Scand, J, Immunol, 36, Suppl. 11, 145-148, 1992
Immunologicai Techniques in and for Developing Countries E. P . W R I G H T Royal Tropical Institute, Amsterdam, The Netherlands Wright EP. Immunologicai Techniques in and for Developing Countries. Scand J Immunol 1992;36(Suppl.Il):l45-8 A review is given of the problems and challenges in using immunologicai techniques in and for developing countries. E, P, Wright. Royal Tropical Institute. Mauritskade 63, 1092 AD Amsterdam, The Netherlands
INTRODUCTION Science, and especially techniques used in science, are usually thought to be international, valuefree, and directly transferable from country to country. There are, however, reasons to discuss immunologicai techniques in and for developing countries, as opposed to those used in the industrialized countries. The most obvious are related to the differences in financial resources which can be applied to obtaining and using immunologicai (as well as other) techniques. Money is needed to build and equip facilities, not only for research but also for routine diagnostics, quality control, etc. They must also be kept running, usually with products (reagents, disposables) that have to be imported. With insufficient financial resources, the training of personnel may also be insufficient, which again sets limitations on what can be done. With all of these constraints, choices must be made; if this is to be done so as to produce the most effective results for the developing countries, they must be able to set their own priorities. The following is based on a talk given to the Zimbabwe Immunology Society in October 1991 on training needs in immunology for developing countries. It is not new information, still less new information in immunology, but my colleagues in Zimbabwe felt that it needed to be said anew and asked me to do that. The points to be made are not limited to immunology, but since my own work and contacts come through teaching immunology in and for developing countries over many years, these observations were made and heard where people are working in immunology.
In the past, and still now, there seemed to be two extremes in the approaches to technology transfer to—and thus to the practice of scientific research in—developing countries (DCs). One view is that the simple, often old-fashioned techniques are most appropriate; because their requirements may be more simple they may be more widely applicable. The other extreme is that we should transfer the most modern technology so that DCs can benefit from, cooperate with and compete with the work going on in the industrialized countries (ICs). As so often, a middle road between these two would be appropriate, with simple techniques needed for certain situations and the latest technology quite appropriate for others. THE CONSIDERATIONS Much of the research in ICs is a basic study of immunologicai systems and mechanisms, to understand the workings of life; sueh basic science, like art, is a luxury, and an expensive one. Many developing countries cannot afford it. When priorities are set, they choose for that which can contribute to development. This is not to say that they cannot contribute to basic research—they can and often do. But in DCs, immunology will mostly be used as a tool aimed at improving health, eventually, by improving knowledge of disease, for example through epidemiology or greater speed and/or accuracy of diagnosis, and as a consequence improving treatment. 145
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E, P, Wright
The vast majority of technical developments takes place, and most research is done, in the ICs. The people doing this work, in the commercial sector or in universities and research institutes, are often not aware of how priorities are set for their own work. There are many fewer people working in science and research in the DCs, for historical reasons related to opportunities for training and for building up the necessary facilities. These people have very often been trained in an IC, but the training usually concentrates on the teaching of technologies and research methodologies, and must of course be done in the context ofthe priorities ofthe IC and the scientist or laboratory concerned. Both parties are often not really aware ofthe needs and priorities in the DC concerned; finding out what these are or should be is not generally part ofthe training of a scientist. Technology transfer is therefore often indiscriminate. Scientists in ICs work in sophisticated laboratories developing advanced techniques which can provide information, useful information, on health problems (or agricultural or environmental ones) important to developing countries. But there is far too little coordination of these research efforts with the realities of the countries concerned, so that solutions are often proudly proposed which would be unworkable in the countries for which they are intended. This is not a criticism ofthe research itself; good research is never useless or wasted. It is a problem of setting priorities since funds are not unlimited, and of maximizing the benefits to the countries which need them the most. CHOICE OF APPROPRIATE TECHNIQUES Researchers from and in developing countries do not, quite rightly, wish to use only simple or oldfashioned techniques. They would usually like to learn and to apply the new and more advanced techniques, because they can see that these are widely applied to great benefit in the ICs. It is important that the new techniques be available to everyone, but more important is that the techniques used are appropriate to the information to be obtained. Often simple, but very elegant, techniques, such as Ouchterlony immunodiffusion, can provide a great deal of information, perhaps preliminary to applying Western blotting or other more complex and expensive techniques. Since most researchers in the ICs have long since
