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Animals in Biomedical Research: What they have given us and what we owe them

Medical research involving human subjects must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for research must be respected. – Helsinki Declaration, 1964

Helsinki Declaration

Bulletin of the World Health Organization, 2001, 79 (4)

Health research has given society medications, devices and procedures that have unequivocally improved the quality and quantity of human life. Indeed, animal-based research is also at the basis for development and approval of medications, devices and procedures that have improved the life of our pets and domestic animals. Thus, the distinction of beneficiaries of research into humans versus animals is somewhat a tautology.

While biomedical research is largely beneficial, great wrongs, as judged through history’s unforgiving lens, have been committed under the guise of “research”. These ethical failures in studies conducted on humans and other animal species have shaped the regulations and policies that guide modern clinical trials in humans and preclinical studies in animals. Examples that are well documented in the field of human research include the collaboration of some German physicians with eugenic-driven genocide in Nazi Germany and the U.S. Public Health Service’s Tuskegee experiments (Figure below). The Tuskegee study, conducted between 1932 and 1972, allowed the natural progression of untreated syphilis in rural African-American men in Alabama while participants were receiving medical care.

The Nazi Doctors
Drawing blood from Tuskegee test subjectAs a result of these (and other) ethical failures all researchers must pass a course in Ethics that teaches the lessons of history and exposes us to the principles of the Helsinki Accord. This remarkable document, adopted by the 18th World Medical Association General Assembly in 1964 primarily discusses the need to protect humans in research. However it notes: Medical research involving human subjects must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for research must be respected.” Thus the role of properly conducted animal research is recognized to be essential to human research and researchers that use animals must treat them with respect.

Queen’s University has strict policies to ensure the care of animals in research and enforces adherence to a policy that reduces, replaces and refines the use of animals (the “3R’s”), as feasible. Every proposed study is reviewed and approved by a committee that ensures the research is conducted in accordance with the “3-Rs”: Replace, Reduce, and Refine. I borrowed this slide from Mrs. Karen Clifford, the Head of Home Office Administration Unit at Oxford University, and a participant in our conference. These principles apply to research in England, Europe and North America. They are self-explanatory but are how those of us who use animals in research function.

Animals Scientific Procedures Act 1986PSDLH= pain, suffering, distress and lasting harm

The use of animals in research is strictly regulated both nationally and locally and is conducted on animals bred for research and housed in facilities that are clean and which increasingly acknowledge the animals’ comfort, ecology and social needs. Locally, the University Animal Care Committee (UACC) is responsible for the review and approval of all protocols proposing the use of animals in research, teaching, or testing at Queen’s. They ensure that the welfare of the animals is a prime consideration in their procurement, care and use and that the highest ethical standards, as defined by the Canadian Council on Animal Care (CCAC), are observed. Prior to every experiment a detailed submission with the proposed protocol is required and these proposals are carefully scrutinized to ensure pain is minimized, anesthesia is adequate, endpoints are humane and sample size is no larger than required for appropriate statistical analysis of results.

This blog attempts to provide some of the transparency around the use of animals in research requested by animal rights groups, including a local organization, Queen’s Animal Defense.

labrats

 The blog aims to:

1) Remind readers of the process of medical discovery, emphasizing the pivotal role that preclinical testing in animals has had in creation of our current state of medical capability.

2) Summarize how animal research is regulated and conducted.

3) Convince those who are open to persuasion that animal research is conducted rigorously with careful attention to minimizing animal pain and suffering and indeed to minimizing the use of animals in research.

4) Remind readers that mammals (humans, mice and rats) share commonalities that while imperfect allow extrapolation, with appropriate caution, of findings made in mice and rats to humans. The extrapolation is imperfect-but we share much of the same genome, proteome and physiology and even some of the same diseases. Did you know mutation in the ether a-go-go gene, which makes the legs of fruit flies shake upon exposure to ether anesthetic is the same gene that causes infantile seizures in babies and sudden cardiac death in adult humans?

5) Emphasize that most animal research is performed in rats and mice, and increasingly in fish and worms. Humans are oddly compartmentalized in our views on the treatment of a house mouse versus a lab mouse. Certainly mice who are not bred for research have no protection and are the routine target of domestic and public health-related pest control.

