Tag Archives: rats

Weekly Roundup: Ebola vaccine hope for apes, gene therapy for dogs, and research into stroke

Welcome to the second of our weekly roundups. These Friday posts aim to inform our readers about the many stories that relate to animal research each week. Do you have an animal research story we should include in next week’s roundup? You can send it to us via our Facebook page or through the contact form on the website.

  • The first orally administered vaccine for Ebola developed for the conservation of wild apes, has completed its first and final biomedical research trial for the foreseeable future. The study, published in the journal Scientific Reports, shows that the vaccine was effective and did not induce health complications or lead to signs of stress in the apes. Lead investigator, Peter Walsh statedIn an ideal world, there would be no need for captive chimpanzees. But this is not an ideal world. It is a world where diseases such as Ebola, along with rampant commercial poaching and habitat loss, are major contributors to rapidly declining wild ape populations.Oral vaccines offer a real opportunity to slow this decline. The major ethical debt we owe is not to a few captive animals, but to the survival of an entire species we are destroying in the wild: our closest relatives.

One of the captive chimpanzees in the research trial receiving the oral Ebola vaccination. Credit: Matthias Schnell, Thomas Jefferson University.

  • A new compound, P7C3-A20, has been shown to prevent brain cell death and to promote new cell growth in a rat model of ischemic stroke. Nearly 87% of all strokes are ischemic strokes. Strokes kill 130,000 Americans yearly, with someone in the USA having a stroke every 40 seconds and with a death occurring every 4 minutes.
  • A new gene therapy, which aims to treat the fatal muscle-wasting disease, myotubular myopathy or MTM, has shown considerable success in dogs. Like humans, dogs naturally get this disease as a result of a genetic defect which tends to lead to breathing difficulty and early death. One year after a single gene therapy treatment, the dogs with the condition were indistinguishable from the control group. This offers huge promise for future human therapies for MTM. Results were published in Molecular Therapy.

Image from Science Daily

  • A team of scientists have prevented and alleviated two autoimmune diseases, multiple sclerosis (MS) and type 1 diabetes, in early stage mouse models. Autoimmune diseases affect an estimated 23 million Americans, and this research using mice highlights the importance of animal research in alleviating these debilitating diseases.
  • A new study finds that Lactobacillus, a common bacteria found in yogurt, may be used to alleviate symptoms associated with depression in mice – providing hope for the 7% of the population that experience a major depressive episode at least once in their lifetime. The study was published in Scientific Reports.

Image by Understanding Animal Research.

  • Canadian animal rights group, Last Chance for Animals, has alleged mistreatment of animals at the Contract Research Organisation, ITR Laboratories. The footage was included in a CTV W5 news report. In response to the infiltration video, ITR Labs released a statement saying they had parted ways with a number of technicians seen inappropriately handling animals in the footage. The Canadian Council of Animal Care also released a statement explaining that an inspection of the ITR facilities was now being organized.

When are rats, mice, birds and fish protected by US federal laws?

There is sometimes confusion about how US law protects rats, mice and non-mammalian vertebrates such as birds and fish. Much of this confusion is rooted in the fact that the US Animal Welfare Act (AWA) explicitly excludes purpose-bred rodents (rats of the genus Rattus rattus, mice of the genus Mus mus), as well as birds that were specifically bred for research. Research with these purpose-bred rats and mice likely comprises the overwhelming majority of vertebrate animals in research in the US, but it is not overseen by the United States Department of Agriculture (USDA).

Sometimes this fact is used mistakenly (or perhaps purposely?) to suggest that all species not covered by the Animal Welfare Act are not protected by any federal laws.

Claims that research with non-AWA-covered species is not subject to care standards, external oversight, and public transparency are demonstrably untrue.

This post aims to address these misconceptions by looking at when and how rats, mice, and birds in research are covered by federal laws.

Mouse Science

Image from Understanding Animal Research

In the US, both the USDA, through the Animal and Plant Health Inspection Service (APHIS), and the Department of Health and Human Services (DHHS), through the Public Health Service (PHS) and National Institutes of Health (NIH) Office of Laboratory Animal Welfare (OLAW), are responsible for the oversight animal research. The table below provides a broad overview of the federal regulation and oversight agencies for different species and types of research.

