of Research

Israeli data from:
2013 – Ido Efrati, Haaretz, Israeli science used 6% more animals in testing last year
2012 – Dan Even, Haaretz, Number of animal experiments up for first time since 2008
2011 – Dan Even, Haaretz, Only 3 percent of animals survive lab experiments
2010 – Ilan Lior, Haaretz, Study shows steady decline in use of animals for lab testing in Israel

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.

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.

 

Animal research: Why are we still using monkeys?

A common argument from animal rights organizations is that animal models cannot tell us anything useful about human medicine, that animal research is outdated, and should be replaced with other methods. But in a recent article, a group of leading scientists argues that “Primate models still matter” — with the right attention to the animals’ social needs and welfare.

The mantra of “Replace, Reduce, Refine” is a common place in the animal research community — with an emphasis on replacing animal models where possible. Yet while most research with vertebrates involves rodents and fish, non-human primates (principally rhesus monkeys) remain a vital model for studying many diseases and conditions. A recent article in the American Journal of Primatology sets out the issues around research with non-human primates.

Research involving nonhuman primates (NHPs) has played a vital role in many of the medical and scientific advances of the past century. NHPs are used because of their similarity to humans in physiology, neuroanatomy, reproduction, development, cognition, and social complexity-yet it is these very similarities that make the use of NHPs in biomedical research a considered decision. As primate researchers, we feel an obligation and responsibility to present the facts concerning why primates are used in various areas of biomedical research. Recent decisions in the United States, including the phasing out of chimpanzees in research by the National Institutes of Health and the pending closure of the New England Primate Research Center, illustrate to us the critical importance of conveying why continued research with primates is needed. Here, we review key areas in biomedicine where primate models have been, and continue to be, essential for advancing fundamental knowledge in biomedical and biological research
http://www.ncbi.nlm.nih.gov/pubmed/24723482

Kimberley Phillips of Trinity University, San Antonio, Texas and co-authors discuss how non-human primate models are ideal for studying heart and respiratory disease; reproduction and pharmacology; immunology and infectious disease, including vaccines and treatments for HIV/AIDS; behavior, cognition and neuroscience, among many other topics.

primate monkey animal testing

Image Credit: CNPRC/Speaking of Research

Primate and monkey models have contributed to the fight against polio, typhoid and yellow fever, and have made possible advances in treating heart disease, AIDS, cancer, diabetes, asthma, and malaria. Efforts are under way to develop treatments for emerging diseases such as Ebola and avian influenza, and conditions that becoming more common, for example Parkinson’s disease, Alzheimer’s, obesity, arthritis, infertility, and aging.

Nonhuman primates provide unique opportunities for scientists and physicians to study human disease, because while we have important differences, their biology is similar to ours in many ways. Yet this similarity also raises ethical issues, especially with the great apes, according to Phillips et al.

The recent decision by the National Institutes of Health to end support for some forms of invasive biomedical research with chimpanzees reflects the development, by scientists, of alternative models for some types of research as well as reflecting a collective desire to involve chimpanzees only in research that is either noninvasive or otherwise essential to scientific progress.

The use of these animals in research must be carefully considered and conducted in a controlled and thoughtful manner, the authors write. They advocate standards of care that consider not just food, housing and veterinary care, but pay attention to the animals’ cognitive, social and psychological needs.

“Efforts are now made to enhance psychological well‐ being through social housing, addressing the specific social and development needs of infants and aged individuals, and providing environmental enrichment,” they write.

“We are at a critical crossroads in our society and unless NHP research is given the philosophical, emotional, and financial support and infrastructure that is needed to sustain it and grow, we are in danger of losing irreplaceable unique models and thus, our ability to continue to explore and understand, and develop preventions and treatments for numerous conditions that inflict great suffering on humans.”

Andy Fell

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.

Speaking of Addiction Research

J. David Jentsch is a Professor of Psychology and Psychiatry & Biobehavioral Sciences at the University of California, Los Angeles. He is the recipient of the 2010 Joseph Cochin Young Investigator Award from the College on the Problems of Drug Dependence and the 2011 Jacob P Waletzky Award for Innovative Research in Drug and Alcohol Abuse from the Society for Neuroscience. He is a member of the Speaking of Research Committee and writes his own blog: the Unlikelyactivist.