6) Propose that while animal research is essential to improving human health in 2015 there is gradual progress to eliminating/reducing the use of animals through the use of new technologies (such as computer simulation, inducible progenitor cells and recombinant DNA technology).

This is not a blog about the:

1) Use of animals in nonmedical research (i.e testing cosmetics).

2) Reliance of much of the world’s population on animals for food and clothing

Currently, diseases cannot be cured in silico and medical devices, like artificial joints, pacemakers and defibrillators cannot be tested solely in computers. We want demonstration that our medications are safe and our medical devices durable and effective in life. There is not a queue of volunteers to participate in experiments that move from the chemistry, physics and engineering labs directly to humans, without passing through preclinical studies in animals (usually rats and mice). We are understandably outraged when a drug, like thalidomide is brought to market with inadequate testing, leading to human death and disability (but more on that later). Some lay people have an imperfect understanding of the rigours that are used to minimize pain and suffering in modern animal-based research and even more fail to understand how drugs, devices and procedures are actually developed and how animal research is a legal requirement to move a potential therapy from the mind of a scientist to a patient’s body.

The reality of drug approval (in the USA and Canada) is that extensive preclinical study in multiple animal species is legally required prior to entering clinical trials in humans, as illustrated below.

Drug approval process

The role of animal based preclinical research in drug approval

Some are fundamentally opposed to animal research and this blog will not alter their position; however, most people have a certain degree of moral ambivalence toward animal-based research, particularly when it uses higher mammals. The use of animals in research does reflect at some level a belief in primate primacy. Some who protest against animal research engage in magical thinking, which allows them to ignore how research and discovery actually occur and to conveniently forget what has been attained using animals in carefully-conducted, well-regulated research studies. As a society we spend a lot of ink and many hours of television time on why the Toronto Maple Leafs can’t win at ice hockey or how to dress for summer; however, little energy is expended on understanding how we came to have open heart surgery or pills that cure diseases like pneumonia, chronic myelogenous leukemia and (recently) hepatitis C.

We often fail to understand how research is actually conducted (with much more rigour, oversight and attention to avoidance/minimization of pain and suffering than recognized). Likewise, we often forget the history of discovery and commercialization of biomedical products, focusing on the last stage of the process of discovery (the clinical trial) while conveniently ignoring the early research, which was conducted in part in animal models of human disease. I say “in part” because there is a temporal nature to the pathway to discovery. There is a stage in discovery, often early, where cells, proteins and DNA are sufficient and the use of animals is less intense (although one might ask from whence the cells, proteins and DNA arise). A discovery may begin on the laboratory bench top (let’s say-recognition that tyrosine kinases are activated in chronic myelogenous leukemia (CML) and that these kinases promote the rapid cell division of leukemia). However if a tyrosine kinase inhibitor is to advance to use in humans (i.e. creation of an inhibitor drug like Gleevec-Imatinib®), it must pass through animal models to assess the drugs safety and efficacy. Drugs that pass this hurdle may then be considered for early phase study in humans in the so-called “Phase 1” clinical trial.

The debate about the use of animals in biomedical research is often misinformed by a false belief in our capacity to use computer modeling or cell based research to fully complete the journey from hypothesis to discovery to application. Unfortunately human disease cannot yet be fully modelled by a computer, although this is improving. In addition there is a common overestimation of our current capacities to discover new therapies solely by the use of computer models of health and disease (so called research in silico research). The use of insulin that keeps many children alive did not spring into this world from a culture plate-it was discovered in dogs (although after a half-century in existence we figured out how to make it in bacteria). Likewise, even cell-based research requires a source of cells. In addition, there is a failure to understand (or lack of interest in) the reality of how animal research is conducted. Because humans are animals we should all be concerned that research-using animals is conducted with rigour and compassion.

Sometimes, objections to animal research are based on misinformation; other times it is based on a perceived lack of relevance of the research to the critic. It is amazing how a lethal disease changes one’s perspective on how valuable it is to develop and test new therapies in rodents. A good example of a battlefield conversion is the case of Ms. Teva Harrison. When diagnosed with an aggressive tumour she modified her beliefs about the use of animals in research from “No animal-based research” to “Animal-based research for medicines-not cosmetics”. Her decision is personal but her evolution of thought is worth considering.

