Tag Archives: animal research

Guest Post: Animal models in research are necessary and ethical

The following post was originally published in The Daily of the University of Washington on April 26, 2015. It has been reproduced with permission from the newspaper and the original author. Benjamin Cordy is a neurobiology student at UW, he is also the Editor-in-Chief of Grey Matters Journal – an undergraduate neuroscience journal whose mission is to educate the public and develop effective science communicators.

Guest editorial: Animal models in research are necessary and ethical

On Saturday hundreds gathered in Red Square to voice their opposition to scientific research. At its core, this is the true message of the animal rights movement, which believes that research should never rely on animal models. The march on UW was about stopping science altogether. Is this really the best move for society?

Debates about animal models in research are emotional, contentious, and unfortunately, often fraught with demonstrably false “facts.” This is a serious problem. It is impossible to have a thoughtful conversation about the role of science and medical research in society if a position is based on misinformation and inaccurate beliefs.

Two of the most frequently repeated claims of the animal rights movement are that animal models are not actually useful in science and that there are more effective, humane ways to engage in research. While appealing, both statements are wrong.

The history of science provides countless examples of the utility of animal research. For example, until as recently as 1940 and the development of the “antibiotic age”, a knee scrape, if it became infected, could be a death sentence.

In 1928 Alexander Fleming discovered that when grown in proximity to one another, the mold Penicillim notatum killed the colonies of the often-fatal bacteria Staphylococcus aureus. Unfortunately, Fleming’s test-tube studies failed to show the antimicrobial properties he expected from Penicillin. These results, and the difficulty of isolating Penicillin, ultimately led Fleming to believe that it might only be useful as a topical antiseptic.

Although Fleming’s work showed some promise, Penicillin was not a high priority for antimicrobial researchers. In addition to being very difficult to isolate, its therapeutic properties seemed to be inactivated in blood — making it a poor candidate for treating systemic infections. But by 1940 enough Penicillin was isolated for testing. In a landmark study Ernst Chain and Howard Florey infected eight mice with a deadly dose of Streptococcus pyogenes. One hour later, four of the mice were injected with Penicillin. These mice survived the infection and changed modern medicine forever.

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(Left to Right) Alexander Fleming, Howard Florey and Ernst Chain – Shared the Nobel Prize for Physiology or Medicine in 1945

The amount of Penicillin required to treat a human infection is 3,000 times greater than for a mouse. If animal models were unavailable to Chain and Florey, they would have had to undergo the perfectly unreasonable task of isolating huge quantities of a substance that, as far as they could understand, had no therapeutic value. Simply put, without animal models Penicillin would not have been developed.

Fortunately, the story of Penicillin is not unique. There are literally thousands of medical interventions, drugs, and procedures whose discovery and development required the use of research animals. Modern therapies that require animal models include: vaccines, organ transplants, cancer treatments, HIV/AIDS drug development, and thousands more. The claim that animal models are “bad science” and fail to provide important insights into biological understanding and therapeutic development is dishonest and wrong.

The second position of the animal rights movement is that there are alternatives that are simultaneously more effective and humane. The three most often suggested alternatives are human cell cultures, computer models, and experimentation on human subjects.

Tissue and cell culture experiments are extremely powerful research techniques. Their use provides important insights into the function of individual cells and helps identify potential targets for future therapeutics. However, these studies, by their very nature, can only reveal a fraction of the whole picture. For example, a few cells could never describe the complexity of an entire organ — much less the entire organism. Though important for reducing the number of animals used, these techniques could never replace them.

Computational techniques are another tremendously valuable tool. With mathematical models and data analysis, computers allow researchers to better understand the systems they study. But again, computation is a supplement to animal research, not a replacement. Every computer model has to be validated against data collected from animal research. There is no other way to ensure that a modeling program is accurate.

Furthermore, animal rights activists overestimate the power of computer models. In 2007 researchers were able to simulate a virtual brain of 8,000,000 neurons, roughly the complexity of half a mouse brain. While impressive, this is less than 1/10,000th the number of neurons in a human brain and likely much less complex. The simulation ran on the fastest supercomputer and could only do so for 10 seconds at 1/10th the speed of a real brain. In all, this program required the world’s most powerful supercomputer to model one second of one half a mouse brain. How could a desktop PC possibly predict the behavior of the human brain?

