Tag Archives: primates

Winners of 2017 Brain Prize announced – Peter Dayan, Ray Dolan and Wolfram Schultz

The one million Euro Brain Prize, awarded by the Lundbeck Foundation in Denmark, has gone to three neuroscientists for their work understanding the mechanisms of reward in the brain. The winners are:

  • Peter Dayan – Director of the Gatsby Computational Neuroscience Unit, University College of London
  • Ray Dolan – Director of the Max Planck Centre for Computational Psychiatry and Ageing
  • Wolfram Schultz – Professor of Neuroscience and Wellcome Trust Principal Research Fellow at the University of Cambridge

Collectively, their work examines the ability of humans and animals to link rewards to events and actions. This capacity has been a foundation of our survival, but can also be the root of many neurological and psychiatric disorders, such as addiction, compulsive behaviour and schizophrenia. In order for the successful survival and reproduction of a species, an animal must be able to make decisions that avoid danger and bring benefits (such as food, shelter, etc.). T decision-making requires predicting outcomes from environmental clues and previously learned responses. For instance, certain smells may indicate that an animal should prepare to chase prey, or to avoid a fruit item. The brain plays a key role in this decision making and learning, and at the centre of this is the neurotransmitter dopamine.

wolfram-schultz

Wolfram Schultz

In the 1980s, Professor Wolfram Schultz developed a way of recording the activity of neurons in the brain that use dopamine to transmit information. He found that the dopamine neurons would respond whenever a monkey was given fruit juice reward. Schultz then showed the animals different visual patterns; whenever a certain pattern was shown, the monkey would receive a reward. After a time the dopamine neurons began to respond to the visual pattern, rather than the juice reward (response to the juice reward itself declined over time). Conversely, when no reward was given (after the correct pattern was shown), the dopamine neuron activity decreased below normal levels. If the reward was given at another time or was bigger than expected, the dopamine neuron activity would spike (1).  This was the first clear demonstration of the neurological basis of one cornerstone of learning theory in Comparative and Behavioural Psychology; Pavlovian conditioning (2).

Building on Schultz’s work, Peter Dayan found the pattern of activity from dopamine neurons described by Schultz resembled the ‘reward prediction error’.  This signal is the difference between predicted and actual reward resulting from an action or event. It continuously updates according to the result of new events and outcomes. Dayan would go on to work with Schultz to create computational models investigating how the brain uses information to make predictions and how this information is updated when new or contrasting information is presented.

Peter Dayan

Peter Dayan

Schultz explains the reward prediction error and resulting learning in the following analogy:

I am standing in front of a drink-dispensing machine in Japan that seems to allow me to buy six different types of drinks, but I cannot read the words. I have a low expectation that pressing a particular button will deliver my preferred blackcurrant juice (a chance of one in six). So I just press the second button from the right, and then a blue can appears with a familiar logo that happens to be exactly the drink I want. That is a pleasant surprise, better than expected. What would I do the next time I want the same blackcurrant juice from the machine? Of course, press the second button from the right. Thus, my surprise directs my behavior to a specific button. I have learned something, and I will keep pressing the same button as long as the same can comes out. However, a couple of weeks later, I press that same button again, but another, less preferred can appears. Unpleasant surprise, somebody must have filled the dispenser differently. Where is my preferred can? I press another couple of buttons until my blue can comes out. And of course I will press that button again the next time I want that blackcurrant juice, and hopefully all will go well.

Which button to push?

Which button to push?

What happened? The first button press delivered my preferred can. This pleasant surprise is what we call a positive reward prediction error. “Error” refers to the difference between the can that came out and the low expectation of getting exactly that one, irrespective of whether I made an error or something else went wrong. “Reward” is any object or stimulus that I like and of which I want more. “Reward prediction error” then means the difference between the reward I get and the reward that was predicted. Numerically, the prediction error on my first press was 1 minus 1/6, the difference between what I got and what I reasonably expected. Once I get the same can again and again for the same button press, I get no more surprises; there is no prediction error, I don’t change my behavior, and thus I learn nothing more about these buttons. But what about the wrong can coming out 2 weeks later? I had the firm expectation of my preferred blackcurrant juice but, unpleasant surprise, the can that came out was not the one I preferred. I experienced a negative prediction error, the difference between the nonpreferred, lower valued can and the expected preferred can. At the end of the exercise, I have learned where to get my preferred blackcurrant juice, and the prediction errors helped me to learn where to find it.

Professor Ray Dolan’s work has involved imaging the human brain in order to understand the mechanisms for learning and decision-making. Advancing the work of Schultz and Dayan, he showed that the reward prediction error can account for how humans learn, and the role that dopamine plays within it. He has collaborated with Dayan for the past decade to investigate human motivation, variations in happiness, and human gambling behaviour.

