Tag Archives: animal research

Crash course in medical history

Opponents of animal research often portray two of the pioneers of experimental physiology, François Magendie (1783-1855) and his student Claude Bernard (1813-1878), as deranged, vicious, and sadistic individuals who derived pleasure in harming animals. Moral philosophers Peter Singer and Lori Gruen convey this sort of message in their book “Animal Liberation: A graphic guide”.

Portrayal of Claude Bernard in Singer and Gruen's book

Portrayal of Claude Bernard in Singer and Gruen’s book

A quick look at how Claude Bernard’s face is portrayed in their book is sufficient to get a sense of Singer and Gruen’s feelings towards scientists who engage in animal research. The peculiar use of quotes around ‘experiment’ in the caption suggests they believe the work did not qualify as legitimate scientific research, nor that it could contribute any benefits to mankind. Such view fails to consider the historical context of their experiments.  In particular, one could ask how were human patients treated by their physicians of the time.

Here is a brief summary of 19th century medicine —

The theory of counter-irritation was in vogue. To counter-irritate basically meant causing additional wounds to the patient as a form of treatment. One technique involved inserting inflamed limbs were into giant anthills. More convenient was produce large blisters by means of a fire iron or acid. In 1824, an article in the Lancet by Dr. Abernathy suggested that a 1 foot square blister was probably a bit too large — several small blisters were indicated instead.  A third method of counter-irritation involved making a saw-shaped wound and inserting dried peas or beans into it. The doctor would then ensure the wound remained open, keeping it from healing, from weeks to months, replacing the peas and/or beans as necessary.

Leeches were used in vast quantities and for many purposes.  Physicians would lower leeches down patient’s throats.  Hundreds of them would be used to bleed a man’s testicle over days. Leeches were also applied to the vagina to relieve “sexual excitement” and, not to discard other orifices, doctors would push them up the anus. It was noted that during these procedures there was always a possibility that some of the leeches would get lost inside the patient body which, according to the physicians of the time, resulted in  “very annoying accidents”.

What about mental disease? A common treatment involved psychiatrists spinning patients in centrifuge-like machines a hundred of times per minute. This is how unruly patients came to understand the authority of the doctor, with one of them asserting that the more lively his intimidation towards the apparatus the more charitable the effects of the therapy.”  

rush

Benjamin Rush’s tranquilizer chair

Benjamin Rush, one of the founding fathers and signatories of the Declaration of Independence, adopted some of these same methods and developed them further.  He would pour acid on his patients backs and cut them with knives to allow the discharge “form the neighborhood of the brain”.  Rush also developed the famous “tranquilizer chair” where patients were restrained for up to entire days — the chair had a convenient hole for defecation at the bottom.

Bloodletting was used to treat a number of ailments.  It also often led to death.  One famous incident involves George Washington, who in 1799 suffered from a bad sore throat and died shortly after a visit by three different doctors who, altogether, took about half of his blood volume. The famous medical journal The Lancet derives its name from the tool used in these procedures.

Given Singer and Gruen’s depiction of animal research one must also ask — How did human surgeries look back then?  By all accounts they were the most excruciating, traumatic and dangerous experience for patients.  As an example, the novelist Fanny Burney recounted part of her experience with a mastectomy as follows:

I mounted, therefore, unbidden, the Bed stead & M. Dubois placed me upon the Mattress, & spread a cambric handkerchief upon my face. It was transparent, however, & I saw, through it, that the Bed stead was instantly surrounded by the 7 men & my nurse. I refused to be held; but when, Bright through the cambric, I saw the glitter of polished Steel I closed my Eyes. I would not trust to convulsive fear the sight of the terrible incision. Yet — when the dreadful steel was plunged into the breast cutting through veins arteries flesh nerves I needed no injunctions not to restrain my cries. I began a scream that lasted unintermittingly during the whole time of the incision & I almost marvel that it rings not in my Ears still? so excruciating was the agony. When the wound was made, & the instrument was withdrawn, the pain seemed undiminished, for the air that suddenly rushed into those delicate parts felt like a mass of minute but sharp & forked poniards, that were tearing the edges of the wound. I concluded the operation was over Oh no! presently the terrible cutting was renewed & worse than ever, to separate the bottom, the foundation of this dreadful gland from the parts to which it adhered Again all description would be baffled yet again all was not over, Dr. Larry rested but his own hand, & — Oh heaven! I then felt the knife (rack)ling against the breast bone scraping it!

