Category Archives: Science News

PR, ethics, and the science of head transplants

There has been a lot of media coverage on the recent claims by Dr. Sergio Canavero that he has successfully transplanted the head of a monkey on to a donor body of another monkey. This story, originally posted by the New Scientist, has since gone viral with some touting miracle cures for paralysis, while others have publicly expressed outrage and disgust. As pointed out by the New Scientist, this is not science, or at the least, not yet. Until the veil of secrecy concerning the conduct of this study is made transparent – no formal conclusions can be made and one can only speculate in regards to the quality of the experiment that was performed. Moreover, as this work still has to pass through the peer-review process, it remains unclear whether this is simply an attempt at publicity. As Arthur Caplan, a New York University bioethicist told New Scientist:

It’s science through public relations. When it gets published in a peer reviewed journal I’ll be interested. I think the rest of it is BS”

So far, the only evidence that Dr Canavero has produced is a picture of a monkey which appears to have had a head/body transplant, as well as a short video of a mouse moving around (despite significant impairments), which also appears to have a transplant (but how long did they live for? When Dr Canavero’s colleague Dr Xiaoping Ren of China’s Harbin Medical University carried out similar head transplants in mice in 2015 they all died within a few minutes of being revived after surgery). While the monkey “fully survived the procedure without any neurological injury of whatever kind”, according to Canavero, it was euthanized after 20 hours for “ethical reasons”. The media storm surrounding this story appears to play up to the researcher’s aims – to find financial backing to continue his research and then move it into humans.

Canavero at TEDx

Two pieces of information in the article by the New Scientist bear scrutiny. The first is that Canavero is quoted as saying “this experiment, which repeats the work of Robert White in the US in 1970, demonstrates that if the head is cooled to 15°C, a monkey can survive the procedure without suffering brain injury.” Second, Sam Wong, author of the article in the New Scientists stated “they connected up the blood supply between the head and the new body, but did not attempt to connect the spinal cord.” Careful reading highlights a simple fact, this study is not novel in any regard – this is a replication of the work by Robert White and is quite simply a “head transplant”. Thus, the same criticisms that were levied in regards to the original experiment by Robert White apply here. As Stephen Rose, director of brain and behavioural research at Open University can be quoted as saying in 2001:

This is medical technology run completely mad and out of all proportion to what’s needed. It’s entirely misleading to suggest that a head transplant or a brain transplant is actually really still connected in anything except in terms of blood stream to the body to which it has been transplanted. It’s not controlling or relating to that body in any other sort of way. It’s scientifically misleading, technically irrelevant and scientifically irrelevant, and apart from anything else a grotesque breach of any ethical consideration. It’s a mystification to call it either a head transplant or a brain transplant. All you’re doing is keeping a severed head alive in terms of the circulation from another animal. It’s not connected in any nervous sense.”

And so, it is worth reflecting at this juncture on the moral and ethical issues surrounding this controversial procedure. Let us assume for a moment that this procedure is in fact feasible. In the original studies by Robert White and Vladimir Demikov, it was made clear that these experiments were lethal for the animal. Simply put, while the head of the animal was capable of “seeing, hearing, tasting, smelling”; none of the other regulatory processes were intact (e.g. breathing) as there was no control over the donor body. Furthermore, like many tissue transplants, rejection of the donor body from the immune system is a large possibility, immunorejection was after all the cause of death in the monkey whose head Dr White transplanted in 2001. Indeed, Canavero has yet to demonstrate any kind of proof of principle with regeneration of nervous tissue with any meaningful metric of control of the donor body.

Perhaps the most interesting insight into Canavero’s thinking comes from a quotation in the New Scientist article where he says:

Gene therapy has failed. Stem cells, we’re still waiting. Even if they come now, for these patients there is no hope. Tetraplegia can only be cured with this. Long term, the body decays, organs decay. You have to give them a new body because even if you take care of the cord, you’re going nowhere.”

These remarks by Canavero are somewhat naive as both gene therapy and stem cell therapy have made substantial advances in recent years, with many therapies now in clinical trials. Furthermore, the claim that “Tetraplegia can only be cured with this [head transplant]” flies in the face of evidence from recent successful animal and clinical trials on a variety of innovative therapies for paralysis, including epidural stimulation, intraspinal microstimulation, neuroprosthesis, and stem cell therapy.

There have recently been a series of major advances in treating paralysis, including epidural stimulation.

There have recently been a series of major advances in treating paralysis, including epidural stimulation.

While there is mounting evidence from studies in rodents that the polyethylene glycol (PEG) implantation approach favored by Canavero may be able to promote repair of injured spinal cord and recovery of motor function in paralyzed limbs, his casual dismissal of the work of other scientists – while often simultaneously citing their work in support of his own approach – exemplifies his arrogance. He would be better off lending his expertise to the work of others who are exploring the potential for PEG in spinal cord repair, work that has the potential to benefit millions of people, but instead appears set on a self-aggrandizing PR campaign in support of an approach that if successful – which seems highly unlikely even if the surgery is a technical success – can only benefit a tiny number of people…potentially at the cost of depriving many other transplant patients of much needed organs.

The reality, however, remains that the procedure exposes the patient (be it mouse, monkey or human) to far greater risks compared to the potential benefits. Indeed, these experiments would never be approved in countries which have strict review criteria, with a clear harm/benefit analysis needing to be performed before such a study is given approval. In these circumstances, the news that leading experts in animal research in China are currently undertaking a major revision to the country’s national regulation on the management of laboratory animals is timely.