Ray Dolan

Ray Dolan

Schultz continues to study both animals and humans, using neuroimaging to study changes in neuron signals in Parkinson’s patients, smokers and drug addicts. The more we understand the process which leads people to take certain actions, the better positioned we are to intervene.

Professor Sir Colin Blakemore (University of London), chairman of the Brain Prize selection committee said,

“The judges concluded that the discoveries made by Wolfram Schultz, Peter Dayan and Ray Dolan were crucial for understanding how the brain detects reward and uses this information to guide behaviour. This work is a wonderful example of the creative power of interdisciplinary research, bringing together computational explanations of the role of activity in the monkey brain with advanced brain imaging in human beings to illuminate the way in which we use reward to regulate our choices and actions. The implications of these discoveries are extremely wide-ranging, in fields as diverse as economics, social science, drug addiction and psychiatry”.

Primate research remains today an invaluable tool for comparative research into human health and disease. While other animals remain useful as models for such investigations, non-human primates are arguably the best species to be used for such investigations due to their remarkable similarity to humans. The research performed by Schultz, and built upon by Dayan and Dolan, highlight this simple fact and perhaps also exemplifies why critical consideration against the use of non-human primates for research is needed. The Brain Prize also shows how animal and non-animal methods are often used together to build our understanding of how the brain works.

Speaking of Research

  1. Schultz, W., 2015, Neuronal Reward and Decision Signals: From Theories to Data, Physiol Rev 95(3)
  2. Schultz, W. et al, 1993, Responses of Monkey Dopamine Neurons to Reward and Conditioned Stimuli during Successive Steps of Learning a Delayed Response Task, Journal of Neuroscience 13(3)

Device to help stroke patients to recover moves from primates to people

Every year, 15 million people worldwide suffer a stroke, resulting in almost six million deaths and five million people left permanently disabled. It occurs when blood supply to the brain is blocked, or a blood vessel bursts. This prevents oxygen reaching the brain and can cause brain cells to die.

Many people who suffer strokes will subsequently experience spasticity, where the arm and leg muscles cramp or spasm as a result of message between the brain and muscle being blocked. This can cause long periods of contraction in major muscles resulting in bent elbows, pointed feet, arms pressed against the chest, or the distinctive curled hand common to many stroke survivors.

Neuroscientists at Newcastle University have developed a new device which aims to help stroke patients by strengthening a spinal connection known as the reticulospinal tract that can take over some of the function of more major neural pathways connecting the brain to spinal cord when they are damaged following a stroke. This strengthening can alleviate the symptoms of spasticity in the hand and arm of patients, allowing them additional control that can help them regain an important degree of independence in their life.

An article published yesterday in the Journal of Neuroscience (1) reports on the early success of this device, which is about the size of a mobile phone and can deliver an audible click followed by a small electric shock to the arm of patients. Electrical stimulation has previously been used to improve nerve function in other types of injury, but the combination with an auditory signal is new. The study shows that the device is able to strengthen the connections in the reticulospinal tract – the nerve tract in the spine which passes messages from the brain to the limb muscles. After a stroke, the body tends to recover the strength of connections to flexor muscles  (which allow you to close your hand)  more than extensor muscles (which allow you to open your hand). This is why many stroke patients suffer from a curled (semi-closed) hand.

stuart-baker-fits-the-electronic-device-to-a-patient

Stuart Baker attaches the device to a patient

Healthy patients were wired up to receive weak electric shocks to their arm muscle alongside a click sound. The individuals were then sent about their day. By altering the timing of the clicks and shocks they could strengthen or weaken the patients’ reflexes. By wearing the portable electronic device for seven hours, during which time the patients could carry out their daily work, the scientists were able to show that the signal pathways were strengthened in more than half of the patients (15 of 25).

So how did they discover that following a small electric shock with a click could strengthen the nerve pathways between the brain and the arm? Well, it’s a classic case of “Fortune favours the prepared mind”!

Stuart Baker, Professor of Movement Neuroscience at Newcastle University who has led the work said: “We were astonished to find that a small electric shock and the sound of a click had the potential to change the brain’s connections. However, our previous research in primates changed our thinking about how we could activate these pathways, leading to our study in humans.

In 2012 Baker and his colleagues published a paper reporting on their evaluation of a non-invasive transcranial magnetic stimulation (TMS) in stimulating nerve cells in a part of the brainstem called the reticular formation –  where the reticulospinal tract begins – in anaesthetised macaque monkeys, which they undertook as preparation for using TMS in studies in monkeys and human volunteers.   They observed that while the TMS stimulus produced a the expected quick response in the nerve cells, they also produced a puzzling delayed response, which they thought might be triggered not by the changes in the magnetic field but rather to the audible click that the TMS making made when its coil discharged. To test this idea they used a miniature bone vibrator to generate the same kind of click, and found that it stimulated a very similar pattern of nerve activation to that evoked by the sound of the  TMS coil discharge.

