Key Factors in Immunological Research
The importance of the use of animals in immunological research and drug development
Although animals are used for many purposes, such as farming and the production of food, their use in scientific research continues to be a source of great discussion throughout the world. Many of the main advances in Immunology have arisen as a result of the use of animals. The development of transplantation surgery and the development of new medicines and vaccines would not be possible without animal research. However, many of those opposed to animal research argue that the results from animals cannot be reliably applied to humans, as we are biologically different. Anti-animal research proponents also argue that despite all the testing that is done in animals, drugs and medicines still cause adverse reactions in many people.
The controversy over the use of animals in research is often presented in a polarised manner, with opinions pigeon-holed as being either 'for' or 'against' their use. In reality, such views exist along a spectrum. What is self-evident is that the use of animals in immunological research has played a critical role in many landmark achievements of the past.
Developing vaccines to prevent infectious disease
The use of animal models has helped us understand how infectious diseases occur. This has led scientists to develop preventative treatments in the form of vaccines to help reduce the likelihood of someone being infected with a dangerous microbe, such as those responsible for causing polio, diphtheria, and hepatitis C. Vaccinations also offer the best solution for people in developing countries being infected HIV (the virus that causes AIDS), and the parasite responsible for causing malaria (which kills millions of people each year). Such vaccines cannot be developed without some form of animal research.
Producing drugs to manage and treat diseases
The development of several revolutionary drugs and treatments, such as insulin for diabetes, antibiotics to treat bacterial infections, and anti-retroviral drugs to delay the onset of AIDS, are all examples of medical advances that depend on animal research. Efforts to improve drugs that are already being used to treat diseases are also dependent on animal research. For example, in transplantation immunology, further research will soon help scientists produce drugs that can better prevent the all-too-common problem of rejection.
Development of new diagnostic methods
Experiments in animals have been vital for developing immunological techniques that allow diseases to be diagnosed quickly and accurately. The diagnosis of cancer relies on techniques that use immunological tools that were first discovered in animal experiments.
Treating other animals
It is not only humans that benefit from treatments derived from the use of animal research. Animals also benefit from medicines initially developed for people. These include vaccines, antibiotics, anti-parasitics and insulin. They have all been developed to protect our pets, farm animals and animals living in the wild from undue suffering and death, thus saving millions of animal lives each year.
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Alternatives to animals
Various alternatives to research with animals have been proposed, including the use of plant and tissue cultures, and computer simulations. Unfortunately, there is currently no viable replacement that would enable researchers to completely rely on non-animal methods. Plants lack a nervous and immune system and, therefore, cannot be used to help us learn about immunological phenomena. Also, computer simulations are only useful when they are based on knowledge obtained from live immunologically responsive animals. Therefore, they cannot be used as a substitute for studies in live animals.
Although animal laboratories are expensive to run and require a lot of work, at the present time the use of animals in immunological research is essential, and must continue so that huge advances continue. There are still many serious diseases in both humans and animals that science will be unable to cure or treat effectively unless research in animals continues.
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Types of animals used in immunological research
Many different species of animals are used for research purposes, although the majority of procedures use rats and mice (rodents).
Use of rodents in Immunology
Rodents are the main engine for immunological discoveries. They are the preferred option to test basic ideas and theories. This is partly because they are cheap, convenient, and easy to handle. There is also a plethora of rodent-specific research tools already available to help investigators study many different types of immunological phenomena. The use of rodents has led to many important advances, not least, helping scientists to identify the cells which make up the immune system and the molecules they produce.
Since the late-1960s, a specific type of rodent has been used in research due to its natural inability to mount an immune response to foreign substances. These rats and mice, known as 'nude rodents', have an alteration in their genes that causes them to be immunodeficient i.e. they lack an ability to protect their body and so are immunologically 'nude'. Scientists have exploited this feature to study how chemicals and drugs stimulate or suppress the immune system. Nude rodents also provide very useful models in the transplantation field, and have helped us understand the effects of drugs (including any possible side effects these drugs may have) without interference of the immune system.