forgotten that simple techniques exist, they will usually not make such suggestions to their colleagues from DCs. New techniques always go through a phase of growth from infancy to adulthood, changing from cumbersome and hypersensitive to streamlined and stable. That growth phase is better passed through in countries with resources to spare for working out how to streamline and simplify the technique, but it would be useful if the needs and possibilities in DCs could sometimes be considered during this process. Examples are standardization of incubation temperatures (consider the differences in 'room temperature' in different countries) and development of protocols to re-use as many as possible of the components, or to reduce the excess of reagents added to a test (most commercial agglutination tests, such as for hepatitis B, work quite well when all the reagents are diluted up to ten times), and stabilization of reagents by lyophilization (so they survive long waits in customs sheds, for example). Since the obtaining, maintenance and use of experimental animals is often a difficulty in DCs, the drive to replace them with in vitro or other techniques which is taking place in the ICs (for other reasons) should be followed up for the DCs. Production of monoclonal antibodies is one technique which is usually in high demand in DCs. Monoclonal antibodies have many obvious advantages over conventional antisera, which is why so many researchers and commercial producers of tests kits now use them. The antibodies that have been produced, however, are mainly, although not quite totally, those of interest/use/ commercial value in the ICs. In the DCs, many people are keen to obtain them, but they are prohibitively expensive, or available only in limited amounts as gifts from researchers. Also, many people in the DCs are keen to make their own antibodies, either to do what is done in the ICs or because the reagents they need for research and/or diagnosis in their own situation are not available at all from the ICs. Making monoclonal antibodies requires a very large investment, both in facilities and in running costs. Commercial firms recuperate this by selling thefinalproduct at high cost. Those in the DCs often do not have the resources to invest in production even for research, or for the necessary production standards and quality control in order to sell the product on the profitable international market. What is needed is training not only in making
Immunologicai Techniques in and for Developing Countries monoclonal antibodies, already available in various courses, but also in deciding when it is useful to make them or when conventional sera would serve as well or better, and possibly training in making a product which can be sold to help finance further development. Most researchers are not experienced in this kind of thinking, and there is too little coordination with the agencies familiar with it, such as the vaccine makers. The area of infectious disease research has been exceptionally susceptible to changes in 'fashion' over the years. In DCs, infectious diseases are an important cause of morbidity and mortality. But which of these receive attention, and therefore money, in international circles is not necessarily determined by the health priorities in the DCs. Research, and immunologicai research in particular, is also largely directed towards finding technical solutions for problems, which are not only technical but also socio-economic problems. The practice of scientific parachuting, in which researchers from an IC fly into a DC having lots of patients or organisms, collect samples and fly back to their laboratories to analyse them, has been very common. There are some reasons for this; there will be instruments and facilities available in the IC which could not easily be transplanted to the DC. But this practice does not seem to be dying out quickly enough, and it is one of the reasons that the research is so often not consistent with local priorities. There are advantages not only for the DC but also for the IC in transferring as much as possible ofthe technology for the research to the DC. It will improve the quality of that part of the work done in the DC (collecting, storing and recording samples, making diagnoses, etc.), because it then becomes real collaboration. Another advantage is that studies can be done which would otherwise be difficult, such as long-term follow up in chronic diseases like leprosy and tuberculosis, or in recurrent infections with parasites. With some exceptions, researchers in the ICs tend to neglect the fact that diseases occur in a socio-economic context which may have great influence on the course of the disease and on the immunologicai phenomena which appear. The role of lifestyle in, for example, cardiovascular diseases or some kinds of cancer has been clearly demonstrated in the ICs. When the diseases or conditions under study are in countries with quite different and often highly varying lifestyles, the importance of such factors is often overlooked.