I believe in kindness where possible, and I don’t think it’s terribly kind to test drugs on animals. But I’m really glad we do it, which is a surprise to me. Teva Harrison

Teva Harrison CartoonSo how should scientists and their universities address the concerns of individuals and groups who object to the use of animals in research? I recently attended a meeting to discuss just this subject. Convened by Dr. Andrew Winterborn, the Chief Veterinarian and Director of the Research Ethics Unit at Queen’s University, the meeting in Kingston was attended by research administration leaders from universities across Canada. The goal of the meeting was to discuss how to best ensure health research using animals is conducted in an environment where society is polarized, despite more than a century of progress in medicine and surgery that has animal research at its foundation. One concept that emerged from the meeting and resonated with me was that the best approach to the public is openness and transparency. The public should be exposed to what animal-based research actually is, what it is not and should be educated regarding the benefits derived from this enterprise.

Mrs. Clifford discussed the Oxford University experience in dealing with public concerns the use of animals in research. Animal rights activists used threats of mass protests and threats to public safety to coerce a local council to throw out Cambridge University’s plan to build a new primate experimentation laboratory. South Cambridgeshire district council rejected the university’s application to build the facility at Girton (see below). The lab was intended to conduct research into brain diseases. This would have involved experiments on macacques and marmosets. Ultimately the project was cancelled because the cost of security (protection of people from animal rights activist was unsustainable: Cambridge university warned of the adverse consequences of the council’s decision:
Protest fears halt animal research planhttp://www.theguardian.com/uk/2002/feb/07/research.businessofresearch

Brian Cass, the managing director of Huntingdon Life Sciences, reported that the company spent millions of pounds protecting its 1,200 employees and was quoted as saying the decision not to proceed was a victory for a “very small number of militants”.

The animal right group used intimidation and misinformation successfully. Chris Boffey writing in the Jan 28 2004 edition of the Telegraph quoted a Mr. Cass, age 54, who was hospitalized three years prior to the Girton retreat after being attacked by activists carrying pickaxe handles. “We in the research community have been assured of the support of the Government, including personal endorsements from Tony Blair, but this decision is saying that violence and illegal protest works.”

The animal rights groups have a different view. Andrew Tyler, of Animal Aid, which has been one of the main opponents to the laboratory, noted “It would have been a factory to mutilate the brains of monkeys and then dispose of them. It would have made Cambridge University the monkey torture capital of Europe”.

For examples of the types of research Cambridge won’t be doing as a result of the failure to create an animal facility to focus the study of neurological diseases see: the Brainfacts webpage (below). In case you think that Cambridge no longer needs to do research in the neurological diseases because there are already so many successful treatments: stop by a neurology clinic. The number of people with refractory seizures, Parkinsonism, ALS and tremors is staggering.

Success StoriesAfter extreme animal rights activists prevented the building of an animal research facility at Cambridge University UK they turned their tactics of harassment, intimidation and propaganda on Oxford University.

They fully intended to ring Oxford’s academic neck..but to paraphrase Winston Churchill, Oxford proved to have a thick neck and was not so easily intimidated. This quote relates to Churchill’s response to a derisive comment by French Marshal Philippe Pétain, future leader of the collaborationist Vichy French government who, believing Nazi Germany would successfully invade Britain, told Churchill that in three weeks Britain would “have its neck wrung like a chicken.” Churchill’s response: “When I warned them that Britain would fight on alone whatever they did, their generals told their Prime Minister that ‘In three weeks England will have her neck wrung like a chicken.’ Some chicken! Some neck!” — Winston Churchill, Ottawa, Dec. 30, 1941

Churchill

Oxford’s approach was resolute and relied of transparency. By exposing and demystifying the use of animals in research they conferred dignity to the animals at whose expense we learn and perfect both human and veterinary medicine. They also disarmed radical elements who misrepresent biomedical research as secretive, vile and hidden. So rather than hiding animal research and locking it away Oxford adopted the commitment to openness and transparency that is now becoming the common direction for research establishments across the United Kingdom  (see Figure below). This openness is visible on their web pages in which they provide “unbiased information on animal research”.