Use of chicken eggs
Chicken eggs are typically used to produce vaccines on a large scale. The viral (pathogenic) part of vaccines is produced by injecting the virus into the eggs. The virus then replicates in large quantities within the embryo. Indeed, producing vaccines this way requires a large supply of chicken eggs, usually at the ratio of 1-2 eggs for every dose of vaccine.
Pigs
Pigs are used in transplantation research mainly because they have similar sized organs to humans. They also breed very rapidly, which suggests that they could [theoretically] be used to supply transplant material for humans on a large scale. This process of transplanting pig organs into humans (known as xenotransplantation) is not without problems. Since pigs are not closely related to humans, transplanting their organs into humans would induce a huge immune response, causing the organ to be automatically rejected. Therefore, scientists are currently attempting to address this by modifying pig genes to reduce the strength of the immune response and the likelihood of the transplant being rejected.
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Primates
Primates are more closely related to humans than any other animal species. This renders them very useful potential models in xenotransplantation research. However, they are more commonly used to investigate diseases such as AIDS.
Large animals vs rodents
The use of animals in scientific research remains a hot debate. But within the field of Immunology itself, there is also concern over the type of animals used. The current excessive use of rodents is believed by some researchers to hinder the transfer of discoveries made in basic research to their more useful clinical applications. It is claimed that experiments in rodents alone cannot find cures for all human and animal diseases. Furthermore, it is argued that they can never provide all the answers required to understand immunity properly. Indeed, the use of rodents in DNA technology research is commonly used as an example to support these claims. DNA vaccine technology was developed using mice as models and this led to clinical trials being conducted in humans. However, when tested in humans the technology failed and has yet to lead to a successful transfer to clinical medicine. Despite this, rodents continue to be used to test the concept.
Advantages of using larger animals
Larger animals are considered to have more things in common with humans compared to smaller animals. The use of larger animals would [in theory] provide better models for research, as:
- their size allows for a more frequent collection of blood, which is important for analysing the rate at which the immune response changes after being challenged with an antigen;
- larger animals are more likely to carry a zoonotic disease, which crosses the species barrier and can develop in humans;
- the organ size of larger animals is regarded as being more suitable for developing surgical techniques for use in human organ transplantation.
Disadvantages of using larger animals
As with most tools of scientific research, there are disadvantages associated with the use of larger animal models, for instance:
- the cost of individual animals can be high;
- different human cultures/societies often prescribe a privileged or taboo status to some species of animals, which can prohibit their use in research;
- larger animals are still not humans, so differences in the way their immune system works will always remain an issue.
Regardless of which type of animal is used for immunological research, it is clear that there must be greater dialogue between basic and clinical immunologists. Better communication between both fields would strengthen efforts to identify the most relevant animal model for use in a particular research project, and thus ultimately reduce the number of animals used.
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The importance of effective funding
Research in Immunology carries huge health benefits to society and has contributed enormously to the quality of life we enjoy today. To ensure that we continue to meet the healthcare needs of the present, and those for future generations, it is vital that effective funding strategies are developed that uphold and maintain the highest level of immunological research. Without sustained funding, significant advances in the medical and veterinary sciences will be severely compromised.
Funding sources
The funding of scientific research in the UK arises largely through government public money (e.g. through the Higher Education Funding Council for England (HEFCE)), private industry and charity donations.
Public funding
In 2001, the UK spent approximately 1.8% of its gross domestic product (GDP) to fund research (about £17.5 million), which is well below the average spend of our competitor nations who spent on average 2.1% of their GDP. The UK Government is committed to increasing funding for scientific research and development (R&D) to 2.5% GDP by 2014. And it is the medical and health services that are set to gain most from this increase.