Covered species are defined as: "with certain exceptions, any live or dead dog, cat, monkey (nonhuman primate mammal), guinea pig, hamster, rabbit, or such other warm-blooded animal, as the Secretary [of Agriculture] may determine is being used, or is intended for use for research”

Overview of animal research regulation in the US. The Animal Welfare Act (AWA) states that covered species are defined as: “with certain exceptions, any live or dead dog, cat, monkey (nonhuman primate mammal), guinea pig, hamster, rabbit, or such other warm-blooded animal, as the Secretary [of Agriculture] may determine is being used, or is intended for use for research” (7 U.S.C. 2132(g) The 2002 Farm Bill amended this definition to exclude purpose-bred rats, mice, and birds from the provisions of the AWA. Note that certain types of research with animals and most animal testing are also subject to regulation and oversight by the US Food and Drug Administration (FDA).

Animal Welfare Act (AWA) and USDA. The USDA is charged with enforcement of the AWA. The AWA applies to research with a range of species that includes: “with certain exceptions, any live or dead dog, cat, monkey (nonhuman primate mammal), guinea pig, hamster, rabbit, or such other warm-blooded animal, as the Secretary [of Agriculture] may determine is being used, or is intended for use for research” (7 U.S.C. 2132(g), referred to here as “USDA-covered species.” Institutions that engage in research with covered species must be registered with the USDA.  The AWA also applies to zoos, entertainment facilities, breeders, and other facilities that engage covered species in activities that involve public contact. All such facilities must be licensed by the USDA and research may also be conducted in facilities licensed for non-research purposes.

An amendment to the 2002 Farm Bill  specifically excluded from AWA oversight rats of the genus Rattus rattus, mice of the genus Mus mus, and birds specifically bred for research. Thus, research with these rats, mice, and birds, which likely comprises the overwhelming majority of vertebrate animals in research in the US, is not overseen by the USDA.

Does that mean rats, mice, and birds are not covered by federal animal welfare laws?

It depends on the funding! In fact, many rats, mice, and birds bred for research are covered by federal law.

Why?  Because, for federally-funded research, another federal regulation specifies the conditions for animal care, animal research, external oversight, and associated public transparency via a second federal agency. This includes, for example, university research funded by the National Institutes of Health, the National Science Foundation, or other federal agencies.

PHS and OLAW. The Health Research Extension Act (HREA; 1985) provides the statutory authority for the PHS Policy on Humane Care and Use of Laboratory Animals (PHS Policy), which applies to all PHS-funded research with live vertebrate animals.  In brief, such research must follow the National Research Council’s Guide for the Care and Use of Animals in Research (The Guide) (NRC, 2011).  Each institution receiving PHS funding for research with vertebrate animals is required to have an Assurance of Compliance (Assurance) with OLAW. The Assurance describes policies and procedures adopted by the institution in order to comply with PHS Policy.

The NIH website provides extensive information about PHS policy and OLAW.

http://grants.nih.gov/grants/olaw/faqs.htm

Guide for the Care and Use of Laboratory Animals

Guide for the Care and Use of Laboratory Animals

Food and Drug Administration (FDA). Certain types of research with animals and most animal testing are also subject to oversight and regulation by the US FDA.

Part of the federal regulation governing animal research also requires that each institution engaged in research has a mechanism for ethical consideration, approval, oversight and monitoring of animal care and research. Thus, there are also oversight bodies at each institution that are charged with the approval, monitoring, and reporting of activities with animals.

Institutional Animal Care and Use Committees (IACUC). Animal research oversight at the institutional level is entrusted to an Institutional Animal Care and Use Committee or “IACUC.” The responsibilities of the IACUC are spelled out in the AWA regulations and the PHS policy. Read more about IACUC here: http://grants.nih.gov/grants/olaw/tutorial/iacuc.htm

What about rats, mice, and birds that are not in federally-funded research?

While privately-funded research is not subject to the AWA or PHS Policy, there are other mechanisms that are used to ensure standards of animal care and research review, such as voluntary accreditation of the institutions’ animal care program. Such research may also fall under FDA oversight and, as such, be required to follow PHS Policy.