But these issues are not unknown to Dr. Canavero. Indeed, as can be seen here (scroll to see response), and in what can only be described as derision and a willful skirting of the law, Dr. Canavero remains set to push forward with his ideas regardless of the consequences. For these reasons we have the gravest of reservations about the course being followed by Dr. Canavero and his colleagues, and call on them to halt this research until a full independent review of the scientific evidence and impact on potential patients can be undertaken.

Jeremy Bailoo and Justin Varholick

The opinions expressed here are our own and do not necessarily reflect the interests of the the University of Bern or the Division of Animal Welfare at the University of Bern.

Can animal research be applied to humans?

Animal rights proponents defend the idea the we do not have the right to use animals for anything, including food, clothing, entertainment and scientific research. However, they seem to be having a hard time convincing people to stop eating meat, wearing leather and having pets, so they have disproportionately targeted animal research, where the link between animal use and the benefit that we derive from it seems less obvious [1]. Still, once they start thinking about it, people soon realize that using animals to find new cures is far more ethically justifiable than eating a steak or wearing a leather jacket [2]. For that reason, animal rights proponents have found it necessary to put forward an additional argument: that in fact animal research does not accomplish its stated goals. Lately, we have seen this idea repeated over and over again as a key argument against animal research. In this article I will argue against it. To be absolutely clear what I’m arguing against, I am spelling out that claim as follows:

“Animal research is useless because disease mechanisms are very different between animals and humans, so drugs that work on animals do not work on humans.”

The first part of the claim implies that there are fundamental differences in physiology between animals and humans. Is that true? Quite the opposite: the great many discoveries made in biochemistry and molecular biology show that all the basic mechanisms of life are common to all living beings. Perhaps one day we will discover extraterrestrial life that is radically different for ours, but all living beings on Earth work pretty much the same way. All use DNA to store genetic information and RNA and ribosomes to translate that information to proteins. That translation is based on the genetic code, which is common to all living beings. All living beings have proteins made with the same 20 amino acids, and only with the L stereoisomers of these amino acids. All living beings use glycolysis, the Krebs’s cycle and the respiratory chain to generate ATP for energy. All living beings have a double-layer of lipids as a cell membrane. And these are just a few examples. It seems that the basic functioning of cells was set by chemical evolution billions of years ago, even before multicellular systems started to evolve, and has not changed ever since. There are more similarities than differences even between the mayor kingdoms of bacteria, fungi, plants and animals. If we focus just on animals, we find that their nervous systems are formed by neurons of similar characteristics, with similar neurotransmitters and receptors. Mammals have a majority of genes in common and their organs are very similar.

animal research, knockout mouse

“Mammals have a majority of genes in common and their organs are very similar”

Moving on to the second part of the claim, is it true that some drugs work on animals but not on humans, and vice versa? Yes, this is true for a few drugs. For example, take catnip: cats can get high on catnip but this doesn’t happen to humans or to most other mammals. Nevertheless, many other psychoactive drugs, like morphine and barbiturates, have similar effects in all mammals. The important thing, however, is that even if some drugs do not have the same effect in animals and humans, this does not represent a major problem for animal research. To understand why, we need to go into the details of why there are differences in the action of drugs between species. The key lies in the structure of proteins. Proteins are like nanomachines that carry all the essential functions in life: catalyzing chemical reactions, moving chemicals in and out of the cell, processing signals inside the cell, generating action potentials in neurons, contracting muscle, copying DNA, making other proteins by translating DNA, etc. They are made of 20 amino acids linked to each other in long chains. The amino acid sequence is what determines what a protein does, just like the sequence of the 26 letters of the alphabet determines what this article says. The amino acid sequence of all the proteins in the body is encoded in the sequence of the DNA, so that each gene in the DNA is translated to a particular protein. This long string of amino acids folds itself into a blob whose shape determines what the protein does. In particular, there are nooks and crannies in these blobs where different chemicals (a neurotransmitter, a hormone, a metabolite, etc.) can attach themselves like a key to its lock, subtly changing the shape of the protein and its function. Drugs works by binding to the protein instead of its natural ligand, acting like a key to turn the protein on or off. The shape of the binding site is determined by the few amino acids that configure it, whose sequence is encoded in the DNA. Now, here is the catch: a small mutation in the DNA can change one of the amino acids that configure the binding site and this would cause a drug that before fitted into it, like a key into a lock, to not fit any more. So small changes in DNA from one species to another can cause a drug that worked in one species to not work on another species.

A protein binding site

A protein binding site

Then, doesn’t this problem prevent us from developing drugs in animals? Not at all! There are many ways to work around this problem. First, nowadays it is very easy to sequence a protein, so that we know the amino acids that form its binding sites in every species. Then we can select a particular species whose protein has a binding site similar to a human protein. That is why we need a wide choice of animals in which to perform research, not just mice and rats. Recently, the perfect solution was found: we can take the human gene for a given protein and swap it for the original protein in a mouse, so the mouse now has a protein identical to humans. Hence, differences in protein binding sites are no longer a problem. In fact, today this represents only a minor inconvenience in animal research. We have much bigger problems to tackle. Contrary to the view presented by animal rights organizations, drug testing is just a very minor part of the animal research enterprise. We use animals in scientific research to accomplish four different goals.