This post is the full version of a piece originally written for Substance.com under the title “A Scientist Comes Out Swinging at PETA’s Addiction Research Stance”.

Biomedical research seeks to expose biological principles and mechanisms that cause disease in order to advance from a time where medications and treatments were discovered by chance to one where we reason our way to solutions for human and animal health through scientific discovery. Since the founding of the National Institute on Drug Abuse (NIDA) in 1974 (only 40 years ago), immense progress has been made into understanding, at the level of brain cells and molecules, why some drugs are addictive, why some people are particularly prone to addictive behaviors and how to treat drug use disorders. One of the reasons that so much progress has been made so quickly is that animal models for drug abuse are remarkably accurate and informative.

In the clearest example of all, if you place a laboratory rat into a chamber and allow it to trigger delivery of cocaine, methamphetamine, nicotine, alcohol, heroin, etc., into their bloodstream by voluntarily pressing a button, they will do so. Rats will seek out and voluntarily “self-administer” drugs of abuse, just like people do, precisely because of the remarkable similarity in the reward pathways in the human and rat brain, as well as due to the fact that these drugs act upon brain chemicals in nearly identical ways in rodents and humans. Moreover, if you allow rats to consume the drug daily over a long period of time, a subset of them will progressively become “dependent” upon the drug, just the same way a subset of people that abuse drugs do. Dependence is indicated by the fact that the subject loses control over their drug use and continues to use the drug, despite efforts to abstain. Because of these incredible parallels between humans and animals, we now understand the mechanisms by which drugs of abuse produce reward at a deep level, as well as how these agents encourage drug-seeking and –taking behaviors. For example, we now know how parts of the brain like the nucleus accumbens, amygdala and prefrontal cortex participate in the development of drug-taking behaviors, and we know how crucial brain chemicals like dopamine and glutamate are to these phenomena. This information would not have been possible without responsible and humane research involving a variety of animal models – ranging from invertebrates (fruit flies, roundworms) to rodents (rats and mice) to non-human primates (mostly monkeys).

Rat Rodent Addiction Animal Testing Research

It is reasonable to ask why, given these advances and the value of animal models, we have not yet cured addictions. The answer is simple. When NIDA was founded 40 years ago, we actually knew very little about the basic biology of the brain and its relationship to drug abuse. Decades of basic research were required before we knew enough about the brain pathways involved in reward to further understand how drugs acted on these pathways and changed them in response to long-term drug intake. Decades of basic research, still on-going, was and remains required to identify all the genes, molecules and cell processes that drugs act on but which were unknown to us as recently as 10 years ago. Basic research continues in an attempt to fully describe how the hundreds of billions of nerve cells in the brain work together to create behavior and how the tens of thousands of genes in our genome affect the function of our bodies. Coupled with amazing advances in the technology needed to study the brain, this knowledge from basic research will yield unprecedented progress towards treating addictions, as well as other disorders of the brain (from Alzheimer’s Disease to schizophrenia) will be possible.

So, what has research into the biology of addictions done for us so far? In a recent blog post, Katherine Roe from PeTA claims that only one new medication has been approved for the treatment of alcoholism/alcohol use disorders based upon animal research in recent years, that it has only “limited” effect and that animal research has “green-lighted” decades of failed medication trials. Not only are each of these statements factually wrong, the truth that is subverted by her points actually demands more animal research, not less.

Firstly, there are actually three medications approved for the treatment of alcohol use disorders (one is old and two are new). One new drug naltrexone (that blocks opioid systems in brain) was approved in 1994; in 2004, the FDA approved another medication (acamprosate). Both specifically target brain chemical systems discovered to be important to alcohol’s effects though animal research. In addition, the development of both medicines required animal research since they act on molecules in brain that might be unknown at all without basic research studies in rodents and non-human primates.

