Having a full understanding of all the issues surrounding animal research can be a challenge for even science-specialist journalists, let alone general journalists, editors and broadcasters who have to handle many unrelated issues each and every day. Speaking of Research have produced a two-page summary of the key information which general news producers, journalists, presenters and editors, can use to quickly inform themselves about this issue.

Download the Background Briefing on Animal Research in the US

We encourage those working in universities, pharmaceuticals, and other research institutions, to help share this document when contacting or responding to journalists about research stories relating to their institution. By attaching this background briefing to proactive stories, or reactive statements, it can help ensure that your research is understood within the context of the wider research environment.

We permit anyone to redistribute this briefing unchanged, and in whole, with credit to Speaking of Research.

We would like to produce more of these for different countries in the future. However, those wishing to see a similar briefing for the UK should consult the Science Media Centre’s “Briefing Notes on the Use of Animals in Research”. We thank the Science Media Centre for offering their support in producing this briefing.

Speaking of Research

Pictures of a cat spay clinic misrepresented as a laboratory horror shop circulated the internet recently to support appeals to “end animal testing.” Speaking of Research wrote about it here “Fact into fiction: Why context matters with animal images,” noting the importance of understanding the facts and context for photographs.

This picture was used to misrepresent animal research

In the cat spay clinic case, the photos were from a newspaper article. We have written previously about images of laboratory animals that have made their way to the internet via leaks, undercover operations, and open records release. In all cases, several points remain true. Images are powerful. Providing accurate information about the images is important. It is also true that there are important differences between the sources and ways that images are obtained. Those obtained via infiltrations and undercover operations may be from manipulated situations, or  small fractions of hours of recording, in both cases providing a deliberately misrepresentative view. Photos obtained from institutions via open records release can also be used to misrepresent laboratory animals’ care and treatment and can be the centerpiece in “shock” campaigns. Their value is obvious from even a quick survey of high profile attacks on research, as we’ve written about previously (here, here, here). As in the case of the spay clinic images, conflating veterinary and clinical care with scientific research is also common and further serves to confuse the issues.

Can the laboratory animal research community do a better job of providing context for images of animals?  Yes.

Knowing what the images show and why matters, particularly to people who would like to engage in serious and thoughtful consideration to inform their point of view and judgments. In absence of context and facts, the audience is left without key knowledge and an opportunity to educate is missed. Yet all too often the opportunity is missed and the images remain in public view without comment or context from those who could provide a better understanding of what the photographs show.

In reviewing laboratory animal photographs that appear on animal rights sites, it is obvious that there are generally two types: those from activities directly related to the scientific project and those related to veterinary care or housing and husbandry. In terms of providing context and information, the two differ with respect to their source and which personnel may best explain the content of the photographs.

Some images may be of actual scientific research activities. These may be of animals engaging in an activity directly related to the science question under study. For example, the images may illustrate how animals perform a cognitive or memory task, how they navigate a maze, or how a particular measurement is obtained. The Max Planck Institute for Biological Cybernetics website provides an example of this, with description and photographs of rhesus monkeys and cognitive neuroscience research. Another type of image directly related to the scientific project may be of a surgery or procedure. An example of this is found in pictures of a surgery involved in cat sound localization research (photos here, video here). In each case, it is not particularly challenging to provide additional information and context because the activities are typically also explained in the protocols, grants, and scientific papers about the study.

Images of clinical veterinary care, husbandry, and housing appear frequently in activist campaigns and public view. For example, pictures of routine physical examinations, health tests, unexpected injuries unrelated to scientific procedures, or photos of animals in their normal housing, have all appeared via various sources. Many times– perhaps more often than not– the activity depicted in the images would not be obvious to a lay audience because it remains unexplained.

A common image – tuberculosis skin test

One of the best examples of misunderstood images is found in pictures of an anesthetized macaque monkey with a needle injecting something in its eyelid. The picture circulates the internet with various captions opposing “animal testing.”   What does this picture show?

It is a skin test, commonly used in human and nonhuman primates, for early detection of tuberculosis. A small amount of tuberculin (non-harmful) is injected just under the skin. In almost all cases, the primate does not have tuberculosis and the skin remains normal. If the primate—human or not—does have a reaction to the test, indicated by redness and some swelling, it provides evidence of possible tuberculosis infection. That person, or monkey, then receives additional testing and preventive measures for treatment and to avoid infecting and harming others.

Tuberculosis testing is routinely performed as a health procedure in humans who work in hospitals, schools, with children and with others who may be vulnerable. In settings where nonhuman primates are housed, tuberculosis testing is often routinely performed with all human personnel and with the other animals. Why? Because tuberculosis is a rare disease, but one that can be a threat to the animals’ health and thus, precautions are necessary to ensure their health. The difference between human and monkey tb testing is that for humans, the injection is given without pain relief or anesthesia, via a needle inserted into the forearm.

Aside from the momentary discomfort of the injection, the test is painless and without irritating after-effects. In monkeys, the injection is typically given while the animal is anesthetized and is placed just under the skin of the upper eyelid. Why the difference? It is a simple reason—the key to the test is looking for redness or slight swelling. In monkeys, the forearm is fur-covered and it would be very difficult to detect a reaction in an unobtrusive way.

University of Florida monkey pictures

Not surprisingly, the monkey tb test photo is one that seems to appear in an ongoing campaign against the University of Florida. In response to several years of attacks on their animal research programs, public universities in Florida are pursuing new action to shield personal information about their personnel from public disclosure.   We’ve written previously about an ongoing campaign of violent threats, harassment, and protest by local activists (here, here, here).

In parallel to other campaigns, photographs are a centerpiece of the current attacks on animal research. As reported by Beatrice Dupuy in the Independent Alligator:

“Disturbing pictures of primates being examined by researchers are featured on the organization’s website along with posters with quotes like “stop the holocaust inside UF, free the monkeys.” After a three year lawsuit, the organization, formerly named Negotiation is Over, obtained UF’s public veterinary records last April. The researchers named in public records were the first ones to be targeted by animal rights activists, said Janine Sikes, a UF spokeswoman.”

What are these “disturbing pictures of primates being examined by researchers”?

The photographs <warning: link to AR site> are of macaque monkeys that appear to be receiving routine veterinary care or are simply in fairly standard housing. While the activists claim these photos are evidence of maltreatment at the hands of researchers, they likely are mostly of routine veterinary procedures. For example, two appear to be of an anesthetized macaque monkey receiving a tattoo, another two of an anesthetized monkey receiving a tuberculosis test, while others show the reddened skin that rhesus macaques exhibit normally in the wild and captivity. One photo depicts what looks like a stillborn infant macaque. Without context or confirmation, it isn’t surprising that the photographs can be interpreted in many ways.

UF’s spokesperson says: “The university wants to be very open and honest about its research,” … “It wants to stop these personal attacks against our researchers.”

One place to begin is to provide straightforward and accurate context for the images of laboratory animals that have been released. While those with experience in laboratory care of nonhuman primates can view the images and be reasonably certain that they are mostly of clinical veterinary care, it is only the UF veterinary, animal care program, and scientific personnel that can provide accurate information. Other universities have done exactly that when faced with the same situation. In “An Open Letter to the Laboratory Animal Veterinary Community and Research Institution Administration”   we wrote:

“While scientists can address questions about the scientific side of animal research, we need the laboratory animal care and veterinary staff to provide their expertise in service of addressing public questions about clinical care and husbandry.  If they do not, it will be no surprise if the public view of animal research is disproportionately colored by the relatively rare adverse events and the misrepresentations of animal rights activists. Many believe that it is possible—and perhaps acceptable—to ignore this part of reality in order to focus on more immediate demands for time, energy, and resources. Consider, however, that a fundamental part of the AWA, accreditation, regulation, and professional obligation is actually to ensure communication with the public that supports animal research.  Thus, it is our entire community who share a primary obligation to engage in the dialogue that surrounds us.”

We have consistently condemned the extremists who have targeted UF scientists and others with outrageous harassment. Tactics designed to elicit fear and terror do not have a place in democratic society and do nothing to promote fair and civil dialogue about complex issues.

At the same time, we believe and have written often, that the scientific and laboratory animal community, including scientists, veterinarians, and institutional officials should consider that better education and explanation are key to building public dialogue and understanding of research. Furthermore, as highlighted in this case and others, releasing photographs, records, and other materials without providing context serves no one well. Providing straightforward explanation of the veterinary practices, housing, husbandry, and care of laboratory animals not only gives context to photographs, but also should not be that hard to do.

Allyson J. Bennett

More information and resources:

Raising the bar: What makes an effective public response in the face of animal rights campaigns:  http://speakingofresearch.com/2013/02/20/raising-the-bar-what-makes-an-effective-public-response-in-the-face-of-animal-rights-campaigns/

Time for a change in strategies? http://speakingofresearch.com/2013/06/24/time-for-a-change/

A detailed response to a PETA video accusing a primate lab of mistreatment:  http://speakingofresearch.com/2008/07/04/peta-out-with-the-new-in-with-the-old/

Speaking of Research media briefing (pdf):  Background Briefing on Animal Research in the US

To learn more about the role of animal research in advancing human and veterinary medicine, and the threat posed to this progress by the animal rights lobby, follow us on Facebook or Twitter.

In February we announced the publication of our US Background Briefing on animal research. Today we are publishing our Canadian counterpart briefing. We hope this will offer journalists, editors and broadcasters who may need to discuss this issue, a handy overview of the facts. Our two-page summary provides key information including the number of animals used for research purposes, the laws and regulations surrounding animal research, and some key questions people have.

Download the Background Briefing on Animal Research in Canada

As with our previous briefing, we encourage those working in universities, pharmaceuticals, and other research institutions, to help share this document when contacting or responding to journalists about research stories relating to their institution. By attaching this background briefing to proactive stories, or reactive statements, it can help ensure that your research is understood within the context of the wider research environment.

We permit anyone to redistribute this briefing providing it remain unchanged, and in whole, with credit to Speaking of Research.

We would like to produce more of these for different countries in the future, to add to our American and Canadian briefings. Those wishing to see a similar briefing for the UK should consult the Science Media Centre’s “Briefing Notes on the Use of Animals in Research”. We thank the Science Media Centre for offering their support in producing our briefings.

Speaking of Research

To learn more about the role of animal research in advancing human and veterinary medicine, and the threat posed to this progress by the animal rights lobby, follow us on Facebook or Twitter.

This post by Dr. Kausik Datta, a biomedical researcher in immunology, was originally posted on his SciLogs blog, In Scientio Veritas. In it he looks at some of the scientific quotes used by PETA to defend their position, and finds that all of them have been taken out of context to misrepresent the position of the original researcher.

I work with immunology of infectious disease and study host-pathogen response. My work has naturally involved a good amount of animal experimentation, especially mouse models of various infections. These mouse models are incredibly useful, because they offer a valuable window into the process of infection, pathogenesis (‘disease production’), and the kind of immune response a vertebrate mammal generates to the infection. The same broad reasoning applies to rodent models of various metabolic and endocrine diseases, as well as cancer. These models are attractive because most often these research animals are genetically homogenous, and therefore, provide a less complex (and more manageable) environment to study the genesis, as well as treatments, of a disease – while mimicking much of the same physiological responses seen in larger and more complex animals.

Ironically, the lower complexity has also been the main argument against over-reliance on animal research. Not all the results seen in the animal models directly translate to human beings, who are physiologically and genetically more diverse and complex. But regardless of immediate translatability of observations, these results always offer crucial and pertinent clues about the disease process, and therefore, are seen as valuable stepping-stones for the journey towards bringing cures to both humans and animals alike. (Yes, an oft-forgotten aspect of animal research is that the results benefit animals, too.)

For example, studies in the lowly fruit-fly (Drosophila) revealed a protein called Toll which is essential for the fly’s immunity to fungal infections. And lo and behold! Various vertebrates (humans and other animals) as well as invertebrates were found to have a collection of very similar proteins, called Toll-like receptors, which are engaged in protecting the body against various infections. Another example is that of the Simian immunodeficiency virus (SIV), a close cousin of HIV; SIV does not affect humans, but depending upon the species, it does cause a disease (simian AIDS, or SAIDS) that is very similar to AIDS in the humans, and chimpanzees in the wild have died from SAIDS. Not only has SIV provided important indications as to how HIV may work, vaccine research against SIV has been able to generate a successful treatment for infected Rhesus monkeys. At the same time, studies in Bonobos are on to find out how they seem to be impervious to SIV’s effects.

These advances would not have come without animal experimentation. This is important to understand. Yes, we don’t yet have a successful vaccine against HIV, but then, HIV has unique characteristics which allow it to evade immunity, hide and survive in the body. The clues obtained from animal as well as human research will continue to provide directions for humankind’s fight to eradicate this dreaded scourge.