Goal 1: describing physiological mechanisms

The human body is the most complex thing that we know. We have many different organs regulated by a multitude of signals from the endocrine, the immune and the nervous system. Each organ is formed by different types of cells that interact which each other. Inside each cell, specialized signal transduction pathways ensure that the cell perform its particular function. Before we can alter this enormously complicated system with medications, we need to know how it works. Fortunately, organs and cells work in the same ways in all mammals, so we can use a variety of mammal species to investigate these phenomena. The human brain is quite different from the rodent brain, but similar enough to the monkey brain to study some higher brain functions in it. We have at our disposal a vast collection of experimental techniques that can be used to study the organization of the body (anatomy), the functioning of every organ (physiology) and the behavior of the animal as a whole. Advanced technologies include electrophysiology (patch-clamp, multiple neurons, single nerve fiber, etc.); optogenetics to stimulate or inhibit neurons using light; DREADD to change the behavior of an specific population of cells with a harmless drug; functional imaging (PET, fMRI); immunohistochemistry; confocal microscopy; electron microscopy; behavioral tests to study pain, anxiety, drug abuse, etc. These methodologies are incredibly sophisticated and took decades to develop. Yet, they all have in common that they used animals in their development. Thanks to the application of these methodologies in experimental animals, we are discovering how the mammalian body works. However, given its enormous complexity, much work still remains to be done.

Optogenetics involved using light to control genetically modified cells inside the body

Optogenetics involved using light to control genetically modified cells inside the body

Goal 2: create animal models of disease

Understanding physiology in the healthy condition is not enough, to cure a disease we also need to know how it is changed by the disease. In fact, many of the most challenging diseases that we face nowadays, like Alzheimer’s disease, heart disease, chronic pain and cancer, are alterations of physiological mechanisms. Since there are obvious ethical limits to do invasive procedures in human patients, we need to study diseases in animals. In the best case scenario, the disease that we are investigating also occurs in the animals, so we just need to get some animals that have it. However, there are diseases that are unique to humans, like Alzheimer’s, or that rarely occur in animals, like heart disease and some forms of chronic pain. In these cases we need to create a condition in the animal that resembles as much as possible the human disease. We call that an “animal model” of the disease. For example, mouse models of Alzheimer’s disease have been created by changing some of their genes [3, 4]. In another example, models of chronic pain can be generated by injecting chemicals in the paw of mice and rats [5]. The problem here is that the animal model is based on a hypothesis on how the disease works; if the hypothesis is wrong, so is the animal model. Therefore, much work has to be devoted to the validation of an animal model before it can be used to study the disease. Inevitably, some animal models turn out to be invalid. Instances of this have been taken as a proof that the whole concept of animal models of disease is wrong [6]. It is actually the opposite: the creation of the models is already an investigation of the disease. Discarding a model is progress, the same way that discarding a hypothesis is part of the scientific method.

Goal 3: finding targets for drug development

Unraveling a physiological mechanism leads to the identification of the proteins that are involved in it, working together like machines in an assembly line. This way we can find key proteins whose function we can tweak to adjust that physiological mechanism the way we want. These are what we call “target” proteins, because that is where the drugs that we want to develop will act. Once we know which ones they are, we can compare their amino acid sequence across species to identify differences from the same protein in humans. Of course, it is a bit more complicated than that, because entire signal pathways may differ between species, but once we know them in one species we can explore what these variations are. Again, this is why we need to use species other than rodents for biomedical research to be successful.

Goal 4: Drug screening

This is, indeed, the “animal testing” that is often presented as the sole endeavor of animal research. In fact, a lot of drug screening is not done in animals at all! If we have found the physiological mechanism (goal 1) involved in a particular disease (goal 2), and identified a target protein (goal 3), we can simply express that protein in a cell culture and use it to test thousands of drugs very quickly to find the ones that have the best effect. The drugs that are validated this way are then tested in animals. For that we will choose an species in which the protein is similar to its human version. Most likely, a drug will be tested in several species and animal models of the disease before moving it to clinical trials in human patients.

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When a target protein is identified it is possible to test thousands of drugs very quickly to find the most effective ones. These drugs are then candidates to move on to animal tests. Credit: ECVAM

Therefore, both parts of the claim made by animal rights proponents are false. Physiology is similar enough between humans and the rest of mammals to make it possible to translate discoveries from animals to humans. Furthermore, science has developed the right strategies to investigate human diseases in animals and use the findings to develop medications that work in humans (and in animals as well, in the case of veterinary medicine). Of course, I can only provide here a very general overview of tremendously difficult problems that are trying to be solved by some of the best minds in the world. Not everything is smooth sailing, there are some big obstacles in translating discoveries made in animals to humans. Nobody said that science was easy. However, giving up animal research following the advice of animal rights ideologues would the most foolhardy thing to do. The ultimate proof that animal research is able to produce cures for human diseases is that it has done so on countless occasions in the past.

Juan Carlos Marvizon, Ph.D.

References

  1. Morrison, A.R., Perverting medical history in the service of “animal rights”. Perspect Biol Med, 2002. 45(4): p. 606-19.
  2. Ringach, D.L., The Use of Nonhuman Animals in Biomedical Research. American Journal of Medical Sciences, 2011. 342(4): p. 305-313.
  3. Van Dam, D. and P.P. De Deyn, Animal models in the drug discovery pipeline for Alzheimer’s disease. British Journal of Pharmacology, 2011. 164(4): p. 1285-1300.
  4. Sturchler-Pierrat, C., et al., Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proceedings of the National Academy of Sciences, 1997. 94(24): p. 13287-13292.
  5. Marvizon, J.C., et al., Latent sensitization: a model for stress-sensitive chronic pain. Curr Protoc Neurosci, 2015. 71: p. 9 50 1-9 50 14.
  6. Shanks, N., R. Greek, and J. Greek, Are animal models predictive for humans? Philos Ethics Humanit Med, 2009. 4: p. 2.