Secondly, referring to the efficacy of these medicines as limited seems to misunderstand the nature of pharmacology. These medications do not effectively treat everyone that is medicated with them – but then, no drug used for any disease does. That’s not the way pharmacology works. That said, for tens of thousands of people with alcohol use disorders around the world, they achieve and maintain abstinence thanks to one or both of these medications: something that wouldn’t be possible for them without the medicines. For those people, animal research on alcohol addiction has literally saved their lives.

Thirdly, the fact of the matter is that the desperate need for medications for drug and alcohol abuse has led both NIDA and the National Institute on Alcoholism and Alcohol Abuse (NIAAA) to undertake many clinical trials for medications before there was adequate evidence for efficacy in animal models. Many of the failed clinical trials involved these kinds of medicines. Therefore, if one is concerned about the failure of clinical trials (and we certainly should be), we should be calling for more investment in research, including in research involving animal models. Saying that animal research had “green-lighted” every single medication is simply and unequivocally wrong.

It is for all these reasons that the drug abuse research community is incredibly supportive of animal-based research. The pre-eminent professional society in this area – the College on the Problems of Drug Dependence – which includes epidemiologists, neuroscientists, clinical psychologists and psychiatrists and policy experts has published a statement clarifying their position on animal research:

There is an urgent need to know more about psychoactive drugs, particularly those features that lead some individuals to escalate initial use into regular use or dependence.  Research with laboratory animals will play a key role in these and related efforts… The College on Problems of Drug Dependence recognizes the value and importance of drug abuse research involving laboratory animals and supports the humane use of animals in research that has the potential to benefit human health and society. Such research plays a vital role in acquisition of the new knowledge needed to understand and reduce drug abuse and its associated problems.

Because drug and alcohol abuse are diseases with far-ranging health effects, contributing to death from overdose, cancer, stroke and metabolic disease, all of the National Institutes of Health (NIH) have a clear interest in seeing research end addictions. Animal activists’ claims that former NIH director Elias Zerhouni has spoken against the value of animal research are misleading given that he has recently made his opinion clear:

I understand that some have interpreted these comments to mean that I think that animals are no longer necessary in medical research. This is certainly not what I meant. In fact, animal models and other surrogates of human disease are necessary — but not sufficient — for the successful development of new treatments. In short, animal models remain essential to the basic research that seeks to understand the complexities of disease mechanism.

Overall, opposition to animal research on addictions seems to require a deep misunderstanding of basic science research, of the state of current scientific understanding of addictions and their treatment and of basic principles of biology, like pharmacology. It also defies the overwhelming consensus of the scientific and drug abuse treatment community that emphasizes the critical need for more research, including animal-based research, in that effort.

J. David Jentsch

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.

Better Mice, Better Research, Better Results

This guest post was written by Mark Wanner from The Jackson Laboratory. He has previously written a guest post for us in 2013 responding to an article in the New York Times. This article is adapted from his earlier post on the The Jackson Laboratory blog, Genetics and your health, here. This focuses on a recent Nature commentary by Steve Perrin, which has been misunderstood by many in the animal rights community. Mark also discusses ways of improving the accuracy of the mouse model.

In February 2013, I wrote a post about the use of mice in preclinical research. It was largely in response to a New York Times article about a scientific paper that impugned data obtained from mice used in trauma and sepsis research. The NYT article in turn implied that research using mouse models for human disease was pretty much useless, or misleading at best.

Laboratory Mice animal testing

My counterpoint at the time was that research using inbred mouse strains (or in this case a single inbred mouse strain), while valuable for understanding basic biology, can be very difficult to translate to human medicine for a variety of reasons. It also does nothing to address human genetic variation and the accompanying variability of responses to any one therapy or drug.

So can mice be good experimental models for human disease? Yes, they certainly can, but it’s imperative that changes be made on a broad scale to preclinical (both biomedical and pharmaceutical) research. That’s something that scientists at The Jackson Laboratory have long advocated, and now it’s the point of a comment piece in Nature published in late March titled “Preclinical research: Make mouse studies work” that has generated significant coverage and discussion.

Noise in the data

In the commentary, Steve Perrin, chief scientific officer at the ALS Therapy Development Institute, describes how findings in mice have failed to translate to more effective ALS therapies. Unlike the NYT article, however, Perrin doesn’t imply that mice are necessarily a poor disease model system. He instead asserts that much preclinical research uses mice quite poorly, with specific examples from the ALS field.