At first they viewed this nerve response to the click sound made by the TMS machine as a complication that needed to be accounted for in future studies of the reticular formation, but very quickly realised that the click response could itself be useful as a non-invasive experimental tool, and might even be useful in the clinic.

Baker wanted to know exactly how much the arm-brain connections were controlled by the reticulospinal pathway they were studying, and determine if the timing of a click following the small electric shock made any difference. To assess this, they got primates to do a similar task to that later evaluated in human volunteers. What they found was that by changing the timing between clicks and small electrical shocks, they could change the strength of reflex of the monkeys by as much as 50%. This has given the researchers the confidence to move this into a clinical trial of stroke patients.

primate-in-stroke-research

The macaques monkeys were given food rewards for performing a simple movement based task.

Baker recently published an article on The Conversation entitled “Using monkeys for research is justified – it’s giving us treatments that would be otherwise impossible“. An extract is provided below:

In my own work, we use a small number of macaques to gain this fine-grain understanding. Many pathways for movement control are different between primates such as humans and other animals such as rats. Only a primate model can give us information which is relevant to human diseases.

To learn how these pathways are actually used to control movements, in some studies we first teach the macaque to perform complex tasks with their hands or arm. Getting it right is rewarded with a treat (typically fruit or nuts, but chocolate or strawberry yoghurt also sometimes feature). Once they know what to do, we carry out a surgical implant to allow us to record from the brain using fine electrodes, with tips around the same size as single cells.

All surgery is done in a fully equipped operating theatre, with sophisticated anaesthetics and painkilling medication borrowed from state-of-the-art human care. Once the macaque has recovered, we can record from the brain cells while they do the trained task. An animal that is stressed or in pain would not willingly cooperate with the experiments. The animals seem to enjoy the daily interaction with the lab staff and show no distress.

Our studies are right at the crossroads of basic and clinical sciences. We are trying to understand fundamental brain circuits, and how they change in disease and recovery. Over the past ten years, we’ve shown that a primitive pathway linking brain to spinal cord can carry signals related to hand use. That was a surprise, as until now it was assumed that the primate hand was controlled only by more sophisticated pathways that developed later in evolution.

A clinical trial will now start in Kolkata, India, involving 150 stroke patients. It aims to see whether this new device can improve hand and arm control. The work at Newcastle University has been funded by the Medical Research Council and the Wellcome Trust.

chris-blowerChris Blower, 30, suffered a stroke at the age of seven, which paralysed him down onside, slurred his speech and caused him to lose bowel control and move unaided. Though he recovered from these immediate effects, he still suffers slow, limited and difficult movement in his right arm and leg. Here is an extract from his story:

My situation is not unique and many stroke survivors have similar long-term effects to mine. Professor Baker’s work may be able to help people in my position regain some, if not all, motor control of their arm and hand. His research shows that, in stroke, the brains motor pathway to the spinal cord is damaged and that an evolutionarily older signal pathway could be ‘piggybacked’ and used instead. With electrical stimulation, exercise and an audible cue the brain can be taught to use this older pathway instead.

This gives me a lot of hope for stroke survivors. My wrist and fingers pull in, closing my hand into a fist, but with the device Professor Baker is proposing my brain could be re-taught to use my muscles and pull back, opening my hand out. The options presented to me so far, by doctors, have been Botox injections and surgery; Botox in my arm would weaken the muscles closing my hand and allow my fingers to spread, surgery would do the same thing by moving the tendons in my arm. Professor Baker’s electrical stimulations is certainly a more appealing option, to me, as it seems to be a permanent solution that would not require an operation on my arm.

Keith toured the animal house at Newcastle University. He noted after:

The macaque monkey that I observed was calmly carrying out finger manipulation tests while electrodes monitored the cells of her spinal cord.

Although this procedure requires electrodes to be placed into the brain and spine of the animal, Professor Baker explained how the monkey had been practising and learning this test for two years before the monitoring equipment was attached. In this way the testing has become routine before it had even started and the animal was in no pain or distress, even at the sight of a stranger (me).

The animals’ calm, placid temperaments carry over to their living spaces; with lots of windows, natural light and high up spaces the macaques are able to see all around them and along the corridors.

It is great to see Newcastle University being clear about the contribution of animal studies to clincal work. In their press release they noted that “the research published today is a proof of concept in human subjects and comes directly out of the team’s work on primates”.

Baker notes in his recent article,” In my opinion, we should not condemn large numbers of people to disability and dependence, but need to use all of the tools of modern science to discover and innovate the solutions. I am confident that the next 50 years will see wonderful progress in treatments for these terrible disorders and primate research will be central to this effort.

You can read more about animal research at Newcastle University from their website.