Where should US chimpanzees live?

Understanding what research is, what it means, and how chimpanzees are cared for in captive settings matters to decisions, the animals, public interests, and preventing unintended consequences.

Photo credit: Kathy West

Photo credit: Kathy West

Ongoing decisions and news coverage about US chimpanzee research have provoked continuing debate and raised questions about the best course of action for the animals, science, and public interests. Like many complex, emotional, topics the arguments and language that have surrounded the discussion have been polarized and have left many with impressions that are less than accurate. In turn, thoughtful and serious consideration has often been stymied.

One of the primary areas of confusion surrounds what exactly is meant by the term “research.” Another is what standards of care best provide for chimpanzees’ welfare. Here we cover some common questions about chimpanzee research in the US and the implications and consequences of decisions about chimpanzees living in dedicated research facilities. We also highlight and compare standards for care, external oversight, and public transparency for chimpanzees living in different settings in the US. We share two documents that provide details about the many scientific discoveries published over the past several years from scientists working in dedicated chimpanzee research facilities. One is a list of over 175 representative publications from recent years. The great majority of these scientific publications report discoveries from behavioral, cognitive, and neurobehavioral research. The second document highlights media coverage that demonstrates public interest in these discoveries and studies.

Pdfs here:  Chimpanzee Research Representative Publications (2007-2015)  and Chimpanzee Media List

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1) Isn’t chimpanzee research in the US finished?

On November 18, 2015, the US National Institutes of Health Director Francis Collins issued a public statement that NIH will no longer support biomedical research on chimpanzees. While the statement (and ensuing media coverage – here, here, here) clearly references biomedical research, what is unclear is the impact of this decision on non-invasive behavioral and cognitive research with chimpanzees. Much, if not all, of the media coverage on the issue of chimpanzee retirement has focused on research with chimpanzees for developing vaccines for Ebola and studying infectious disease. At present, it does appear that NIH’s decisions will truncate infectious disease research with chimpanzees.

Infectious disease research is not, however, the entirety of chimpanzee research. It is important, but also a relatively small part. Thus, conclusions about the need, value, or future of infectious disease research should not be mistaken for conclusions about chimpanzee research itself. In fact, in the public discussions and headlines about NIH’s decisions, very little attention has been paid to the enormous amount of non-invasive and minimally-invasive research that has contributed to new discoveries and knowledge about behavior, cognition, genetics, social, emotional, and neural processes in chimpanzees. Such research is vibrant, ongoing, and makes substantial contributions, as is evidenced by the many cognitive and behavioral studies that dominate this representative list of over 175 scientific publications over the past several years (Chimpanzee Research Representative Publications (2007-2015)

The work also has broad support. Public fascination and support of research that helps us better understand these animals is illustrated by the plethora of news stories in just the last several years, since the initial NIH decision on retiring chimpanzees from research (Chimpanzee Media List).  Furthermore, NIH—as well as NSF and other agencies and foundations—continue to fund this type of chimpanzee research. Last, but certainly not least, much—if not all—of the behavioral and cognitive research with chimpanzees meets the principles and criteria elucidated by the Institute of Medicine panel that reviewed the need and value of chimpanzee research. The panel’s conclusions were accepted by NIH, and their recommendations are reflected in ongoing behavioral and cognitive studies with chimpanzees.

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2) Why does chimpanzee behavioral and psychological research matter?

A psychologist who works with chimpanzees was once approached at a conference by an animal-rights activist who heatedly accused the researcher of being a terrible person for confining chimpanzees and doing research with them.  The activist argued that chimpanzees were too smart to be kept in captivity.  He argued that they could learn language, mathematics, had theory of mind, and showed sophisticated cognitive skills and social skills.  The researcher asked this activist how he knew these things, and whether he had worked with chimpanzees or had ever been around them.  No, was the response, but the activist had seen all of these things demonstrated in videos and documentaries, and he countered that everyone knew how smart chimps are.  The researcher then asked him exactly where he thought those documentaries were filmed, and explained that nearly all of those amazing capacities were discovered and documented with chimpanzees studied, and in many cases nurtured through decades of excellent care, in research facilities in the US.

This discussion highlights the point that it is exactly the behavioral research that is becoming difficult, or impossible, to do in this country that originally led to the public’s recognition and support as they came to see chimpanzees as being worthy of protection.  If such behavioral research ceases to exist with captive chimpanzee groups, or only occurs in settings in which longitudinal cognitive and behavioral science is secondary to other management aims, we will lose the chance to learn more about the mental lives of our primate cousins.  Imagine that 50 years ago all chimpanzee behavioral research stopped in laboratories.  If it had, chimpanzees likely would have been zoo curiosities and little more.  Ape language, numerical cognition, metacognition, bartering, reciprocity, episodic memory, and other similar capacities would never have been demonstrated. Considering that makes one wonder whether, in that reality and in absence hallmark demonstrations of chimpanzees’ human-like intelligence, present-day activists would even care about chimpanzees in captivity.