The mindlessly agenda-driven organizations like PeTA know this. That’s why, in order to peddle their anti-science, anti-research agenda, they take recourse to outright lies, misrepresentations of the research and people who are engaged therein, as well as using quotes from well-known people in a way that appears to suggest their consonance with the PeTA agenda. However, there is an important aspect to it; credit where due, PeTA has long understood, and successfully exploited, the power of visual imagery. As with their celebrity endorsements across many countries, not to mention their objectification of women, PeTA continues to create visual campaigns – ‘memes’ – for television, internet, as well as billboards, projecting the same lies and misrepresentations, and playing fast-and-loose with the truth, in order to propagate their agenda.

And they have been immensely successful, because these memes, regardless of their lack of veracity, don’t die. PeTA takes care to put images – as gruesome as they can find, and those which would seem horrifying when seen in absence of any context – with their anti-science, anti-research memes, and those images stick with people. As a result, well-intentioned but gullible folks keep foolishly spreading those memes, and now with the power of social media, they reach far and wide, wreaking immeasurable havoc with the public understanding of science and the need for animal experimentation, and making the researchers the villains of these pieces.

One appeared on my Facebook feed this morning. This one is from a 2013 PeTA blog post, purportedly providing “8 reasons why animal testing doesn’t help humans”. In line with PeTA’s usual memes, it has distress-inducing images of cute animals being experimented upon. The images are accompanied by a slew of quotes from “esteemed scientists, government officials, and doctors” (a veritable paean to the Argument from Authority fallacy), which appear to bolster PeTA’s position on animal experimentation; however, as you will see, not all are what they seem at the first glance.

I shall spare you the gruesome images, dear reader; if you must look at them, you can click on the above-mentioned link to the PeTA blog post and see for yourself. I have, instead, chosen to use the text of the specific quotes that PeTA presented on those images, and made the effort to hunt down the sources (because, of course, PeTA doesn’t provide references) of those quotes. What I discovered was most revealing, and I present them below.

“Traditional animal testing is expensive, time-consuming, uses a lot of animals and from a scientific perspective the results do not necessarily translate to humans.” — Dr. Christopher P. Austin, director of NIH Chemical Genomics Center.

EXCEPT that this quote – found in a 2008 report in The Telegraph UK – was intended EXCLUSIVELY for the context of toxicological testing. Austin also said, “It’s a bold, ambitious thing to try to do but our goal is to eliminate animal use in toxicology in ten years” — a laudable goal in itself. He was speaking in terms of a high-throughput screening system involving various animal cell-types, in which the toxicity studies could be done for thousands of chemical substances at one go. The availability of this technology is a great achievement, but it is important to remember that this can be done because the measurable outcomes of toxicity studies, especially toxic effects on a given cell, are reasonably straightforward, as well as local, and don’t require the use of a whole animal, unless the effects of the toxicity are more global and complicated in nature. These animal-free screens can be employed gainfully to test toxicities of environmental toxins, as well as personal care products.

You can read and hear Dr. Austin’s own words in this description of a collaborative governmental effort to move toxicity studies to an animal-free system, while recognizing the tremendously valuable contribution that animal testing has made towards identifying many toxins dangerous to human and animal health.

It is also important to understand that this particular technology is a result of the constant effort by scientists under the guiding principles of 3Rs – reduction, refinement, replacement – for animal-based research. In situations such as ordinary toxicity studies, where the technology allows us not use animals but get meaningful results, we should absolutely, wholeheartedly adopt them. This has long been the stance of animal-researchers, which is something PeTA deliberately chooses to ignore and obfuscate.

“The history of cancer research has been a history of curing cancer in the mouse. We have cured mice of cancer for decades and it simply didn’t work in humans.” — Dr. Richard Klausner, former director of the National Cancer Institute.

EXCEPT that this quote – lifted from a 1998 Los Angeles Times feature – was meant as a comment on the pleas made by desperate cancer patients for new cures to be tried, whenever researchers published (and the media jumped upon) some study looking at the potential for some chemical substances, including those isolated from natural substances (such as garlic), to modulate the changes in cells that lead to cancer. PeTA’s use of this quote deliberately obscures the fact that many such substances are primarily tried upon static cells in cultures (something that PeTA favors as an ‘animal alternative’ method), where either they don’t show adequate effects, or their effects cannot be translated to complex organisms because of many different factors.

Tumorigenesis is complex process involving many cells in a given environment, and it is often not possible to mimic that environment appropriately in an ex vivo, animal-free, cell-based system. Positive results found in animal experiments in cancer are not the be all, end all in themselves. But they provide the scientific basis based on which human experiments and trials for new therapeutic modalities can be conceived; they engender hope. It is downright cruel of organizations like PeTA to attempt to take that important aspect from cancer patients.

“Prevention [of polio] was long delayed by the erroneous conception of the nature of the human disease based on misleading experimental models of the disease in monkeys.” — Dr. Albert Sabin, developer of the oral polio vaccine.

EXCEPT that this single phrase by Dr. Sabin – said in 1984 during a Congressional testimony and used by organizations like PeTA to signify his opposition to the use of animals in research – did not at all represent his complete position in this regard. In a letter written in 1992, Dr. Sabin stated unequivocally:

“… my own experience of more than 60 years in biomedical research amply demonstrated that without the use of animals and of human beings, it would have been impossible to acquire the important knowledge needed to prevent much suffering and premature death not only among humans but also among animals.”

Do read more about Dr. Sabin’s and others’ lifelong association with animal research for finding cures for dreaded diseases that afflict both humans and animals in this 2011 post in the Speaking of Research blog.

“Mice are mice, and people are people. If we look to the mouse to model every aspect of the disease for man, and to model cures, we are just wasting our time.” — Dr. Clif Barry, chief Tuberculosis Research section, National Institute of Allergy and Infectious Disease.

EXCEPT that this quote – lifted from a 2011 Slate feature – has been modified by PeTA to omit the first part. The COMPLETE quote said, “The truth is that for some questions, mice give you a very nice and easy model system for understanding what’s happening in humans, but mice are mice, and people are people. If we look to the mouse to model every aspect of the disease for man, and to model cures, we’re just wasting our time.“.

The duplicity of PeTA in cherry-picking quotes apparent to you, yet?

The feature article does mention the background for this comment by Dr. Clifton Barry: the form of tuberculosis that mice get is different from the form humans get, and that is because of differences inherent in their respective immune systems. While this has restricted the efficacy of some tuberculosis studies in a rodent model, there is no doubt that this knowledge of differences in immune system was important to have, because it provided valuable clues to the differences in the disease process between mice and humans. The same article provides an instance where the indications from the mouse studies were crucial in figuring out why a specific immune-treatment failed spectacularly in human beings.

Most scientists who work with animal models are not blind to their shortcomings, which is a reason why tuberculosis research, for example, has progressed from rodents to primates to zebra-fish. Animal models can help answer specific questions, and each such answer contributes to the overall understanding of a disease, its progression, as well as its treatment. Research in nine-banded armadillos showed that aside from humans, these animals are the only natural hosts of the leprosy bacteria, which are difficult to grow in in vitro culture; the knowledge gained during his work with isolating leprosy bacteria DNA from armadillos allowed the legendary tuberculosis researcher Bill Jacobs to transport the same techniques to the study of the tuberculosis bacteria, and make a fluorescent TB bug which glows under the microscope, allowing researchers to immediately see if a drug is effective on the bug or not.

“Currently, nine out of ten experimental drugs fail in clinical studies because we cannot accurately predict how they will behave in people based on laboratory and animal studies.” — Michael O. Leavitt, former secretary for the US department of Health and Human Services.

EXCEPT that this quote – lifted from a 2006 FDA Press Announcement – pertained to a COMPLETELY DIFFERENT CONTEXT; the second part of the quote, which PeTA obscured, said, “The recommendations announced today will help more researchers conduct earlier, more-informed studies of promising treatments so patients have more rapid access to safer and more effective drugs.“

In this announcement, FDA was offering specific approaches for performing appropriate safety-testing with small amounts of investigational new drugs in people, which would improve and hasten the process of getting safe and effective drugs to people. This was not a commentary on the pre-clinical testing – both in vitro and animal studies – that must be done in order to show efficacy before taking the drug to the next higher level, for testing in human subjects. This announcement also pertained particularly to serious and life-threatening conditions, such as cancer, heart disease and neurological disorders, for which there was (and still is) an extreme demand with non-commensurate supply, and the traditional timeline from drug-design to marketing, along with the existing regulatory requirements, was considered too long and burdensome to provide benefit to the patients.

I hope you can understand, dear reader, how knowing the context changes the import of these quotes, cherry-picked by PeTA with deliberate dishonesty. Why they do this? I have no clue. For a better understanding how the presentation of facts outside of their contexts can skew the readers’ perception of the idea surrounding those facts, do read this 2013 post in the Speaking of Research blog.

“[Researchers] are so ingrained in trying to cure mice that they forget that we’re trying to cure humans.” — Dr. Ronald W. Davis, Stanford University.

EXCEPT that this quote – lifted from a New York Times highlight of a study published in 2013 in the Proceedings of the National Academy of Sciences, USA – doesn’t provide the context, which pertained exclusively to the study of sepsis. It also doesn’t indicate that this crucial study comparing human and animal models, of which Dr. Davis was a lead author, was the first to figure out that mice used different groups of genes to deal with acute conditions such as burns, trauma and sepsis, whereas humans use a similar genes for all three. While this work highlighted the need to use human cells in order to study human sepsis, the condition and its treatment, in no way does it diminish the importance of the discovery that mice use different genes for these conditions, and that there is a difference between mice and human subjects in this regard.

“Patients have been too patient with basic research. Most of our best people work in lab animals. Not people. But this has not resulted in cures or even significantly helped most patients.” — Dr. Ralph Steinman, Immunologist at Rockefeller University.

EXCEPT that Dr. Steinman made this comment in a COMPLETELY DIFFERENT CONTEXT. In 2002, Steinman wrote in the journal Cerebrum about the crucial need for training more physician-scientists, scientists who are trained as physicians, and are able to bring that perspective to scientific and clinical research; the lack of such physician-scientists, he considered, was the reason why there was a failure to “maintain a crucial transmission belt between basic research and clinical applications” and why “potential benefits [of basic research] for treating serious illnesses [were] taking too long to reach patients”, even if the basic research, with animal experimentation, has been immensely productive. In absence of properly-trained physician-scientists, he wrote, “We risk being able to treat models of diseases such as multiple sclerosis (MS), cancer, and depression in rats and mice, but not having enough scientists, expertise, or funding to test much of this critical work on humans in a timely fashion”.

Giving examples of his own research from more than two decades ago, Steinman described how animal experiments helped him identify an important component of cellular immunity in the body. He lamented that this knowledge needed to be applied appropriately in human populations, in order to further our understanding of the immune process and diseases, in order to accomplish which more physician-scientists were needed.

Puts quite a different perspective, doesn’t it, on that Steinman quote, cherry-picked by PeTA and placed out of context to further their own anti-science agenda?

“We have moved away from studying human disease in humans. We all drank the kool-aid on that one, me included. The problem is that it hasn’t worked, and it’s time we stopped dancing around the problem… We need to refocus and adapt new methodologies for use in humans to understand disease biology in humans.” — Elias Zerhouni, former director of the National Institutes of Health.

EXCEPT that this quote – gleaned from Dr. Zerhouni’s 2013 lecture at the NIH – is, again, NOT the complete quote, which is (from the link):

“We have moved away from studying human disease in humans,” he lamented. “We all drank the Kool-Aid on that one, me included.” With the ability to knock in or knock out any gene in a mouse — which “can’t sue us,” Zerhouni quipped — researchers have over-relied on animal data. “The problem is that it hasn’t worked, and it’s time we stopped dancing around the problem… We need to refocus and adapt new methodologies for use in humans to understand disease biology in humans.” — Note how the complete quote mentions the specific context of the ability of performing genetic manipulation relatively easily in mice, which in his opinion has led the researchers to rely over-much on animal model data?

Without a doubt, there is an important lesson to learn and remember. The relative ease of working with animal models and the ability to answer specific, directed questions with these models have sometimes swayed some researchers away from the bigger picture, the ultimate goal of delivering a cure to the patients who need them. However, it is basic science research, utilizing the animal models precisely for those reasons, which makes the seminal contributions to the understanding of disease mechanisms; animal models are necessary, and they complement well the knowledge gained from other, equally necessary, non-animal based models as appropriate, such as cell-culture, computer simulations, and the ultimate test, human trials. When asked to clarify his remarks, Dr. Zerhouni said as much; he wrote:

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

Do read the whole response from Dr. Zerhouni and the relevant discussion regarding animal experimentation in this 2014 post in the Speaking of Research blog. Not the kind of nuance you’d find in a PeTA screed, is it?