Private accreditation.  An institution may choose to seek and maintain voluntary accreditation by a private agency, AAALAC, International (AAALAC). In the US, AAALAC accreditation depends on demonstrating compliance with the The Guide; thus, institutions that are not overseen by APHIS or OLAW may choose to be accredited and adopt the same standards for the care and treatment of research animals. Private accreditation for the care of captive animals is common across different kinds of facilities that house nonhuman animals, including those in research, but also in zoos and sanctuaries, who have their own accreditation organizations (e.g., American Zoological Association, AZA; Global Federation of Animal Sanctuaries, GFAS). Importantly, however, unlike oversight by a federal entity, voluntary accreditation does not provide a venue for public oversight and enforcement, nor does it allow for public transparency. For example, both USDA’s APHIS and PHS’s OLAW are responsive to public requests for investigation of facilities and records relating to oversight of those facilities. Private accreditation agencies do not provide public transparency of the accreditation process and/or inspection reports.

In Conclusion:

There are many sources of federal and local protection of animals in laboratories. Any research on AWA-covered species OR research that receives federal funding will be covered by federal laws aimed at ensuring laboratory animal welfare. Those laws provide for external oversight and for public transparency of records including, for example, inspection and investigation reports.

Most research is also covered by the IACUC system, which provides for oversight and, for many public institutions, another route of public transparency via state open records. Finally, many facilities– both public and private– maintain voluntary accreditation, which also should have a positive impact on animal welfare.

Speaking of Research

For more information about regulation, also see:

Update 5/24/16:  “New MOU Among NIH, USDA, and FDA.  NIH, USDA, and FDA have participated under a Memorandum of Understanding (MOU) Concerning Laboratory Animal Welfare for over 30 years. Each agency, operating under its own authority, has specific responsibilities for fostering proper animal care and welfare. This agreement sets forth a framework for reciprocal cooperation intended to enhance agency effectiveness while avoiding duplication of efforts in achieving required standards for the care and use of laboratory animals. The new MOU is available at: http://grants.nih.gov/grants/olaw/references/finalmou.htm.”

 

Guest Post: The Importance of Animals in Neuroscience Research

Our guest post today is from Dr. Stacey A Bedwell, a postdoctoral researcher at Nottingham Trent University, whose work focuses in the prefrontal cortex of the mammalian brain. In this post she discusses her work with rats, and why it is important for neuroscience. If you are interested in writing a guest post for us, please contact us today.

My research interests are in brain connectivity, studying how the billions of neurons in the human brain are connected and how their complex organisation allows us to carry out high order functions such as forward planning and decision making. I am specifically interested in the most frontal part of the mammalian brain, the prefrontal cortex. This region is known to be involved in complex processes such as decision making, forward planning and social inhibition – the behavioral restraint a person has in social situations.

Why study the prefrontal cortex?

It is not always clear to people outside of the area why basic research like mine is important for medical science in the long term and how it will indirectly benefit us as humans (and also often benefit animals). A lot of people don’t realise that a lot of work needs to be done to provide the knowledge that is required before exciting new drugs and treatments are developed. For instance, the development of treatment for spinal cord injury has been built upon an increased knowledge the underlying structure. In my area of neuroscience research it is really important to develop a clear picture of the underlying anatomy and organisation before we can improve our understanding of how the prefrontal cortex as a region functions, and ultimately lead to a better understanding of prefrontal associated neurological deficits that will help us to develop improved treatments and prevention strategies.

animal testing, animal research, vivisection, animal experiment

The prefrontal region has been associated with a range of neurological deficits including schizophrenia, depression and autism. Autism in particular is thought to involve abnormalities in prefrontal connectivity. We cannot begin to fully understand how these functions work and how deficits come about until we gain a clearer understanding of the structure and organisation of the neuro-typical prefrontal cortex, beginning with the underlying anatomical circuitry. My research for the past few years has focussed on revealing the complex neuronal circuitry that comprises this fascinating brain region.

Why do I use rats in my research?

People often ask me why I used animals in my research, whether it was necessary and why I couldn’t use another non-invasive approach in human subjects such as MRI. My most frequent observation, particularly from non-scientists, is that it is hard to see the importance of research using animals, if like mine, it doesn’t focus on a specific disease or produce findings that will lead immediately to the development of a new drug or therapy..