147
There is relatively little attention paid, for example, to the role of mild or even severe malnutrition on many infectious diseases. Not to mention the effects of concurrent infections with other similar organisms, or for example, with intestinal parasites. Even the dynamics of infection in the natural situation are often ignored. Studies on family occurrence of diseases tend to concentrate on demonstrating a genetic factor, with little consideration for the living conditions and other habits. How many people sleep in one bed, or the different agricultural duties of men, women and children may be equally important as factors in the transmission and the course of communicable diseases as the production of lymphokines upon contact with antigen presented by macrophages with different MHC types. The possibility of combining immunology studies with other kinds of studies is an additional reason to do as much of the research as possible locally. Perhaps because those from DCs trained in ICs so often learn the technology but not the criteria for its application, there is often a surprising lack of communication between those who need diagnostic techniques and those who do research to develop them. For example, there is a difference between these two groups in what is meant by sensitivity and specificity of a given diagnostic test. The person working in a laboratory thinks of a very sensitive test as one that can detect a very small amount ofthe target substance, for example antibodies reacting with a certain antigen. In the laboratory, a specific test detects reactions with that antigen, and not with other antigens of related, or unrelated, structure. But when the test is to be applied in the field for epidemiological studies, or in the clinic as an aid to diagnosis, these terms take on a different meaning. Specificity then becomes a question of whether the test provides information relevant to that one disease or condition and not to other, related or unrelated, conditions. For example, a test might be able to detect rheumatoid factor very specifically, but if rheumatoid factor is found in many different conditions, the test is not specific for any of them. Sensitivity changes in a similar way: the test may be able to detect very low amounts of a certain antibody, but if the antibody is not found in all patients having the condition of interest, the test is not a sensitive indicator of that condition and will not be able to identify it when it appears infrequently in a population. These two factors are, in an epidemiological or clinical sense.
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greatly influenced by the prevalence ofthe disease in the population, which is another factor often forgotten by the laboratory people, who generally only receive those samples already suspected on other grounds of being positive. Communication is needed; each user group needs to be aware of the requirements and abilities of the other. CONCLUSIONS Most technological developments proceed at a pace and in a direction related to their commercial value. This means that some will not be developed at all, or will be developed in a way that makes them viable only in well-equipped laboratories with stable conditions in ICs. Researchers in ICs working with concepts or diseases of importance for DCs could keep this in mind and develop their techniques in such a way that they are more widely useful. And they could train the students from DCs in this kind of standardization. The rapid development of simple and reliable tests for HIV infection shows what can be done when there is a financial incentive. Researchers in ICs could also stop to think about how their own priorities are set, at the macro and micro levels, and discuss with their guests and students from DCs how it can be done in their countries. Training of research scientists, in both ICs and DCs, should include looking at the real needs in the country; for countries with limited
resources that also means setting priorities and making choices based on priorities. Very interesting research may have to be set aside for the future while directly applicable and beneficial research is done on problems of more immediate or broader concern. Cooperation in research should mean not only exploitation of the resources (patients, new organisms, freedom from restrictive legislation) of the DCs but also, as much as possible, paying attention to the needs and priorities of those countries. Collaboration should always include training components and provision of a certain amount of equipment and materials to enable some of the work to be done locally. Appropriate selection and adaptation of techniques requires sufficient information, and one of the great lacks in most DCs is up-do-date information about new methods and advances in immunology, among other subjects. Reduced rates for subscriptions to 'international'journals, waiving page and handling charges for those from developing countries, assistance with editing of their papers, are examples of what could be done to improve access to information for those in DCs and to improve their opportunities to communicate what they are doing in the field. Immunologists interested in working with and for developing countries should keep all of these points in mind while developing their proposals and programmes for collaboration.