I have earlier written about this opposition of animal research from PeTA, and how such mindless opposition actively harms the cause of biomedical research that benefits both people and animals. If PeTA and their ilk did indeed have solid arguments to present in support of their position, why all these lies, misrepresentations, subterfuge, cloak-and-dagger stage-show? In view of this, I must again ask, who really benefits from this stance of PeTA, if not PeTA’s coffers?

Dr. Kausik Datta

To learn more about the role of animal research in advancing human and veterinary medicine, and the threat posed to this progress by the animal rights lobby, follow us on Facebook or Twitter.

When Speaking of Research first started we had a wonderful leaflet which was produced for us by Americans for Medical Progress. In the following six years, Speaking of Research has changed and evolved and as such we have been long overdue for a new leaflet, which we can now unveil.

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Tonight, if everything goes according to plan, a young person will stand up in front of a global audience numbering in the hundreds of millions, walk a few paces, and kick a football.  This by itself may not seem remarkable, after all this is the opening ceremony of the World Cup, but for the Miguel Nicolelis and the more than 100 scientists on the Walk Again project – and the millions watching from around the world – this will mark the triumph of hope and dedication against adversity, for the young person in question is paraplegic.

Image: Miguel Nicolelis

The exoskeleton that is being used in this demonstration is a formidable technological achievement, collecting nerve signals from non-invasive EEG electrodes placed on the scalp of the operator, and converts these into commands for the exoskeleton, while sensors on the operators feet detect when they make contact with the ground and send a signal to a vibrating device sewn into the forearm of the wearer’s shirt. This feedback, which has never been incorporated into an exoskeleton before, allows the operator to control the motion of the exoskeleton more precisely. While this is not the first EEG controlled exoskeleton to be tested by paraplegic individuals, videos released by the Walk Again suggest that it has allows for far quicker and more fluent movement than existing models.

A late substitution

What many viewers may not know is that the use of EEG (Electroencephalography) was not part of Miguel Nicolelis’ original plan, as late as spring 2013 he was planning to use an alternative technology, implanted microelectrode grids within the cerebral cortex of the operator. Unfortunately about a year ago it became clear that the implant technology he was developing would not be ready for use in humans in time to meet the deadline of the opening ceremony of the 2014 FIFA World Cup, so the team had to fall back on the more established technique of EEG.

Is this an issue? Well, to understand this you first have to know a little about the two approaches.

EEG is a very mature technology. Its development dates back to 1875 when Richard Caton observed electrical impulses on the surface of the brains of rabbits and monkeys. In 1912 Vladimir Pravdich-Neminsky published the first EEG in dogs, and in 1924 the first EEG in human subjects was recorded by Hans Berger. It has the advantage that it doesn’t require surgery, but also serious disadvantages. The main disadvantage is that it records the combined signals from millions of neurons across wide areas of the cortex simultaneously, and this makes it difficult to separate out the signal from the noise. By contrast microclectrode implants record the individual signals from just a few neurons.

A common analogy is that EEG records the sound made by the whole orchestra, whereas microelectrode implants record individual instruments.  The result is that EEG can only be used to give relatively simple commands “move leg forward” “back” “stop” “kick” and requires a great deal of concentration by the operator. It is unlikely that the performance cam be improved upon very much. By contrast the microelectrode implants, while requiring invasive surgery, have the potential to enable much finer control over movement.

A pioneer of brain implant technology

There is no doubt that for over a decade Miguel Nicolelis and his colleagues at the Duke University Center for Neuroengineering have been among a very select group of scientists at the forefront of brain implant research, demonstrating that implanted electrodes could be used to control a simple robotic arm in rats in 1999 and in monkeys in 2000 (1). In 2012 Nicolelis highlighted the importance of animal studies to progress in the field in an article for Scientific American:

The project builds on nearly two decades of pioneering work on brain-machine interfaces at Duke—research that itself grew out of studies dating back to the 1960s, when scientists first attempted to tap into animal brains to see if a neural signal could be fed into a computer and thereby prompt a command to initiate motion in a mechanical device. Back in 1990 and throughout the first decade of this century, my Duke colleagues and I pioneered a method through which the brains of both rats and monkeys could be implanted with hundreds of hair-thin and flexible sensors, known as microwires. Over the past two decades we have shown that, once implanted, the flexible electrical prongs can detect minute electrical signals, or action potentials, generated by hundreds of individual neurons distributed throughout the animals’ frontal and parietal cortices—the regions that define a vast brain circuit responsible for the generation of voluntary movements.”

In 2008 the Duke University team showed that microelectrode arrays implanted in the cortex could be used record the neuron activity that controls the actions of leg muscles (2), and that this could be used to control the movements of robotic legs.

It was this that spurred Nicolelis to try to develop a mind-controlled exoskeleton that would be demonstrated at the World Cup opening ceremony.

Brain Machine Interfaces – from monkeys to humans.

So, if brain implant technology to control an exoskeleton wasn’t ready for 2014, when will it be ready?

The answer is probably very soon, as this approach has already been demonstrated successfully in humans.

In 2008 we discussed how Andy Schwartz and colleagues at the University of Pittsburgh had succeeded in developing a brain-machine interface system where microelectrode arrays implanted in the motor cortex of macaque monkeys allowed them to control the movement of a robotic arm with a degree of dexterity that surprised even the scientists conducting the study.

Then in 2012 we reported that Jan Scheuermann, quadraplegic for over a decade due to a spinal  degenerative disease, was able to feed herself with the help of two intracortical microelectrode arrays developed by the University of Pittsburgh team.

What happens now?

Tonight’s demonstration will mark the culmination of an extraordinary year-long effort by scientists and patients, but it also marks the public debut of a revolution in brain machine interface technology that has been gathering pace over the past decade, largely unnoticed by the mass media.

Miguel Nicolelis has come in for some heavy criticism for the cost of the Walk Again project, and for raising hopes too high, but the criticism is largely unfair. His team set themselves an extraordinarily ambitions target, and that they have fallen a little short is understandable. Once they have recovered from their exertions they will no doubt set to integrating the exoskeleton technology that they have developed with the implant technology that they are developing back in the lab at Duke University.

And that technology is increasingly impressive, more advanced implant systems that allow monkeys to simultaneously control two virtual arms, microelectrode arrays that allow signals from almost 2,000 individual neurons to be recorded simultaneously (3) (in contrast the already very capable BrainGate implant system used by the University of Pittsburgh team records from less than 100 individual neurons) potentially allowing for much more subtle and delicate control, and interfaces that will allow sensory information from prosthetics to be transmitted directly into the brain. We will certainly be hearing from Miguel Nicolelis and his colleagues at Duke – and their colleagues and competitors around the world - again very soon.

So tonight, as you watch the opening ceremony, remember this; for Brain Machine Interface technology as much as for the World Cup itself, this is just the warm up!

Paul Browne

p.s. And of course BMI controlled robotic exoskeletons are just one promising technology under development to help paralysed people, stem cell therapy, epidural stimulation and intraspinal microstimulation have all delivered impressive results in recent studies.

1) Wessberg J, Stambaugh CR, Kralik JD, Beck PD, Laubach M, Chapin JK, Kim J, Biggs SJ, Srinivasan MA, Nicolelis MA. “Real-time prediction of hand trajectory by ensembles of cortical neurons in primates.” Nature. 2000 Nov 16;408(6810):361-5.

2) Fitzsimmons NA, Lebedev MA, Peikon ID, Nicolelis MA. “Extracting kinematic parameters for monkey bipedal walking from cortical neuronal ensemble activity.” Front Integr Neurosci. 2009 Mar 9;3:3. doi: 10.3389/neuro.07.003.2009. eCollection 2009.

3) Schwarz DA, Lebedev MA, Hanson TL, Dimitrov DF, Lehew G, Meloy J, Rajangam S, Subramanian V, Ifft PJ, Li Z, Ramakrishnan A, Tate A, Zhuang KZ, Nicolelis MA.”Chronic, wireless recordings of large-scale brain activity in freely moving rhesus monkeys.” Nat Methods. 2014 Jun;11(6):670-6. doi: 10.1038/nmeth.2936.

To learn more about the role of animal research in advancing human and veterinary medicine, and the threat posed to this progress by the animal rights lobby, follow us on Facebook or Twitter.

The industry magazine Lab Animal occasionally reviews websites applicable to it’s readers. Earlier this year, they reviewed the Speaking of Research website. The article does a good job of relaying the history behind how Speaking of Research began and some background on the people involved. They also note that SR does a lot of reporting on situations with animal extremists in Europe and North America.

The reviewer goes through each section of the website giving their readership the basic idea behind each of the sections and points out a few of the more interesting items beyond just news items, including games, quizzes and an article on Gorgon aliens.

In reviewing our “AR Undone” section (now called “Animal Rights Pseudoscience”), which responds to 19 common myths used by animal rights groups, the reviewer described SR’s responses as “authoritative, heavily references and, in some cases, linked to other websites and documents.”

“This is an excellent, informative site … It’s a must read for any animal researcher.”

The Speaking of Research website is then graded on content, appearance and usability, receiving the maximum of five out of five paws in each category.

Read the full article

We are very pleased to have received such high marks from Lab Animal and truly appreciate the review.

Pamela

We have written thousands of tweets about animal research since we opened our accounts a little over five years ago. Now we want you to help us spread our Twitter messages.

We have created a list of short, tweet-able, facts on our new “Arguments For Animal Research” page. Each fact is followed by a “Tweet This” button which will automatically open your Twitter status page, with the tweet ready to go – all you have to do is press Tweet.

Clicking the Tweet this button will bring in up page like this

These short facts were inspired by Understanding Animal Research’s successful page entitled “40 reasons why we need animals for research”. While our list is currently limited to 29 facts, we hope to continue to add to our list until we surpass even UAR’s impressive list.

Have you got ideas for some more tweetable facts? Tell us in the comments below. They need to be 102 characters (including spaces) so that we can fit a link back to the page and our Twitter after it.

Remember to shout “For Science!” when clicking the Tweet this button. Cartoon by Saturday Morning Breakfast Cereal

So, for science, it is time to get tweeting and make sure those around you know the important role that animals play in medical research. Perhaps try to post a pro-research message each week on Twitter.

Speaking of Research

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

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

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

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

Animal rights activists agreed, saying:

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

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

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

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

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

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

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

Statement from Psychologists:

Harlow’s career spanned 40+ years and produced breakthroughs in understanding learning, memory, cognition and behavior in monkeys¹ (see Figure 1). In a time period where other animals were generally thought of as dumb machines, Harlow’s work demonstrated the opposite — that monkeys, like humans, have complex cognitive abilities and emotional attachments. Harlow and his colleagues developed now classic ways to measure cognition^2,3. For example, the Wisconsin General Test Apparatus (WGTA; see Figure 1), in which monkeys uncover food beneath different types of colored toys and objects, allowed scientists to understand how monkeys learn new things, remember, and discriminate between different colors, shapes, quantities, and patterns.

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

Figure 1

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

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

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

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

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

Looking back while moving forward

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

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

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

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

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

Allyson J. Bennett, PhD

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

¹  Suomi SJ & Leroy, HA (1982) In Memoriam: Harry F. Harlow (1905-1982). American Journal of Primatology 2:319-342. (Note: contains a complete bibliography of Harlow’s published work.)

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

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

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

Antibodies Part 1

There has been considerable discussion on this website about the use of animal studies to develop new medical treatments. But some animal-derived products such as antibodies also play a crucial role in diagnostic tests for some diseases and targeted treatments for others. In the last week, antibodies hit the front pages of newspapers and websites with the news that the ZMapp serum given to 2 Americans aid workers stricken with the deadly Ebola virus was a cocktail of antibodies. Developed through research in mice, the two components of this experimental serum – ZMab and  MB-003 – had only previously been tried in monkeys, but the results were very promising. As of this writing, both aid workers’ conditions had improved.

Antibodies are proteins the immune system produces to identify and neutralize foreign objects such as bacteria and viruses. Antibodies “recognize” specific proteins, a property that makes them highly useful for a variety of purposes. For instance, antibodies can be used in diagnostic tests to determine whether a protein associated with a particular disease or medical condition is present in a patient’s blood, urine, saliva, or tissues. The home pregnancy test is an example of a diagnostic test that relies on antibodies. These tests detect the hormone human chorionic gonadotropin, a protein that is only present during pregnancy.  Many other medical tests also utilize antibodies; a few examples are:

1. Tests to look for heart proteins in the blood such as troponin that indicate that a heart attack has occurred.
2. Tests for the presence of the HIV (AIDS) virus in the blood.
3. Tests for proteins present in the blood of patients with Lupus, an autoimmune disease where the immune system attacks the body’s own tissues.

