Setting the record straight: Environmental enrichment in animal research.

One of the most important goals of Speaking of Research is to counter the misinformation and mistaken beliefs about animal research that are so prevalent in society, even among those who ought to know better, and a recent series of articles in Ampersand –  the blog of the organization PRIM&R (Public Responsibility in Medicine & Research) – illustrates the value of taking the time to correct these errors when they occur.

PRIM&R is an organization whose goals are to create a “a strong and vibrant community of ethics-minded research administration and oversight personnel, and providing educational and professional development opportunities that give that community the ongoing knowledge, support, and interaction it needs to raise the bar of research administration and oversight above regulatory compliance“. It’s membership includes over 4,000 individual members, and its educational and professional development programs address a range of issues surrounding research involving human subjects and animals.

SBER11

So it was rather disappointing to read a blog post entitled 40 years of Research Ethics: Environmental Enrichment which presented the development of environmental enrichment guidelines and practice in a rather superficial manner, and in particular presented PeTA propaganda concerning the 1981 Silver springs case as fact:

The regulatory mandate for environmental enrichment has a long history. In 1970, as a result of amendments to the Animal Welfare Act (AWA), enclosure standards for all warm-blooded animals were developed.  The need for additional regulations became apparent in 1981 when Alex Pacheco, an animal rights activist and cofounder of the then-newly formed organization People for the Ethical Treatment of Animals, discovered and documented violations of the AWA as a volunteer at the Institute for Biological Research in Silver Spring, MD. Pacheco’s work drew public attention to the care of laboratory animals.

In the years following the Silver Spring Monkey case, a number of bills advancing standards for the care of laboratory animals were introduced in the US House and Senate. In 1985, the Food Security Act amended the AWA to mandate exercise for dogs and a “physical environment adequate to promote the psychological well-being of primates.” While initially the research community responded to the mandate for environmental enrichment with hesitation, today such programs are considered fundamental to a comprehensive animal care and use program

In response to this Allyson J. Bennett, PhD, former chair of the Committee on Animal Research and Ethics at the American Psychological Association (APA) – and  Speaking of Research member – , and Sangeeta Panicker, PhD, director of research ethics at the APA, contacted PRIM&R to express their concerns, and to their credit PRIM&R published their email in new post. In their email Allyson Bennett and Sangeeta Panicker pointed out (among other points) that:

Contrary to well established facts, the post implicitly maligned a distinguished member of the psychological science community (involved in the ‘Silver Spring Monkey case’), and lauded the less than honorable tactics of the individual associated with a group, People for the Ethical Treatment of Animals (PETA), that is publicly opposed to research with nonhuman animals. Furthermore, based on scant, if any, credible evidence, the blog post credited PETA for almost singlehandedly achieving changes to the Animal Welfare Act (AWA) that led to environmental enrichment requirements for research animals.

and that:

Finally, circling back to the events described in the PRIM&R blog post, we note that not only was the researcher in question exonerated on all but one count of AWA violation by USDA, as well as the US judicial system, but three highly respected scientific organizations—the American Association for the Advancement of Science, the Society for Neuroscience, and the American Psychological Association—independently investigated the so-called ‘animal abuse’ and found his conduct to be beyond reproach. Furthermore, in light of the baseless accusations against the researcher, we believe it is incumbent upon PRIM&R, the premier organization in the continuing education of institutional animal care and use committees, to acknowledge the impact of this ethically and scientifically sound research with nonhuman primates on the rehabilitation of individuals recovering from strokes and spinal cord injuries.

Mice in a research laboratory. Image courtesy of Understanding Animal Research.

Mice in a research laboratory. Image courtesy of Understanding Animal Research.

So far, so good, but what is really interesting is that it didn’t stop there. A few months later PRIM&R published another article entitled The Evolution of Environmental Enrichment which gave a far more balanced account which acknowledged that the history of environmental enrichment reaches back far longer than 40 years, and how animal researchers, in particular behavioral researchers, have played a key role in shaping its development. In the introduction to their post the writers acknowledge that the impetus for writing this second post came from the email sent by Drs Bennett and Panicker:

In the spirit of transparency and respectful dialog, PRIM&R has written this second post, which we believe is a more considered treatment of an important and complex issue. We thank Drs. Bennett and Panicker for their feedback and for prompting us to take this second look.

What can we learn from this series of posts?

Firstly, the first post shows  how the myths and misrepresentations spread by animal rights organizations have become so pervasive that even many people who should know better take some of them for granted. This is something we have  encountered time and again, and even many scientists who support the use of animals in research don’t appreciate just how high a proportion of the claims made by animal rights groups are pseudoscience.

Secondly, the next two posts show how some (regrettably not all) people are willing to listen when presented with the facts, and how this can spur them to become better informed and reconsider their prior assumptions. This is why it is so important that scientists and supporters of scientific research who know the facts take the opportunity to engage with both specialist and general media to correct misapprehensions and misrepresentations.

You can make a difference!

Speaking of Research

Guest Post: CRPS Animal Models Explained

The following guest post is by Dr Rosie Morland. Dr Morland recently completed a PhD in neuroscience and pain studies at Imperial College, London, and she has a particular interest in how animal models can help increase understanding of complex pain disorders. You can read more from her on her blog. The article was originally published on the Burning Nights website which seeks to raise awareness about Complex Regional Pain Syndrome (CRPS) in the UK and Worldwide. It is republished with permission from the original author and Burning Nights website. CRPS, formerly called Reflex Sympathetic Dystrophy (RSD) is a chronic pain condition which usually affects the limbs and can result in prolonged pain. More information on CRPS can be found in this leaflet.

Developing Animal Models of CRPS/RSD Explained

In the last 20 years, research into Complex Regional Pain Syndrome (CRPS) has seen huge advances, taking it from a little understood and assumed-rare condition, to the realisation that it is an incredibly complex disorder that may in fact describe a whole group of related pain conditions.

Defining CRPS

CRPS often develops after a seemingly minor injury, which instead of healing normally triggers an over-reaction of pain and inflammation systems in the body.

The Budapest criteria are often used to diagnose CRPS. These look at four main categories of symptoms as shown below:

The Budapest Criteria CRPS

These symptoms are used to identify CRPS according to the following checklist:

  • A: Ongoing pain at an intensity which cannot be explained by the triggering event (e.g. a fall or fracture)
  • B: at least one sign (i.e. measured experience) from two or more of the four categories above
  • C: at least one symptom (i.e. reported experience) from three or more of the four categories above
  • D: A lack of alternative diagnosis

Hypothesis Experiment Results Conclusion

Developing Animal Models of CRPS

This last point highlights the difficulties both doctors and researchers face when trying to develop animals models of CRPS. Animal models can be incredibly informative when trying to understanding how painful conditions develop – they have been used to identify changes that occur at the cellular level in pain, helping to understand the changes that take place when pain changes from acute (useful & teaches us to avoid the dangerous things in life), to chronic (pain that just won’t go away). So far, pain researchers have found that the way the body reacts to pain depends on what caused the pain, and also to some extent on individual factors such as genetics, previous life experience, and lifestyle.