Speaking of Research

REFERENCES

  1. K.M. Riashad Foysal, Felipe de Carvalho, Stuart N. Baker. Spike-timing Dependent Plasticity in the Long Latency Stretch Reflex Following Paired Stimulation from a Wearable Electronic Device.  Journal of Neuroscience, 

Of White Papers And Commentators: The Use Of Nonhuman Primates In Research

Two weeks ago, nine scientific societies, including the American Physiological Society, the Society for Neuroscience, and the American Academy for Neurology, published a white paper entitled “The critical role of nonhuman primates in medical research“. The paper, which notes how nonhuman primates are critical to all stages of research, provides a huge number of examples of medical breakthroughs made possible thanks to studies in nonhuman primates. Among the paper’s appendices is a list of over fifty medical advances from the last fifty years alone; these include: treatments for leprosy, HIV and Parkinson’s; vaccines for measles, mumps, rubella and hepatitis B; and surgeries such as heart and lung transplants. This is no small feat considering the group of species accounts for around only 0.1% of animal research in most countries (that provide data).

critical-role-of-non-human-primates-in-medical-research

On September 2nd, 2016, John P. Gluck wrote an op-ed for The New York Times called “Second Thoughts of an Animal Researcher“. Gluck is a Professor Emeritus in the Department of Psychology at the University of New Mexico. However, this Op-Ed has not come out of the blue. Gluck has long worked alongside PETA and other animal rights groups to condemn nonhuman primate studies. This op-ed is timed for just before today’s NIH workshop on “Ensuring continued responsible research with non-human primates” – a workshop that PETA is petitioning congress about. The article explains why Gluck stopped conducting animal research, his ethical stance against it, and concludes by saying:

“The federal government should establish a national commission to develop the principles to guide decisions about the ethics of animal research. We already accept that ethical limits on experiments involving humans are important enough that we are willing to forgo possible breakthroughs. There is no ethical argument that justifies not doing the same for animals.”

This is disingenuous of Gluck. The strict regulatory system that exists in the US, and most other developed nations, is the very embodiment of principles aimed to guide decisions on when and how we should conduct studies on nonhuman primates (as well as other species). Some countries have specific regulations surrounding primate research (e.g. the UK considers them a specially protected species and researchers must explain why no other species can be used instead). In the US, all primate research is governed by the Animal Welfare Act (enforced by the USDA), and any research receiving federal funds will also be subject to the Public Health Service Policy on Humane Care and Use of Animals (PHS policy; enforced by OLAW). The PHS Policy also endorses the US Government Principles for the Utilization and Care of Vertebrate Animals Use in Testing, Research and Training, which forms the foundation for ethical and humane care and use of laboratory animals in the US. Every research protocol must be approved by an Institutional Animal Care and Use Committee – a group made up of including scientists, veterinarians and lay-persons – who review and evaluate the study, recommending ways in which it could be improved (both scientifically and from an animal welfare perspective).

Other commentators have noticed this as well. As Wesley J Smith writes in the National Review:

Gluck would have readers believe there are no strict ethical regulations that govern primate research. Nothing could be further from the truth. The Animal Welfare Act already has many stringent requirements governing research on monkeys-as the law should-including cost-benefit analyses, the requirement that any pain experiments cause be palliated, and the requirement that oversight boards approve the purpose and approach of proposed experiments.

Ultimately, Gluck’s article reads as an ethical objection to animal research with some scientific gloss. The heart of his objections is Singer-esque in nature (he mentions Peter Singer earlier in the article). He almost directly condemns our different treatment of humans and nonhuman primates as speciesist:

The ethical principle that many of us used to justify primate experiments seemed so obvious: If you are ethically prevented from conducting a particular experiment with humans because of the pain and risks involved, the use of animals is warranted. Yet research spanning the spectrum from cognitive ethology to neuroscience has made it clear that we have consistently underestimated animals’ mental complexity and pain sensitivity, and therefore the potential for harm. The obvious question is why the harms experienced by these animals, which will be at least similar to humans, fail to matter? How did being a different member of the primate grouping that includes humans automatically alter the moral universe?

No doubt our understanding of the cognitive abilities of animals has improved, and with it has come a greater appreciation for their capacity to suffer. We are a long way from the 17th century philosophers, like Malebranche, who thought animals could not suffer. Our greater understanding of the capacity of animals to suffer pain or distress informs the way we treat animals in laboratories. For example, it was not until the early 1990s that the USDA adopted regulations requiring group housing of nonhuman primates (DiVincenti and Wyatt, 2011), this was thanks to many years of studies showing that nonhuman primate welfare was best met by keeping primates in social groups. As such, it is wrong for Gluck to claim that harm to animals “fail to matter”. While we may give animals a different consideration compared to humans (it is legal to eat animals and keep them as pets), it would be wrong to say they exist outside our moral sphere. The UK’s House of Lords set up a select committee in 2002 to look at animal studies; when assessing the ethics they concluded (s 2.5):

The unanimous view of the Select Committee is that it is morally acceptable for human beings to use other animals, but that it is morally wrong to cause them unnecessary or avoidable suffering.