A diagram showing the characteristic Y shape of an antibody molecule. It is able to grab two of its target molecules with the ends of the two arms of the Y.

Antibodies can also be used to treat disease. Certain antibodies can neutralize toxins such as snake venom.  Other antibodies are coupled to a toxin or other chemical, such that it is delivered only to cells carrying the protein that antibody recognizes.  For example, some cancer cells generate unique proteins so antibody-coupled drugs can be used to deliver a toxic agent to the cancer cells without harming other cells in the body. Antibody therapies have been effective in treating a number of types of cancer, including Hodgkin lymphoma and non-Hodgkin lymphoma, some forms of skin cancer, and some forms of breast cancer. Now we learn that antibodies may also be effective in treating Ebola.

Unique cell surface proteins on a cancer cell, which can be detected using antibodies.

There are two types of antibodies used for medical diagnostics and treatments: polyclonal antibodies and monoclonal antibodies. Both require animals in their production.

Polyclonal antibodies are produced by injecting the protein of interest (or part of it, called an antigen) into an animal.   Since this is a foreign substance, the animal’s immune system reacts to it by generating antibodies to fight off the intruder. Later, samples of the animal’s blood are removed and the antibodies isolated. Larger animals such as sheep, goats, and rabbits are often used for antibody production because they have enough blood in their bodies that large blood samples can be removed without harming them. Antibodies generated using this method are called “polyclonal,” because they came from many different immune cells known as B cells or B-lymphocytes.

Process for producing polyclonal antibodies

To produce monoclonal antibodies, an animal (often a mouse) is injected with the partial protein or antigen of interest. Antibody-producing cells are later isolated from the animal, often from its spleen. Fast-growing but harmless tumor cells are cultivated in the lab and fused with the isolated antibody-producing cells. This produces a new cell type called a hybridoma that can be grown in the lab. Once it is confirmed that the hybridomas are generating antibodies against the right antigen, these hybrid cells can serve as factories to grow large numbers of pure monoclonal antibodies in the lab.

Monoclonal antibody production process

Alice Ra’anan and Bill Yates

To learn more about the role of animal research in advancing human and veterinary medicine, and the threat posed to this progress by the animal rights lobby, follow us on Facebook or Twitter.

Health research with nonhuman primates takes place at many universities and research institutions in the US, among them centers funded by the National Institutes of Health (NIH).  A broad range of research aimed at better understanding maternal and child health takes place at these centers and depends, in part, upon humane, ethical scientific studies of infant monkeys.

A sample of the research areas and findings are highlighted below and provide a view of the value of developmental research. What even a short list shows is that the scope of scientific and medical research that informs pediatric health issues is large. It ranges from autism to childhood diabetes to leukemia to mental health to stem cell therapies.

Together, the findings from studies of infant monkeys have resulted in a better understanding of prenatal, infant, child, and maternal health. The scientific research has resulted in basic discoveries that are the foundation for a wide range of clinical applications and have also improved outcomes for premature and critically ill human infants.

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

Studies of monkeys are a tiny fraction of all animal studies and are only conducted when studies of fish, mice, rats, or other animals are not sufficient to address the scientific question. Like all nonhuman animal studies, those of young monkeys are subject to rigorous ethical evaluation by scientists, by federal review panels, and institutional review boards that include veterinarians and members of the public.

The decision to conduct a study in nonhuman animals is one that rests on weighing both the potential benefit the work may provide and any potential for harm. The research below provides many specific examples of how and why the studies are conducted and their benefit. For each and every study, scientists, review panels, and ethics boards also consider the potential for harm that may result to the nonhuman animals that are involved. Whether there are any alternatives to the animal study is a requirement of the US system for ethical review and oversight. If there is no alternative, reduction in potential for harm is explicitly addressed not only by a set of standards for animal care, housing, handling, environmental enrichment, and medical care, but also by including only the number of animals needed to answer the scientific question. (You can read more about the review process, regulation, and care standards here and here).

Like other studies of nonhuman animals, those in young animals require serious and fact-informed ethical consideration. At the most fundamental level they challenge us to evaluate how we should balance work that ultimately can help children, the harm that may result from a failure to act, potential harm to animals in research. Consideration of how to balance the interests of children, society, and other animals is not an easy task. Nor is it one that is well-served by simple formulations.

Primate studies of early development have, and continue, to contribute valuable new insights and discoveries that improve the health and lives of many.  The examples below, from NIH-funded research programs across the US, demonstrate how the work contributes to public health.

Sources:  National Primate Research Centers Outreach Consortium. For more information about the NPRCs, see:  http://dpcpsi.nih.gov/orip/cm/primate_resources_researchers#centers

EXAMPLES OF PEDIATRIC RESEARCH WITH MONKEYS

Autism

• In a major advance, California National Primate Research Center (CNPRC) research defined a link between maternal auto-antibodies and increased risk of a child having autism (http://www.cnprc.ucdavis.edu/maternal-antibodies-linked-to-autism/)
• Research at the CNPRC has focused on oxytocin and vasopressin in social bonding and male parental care, as well as on the effects of early experiences on the development of these behaviors. Studies have begun on the long-term effects of oxytocin; a new treatment is already being used in children with autism without an understanding of the long-term effects. (http://www.cnprc.ucdavis.edu/unknown-effects-of-long-term-oxytocin-use-in-children/)

Cerebral Palsy

• One outcome of premature birth and accompanying brain injury can be Cerebral Palsy (CP). To date, studies at the Washington National Primate Research Center’s (WaNPRC) Infant Primate Research Laboratory (IPRL) have described the metabolome of normal birth and discovered new acute biomarkers of acute hypoxia‐ This multi‐modal approach will increase the likelihood of identifying reliable biomarkers to diagnose the degree of injury and improve prognosis by tracking the response to treatment after neonatal brain injury. (http://www.ncbi.nlm.nih.gov/pubmed/22391633, http://www.ncbi.nlm.nih.gov/pubmed/21353677)

Childhood Leukemia

• Wisconsin National Primate Research Center (WNPRC) scientists James Thomson and Igor Slukvin turned diseased cells from a leukemia patient into pluripotent stem cells, providing a way to study the genetic origins of blood cancers as well as the ability to grow unlimited cells for testing new drugs for chronic myeloid leukemia, childhood leukemia and other blood cancers. (http://www.news.wisc.edu/18933 and http://www.ncbi.nlm.nih.gov/pubmed/21296996)

Diabetes and Childhood Obesity

• Normal and obese marmosets were followed by Suzette Tardif at the Southwest National Primate Research Center (SNPRC) from birth to 1 year. At 6 months, obese marmosets already had significantly lower insulin sensitivity and by 12 months, they also had higher fasting glucose, demonstrating that early-onset obesity in marmosets resulted in impaired glucose function, increasing diabetes risk. (http://www.ncbi.nlm.nih.gov/pubmed/23512966)
• Infant marmosets were followed by Suzette Tardif at the SNPRC from birth to 1 year. Feeding phenotypes were determined through the use of behavioral observation, solid food intake trials, and liquid feeding trials. Marmosets found to be obese at 12 months of age started consuming solid food sooner and drank more grams of diet thus indicating that the weaning process is crucial in the development of juvenile obesity in both NHPs and human. (http://www.ncbi.nlm.nih.gov/pubmed/23512878)

Diet

• Studies at the CNPRC have demonstrated that breast and bottle fed infants develop different immune systems, with breast-fed infants retaining a stronger immune system even months after weaning (http://www.cnprc.ucdavis.edu/breast-and-bottle-fed-infant-monkeys-develop-different-immune-system/)
• Work conducted by Martha Neuringer at the Oregon National Primate Research Center (ONPRC) on visual development established the importance for infant nutrition of two nutrients, taurine and omega-3 fatty acids, and led to the addition of these substances to infant formulas worldwide. (http://www.ncbi.nlm.nih.gov/pubmed/8915371, http://www.ncbi.nlm.nih.gov/pubmed/19369246)

Environmental threats

• Understanding lead poisoning effects and development of safe succimer chelation therapy to treat lead poisoning in children was advanced by Harlow Center for Biological Psychology scientist Nellie Laughlin and collaborators. (http://www.ncbi.nlm.nih.gov/pubmed/?term=Laughlin+lead+poisoning+rhesus)
• Prenatal BPA exposure has been shown to alter the fetal lung, oocyte, and mammary gland developmentin CNPRC studies (http://www.cnprc.ucdavis.edu/bpa-affects-lung-development/) (http://www.cnprc.ucdavis.edu/bpa-and-female-development/) (http://www.cnprc.ucdavis.edu/bpa-shows-two-generation-effect/)

HIV/AIDS

• Scientists at the CNPRC developed the SIV/rhesus macaque pediatric model of disease, to better understand the pathogenesis of SIV/HIV in neonates and test strategies for immunoprophylaxis and antiviral therapy to prevent infection or slow disease progression. Drug therapies used to prevent the transmission of HIV from mother to infant were developed in nonhuman primate models at the CNPRC, and are now being successfully used in many human populations to protect millions of infants from contracting HIV. (http://www.cnprc.ucdavis.edu/koen-van-rompay/)
• Development of topical vaginal microbicides to prevent babies from contracting HIV from their mothers during delivery was advanced by Eva Rakasz at the WNPRC and her collaborators. Dr. Rakasz was also a member of the National Institutes of Health study section, Sexually Transmitted Infections and Topical Microbicides Clinical Research Centers. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3032991/, http://www.who.int/hiv/topics/microbicides/microbicides/en/)
• In a model of mother to child transmission, research at the WaNPRC and the ONPRC has shown that neutralizing antibodies can block infection at high doses and prevent disease and death at lower doses in one-month old monkeys exposed to a chimeric SIV that bears the HIV Envelope protein. Human monoclonal antibodies currently in clinical trials are in testing alone and in combination with drug therapy in this primate model as a less toxic alternative to supplement or supplant drugs in newborns. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2952052/, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3807376/)
• In women who are HIV positive, prenatal consumption of AZT is useful for reducing the risk that the unborn fetus will contract HIV. Research done at the WaNPRC IPRL demonstrated that the effects of AZT on maternal reproduction and infant development were minimal and at the doses studied, no significant adverse health effects from prenatal exposure to AZT were predicted for pregnant women. (http://www.ncbi.nlm.nih.gov/pubmed/23873400, http://www.ncbi.nlm.nih.gov/pubmed/8301525)
• A goal of Yerkes National Primate Research Center (YNPRC) infectious disease researchers is to identify the sources of the latent HIV reservoir so targeted cure strategies can be developed. A first step is to develop a novel model of SIV infection and cART treatment of nonhuman primate (NHP) infants to interrogate the SIV reservoir. The development of such a model will greatly facilitate future studies of SIV reservoirs and the design and testing of novel reservoir-directed therapeutic strategies before scaling to clinical trials in HIV-infected patients.
• YNPRC infectious disease researchers found the percentage of CD4+CCR5+ T cells was significantly lower in all tissues in infant sooty mangabeys (SMs) as compared to infant rhesus macaques (RMs) despite robust levels of CD4+ T cell proliferation in both species. The researchers propose that limited availability of SIV target cells in infant SMs represents a key evolutionary adaptation to reduce the risk of mother-to-infant transmission (MTIT) in SIV-infected SMs. The researchers are applying their findings toward reducing the more than 300,000 cases diagnosed in children each year. (http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1003958)

Huntington’s Disease

• YNPRC researchers have successfully created a transgenic, preclinical animal model of Huntington’s disease (HD). These animals, when followed from infancy to adulthood, show progressive motor and cognitive associated with neural changes similar with the disease patterns seen in humans. Not having such a model has been a major roadblock to developing effective therapies for the disease.
  (http//www.ncbi.nlm.nih.gov/pubmed/18488016; http//www.ncbi.nlm.nih.gov/pubmed/24581271)

Lung Development and Function

• CNPRC research discovered a link between an infant’s temperament and asthma– research is leading towards the screening, prediction and prevention of lung disease in children. (http://www.ncbi.nlm.nih.gov/pubmed/21536834)
• Research at the CNPRC has shown that exposure to high levels of fine particle pollution (e.g. wildfire smoke) adversely affects both development of the immune system and lung function(http://www.cnprc.ucdavis.edu/long-term-impact-of-air-pollutants/)
• Childhood asthma research by the CNPRC focuses on understanding why children are highly susceptible to asthma, with the goal of identifying predictive biomarkers and discovering preventive treatments. These studies use a novel rhesus monkey model of house dust mite sensitization to investigate the pathogenesis of allergic asthma in pediatric and adult asthma. The goal is to define the relationship between pediatric asthma, development of mucosal immunity in the respiratory system, and exposure to the house dust mite allergen. (http://www.ncbi.nlm.nih.gov/pubmed/21819959)
• Eliot Spindel at the ONPRC has shown that large doses of Vitamin C can protect developing lungs from the damage caused when mothers smoke. This work has been duplicated in clinical trials. (http://www.ncbi.nlm.nih.gov/pubmed/15709053)