Ms Burney was lucky to have survived to describe her experiences.  Most surgeries taking place in surgical theaters simply ended up in death.

The above were some of the common practices of medicine a mere 200 years ago. Magendie was one among the main critics of the dominant medical theories (humorism and vitalism) and the use of unproven methods on human patients. On the use of animals in research he said at a meeting [] I beg my honorable colleague to observe that I experiment on animals precisely because I do not wish to experiment on men.  That is what he felt about medicine — it was nothing short of human experimentation.

In the introductory pages of his Journal de Physiologie Expérimentale Magandie, he added:

“What subject is indeed more fertile in gross errors and absurd beliefs than that of health and disease? Consider the painful disquietude you would produce in the minds of the majority of men if you said to them:There are no such things as rheumatismal humour, gouty humour, scabby virus, venereal virus, and so forth.  Those things which are so designated are imaginary things, which the human mind has created to hide from itself its own ignorance.’   The chances are that you would be taken for a lunatic just as it but recently befell those who maintained that the sun was immovable and the earth turned.”

Any honest reading of medical history has to give credit to the experimental physiologists who put medicine in the right track to become what it is today. The handful of physicians and psychiatrists that speak against animal research should remember that from Hippocrates to the early 19th century, their profession caused more harm than good to their patients.  They ought to be reminded that it was the work of the experimental physiologists that turn this around.  Charles Darwin acknowledged this fact when he wrote:

[] I know that physiology cannot possibly progress except by means of experiments on living animals, and I feel the deepest conviction that he who retards the progress of physiology commits a crime against mankind.

As experimental medicine advanced, so did our ability to treat the potential pain and suffering animals may experience in research.  Animal welfare laws were established. Today, the vast majority of animals participating in research benefit from the use of modern anesthetics and analgesics. The public and our representatives recognize that responsible, regulated animal research has continued to produce new therapies and cures through the years — benefiting humans and non-human animals alike. Stopping the work and depriving future generations of new advances would be immoral.

Harlow Dead, Bioethicists Outraged

harlow plaque jpeg (2)

The philosophy and bioethics community was rocked and in turmoil Friday when they learned that groundbreaking experimental psychologist Professor Harry Harlow had died over 30 years ago. Harlow’s iconic studies of mother and infant monkeys have endured for decades as the centerpiece of philosophical debate and animal rights campaigns.  With news of his death, philosophers worried that they would now need to turn their attention to new questions, learn about current research, and address persistent, urgent needs in public consideration of scientific research and medical progress. Scientists and advocates for a more serious contemporary public dialogue were relieved and immediately offered their assistance to help others get up to speed on current research.

To close the chapter, psychologists at the University of Wisconsin provided the following 40 year retrospective on Harlow’s work and its long-term impact (see below).

Internet reaction to the scientists’ offering was swift, fierce, and predictable.

“We will never allow Harlow to die,” said one leading philosopher, “The fact is that Harlow did studies that are controversial and we intend to continue making that fact known until science grinds to a halt and scientists admit that we should be in charge of all the laboratories and decisions about experiments. It is clear to us that we need far more talk and far less action. Research is complicated and unpredictable–all that messiness just needs to get cleaned up before research should be undertaken.”

Animal rights activists agreed, saying:

“For many decades Harlow and his monkeys have been our go-to graphics for protest signs, internet sites, and articles. It would simply be outrageously expensive and really hard to replace those now. Furthermore, Harlow’s name recognition and iconic monkey pictures are invaluable, irreplaceable, and stand by themselves. It would be a crime to confuse the picture with propaganda and gobbledygook from extremist eggheads who delusionally believe that science and animal research has changed anything.”

Others decried what they viewed as inappropriate humorous responses to the belated shock at Harlow’s passing.

“It is clear to us that scientists are truly diabolical bastards who think torturing animals is funny. Scientists shouldn’t be allowed to joke. What’s next? Telling people who suffer from disease that they should just exercise and quit eating cheeseburgers?” said a representative from a group fighting for legislation to outlaw food choice and ban healthcare for non-vegans and those with genetic predispositions for various diseases.