The most troubling alternative proposed by animal rights activists is the use of human volunteers for basic science. In practice, such policies would effectively halt biomedical research. For one, the cost of recruiting and paying human subjects would bankrupt already sparse science funding within months. This of course, assumes that enough people volunteer to participate. Considering that clinical researchers already have difficulty in recruiting people for fairly benign studies, it is highly improbable that eight people would volunteer to receive a deadly dose of Streptococcus pyogenes, for example.

Beyond the practical limitations of using only human subjects, there are serious questions about the morality of doing so. Which population is likely to accept payment for becoming test subjects: the socioeconomically disadvantaged or the wealthy? The argument that humans ought to replace research animals raises real concerns about the exploitation of disadvantaged communities.

It was not long ago that I was sympathetic to some of the positions of the animal rights activists. But, as I learned the science behind biomedical therapeutics, it became clear that because animal models save millions and millions of lives, they are necessary. A powerful research program, which includes the use of animal models, is the responsibility of an ethical society.

Benjamin Cordy, UW neurobiology student

Animal research openness in action – from Cambridge to Florida

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.

Primate products

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

World Week to Speak Up About Animal Research

Banner at UW-Madison, April 2015.

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).

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).

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

En Passage, an Approach to the Use and Provenance of Immortalized Cell Lines

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

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.

Download original file2400 × 1999 px jpg View in browser You can attribute the author Show me how 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).


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.

Pioneering non-beating heart transplant success – thanks to animal research!

Yesterday a team led by Consultant Surgeon Stephen Large at Papworth Hospital near Cambridge in the UK announced the successful transplant of a non-beating donor heart to heart failure patient Huseyin Ulucan, the first time such an operation has been performed in Europe.

Current practice is for donor hearts are obtained when the donor has been declared brain dead, but their heart is still beating, and the heart is then cooled and transferred to the recipient.  The technique used in Mr Ulucan’s operation involves re-starting the heart in the donor five minutes after death and perfusing it and other vital organs with blood and nutrients at body temperature using the Transmedics Organ Care System (OCS). In this case the donor heart was kept nourished and beating for three hours before being transplanted into Mr Ulucan. The main importance of the technique it that it has the potential to substantially increase the  number of donor hearts available for transplant, though it also enables the surgical team to assess the health of the donor heart more thoroughly.

Transmedics_OCS

The Transmedics Organ Care System.

 

The technique they used was developed by Cardiothoracic Transplant Registrar Simon Messer, who developed it with Consultant Surgeon Ayyaz Ali, and commented:

Using techniques developed to recover the abdominal organs in non-heart beating donors, we wanted to apply similar techniques to hearts from these donors.

“Until this point we were only able to transplant organs from DBD (Donation After Brain-stem Death) donors. However, research conducted at Papworth allowed us to develop a new technique not used anywhere else in the world to ensure the best possible outcome for our patients using hearts from non-heart beating donors.”

This approach, known as normothermic donor heart perfusion, is an example of a technique that is showing great promise in surgery, in 2013 we discussed how the normothermic transplantation technique using the OrganOx system – developed through research in pigs – had been used successfully in a liver transplant operation, and large scale clinical trials are now underway.

In a review entitled “Normothermic donor heart perfusion: current clinical experience and the future” published in 2014 (1) Simon Messer and colleagues highlights the role of research in animals including dogs, pigs and monkeys in demonstrating that Donation After Cardiac Death (DCD) heart transplantation is possible, and that normothermic donor heart perfusion improves the success rate.

DCD heart transplantation has been shown to be possible in animal models [32-34] and in humans [35, 36] provided that the warm ischaemic time could be kept below 30 min. However, we suspect that the only safe way to adopt DCD heart transplantation into routine clinical practice is by ex vivo functional and metabolic assessment following appropriate reconditioning. Normothermic blood perfusion has been shown to be superior to cold storage in preserving DCD hearts in dogs [37]. In the pig, reconditioned DCD hearts were shown to have comparable function to BSD donor hearts [38]. In an asphyxiation pig model, DCD hearts exposed to 30 min of warm ischaemia were evaluated on the OCS using lactate assessment. Four of seven transplanted DCD hearts were subsequently weaned off cardiopulmonary bypass on low dose inotrope [39].”

In a key paper published in 2013 (2) – reference 38 above – an Australian team assessed whether the Transmedics OCS system could be used to successfully transplant non-beating hearts in pigs, concluding that:

The Transmedics OCS provides an excellent platform to assess DCD heart recovery following warm ischemia. Using a clinically applicable model, we have shown that DCD hearts with WIT ≤30 mins appear to be a viable source of additional organs in cardiac transplantation and warrant human studies.”