Kidney Disease, Organ Transplants, Lupus

• WNPRC scientists and surgeons at UW Hospital successfully tested a new compound, mycophenolate mofetil, in combination with other drugs in monkeys and other animals, and then in human patients in the 1990s. Their work has saved the lives of patients needing kidney or other organ transplants. These new therapies have also kept patients with chronic kidney diseases, including lupus nephritis, which strikes many children and teens, from needing transplants. (Hans Sollinger, Folkert Belzer, Stuart Knechtle, others.) (http://www.ncbi.nlm.nih.gov/pubmed/8680054, http://www.ncbi.nlm.nih.gov/pubmed/9706169, http://www.ncbi.nlm.nih.gov/pubmed/8821838

Memory Impairment

• Studies at the YNPRC have provided important clues on the debilitating cognitive deficits resulting from perinatal medial temporal lobe dysfunction. Longitudinal studies with monkeys have provided unique insights into the neural underpinning of memory impairment found in developmental neurological and neuropsychiatric disorders. (http//www.ncbi.nlm.nih.gov/pubmed/2913301; http//www.ncbi.nlm.nih.gov/pubmed/4112569; http//www.ncbi.nlm.nih.gov/pubmed/3804023)

Polycystic Ovary Syndrome

• WNPRC scientist David Abbott has collaborated with physician Dan Dumesic at the Mayo Clinic and others to understand how polycystic ovary syndrome (PCOS) develops prenatally and to help identify better diagnostic tools and treatments for patients with this disease. (http://www.ncbi.nlm.nih.gov/pubmed/19367587, http://www.ncbi.nlm.nih.gov/pubmed/20682841, http://www.ncbi.nlm.nih.gov/pubmed/19966179)

Puberty Disorders

• Neuroendocrine triggers of puberty were discovered and characterized by WNPRC scientist Ei Terasawa. Her body of work, along with that of her collaborator Craig Atwood at UW-Madison, contributed to a medicine called leuprolide acetate, which is used to treat precocious puberty in infants. (http://aging.wisc.edu/pdfs/33.pdf, http://www.ncbi.nlm.nih.gov/pubmed/7648606)

Prenatal and Mental health

• Studies at the WaNPRC IPRL have provided important and therapeutically relevant information on the fetal risk associated with maternal exposure to antiseizure medication in infants born to women who have epilepsy (Phillips & Lockard, 1985, 1993). (http://www.ncbi.nlm.nih.gov/pubmed/23873400)
• Human and animal studies at the SNPRC revealed that the intrauterine environment can predispose offspring to disease in later life. Mark Nijland showed that maternal obesity can program offspring for cardiovascular disease (CVD), diabetes and obesity. This study revealed significant changes in cardiac miRNA expression (known to be affected in human cardiovascular disease) and developmental disorders in the fetuses of obese baboons. (http://www.ncbi.nlm.nih.gov/pubmed/23922128)
• Studies in the WaNPRC IPRL have demonstrated that prenatal exposure to relatively high levels of ethanol (alcohol) was associated with significant changes in the structure of the fetal brain. (http://www.ncbi.nlm.nih.gov/pubmed/23873400)
• Recent findings from nonhuman primates studied by Ned Kalin at the WNPRC suggest that an overactive core circuit in the brain, and its interaction with other specialized circuits, accounts for the variability in symptoms shown by patients with severe anxiety. The ability to identify brain mechanisms underlying the risk during childhood for developing anxiety and depression is critical for establishing novel early-life interventions aimed at preventing the chronic and debilitating outcomes associated with these common illnesses. (http://www.ncbi.nlm.nih.gov/pubmed/23538303, http://www.ncbi.nlm.nih.gov/pubmed/23071305)
• Developmental studies with nonhuman primates at the YNPRC have revealed that neonatal dysfunction of the amygdala, a key brain structure, has long-lasting effects on the typical development of brain circuits that regulate behavioral and neuroendocrine stress, resulting in long-term hyperactivity.  These findings may provide clues on the neural source of HPA axis dysregulation found in autism spectrum disorder, schizophrenia and affective disorders.  (http://www.ncbi.nlm.nih.gov/pubmed/23159012, http://www.ncbi.nlm.nih.gov/pubmed/24986273, http://www.ncbi.nlm.nih.gov/pubmed/25143624)

Preterm Birth and Neonatal Outcomes

• Current research at the ONPRC incorporates studies directed at understanding the mechanisms of parturition, with emphasis on therapeutic interventions for preterm labor associated with reproductive tract infections and the prevention of subsequent adverse neonatal outcomes. Intra-amniotic infection by genital Ureaplasma species is a predominant cause of early preterm birth. Preterm infants often have life-long health complications including chronic lung injury, often leading to asthma and neurodevelopmental disabilities such as cerebral palsy. Research by ONPRC’s Dr. Grigsby has shown that administration of a specific macrolide antibiotic delays preterm birth and reduces the severity of fetal lung injury and most importantly central nervous system injury. Recently Dr. Grigsby has expanded the infant care facilities at the ONPRC with the addition of a specialized intensive care nursery (SCN); this has enabled new research initiatives to expand beyond the maternal-fetal environment to a critical translation point between prenatal and postnatal life. This one-of-a-kind nursery has the look and feel of a human neonatal intensive care unit and supports the cardiopulmonary, (including mechanical ventilation), thermoregulatory, and nutritional needs of prematurely born infants. (http://www.ncbi.nlm.nih.gov/pubmed/23111115, http://www.ncbi.nlm.nih.gov/pubmed/24179112)

Regenerative Medicine

• Studies at the CNPRC have advanced the understanding of developmental timelines in the kidney, and applied these findings to new protocols and tissue engineering approaches to someday regenerate kidneys damaged by obstructive disease. (http://www.ncbi.nlm.nih.gov/pubmed/23997038)

Stem Cells and Gene Therapy:

• The first pluripotent stem cell derived clinical trials to treat childhood blindness are now underway, using stem cell technologies discovered using monkeys first, then humans, by WNPRC scientist James Thomson in the 1990s-2000s. (https://clinicaltrials.gov/ct2/results?term=juvenile+macular+degeneration+stem+cell&Search=Search, http://www.ncbi.nlm.nih.gov/pubmed/18029452, http://www.ncbi.nlm.nih.gov/pubmed/9804556, http://www.ncbi.nlm.nih.gov/pubmed/7544005
• To successfully treat human disease with stem cells, physicians will require safe, reliable, and reproducible measures of engraftment and function of the donor cells. Innovative studies at the CNPRC have revolutionized the ability to monitor stem/progenitor cell transplant efficiency in fetal and infant monkeys, and have used new noninvasive imaging techniques that demonstrated long-term engraftment and safety. (http://www.ncbi.nlm.nih.gov/pubmed/24098579)
• Studies at the CNPRC have proven critical in gaining approval for investigational new drug (IND) applications to the FDA and conducting first-in-human trials of (1) an expressed siRNA in a lentiviral vector for AIDS/lymphoma patients,, and (2) achieving the overall goal of utilizing adeno-associated virus (AAV) expression of human acid alpha-glucosidase in 3 to 14-year-old Pompe patients who have developed ventilator dependence.

Tuberculosis and HIV

• Mycobacterium tuberculosis (Mtb) is the causative agent of human tuberculosis (TB) with an estimated 8.8 million new TB cases and 1.4 million deaths annually. Tuberculosis is the leading cause of death in AIDS patients worldwide but very little is known about early TB infection or TB/HIV co-infection in infants. SNPRC scientist Marie-Claire Gauduin and colleagues have successfully established an aerosol newborn/infant model in nonhuman primates (NHPs) that mimics clinical and bacteriological characteristics of Mtb infection as seen in human newborns/infants. Aerosol versus intra broncho-alveolar Mtb infection was studied. After infection, specific lesions and cellular responses correlated with early Mtb lesions seen on thoracic radiographs were observed. This model will also allow the establishment of a TB coinfection model of pediatric AIDS. (http://www.ncbi.nlm.nih.gov/pubmed/24388650)

Today’s guest post  is by Dr. Cindy Buckmaster, chair of Americans for Medical Progress.

Activists at the Beagle Freedom Project (BFP) continue to gather support for their agenda to end animal-based research – and some in the research community are unknowingly helping them.

Many of you have seen recent TV news items or read news articles that feature beagles said to have been saved from laboratories where they never had a toy, played with other dogs, or experienced kindness and love from people in research settings. The Beagle Freedom Project uses the limitations of the news media to create this one-sided and false impression of the lives of research dogs.

Individuals at research institutions interested in rehoming post-study animals are approached by adopters representing themselves as private citizens, eager to adopt dogs retired from research. These applicants don’t indicate that they are working with the Beagle Freedom Project. We know of several institutions that have fallen prey to this misrepresentation by the BFP: within days of adoption, their freely released animals are listed as ‘rescued’ by BFP, along with the activists’ usual anti-research propaganda.

As Chair of the Board of Directors of Americans for Medical Progress, as well as an animal lover and someone who directs an animal care program for a major research center in the US, I would like to tell you the real story.

Beagle in research

These dogs are NOT ‘rescued’ from research facilities. They’re voluntarily released by the lab animal caregivers who love and cherish them. Research institutions have been rehoming dogs for years, over forty in some cases, without ‘help’ from the Beagle Freedom Project.  That’s how BFP acquired these dogs to begin with: they adopted them from research animal caregivers who were fooled into believing that the adopters’ only intention was to provide research dogs with a good home. The truth is that these dogs were adopted for use as props to support an animal rights agenda that is harmful to public health and safety.

Readers should be aware that BFP is led by animal rights activists, including Kevin Chase (formerly Kevin Kjonaas) who was convicted and served several years in prison for violating the Animal Enterprise Protection Act. Kevin Kjonaas is the Director of Operations of BFP. The Founder and President of BFP is Shannon Keith. Ms. Keith was one of Kevin’s defense attorneys during his domestic terrorism trial. She also produced and directed “Behind the Mask”, a film released in 2006 that glorifies the Animal Liberation Front, a group known for illegal animal rights activity.

The bottom line is this: BFP personnel and associates misrepresent their intentions to the research institutions they target and then deceive the public about the condition and treatment of dogs in research. Why? To demonize the scientific quest for cures that you and I demand.

The welfare and well-being of research animals and our animal care programs are inspected and evaluated by local and federal authorities multiple times per year. Moreover, most of us VOLUNTEER for an intense accreditation review by international experts every three years to ensure that we are providing our animals with the best quality of life possible. A review of the photos and video BFP itself offers of recently released dogs reveals the truth behind BPF’s deception. The dogs’ body condition and coats are gorgeous because they receive top notch nutrition and veterinary care while they are with us. They’re friendly because they have enjoyed socialization and playtime with other dogs and with our caretakers who adore them. The public fails to see this with their own eyes because they have been brainwashed by animal rights extremists for decades…and they seem to prefer drama over the truth.

Tell me something: Why would people who allegedly care so little about these dogs, as BPF claims, offer them for adoption? It’s not a trivial process. Records of animal health and release have to be generated, and adopters have to be located and screened. If our institutions really wanted to hide their ‘dirty little research secrets’, why wouldn’t they just euthanize all of these dogs, rather than risk ‘exposure’ by offering them to the public, as has been suggested by BFP?

Our dogs are offered for adoption because we love them and are grateful for their contributions to human and animal well-being. We want these heroes to live long, healthy, fun lives with loving adopters who have the patience and information needed to help them adjust to their new families. What is heartbreaking is that some of our institutions have closed their adoption programs because they were either exploited directly by BFP, or they don’t know who to trust anymore.

When are you and I going to hold the Beagle Freedom Project accountable for caring more about its agenda than our precious heroes?!

We all love these dogs and we all wish that they weren’t still necessary for the development of treatments and cures for conditions like cancer, Hepatitis C and Ebola. For now, they are still needed. Until we find a better way – and we are working on it – this research will continue to improve the lives of our friends, families and pets. The public is grossly misinformed about the care of animals in biomedical research and thus, unwittingly, people are supporting agendas that will harm them and their loved ones. Our faith is with our fellow citizens – but they must hear both sides of this issue, presented fairly. The media has an especially critical role in getting this right and they have, in most cases, fallen short of the mark. I am hopeful that they will do better by our citizens in the future.