This is the heart of sensible moral consideration – that we should minimise the suffering of animals wherever possible while realising that we also have a moral imperative to conduct animal studies to reduce greater suffering among humans and animals.

Image from Californian National Primate Research Center

Photo by Kathy West.

Primates at the Californian National Primate Research Center. Reproduced with permission.

And there is no doubt we have a moral imperative. To return to the recent white paper:

Research with monkeys is critical to increasing our knowledge of how the human brain works and its role in cognitive, motor and mental illnesses such as Alzheimer’s, Parkinson’s and depression. This research is also fundamental to understanding how to prevent and treat emerging infectious diseases like Zika and Ebola. NHP research is uncovering critical information about the most common and costly metabolic disorder in the U.S. – type 2 diabetes – as well as the obesity that leads to most cases.

Without NHP research, we lose our ability to learn better ways to prevent negative pregnancy outcomes, including miscarriage, stillbirth and premature birth. This research is also helping scientists to uncover information that makes human organ transplants easier and more accessible, literally giving new life to those whose kidneys, hearts and lungs are failing.

The eradication of these diseases is not worth giving up on. For some animals such research could be the difference between survival and eradication. Ebola has a 95% mortality rate for gorillas. An outbreak in 1995 reportedly killed more than 90% of the gorillas at a national park in Gabon. Overall it is estimated that one third of all the world’s gorillas have been wiped out by Ebola in the last 20 years. If nonhuman primate research (primarily in monkeys rather than great apes), can come up with a vaccine then it will be both animals and humans who can benefit. Humans are unique in that they are the only species with the cognitive capability of making a decision of this magnitude. In the words of Wesley J Smith:

This is the difficult fact that can’t be avoided: We need primate research if we are going to advance science, relieve human suffering, and bring new treatments into medicine’s armamentarium. At some point, we have to decide whether to help humans or not experiment on monkeys.

Looking forward to today’s NIH workshop (which will be streamed live online), it would seem they have struck the right tone. Reviewing the evidence, reviewing the policies, and looking to see what can be improved – that is the essence of science – while still appreciating that the duty of the NIH is to improve the health of a nation.

[T]he Office of Science Policy is taking the lead in planning a workshop on September 7th, 2016 that will convene experts in science, policy, ethics, and animal welfare. Workshop participants will discuss the oversight framework governing the use of non-human primates in NIH-funded biomedical and behavioral research endeavors. At this workshop, participants will also explore the state of the science involving non-human primates as research models and discuss the ethical principles underlying existing animal welfare regulations and policies. NIH is committed to ensuring that research with non-human primates can continue responsibly as we move forward in advancing our mission to seek fundamental knowledge and enhance health outcomes.

Tom Holder

Confusing public agendas: Is it animal welfare? Or an absolutist campaign disguised as a call for “dialogue”?

A recent symposium at the joint meeting of The American Society of Primatologists and International Society of Primatologists focused on questions about the oversight and regulation of the housing, care, and treatment of nonhuman primates in research. Presentations of scientific research that primatologists conduct in order to inform animal care practices are a regular occurrence at ASP. This session, however, was billed as a call for dialogue. The organizers and participants included affiliates of groups and campaigns, including HSUS and PETA, that are often opposed to many types of primate research. ASP and ISP members conduct primate research in field, laboratory, zoo, and other settings across the world. The focus of this conference session appeared to be largely on laboratory  research, and particularly, that work funded by the US federal agency—the National Institutes of Health—that is charged with scientific research relevant to advancing public health.

Macaque. Photo credit: Kathy West. CNPRC.

Macaque. Photo credit: Kathy West. CNPRC.

Such research is a popular target for PETA and other groups opposed to the use of nonhuman animals in research, yet it remains a fact that the great majority of US facilities that house nonhuman primates are not dedicated research facilities (see graphic; summary illustration of data from USDA). As shown here, of the just over 1,000 US facilities that are either USDA-registered for research or USDA-licensed to house nonhuman primates for other purposes,  roughly 1/5th hold research registration. The majority are exhibitors. That includes zoos and other facilities that display animals to the public or engage in public interaction with the animals. In the US, the number of primates housed within each facility is reported annually for research institutions and is published by the USDA (for example, see here); however, the number of primates housed in licensed facilities is not easily accessible. This is similar to other countries.

Number of facilities by type of USDA-registration or license. Exhibitors include zoos and other facilities with public interaction.

Number of facilities by type of USDA-registration or license. Exhibitors include zoos and other facilities with public interaction. (Note: Although not necessarily required by federal law, sanctuaries may choose to be licensed as exhibitors because there is no separate category for sanctuaries.)

We’ve written previously about the standards of care, external oversight, and public transparency of federally-funded research within dedicated research facilities in comparison to zoos, sanctuaries, breeders, dealers, and private owners of nonhuman primates (Bennett & Panicker, 2016). In fact, some of these comparisons are central to discussions in recent months about decisions to ensure the best outcomes and long-term care of retired chimpanzees (1, 2, 3, 4, 5).