Pigs are a excellent species for many transplant research studies. Image courtesy of Understanding Animal Research.

Pigs are a excellent species for many transplant research studies. Image courtesy of Understanding Animal Research.

Results such as this led to Simon Messer and colleagues concluding in their 2014 review (1) that:

It is estimated that use of DCD hearts may increase the number of heart transplants by 11–15% [40]. We believe that functional assessment during ex situ normothermic donor heart perfusion must be made prior to transplantation in this setting. In Papworth Hospital, we are currently investigating whether DCD human hearts can be assessed on the OCS using pressure volume loop measurements.

In conclusion, cold ischaemic preservation for the donor heart has been universally adopted into clinical practice over the last 45 years. However, the diminishing pool of ideal donors coupled with the drive to further improve heart transplant outcomes mandate a rethink in this area. Normothermic donor heart perfusion is the logical next step and from the clinical experience to date, appears to hold promise.”

We congratulate Stephen Large, Simon Messer, Ayyaz Ali and colleagues at Papworth Hospital for taking this next important step successfully, and we wish Huseyin Ulucan a full recovery and long life.

Yesterday’s announcement was a reminder that more than 50 years after Norman Shumway’s pioneering heart transplants studies in dogs, animal research remains crucial to progress in this important field of medicine.

Paul Browne

1) Messer S1, Ardehali A, Tsui S.”Normothermic donor heart perfusion: current clinical experience and the future.” Transpl Int. 2014 May 23. doi: 10.1111/tri.12361. PubMed:24853906

2) Ali AA, White P, Xiang B, et al. “Hearts from DCD donors display acceptable biventricular function after heart transplantation in pigs.” Am J Transplant 2011; 11: 1621. Link

 

Animal research successes spur growth in science…but PeTA can only complain

What do multiple myeloma, influenza, advanced breast cancer, atrial fibrillation, thyroid cancer, ear infection, advanced ovarian cancer and obesity all have in common? One commonality is obvious – they cause suffering, sickness and sometimes death in people around the world. Another commonality is less obvious – these are each conditions that are now being treated with new drugs just approved by the U.S. Food and Drug Administration (FDA) in the past three months alone. That’s right… in the period from Thanksgiving 2014 until now, new drugs that treat each of these conditions have become available, and these agents will be used to treat the illnesses that may affect millions of Americans. Eventually, they will likely have enormous worldwide impacts on these diseases. That’s something to be thankful for.

While some are thankful that the scientific progress is successfully tackling human suffering and disease, others cast doubt on the way that progress is achieved. In a newly published analysis entitled “Trends in animal use at US research facilities” [1], employees of People for the Ethical Treatment of Animals (PeTA) – a self-avowed animal rights organization – report that, amongst the largest research universities in the United States, the number of animals involved in research has grown by over 70% during the past 15 years. In their publication, the authors express alarm over the growing use of animals not covered by the Animal Welfare Act (AWA), mostly mice and fish, in biomedical research, without making any mention of the impact of this research growth.

This growth in animal research in the US is directly linked to an accelerating pace of scientific study and its benefits. A brief visit to the FDA’s “New Drugs at FDA page” makes it quickly apparent that the rate of approval of new medications is astounding. Where is this progress coming from? At least in part, it’s coming from the scientific discoveries that are pouring out of the research laboratories located in colleges and universities, institutes and pharmaceutical and biotechnology companies around the globe. A good example is the innovative BiTE antibody Blincyto (blinatumomab) which was approved for use in treating B-cell acute lymphoblastic leukemia in December 2014 (clinical evaluation against other cancers is ongoing); as we discussed in a blog post in 2008, animal research – particularly studies in mice – played a key role in its development and early evaluation.

Thanks to the researchers that occupy laboratories around the world, scientific discoveries are coming faster than ever, and all of us benefit. It’s not just that there is more research being done – it’s that the impact of the science is better than ever thanks to more advanced technologies, accumulating knowledge of how the body works and more advanced animals models, including ones that mimic human disease processes in increasingly sophisticated ways that promote new discoveries and new opportunities to develop novel drugs.

Why is the scale of animal research growing in the US? The answer is clear: scientific progress is cumulative. One discovery often enables multiple other lines of work. The discovery of the structure of DNA, for example, enabled thousands of efforts to find the genetic causes of disease. Because of this, successes build on successes and research grows.