When developing animal models, the researcher must first establish that what they are doing is a valid and accurate representation of the human condition. This applies to both how the model is induced (i.e. what causes the condition), and what signs/symptoms can be detected. For CRPS, this situation is complicated by a lack of understanding of what causes the disease, huge variation in how patients experience the condition, and a reliance on reported symptoms. For researchers trying to develop accurate models, reported symptoms are the greatest challenge.

In CRPS, animal models usually take one of two forms:

  • A: Traumatic – based on traumatic conditions that can trigger CRPS, such as accidents
  • B: Immune – looking at how a dysfunctional immune system can contribute to CRPS

Most models are in this first category, and are based on evidence that CRPS develops following a relatively minor accident, such as a fall resulting in broken skin and/or bones. Such injuries affect the body in a number of different ways, and so are best looked at by breaking them down into elements, such as the effect of a fracture and subsequent bed-rest (‘immobilisation’); how nerves change the way they transmit pain signals when they are crushed by swelling, fractures, or other injuries; and how damage can happen when the blood supply is restored to an injured limb. Together, these models can identify how each different element of an injury contribute to the symptoms experienced.

Background concept illustration Immune system health medical word cloud wordcloud

Background concept illustration Immune system health medical word cloud wordcloud

As the immune system is incredibly complex, and it has been difficult to identify a unique “signature” for the immune response in CRPS, there are fewer researchers looking at the immune aspects of CRPS. However, a recent study found that disrupting the activity of a certain type of immune cell (B cells) in mice decreases CRPS-like behaviours such as pain and negative vascular changes following a fracture. This suggests that being able to control the immune reaction could decrease the chances of developing CRPS following an injury. Other studies have looked at the effect of nerve inflammation, as present following a minor injury, and what factors are responsible for the transition from normal immune response to injury, and the uncontrolled response immune seen in CRPS.

Another recent study looked at the role of the immune system from a different angle, by injecting serum from CRPS patients into mice. Samples from CRPS patients have been shown to have high levels of inflammation, and when this was injected into mice, they showed CRPS-like symptoms that not seen in mice injected with serum from healthy volunteers. This suggests there is something different in the serum of CRPS patients that could explain the different reaction to injury. However, in this study, the patient group was selected to be similar, and as CRPS can present in a wide variety of ways, these results are only relevant to that specific patient group. Studies are already in progress to try and link what is seen in serum to specific symptoms experienced, so in the years to come, we can expect a lot more work like this.

Measuring Symptoms in Animal Models

Once a model has been made, the researcher must then find ways of testing for the signs/symptoms reported by patients. Not all of these are easy to detect in animals, pain being one of the most difficult. Most methods of measuring pain in animals look only at hypersensitivity. Hypersensitivity, or the perception of pain greater than would be expected, can be measured in animals by looking at how different models change responses to increasing temperature (up to 48°C), and increasing force (using a hair-like instrument – von Frey Hairs). However, pain is not just a sensory experience, and is always associated with emotional symptoms, which are just as damaging to the sufferer, and much more difficult to measure in animals. To study this aspect of pain, researchers look at changes in the natural behaviour of the animal, such as how readily they explore a new space (theory: pain decreases the perceived risk of exploration), and also how they react to other animals (theory: animals in pain behave differently around other animals based on whether they are familiar or a risk). It is very important when studying pain to ensure that any treatments developed tackle both the sensory and emotional aspects of pain.

As discussed, most models used to study CRPS are limited in their application, as they focus on a very specific set of conditions, such as bone fracture models only being applicable to CRPS patients who developed the condition via fractures, or the immune serum study only applying to patients which fit the same profile.

By looking at a range of different symptoms of CRPS, and how they compare across different models, researchers should be able to build up a detailed picture of what factors contribute to each symptom and how they can be combatted.

It is important to recognise that advances in CRPS research are reliant on identifying the biological changes responsible for the symptoms of CRPS, and without a definitive cause the only way to do this is to look at a range of different models. As we learn more about the processes happening in the body that are responsible for each symptom, and how they change during disease progression, we get closer to developing useful treatments that take into account all the different ways CRPS patients experience the condition. The personal nature of the pain experience, combined with the variation in symptoms experienced in CRPS mean there is never, alas, going to be a one-size-fits-all treatment, but with greater understanding, diagnoses could become more accurate, and appropriate treatments, based on the unique symptom profile of the patient could become a reality.

Some interesting open access articles on models of CRPS:

Linnman, C et al. (2013) ‘Inflaming the brain: CRPS a model disease to understand neuroimmune interactions in chronic pain,’ Journal of Neuroimmune Pharmacology & NCBI NIH. June 2013. Vol 8 (3) pp 547-563. Available from: < http://www.ncbi.nlm.nih.gov/pubmed/23188523> doi: 10.1007/s11481-012-9422-8

Cooper, M.S., Clark, V.P. (2013) ‘Neuroinflammation, neuroautoimmunity, and the co-morbidities of complex regional pain syndrome,’ Journal of Neuroimmune Pharmacology & NCBI NIH. June 2013. Vol 8 (3), pp 452-469. Available from: <http://www.ncbi.nlm.nih.gov/pubmed/22923151&gt; doi: 10.1007/s11481-012-9392-x

Dr Rosie Morland

ALF Claims Responsibility for Arson in Mississauga, Canada

In an anonymous communique the ALF claimed responsibility (ALF site) for the destruction of two trucks owned by Harlan Laboratories. In the early morning of June 7, 2015, incendiary devices were ignited and the trucks were destroyed. Thankfully no one was injured and the fire was quickly contained by first responders. Harlan was targeted because of its corporate focus to provide laboratory customers with animals, products and services that optimize the discovery and safety of new medicines and compounds. Harlan significantly contributes to research endeavours in Canada and was recently acquired by Huntingdon Life Sciences, who has been the target of several animal rights campaigns. Ultimately this type of illegal activity is counterproductive as is evident with the ending of the Stop Huntingdon Animal Cruelty campaign and the convictions of numerous perpetrators of violence and harassment in the US and UK.

Fire Canada

It is unclear if those involved in this incident are the same as the people who released 1600 mink in St. Mary’s Ontario on May 30, 2015, or vandalized the CALAS national office in July 2014. What is clear is that this type of illegal activity is unacceptable and undermines informed discussions surround this important issue. The majority of Canadians support the ethical use of animals in science. Canadian scientists, laboratory animal professionals, institutions and companies need to resist the temptation to “circle the wagons” and shut the public out. That strategy is also counterproductive in the long term. We can use this as an opportunity to expand public outreach programs. Once presented with accurate and transparent information the public can make informed opinions. Knowledge is power and sharing that knowledge empowers the public to understand animal research.