The optimum method for investigating brain connections is to physically visualise them, and the best method for visualising brain connections is the use of neuroanatomical tract tracers, fluorescent molecules, taken up by neuronal cells, that enable us to map pathways and the connections between brain regions. There are several different tract-tracing methods available, but I use fluorescent tracers injected into the prefrontal cortex in rats. With the use of a fluorescent microscope it is possible to visualise neuronal connections down to individual cells, something which we are far from being able to do with non-invasive imaging in humans. Being able to visualise and analyse the 3 dimensional location of connections on such a systematic and fine scale has allowed us to reveal properties of prefrontal cortex connectivity which had previously been undescribed (Bedwell et al 2015 & 2014). Our most prominent and surprising finding is that of non-reciprocal connections in PFC pathways, which is inconsistent with our knowledge of cortical organisation from other complex brain regions – cortical connections have long been assumed to be largely reciprocal in nature. This shows that PFC is organised very differently to other brain regions. These novel organisational properties provide an important basis on which to build a clearer understanding of how this complex region of the brain is organised and offer an insight into how and why the prefrontal cortex is able to carry out complex processes.

What happens to the rats?

I used rats in all of my experiments. The rats were all obtained from a Home Office licensedbreeding facility in the UK and were acclimatised to their new environment for a couple of weeks before they were used in any experiments to reduce their stress. Our rats were housed in groups of at least two and were kept in climate controlled specialist cages – they were very comfortable. There are strict Home Office guidelines in the UK as to how rats used in experiments are kept and cared for to ensure their welfare needs are met, this applies to before, during and after experiments and they are followed to the letter. A lot of effort goes into ensuring no animal suffers as part of an experiment.

Image from Understanding Animal Research

Image from Understanding Animal Research

My experiments required the rats to undergo surgery so that the tracers could be injected directly into the brain at a very precise location. This was always carried out to a very high standard. We received advice from a vet, who also sat in on the first few surgeries to ensure we were performing the procedure in accordance with regulations. The surgery always involved a team of at least three people and the welfare of the rat was the greatest priority. This included the correct use of anaesthesia, analgesics pre and post operatively, as well as continued behavioural observation in order to identify any post-operative complications before they could cause suffering to the rat. At the end of the experiment each rat was euthanised and the brain removed for microscopic analysis of the labelled connections.

What next?

I am now developing studies of cortical function and functional connectivity, that can be carried out on human participants with non-invasive methodologies such as transcranial magnetic stimulation (TMS) and electroencephalography (EEG), and will complement the earlier studies undertaken in rats. Unfortunately, the technology is not yet available to investigate fine scale anatomy in such a non-invasive manor, so both animal and human studies are required in order to understand how the underlying brain structure relates to function. Until such techniques are developed, animal experiments will continue to be vital for the continued progress in neuroscience, as it is in so many areas of medical science.

Dr Stacey A. Bedwell

Empathy and Altruism in Rats?

A recent paper in Science discussed behavioral data in rats suggestive of empathically motivated behavior. This is a potentially very important report for two major reasons. First, a deep understanding of the mental and psychological abilities of rats, and other species, is a crucial goal for comparative psychologists, evolutionary biologists and other basic scientists. Second, the autism spectrum disorders are characterized by atypical reciprocal social interactions, and difficulty with experiencing and understanding the emotions of others appear to contribute; therefore, an animal model system in which we can learn how the brain responds to and processes the emotions of others is crucial to progress in this area. For these reasons, the experiments address a very significant question.

The experiment consisted of having a rat placed in an arena (the free rat) who is able to see and interact  with a companion that is trapped in a cylindrical restrainer with a door (the trapped rat).  It was found that the free rat learned over time to free the trapped rat by intentionally opening the door.  In control experiments, rats did not open empty tubes or ones containing an inanimate object.  When given a choice between getting access to chocolate and freeing the trapped rat, they would often free the rat even before eating the chocolate, suggesting that the motivation to liberate its companion trumped even its desire for the chocolate, a potential sign of altruism.

The authors concluded that “the free rat was not simply empathically sensitive to another rat’s distress but acted intentionally to liberate a trapped conspecific.”