A journalist reporting on the controversial discovery of Harlow’s death was overheard grumbling, “But what will new generations of reporters write about? Anyway, the new research is pretty much the same as the old research, minus all the complicated biology, chemistry, and genetic stuff, so it may as well be Harlow himself doing it.”

A fringe group of philosophers derisively called the “Ivory Tower Outcasts” for their work aimed at cross-disciplinary partnerships in public engagement with contemporary ethical issues made a terse statement via a pseudonymous social media site.

“We told you so. Harlow is dead. Move on. New facts, problems require thought+action (ps- trolley software needs upgrade, man at switch quit)”

Harlow himself remained silent. For the most part, his papers, groundbreaking discoveries, and long-lasting impact on understanding people and animals remained undisturbed by the new controversy.

Statement from Psychologists:

Harlow’s career spanned 40+ years and produced breakthroughs in understanding learning, memory, cognition and behavior in monkeys1 (see Figure 1). In a time period where other animals were generally thought of as dumb machines, Harlow’s work demonstrated the opposite — that monkeys, like humans, have complex cognitive abilities and emotional attachments. Harlow and his colleagues developed now classic ways to measure cognition2,3. For example, the Wisconsin General Test Apparatus (WGTA; see Figure 1), in which monkeys uncover food beneath different types of colored toys and objects, allowed scientists to understand how monkeys learn new things, remember, and discriminate between different colors, shapes, quantities, and patterns.

The discoveries of Harlow and his colleagues in the 1930s and forward provided the foundation not only for changes in how people view other animals, but also for understanding how the brain works, how it develops, and –ultimately–how to better care for people and other animals.

Figure 1

Figure 1

In the last decade of his long career, Harlow, his wife Margaret– a developmental psychologist, and their colleagues, again rocked the scientific world with a discovery that fundamentally changed our biological understanding.3 Contrary to prevailing views in the 1950s and before, the Harlows’ studies of infant monkeys definitively demonstrated that mother-infant bonds and physical contact—not just provision of food—are fundamentally important to normal behavioral and biological development. Those studies provided an enduring empirical foundation for decades of subsequent work that shed new light on the interplay between childhood experiences, genes, and biology in shaping vulnerability, resilience, and recovery in lifespan health.

For a brief time at the very end of his career, Harlow performed a small number of studies that have served as the touchstone for philosophers, animal rights groups, and others interested in whether and how animal research should be done. The most controversial of the studies are known by their colloquial name “pit of despair” and were aimed at creating an animal model of depression. In this work, fewer than 20 monkeys were placed in extreme isolation for short periods (average of 6 weeks) following initial infant rearing in a nursery.

At the time, the late 1960s, the presence of brain chemicals had recently been identified as potentially critical players in behavior and mental illnesses like depression and schizophrenia. New understanding and treatment of the diseases was desperately needed to address the suffering of millions of people. Available treatments were crude. They included permanent institutionalization– often in abject conditions, lobotomy (removing part of the brain), malaria, insulin, or electric shock therapies. As some scientists worked to uncover the role of brain chemicals in behavior and mood, others worked to produce drugs that could alter those chemical networks to relieve their negative effects. In both cases, animal models based on similar brain chemistry and biology were needed in order to test whether new treatments were safe and effective. It was within this context that Harlow and his colleagues in psychiatry studied, in small numbers, monkeys who exhibited depressive-like behaviors.

By the 1970s and over the next decades, scientists produced medications that effectively treat diseases like schizophrenia and depression for many people. The therapies are not perfect and do not work for everyone, which is why research continues to identify additional and new treatments. Regardless, there is no question that the suffering of millions of people has been reduced, and continues to be alleviated, as a result of new medications and new understanding of the biological basis of disease.

Infant rhesus monkeys playing in nursery.  Wisconsin National Primate Research Center. @2014 University of Wisconsin Board of Regents

Infant rhesus monkeys playing in nursery. Wisconsin National Primate Research Center. @2014 University of Wisconsin Board of Regents

Looking back while moving forward

Nearly 50 years later, it is difficult to imagine the time before MRI and neuroimaging and before the many effective treatments for depression, schizophrenia and other diseases. It is perhaps even more difficult to imagine a time in which people believed that genes and biology were destiny, that other animals were automatons, or that mothers were only important because they provided food to their children. Casting an eye back to the treatment of monkeys, children, and vulnerable human populations in medical and scientific research 50 years ago, or even 30 years ago, is difficult as well. Standards for ethical consideration, protections for human and animal participants in research, and the perspectives of scientists, philosophers, and the public have all continued to change as knowledge grows. Yet, what has not changed is an enduring tension between the public’s desire for progress in understanding the world and in reducing disease and the very fact that the science required to make that progress involves difficult choices.