Michael Brunt

The antivivisection movement and how to stand up to it

Tom Holder at the Pro-Test for Science RallyIn April 2014 Speaking of Research founder, Tom Holder, published a paper in EMBO reports looking at the structure and motivations of antivivisection groups and organizations, as well as how he got involved in defending animal research. Now, a year after its publication, this article is free-to-view online, or as a pdf. We are reproducing it below with the permission of EMBO reports (long form links have been converted into hyperlinks for the sake of the web format).

Standing up for Science

The antivivisection movement and how to stand up to it

Animal research has been and remains crucial to the development of modern medicine. The reasons for ongoing research are manifold from finding ways to treat cancer to understanding the mechanisms behind neurodegeneration to developing new vaccines against HIV/AIDS, malaria and other diseases. Nearly all of us benefit from medical treatments made possible through animal research, and with so much at stake, it is important that scientists make the case for the importance of using animals in research. With animal rights extremism at an all‐time low, there has never been a better time for scientists to overcome their reluctance to talk about the benefits of their work.

Sadly, polls show that opposition to animal research among young people, for example in the UK and USA, is significantly higher than among those aged over 65 [1], [2]. In my view, this is in part because of the large amount of misinformation propagated across the Internet by opponents of animal research—the “antivivisection” (AV) movement. Moreover, the past decades have seen bouts of intense activism—including harassment, threats and violence directed towards scientists—aimed at shutting down animal research. During the same period, the scientific community have worked diligently to replace, refine and reduce the use of animals in research, making much progress; however, these efforts have not been sufficient to satisfy the passions of some activists.

Part of the problem is that scientists rarely engage with those who are opposed to animal research, which can leave them detached from the need to justify or explain their work. This lack of communication also creates an information vacuum in the public sphere about the need to use animals. In a recent poll in the UK, only 31% of respondents felt “fairly well informed […] about science and scientific research/development” [2].

“With animal rights extremism at an all‐time low, there has never been a better time for scientists to overcome their reluctance to talk about the benefits of their work.”

Ignoring the animal rights community has not worked. Wherever there has been a vacuum of understanding about research, they have filled it with disinformation based on rare instances of negligence and shocking examples of seemingly barbaric experiments, accompanied by stories describing animal research as unnecessary and out‐dated. Some animal rights groups mask their aim to ban animal research behind the noble banner of animal welfare—legitimately criticising incidents involving substandard animal care but then implying that these represent not the exception, but the rule. Yet, the huge improvements in laboratory animal welfare will never satisfy those animal rights groups that have a fundamental ideological opposition to such experiments. Instead, AV groups often buttress their position with unfounded assertions that such methods can be entirely replaced or cannot provide useful results. As activists build a seemingly stronger—even if bogus—case against the value of using animals in research, the public support for, or indifference to, some illegal activities rises.

I actually dislike the term “antivivisection.” It is scientifically inaccurate, as much animal research is non‐invasive and does not involve cutting live animals (vivisection). Nonetheless, those opposed to animal research, particularly in the UK, have taken the word to describe their movement and it is a useful term for their subsection of the wider animal rights movement.

Sidebar A:  Activism and extremism
It is useful to make a distinction between activism and extremism. Activism is the use of legal campaigning techniques to bring about a change. Such activities include letter‐writing campaigns, producing leaflets and peaceful demonstrations—all hallmarks of an open democracy. Extremism is where activism moves beyond the law. This can include vandalism, harassment, breaking into research facilities, and even arson and physical violence.

I first became interested in the issue of animal research and animal rights as a student at Oxford University in the UK in 2005. Studying Philosophy, Politics and Economics, I was probably more qualified to become a politician than I was to discuss animal research, but as I returned to my second year at Oxford, the hot topic was that AV extremists had burned down our student boathouses in protest against the new animal research facility the university was building. I became interested in the subject and spent some time researching AV websites. I was surprised to discover claims that animal research does not work and that it has held back science by many decades. The “33 facts of vivisection”, for example, references 33 claims (sometimes this list is expanded or reduced) as to why animal research does not work. What I found most concerning at the time was that the claims seemed to me to be the result of purposeful misrepresentation.

In early January 2005, it became apparent that a number of Oxford students felt the same way. The (now defunct) Oxford Gossip Internet forum was full of heated debates about animal research, and pro‐research/anti‐AV groups were gathering support on Facebook. At the same time, animal rights groups were posting calls to action to harass students, professors and partners of the university. On 22 January 2006, a communiqué from the Animal Liberation Front read: “This ALF team is calling out to the movement to unite and fight against the University on a maximum impact scale, we must stand up, DO WHATEVER IT TAKES and blow these fucking monsters off the face of the planet. Information, tools and resources are out there for everyone to take part in smashing the University of Oxford, all you need do is find them! All that stands between the animals and victory is our fear, GET OVER IT! Fear is their most valued weapon and the animals cannot afford for us to work within their boundaries. We must target their construction companies and the University’s current and future building projects. We must target professors, teachers, heads, students, investors, partners, supporters and ANYONE that dares to deal in any part of the University in any way. There is no time for debate and there is no time for protest, this is make or break time and from now on, ANYTHING GOES. We cannot fail these animals that will end up in those death chambers.”. This climate of hostility and fear understandably deterred many scientists from speaking up for research, which left the animal rights movement free reign to control the arguments presented in the media.

Ultimately, the galvanisation of the animal research advocacy movement fell to Laurie Pycroft, a then 16‐year old boy of whom British professor Sir Robert Winston described as having: “put the medical and scientific establishment, drug companies and universities to shame”. On 28 January 2006, while visiting his girlfriend, Laurie came across an animal rights demonstration protesting against the construction of the new Oxford Biomedical Research Facility. Frustrated with what he saw, he entered a shop, bought a large piece of card and marker pen and made a placard saying “Support Progress—Build the Oxford Lab!” He stood near the animal rights protest and held up his sign, despite the abuse hurled at him by AV activists.

Laurie wrote a blog entry about his day, announcing that he would hold a pro‐research rally in Oxford on February 25 to coincide with a national animal rights march through Oxford (a “pro‐test,” one of his blog followers wryly noted). In response, a handful of Oxford students approached Laurie and the “Pro‐Test” committee was born. The committee came to the decision that if we wanted people to follow us, we would have to shed our anonymity and come out publicly. To date, none of the committee has received anything nastier than a few vitriolic emails.

The Pro‐Test rally was hugely successful and the headline in the Guardian said it all: “The silent majority finds a voice”. Outnumbering the AV rally more than five‐to‐one, 850 students, scientists and members of the public marched through the streets of Oxford. From this point on, the pro‐research movement expanded rapidly, engaging in school, university, radio and TV debates up and down the country. Tony Blair, the British Prime Minister at the time, signed the Coalition for Medical Progress’s “People’s Petition,” which accumulated more than 20,000 signatures in support of animal research. Moreover, Blair wrote an open letter to the Telegraph newspaper stating his support for animal research and the Pro‐Test movement. In June 2006, Pro‐Test held a second rally, once again bringing hundreds of people to the streets of Oxford.