Perrin has ample reason to broadcast his concerns. He’s working with a patient population that is inexorably dying. As he says, “patients with progressive terminal illnesses may have just one shot at an unproven but promising treatment.” Sadly, trials of about a dozen treatments that showed survival benefits in a mouse model yielded only one that “succeeded” in human patients in recent years. And even that one, a drug called Riluzole, had minimal benefits.

With the stakes so high, you would think that any experimental therapy that reaches the clinical trial stage would have robust animal data backing it up. That is often not the case, however. As Erika Check Hayden points out in a follow-up piece in Nature News, a particular ALS mouse model that carries a mutation in a protein called TDP43, has a disease phenotype that is quite different from that of humans: “TDP43 mice usually died of bowel obstructions, whereas humans with the disease tend to succumb to muscle wasting, which often results in the inability to breathe.”

TDP43 is but one example of what Perrin calls “noise,” preclinical data that may look good but provides no insights into clinical realities because the research was not sufficiently careful or rigorous. Care and rigor don’t come easily, however, especially for the behind-the-scenes work of developing and characterizing the mouse models needed before good research can even begin. Perrin acknowledges in conclusion: “This is unglamorous work that will never directly lead to a breakthrough or therapy, and is hard to mesh with the aims of a typical grant proposal or graduate student training programme. However, without these investments, more patients and funds will be squandered on clinical trials that are uninformative and disappointing.” Or, as Derek Lowe states more bluntly in a commentary on his “In the Pipeline” blog, which covers the pharma industry: “Crappy animal data is far worse than no animal data at all. . . . If you don’t pay very close attention, and have people who know what to pay attention to, you could be wasting time, money, and animals to generate data that will go on to waste still more of all three.”

Driving change

For decades, The Jackson Laboratory (JAX) has worked to improve the efficacy of its mouse models for preclinical research. It has long recognized the limitations inherent in working with only one or two strains of inbred mice—imagine testing a drug in only one or two people!—and has spearheaded the development of mouse populations (Collaborative Cross and Diversity Outbred) that provide effective models of human genetic variation. It works to fully characterize both the genotypes and phenotypes of the mouse strains it distributes and to share the data with the research community. It has been at the forefront of developing mice that express human disease genes and/or recreate the human immune response.

“JAX has provided leadership from the beginning, even before disease foundations and funding agencies realized this was a problem,” says Associate Professor Greg Cox, Ph.D., who studies neuromuscular degeneration, including forms of ALS, at JAX. “It is nice to finally hear the message coming from someone other than the ‘fanatical’ mouse biologists. It is up to us to make sure that poorly designed mouse genetics experiments stop, both for the sake of good biology and for future decisions regarding clinical applications of the research.”

So how do you design experiments well? Perrin lists four ways to fight “noise.” The first three are basic ways to correctly manage research animal populations—exclude irrelevant animals (i.e. unrelated mortality), balance for gender and split littermates—but the fourth, track genes, may be the most vital. If you don’t know the animals’ precise genotypes and as much as you can about normal and disease phenotypes, it’s just about impossible to generate relevant data. Differences between background strain genetics can yield highly misleading results, making correct strain characterization essential. Also, inheritance between generations needs to be carefully tracked.

Another way to significantly improve the power of preclinical research is to use mouse panels that reflect human genetic diversity rather than one or two inbred strains. As long ago as 2009, JAX Professor Ken Paigen and collaborators at the University of North Carolina at Chapel Hill effectively implemented a new approach to testing drugs for potential toxicity. Paigen and colleagues tested acetaminophen, the commonly used NSAID, on 40 different mouse models chosen specifically for their strain genetics. The research revealed several gene variations associated with toxic reactions, which the researchers then matched with those in human patients experiencing adverse reactions to the drug. Such screening, which could also provide essential information regarding the effects of genetic variation on efficacy and general side effects, is not part of the current standard drug testing process.