The success of behavioral research in highlighting the social and cognitive sophistication of chimpanzees (and, more recently, the complementary neuroimaging data that show even more similarities between ape and human cognition) has become its own worst nightmare rather than a natural justification for asking new questions of these animals.  What we have learned has changed the way that the public and scientists view and treat animals. And it demonstrably has changed perspectives, policies, decisions, and care practices. But it should not result in a blanket prohibition against research with animals. Nor should it be used to support a default conclusion that research captivity is inherently bad, and sanctuary housing is inherently good. Both restrict the apes for their protection and the public’s, and both provide environments that support the animals’ physical and psychological well-being. But it would seem that the best place to ensure that chimpanzees are optimally cared for would be a place that is dedicated to studying chimpanzee behavior and mental health—a dedicated research facility.

If—on the hand—the ultimate result of new discoveries is to truncate research, the costs will be severe not only to our knowledge about these animals’ mental lives, but also to the perceived value of the animals to future generations of humans who will be faced with the imminent extinction of wild great apes and will have to address that threat.

CC-BY-NC-SA3) Can’t behavioral, cognitive, genomic, and other minimally-invasive research be done in zoos and sanctuaries?

Zoos and sanctuaries have always played an important role in studying the cognition of great apes, and other species.  And, that will continue.  But, it would be patently false to argue that many of the discoveries of sophisticated chimpanzee cognitive abilities would have been possible in those settings.  To give just one example, the ape-language studies with chimpanzees all were undertaken in traditional “laboratories” and often under the support of federal grants to universities.  Those projects showed that rearing conditions were critical to demonstrating (and instantiating) the highest degrees of language and communication skills in apes. This research was done in laboratories, not zoos, sanctuaries, or field sites.

Most critically, the research could only have been done in laboratories—in settings where researchers could control the animals’ experiences and maximize the chimpanzees’ opportunities to learn; where the apes’ lifelong health and participation could be ensured, and where researchers could make use of the chimpanzees’ natural curiosity and motivation; and where the chimpanzees’ full-time job could be learning and partnering with researchers in the science. Those facilities, some of which still exist, are research laboratories, and so those who advocate against laboratory chimpanzee research are advocating against the very places that have defined the (current) upper limits of ape cognitive abilities.  To cease research with chimpanzees in laboratories would cease those research programs and others that are currently funded to push even further our knowledge of chimpanzee cognition.

4) What is the difference between standards of care for chimpanzees in dedicated research facilities, in zoos, and in sanctuaries in the US?

The picture below shows chimpanzees in four settings. Where are they?  Two are current research facilities, one is an NIH-funded sanctuary, and one is a publicly-funded zoo. The settings look remarkably similar because they are in many ways. And to the chimpanzees, the sign over the door – research, zoo, sanctuary—doesn’t matter, as long as it doesn’t affect the animals’ care, housing, and welfare.

chimp housing [Autosaved]

Clockwise: Top – Yerkes National Primate Research Center, Atlanta, GA (Note: Yerkes’ chimpanzees are not NIH-owned or supported); Lincoln Park Zoo, Chicago, IL; MD Anderson Keeling Center for Comparative Medicine, Bastrop, TX; Chimp Haven, Keithsville, LA.

The question then, is what kind of housing and care matters to the animals’ well-being. In fact, the majority of research chimpanzees in the US live in settings that are similar. The facilities provide outdoor housing, including natural ground and sunlight. They also provide extensive and complex climbing structures, opportunities for foraging and tool-use, toys, fresh produce and treats, bedding, interaction with expert and compassionate caregivers, and state-of-the-art medical care and facilities.

The standards that govern housing and care of chimpanzees vary, as does the level of external oversight and public transparency. The figure below shows aspects of that variation in terms of federal, public, non-voluntary requirements. Dedicated research facilities that receive NIH or other federal funding are required, by federal law, to provide care and housing exceeds the standards specified by the Animal Welfare Act. By contrast, zoos and other facilities licensed by the United States Department of Agriculture (USDA) must only meet the AWA standards. Any facility registered or licensed by the USDA is subject to oversight by the federal agency. Furthermore, records of registration, inspection, or investigation of complaints are available to the general public via Freedom of Information Act (FOIA) requests. For NIH-funded research facilities, additional oversight and public transparency is provided via the NIH’s Office of Laboratory Animal Welfare (OLAW).

Private sanctuaries are neither required to be licensed by the USDA, nor required to meet AWA standards. It is important to note, however, that some sanctuaries voluntarily elect to be licensed by the USDA as exhibitors. Private sanctuaries do not fall under the type or extent of public oversight or transparency as do dedicated publicly-funded research facilities. That does not mean that the care provided in private sanctuary facilities is insufficient; but it does mean that the public has little venue to ensure the animals are well cared for and virtually no means to evaluate evidence of that care, request investigation, or receive information.

One of the primary points often offered in response to observation of this regulatory unevenness is that there are also accreditation agencies and programs. It is true that each type of facility has voluntary, private accreditation agencies. For many dedicated research facilities, this is AAALAC accreditation. For many zoos, it is the American Zoological Association (AZA) accreditation. For many sanctuaries, it is accreditation via the North American Primate Sanctuary Alliance (NAPSA) or the Global Federation of Animal Sanctuaries (GFAS).

The question for the public, however, is the extent to which standards of care, external oversight, and maintenance of records and information should be left to private, rather than public, agencies. For animals and facilities that are privately owned and administered, this may be entirely appropriate. But for animals and facilities that are public – as are NIH’s chimpanzees and chimpanzee research – it is the public standards, oversight, and transparency that ensure the animals’ care and the public interests. Indeed, when those facilities also support research, additional levels of public oversight exist in the form of peer review (which formally includes review of ethical treatment of animals) when this research is published or submitted for grant support.