Oxford University opened its new Biomedical Sciences Building in October 2008, offering state of the art equipment and a “gold standard” in animal care. Perhaps Pro‐Test’s biggest contribution was breaking the taboo that said that those who supported animal research should not say so openly. It is a taboo that must continue to be broken.

In March 2008, I became a fellow in public outreach at Americans for Medical Progress (AMP, USA) and founded Speaking of Research (SR), which aimed to provide accurate information about animal research and help mobilise students and staff to defend it. Over the next year, a committee of researchers, advocates technicians and science communicators came together to help run SR, giving talks, writing articles and reaching out to those affected by AV extremism.

The USA presented different challenges to the UK. National coverage is much harder to come by: incidents in one state are often not reported in the next, causing institutions to believe that tackling activism is “someone else’s problem.” I spent much time touring facilities and it was easy to see stark differences in approach. Those who had been targeted by animal rights protesters in the past had opened up their facilities for local journalists and residents to see. In this way, their local communities could assess for themselves the veracity of animal rights accusations. Those universities that were less open sometimes found themselves on the end of a protracted animal rights campaign. Scientists at UCLA, for example, had their houses flooded and were sent bombs and razor blades by mail. It was beginning to look like Oxford all over again.

In 2009, several weeks after David Jentsch, Professor of Psychology and Psychiatry & Behavioural Sciences at UCLA, had his car firebombed by the Animal Liberation Front (ALF), he and a small committee, myself included, organised a rally to stand up against this extremism. UCLA Pro‐Test was born; it was later renamed Pro‐Test for Science.

On 22 April 2009, 40 animal rights activists gathered for World Week for Animals in Laboratories. Across the road, approximately 800 scientists, animal technicians and other members of UCLA marched in support of science and in opposition to animal rights extremism. The rally gave scientists an opportunity to explain the importance of animal research to journalists and members of the UCLA community. The Pro‐Test petition launched at the event garnered more than 11,000 signatures and was handed to representatives of the NIH at a second pro‐research rally 1 year later.

As SR marks its sixth birthday, I have learnt the importance of scientists supporting one another. Many researchers have felt isolated by their institution’s leadership, some of whom would rather end controversial research than stand up to activists. SR has always aimed to reach out to those researchers who have been targeted, giving them an outlet to discuss their research when their institution will not.

During 8 years of involvement, I have seen many different approaches to communicating the role of animals in research—everything from open discussion to a complete unwillingness to even acknowledge such research is conducted at an institution. I have also had many opportunities to interact and discuss with those opposed to animal research. This has allowed me to build a picture of how I believe the AV movement functions, how it is structured and the factors affecting its size and strength.

“Many researchers have felt isolated by their institution’s leadership, some of whom would rather end controversial research than stand up to activists”

AV groups and organisations vary in size and structure. Some can count their members on the one hand, while others, such as People for the Ethical Treatment of Animals (PETA, USA), claim their membership in millions. Many of the larger animal rights organisations deal with a variety of related issues including animals for food, fur farming, pet ownership and hunting, while smaller groups often focus on just one issue.

Activists are those employed, either professionally or as volunteers, by AV groups (AVGs) and AV organisations (AVOs). While the line between AVGs and AVOs is not clear‐cut, AVOs are usually formal organisations that employ staff and tend to have a much larger turnover and greater assets. Examples of AVOs would include the British Union for the Abolition of Vivisection (BUAV; UK), Physicians Committee for Responsible Medicine (PCRM; USA) and PETA. Conversely, AVGs tend to be smaller, usually less established groups that do not salary their members, but may remunerate them for work done. Examples include Stop Huntingdon Animal Cruelty (SHAC; UK), SPEAK (UK), Negotiation is Over (NIO; USA) and Fermare Green Hill (Stop Green Hill; Italy). AVGs may grow into AVOs; both PETA and SAEN (Stop Animal Exploitation Now!, USA) grew from being groups of like‐minded people into tax‐registered non‐profits. However, many AVGs appear to prefer the flexibility associated with their informality and small size.

To study the AV movement, it is important to keep in mind that animal rights activism has become a profession for many of those involved. While many sociologists originally believed that social movements were simply forms of collective action by individuals with common grievances, the view was later criticised as incomplete since many such grievances exist without associated social movements. The development of Resource Mobilisation Theory (RMT) noted that individuals require sufficient resources to be available to form a movement and that this has a significant impact on the potential success of a movement [3]. Figure 1 uses RMT to illustrate the movement of people and resources in the AV movement. Key resources include money, communication tools, influential networks and the activists themselves.

Image Credit Tom Holder, Originally Published in EMBO Reports DOI: 10.1002/embr.201438837

Click to Enlarge

Figure 1. A model of the antivivisection movement
The blue dashed arrows indicate the movement of people within the antivivisection movement: a person might read the website of an AVG and decide to change from non‐supporter (either someone who disagrees with the AV views or has not formed an opinion either way) to a supporter, donating money or spending their time and effort signing petitions. The green arrows denote the movement of resources (e.g. time and money), though it should be noted that these are not exhaustive lists of resources. In return for their time and effort, that person might get a “feel‐good buzz” about helping animals, or from the acceptance of their peers. Later, they might decide to get more involved. This change is the movement from supporter to activist (though the divisions are not clear‐cut). The activist still feels good about what he or she is doing—possibly with a greater social acceptance from their newfound colleagues—and might also find himself or herself remunerated. Note that by giving time or money to any one AVG/AVO, they are choosing not to give those resources to another, so there is a natural competition between these AVGs/AVOs. Years later, the person might find they have less time and will drop back to supporter status, or might find that the massive publicity surrounding an associated movement draws their time and effort (turquoise dashed arrows), such that they stop their involvement with the original AV movement. Such associated movements need not have any relation to animal rights, but the more similar they are to the AV movement, the more competition there will be. Legitimacy is an important resource that both supporters and activists provide. An animal rights group that can only muster 20 supporters at important demonstrations will eventually find its supporters moving to competing AVG/AVOs. When the entire antivivisection movement comes under negative media spotlight, or as laws or police activities make certain activities more difficult, many supporters may move to other associated movements, and many activists may choose to put their expertise into other areas.

The amount of money provided by supporters is not small. In the USA, PETA had an income of US$35.3 million in 2013, while the Humane Society of the United States (HSUS) received US$180 million in 2012 from its 11 million supporters. The combined income of the three largest AV organisations in the UK exceeds £5 million. Even non‐registered groups can accrue large sums of money. SHAC activists amassed “around £1 million in donations to SHAC’s collection buckets and bank account”.