Concordat[1] copy

The Commitments:

Signatories to the Concordat have agreed to be more open about their use of animals in research, and to abide by the following four commitments.

Commitment 1: We will be clear about when, how and why we use animals in research

Commitment 2: We will enhance our communications with the media and the public about our research using animals

Commitment 3: We will be proactive in providing opportunities for the public to find out about research using animals

Commitment 4: We will report on progress annually and share our experiences

All signatories agree that they will work to fulfil the four Commitments, initiating projects and strategies that are relevant and appropriate to their organisations to be more open about their use of animals in research. The signatories will be asked to report on their progress in taking these steps.

In Canada, University of British Columbia (UBC) has adopted a similar approach. Their website unapologetically discusses how animals are treated and reminds us all of the discoveries that have resulted directly from research.

Animal Research UBCEnough rhetoric about animal research. How about a couple of real world examples.

Discovery of insulin: Diabetes is an autoimmune disease in which the beta-cells in the pancreas are destroyed. As a result the hormone insulin that controls the level of blood sugar is not produced. Type 1 diabetes results in insulin deficiency and was, throughout history, a fatal metabolic disorder in which afflicted children gradually wasted and died. The discovery of insulin and its translation into a therapy for human diabetes is a great Canadian success story. The work of Frederick Banting, Charles Best, John McLeod (at the University of Toronto) and J. B. Collip (at the University of Alberta) was only possibly because of animal research. The search for insulin, its isolation and the story of the rapid transition for lab bench to patient bedside is eloquently summarized by my friend and colleague, Dr. Michael Bliss, one of the world’s leading medical historians, in his book, The Discovery of Insulin. This is a read that reveals the anguish and ecstasy that is research.

The discovery of Insulin

For the purpose of this blog however it is the animals not the humans that are key to the story. The discovery of insulin required the sacrifice of many dogs, from whom the peptide was isolated. Banting wrote a note to himself, “Diabetus/Ligate pancreatic ducts of dog. Keep dogs alive till acini degenerate leaving Islets. Try to isolate the internal secretion of these to relieve glycosurea.”

Banting and Best with dogBanting and Best with one of their research dogs

As children were dying the pancreatic extracts containing insulin quickly moved to patients. The results of treatment with insulin (called Isletin in those days) was dramatic, as illustrated by the “Before and After” photos below of a young girl with type 1 diabetes who was treated with the new therapy.

Patient before and after insulin 1922

Patient of Dr. H. Rawle Geyelin, before and after Treatment with Insulin, 1922.

Impact of animal based researchDocumentation of “Impact” of animal-based research: “N = 1”.

The insulin was commercially prepared from pigs. Eli Lilly stepped in and perfected the manufacture of insulin but once again it was animal research that was key. In fact two tons of pig parts were needed to extract just eight ounces of purified insulin.

Eli Lilly's InsulinEli Lilly’s insulin (Iletin)-circa 1920

It is true that in time we learned to make insulin bacteria using recombinant DNA technology..but the journey began in animals. As some reassurance to those opposed to animal research, the use of large animals in research is decreasing as our biologic precision increases. In the case of insulin, science overtook the need for porcine sources for insulin and in 2005 Eli Lilly issued the announcement that it was discontinuing porcine insulin production.Lilly Letterhttps://investor.lilly.com/releasedetail.cfm?ReleaseID=168048

Recombinant DNA technology: creating insulin without using animals

It was recombinant technology (meaning inserting a human gene into the genetic material of a common bacterium) that removed the need for animals in allowing the bacteria to become a factory that makes the human insulin (Figures below). Like the original production of insulin, a collaboration between the University of Toronto and Eli Lilly Pharmaceuticals, creation of the recombinant DNA technology to produce insulin in E. Coli bacteria from the human insulin gene was accomplished by a partnership between academia (City of Hope Medical Center- Roberto Crea, Ph.D., and Keichi Itakura, Ph.D) and industry (Genentech- David Goeddel, Ph.D. and Dennis Kleid, Ph.D).