Cindy Buckmaster, PhD, CMAR, RLATG; Chair, Americans for Medical Progress

See also:

http://speakingofresearch.com/2013/11/26/jerry-the-beagle-and-the-liberation-that-wasnt/

This guest post is by Jordana Lenon, B.S., B.A., Senior Editor, Wisconsin National Primate Research Center and University of Wisconsin-Madison Stem Cell and Regenerative Medicine Center. The research will also be featured this evening in a public talk at UW-Madison’s Wednesday Nite at the Lab. WN@tL: “Twenty Years of Stem Cell Milestones at the UW.”  Details and link are below. Update 1/8/15:  Dr. William Murphy’s talk  can now be viewed at:  http://www.biotech.wisc.edu/webcams?lecture=20150107_1900

As we enter 2015, the 20^th anniversary of the first successful isolation and culture of primate pluripotent stem cells in the world, it’s time to look back and see how far we’ve come. Thanks to a young reproductive biologist who came from the University of Pennsylvania’s VMD/PhD program to the Wisconsin National Primate Research Center at the University of Wisconsin-Madison in 1991, and to those whose research his groundbreaking discoveries informed, the fields of cell biology and regenerative medicine will never be the same.

Pluripotent stem cells are right now being used around the world to grow different types of cells—heart muscle cells, brain cells, pancreatic cells, liver cells, retinal cells, blood cells, bone cells, immune cells and much more.

Cultures of these cells are right now being used to test new drugs for toxicity and effectiveness.

More and more of these powerful cells are right now moving out of the lab and into preclinical (animal) trials and early human clinical trials to treat disease. The results are being published in peer-reviewed scientific journal articles on stem cell transplant, injection and infusion, reprogramming, immunology, virology and tissue engineering.

Pluripotent stem cells and their derivatives are right now being studied to learn more about reproduction and development, birth defects, and the genetic origins of disease.

Embryonic, induced pluripotent, tissue specific (adult), and other types of stem cells and genetically reprogrammed cells are all being used by researchers due to the open and collaborative environment of scientific and medical enterprises in the U.S. and around the world.

All of this is happening right now because of discoveries made 20 years ago by researchers at the Wisconsin National Primate Research Center.

Here is a brief timeline of stem cell breakthroughs by WNPRC scientists:

• 1995-James Thomson becomes the first to successfully isolate and culture rhesus monkey embyronic stem cells (ES cells) at the Wisconsin Regional Primate Research Center (PNAS)
• 1996-Thomson repeats this feat with common marmoset ES cells (Biol Reprod).
• 1998-Thomson publishes the neural differentiation of rhesus ES cells (APMIS).
• 1998-Thomson’s famous breakthrough growing human ES (hES) cells is published in Science. (This research occurred off campus, with private funding.)

Many subsequent stem cell “firsts” were accomplished by scientists who conducted lengthy training with James Thomson or Ted Golos, reproduction and development scientists at the Wisconsin National Primate Research Center. These highlights include the following accomplishments by Primate Center researchers:

• 2003-WNPRC Post-doctoral trainee Thomas Zwaka achieves homologous recombination with hES cells. A method for recombining segments of DNA within stem cells, the technique makes it possible to manipulate any part of the human genome to study gene function and mimic human disease in the laboratory dish (Nature Biotechnology).
• 2004-WNPRC Post-doctoral trainee Behzad Gerami-Naini develops an hES model that mimics the formation of the placenta, giving researchers a new window on early development (Endocrinology).
• 2005- WNPRC scientist Igor Slukvin and post-doc Maxim Vodyanik become the first to culture lymphocytes and dendritic cells from human ES cells (Blood, J Immunol).
• 2005-WiCell’s Ren-He Xu, who completed his post-doctoral research at the WNPRC, grows hES cells in the absence of mouse-derived feeder cells (Nature Methods).
• 2006-WiCell’s Tenneille Ludwig, a graduate student/post-doc/assistant scientist through the Primate Center with Barry Bavister, then James Thomson, formulates a media that supports hES cells without the need for contaminating animal products (Nature Biotechnology). Co-authoring the work is another former Primate Center post-doc, Mark Levenstein.
• 2007-Junying Yu, WNPRC and Genome Center, in Jamie Thomson’s lab, grows induced pluripotent stem cells, or iPS cells. (Science). These are genetically reprogrammed mature cells that act like embryonic stem cells, but without the need to destroy the embryo.

Researchers at all of the National Primate Research Centers continue to make advances in this remarkable field of research and medicine. A few more milestones include the following:

• 2007- Shoukhrat Mitalipov at the Oregon National Primate Research Center successfully converted adult rhesus monkey skin cells to embryonic stem cells using somatic cell nuclear transfer (Nature)
• 2012- Shoukhrat Mitalipov at the Oregon National Primate Research Center generation chimeric rhesus monkeys using embryonic cells (Cell)
• 2012-Alice Tarantal at the California NPRC successfully transplants human embryonic stem cells differentiated toward kidney lineages into fetal rhesus macaques.
• 2013-Qiang Shi at the Texas Biomedical Research Institute and Gerald Shatten at the University of Pittsburgh – and previously with the Oregon National Primate Research Center and Wisconsin National Primate Research Center – genetically programs baboon embryonic stem cells to restore a severely damaged artery.
• 2013-Shoukhrat Mitalipov at the Oregon National Primate Research Center produces human embryonic stem cells through therapeutic cloning, or somatic cell nuclear transfer (Cell)

Before all of this happened, we must note that non-primate mammalian embryonic stem cells were first successfully isolated and cultured in 1981, by Martin Evans and Matthew Kaufman at the University of Cambridge, England. That breakthrough occurred almost 35 years ago. Jamie Thomson studied mouse embryonic stem cells in Pennsylvania before working on primate cells.

Even before that, in 1961, Ernest McCulloch and James Till at the Ontario Cancer Institute in Canada discovered the first adult stem cells, also called somatic stem cells or tissue-specific stem cells, in human bone marrow. That was 55 years ago.

So first it was human stem cells, then mouse, then monkey, then back to humans again. Science speaks back and forth. It reaches into the past, makes promises in the present, and comes to fruition in the future.

In every early talk I saw Jamie Thomson give about his seminal stem cell discoveries in the late 1990s and early 2000s – to staff, scientists, to the public, to Congress, to the news media – he would explain why he came to UW-Madison in the early 1990s to try to advance embryonic stem cell research. In large part, he said, it was because we had a National Primate Research Center here at UW-Madison, and also that we had leading experts in transplant and surgery at our medical school. After he joined the WNPRC as a staff pathologist and set up his lab, first he used rhesus and then marmoset embryos before expanding to cultures using human IVF patient-donated embryos off campus with private funding from Geron Corporation in Menlo Park, California.

In these early talks, Jamie included images (see above) showing how very differently the mouse blastocyst (a days-old embryo, before implantation stage) is structured from the nonhuman primate and human primate blastocysts concerning germ layer organization and early development (ectoderm, mesoderm and endoderm). He also was able to show for the first time how differently stem cells derived from these early embryos grow in culture. In contrast to the mouse ES cells, the monkey cells, especially those of the rhesus monkey, grow in culture almost identically to human cells.

At the time, Thomson predicted that more scientists would study human ES cells in their labs over monkey ES cells, if human ES cells could become more standardized and available. Yet he emphasized that the NPRCs and nonhuman primate models would continue to play a critical role in this research, especially when it would advance to the point when animal models would be needed for preclinical research before attempting to transplant cells and tissues grown from ES cells. Both predictions have come true.

Jamie closed his talks, and still does, with this quotation:

“In the long run, the greatest legacy for human ES cells may be not as a source of tissue for transplantation medicine, but as a basic research tool to understand the human body.”

This simply and elegantly reminds us how basic research works: Many medical advances another 20 years from now will have an important link to the discoveries of today, which have their underpinnings in that early research in Jamie Thomson’s lab 20 years ago. It will become easy to forget where it all started, when many diseases of today, if not completely cured, will become so preventable, treatable and manageable that those diagnosed with them will spend more time living their lives than thinking about how to survive another day.

Just as I did not have to worry about polio, and my children did not have to worry about chicken pox, my grandchildren will hopefully see a world where leukemia, blindness, diabetes and mental illness do not have the disabling effects or claim as many young lives as they do today.

***

_______________________________________________________

WN@tL “Twenty Years of Stem Cell Milestones at the UW”

http://www.uwalumni.com/event/wntl-twenty-years-of-stem-cell-milestones-at-the-uw/

The British Union for the Abolition of Vivisection (BUAV) is a UK anti-vivisection group with a history of infiltrations to labs and unsubstantiated allegations against labs. A newly published report from a government investigation reveals just how far the BUAV bent the truth when they made false allegations against the University of Cambridge last year.

Fool Me Twice

In October, 2014, we wrote about how two separate investigations by the Animals in Science Regulation Unit (ASRU; the Government’s inspection unit) found allegations by the BUAV to be almost entirely groundless. In both cases the allegations had followed an infiltration by a BUAV activist.

The first report investigated the BUAV’s allegations against Imperial College London:

Over 180 individual allegations, made by the animal rights organisation, of non-compliance were investigated. Of these, all were found to be unsubstantiated apart from five formal non-compliance cases which have been completed – one category A and four Category B [none of which involved significant, avoidable or unnecessary pain, suffering, distress or lasting harm to the animals].

A second ASRU report into BUAV allegations against a pharmaceutical company conducting tests on veterinary medicines found:

No non-compliance with authorised programmes of work was detected apart from two minor issues with no welfare implications.
[…]
Our detailed investigations and review of available records and other evidence, does not support the allegations in the investigation report.

So twice last year the BUAV has been found misleading the public with their unsubstantiated claims.

Third Time Lucky?

In the post “The BUAV – Spies, Lies and Videotapes” we discussed an infiltration by the BUAV at Cambridge University. The infiltration and subsequent “expose” regarded research on sheep into Huntington’s and Batten’s disease. The allegations made were that there was “…distressing animal suffering, unlawful regulation by the Home Office, in adequate care of animals and inadequate enforcement by the inspectorate”. The 32-page report by the BUAV was supplemented by a four-and-a-half minute edited video (put together from hours and hours of footage by the infiltrator) but when ASRU officials wrote to them requesting further video footage they might have, the BUAV replied that “there was nothing further they wished to share with ASRU”. One guesses hours of footage of Cambridge University researchers abiding by the laws and regulations was not in BUAV’s interest to share. It also proves that the BUAV’s aim is not to address animal welfare issues at Cambridge, but to score points in their stated effort to “end all animal testing”. This month ASRU released their report into the allegations.

A sheep with Batten’s involved in the study at the University of Cambridge (Image credit: University of Cambridge)

Cambridge had previously provided a strong rebuttal of each the claims made by the BUAV. These claims appear to be a mix of exaggerated information and flatly false information. For instance Cambridge noted:

It is alleged that a lamb had to be euthanized at a UK airport after becoming sick during transit from New Zealand. One of the lambs did appear disorientated on arrival in London, but was cleared by the Veterinary surgeon as being fit to continue his travels. No adverse effects were seen in any of the animals on arrival in Cambridge a few hours later.

ASRU’s report is equally clear about this claim [p.13]:

In summary, we conclude that this allegation is simply untrue in relation to the sheep imported for the Project Licence holder’s research. No animals required euthanasia or were found dead on arrival a Heathrow Airport.

And some of their allegations appear to be of the BUAV’s own making. Cambridge noted:

We are careful to avoid causing stress to the Batten’s disease sheep. As their disease develops, they become confused and can become agitated, particularly when approached by unfamiliar people or surroundings. Thus the animal care team is careful not to isolate any sheep from its flock-mates, allow interaction with strangers, or make sudden or unnecessary changes to their routines. It appears that the BUAV infiltrator not only disrupted their routines in the making of the undercover videos, but also isolated the animals. This will have made the sheep appear more agitated than they are when under routine care.

ASRU have added that [p.13]:

The Establishment has mechanisms in place for whistle-blowing, and it is of note that no animal welfare concerns had been raised by any staff at the Establishment, including the animal rights organisation’s infiltrator…

A similar comment was made in the ASRU report into the Imperial allegations. The conclusion to the ASRU report makes damning reading for anyone who believed in the integrity of the BUAV.

Our detailed investigations, and review of available records and other evidence to do not support any of the allegations made by the animal rights organisation
[…]
None of these allegations has been substantiated nor has any allegation given us further cause for concern with regard to compliance with the requirements of the legislation at this Establishment.

Sound familiar? Once again the inspection reports have found the BUAV telling lies, with their spies and their videotapes.

The BUAV

Of the £1.3 million that BUAV spent in 2014 (not including money spent by their three associate companies, Animal Properties, BUAV Charitable Trust and Cruelty Free International), around £200,000 was spent on “Investigations”. Any curious journalist should be asking the BUAV whether they were paying these infiltrators, how much these payments were, and what they expected (video wise) from their employees.