Given these sums, it is not surprising to see a certain level of competition for supporters and funding between organisations. The AVOs work hard to break the biggest stories, for example through undercover filming or by trawling through research papers or reports for sensational and often groundless claims about animal abuse. Between 2007 and 2011, for example, SAEN made more than six complaints per year to the USDA, often following up on rejected complaints with accusations that the USDA was failing in its role of regulator (e.g. here). In 2012, PETA alleged animal cruelty relating to sound localisation experiments on cats at the University of Wisconsin‐Madison. Both the USDA and the National Institutes of Health Office of Laboratory Animal cleared the university and found the allegations baseless.

Despite the competition and some friction between animal rights groups, many appear to be closely intertwined, with activists moving between them. Jerry Vlasak, who is currently a press officer for the Animal Liberation Press Office—the mouthpiece for the ALF—has been involved in SPEAK, the Animal Defence League, Sea Shepherd and PCRM. These fluid movements are reminiscent of the way top businessmen move between the boards of firms as the skills gained within the animal rights movement are easily transferable. Alistair Currie moved from Campaign Director at BUAV to Campaign Coordinator at PETA and finally left the AV movement to become a spokesman for Free Tibet. Just as an experienced marketing consultant may move from a clothes firm to a car manufacturer, so a professional activist moves from movement to movement as the relative tides change. This reflects the professional nature of activism; however, some activists have suggested a “contamination” effect from animal rights activism that can make it harder to move out of the AV movement and into unrelated areas of campaigning.

However, it would seem that some prominent activists have also risen through the ranks, particularly of AVGs, on the back of extreme activities they have carried out under the banner of the Animal Liberation Front (ALF), an extremist group made up of small autonomous cells. Mel Broughton was convicted of conspiracy to commit arson in 1999 but went on to lead several campaigns, including against Oxford University. Luke Steele was sentenced to 18 months in 2012 for “harassing staff at Harlan laboratories” and now runs several AV organisations including the Anti‐Vivisection Coalition. Those serving prison sentenced gain prestige among parts of the AV community who support them and are quick to welcome them back into the fold upon release.

The tide of resources into the AV movement has ebbed and flowed over time. In 1903, after Stephen Coleridge, head of the National Anti‐Vivisection Society, lost £2,000 (over £200,000 in today’s money) in a libel action brought by the researcher William Bayliss during the Brown Dog Affair [4], the issue of animal research came to the attention of the media. As a result, resources flowed in; NAVS raised £5,735 (over £500,000 in today’s money) in just 4 months. Growing public disquiet about animal research also led to a string of dog protection bills being presented to parliament including the 1906 Dogs Act.

Activism waxed and waned in the following decades. In the 1960s, Ronnie Lee founded Band of Mercy, a direct action hunt saboteur group. Such groups helped to train animal rights activists in direct action methods. In 1975, the Australian philosopher Peter Singer wrote the seminal book, Animal Liberation, which provided the moral case for a new generation of activists [5]. The following year Ronnie Lee founded the Animal Liberation Front (ALF). The 1980s saw the founding of the Animal Rights Militia, who sent bombs to politicians and animal researchers. By the early 1990s, AVGs were becoming more active. Extreme groups such as the Justice Department and Animal Rights Militia were abandoning the doctrine of non‐violence. There were dozens of bomb attacks against researchers and organisations.

In 1996–1997, activists Greg Avery and his first wife Heather Nicholson ran a 10‐month campaign that closed the Consort Kennels, a facility that bred dogs for medical research. In 1997, activists began a similar campaign that would eventually close Hillgrove Cat Farm. These campaigns were, on the face of it, legally conducted protests. Nonetheless, as support flowed in, some activists believed they had licence to take more extreme, illegal, actions: the Hillgrove Cat Farm campaign resulted in 21 jail sentences.

In 1999, Avery founded SHAC, whose members harassed and threatened staff at Huntingdon Life Sciences (HLS), HLS’s clients and HLS’s clients’ other clients over a period of 10 years. These tactics have spread widely: the same were used in Oxford to target the contractors, and the HLS campaign was exported to the USA in 2004 under the leadership of Kevin Kjonaas, who had spent 2 years working with Avery in the UK. John Cook, the author of a Salon article on SHAC, summarises their tactics thus: “SHAC’s modus operandi is simple, elegant and shockingly effective: Publish the names, home addresses and telephone numbers of executives and employees of Huntingdon and any companies it does business with; identify these individuals as ‘targets’” [6].

The approach of seasoned activists is professional: they take on a campaign, complete it and then look for the next one to start. It seems to me that the speed and size of a campaign is often determined by the donations to the previous campaign; in my analysis, each of Greg Avery’s campaigns was bigger than the last. As such, successful campaign leaders become role models and groom supporters to become activists (Fig 1).

Most campaigns have been relatively short. Consort Kennels was closed in 10 months, Stop Primate Experimentation at Cambridge achieved its goals within 1 year and its successor, SPEAK, forced out the first Oxford lab building contractors in less than 6 months. As a campaign drags on, it can become harder to find supporters to volunteer time and money to the cause. This can increase the pressure to take more desperate measures. Perhaps the most drastic was the grave‐robbing of Gladys Hammond’s body by the Animal Rights Militia (ARM) in 2004. As the Save the Newchurch Guinea Pigs campaign (SNGP) dragged into its fifth year, ARM extremists stole the remains of the deceased mother‐in‐law of one of the guinea pig farm’s owners. Four members of SNGP were later convicted of using the desecration to blackmail the family into shutting down the farm, which happened the following year.

Such actions brought widespread public condemnation and the British police were granted new powers to tackle animal rights extremism. The UK Government set up the National Extremism Tactical Coordination Unit (NETCU) to deal with domestic extremism. The crackdown and subsequent arrests included Mel Broughton (10 years), Greg Avery (9 years) and Kevin Kjonaas (6 years). Suddenly young activists were deprived of experienced mentors and many AV activists moved into other related movements. For example, Amanda King, a British protester who was previously involved in the campaign against Oxford University and the Newchurch guinea pig campaign, was most recently involved in protesting against the UK Government’s proposed badger cull. Alongside her were veteran hunt saboteurs and campaigners who had protested against HLS and Hillgrove Cat Farm, UK.

AV extremism fell steadily from around 2005, which was likely due to a number of factors. NETCU focused heavily on animal rights extremism, with judges handing down harsher sentences. Pro‐research communication was also increasing with the Coalition for Medical Progress and the Science Media Centre both founded in 2002, and the Pro‐Test movement was gaining widespread media and public support. Finally, the public condemnation that followed high profile incidents, such as the grave‐robbing of Gladys Hammond, made animal rights a less attractive issue for young activists.