Immunologicai Techniques in and for Developing Countries E. P . W R I G H T Royal Tropical Institute, Amsterdam, The Netherlands Wright EP. Immunologicai Techniques in and for Developing Countries. Scand J Immunol 1992;36(Suppl.Il):l45-8 A review is given of the problems and challenges in using immunologicai techniques in and for developing countries. E, P, Wright. Royal Tropical Institute. Mauritskade 63, 1092 AD Amsterdam, The Netherlands
INTRODUCTION Science, and especially techniques used in science, are usually thought to be international, valuefree, and directly transferable from country to country. There are, however, reasons to discuss immunologicai techniques in and for developing countries, as opposed to those used in the industrialized countries. The most obvious are related to the differences in financial resources which can be applied to obtaining and using immunologicai (as well as other) techniques. Money is needed to build and equip facilities, not only for research but also for routine diagnostics, quality control, etc. They must also be kept running, usually with products (reagents, disposables) that have to be imported. With insufficient financial resources, the training of personnel may also be insufficient, which again sets limitations on what can be done. With all of these constraints, choices must be made; if this is to be done so as to produce the most effective results for the developing countries, they must be able to set their own priorities. The following is based on a talk given to the Zimbabwe Immunology Society in October 1991 on training needs in immunology for developing countries. It is not new information, still less new information in immunology, but my colleagues in Zimbabwe felt that it needed to be said anew and asked me to do that. The points to be made are not limited to immunology, but since my own work and contacts come through teaching immunology in and for developing countries over many years, these observations were made and heard where people are working in immunology.
In the past, and still now, there seemed to be two extremes in the approaches to technology transfer to—and thus to the practice of scientific research in—developing countries (DCs). One view is that the simple, often old-fashioned techniques are most appropriate; because their requirements may be more simple they may be more widely applicable. The other extreme is that we should transfer the most modern technology so that DCs can benefit from, cooperate with and compete with the work going on in the industrialized countries (ICs). As so often, a middle road between these two would be appropriate, with simple techniques needed for certain situations and the latest technology quite appropriate for others. THE CONSIDERATIONS Much of the research in ICs is a basic study of immunologicai systems and mechanisms, to understand the workings of life; sueh basic science, like art, is a luxury, and an expensive one. Many developing countries cannot afford it. When priorities are set, they choose for that which can contribute to development. This is not to say that they cannot contribute to basic research—they can and often do. But in DCs, immunology will mostly be used as a tool aimed at improving health, eventually, by improving knowledge of disease, for example through epidemiology or greater speed and/or accuracy of diagnosis, and as a consequence improving treatment. 145
146
E, P, Wright
The vast majority of technical developments takes place, and most research is done, in the ICs. The people doing this work, in the commercial sector or in universities and research institutes, are often not aware of how priorities are set for their own work. There are many fewer people working in science and research in the DCs, for historical reasons related to opportunities for training and for building up the necessary facilities. These people have very often been trained in an IC, but the training usually concentrates on the teaching of technologies and research methodologies, and must of course be done in the context ofthe priorities ofthe IC and the scientist or laboratory concerned. Both parties are often not really aware ofthe needs and priorities in the DC concerned; finding out what these are or should be is not generally part ofthe training of a scientist. Technology transfer is therefore often indiscriminate. Scientists in ICs work in sophisticated laboratories developing advanced techniques which can provide information, useful information, on health problems (or agricultural or environmental ones) important to developing countries. But there is far too little coordination of these research efforts with the realities of the countries concerned, so that solutions are often proudly proposed which would be unworkable in the countries for which they are intended. This is not a criticism ofthe research itself; good research is never useless or wasted. It is a problem of setting priorities since funds are not unlimited, and of maximizing the benefits to the countries which need them the most. CHOICE OF APPROPRIATE TECHNIQUES Researchers from and in developing countries do not, quite rightly, wish to use only simple or oldfashioned techniques. They would usually like to learn and to apply the new and more advanced techniques, because they can see that these are widely applied to great benefit in the ICs. It is important that the new techniques be available to everyone, but more important is that the techniques used are appropriate to the information to be obtained. Often simple, but very elegant, techniques, such as Ouchterlony immunodiffusion, can provide a great deal of information, perhaps preliminary to applying Western blotting or other more complex and expensive techniques. Since most researchers in the ICs have long since