The media reported on the finding by declaring science has shown altruistic behavior in rats.  Some media titles include “Rats: Holiday spirit in rodent form”, “If someone calls you a rat, take it as a compliment”, “Rats kind-hearted, generous creatures”, “Rats show Empathy and Altruistic Behavior”, “Rats are as compassionate as humans” and so on.

It appears that both the press, and perhaps even the authors, interpret the findings as implying the following:

  1. The free rat has a mental state that represents the well-being of a conspecific.
  2. This representation generates a distressful response in the free rat.
  3. The free rat learns it can act in a way to relieve the distress of the caged rat by opening the door of the cage.
  4. The rat intentionally acts to relieve the caged rat from distress even when there it has nothing to gain from the action.

Dr. Daniel Povinelli, in a Nature coverage of the paper, had a different view, saying that “This work is not evidence of empathy — defined as the ability to mentally put oneself into another being’s emotional shoes.”

Though the view that rats exhibit empathic behavior may be consistent with the data, we must ask if there could be alternative, simpler explanations that do not necessarily involve invoking assumptions 1-4, above.

One possibility is that the trapped animal is generating an alarm signal, either in the form of vocalizations or pheromones, that generates stress in the free rat.  The free rat may then learn it can stop the distressing signal by opening the door (so-called negative reinforcement).  In acting in such a way, the free rat would then be relieving its own distress rather than the perceived and shared stress of a conspecific.

Is this possible?

The authors did not measure chemical signals but did measure vocalizations during their experiments and found that “significantly more alarm calls were recorded during the trapped condition (13%) than during the empty and object conditions.”

So this alternative scenario is, in principle, a possibility.  The authors dismissed this alternative explanation because the rate of alarm calls was relatively low and yet they remained open to the possibility when they concluded:

Thus, the most parsimonious interpretation of the observed helping behavior is that rats free their cage-mate in order to end distress, either their own or that of the trapped rat […] This emotional motivation, arguably the rodent homolog of empathy, appears to drive the pro-social behavior observed in the present study.

This is a bit confusing and requires clarification.

There are at least two different interpretations of the data.  Not one.

Either the rat is freeing the companion to end its own stress (caused by an alarm signal) or it is doing it to end the perceived stress of the caged rat.   The interpretation of a pro-social, empathically motivated, altruistic behavior is only applicable to the second interpretation and not the first one.

To differentiate among these possibilities one can conduct some additional control experiments.  One could, for example, just play alarm calls that are stopped once a rat presses a lever once placed in the arena.  Or we could use chemical signaling if we learn the behavior is mediated by pheromones and identify the pheromone in question. One could have offered the free rat the option to leave the arena to a dark, quiet place, potentially ending its own distress and leaving the companion trapped.  Or the free rat could be offered the possibility of a “personal sacrifice” (such as a mild shock) to free the other rat, thus paying a price to help his companion.  These are all doable experiments that would help tease apart the different interpretations of these data.

Another potential explanation of the data is raised by video records of these experiments provided as part of the Science article shown below.

In this example, taken after the rat has learned to free its counterpart, we see the free rat going right into the restraint immediately after opening the door.  Why would the rat enter the tube if it truly felt and understood the distress the other rat experienced by being confined?

If one has ever seen rats at the pet store, you know that you will often find them snuggled up together in tubes and tight spaces because they apparently enjoy the safety and security of these types of experiences. This view was raised in an online discussion of the data:

Rats enjoy access to tight enclosures.  We routinely put plastic tubes in home cages for “environmental enrichment” and the rats are often found “snuggled” together in them, especially when resting – presumably an inherent protective response.  In fact, if you try to grab a rat in a cage with a tube, the rat will immediately go for the tube and try to stay in it.  Thus the “trapped” rat could also be seen by the “free” rat as enjoying a protected situation, and the free rat could in fact be displaying “envy” by freeing his companion so that he can enjoy the same protection and/or being motivated for social reasons to have a companion to “snuggle” with.  Indeed, the first thing the free rat did in the video after opening the enclosure was to go right into the tube with the other rat! 

So the basic question is, does the free rat want to get in, believing that his cagemate enjoys the privilege of a protected space, or does he fear for his cagemate and want to release him?   