What is the consequence of the growth in animal research? The answer is: new treatments, new cures, less sickness and longer, healthier lives.

In their paper, the PeTA employees fail to mention any of the following accomplishments, allow of which resulted from the growing scientific research efforts around the world:

But this isn’t the end. To these existing accomplishments, add the work that was started in the past 15 years and will yet unfold in the forthcoming decade AND the overwhelming progress in basic/fundamental research that will lead to new treatments and cures throughout the first half of the 21st century, and you have the recipe for a growing animal research infrastructure in this country.

As recent statistics from the UK indicate, the increase in the use of mice and fish in research is driven almost entirely by the increasing number of studies that involve the use of genetically-modified (GM) animals. In other words, the increase is driven by scientific and technological advances that had a profound impact on biomedical research over the past 15 years, rather than any desire to avoid using species regulated by the AWA (while mice and fish studied in Universities are not covered by the AWA, research involving them is regulated in multiple ways, including through the federal Office of Laboratory Animal Welfare which issues the PHS Guide for the Care and Use of Laboratory Animals).

“Recent statistics from the UK indicate, the increase in the use of mice and fish in research is driven almost entirely by the increasing number of studies that involve the use of genetically-modified (GM) animals.”

Growing study of GM animals has occurred because these models are enormously useful. To take just one example, the National Institute of Child Health and Development recently published an online article entitled “It’s in the DNA: Animal Models Offer Clues to Human Development”, discussing the role of animal models in helping to understand human development and developmental disorders. But this is far from the only example, studies in GM mice are key to many of the state-of-the-art emerging fields in biomedical research. These range from the very new areas of optogenetics – which uses light to control activation of individual cells – and gene editing techniques such as CRISPR that have the potential to cure genetic disorders, to new therapies such as cancer immunotherapy and treatments for rare genetic disorders such as progeria and Pompe disease which are being used to successfully treat patients for whom effective therapies were previously unavailable.

The rise in the numbers of zebra fish is also driven by their value as research models. As vertebrates they share over 84% of the genes that cause disease when defective in humans, while their rapid reproduction and transparent eggs make them ideal subjects for genetic and developmental studies. It’s not surprising that they are both an increasingly popular species in basic biomedical research, and in the preclinical evaluation of potential new therapies and of the environmental safety of chemicals.

In recent years zebra fish have become an increasingly popular species in biomedical research.

What the statistics presented by PeTA in their article don’t tell you is that, while the number of experiments and studies have increased, animal research increasingly involves Refined techniques that produce minimized harm to the subjects and Reduced numbers of animals per study. And of course, animal research directly led to the ability to Replace animals in some types of studies, altogether. The efficacy and efficiency of animal research is advancing, and individual discoveries are, on average, being made with fewer animals. That is a fact missed entirely by the PeTA article.

Furthermore, within the concept of refinement is the idea that researchers should use animals that will suffer less in a laboratory setting wherever possible [2]. So replacing a small number of “higher” mammals with a high number of “lower” animals is consistent with the 3Rs principles of animal welfare. PeTA neglect to mention that USDA statistics show a 40% fall in the use of AWA-covered species over the last 15 years, and it is likely that a small proportion of the rise in use of non-AWA covered species is due to technological advances that have allowed non-AWA species (e.g. GM mice) to replace AWA species (e.g. monkeys) in some studies, for example to develop new treatments for HIV/AIDS, in line with the principle of Refinement we have outlined.

Number of animals used annually for research in the US

“PeTA neglect to mention that USDA statistics show a 40% fall in the use of AWA-covered species over the last 15 years”

Through the implementation of these 3Rs, scientists ensure that they engage in socially-responsible and ethical work. What the authors of the PeTA study should do is to explain how achieving their end goal of a virtual end to animal research, which will reverse the trend of accelerating discovery and medical progress upon which it depends, is ethical or defensible.

  1. Goodman, J., Chandna A., and Roe K. 2015. Trends in animal use at US research facilities in: J Med Ethics. 0:1-3
  2. Richmond, J., 2014. Refinement Alternatives: Minimizing Pain and Distress in Allen, D. and Waters M. ed. In Vivo Toxicity Testing” in: Reducing, Refining and Replacing the Use of Animals in Toxicity Testing. Cambridge: RSC. pp. 133

David Jentsch

Implementing the 3Rs at the University of Oxford

This Guest Post is by Stuart Peirson, Associate Professor in the Nuffield Laboratory of Ophthalmology and chair of the 3Rs sub-committee at The University of Oxford. This article was originally posted on the website of the National Centre for the Replacement, Refinement & Reduction of Animals in Research (NC3Rs) and is reprinted with full permission. This article explains how Oxford is supporting the 3Rs, please read out page on UK research regulations and the 3Rs for more information.