forgotten that simple techniques exist, they will usually not make such suggestions to their colleagues from DCs. New techniques always go through a phase of growth from infancy to adulthood, changing from cumbersome and hypersensitive to streamlined and stable. That growth phase is better passed through in countries with resources to spare for working out how to streamline and simplify the technique, but it would be useful if the needs and possibilities in DCs could sometimes be considered during this process. Examples are standardization of incubation temperatures (consider the differences in 'room temperature' in different countries) and development of protocols to re-use as many as possible of the components, or to reduce the excess of reagents added to a test (most commercial agglutination tests, such as for hepatitis B, work quite well when all the reagents are diluted up to ten times), and stabilization of reagents by lyophilization (so they survive long waits in customs sheds, for example). Since the obtaining, maintenance and use of experimental animals is often a difficulty in DCs, the drive to replace them with in vitro or other techniques which is taking place in the ICs (for other reasons) should be followed up for the DCs. Production of monoclonal antibodies is one technique which is usually in high demand in DCs. Monoclonal antibodies have many obvious advantages over conventional antisera, which is why so many researchers and commercial producers of tests kits now use them. The antibodies that have been produced, however, are mainly, although not quite totally, those of interest/use/ commercial value in the ICs. In the DCs, many people are keen to obtain them, but they are prohibitively expensive, or available only in limited amounts as gifts from researchers. Also, many people in the DCs are keen to make their own antibodies, either to do what is done in the ICs or because the reagents they need for research and/or diagnosis in their own situation are not available at all from the ICs. Making monoclonal antibodies requires a very large investment, both in facilities and in running costs. Commercial firms recuperate this by selling thefinalproduct at high cost. Those in the DCs often do not have the resources to invest in production even for research, or for the necessary production standards and quality control in order to sell the product on the profitable international market. What is needed is training not only in making
Immunologicai Techniques in and for Developing Countries monoclonal antibodies, already available in various courses, but also in deciding when it is useful to make them or when conventional sera would serve as well or better, and possibly training in making a product which can be sold to help finance further development. Most researchers are not experienced in this kind of thinking, and there is too little coordination with the agencies familiar with it, such as the vaccine makers. The area of infectious disease research has been exceptionally susceptible to changes in 'fashion' over the years. In DCs, infectious diseases are an important cause of morbidity and mortality. But which of these receive attention, and therefore money, in international circles is not necessarily determined by the health priorities in the DCs. Research, and immunologicai research in particular, is also largely directed towards finding technical solutions for problems, which are not only technical but also socio-economic problems. The practice of scientific parachuting, in which researchers from an IC fly into a DC having lots of patients or organisms, collect samples and fly back to their laboratories to analyse them, has been very common. There are some reasons for this; there will be instruments and facilities available in the IC which could not easily be transplanted to the DC. But this practice does not seem to be dying out quickly enough, and it is one of the reasons that the research is so often not consistent with local priorities. There are advantages not only for the DC but also for the IC in transferring as much as possible ofthe technology for the research to the DC. It will improve the quality of that part of the work done in the DC (collecting, storing and recording samples, making diagnoses, etc.), because it then becomes real collaboration. Another advantage is that studies can be done which would otherwise be difficult, such as long-term follow up in chronic diseases like leprosy and tuberculosis, or in recurrent infections with parasites. With some exceptions, researchers in the ICs tend to neglect the fact that diseases occur in a socio-economic context which may have great influence on the course of the disease and on the immunologicai phenomena which appear. The role of lifestyle in, for example, cardiovascular diseases or some kinds of cancer has been clearly demonstrated in the ICs. When the diseases or conditions under study are in countries with quite different and often highly varying lifestyles, the importance of such factors is often overlooked.