To remind people of what we have said before. These are not casual whistle blowers, but people who are working at animal research facilities with the express intention of creating horrifying videotapes. Be it a school, a hospital, a factory or a restaurant, there are few businesses for which you could not create a cleverly edited 5 minute shock video having secretly filmed for hundreds of hours.

One has to wonder how many BUAV infiltrators are in labs around the UK. Moreover, one wonders, how many BUAV infiltration videos were never publicised due to the lack of shocking footage (even after clever editing)?

Speaking of Research

This guest post is by Lisa Krugner-Higby, DVM, PhD.  Dr. Krugner-Higby is a scientist and also a research veterinarian within the Research Animal Resource Center at the University of Wisconsin-Madison. Dr. Krugner-Higby’s research is in development of extended-release formulations of analgesic and antimicrobial drugs. She previously worked in anti-HIV drug development.

I am always fascinated by the idea promoted by some animal rights activists – repeated in many versions and for many decades – that all preclinical biomedical research can be conducted using in vitro cell culture. I have never found one of them who has spent much time working with cell culture. On the other hand, I have spent approximately seven years of my life working with cell cultures, looking at the stainless steel back wall of a laminar flow work station day after day. One thing I can say about immortalized cell lines, or cells that reproduce indefinitely, is that they are not alive in the same way that a mouse is alive.

Cell culture

The first thing that a graduate student learns when they begin to work with cell culture is how to take cells that have overgrown the sterile plastic flask they inhabit and put them into a fresh flask with fresh growth medium. It’s called ‘splitting’ the number of cells and ‘passaging’ them into a new home. Split and passage, split and passage… I knew that with every passage, the cell line became a little more different than normal cells and even a little more different than the original cell line. The remedy for this type of genetic drift was to freeze low passage cells in liquid nitrogen and re-order the line from the repository when the low passage stocks were depleted. I was careful with my sterile technique, cleaned the laminar flow hood, and used a new sterile pipet every time in order to avoid contamination of my cells. Unfortunately, the day came when I opened the incubator door and the flasks were black and fuzzy with fungus, and all of my carefully tended cells were dead. An anguished conversation with the tissue culture core technician revealed that this happened every Spring in North Carolina when the physical plant turned on the air conditioning for the year, blowing a Winter’s worth of fungal spores out of the ductwork and into the air. She recommended doing other things for about 6 weeks until the spore load had blown out of the ducts. I have had other cell line disasters in my scientific career: the malfunctioning incubator thermostat that turned a colleague’s two months’ worth of cell culture growth into flasks of overheated goo or that generally reputable vendor that sold us a case of tissue culture flasks that were not properly sterilized resulting in clouds of bacteria in the warm, moist, nutrient-rich environment of the incubator.

I never thought to ask, in those early days, if the cells that I fussed, worried, and wept over, were actually the cells that they were supposed to be. Raji Cells, A549s, U937s, I knew them all, worked with them every day, and never doubted that they were the cells that I thought that they were. I knew that some cell lines had been contaminated with the HeLa cell line. HeLa cells are very hardy and could spread quite easily from one flask to another. But I thought that was in the past. It turns out that there was more to the story than I realized. Cell lines have a provenance, like paintings or other works of art. They have an origin, a laboratory where the line was first isolated and propagated. From there, it may have been distributed to other laboratories and to repositories like the American Type Culture Collection or ATCC. Some cell lines are used by only a few laboratories, and some become used very widely and in a large number of biomedical disciplines. Whereas some paintings are intentionally forged, many cell lines have now been shown to be unintentionally forged. A recent article in the journal Science estimated that 20% of all immortalized cell lines are not what they were thought to be¹.

Multiphoton fluorescence image of cultured HeLa cells with a fluorescent protein targeted to the Golgi apparatus (orange), microtubules (green) and counterstained for DNA (cyan). Nikon RTS2000MP custom laser scanning microscope. National Institutes of Health (NIH).

We now have better methods of identifying cell lines by their DNA, called short tandem repeat (STR) profiling, and scientific journals are beginning to require this testing for cell lines prior to publication. Currently, 28 scientific journals require STR profiling to establish cell line provenance prior to publishing a manuscript from a particular laboratory. Some scientists are also beginning to create catalogs of contaminated cell lines in an attempt to quantitate the damage done by some misidentified, but widely studied, cell lines. The same Science article, notes that the International Cell Line Authentication Committee (ICLAC) maintains a database of misidentified cell lines that now numbers 475 different lines. A cell line geneticist, Dr. Christopher Korch, recently estimated that just two of the immortalized cell lines that were found to be misidentified, HEp-2 and INT 407, have generated 5,789 and 1,336 articles in scientific journals, respectively. These studies cost an estimated $713 million dollars and generated an estimated $3.5 billion in subsequent work based on those papers¹. This is because the usual trajectory for testing a new therapeutic modality, especially in cancer research, is to test a compound or technique in cell culture. It will then be tested in mice that express a tumor derived from the cultured cancer cells. If those studies are successful, the compound and/or technique undergoes further toxicity testing in other animal models before entering its first Phase I trial in human volunteers.

A lot of compounds that show early promise in cell culture and in cell line-injected mice turn out not to have efficacy in animal models or in human patients. Sometimes this is simply a matter of the compound being too toxic to organs or cell types that are not represented in the initial cell culture. Often, the reason why particular compounds or strategies fail is not known, and most granting agencies are not keen to fund laboratories to find out why things don’t work. I have wondered if the failure of some compounds or techniques is in part due to misidentified cell lines. I have also wondered if it is a reason why testing in animal models, particularly in animal models with spontaneously-occurring tumors, is necessary.

Testing anti-cancer compounds in models of spontaneously-occurring tumors in animals and/or testing in human tumor cells taken directly from patients and injected into mice (the ‘mouse hospital’ approach) is more time and resource intensive than screening in immortalized tumor cell lines. This approach, however, has the advantage of knowing that the investigator is not just treating misidentified HeLa cells in error. It is always necessary to go from in vitro cell culture models to in vivo animal models to confirm the viability of a therapy.

Science makes claim to no enduring wisdom, except of its method. Scientists only strive to be more right about something than we were yesterday, and efforts are underway to weed out misidentified cell lines. But the fundamental issues behind cell line misidentification highlight one of the reasons why we should not rely on immortalized cell lines without animal models, and why granting agencies should fund more studies to try to identify the disconnect between the results of in vitro and in vivo studies when things do not go as planned. That is a part of good science and part of creating better cell culture models to refine, reduce, and sometimes replace the use of animals in biomedical research.

Lisa Krugner-Higby, DVM, PhD

1) Line of Attack. Science. 2015. Vol. 347, pp. 938-940.

Banner at UW-Madison, April 2015.

Each April a group of people committed to ending all use of animals for any purpose, including medical and scientific research, orchestrate events for a week they designate World Week for Animals in Laboratories (WWAIL). Among the primary objectives of WWAIL is to generate media coverage via picketing and protests. The event often culminates in World Day for Animals in Laboratories (WDAIL).

WWAIL events are primarily coordinated by Michael Budkie, leader of Stop Animal Exploitation Now (SAEN). Budkie is also known for previous misrepresentation of animal research and its rebuttal by federal agencies. Budkie’s group is funded primarily by the Mary T. and Frank L. Hoffman Foundation, a “Biblically based organization” that believes “our call to mission is to restore God’s original creation intent of a plant based diet (Genesis 1:29-30).”  The  mission of the Hoffman Foundation  is quite clear: “To promote through education the elimination of the use of animals in biomedical research and testing, their use as food, or their use for any and all commercial purposes…

Sit-in at UW-Madison during WWAIL (April 18, 2015).

SAEN is like other absolutist groups whose 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.

WWAIL protests are focused specifically on research. Thus, the sites for protest tend to be universities and other research institutions where scientists engage in work that produces the new knowledge and discoveries that drive scientific and medical progress to benefit humans, other animals, and the environment. The protests also target individual scientists with the kind of “home demonstrations” we’ve written about before (see more here and here).  In some cases the protests target businesses that support animal research.

Although the WWAIL activities vary some each year, they have a few consistent themes:

• First, the primary objective appears to be media coverage. In fact, a quick view of the “successes” claimed by the primary organizing group shows that number of news stories is the prize accomplishment.
• Second, the number of people participating in the activities is typically a few to a dozen.
• Third, most of the materials used in the protests, social media coverage, and news releases reliably rely on outdated, out-of-context images and little reference to the protestors’ broad agenda and position.

We agree that public consideration of animal research is important. Stimulating serious, thoughtful education efforts and inclusive public dialogue about science, public interests, medical progress, and animal research are critically valuable to public decision-making and, ultimately, to global health. Informed decisions based in accurate information and in an understanding of the complex issues involved in animal research are in the best interest of the public, science, and other animals.

For that reason, many scientists, universities, educators, advocacy groups, and individuals engage in public outreach, education, and dialogue about scientific research with nonhuman animals. Their goal is to provide the public with accurate and thoughtful information about the range of issues that bear on decisions, policies, and practices related to animal research. Among those topics are:  how science works, its process, timescales between discovery and application, why animal research is conducted, in absence of alternatives; who benefits and what would be lost if it did not occur;  how animals in research are cared for, how ethical review occurs, and how regulation and oversight function.

None of these are simple issues, which is why there are many websites, books, articles, and interviews on the topic. WWAIL provides a unique opportunity for the research community to help point people towards these resources for education, dialogue, and serious consideration of animal research.

At the University of Wisconsin-Madison, we have one example of how to do just that.  The website referenced in the banner shown in the photos here (animalresearch.wisc.edu) provides extensive information about animal research.  The site provides facts, interviews, videos, photos, and links for those interested in learning more about why animal studies occur, the role that they play in scientific and medical progress that serve public interests, how research is conducted, its ethical consideration, and the practices, policies, regulation and oversight that govern animal care.

By contrast, we have the signs held by those below participating in a WWAIL sit-in at UW-Madison on Saturday.  Among the signs are photos of animals from other decades and other countries.  For example, note the repetitive use of a picture of Malish, a monkey who was involved in research in Israel in 2001 (not exactly relevant to UW).  We also see quotes by an actor and numbers that do not reflect those from UW-Madison.  None of these are difficult errors or misrepresentations to correct; but they probably won’t be corrected in absence of voices and sources to provide accurate information.

Sit-in at UW-Madison during WWAIL (April 2015).

This year, if your university or facility is among those that attract attention during WWAIL,  we ask that you join in the conversation by providing protestors, public, and media your own voice.  Whether it is via banners, websites, or talking with reporters– speak up for science and for public interests in advancing scientific understanding and medical progress. Although it may not matter to those committed to an absolutist agenda, it can matter to those who are interested in building a dialogue based in fact and serious consideration of the complex issues that surround public interests in the future of science, health, and medicine.

Speaking of Research

Last week we published an article calling on all involved in animal research to speak up for science as animal rights activists held their annual World Week for Animals in Laboratories (WWAIL), writing:

This year, if your university or facility is among those that attract attention during WWAIL, we ask that you join in the conversation by providing protestors, public, and media your own voice.  Whether it is via banners, websites, or talking with reporters– speak up for science and for public interests in advancing scientific understanding and medical progress. Although it may not matter to those committed to an absolutist agenda, it can matter to those who are interested in building a dialogue based in fact and serious consideration of the complex issues that surround public interests in the future of science, health, and medicine.”

The past few days have seen several great examples of just the sort of engagement with the public that we had in mind, including videos form two top universities in the UK that take viewers inside their animal research facilities.

The first comes from the University of Cambridge, who have published a video entitled “Fighting cancer: Animal research at Cambridge”, which focuses on how animals used in research are cared for and how the University implements the principles of the 3Rs. It includes interviews with Professor Gerard Evans of the Department of Biochemistry, who uses mice in studies of lung and pancreatic cancers, and Dr Meritxell Hutch of the Gurdon Institute, who has developed 3D liver cell culture models that she uses to reduce the number of mice required for her studies of tissue repair and regeneration, as well as with members of staff as they care for the animals.

The second example is another video, this time from Imperial College London, which also show how research staff care for the animals used in research, and features an interview with Professor of Rheumatology Matthew Pickering, who studies the role of complement proteins in liver damage in mice.

For the third example we cross the Atlantic to South Florida, where animal rights activists are trying to close down several facilities in Hendry County  that are breeding monkeys for medical research, a service that is hugely important to biomedical research. One of the companies being targeted by the animal rights campaigns is Primate Products, so we were delighted to see Dr. Jeff Rowell, a veterinarian and President of Primate Products, speak up about the vital work they do in an interview with journalist Amy Williams of local news outlet News-Press.com.