The limited focus of the recent ASP/ISP conference session to nonhuman primates used in research in the US (18% of facilities) could have many explanations. We will return to consideration of these points, and to a fuller discussion of the session, in subsequent posts. To begin, however, we return to excerpts from a post we made in 2013, with points that are foundational and key to a fair dialogue.

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Macaque. Kathy West. CNPRC.

Macaque. Kathy West. CNPRC.

Fair partners in dialogue: Starting assumptions matter and they should be spelled out

The importance and need for civil, open dialogue about the complex set of issues involved in use of animals is among the points of agreement between members of the scientific community, the public, animal rights activists, and others. Speaking of Research, along with others, has consistently advocated for and engaged in such dialogue via a number of venues, including our blog, public events, conference presentations, and articles.

One of the important purposes of dialogue is to communicate diverse viewpoints and values on animal research and one key to understanding those viewpoints and values is consideration of the basic starting assumptions, or positions, from which they arise. However, such dialogue often takes place without clear specification of the starting positions held by the people engaged in the conversation. Speaking of Research has previously highlighted the problem with this approach– for example, see Prof. Dario Ringach’s posts on a series of public forums on ethics and animal research (here, here, here).

Image of mice courtesy of Understanding Animal Research

Image of mice courtesy of Understanding Animal Research

The basic position of those engaged in animal research is obvious in part by the nature of their work. Furthermore, the very structure of the current regulations and practices reflect– both implicitly and explicitly – a set of positions on the ethical and moral considerations relevant to the use of animals in research (*see below).

What are the positions of those who oppose laboratory animal research?

In some cases, these are clearly stated. In the case of absolutists, the position is that no matter what potential benefit the work may result in, no use of animals is morally justified. This extends across all animals – from fruit-fly to primate. Furthermore, all uses of animals, regardless of whether there are alternatives and regardless of the need, are treated identically. In other words, the use of a mouse in research aimed at new discoveries to treat childhood disease is considered morally equivalent to the use of a cow to produce hamburger, the use of an elephant in a circus, or a mink for a fur coat.

In this framework, the focus often excludes consideration of the harms that would accrue as a consequence of enacting the animal rights agenda. For example, the harm to both humans and other animals of foregoing research or intervening on behalf of animals. As a result, while the absolutist position is often represented as one that involves only benefits and no harms, this is a false representation. While some animal rights groups are clear about their absolutist position, others—to our knowledge—are not.

On the other hand are those who avoid identifying directly with an absolutist position, but instead focus on the need for development of alternatives to use of animals in invasive research. This is a goal that may be widely desired and shared. It does not, however, address the question of what should be done in absence of alternatives and in light of current needs that can only be addressed by animal studies. In turn then, this position is silent with respect to moral and ethical consideration of a broad swath of research and fails to offer a framework to guide current actions.

Pigtail macaques at the Washington National Primate Research Center

Pigtail macaques at the Washington National Primate Research Center

We believe that the goal of promoting better dialogue would be assisted by making these positions clear and we provide a starting place below. We welcome additions by individuals and groups, as well as clarification or correction if any are unintentionally misrepresented. (For additional groups see original post).

People for the Ethical Treatment of Animals: Offers clear statement of absolutist position. “PETA has always been known for uncompromising, unwavering views on animal rights. PETA was founded in 1980 and is dedicated to establishing and defending the rights of all animals. PETA operates under the simple principle that animals are not ours to eat, wear, experiment on, or use for entertainment.”

New England Anti-Vivisection Society: Offers clear statement of absolutist position. “Is NEAVS against all animal experiments? Yes. For ethical, economic and scientific reasons, NEAVS is unequivocally opposed to all experiments on animals and works to replace them with humane and scientifically superior alternatives that are more relevant and predictive for humans.”

Humane Society of the United States (HSUS): Does not, to our knowledge, offer a clear position on whether it is morally acceptable to use animals in research when there is no alternative. What they do say: “As do most scientists, The HSUS advocates an end to the use of animals in research and testing that is harmful to the animals. Accordingly, we strive to decrease and eventually eliminate harm to animals used for these purposes.”

Physicians Committee for Responsible Medicine (PCRM/Physicians Committee): Does not, to our knowledge, offer a clear position on whether it is morally acceptable to use animals in research when there is no alternative. What they do say: “We promote alternatives to animal research and animal testing.”

How is this relevant to building productive dialogue?

For those engaged in dialogue about the ethical and moral considerations related to the use of non-human animals in research, even this brief list makes clear that it is important to ask participants to begin by putting their basic starting assumption forward. Why? For one reason, because those assumptions are key to identifying whether there are potential areas of agreement or none at all.