Again, only additional experiments can address this. Resolution of these alternative views is crucial in terms of both of the prevailing motivations for conducting the study. Either rats are acting to relieve their own distress, or that of another – the difference bears strongly on our understanding of their mental abilities. In addition, if the former, but not latter, phenomena is correct, the value of studying the biology of empathy using rats is significantly challenged.

Still, we are left with a provocative phenomena —  rats freeing one another, invoking similarities with human behavior. There are plenty of other examples in nature where individuals of a species cooperate and interact in ways that could be described in terms of our own (human) mental states as altruistic or empathic behavior.  The examples range from bonobos, to bats, to even single-cell organisms, such as social amoeba (see here and here.)  The behavior is essentially the same across all these species and yet one would be hard pressed to argue that single-cell organisms have a notion of altruism and empathy in the same sense humans do.

Our brains (including those of scientists) are wired in such a way that they readily interpret the behavior of others in terms of our own mental states.  Such ability is useful in many situations, form navigating daily social interactions and even in the description of scientific data.  Care must be exercise in descriptions based on our own mental states when the outcome can have clear moral and scientific consequences.

Scientists must always keep an open mind.  But before rushing to declare that humans must seek moral guidance from rats, we should pause and try to understand exactly what the data say.  As new experiments are done and more information is available, we will surely be able to discern which of the alternative explanations is the correct one. If additional work confirms the (premature) conclusions of the authors, it will lay the ground work for developing new animal models for human psychological disorders, which will be a welcome development. For now, however, we must await that conclusive work.

J. David Jentsch and Dario Ringach

Symposium Explores Animal Rights Tactics, Responses

On Saturday April 24, 2010, the American Physiological Society sponsored a symposium on Trends in Animal Rights Activism and Extremism. This event, attended by about 100 people,  was part of the Experimental Biology 2010 meeting, which was recently held in Anaheim, California. In introducing the symposium, session chair Bill Yates noted the importance of animal welfare, and the obligation of human beings to provide for the well-being, humane care, and judicious use of animals in research. However, some individuals reject the notion that research with animal models plays a critical role in advancing our understanding of biological processes and is essential to the search for cures. Some with this belief use tactics such as violence and intimidation to prevent researchers from conducting studies using animals. The intent of the symposium was to inform researchers about the tactics of animal rights extremists and what researchers and their institutions can do to protect themselves and their work.

Bill Yates opens the discussion

UCLA Senior Campus Counsel Amy Blum opened the symposium by explaining what kinds of protected information may be subject to the federal Freedom of Information Act (FOIA) or state open records laws. Animal rights extremists have used information obtained under FOIA to target investigators for intimidation and harassment. While FOIA is a mandatory disclosure statute, certain kinds of information may be exempted from disclosure, such as privileged communications between attorneys and clients; trade secrets or confidential commercial or financial information; personnel and medical files; or information that might endanger a person’s life or safety. Researchers should exercise care in how documents and communications are written to avoid unnecessary disclosure of personal information or intellectual property. This effort may be “difficult in the short run” but will “make your life easier in the long run,” Blum said.

University of Iowa (UI) Attending Veterinarian and Office of Animal Resources Director Paul Cooper reviewed the 2004 Animal Liberation Front (ALF) break-in during which some 400 rats and mice were removed from the facility. Four individuals were involved in that break-in, and they made a video. It shows them dumping animals into plastic storage bins, destroying laboratory equipment; trashing researchers’ offices, and pouring acid over research records. Cooper noted that the animals in the storage bins were clearly having trouble getting enough air and probably died of suffocation. Based upon the ALF video and images captured by UI security cameras before and after the break-in, it was evident that the intruders included someone who was familiar with the facility. ALF break-ins have been rare occurrences, but Cooper’s message was clear: Every research institution has to take its security seriously because while if an ALF break-in can happen in Iowa City, it can happen anywhere.

