Why using human-based strategies in health research? In the context of health research, the systematic review of animal models that are used to study human diseases or assess toxicological risks are missing. In fact, animal model reviews do little to assess the value or clinical relevance of animal models but rather insist on what the model is used for and what has been done with the animals. Furthermore, meta-analyses (combining and pooling the results of many experiments) are even more difficult to find. This lack of careful evaluation of animal models used in research causes a waste of resources and misleads investigators.

Historically, animal models have been used to obtain information on health disorders and test the safety of other chemicals before putting them on the market for human use. Animal research represents the principal category of studies funded by the Canadian Institutes of Health Research, since it takes up more than 60% of the grants and is 3 times the number of clinical studies. In practice, grants are directed to clinical research if there is prior animal data supporting further testing on human subjects. In addition, Health Canada requires evidence that drugs, for instance, are acceptably safe; a checklist of animal tests is reviewed before authorizing further testing on human subjects. All of this demonstrates how both health research and product safety rely heavily on animal-based research.

The few reviews published stress how difficult it is to compare the results of animal experiments due to the number of experimental designs, the different animal models, the various methods employed, and the lack of precise description in scientific journals.

There are inherent problems to using animals in research, such as the lack of rationale for the use of live animal species when other methods are available or could be investigated. Cross species differences make extrapolation very difficult due to the lack of analogy-isomorphism with the human species, especially at the cellular and molecular levels where diseases occur. Subtle differences between animal species are the result of millions of years of evolution. Molecular taxonomy has shown important genetic differences between chimpanzees and humans, although we have 98.7% of DNA sequence homology in common. In toxicology, primates are known to be poor predictors of the toxicological risks in the human species.

In particular, the inability to translate the majority of findings gathered through animal research into some practical benefits for society is notoriously recognized in the animal research community. For some, the practical application of animal research to benefit human health is actually of little importance; new knowledge alone justifies animal experiments, even though this means harming sentient animals and no gains at the end.

One area, which is an important concern for many people, is the discovery of cures and treatments for serious diseases and the safety of every day life products. The incidence of some diseases (neurological diseases, diabetes, cardiovascular disease, stroke, respiratory disorders) has been on the rise, as are injuries and mortality due to the side effects of drugs. There is now a palpable concern regarding the safety of drugs and all other chemicals, some of which injure or kill millions of consumers. In addition to the lack of monitoring and post-marketing surveillance, there is also a lack of appropriate testing at the very beginning. It is common knowledge that 80% of clinical studies are uninformative, and most, if not all, are derived from preclinical research on animals.

As animal testing receives most of the available subsidies and grants, there is less funding available for clinical research. Ironically, the findings of animal experiments in fields such gene therapy, pancreatic islets transplantation and other techniques are not further investigated in human subjects because of a lack of resources. The approximate cost of the Canadian public health care system is over 100 billion dollars per year and there is no indication that this situation is going to improve. One of the best ways to deal with the problems associated to health care management is to emphasize on prevention, education, better health research and scientific testing, that will result in more effective and safer drugs. Unfortunately, educating the public has been many times ineffective (eg, failure of anti-smoking campaigns)and coercive laws/taxes may be deemed necessary.

Animal-based research is endorsed and carried out by industry and the government, and seen as a legally acceptable practice. As a consequence, such methodology has been widely accepted by society, regardless of its productivity and cost, and regardless of the alternatives to it. Not surprisingly, unproductive research and non-scientific testing have become standard procedures.

Research and testing can be made more efficient by using models that closely reproduce some aspects of human biology and this is precisely why human cells and tissues are becoming attractive alternatives to the use of animal tissues and cells. From an historical point of view, the use of human cadavers in autopsies and anatomic studies has been prohibited for a long time because of moral and religious sentiments, and this until Renaissance, which saw the rise of modern human anatomy.