While extremism in the UK and USA has fallen to an all‐time low, there are signs that activism is on the rise in other countries. In particular, activists from across Europe are targeting Italian pharmaceutical companies, universities and breeders in a sustained campaign that may pose a serious threat to research in Italy. In the past 2 years, activists have broken into a beagle breeding facility at Green Hill, “liberating” dozens of dogs; blockaded a shipment of beagles to the pharmaceutical company Menarini until the dogs were given to activists; and broken into the University of Milan, where they mixed up the animals’ records and seized approximately 100 animals. Fortunately, a vigorous response is already underway, with the newly formed Pro‐Test Italia attracting hundreds of scientists to rallies in Milan and Rome. Nonetheless, such strong responses are few and far between—after a Brazilian research facility recently shut down after activists raided it, taking almost 200 dogs, there was only minimal response from the scientific community.

“In particular, activists from across Europe are targeting Italian pharmaceutical companies, universities and breeders in a sustained campaign”

Back in the UK, online campaigns against universities seem to be increasing in number and magnitude, while a multi‐faceted campaign by many AVGs and AVOs to prevent airlines transporting primates has left only a few willing to do so. In January 2012, the last of the ferry companies transporting laboratory animals across the English Channel stopped its service as a result of pressure from AV groups.

So what should we be doing now? Thanks to the efforts of pro‐advocacy groups and the outreach activities of many research institutions and scientists, there have been positive developments in how we discuss the use of animals in research. Furthermore, as many extremists in the UK and USA are in jail, or are recently released and under control orders that ban them from being involved in AV activism, there is little danger of extremism.

Scientists must spend more time explaining their work to the public, why animals are vital to biomedical research and the measures taken to minimise their suffering in laboratories. Social networks and online outlets, such as university departmental webpages, science blogs, Facebook, Twitter and YouTube, all offer ways for scientists to interact with the public—particularly younger audiences. Understanding Animal Research’s (UAR) “Science Action Network” points the scientific community towards articles that misrepresent animal research and posts links to Twitter with the hashtag #ARnonsense. Scientists who search for this hashtag, or who follow @ARnonsenseRT, can then go to these articles and leave comments correcting the misinformation within them. The result is that members of the public who come across these articles can quickly reassess their content.

Younger scientists often find it the hardest to speak up. Nevertheless, their voices are important. Start small; conversations with friends and family play a crucial part in “normalising” the issue of animal research, as well as practising science communication skills. Simple things like sharing animal research stories on Twitter or making mention of animal research on Facebook provide another avenue for discussion. A step further would be to write for a blog, student or local newspaper. Speaking of Research started a series of guest posts entitled “Speaking of Your Research” to provide scientists and animal care staff with a safe environment to discuss why they use animals. With science becoming more popular with the general public, there has never been a better time to discuss this issue (note the 12+ million likes for the “I Fucking Love Science” Facebook page).

“… scientists still go surprisingly quiet about animal research.”

While researchers directly involved in animal research are in the best position to talk about what they do, they are also open to accusations of bias. Therefore, it is important that the rest of the scientific community helps to explain why such research is carried out. All scientists should promote the value of both basic and applied science in all fields. I know plenty of researchers who have defended the Rothamsted Research Institute’s genetically modified wheat trials in the UK in the face of anti‐GM protests in May 2012. Yet, scientists still go surprisingly quiet about animal research.

Institutions must also speak louder. It was reassuring, for instance, that the Bremen University in Germany legally and financially supported researcher Andreas Kreiter against attempts to shut down his research on macaque monkeys. Yet, in my view, too many research institutions, particularly in the USA, lack clear and open statements about the existence and importance of their animal research programmes. This is especially true of those organisations which fund, but do not carry out, animal research, such as medical research charities. The more details provided, along with pictures and videos, the better; otherwise, activists will be happy to supply their own, unrepresentative images. Organisations also need to work with local communities, inviting residents and journalists to tour facilities and sending scientists to schools in the local area. This can help minimise the resources (of local supporters) available to a new AV campaign (Fig 1). Importantly, such actions must happen in the good times, or else risk being perceived as a cheap public relations stunt.

“The more details provided, along with pictures and videos, the better; otherwise, activists will be happy to supply their own, unrepresentative images”

While we still have a way to go, the UK continues to provide the best practice in pro‐research advocacy. Newspapers regularly report on interesting or promising research involving animals, thereby normalising the animal research issue. Universities and other institutions have driven this change by mentioning the animals used in research more regularly. Nonetheless, the long wait between initial studies in animals and the launch of new treatments means that the public can often lose sight of the link between the two. Those working on clinical research have a duty to recognise the contribution of animals when discussing new therapies with the press. In 2012, more than 40 institutions and organisations signed the Declaration on Openness, pledging to do more to communicate the important research they carry out. This is a positive step that could be emulated in other countries.

Medical research involving animals is important to all of us, and we all have a duty to provide the accurate information the public needs to make up their mind.

References

  1. Pew Research (2009) Scientific Achievements Less Prominent Than a Decade Ago. Washington, DC: The Pew Research Center. http://www.people-press.org/2009/07/09/section-5-evolution-climate-change-and-other-issues/
  2. Ipsos Mori (2012) Views on the Use of Animals in Research. London, UK: Ipsos Mori. http://www.bis.gov.uk/assets/biscore/innovation/docs/I/ipsos-mori-views-on-use-of-animals-in-scientific-research-September-2012
  3. <em>McCarthy JD, Zald Z N (1977) Resource mobilization and social movements: a partial theory. Am J Sociol 82: 12121241 CrossRef
  4. Illman J (2008) Animal Research in Medicine: 100 years of Politics, Protests and Progress. The Story of the Research Defence Society. London: Research Defence Society
  5. Singer P (1985) The Animal Liberation Movement: its Philosophy, its Achievements, and its Future. Nottingham: Russell Press
  6. Cook J (2006) Thugs for puppies. Salon, Feb 7. www.salon.com/2006/02/07/thugs_puppies/

DOI: http://dx.doi.org/10.1002/embr.201438837

Pro-Test Deutschland: Standing up for science in Germany!

Today we welcome the launch a brand new science advocacy organization, and a new member of the Speaking of Research Family, Pro-Test Deutschland!

Pro-Test_Deutschland_image

Pro-Test Deutschland is a grassroots science organization founded by 18 young scientists and supporters of medical progress in the German university town of Tübingen.

The need for such a grassroots campaign in Germany has never been greater, as over the past few years the rhetoric of animal rights activists in Germany has been getting steadily more extreme. This culminated last month with the announcement by Professor Nikos Logothetis, a leading neuroscientist at the Max Planck Institute for Biological Cybernetics in Tübingen, that he would be ending his research with non-human primates. His decision followed a series of false allegations by animal rights activists, and a campaign of vilification and intimidation against him, his family and his colleagues.

A lot can change in a month. Within days of Prof. Logothetis announcement over 4,000 scientists in Germany and beyond had signed a motion in solidarity with him and his colleagues, and the Max Planck Society issued a strong statement of support. The events in Tübingen spurred the wider European scientific community to take a strong public stance on the necessity of animal research, and its intervention played an important role in yesterday’s decision by the European Commission to reject the Stop Vivisection Initiative.