David Jentsch discusses events at UCLA with symposium participants

David Jentsch, a UCLA professor of psychology and psychiatry and bio-behavioral sciences, reviewed the history of animal rights extremism at UCLA. From 2001 to 2003, there were annual demonstrations where animal rights demonstrators criticized the university, researchers, and their work. “When they do that and you make no response, you are contributing to the decline in public confidence,” Jentsch noted. Starting around 2003, extremists began sending threatening emails and vandalizing researchers’ homes during late-night visits, which led to a climate of increasing fear. Extremists left a Molotov cocktail on the doorstep of one UCLA researcher—except that they actually left it at the home of the researcher’s elderly neighbor (Fortunately, the device failed to detonate). Another faculty member and his family were subjected to repeated home demonstrations and threats. The university’s only public comment during this period was a statement denouncing terrorism. This was consistent with views widely held across many institutions that they should not respond to accusations against researchers because that would add to the critics’ credibility. It was the university’s pursuit of this strategy of silence in the face of increasingly hostile and violent attacks that ultimately precipitated a crisis: In the fall of 2006, a researcher who was studying how the brain processes visual information announced that he would terminate his research program. He asked in return that animal rights activists leave him and his family alone. He delivered his plea in an email message to the North American Animal Liberation Press Office with the subject line “You win.”

Over the next couple of years, the University’s responses improved, however the activists’ attacks did not abate. In 2007, there was an unsuccessful attempt to firebomb one faculty member’s car, the home of another faculty member was deliberately flooded. In 2008, the door to the same individual’s home was set on fire; a commuter van belonging to the university was burned; and cars were vandalized in the driveway of a post doc’s home and at the home of a researcher’s neighbor. Finally, in early 2009, Jentsch’s car was firebombed in the driveway of his home. This “intensification to a climax of violence” demonstrated to Jentsch that the “strategy that the university was using wasn’t working and wasn’t going to work.” His response was to found Pro-Test for Science, an organization that subsequently staged the first major public demonstration in support of animal research in the United States.

The first Pro-Test for Science Rally was held April 22, 2009. The goal of the rally was to let the public know that “animal research is contributing to basic science understanding of physiology and helping us to solve an array of problems in biomedicine.” Although counter-protesters showed up to take pictures, Jentsch said that not only did this fail to intimidate the participants, it was “fair to say that everyone who came left feeling that there was something they can do” to support research. It should further be noted that since the 2009 Pro-Test rally, there have been no further violent attacks against UCLA researchers.

“Get ahead of the issue,” Jentsch urged. “Don’t wait.” He recommended that every individual scientist get into the habit of engaging the public about science: “Tell them what you do—be your own advocate.”

Hayre fellow Megan Wyeth emphasizes the importance of public outreach

Americans for Medical Progress Hayre Fellow Megan Wyeth spoke about public outreach for the early career scientist. Public outreach can take many forms, she noted, recommending that everyone work within his or her own comfort levels. She urged those who teach to cite the basic animal research that led to the breakthroughs in order to raise their students’ awareness of what animal research has contributed. “Tell people what you do,” Wyeth said. She suggested emphasizing that animal research is necessary for medical progress, that is irreplaceable for the foreseeable future, and that it is a humane and highly regulated activity.  This was a point that was appreciated by many attendees, including session chair Bill Yates who had earlier stressed the importance of developing good relationships with local journalists and conveying this positive message before a crisis occurs.

Alice Ra’anan

Director of Government Relations and Science policy

The American Physiological Society

Bill J. Yates

Chair, Animal Care and Experimentation Committee

The American Physiological Society

Public outreach is an important duty for all involved with medical research, though as Megan said it takes many forms. Allyson Bennett has discussed how scientists can become involved in debates and web-based advocacy , and organize community outreach programs, while Paul Browne has stressed the need for scientists and physicians to explain how animal research has contributed to the latest advances in medicine. There are many ways to improve public understanding of the importance of animal research to medical progress, but they can all be summed up by David Jentsch’s call to “Tell them what you do—be your own advocate”.