Now, some academic and industrial scientists have learned to recognize the increasing need for in vitro human tissue and cell systems. Besides, a significant number of researchers emphasize the need to test products and hypotheses in a whole animal before testing in human subjects. Without precise evaluation of animal models, this methodology remains empirical. The real question at issue is the scientific risk assessment of drugs and chemicals through the use of valid models. Compared to the pioneers of the 19th century, there are now numerous methods available for research and testing of drugs and other chemicals. However, new alternatives can be investigated if a political will emerges and if actual funds support that endeavour.

In fact, using human cells and tissues to study human biology is a sound approach and the information we can get is of considerable value. Due to the amount of information we have and the technologies we know, in addition to the moral and scientific pressures to do better science, we are entering a new era; academy and industry scientists consider to replacing in vivo and in vitro tests using animals with in vitro tests on human cells or tissues because they recognize the ethical and scientific superiority of this methodology. Also, alternatives to the use of animals in research are necessary to help us protect the rights, safety and well being of individuals.

How do collection, distribution and research on human tissues and cells work in Canada and some other countries?

Canada's Criminal code, the Privacy Act and provincial laws and regulations control the use of human tissue and research on human subjects. The Research Ethics Board that has expertise in this type of research governs the procedures and applies ethical guidelines to protect test subjects, as established by the Tri-Council that is composed of members of the CIHR, NSERC and SSHRC. Those guidelines emphasize the respect of human dignity, informed consent, privacy and confidentiality, equity, and free donation. Regarding research on human embryos, as passed recently by the House of Commons on Oct. 28 of last year, C-13 actually bans human cloning, but allows the use of human embryos for research.

Researchers may obtain human tissue that is left after surgery, biopsies, foetal abortion, and when brain death is ascertained by two doctors in a patient who has donated the tissue or whose next-of-kin agrees to the donation. Cadaveric tissue can also be collected. Researchers must first submit an application to the Research Ethics Boards (REB) that evaluates the ethical and scientific aspects of the experimental design. If the application is rejected, the researcher may appeal the decision to a special board. As well, donors must be given information regarding the purpose of the research, the type of tissue collected, the potential uses of the tissue, and whether the tissue is traceable to the donor. In cases where tissue is not available, it may be obtained from tissue banks located in the USA or elsewhere, and shipped to Canadian laboratories. There is no research tissue bank in Canada, and little public information/education campaigns to show the potential benefits of using human tissue and cells for research.

In England, there are laws that exist to protect the donor's identity and rights to privacy, and rules of informed consent apply too. The 'Human Tissue Act' (1961) permits the use of human tissues for therapeutic and research purposes as long there is no opposition from the donor or the donor's next of kin. The 'Human Organ Transplant Act,' (1989) prohibits payment in connection with organ or tissue removal for transplantation in another individual. The Peterborough Hospital Human Tissue Bank (PHHTB) and the National Blood Service Tissue Services (NBSTS) operating within the UK National Health Service have a system in place to retrieve cadaveric tissues for the commercial sector research. There is also an online registry for people willing to donate their body for research. One company in particular, Pharmagene Laboratories in Royston, England, uses human tissues and sophisticated computer technologies to develop and test new drugs.

In the USA, tissue banks have also been developed. In 1986, when the International Institute for the Advancement of Medicine was established, public awareness on the option of donating organs and tissues for research was virtually zero. The 'National Organ Transplant Act' prohibits buying and selling human organs and tissues. The American Association of Tissue Banks (AATB) has established and monitors compliance with standards of quality and safety among transplant tissue banks. About two years ago, the Food and Drug Administration published a final rule that requires human cells, tissue, and cellular and tissue-based product establishments to register with the agency and list their human cells, tissues, and cellular and tissue-based products (HCT/Ps)

In Europe, the European Network of Research Tissue Banks was created as an organization with expertise in human tissue banking and as a centre for advice on this type of service to academia and industries of state members.

What can be done to enhance the collection of human parts for research purposes? What sort of tissue can be collected and what can be done with it?

Human tissues can be collected for teaching, training, basic research, and safety and efficacy testing. Unlike animal tissue, human tissue possesses the full range of human target enzymes essential for pharmacokinetics studies. It is also true for the range of human genes, and proteins encoded by those genes. Such testing cannot be fully reproduced in any non-human animal cell. Diseased human tissue is also required to test the potency, for instance, of anti-cancer drugs. Increasing the availability of human tissue can only improve biomedical research and drug testing.