HEFCE provides block grant funding to generally support the research infrastructure in general. Grants for specific projects are provided by Research Councils, charities, the European Union and Government Departments. The Medical Research Council (MRC) is responsible for funding specific projects in basic biomedical research in many research centres and academic institutions. It remains the largest public funder of clinical trials. Indeed, the MRC's contribution to clinical trials has lead to groundbreaking work in viruses, penicillin, vaccines and antibody drugs.
Private Industry funding
In 2003, pharmaceutical companies invested £3bn into R&D with £250 million going to universities and the rest for in-house research.
Charities
Charitable donations also account for a considerable amount of funds for university research (around £600 million). In the UK, The Wellcome Trust alone contributes more to the university sector than the whole of the private industry sector put together.
Nonetheless, despite the funds set aside for scientific research there is concern that research into Immunology is not being funded effectively.
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What do we mean by effective funding?
Effective funding relates to the strategic investment of funds into areas of immunological research that are most likely to generate maximum healthcare benefits. Analysis of research funding shows that the majority of funds are spent on basic research and understanding the causes of disease. Much less is spent on prevention, diagnosis and treatment, which all define areas in which Immunology plays a huge role.
In the UK, there is currently a general urgent need for more financial support of clinical research. There is also concern over the dissolution of Immunology departments in academia, which impacts on the amount of funding the subject receives. Indeed, the multidisciplinary nature of Immunology means that as a discipline it is at risk of losing its distinct presence in the undergraduate and graduate curricular of many universities. This would be hugely damaging for the field as would any loss of identity.
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Funding strategies
Research Assessment Exercise (RAE)
In the UK, the amount of funding an academic department receives is largely dependent on its performance in HEFCE's Research Assessment Exercise (RAE). This evaluation procedure assesses the quality of UK research and bases the amount of funding it distributes on the quality of research submitted for the RAE.
Research regarded as being of international excellence receives a 5 or 5* grade and subsequently a large proportion of funding. Those departments with grade 4 or less receive fewer funds and often end up having to cut staff to reduce costs. This can lead to departments being unable to conduct research or even teach.
RAE has been criticised by many scientists as a flawed system that is costly and no longer needed. It is argued that the system is particularly inappropriate for clinical research, which is unlikely to achieve favourable RAE ratings. RAE is believed to be responsible for clinical academic posts being cut to recruit basic scientists whose research is more likely to generate high RAE ratings. The RAE system is also criticised for failing to recognise the value of the interdisciplinary approach to medical research and practice. The government is currently undertaking a wide-ranging consultation exercise regarding proposed reforms of the RAE funding system.
Funding of clinical research
Clinical research in the UK is on the decline. This is largely due to a shift in focus from clinical to more basic molecular and genetic research. The knock-on effect of less money being spent on clinical research is a reduction of the research itself, and dwindling numbers of researchers entering/remaining in the field. More clinical research is needed to speed up the rate at which biomedical discoveries are translated into clinical applications. The MRC has made a strategic commitment to increase its investment in translational, clinical and public health research.
Funding of veterinary immunology
Increased investment in veterinary immunology is also required to facilitate advances in animal health. Within the pharmaceutical industry in particular, consolidation directives and regulations on the use of drugs in animals for consumption, has resulted in a decrease of investment for developing new drugs and vaccines.
Summary
Despite the huge strides already made in immunological research, there are still many diseases that we are unable to treat effectively and new threats are constantly emerging. To generate and pursue innovative ways of tackling these diseases and ensure advances in Immunology continue, it is important that immunological research is funded effectively. Furthermore, to ensure that the UK plays a leading role in immunological research, it is crucial that there is a continual stream of talented researchers entering the field. It is also vital that key infrastructural support mechanisms exist to facilitate the development of robust research programs, training and teaching in institutions.
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The ethical dimension
The term ethics defines a system of moral principles, rules and standards of conduct. It provides guiding principles for various concepts of human conduct i.e. what is considered to be right or wrong, good or evil, as well addressing the matter of responsibility and accountability.