There are no guarantees that a specific scientific research project will succeed in producing the discoveries it seeks. Nor is there a way to know in advance how far-ranging the effect of those discoveries may be, or how they may serve as the necessary foundation for work far distant. In the case of Harlow’s work, the discoveries cast a bright light on a path that continues to advance new understanding of how the brain, genes, and experiences affect people’s health and well-being.

Mother and infant swing final

Mother and juvenile rhesus macaque at the Wisconsin National Primate Research Center. @2014 University of Wisconsin Board of Regents

 

 

 

 

 

 

 

In the 30 years since Harlow’s death, new technologies and new discoveries—including brain imaging (MRI, PET), knowledge about epigenetics (how genes are turned on and off), and pharmacotherapies—have been made, refined, and put into use in contemporary science. As a result, scientists today can answer questions that Harlow could not. They continue to do so not because the world has remained unchanged, or because they lack ethics and compassion, but because they see the urgent need posed by suffering and the possibility of addressing global health problems via scientific research.

Harlow’s legacy is a complicated one, but one worth considering beyond a simple single image because it is a legacy of knowledge that illustrates exactly how science continues to move forward from understanding built in the past. An accurate view of how science works, what it has achieved, what can and cannot be done, are all at the heart of a serious consideration of the consequences of choices about what scientific research should be done and how. Harlow and his studies may well be a touchstone to start and continue that dialogue. But it should then be one that also includes the full range of the work, its context and complexity, rather than just the easy cartoon evoked to draw the crowd and then loom with no new words.

Allyson J. Bennett, PhD

The author is a faculty member at the University of Wisconsin-Madison.  The views and ideas expressed here are her own and do not necessarily represent those of her employer.

Suomi SJ & Leroy, HA (1982) In Memoriam: Harry F. Harlow (1905-1982). American Journal of Primatology 2:319-342. (Note: contains a complete bibliography of Harlow’s published work.)

2Harlow HF & Bromer J (1938). A test-apparatus for monkeys. Psychological Record 2:434-436.

3Harlow HF (1949). The formation of learning sets. Psychological Review 56:51-65

4Harlow HF (1958). The nature of love. American Psychologist 13:673-685.

Why is alcohol research with nonhuman animals essential?

The following guest post is from Jeff Weiner, a Professor in the Department of Physiology and Pharmacology at Wake Forest School of Medicine.  Dr. Weiner is the Director of an NIH-funded translational research grant that employs rodent, monkey and human models to study the neurobiological substrates that contribute to alcohol addiction vulnerability.  He is also a founding Co-Chair of a new Animal Research and Ethics committee established by the Research Society on Alcoholism.

Jeff Weiner

Jeff Weiner

I am a neuroscientist who directs a translational research program which uses humans, monkeys, and rodents to study  the neurobiological mechanisms associated with increased vulnerability to alcoholism. As an addiction researcher, I am frequently asked why we need to study this topic or why we need to use animal models in our work. I’ve often heard people say that “alcoholism is not really a disease” or that “alcoholics just lack the will to quit drinking”. Others have asked “what can we possibly learn about alcoholism by studying monkeys or rats”?   Well, there are some very good answers to these questions.

First of all, alcoholism is most definitely a disease. While it may be more difficult to diagnose than other illnesses like cancer or diabetes, there is overwhelming evidence, from human and animal studies, that excessive alcohol exposure profoundly changes the brain (and many other organ systems). We now know that alcohol-induced changes in brain activity can last for a very long time, even after the drinking behavior stops, that these neuronal alterations actually make it harder for an addict to quit, and much more likely to relapse when they finally do stop drinking. This research may help to explain why alcohol use disorders affect 5-8% of the US population at a cost to the economy in excess of 180 billion dollars and that alcohol accounts for 4% of the global burden of disease1.