Progress to be made

There are indications by health professionals that human tissue that could be used in research is being wasted. Health professionals who would like to make use of human tissue for research may not know the researchers who are likely to make the most efficient use of the tissue. The researchers willing to use human models or systems may not know the health professionals or may be unwilling to go through the REB, applications, and multiple social, ethical and political obstacles in their way. As a result, the use of tissue is being made on a collaborative basis between researchers and health professionals, usually at the same hospital. One important aspect is the regular and consistent supply of tissue. The regulatory system is already stringent enough, but there is room for improvements in logistics, public education, funding and other resources to improve collection, distribution and use of human tissue throughout Canada. Below are listed some guidelines and observations that health officials and politicians may consider:

1. The actual shortage of human tissue for research prevents the development of in vitro systems. It also prevents the introduction of rational testing on human tissue that should replaced animal tests as part of the regulatory requirements for the evaluation of drug toxicity.

2. In addition, a significant fraction of the public seems to be reluctant to donate tissues for moral or religious reasons, or simply out of the fear that the tissue could be misused, traded, or could interfere with transplantation programmes. No religion forbids the donation and use of human tissue for research. The actual process of tissue collection and use is already strictly regulated. There is a need to bring awareness; donation can ultimately save lives.

3. An 'opt out' system, in which everyone is a potential donor unless the individual is opposed to donation, this way the burden is placed on those who object to donation. Such legislation could not only solve the shortage of donors, but also contribute to increasing the collection of human parts for research purposes. This system already exists in other countries where organ donation has doubled. (Belgium, Poland, France) As well, a simple donor card should alleviate the need to obtain the family's approval, which is presently not the case. Informed consent could be added to an existing medical document (anaesthetic and surgical procedure authorization) to facilitate the delicate issue of informed consent.

4. Creation of non-profit tissue banks to avoid legal and ethical problems, and that are involved in the collection, registry and distribution at the provincial levels.

5. Industries allowed and wishing to obtain human tissue, and that meet the regulatory requirements, would have to pay a fee that could serve to recoupe the cost of the non-profit tissue banks.

6. Put in place a system that is transparent and accountable to a public commission that represents the various members of society. Public trust, which is largely undermined in these days of political and financial scandals, is crucial.

7. Design a system of accreditation of researchers to assess credentials, scientific merit of the project, and adequate facilities and safety issues regarding the handling and disposal of human parts.

8. Create structures within hospitals to serve as mediators between researchers, health professionals, provincial tissue banks and the public, to ensure transparency and constant circulation of information.

Conclusion: Canada's Liberal government has promised to raise Canada at the top level of science and technology. During the past decades, Canada has become an offshore shelter for animal experimenters. There is no federal legislation governing animal research, and interest groups have created a self-regulatory system that excludes public scrutiny on matters regarding their health and how research money is spent. As such, it is little surprise that the possible avenues to optimize the use of human tissue and the alternatives to animal research have been, to say the least, neglected. It is everyone's responsibility to change this situation and to pressure whatever government and our federal and provincial bureaucrates to modernize health research.

Bibliography and further readings

• Ian Roberts et al. Does experimentation inform Human Healthcare? Observations from a systematic review of international animal experiments on fluid resuscitation? BMJ Vol. 324, 23 Feb. 2002
• Pandora Pound et al. Where is the evidence that animal research benefits humans? BMJ Vol 328, 28 Feb. 2002
• Robin Rowland. Human Research, Human Dignity: Human Organs in Medical Research. CBC news December 2002
• Robert Anderson et al. The Availability of Human Tissue for Biomedical Research ATLA 26, 763-777 1998
• Robert Anderson et al. The Establishment of Human Research Tissue Banking in the UK and several Western European Countries ALTA 29, 125-134 2001
• Christopher Womack et al. Cadaveric tissue supply to the commercial sector for research: Collaboration between NHS pathology and NBS Tissue Services in the UK, extending the options for donors.

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