Bioethics is often used to describe the ethical concerns that arise specifically within the biological sciences and medicine. Therefore, since Immunology is a branch of the biological sciences, ethical issues that are specific to immunological research are only highlighted where appropriate.
Policing of research
The control and regulation of scientific research arose largely from the belief that society is entitled to control what scientists may do. This is partly because the majority of funding for scientific research arises out of the public's purse. However, there is also the fear within society that science can go too fast without any consideration of the societal impact it may have or the technology being misused.
Research within the biological sciences is particularly open to non-expert criticism. Indeed, many biomedical/clinical scientists question why it is necessary that they should submit to regulation and controls imposed on them by sources of authority outside their own discipline; other disciplines, such as the social sciences, are not told what type of research they can pursue by people less qualified than themselves.
However, since living creatures are both tools and potential beneficiaries of biological research this makes it a moral issue. And because there are no experts or specialists in morality, the opinions of the lay are considered to be just as important. In addition to concerns over the implications of scientific research, there is also concern about the methods and procedures of the research itself.
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Morality of methods of research using animals
The most longest-standing moral objection to biological research has been the use of live animals. The concept that humans are inherently more important than animals thus rendering it morally acceptable to cause pain and suffering and death to animals remains a highly contentious issue.
A key matter of concern relates to whether the animals used for research, possess high cognitive capacities i.e. feel pleasure and pain. Higher organisms/mammals that are self-aware would find suffering and death painful and would be able to sense that damage is being done to his or her self and future.
Within the immunological field, the use of primates in HIV/AIDS research and pigs in transplantation research is a particularly contentious topic for this reason. Furthermore, developments in xenotransplantation research that could lead to pigs and other animals being used for human organ transplantation concern many people because of the increased opportunities for zoonotic infections.
Current legislation on use of animals for research
The welfare of animals in research is protected by national and international legislations and also by local laws and ethical committees. In the UK (which is recognised for having the most comprehensive regulations covering laboratory animal welfare), researchers must comply with stringent national regulations and also submit their research proposals to local ethical review. The Animals (Scientific Procedures) Act 1986 requires that researchers are properly trained in handling and looking after animals. It also stipulates that research ideas must demonstrate that the benefits of using animals as a tool, outweighs the cost to the animal in terms of possible pain, suffering and distress.
Before a researcher is allowed to use animals in their study, they must first be able to show that:
- They have done all that is possible to reduce unnecessary suffering in animals.
- Their desired results cannot be achieved by any other method.
Morality of using humans in biomedical/clinical research
The use of humans and human material in scientific and medical research has been, and continues to be vital for ongoing medical and scientific advances. However, the public must feel confident that all studies are carried out responsibly without detriment to those involved. In Immunology, clinical research trials are specifically conducted in humans to evaluate the effectiveness of newly developed therapeutic or preventative drugs and vaccines. These research studies are normally performed in patients with a particular illness, as well as in healthy volunteers to help clinical scientists/physicians assess the safety of a particular drug or vaccine.
Potential for exploiting the vulnerable
Pharmaceutical companies that develop drugs for treating infectious diseases in poorer parts of the world, have to ensure that their work is not exploiting the vulnerable and weak. The motives for conducting externally sponsored research must be ethically sound and justified to the appropriate research ethics committee. For example, the testing of AIDS vaccines in people from developing countries should be conducted using potential vaccines that will protect against the HIV strain(s) that are prevalent in those countries.
In the past, vaccines were sometimes tested in vulnerable or captive populations, such as prisoners or institutionalised mentally ill people. However, the most pronounced exploitation of individuals for human experimentation occurred during the Second World War. Nazi German scientists used many Jews as 'guinea-pigs' for inhumane human experiments.
The Declaration of Helsinki, developed by the World Medical Association, also provides a set of ethical guidelines for the medical community regarding human experimentation. Like the Nuremberg Code, the Declaration made informed consent a central requirement for ethical research, allowing for surrogate consent when the research participant is either incompetent, physically or mentally incapable of giving consent, or a minor.