Screen Shot 2015-06-29 at 1.36.26 PM

Insulin was an early example a translational discovery in which animals were invaluable. The story of insulin is interesting because it illustrates that while the use of animals was critical for the discovery advances in science eventually allowed insulin production to morph into an animal-free enterprise. It is likely that, as in the insulin story, we will increasingly use animal research and production for more limited periods of time in the lifecycle of discovery and translation. However, with each new discovery there remains a need to test and perfect the drug/device in animals.

Thalidomide and animal research:

There are often cries from the animal rights world that research in animals is misleading, otherwise why have we not cured cancer or sepsis, why did we have the thalidomide tragedy of animal research is so valuable in protecting humans? The devil is of course in the details. While there are species differences in pharmacology and disease pathophysiology, the predominant flaw in most cases is sloppy science and overstatement of results. The much-touted ease of curing diseases in mice is often the result of preclinical trials with small sample sizes and short duration. Paradoxically, the substitution of “failure to thrive” criteria (such as a 10-20% weight loss or failure to groom) as a surrogate endpoint for mortality, while well intentioned, overstates the efficacy of interventions. If we could conduct survival studies (rather than euthanizing animals when they failed to thrive) it would be hard to cure cancer in mice too! When we add inadequate sample size and invalid endpoints to the mix we quickly realize the flaw with many animal studies is not the use of the animal but a sloppiness that leads to flawed conclusions. Moreover, scientists and the media often do a disservice to the public by overstating findings, failing to stress limitations and failure to use meaningful endpoints that can be extrapolated to human disease. We owe it to animal and human subjects to do the studies with rigour, in a blinded, placebo controlled design with adequate power (numbers of animals) to reach a robust conclusion. That said, there are few examples of therapies that only work in humans.

So what of thalidomide? Did animal studies fail to detect the toxicity of this drug?

Like human research the validity depends in large part on the rigour with which the study is conducted. As you will see below, thalidomide, the disastrous anti-emetic was marketed to pregnant women in Canada with inadequate animal research (and catastrophic consequences). Approval was not preceded by proper testing in animals. When (too late) it was tested in various species of pregnant animals it caused the same birth defects as in humans. In the USA, the drug was withheld form the public for lack of evidence, ironically by a Canadian. Dr. Frances Kelsey, a BC native who is now over 100 years of age. Dr. Kelsey was recently interviewed regarding how she declined to recommend thalidomide. As a rookie Food and Drug Administration (FDA) scientists handling the Thalidomide file, she felt the preclinical and clinical evidence was inadequate and, much to the dissatisfaction of the manufacturer, the William S. Merrell Co. of Cincinnati, slowed the approval of thalidomide. Unfortunately this damage to fetuses was not anticipated in Canada and the drug was approved and used.

Canadian doctor averted disaster By keeping Thalidomide out of US

Could Thalidomide’s toxicity have been detected by animal-based research?

Thalidomide 1

Screen Shot 2015-06-29 at 1.43.59 PM

In short, thalidomide was a preventable tragedy. Had appropriate preclinical studies been conducted in animals much human suffering would have been prevented.

Conclusion: We are trying to improve animal research by mandatory ethics training, adherence to the 3Rs (which ultimately tries to replace animals with other reductionist tools for discovery) and greater public transparency. In time, the use of inducible progenitor cells (IPSCs), stem cells derived from differentiated cells that allow modeling of human disease, as well as recombinant DNA technology and in silico modeling will reduce our reliance on animals in research. Perhaps one day this need will be eliminated…and who would not wish this? However, for the foreseeable future the value of animal based research is unassailable (and the lack of a substitute for this scientific approach is clear).

If after all this you remain fully opposed to animal research than I encourage you to consider signing the form below and carry it with you in the event you are exposed to an illness requiring medical care. In so doing you will consider the consequences that a ban on animal research would have for you and your loved ones.

Screen Shot 2015-06-29 at 1.45.20 PM

In the end, I understand the ethical challenge of animal research and approach it from the perspective embodied in this quote (which I generated myself). I acknowledge similar quotes by everyone from Mark Twain to Carrie Underwood.

Some of the greatest souls I know belong to canines; indeed I prefer most dogs to many people. Stephen Archer

 

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Dr. Archer, Dept. Head
Dr. Archer, Dept. Head