The launch of Pro-Test Deutschland comes at a critical time for science in Germany, and indeed in the EU as a whole, and we look forward to working with our new friends to support animal research that is so crucial to advancing science and medicine.

Below is the text of a press release that Pro-Test Deutschland issued yesterday to announce their launch. They have also issued an invitation letter to anyone who would like to get involved with details on how to get in touch.

Press Release June 3rd, 2015

Pro-Test Germany, a supplier of reliable information and advocate for animal testing in research

Tübingen, June 3, 2015

Pro-Test Germany is an initiative intended to lend a voice to science. Its primary goal is to educate the public on scientific, ethical, legal, social and psychological aspects of animal research. In addition, Pro-Test Germany will provide reliable information to help those better understand the role of animals in research and the benefits to society.

Today the European Commission decided that the 2 010/63/EU directive for the protection of research animals will not be affected by zealous antivivisectionists. This is good news for animal welfare. And it is good news for our society as a whole, as this decision issues a clear vote for science and research in the EU.

The often one sided campaign led by animal research opponents has recently left a huge impression on Tübingen, Germany. For one instance, the renowned neuroscientist Nikos Logothetis had decided to withdraw from his primate research to escape ongoing threats and harassment. Until now there has been very little public support for this research, especially from the scientific community, even Logothetis lamented a lack of support in his decision letter.

A powerful voice in the public debate is largely absent. Where have the scientists been during these one sided discussions? Scientists, whom are the most familiar with this research, are largely afraid to speak out because of the potential hostility or because they may not be understood or able to convey a message that the public understands. Not all scientists are adept at speaking out about their research; however, Pro-Test Deutschland aims to educate and provide a secure platform for scientists to speak and the community to get involved.

The view that animal testing in research is not only ethical but also necessary may be widespread, but it is rarely openly professed. For many people outside of science, it is also often difficult to obtain reliable information, such as reports on the outcomes of animal research and their public benefit. This fundamental problem has been acknowledged by young scientists in Tübingen. So by now, it is time to release Pro-Test Germany, an advocacy group for animal research and a voice lent to science. The founders of Pro-Test Germany believe that animal testing in research is ethically and scientifically necessary. All the while supporting a broad societal discussion based on information and literature that ranges through all sides of the story. Thus, to promote an informed and fair debate, Pro-Test Germany will provide a point of contact for all those who want to learn about the role of animals in science.

Pro-Test Germany is initially aimed at building a website that collects data, facts and personal testimonies concerning animal research and its final outcomes. The homepage at http://www.protestgermany.org is going live tonight on June 3, 2015. Additionally, a social media campaign has already begun on Facebook and Twitter. In due course, further activities will also be tackled, such as informational events, lecture series, open letters, rallies etc. The objective is to push Pro-Test Deutschland as far past the Swabian university city limits as possible.

Website: http://www.protestgermany.org
FaceBook: https://www.facebook.com/protestdeutschland
Twitter: @ProTestDE

Pro-Test Deutschland_logo

European Commission rejects Stop Vivisection Initiative

Today the European Commission rejected the Stop Vivisection Initiative that sought to repeal European Directive 2010/63/EU on the protection of animals used for scientific purposes and ban animal research in the EU.

Today, there are effective treatments for many infectious diseases, some forms of cancer, and several chronic diseases such as diabetes. These advancements would have been impossible without the insights gained in animal studies.
[…]
However, the Commission does not share the view that scientific principles invalidate the ‘animal model’. Indeed, despite differences with humans, animal models have been the key scientific drivers to develop almost all existing effective and safe medical treatments and prevention measures for human and animal diseases
[…]
The Commission therefore does not intend to submit a proposal to repeal Directive 2010/63/EU and is not intending to propose the adoption of a new legislative framework.

Read the full EU report here.

Dr Paul Browne, Research Editor at Speaking of Research, said:

We welcome the decision by the European Commission to reject the Stop Vivisection Initiative. EU Directive 2010/63 which governs animal experiments has been a step forward for both animal welfare and better science. They put the 3Rs – Replacement, Refinement and Reduction of animals in research – at the heart of the rules governing animal experiments.

Animal research continues to play a key part in medical advances. Only last week we learned about a new lung cancer therapy that performed very well in clinical trials, allowing patients with the disease to live longer; this treatment was only possible thanks to studies in transgenic mice. “

The Commission’s decision is not, however, unexpected. Directive 2010/63/EU was adopted by the EU Council and Parliament in September 2010 after more than 5 years of discussion and debate, including consultation exercises in which scientists, patient organizations, animal welfare experts, animal rights organizations and members of the public were given the opportunity to submit evidence. At a time when the EU is facing some of the greatest political and economic challenges of its history it was always very unlikely that the EU commission would repeal Directive 2010/63/EU and start the negotiation process again from scratch.

EU_Commission

If the organizers and supporters of the Stop Vivisection Initiative were going to have any chance of persuading the Commission to repeal directive 2010/63/EU, they needed to make a very strong case to the MEPs who gathered to hear what they had to say at the European Parliament session held on Monday 11 May 2015.

They didn’t. The hearing was something of a flop, with reports noting that the majority of MEPs present were unconvinced by the arguments put forward by the proponents of the Stop Vivisection Initiative. It’s not difficult to see why this was the case. The Stop Vivisection Organizers and their witnesses failed to put forward any significant new evidence that had not been examined back when the Directive 2010/63/EU was originally negotiated, and at one point in the hearing descended into outright conspiracy theory thinking.

By contrast supporters of Directive 2010/63/EU made a stronger case, especially Nobel laureate Professor Francoise Barré – Sinoussi, who put forward a very strong case for the value of animal research in advancing medicine.

While this was happening scientists and supporters of medical progress in the EU were not taking any chances, and let the European Commission know in no uncertain terms how important animal research is to medical science. More than 170 organizations (Speaking of Research among them) representing scientists, major funders of medical research  and many millions of patients across the EU have signed up to a statement in support of Directive 2010/63/EU and sixteen European Nobel laureates published an open letter in UK and German newspapers to rebut the Stop Vivisection campaign. Several excellent letters on the importance of animal research were published in the national press, including a letter in the Times by Steve Ford, Chief executive of Parkinson’s UK, as well as articles such as that written by Oxford University Duchenne muscular dystrophy researcher Professor Kay Davies. In addition research funders have added information explaining their position on animal research to their websites, for example the Wellcome Trust, one of the world’s top medical research charities, have published a briefing on “Why we support research involving animals”, and a Q&A on European Directive 2010/63/EU.

We congratulate the European Commission on this good decision for science and patients in Europe, and the EU scientific community for speaking up for science with one voice.