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Photo credit:  Kathy West

Summary

In summary, regardless of headlines about the end of US chimpanzee research, there is clearly ongoing work that is humanely-conducted, ethical, of value, and consistent with public interests. The critical questions that remain are about how to best protect the animals and to balance scientific discovery that benefits chimpanzees, other animals, humans, and the environment.

Allyson J. Bennett, Michael J. Beran, Sarah F. Brosnan, William D. Hopkins, Charles R. Menzel, and David A. Washburn

The opinions expressed here are those of the authors and do not necessarily reflect the views of their institutions. The authors are psychological scientists whose research includes studies of chimpanzees and other primates.

 

 

Germany publishes 2014 animal research statistics

Germany has published in statistics that show the number of animals used for research and testing in 2014. Germany carried out 2,798,463 procedures on animals in 2014, 6.6% fewer than in 2013.

Species of animals used in German Research in 2014. Click to Enlarge

Species of animals used in German Research in 2014. Click to Enlarge

The fall in the number of experiments is mainly due to a reduction in the numbers of mice used. There was a significant rise in the number of fish (+35%) and birds (+29%) used. As well as rises in dogs (up 82% to 4,636 procedures) and primates (+31% to 2,842 procedures).

Animal Experiments in Germany in 2014. Click to Enlarge

Animal Experiments in Germany in 2014. Click to Enlarge

Mice continue to be the most commonly used species at 68%. Mice, rats and fish account for 91% of all animal procedures, rising to 95% if you include rabbits. This last point is interesting when compared to most other European countries where birds are the fourth most common species. Of countries we have assessed in Europe, only Spain uses a similar proportion of rabbits. Dogs, cats and primates accounted for less than 0.4% of all animals used despite the rises in number of procedures for these species.

Click to Enlarge

Click to Enlarge

This year was also the first year where there was retrospective assessment and reporting of severity (i.e. reporting how much an animal actually suffered rather than how much it was predicted to suffer prior to the study). The report showed that 60% of procedures were classed as mild, 21% as moderate, 6% as severe, and 13% as non-recovery, where an animal is anaesthetised for surgery, and then not woken up afterwards.

From historical statistics we can see that, like several other EU countries, the number of animal experiments rose steadily between 2000-12, before slowing and reversing in 2013-4. It is likely that some of this reflects the drop in science funding during the recession and economic turmoil of the past seven years. Such cuts to funding can often take some years to take effect as research projects often have agreed funding for several years.

Trends in German animal experiments 2000-14. Note 2014 is in a different color to reflect the different reporting requirements. Click to Enlarge.

Trends in German animal experiments 2000-14. Note 2014 is in a different color to reflect the different reporting requirements. Click to Enlarge.

This final number should be treated with some caution as it is the first year under the new EU reporting guidelines which requires retrospective reporting on severity, and now asks for numbers of procedures of studies ending in the reporting year (rather than starting). The UK statistical release (which follows the same EU guidelines) came with the following notes and word of caution:

As a result of the change to counting procedures completed as opposed to procedures started, all procedures started before 2014 but completed in 2014 should be in both the pre-2014 and 2014 figures. Any procedures started in 2014 but completed after 2014 will not be included in the 2014 figures. It is expected that these opposing effects will partly cancel each other out. Any impact of the change from counting procedures started to counting procedures completed will be temporary and will disappear from future years’ data collections.

Finally noting:

As a result, the 2014 data and comparisons with previous years’ data should be interpreted with some caution.

We will continue to report on national statistics as they are published.

Preventing neuronal death: the future of stroke therapy

In neurological research the importance of neuronal death is well known, as are its implications for the normal functions of your brain. Many serious neurological conditions, such as stroke, epilepsy, traumatic brain injuries, and degenerative diseases like Parkinson’s and Huntington’s Chorea, are a direct consequence of this type of neuronal death, which determines the clinical manifestation of the illness and, as a consequence, the prognosis for the patient.

For example, in stroke an ischemic attack (loss of blood flow), even if it is localized, can initiate the neuronal death program, due to excessive stimulation of neurons (nerve cells) by molecules known as neutotransmitters, the so-called excitotoxic triggers. This in turn leads to a worse clinical development and physical symptoms like palsies, sensory alterations, cognitive impairments and more.

One of the principal triggers of this event is the activation of the N-methyl-D-aspartate receptors on neurons, which are sensitive to glutamic acid, one of the most important excitatory neurotransmitter of the brain.

When these receptors are over activated due to the release of an enormous amount of glutamic acid as a consequence of the lack of oxygen in the affected area of the brain, this triggers a flow of Ca++ ions into the neuron, which activates many enzymes inside the nerve cell that directly damage the internal structure and ultimately cause the cells to die in a process known as apoptosis. (1)

It’s clear at this point how important it is to stop this process in order to prevent progressive damage in areas that are not directly affected by the original ischemic event.

What’s still not so clear is the precise molecular pathway from the liberation of glutamic acid to the neuronal death, but experimental evidence suggests that a membrane protein called JNK (c-Jun-N-terminal-kinase) has an important role in this activation. (2)

Although it has been shown that by blocking JNK it’s possible to reduce infarct size (the size of the damaged area of brain tissue) and neuronal death in an in vivo animal model of cerebral ischemia, the same studies have also shown serious side effects, as JNK has several important physiological functions in the body. As a result researchers have sought to identify means of blocking the role of JNK in ischemia–induced neuronal cell death without blocking its other functions.