During the interview Dr. Rowell discusses how the work of Primate Products is misrepresented by dishonest animal rights campaigns, including the inaccurate and malicious allegations made by the group Stop Animal Exploitation Now (SAEN) in 2010. As we discussed in a post at the time, these allegations were based on the deliberate misrepresentation of photos taken during veterinary care of injuries several macaques received in fighting with other macaques when housed in social groups (a normal though infrequent behaviour in the species in the wild and in captivity).

The News-Press.com article also shows that there is still a lot of work to be done to improve openness in animal research, as the three other companies that are breeding monkeys for research in Hendry County refused to speak with the Amy Williams, a shame considering that it was their decision to base themselves in the county that triggered the current animal rights campaign. While they are justifiably nervous of speaking with the press (some journalists and publications are arguably beyond redemption) the truth is that the “No comment” approach works for no-one apart from those who oppose animal research. In speaking at length with Amy Williams, Jeff Rowell has provided an excellent example that his colleagues in Hendry County would do well to follow.

The initiatives we have seen from the University of Cambridge, Imperial College London, and Primate Products over the past few days are extremely welcome, and we applaud them for their efforts. Nonetheless, we acknowledge that the future of medical science will never really be secure until they are the norm rather than the exception.

Before we conclude, it’s worth noting that it’s not just in the US and UK that researchers are beginning to realise the importance of openness in animal research to counter misleading antivivisectionist propaganda. In Italy Prof. Roberto Caminiti, a leading neurophysiologist at the University La Sapienza in Rome whose work is currently being targeted by animal rights activists, was interviewed recently for an excellent video produced by Pro-Test Italia, in which he discusses his primate research and how it is regulated.

Speaking of Research

In March we discussed a new attempt by animal rights supporters to ban animal research in Europe, The Stop Vivisection European Citizens’ Initiative, which was signed by  1.2 million people (half of them in Italy). The initiative calls for “the European Commission to abrogate directive 2010/63/EU on the protection of animals used for scientific purposes and to present a new proposal that does away with animal experimentation”. On Monday 11th May the organizers of the initiative had an opportunity to present it to a joint session of  several European Parliament committees, in a hearing that was also addressed by scientists who spoke in favor of keeping directive 2010/63/EU.

So how did it go?

Well, an editorial in last week’s edition of Nature gave a fair assessment of it when they described the session as “a pretty grey affair” in which the duo who presented the initiative – Gianni Tamino and Claude Reiss – “spoke calmly but unconvincingly” to a half-filled auditorium. A transcript and summary of the key points made by the European Animal Research Association and put together the key points that were said during the meeting (download here) indicates that the initiative is almost certain to fail in its objective of  persuading the EU Commission to repeal Directive 2010/63/EU.

A look through the EARA report  shows why. Any MEPs (Members of the European Parliament) hoping to hear new evidence from Dr Ray Greek and Dr Andre Menache, the scientific advisors who the Stop Vivisection Initiative organizers had brought along, were in for a  disappointment, as instead they presented a veritable greatest hits of anti-vivisection claims. Their testimony included Dr Ray Greek’s trademark  misrepresentation of what “prediction” means in biomedical research, while Dr Menache reheated the old 0.0004% myth. Surprisingly, these were far from being the worst claims made by supporters of the Stop vivisection initiative. Particularly low points came when MEP, and initiative supporter,  Anja Hazekamp stated that there has been massive increase in animal testing (The EU’s own statistics show the opposite) and when Claude Reiss, one of the organizers of the Stop Vivisection petition, ventured deep into conspiracy theory territory with a claim that there is a patent on HIV treatment that completely cleans the virus from the body, but has not been developed because it is not profitable.

In contrast the voice of science was very ably represented. Professor Francoise Barré – Sinoussi, 2008 Nobel Laureate in Physiology or Medicine for her role proving that HIV causes AIDS, put forward a very strong case for the importance of animal research in advancing medicine, and repeatedly demolished false claims made by anti-vivisectionists, particularly claims that animal research had not made a useful contribution to HIV research and the development of a vaccine against HIV infection. On this she is on safe ground as there is no doubt that animal research has made very important contributions to HIV research and development of therapies (for examples see here, here and here), and while development of an effective vaccine has been slow – because it’s very, very difficult – there has been real progress in recent years, and most HIV experts is that studies in  non-human primate models of the infection have a critical role to play in evaluating potential vaccination strategies.

Francoise Barré – Sinoussi, undoubted star of the EU parliament hearing.

Throughout the hearing one very important voice was conspicuous by its absence, that of the patients who rely on medical research. MEP Françoise Grossetête, who spoke in favor of retaining Directive 2010/63/EU, noted in particular that EURORDIS, the organization that represents rare disease patients in Europe, had not been invited to present evidence at the hearing. We hope that the EU commission will now actively seek the advice of EURORDIS and other European patient organizations before making their final decision.

What happens now?

At the hearing the Vice-President of the European Commission confirmed that the Commission will provide a formal response to the initiative by 3 June 2015. On the basis of what we saw at the hearing, and the fact that the majority of MEPS present were in favor of retaining Directive 2010/63/EU, it is a near certainty that the EU commission will reject the Stop Vivisection initiative and retain the Directive.

In 2017 the Directive will undergo it’s first 5 year review, which is likely to focus on its implementation across the EU, but the commission have also promised to organize a scientific conference that year to discuss the validity of animal research. With that in mind it’s good to see that last week’s Nature editorial noted that scientists across the EU are becoming increasingly – and refreshingly – vocal on the need to support animal research as a pillar of scientific and medical progress. In recent weeks we’ve seen thousands of scientists sign a motion of solidarity with a neuroscientist targeted by animal rights extremists in Germany, more than 140 research organizations, patient organizations, medical research funders and scientific associations sign up to a statement in support of Directive 2010/63/EU, Sixteen European Nobel laureates publish an open letter in UK and German newspapers to rebut the Stop Vivisection campaign. We’ve also seen several excellent letters appear in the national press, including a letter in the Times by Steve Ford, Chief executive of Parkinson’s UK, on the importance of animal research, and articles such as that written by Oxford University Duchenne muscular dystrophy researcher Professor Kay Davies.

The Stop Vivisection Initiative may have almost run its course, but the threat to the future of biomedical science in the EU is sadly never very far away. We hope that the current re-invigoration of the European scientific community continues, and that scientists strengthen and expand their engagement with politicians, journalists and citizens in the run-up to 2017 and beyond.

Speaking of Research

I received an email one morning from James, a Grade 6 student who wanted to know more about beagles used in research and testing for a school project about his passion. He has a pet beagle named Bagel and had recently watched some videos from the Beagle Freedom Project (BFP written about here and here). James was very curious and quite concerned about the beagles that participated in studies in Canada. He requested some information and to visit the Central Animal Facility at the University Of Guelph. James was invited for a tour and the answers to his questions are as follows:

Job Related

• What is your job and what do you teach at the University?

I am a research animal technician and my job is to advocate for the animals that are under my care. I instruct those who have not worked with animals how to do so in a compassionate, respectful and ethical manner.

• Why did you become a technician?

I became a technician because I love animals and people. I also love science and love being a part of making discoveries that improve the lives of millions of people and animals

• My project is on a passion and I am wondering what your passion is?

I’m passionate about a lot! I am passionate about animals that I have the privilege to care for with compassion and respect. I am passionate about the science that continually makes strides towards new therapeutic advancements. I am passionate about alleviating the suffering of our fellow animals and people who agonize with debilitating and painful diseases. I choose this profession in research because it is my passion.

• What research do you do in your Lab?

The majority of the work that is done in the facility where I work is basic or fundamental science in a wide variety of areas including oncology, neuroscience, animal behaviour and welfare, molecular biology, physiology, immunology, among others.

Michael Brunt and James during the laboratory visit

Animal Research/Testing

• Why is it important to use animals/ beagles?

Various non-animal research methods are used together with animal studies to reduce the number of animals needed. These methods include antibodies, stem cells, tissue cultures (all in-directly use animals) and computer models. Non-animal methods account for the majority of biomedical research. Nevertheless, there are important research questions that still require animals. For example, in drug development, a large initial group of chemical candidates may be screened using non-animal methods, and only the most promising ones are taken through animal testing and human clinical trials. Before animal studies can go forward, investigators must detail how they have considered non-animal methods, and why they are not appropriate for answering their research question.

• What kinds of tests are done?

The Canadian Council on Animal Care has 5 classifications for the purposes of animal use (PAU):
PAU1 – Studies of a fundamental nature in science relating to essential structure or function
PAU2 – Studies for medical purposes, including veterinary medicine, that relate to human or animal disease or disorders
PAU3- Studies for regulatory testing of products for the protection of humans, animals, or the environment
PAU4 – Studies for the development of products or appliances for human or veterinary medicine
PAU5 – Education and training of individuals in post-secondary institutions or facilities

• What happens with your research findings once you are finished a project?

The findings are published in scientific journals that are available on the internet for everybody to access. The knowledge gained could be used to answer other scientific questions or be applied in translational science to develop new therapies or cures for those that are suffering.

• What do you do with the animals after you have used them for research/testing?

Ultimately, most of the animals involved in animal research are euthanized. This is because the researchers will often need to further study the body – taking tissue samples and other such tests to make sure they get as much data from any animal they use. To euthanize the animals, researchers use a variety of methods such as an overdose of anesthesia (pain killers) or using CO2 so that the animal slowly drifts into a sleep it never awakes from.

Beagle Research/Testing

• What is your opinion about beagle research?

Animal research plays a vital role in the development of modern medical and veterinary treatments. Much of our understanding about the biological processes in the body, and the diseases that affect them, comes from studies in animals. I believe that animal research should be conducted with the utmost care, responsibility and respect towards the animals. All personnel involved in animal research should strictly follow the pertinent guidelines, regulations and laws.

• When did beagle testing begin?

Hundreds of years ago to begin to understand blood movement and the interactions of organs.

• Why are beagles used for testing?

Health Canada requires that all new drugs, medical devices, and procedures first be evaluated in animals for safety before clinical trials involving human volunteers can begin. The most common “product” that is tested using animal models is new medications. Animals are used to determine that the drug shows a reasonable likelihood of working as conceived and to determine unforeseen side effects. For instance, a researcher may find that a new drug to control high blood pressure does so, but there is a possibility of a side effect such as liver damage. That information needs to be known before it is used in clinical trials with humans.

• How many beagles are used a year?

0.3% of the animals used in Canada in 2011 were dogs. Mice, rats and fish accounted for 78.5% of the animals.

• Where do you get your dogs?

Our beagles are provided by companies who breed dogs for research, teaching or testing purposes.

• How are the dogs treated?

With love, compassion and respect.

• Why don’t some companies let beagles see sunlight play or even touch grass during their testing time?

At our institution our animals go outside for walks every day with their dedicated paid dog walker and our volunteer dog walkers.

• How many beagles die each year from testing?

I don’t have an answer to that question. In Canada in 2011, 10,199 dogs were utilized in science. However, that isn’t how many were humanely euthanized at the end of the projects. Our institution has adopted 100s of beagles into our community.

James and Bagel (Photos reproduced with permissions from copyright owner)

Feedback

James and his parents met a number of our animals, including our beagles, during their tour and I asked him to provide some feedback on his experience.

“At first I thought beagle research and testing was inhumane, unbeneficial and cruel. But when I went to the University of Guelph my perspective changed and I learned that research and testing is very important and it helps 1000s of humans and animals because of the research on animals. The people treat all the animals to a good life like every other animal in the world. They play with all the animals mice/rats/dogs and turkeys. One of the reasons that they euthanize the animals is to further discover the effects of a drug to make it safer for humans and other animals. All the animals there are well cared for, like the animals are their family. If we didn’t have research and testing we would never have a treatment to help the people suffering with cancer. 1000s of products have helped humans and other animals because of the work done with beagles. How many people would have died without animal research and testing on the drugs to know if they are safe. What I thought about beagle testing at first was nothing compared to what it is now. I now know that it very helpful. Most of the websites that say all the bad things are not aware of all the things the beagles and animals have done for advancing medicines. Another part of my visit included seeing Dr Woods and he told me about the research he did on mice for prostate cancer. They use mice cells because they react to the cancer like the humans cells do. Dogs are closer to humans than mice in DNA and they need to see how much of the drug they can give without it being toxic. All chemotherapy has been tested through rats, mice and beagles before humans. In my opinion all the beagles and animals who are involved in research are Heroes.”

My interview and tour with James demonstrates that everyone must seize opportunities to engage with members of the public. It is a chance to present accurate information about the ethical use of animals in science and allow people to make informed opinions. These instances foster a culture of understanding, acceptance, value and recognition for the contributions animal research plays in improving the lives of millions of animals and people every day. They are opportunities that should not be squandered.

Michael Brunt

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.

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).

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.

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