Oxford imageThe University of Oxford is one of the world’s leading centres for biomedical research, with outstanding strengths in both basic science and its clinical application. The University’s Policy on the Use of Animals in Scientific Research outlines the University’s commitment to ensuring that all those involved in animal-based research are proactive in pursuing the 3Rs, engage fully in the ethical review process, and fulfil their moral and legal responsibilities for the care and welfare of animals.

Ethical review

Reflecting the enormous breadth of research across Oxford, the University currently holds over a hundred different project licences, with over a thousand personal licence holders. This poses a number of challenges for the coordination of ethical review as well as the dissemination of best-practice and advances in the 3Rs.

The critical element in this process is the Animal Welfare and Ethical Review Board (AWERB). All applications for project licences require the ethical approval of the University before they are passed to the Home Office. At Oxford, this involves a rigorous and objective process of ethical review that challenges scientists to justify their use of animals, and that requires them, where the use of animals is unavoidable, to minimise animal numbers and maximise animal welfare.

At Oxford the AWERB process consists of two principal elements. Firstly, a central Committee on Animal Care and Ethical Review (ACER) is responsible for setting policy, as well as reviewing applications involving the use of non-human primates, severe protocols or novel techniques. Secondly, Oxford also relies upon a network of Local Ethical Review Panels (LERPs), which consider all other project licence applications. All project licences are required to provide a written retrospective review for their LERP at two years and four years, providing a critical opportunity for the LERP to assess how project licences have applied the 3Rs in their research.

The 3Rs sub-committee

In addition to the ethical review process, the University also has a 3Rs sub-committee reporting directly to ACER, which receives copies of all retrospective reviews to identify key developments in the 3Rs across the University. These developments are combined to form a termly 3Rs newsletter, which also contains information on relevant workshops, lectures and courses, such as NC3Rs notifications.

In addition, the committee also recognises the achievements of particular groups in the application of the 3Rs, providing letters of commendation to those project licence holders who show particular commitment and dedication to the 3Rs.

Since the introduction of the University’s Policy on the Use of Animals in Scientific Research, all departments involved in such research are also required to have termly Departmental Animal Welfare meetings. These are attended by project and personal licence holders, vets, Named Animal Care and Welfare Officers (NACWOs) and animal care staff, and provide a valuable forum for discussion of advances in the 3Rs.

The relationships within the network of animal committees at the University of Oxford

Summary of the role of the 3Rs sub-committee within the ethical review process

The 3Rs sub-committee also arranges lectures and workshops in areas it has identified as being important. For example, in 2013 we held a workshop on ‘Developments in Transgenic Mouse Models’, involving speakers from both Oxford and MRC Harwell, covering subjects ranging from colony management and background strains to existing transgenic resources and developing new transgenic models.

Working together

Biomedical Services (BMS) is an independent University Department of the Medical Sciences Division. BMS provides world class animal facilities that provide accommodation and care for its animals, delivered by professionally trained staff. A central principle of the University’s policy is the commitment to a culture of care, encouraging a team approach to animal work that fosters good communication and collaboration between all those working with animals in scientific research.

To facilitate this, in addition to their role on AWERBs, BMS staff, (including vets and NACWOs), routinely attend Departmental Welfare meetings, providing an informal opportunity for project and personal licence holders to discuss their work. The regular interaction has encouraged BMS staff and academic scientists to work together to achieve both high quality research and animal welfare.

Finally, BMS also provides key central services, such as the University’s new online training and competency records and colony management systems. Furthermore, practical veterinary assistance is also provided, such as a recent series of workshops on aseptic technique.

The future

Whilst Oxford has made great progress in implementation of the 3Rs throughout its scientific research programme, more can still be done. For example, we are currently building a ‘3Rs Knowledge Bank’ containing key and up-to-date references and protocols relating to best practice in the 3Rs.

We are also currently working on a University Strategy for the 3Rs, based upon the NC3Rs publication ‘Implementing an Institutional Framework for the 3Rs’. This will ensure that the 3Rs are thoroughly embedded in the research activities of the University, and that when animal research is necessary, it is conducted to the very highest of standards.

Professor Stuart Peirson