It has been demonstrated that JNK is activated by two upstream molecules, called respectively MKK4 and MKK7, that respond to specific stress situations and represent a key bottleneck, and that in particular MKK7 shows an important role as mediator in the activation of JNK as ain response to cerebral ischemia.

Due to this observation, a team of neuroscience Italian researchers developed a specific MKK7 inhibitor peptide, called GADD45ß-I, to study its possible effects in vitro and in vivo in rodent models.(3)

This molecule showed an interesting neuroprotective effect in vitro and no toxicity itself on neurons, suggesting its application for in vivo treatments; during the in vivo (animal research) phase, the molecule was tested on two different rodent models which demonstrated that this peptide could reduce the infarct area of 43% after 24h, if administrated before the induced stroke. Very importantly this neuroprotective effect was still maintained when GADD45ß-I was administered 6h after the initial ischemic damage, which is critical as analysis of earlier failed candidate stroke therapies have stressed that potential therapies must be able to prevent damage when administered several hours after stroke onset (when treating stroke prompt diagnosis and treatment is vital). These protective effects are maintained for at least a week and show that the molecule does not merely delay apoptosis but actively blocks the process.

To prevent ischemic damage in the immediate aftermath of stroke onset, we can use rt-PA (recombinant tissue plasminogen activator) to promote the breakdown of a possible obstruction inside a cerebral artery and prevent a progressive stroke; and this is an important approach that has saved many lives in the last 20 years.  However, this therapy has side effects such as bleeding, and it can be not use in some specific but common conditions, for example in patients who use anticoagulant as Warfarin for atrial fibrillation, and is only effective if administered within 3,5-4,5 hours of stroke onset (although it may be effective later in some cases where the damaged area is clearly demarcated in brain imaging by MRI or CT scan).

All other therapies that are available to neurologists are only supporting therapy for the blood pressure, active anticoagulation and respiratory support where it is necessary.

GADD45ß-I offers the possibility that we could protect a patient under ischemic insult even when we could not use the thrombolytic therapy with rt-PA, and we could also protect them from future insults by regular administration of this drug, which may be especially useful for multimorbidity patient, those who suffer from two or more chronic health conditions.

This could also lead to reduce post-stroke consequences, to improve the prognosis for these persons and to a reduced need for rehabilitative therapies as physiotherapy, speech therapy and exercise therapy

If these promising early results are confirmed in clinical trials, this therapy could be one of the most important discoveries in the field of neurology in the recent years and could radically change our approach on stroke, allowing us to switch from a supportive therapy to a preventative therapy.

If we think that in 2010 circa 17 million stroke occurred worldwide, and that every 6 seconds a person somewhere suffers a stroke, we can also imagine the potential impact of this therapy.

  1. Lipton SA. Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat Rev Drug Discov 2006; 5: 160–170.
  2. Centeno C, Repici M, Chatton JY, Riederer BM, Bonny C, Nicod P et al. Role of the JNK pathway in NMDA-mediated excitotoxicity of cortical neurons. Cell Death Differ 2007; 14: 240–253.
  3. Vercelli A, Biggi S, Sclip A, Repetto IE, Cimini S, Falleroni F, Tomasi S, Monti R, Tonna N, Morelli F, Grande V, Stravalaci M, Biasini E, Marin O, Bianco F, di Marino D, Borsello T. Exploring the role of MKK7 in excitotoxicity and cerebral ischemia: a novel pharmacological strategy against brain injury. Cell Death Dis. 2015 Aug 13;6: e1854.

Marco

 

UK Government Minister says animal research is ‘vital tool’ for developing new treatments

Patrick Grady, the shadow Scottish National Party spokesman on International Development, recently asked the Government in parliamentary question, on 26th October 2015, if they would “issue a response to EDM 373, Applying Results of Experiments on Animals to Humans.”

Early Day Motion’s (EDMs) are regularly used by lobbyists to push their agenda, however their actual impact is minimal. EDM373 is the product of campaigning group, For Life on Earth which runs under a multitude of names including Patients Campaigning for Cures, NO to Animal Experiments, Oppose B&K Universal, Speaking of human based research and more. The group is inspired by the writing of Dr Ray Greek, and his Trans-Species Modeling Theory (a theory that few have heard of and even fewer subscribe to).

The EDM is the third time the motion has been made in three years (in 2014/15 it was EDM22, in 2013/14 it was EDM263) – with essentially the same message:

That this House notes the science-based campaign, For Life On Earth, which is critical of avoidable experiments on animals; further notes the new initiative, Patients Campaigning For Cures, which opposes animal models on medical grounds; is alarmed that scientific studies reveal that the widespread claimed ability of animals to predict human responses to drugs and disease is demonstrably false; acknowledges that over 90 per cent of drugs which test well in animals harm or otherwise fail humans, and that ignoring this has delayed cures including penicillin; notes that using animals to model humans contradicts currently accepted science, including evolutionary biology and genetics, which supports personalised medical care; further acknowledges the proclamation of the Concordat on Openness on Animal Research to develop communications with the media and public; and calls for thorough, properly moderated public scientific debate on the misleading and costly practice of trying to apply results from animal experiments to human patients.

So we have the usual myths about 90% failure rates, penicillin, and delays in other treatments. There is also typical Ray Greek-inspired fluff about “currently accepted science”. Their demands for a debate might be reasonable (though debating and science are very different kettles of fish), though the conditions being set on the terms for this debate are not (see the last response from Understanding Animal Research on this subject).