Current legislation on clinical research trials
In the UK, reforms in the way the NHS conducts research have led to the development of the Research Governance Framework. This guidance legislation exists to ensure that all clinical research complies with professional, ethical, legal and scientific standards.
All clinical trials must fulfil various criteria before they can receive ethical approval to conduct research in humans:
- Value: The research questions of a particular study must have potential scientific/social value to justify exposing individuals to research risks and inconvenience.
- Validity: The research study must be carefully designed and implemented using validated techniques. Some vaccine trials, known as challenge studies, deliberately infect people with a pathogen to test whether a vaccine will work. In these situations it is vital that the risks of complications associated with infection are low and/or the effects can be easily treated. A recent example of a study that failed to use validated methods is the 'Parexel Drug Trial' in London, UK, which resulted in serious adverse reactions occurring in six healthy volunteers in 2006. Although the drug TGN1412 (an anti-inflammatory drug intended to treat rheumatoid arthritis, multiple sclerosis and other diseases) showed no side effects in animal tests, it unexpectedly caused severe inflammation and multiple organ failure in the men who took part in the study. It is claimed that the study was not adequately tested on human tissue (blood) and no safe human dose was ever determined. The conduct of the staff responsible for administering the drug was also thought to contravene the recommended advice of the medical drug regulatory authority. Despite this, it has been claimed that Parexel acted within all the current guidelines that exist for clinical trials, and that it is the guidelines that are at fault. Therefore, it is possible that this could potentially lead to a review of the entire drug testing regulations in the UK.
- Informed consent: Since vaccine trials typically use large numbers of infants and children (because many vaccines are ultimately used in children), it is important that the principal investigator gets permission from the child's parent or guardian - who themselves must be well informed to give consent.
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Other moral issues in immunological research
Face transplantation
Organ-transplantation techniques are not solely confined to the replacement of damaged hearts, lungs, kidneys and livers. Advances in microsurgical techniques have enabled the skin and its associated blood vessels to replace part or all of a patient's face with that from a donor.
Most recipients of face transplants [which are few] have either been disfigured as a result of severe burns, trauma, disease or birth defects. However, the procedure is still not completely perfect as questions arise over the safety of the surgery itself and the subsequent suppression of the immune system. Furthermore, there are huge ethical concerns associated with the procedure.
Many medical ethicists question whether this high-risk form of surgery should be performed for cosmetic reasons on patients who do not have life-threatening injuries. There is also concern about the psychological impact of receiving another person's face, which defines one's identity, and the consequences of the dead donor's relatives seeing the face of their loved one on another individual.
Stem cell therapy The use of stem cells (i.e. cells that can develop into any other type of cell) to replace damaged tissues, presents another moral issue within transplantation immunology. This is because the best [current] source of stem cells are derived from human embryos, which results in the destruction of an embryo or foetus. Those opposed to its use argue that this constitutes the destruction of a potential human and thus conflicts with moral and religious views of society.
Central to the argument is whether a 14-day embryo constitutes a human being. Also the fact that these embryos (obtained from donated embryos that are no longer required for IVF procedures or from pregnancy terminations) would otherwise be destroyed, causes many stem cell advocates to uphold their view that this type of research represents a potentially significant breakthrough in treating and potentially curing debilitating and life threatening illnesses.
Clearly, it is of paramount importance that research conducted for the benefit of mankind and animals, is regulated under strict codes of conduct and legislation. Without it, animals and humans would not be protected from exploitative regimes, which historically have led to extreme suffering of the vulnerable. Moreover, without strict policing of research, false claims of experimental findings would severely impinge on scientific innovation and thereby threaten the entire process of scientific advancement.
However, restrictions on scientists to pursue the type of research they want challenges the very nature of science, as the pursuit of scientific enquiry operates under the ideal of scientific freedom. These and other issues will no doubt continue to be debated as new scientific advances and diseases in humans and animals emerge.
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