For example, discussing refinement of laboratory animal care with an absolutist—someone fundamentally opposed to animals in laboratories—misses the point. No amount of refinement would make the work acceptable to them. In this case, the more critical questions for discussion would include consideration of the relative risks and potential benefits of failing to perform research for which there are currently no alternatives to animal-based studies. Consideration of species’ capacities and criteria for differential status– if any– would also be a useful starting point.

white-mouse-pair-in-cage-with-cardboard-tubeWhat about dialogue with those individuals and groups who do not provide a clear position? Does it matter?

Some would argue that it does not because the dialogue is only concerned with animal welfare and with reducing harm to nonhuman animals, or with pushing forward to develop non-animal alternatives for some types of research. In fact, framed in this way, most scientists are not only in the same camp, but are also the people who work actively to produce evidence-based improvements in welfare and development of successful alternatives.

The problem, however, is that real-time, critical decision-making about human use of other animals in research is not simple. It does require serious, fact-based consideration of the full range of risks and potential benefits, including consideration of the health and well-being of both human and nonhuman animals. It also requires clarity about alternatives, where they exist and where they do not. And it requires some understanding of the time-scales in which knowledge unfolds – often decades – and a basic appreciation for the scientific process.

It is easy to argue that developing non-animal alternatives for invasive research should be prioritized. But this argument does little to address the question of what to do now, what we do in absence of these alternatives, and what choices we should make as a society. Those questions are at the center of dialogue and the core issues with which the scientific community and others wrestle. To address them productively, and in a way that considers the public interest in both the harms and benefits of research, requires articulation of starting assumptions and foundational views.

Allyson J. Bennett

Excerpted from previous post “Fair partners in dialogue: Starting assumptions matter and they should be spelled out” 6/12/13

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*For example, in the U.S., the laws and regulations that govern animal research mandate that proposals for use of vertebrate animals (including rats, mice, birds) provide, among other things: 1) a justification of the potential benefits of the work; 2) an identification of potential harms and means to reduce them; 3) evidence that alternatives to using animals are unavailable; 4) the use of the least “complex” species necessary to answer that question; and 5) much detail about the animals’ care and treatment, including the qualifications and training of the personnel involved. Consideration of these issues occurs not only at the stage of IACUC evaluation, but throughout the scientists’ selection of questions and studies to pursue, peer review and selection of projects for funding (more here). Furthermore, the entirety of the project must proceed in compliance with a thorough set of regulations designed on the basis of the 3Rs – reduce, replace, and refine (for more about regulation see here, more about 3Rs, here).

In other words, while there is always room for continued improvement, the structure is designed to require that the major ethical and moral considerations relevant to animal research be addressed by those involved in performing and overseeing the work. This structure also incorporates explicit consideration of changes that arise from new knowledge. That includes evolving knowledge about different species’ capacities and needs, as well as the development of alternatives to animal-based studies for particular uses. It also includes advances in our scientific understanding that demonstrate the greater need for basic research that requires use of animals to address key questions.

Primates in Medical Research – Free Literature

The following post by Richard Scrase of UAR discusses a new free e-book (also available as pdf) which Understanding Animal Research (UAR) and Moshe Bushmitz has produced. It’s well worth a download, so please share with friends.

How do researchers work with primates? Which species do they use? What has research with primates revealed? How are the primates looked after?

These are the questions answered in our new iBook, Primates in Medical Research. Making full use of the iBook’s capability to show video, images and sound, Primates in Medical Research shows the vital role of primates in medical research. The iBook feature recent video clips recorded in primate research and breeding facilities in the UK, US and Israel. Its galleries include over 80 images of primates that illustrate the iBook’s 71 pages, along with archive material and a timeline showing medical advances with primates stretching back a century.

Primates in Medical ResearchPrimates in Medical Research is free to download from iTunes. Currently it can only be viewed on iPads. A PDF version can be downloaded from our website here.

Primates in Medical Research was produced by Understanding Animal Research in collaboration with primate specialist Dr Moshe Bushmitz.

Please download here: https://itunes.apple.com/us/book/primates-in-medical-research/id676974662?mt=11

Richard Scrase

Speaking of Statistics

We recently updated the statistics page of the website. Here are the highlights:

  • The numbers of dogs used in research was at its lowest rate since measurements began in the 1970s. The current figure is less than 1/3 of its number in the late 1970s.
  • The number of cats used remains at a general low (up very slightly from its historic low in 2009). The figure of 21, 578 is considerably smaller than the 74, 259 used in 1974.
  • Primate research has risen slightly over the past decade, in part due to increasing amounts of research into neurodegerative diseases such as Alzheimer’s, which is expected to affect four times the number people in 2050 as it does today.
  • Cats, dogs and primates together account for around 0.60% of animals used in research, making 2010 the fourth year this percentage has fallen.

The number of animals covered by the Animal Welfare Act used in medical research since 1973. This graph does not include the use of mice or rats.