Perrin calls for a community effort to generate the mouse models needed to undertake effective preclinical research. JAX has already served as a vital hub to several such efforts, collecting, curating and distributing mouse strains useful for research into many diseases. These mouse repositories provide researchers access to quality control, standardization and mouse genetics expertise unattainable without a central resource of this nature.

Last July I wrote about the pervasiveness of positive bias in preclinical research findings and the associated problems. Now Perrin’s commentary indicates that such positive bias is based on generally poor data. More thought and care are not only important for preclinical research, they’re absolutely necessary. Using mice in a way that provides valuable, translatable preclinical data takes far more up-front time and money, investments that can be difficult to justify in competitive pharma and academic settings. But the costs of not doing good research—and generating “crappy” animal data—are immeasurable on both financial and human scales.

Mark Wanner

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.

Santa Cruz Biotechnology: Dealing with Bad Behavior

We believe that the vast majority of scientists who study animals and the professionals charged with providing them care have a deep regard for animal welfare. However, as in any field, some people lack commitment to the standards of their profession, and this casts a shadow over everyone else. After all, how can people know whether this behavior is the exception or the rule?

Santa Cruz Biotechnology (SCBT) is a major producer of antibody products that stands accused of major animal welfare violations. Antibodies are substances produced by certain white blood cells as part of the body’s immune defenses. Their job is to tag foreign proteins, marking them for destruction by other cells in the immune system. Due to their widespread usefulness, antibodies sales is a multi-billion dollar a year business. Because each antibody targets a specific protein, they are important for both medicine and research. Since antibodies latch onto proteins that are markers for specific diseases, doctors can use them to diagnose these conditions in patients. Doctors also use antibodies to treat certain diseases, including some cancers. Researchers use antibodies to detect the presence of particular proteins and also to isolate proteins within a sample of blood or tissue.

nerve cells, neurotransmitter, antibodies

Brain sample where nerve cells containing a particular neurotransmitter were detected using antibodies.

Commercial antibody production usually involves injecting animals with a foreign protein and then collecting blood to harvest the antibodies generated in response to that protein. When done correctly, this process should not cause any pain or distress to the animal. Antibody production is most commonly done in rabbits, although sometimes large animals such as goats and donkeys are used since they are able to provide larger blood samples without ill effects to them.

Research institutions that conduct animal research must register their facilities with the USDA and comply with the requirements of Animal Welfare Act (AWA). Companies that use large animals to produce antibodies also fall under the AWA. However, as has been widely reported, SCBT stands accused of repeated, severe violations of many of the USDA’s AWA regulations (Nature, The Scientist, The New Yorker, the Mercury News, Santa Cruz Sentinel, and Monterey Herald).

The USDA uses a risk-based inspection system to focus more of its resources on facilities where there is a history of problems. SCBT was subject to a whopping nine unannounced inspections by the USDA in 2012 because of problems noted in previous years. Each of those inspections documented inadequate veterinary care at the SCBT facility. Its record of Animal Welfare Act violations was deemed to be so serious that on July 19, 2012, the USDA issued a formal complaint against the company. The complaint cited such serious problems as a lack of adequate veterinary care, improper handling of the animals, and poorly-trained animal care personnel.

A USDA complaint is a legal document requiring the recipient to address the concerns raised. Most institutions that are subject to such a complaint respond by working with the agency to rectify the situation by bringing their program into compliance with the Animal Welfare Act. However, SCBT has not attempted to do so. Rather, it plans to respond to the charges at a hearing scheduled for July 14-18, 2014.

Even after the USDA issued its July 2012 complaint against SCBT, the company did not mend its ways. On October 31, 2012, USDA inspectors reported finding SCBT animal facilities that had never been registered with the agency or inspected as required by law. The inspectors also said that some of the animals at this secret facility were in poor health.

The New Yorker reportedly contacted SCBT’s attorney, who said that the company “has strong defenses that will be addressed in the litigation.” Our U.S. legal system upholds the principle of innocent until proven guilty so we do not want to jump to conclusions. Nevertheless, if these serious allegations are true, then SCBT deserves condemnation for its callous treatment of animals.

Alice Ra’anan and Bill Yates

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.