Speaking of Research

Lung cancer immunotherapy, from PD-1 knockout mice to clinical trials

This morning many news outlets, including the BBC, covered a very promising development in lung cancer therapy; the successful clinical trial of the cancer immunotherapy Nivolumab in 582 patients with advanced lung cancer. While the extension of survival was modest in most patients, it is to be remembered that these were patients with advanced lung cancer, which is notoriously difficult to treat, so to see the survival time doubling in some patients was quite dramatic. Future trials will examine whether greater benefits are seen when Nivolumab is given earlier in the course of the disease.

Dr Alan Worsley, Cancer Research UK’s senior science information officer, told the BBC that harnessing the immune system would be an “essential part” of cancer treatment, and adding:

This trial shows that blocking lung cancer’s ability to hide from immune cells may be better than current chemotherapy treatments. “Advances like these are giving real hope for lung cancer patients, who have until now had very few options.”

Nivolumab works by blocking the activation of the PD-1 receptor protein found on the surface of many of the immune cells that infiltrate tumours. Another protein named PD-L1 binds to PD-1 and initiates a regulatory pathway that leads to the immune response being dampened down. Usually this is a good thing as it maintains immune tolerance to self-antigens and prevents auto-immune damage to healthy tissue, but unfortunately many solid tumour cells, such as lung cancer cells, also secrete PD-L1, and by activating PD-1 can evade destruction by the immune system. By blocking PD-1 Nivolumab turns off this protective mechanism and allows the immune cells to detect and destroy the tumour cells.

X-ray of a lung cancer patient. Image credit: "LungCACXR" by James Heilman, MD - Own work.

X-ray of a lung cancer patient. Image credit: “LungCACXR” by James Heilman, MD – Own work.

So how was this discovered? This is where the knockout mice come in. Scientists had observed in the 1990’s that PD-1 was highly expressed on the surface of circulating T- and B- immune cells in mice, but didn’t know what role PD-1 played, suspecting that it may be involved in increasing the magnitude of the immune response. To examine the role of PD-1 researchers at Kyoto University in Japan creates a knock-out mouse line where the PD-1 gene was absent, and observed that this lead to some immune responses being augmented. In a paper published in 1998 they reported than rather than being an activator of the immune response PD-1 was actually involved in dampening down the immune response (1).

Subsequent studies in a range of PD-1 knockout mouse strains over the next decade explored the role of PD-1 in regulating the immune system, and also demonstrated that its ligand, PD-L1, could block immune-mediated tissue damage (2).  At the same time as these studies were taking place other research was demonstrating that PD-L1 was produced at high levels by tumour cells, first in   renal cell carcinoma in 2004 (3), but later in many other solid tumours including in lung cancer (4), and that this expression was associated with a decrease in the immune response to the tumour and a poorer prognosis.

This raised an obvious question: would blocking PD-1 improve the immune response against these tumours?

Work was already underway to find out. A paper published in 2007 by scientists from Nara Medical University in Japan demonstrated that blocking PD-L1 binding to PD-1 with monoclonal antibodies enhanced the immune response against established tumours in a mouse model of pancreatic cancer and acted synergistically with chemotherapy to clear the tumours without obvious toxicity (5). Subsequent studies with other monoclonal antibodies in a range of mouse and in vitro models of cancer showed similar results, including the humanized monoclonal antibody MDX-1106, now called Nivolumab, which was obtained by immunizing mice which had been genetically modified to produce human antibodies with human PD-1 (6).

Laboratory Mice are the most common species used in research

Cancer Immunotherapy – adding another accomplishment to an already impressive CV!

MDX-1106/Nivolumab showed promising results in a phase 1 trial against metastatic melanoma, colorectal cancer, castrate-resistant prostate cancer, non-small-cell lung cancer, and renal cell carcinoma, and following larger clinical trials (7) it was approved by the FDA for the treatment of melanoma that cannot be removed by surgery or is metastatic and no longer responding to other drugs, and more recently for metastatic squamous non-small cell lung cancer.

The story of the development of anti-PD-1 cancer immunotherapy is an illustration of how basic or fundamental biological research in animals informs medical science, and drives the discovery of new therapies. As cancer immunotherapy begins to transform the treatment of many previously untreatable cancers, it is well worth remembering that this revolution has its origin in the hard work of countless scientists working around the world, many of whom could only have guessed at the time where their efforts would eventually lead.

Breaking news, 1 June 2015: In another exciting report from the American Society of Clinical Oncology meeting in Chicago, researchers have reported that in a clinical trial of 945 patients with advanced metastatic melanoma a combination of Nivolumab with  Ipilimumab (another cancer immunotherapy that works through a different mechanism) stopped cancer advancing for nearly a year in 58% of cases, with the cancer still stopped in its tracks in many patients when the study period had ended. This is substantially greater effect than is seen with existing therapies, including Ipilimumab when administered alone, and shows how powerful cancer immunotherapies may be when two or more are combined.

Paul Browne

References:

  1. Nishimura H1, Minato N, Nakano T, Honjo T. “Immunological studies on PD-1 deficient mice: implication of PD-1 as a negative regulator for B cell responses.” Int Immunol. 1998 Oct;10(10):1563-72. PubMed: 9796923
  2. Grabie N, Gotsman I, DaCosta R, Pang H, Stavrakis G, Butte MJ, Keir ME, Freeman GJ, Sharpe AH, Lichtman AH. “Endothelial programmed death-1 ligand 1 (PD-L1) regulates CD8+ T-cell mediated injury in the heart.” Circulation. 2007 Oct 30;116(18):2062-71. PubMed 17938288
  3. Thompson RH1, Gillett MD, Cheville JC, Lohse CM, Dong H, Webster WS, Krejci KG, Lobo JR, Sengupta S, Chen L, Zincke H, Blute ML, Strome SE, Leibovich BC, Kwon ED. “Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target.” Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17174-9. PubMed:15569934
  4. Zhang Y1, Huang S, Gong D, Qin Y, Shen Q. “Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer.” Cell Mol Immunol. 2010 Sep;7(5):389-95. doi: 10.1038/cmi.2010.28. PubMed: 20514052
  5. Nomi T1, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, Nakamura S, Enomoto K, Yagita H, Azuma M, Nakajima Y. “Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer.” Clin Cancer Res. 2007 Apr 1;13(7):2151-7. PubMed:17404099
  6. Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, Stankevich E, Pons A, Salay TM, McMiller TL, Gilson MM, Wang C, Selby M, Taube JM, Anders R, Chen L, Korman AJ, Pardoll DM, Lowy I, Topalian SL. “Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates.” J Clin Oncol. 2010 Jul 1;28(19):3167-75. doi:10.1200/JCO.2009.26.7609. PubMed: 20516446
  7. Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, Brahmer JR, Lawrence DP, Atkins MB, Powderly JD, Leming PD, Lipson EJ, Puzanov I, Smith DC, Taube JM, Wigginton JM, Kollia GD, Gupta A, Pardoll DM, Sosman JA, Hodi FS. “Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab.” J Clin Oncol. 2014 Apr 1;32(10):1020-30. doi: 10.1200/JCO.2013.53.0105. PubMed:24590637