Thankfully, the UK Government wasn’t falling for it. Jo Johnson MP, British Minister of State for Universities and Science, gave a strong response to the parliamentary question.

The Government considers that the carefully regulated use of animals in scientific research remains a vital tool in improving the understanding of how biological systems work and in the development of safe new medicines, treatments and technologies.

At the same time, the Government believes that animals should only be used when there is no practicable alternative and it actively supports and funds the development and dissemination of techniques that replace, reduce and refine the use of animals in research (the 3Rs), in particular through funding for the National Centre for the 3Rs, and also through ongoing UK-led efforts to encourage greater global uptake of the 3Rs.

Advances in biomedical science and technologies – including stem cell research, in vitro systems that mimic the function of human organs, imaging and new computer modelling techniques – are all providing new opportunities to reduce reliance on the use of animals in research. As part of this, Innovate UK is awarding £4m this year to fund collaborative projects with industry to support the development and application of new non-animal technologies.

EU and UK law requires safety testing on animals before human trials for new medicines can begin and animal research still plays an important role in providing vital safety information for potential new medicines.

The Early Day Motion (EDM 373) rightly draws attention to the UK life science sector’s Concordat on openness in animal research which was launched last year, and provides new opportunities for transparency and debate in this area. www.understandinganimalresearch.org.uk/news/communications-media/concordat-annual-report-2015/.

Jo Johnson MP tours Cardiff University

Jo Johnson MP tours Cardiff University

Importance of animal research, use and development of alternatives and strict regulations are all mentioned in the response.

This question comes days after the UK Government released the annual statistics on animal research showing a slight dip in the number of procedures carried out.

Speaking of Research

One step closer to a vaccine for cytomegalovirus: Monkeys transmit CMV the same way as humans

Today’s guest post is by Jordana Lenon, Wisconsin National Primate Research Center and Kathy West, California National Primate Research Center.

PregnantWomanResearchers at Duke and Tulane take the lead, the National Primate Research Centers provide critical resources and expertise in this first-ever proof of CMV placental transmission in nonhuman primates.

Researchers now have a powerful new model for working on a vaccine for cytomegalovirus, or CMV, which is the leading infectious cause of birth defects worldwide.

Now, for the first time, a nonhuman primate CMV has been demonstrated to be congenitally transmitted similar to congenital HCMV infection. The discovery was published this week in the high impact journal Proceedings of the National Academy of Sciences and reported in The New York Times and Science Daily, among other news outlets.

Rhesus macaque mothers can transmit CMV across their placentas to their unborn infants, discovered the teams of co-senior study authors Sallie R. Permar, M.D., Ph.D., Duke University, and Amitinder Kaur, M.D., Tulane University. The lead author was Kristy Bialas, a post-doctoral fellow at the Duke Human Vaccine Institute.

Rhesus monkeys at the California National Primate Research Center. Photo credit: Kathy West

Rhesus monkeys at the California National Primate Research Center. Photo credit: Kathy West

The finding establishes the first nonhuman primate research model for CMV transmission via the placenta. The macaque reproductive, developmental, and immunological systems are highly analogous to those of humans. Thus, scientists can now utilize the biologically relevant RhCMV system in a controlled scientific setting to try to find new pathways towards an HCMV vaccine.

“A huge impediment to CMV vaccine development has been our lack of ability to determine what immune responses would be needed to protect against mother-to-fetus transmission,” said Permar, of the Duke Human Vaccine Institute in a Duke Medicine news release Oct. 19.

“It means that we can now use this model to ask questions about protective immunity against congenital CMV and actually study this disease for which a vaccine is urgently needed,” said co-senior author Kaur, of the Tulane National Primate Research Center in a Tulane University release Oct. 19.

The rhesus monkey model for HCMV persistence and pathogenesis has been developed over the past 30 years by co-author Peter Barry, Ph.D., California National Primate Research Center (CNPRC) core scientist, and co-developer of the rhesus intrauterine pathogenesis model with Alice Tarantal, Ph.D., CNPRC core scientist. Barry has recently shown that there is a strong immune response in rhesus monkeys to a potentially paradigm-shifting approach to HCMV vaccine design, and contributed important expertise and resources to this current research.

CNPRCrhesus,K_WestUCD, 4

Rhesus monkeys at the California National Primate Research Center. Photo credit: Kathy West

The work highlights the collaboration of Duke University researchers with experts in rhesus immunology and virology at the National Institutes of Health National Primate Research Centers. Contributing authors also included David O’Connor, Ph.D., and Michael Lauck, Ph.D., experts in macaque virology, pathology and genetics at the Wisconsin National Primate Research Center, Xavier Alvarez, Ph.D., at the Tulane National Primate Research Center, and Takayuki Tanaka, D.V.M., Harvard Medical School and the New England National Primate Research Center, which provided macaques for the study. Additional authors’ contributions are included in the Duke news release.

The research was funded by National Institutes of Health (NIH) Office of the Director, NIH National Cancer Institute, NIH National Institute of Allergy and Infectious Diseases, NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the Derfner Children’s Miracle Network Research Grant.

Reference:

Kristy M. Bialas et al. “Maternal CD4+ T cells protect against severe congenital cytomegalovirus disease in a novel nonhuman primate model of placental cytomegalovirus transmission” Proc Natl Acad Sci U S A. 2015 Oct 19. http://dx.doi.org/10.1073/pnas.1511526112