Alcohol consumption USA alcoholism (2)Unlike Huntingon’s disease, alcoholism is not caused by a single gene defect. However, basic research has shown that a complex interaction between our genes and environmental factors, like chronic stress and exposure to traumatic events, can dramatically increase susceptibility to alcohol use disorders. These findings may help to explain why members of our military and their families are disproportionately affected by alcoholism.

Animal research has contributed greatly to the advancement of treatments for alcoholism. Animal models of alcohol use disorders have played an essential role in the discovery of two FDA-approved medications for the treatment of alcohol addiction (naltrexone and acamprosate). In addition, many new pharmacotherapies that have shown promise in animal models are currently being tested in human clinical trials. These new medications may prove even more effective at treating alcohol addiction.

In fact, one recent example illustrates just how powerful animal models of alcohol addiction can be. In 2008, researchers at the Scripps Research Institute in La Jolla, CA used a sophisticated rodent model of alcohol dependence (that they had spent years validating) to show that an FDA-approved anticonvulsant drug called gabapentin might be particularly effective at reducing the escalation in alcohol drinking that occurs after rats have become physically dependent on this drug2. Other researchers at Scripps quickly followed up on these exciting findings and recently completed a carefully controlled, clinical trial testing gabapentin in treatment-seeking alcoholics.   The results of this study, recently published in JAMA Psychiatry, revealed that gabapentin significantly reduced alcohol intake and dependence-associated symptoms like craving, depression, and sleep disturbances3. While much more work needs to be done to confirm these promising initial findings, these studies clearly demonstrate how effective animal models can be in our quest to discover better treatments for this devastating disorder.

It is worth noting that the vast majority of animal research on alcoholism is with rats and mice. Rodents can effectively model many elements of addiction including symptoms of tolerance, dependence, withdrawal, and relapse. Non-human primate models of alcoholism have also proven invaluable in helping to translate discoveries from rodent models to humans.

It is also worth mentioning that all animal research is regulated at multiple levels and by multiple entities. At the federal level the United States Department of Agriculture (USDA) is charged with enforcing the regulations under the Animal Welfare Act (AWA). This Act also requires that animal research be overseen and monitored by local animal care and use committees at the institutional level. Furthermore, research funded by the National Institutes of Health (NIH) must also meet standards for animal care and use as set forth by the Public Health Services (PHS) Policy.

So, while some may still question whether or not alcoholism is really a disease, it seems difficult to argue against the idea that more research is needed to address the huge medical and socio-economic costs associated with alcohol use and abuse. It also seems clear that animal models are a valuable tool that are accelerating the drug discovery process and helping to bring urgently needed treatments to the clinic.

For more information: http://www.niaaa.nih.gov/

References

  1.             Rehm J, Mathers C, Popova S, Thavorncharoensap M, Teerawattananon Y, Patra J. Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders. Lancet. Jun 27 2009;373(9682):2223-2233.
  2.             Roberto M, Gilpin NW, O’Dell LE, et al. Cellular and behavioral interactions of gabapentin with alcohol dependence. J Neurosci. May 28 2008;28(22):5762-5771.
  3.             Mason BJ, Quello S, Goodell V, Shadan F, Kyle M, Begovic A. Gabapentin treatment for alcohol dependence: a randomized clinical trial. JAMA internal medicine. Jan 2014;174(1):70-77.

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.

Unpleasant Truths vs Comforting Lies

Scientists use animals  in research to elucidate basic questions about biological function in health and disease.  Such basic research in the life sciences, like parallel studies in other fields of science, yields knowledge about nature.  Such knowledge, in turn, can be applied to a myriad of problems to alleviate suffering, improve our well-being, and make this a better world.  Our students at UCSF provide this wonderful example of how our work leads to progress and make a solid case for why the public and our government should support basic research:

In contrast, those that oppose the use of animals in medical research find comfort in lies. They deride the work as being “curiosity-driven research” that merely results in “knowledge for knowledge sake”.  They believe basic research is without any value at best, and fraudulent at worst.  In doing so, such activists highlight their lack of knowledge about science in general and about who scientists are as individuals.

Sadly, such grotesque views on basic research is just one of the many comforting lies that form a part of the animal-rights belief system which can be readily summarized in the following form:

comforting lies

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.