Addiction Research as an Example of Translational Biomedical Research

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

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

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

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

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

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

Regards

David Jentsch

Understanding migraines: The blind leading the…err…rats

Chances are that you have either suffered from migraine yourself or have a family member or close friend who have, after all about 1 in 8 of us will suffer from migraine at some stage in our lifetime, and some sufferers experience repeated debilitating episodes over many years . While headache on one side of the brain is typical other symptoms such as nausea are very common, indeed in some migraine victims nausea is the primary symptom of the disorder.  Through a combination of studies in animals and clinical research using techniques such as fMRI and PET scans scientists have learned a lot in recent years about what happens before and during migraine episodes but we do not yet fully understand what ultimately causes the attacks, and debate rages over the relative importance of some mechanisms originating deep in brain regions such as the hypothalamus and others that start in membranes that surround the brain, (1,2).  Current treatments can help prevent migraine, reduce suffering and hasten recovery they do not work for all patients, and a better understanding of what exactly is happening before and during a migraine attack will aid the development of really effective treatments and preventative measures.  A study published in Nature Neuroscience combines clinical research with studies of rats to provide clues about a key characteristic of migraines that has until now remained unexplained, the exacerbation of the pain experienced by sufferers by light (3).

The team, lead by Rami Burnstein of Beth Israel Deaconess Medical Centre in Boston, decided to concentrate of the role of a particular subset of nerve cells in the retina known as intrinsically photosensitive retinal ganglion cells (ipRGCs) which they knew from previous mouse research to be involved in eye functions that are not image forming, such as setting the biological clock to the day night cycle.  The ipRGCs are stimulated by light both indirectly via the rods and cones and directly through a pigment called melanopsin that they themselves contain.  In order to discover if the ipRCGs are important to light sensitivity in migraine they performed a very neat clinical study involving 20 blind patients who also suffered from migraine. Six of these patients lacked any light perception due to removal of their eyes or damage to the optic nerve, while in the remaining 14 the damage to the eyes was less total, affecting the rods and cones but not ipRGCs, so that while they were unable to see images they could detect light. The results were clear, blue and grey light made the headaches of those who retained light sensitivity worse, while having no effect on the six blind individuals who lacked light perception.

Determining that the ipRGCs are involved in the exacerbation of migraine headaches by light is of course only part of the story, and Professor Burnstein’s team next turned to tracing the nerve pathways that are responsible for the increased pain, knowledge that might help to develop new treatments.  This they could not do in human subjects because the available imaging techniques do not have the precision to determine the connections between individual neurons.  In a series of studies they injected labels including Green Fluorescent Protein into particular areas of the eyes and brain, and in some cases even individual nerve cells, of anesthetized rats with and followed the path of the neurons.  They were also able to use tiny electrodes to record the effect of light on the firing of individual nerves in the brain, something that cannot yet be done in human subjects. An exciting observation was that the ipRCGs connected to cells in a region of the brain known as the posterior thalamus, itself part of the trigeminovascular pathway that is strongly implicated in migraine headache through transmission of nerve signals from the irritated outer brain membranes to the deep brain. When they examined the electrical activity of these cells they discovered that the majority of the cells within the posterior thalamus that are involved in mediating migraine pain are also light sensitive.  Finally they demonstrated that the light-sensitive pain-mediating neurons of the posterior hypothalamus connect to nerve cells in several regions of the somatosensory region of the cortex, an intriguing discovery since abnormalities in this region have previously been seen in migraine patients. This discovery is likely to encourage scientists to study the role of the somatosensory cortex in migraine in more detail.

So how important is this study? Well it’s unlikely that this discovery will lead to any treatment breakthrough in the immediate future, though the discovery that grey light can exacerbate migraine headache is new and may help patients to avoid it.  Despite a perhaps natural tendency for the news media to look for “breakthroughs” the majority of scientific papers published are like this one, providing valuable new insights into biology that contribute to our overall understanding of how biological systems work and happens when they go awry but not indicating an easy fix.  I’ve no doubt that this and many similar basic science studies will contribute to better treatments for migraine in the future, but perhaps not tomorrow!

Regards

Paul Browne

1)      Olesen J. et al “Origin of pain in migraine:evidence for peripheral sensitization” The Lancet Neurology Volume 8, Issue 7, Pages 679-690 (2009) doi:10.1016/S1474-4422(09)70090-0

2)      Alstadhaug K.B.  “Migraine and the hypothalamus” Cephalalgia Volume 29, Issue 8, Pages 809-817 doi: 10.1111/j.1468-2982.2008.01814.x

3)      Noseda R. et al. “A neural mechanism for exacerbation of headache by light” Nature neuroscience Advance Publication Online 10 January 2010 doi: 10.1038/nn.2475