Check out the statistics page now for more information

Addiction Research as an Example of Translational Biomedical Research

In science, “translation” embodies the concept that data gathered in one situation is meaningful for data gathered in another. Applied biomedical research seeks to translate laboratory research into effective treatments or cures. It spans many levels of study. In oncology (the field of cancer biology), some individuals study how cancerous cells grown in a dish operate and grow and how best you can destroy them. Others study tumor growth in animal models; they do this because the behavior of cells in a dish does not always fully predict how cancer will grow in a living body. Because we want to understand how cancer occurs and progresses in humans, yet other scientists use epidemiological or imaging techniques to directly study cancer patients. Information gained at one level informs and fosters the understanding of information gathered at other levels. No single experiment or scientist answers everything – it’s the collective work of the larger group of researchers working at all levels that pushes things forwards. This is how translation is made possible.

A hotly debated question in translational research is whether data gathered in animals 1) always, 2) often, 3) rarely or 4) never is meaningful for our understanding of human biology. Though most scientists and clinical practitioners feel strongly that it is often predictive, explicit examples are required to convince the broader public.  Clear evidence of translational value is found in research on the biology of drug addictions – something that I study in my laboratory. A large number of both rats and humans find drugs of abuse (cocaine, heroin methamphetamine, nicotine, etc.), when ingested, to be incredibly rewarding and will engage in significant drug-seeking behaviors to obtain it. In that sense, the study of these drugs’ effects on rats translates well (though not perfectly) to its effects on humans. Importantly, it translates “well enough” to make the rat a useful model organism in which to explore how drugs of abuse take control of some individuals by altering their brain chemistry. We have made excellent progress in this area over the last 15 years.

Of all areas of biomedical research, the study of the brain poses the biggest challenge for translational research because it is this organ that differs most across species. There is no doubt that a mouse’s brain is dramatically different from that of a monkey which is still different from that of a human. But do those superficial differences matter? Not as much as you might think! Let’s go back to the earlier example of drug abuse. Addictive drugs are chemicals that, when ingested, make their way into the brain where they alter the activity of brain cells, consequently changing the function of circuits in the brain that mediate reward. This is why they make people experience euphoria, relaxation and a sense of well-being after they take them. Remarkably, despite obvious differences in the brain, rats also very much enjoy the effects of these drugs. When offered an opportunity, they will take them voluntarily (e.g., press a button to trigger an injection of the drug). Even more impressively, even fish find addictive drugs rewarding. So, actually, despite the superficial differences, there is a huge amount going on in the brain that is similar across model organisms. This is because the anatomical differences between rat and human brains are actually much smaller than what is shared between them: common sets of circuits with similar functions.

This point is crucial. If fish and rats can be used to predict some of the responses of humans to addictive drugs, they can be used in translational research to explore the therapeutic effects of drugs used to treat brain disorders, such as addictions, as well.

It is important, however, to distinguish between what an animal model can reveal and what it cannot. In the case of chemical addictions, animal models can help you to understand the physiological and basic behavioral processes that drugs act on to alter the body. Again, studying the effects of an addictive drug in rats can help us to understand how it alters the reward circuit and how that relates to drug seeking. Here, translation is excellent. At the same time, it does not fully recapitulate the psychosocial consequences of drug taking in people. Because the drug is available for free, rats do not have to steal to get money to buy it. Because they are not expected to show up to work on time and be productive, drug use does not cause them to get fired from their jobs. Because they do not get married, they are not at risk of divorce when their drug-taking behavior gets out of control. Because they do not share needles, they are not at risk of hepatitis C or HIV infection. So, from a biological perspective, study of addiction can be modeled well in rats, but the psychosocial consequences are not. Rat researchers have revealed the neural mechanisms by which addictive drugs act in exquisite detail, and all modern, FDA-approved treatments for drug dependence arose from basic, mechanistic studies in animals (examples include Revia for the treatment of alcohol dependence and Chantix for smoking cessation). Clinical researchers then are able to tell us whether and how these treatments affect psychosocial functions in drug users. In that sense, like our colleagues who study cancer, we integrate study from many levels together to fully understand the biology and psychosocial consequences of drug abuse and its treatment.

It is because research at many levels integrates so well that providers of clinical intervention often closely study and attend to studies conducted in animals. An international society called the College on the Problems of Drug Dependence brings together scientists, physicians and social workers who are particularly interested in solving problems relating to addiction. Here, each attendee carefully studies the results of the other researchers – with studies in humans designed based upon clinical observations, and clinical tests being spurred by rat studies.  There is little doubt in the group – whether one consults patient-oriented researchers or people that examine cells growing in a dish – that studies of living animals are a critical part to the overall translational effort to stem the impact of addictions on affected individuals. Though animal research will not solve all of the mysteries of addiction, or of any complex human disease process, it is a foundational part of most areas of biomedical research and patients, patient advocacy groups and treatment providers overwhelmingly support it.

Regards

David Jentsch