147
There is relatively little attention paid, for example, to the role of mild or even severe malnutrition on many infectious diseases. Not to mention the effects of concurrent infections with other similar organisms, or for example, with intestinal parasites. Even the dynamics of infection in the natural situation are often ignored. Studies on family occurrence of diseases tend to concentrate on demonstrating a genetic factor, with little consideration for the living conditions and other habits. How many people sleep in one bed, or the different agricultural duties of men, women and children may be equally important as factors in the transmission and the course of communicable diseases as the production of lymphokines upon contact with antigen presented by macrophages with different MHC types. The possibility of combining immunology studies with other kinds of studies is an additional reason to do as much of the research as possible locally. Perhaps because those from DCs trained in ICs so often learn the technology but not the criteria for its application, there is often a surprising lack of communication between those who need diagnostic techniques and those who do research to develop them. For example, there is a difference between these two groups in what is meant by sensitivity and specificity of a given diagnostic test. The person working in a laboratory thinks of a very sensitive test as one that can detect a very small amount ofthe target substance, for example antibodies reacting with a certain antigen. In the laboratory, a specific test detects reactions with that antigen, and not with other antigens of related, or unrelated, structure. But when the test is to be applied in the field for epidemiological studies, or in the clinic as an aid to diagnosis, these terms take on a different meaning. Specificity then becomes a question of whether the test provides information relevant to that one disease or condition and not to other, related or unrelated, conditions. For example, a test might be able to detect rheumatoid factor very specifically, but if rheumatoid factor is found in many different conditions, the test is not specific for any of them. Sensitivity changes in a similar way: the test may be able to detect very low amounts of a certain antibody, but if the antibody is not found in all patients having the condition of interest, the test is not a sensitive indicator of that condition and will not be able to identify it when it appears infrequently in a population. These two factors are, in an epidemiological or clinical sense.
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E, P, Wright
greatly influenced by the prevalence ofthe disease in the population, which is another factor often forgotten by the laboratory people, who generally only receive those samples already suspected on other grounds of being positive. Communication is needed; each user group needs to be aware of the requirements and abilities of the other. CONCLUSIONS Most technological developments proceed at a pace and in a direction related to their commercial value. This means that some will not be developed at all, or will be developed in a way that makes them viable only in well-equipped laboratories with stable conditions in ICs. Researchers in ICs working with concepts or diseases of importance for DCs could keep this in mind and develop their techniques in such a way that they are more widely useful. And they could train the students from DCs in this kind of standardization. The rapid development of simple and reliable tests for HIV infection shows what can be done when there is a financial incentive. Researchers in ICs could also stop to think about how their own priorities are set, at the macro and micro levels, and discuss with their guests and students from DCs how it can be done in their countries. Training of research scientists, in both ICs and DCs, should include looking at the real needs in the country; for countries with limited
resources that also means setting priorities and making choices based on priorities. Very interesting research may have to be set aside for the future while directly applicable and beneficial research is done on problems of more immediate or broader concern. Cooperation in research should mean not only exploitation of the resources (patients, new organisms, freedom from restrictive legislation) of the DCs but also, as much as possible, paying attention to the needs and priorities of those countries. Collaboration should always include training components and provision of a certain amount of equipment and materials to enable some of the work to be done locally. Appropriate selection and adaptation of techniques requires sufficient information, and one of the great lacks in most DCs is up-do-date information about new methods and advances in immunology, among other subjects. Reduced rates for subscriptions to 'international'journals, waiving page and handling charges for those from developing countries, assistance with editing of their papers, are examples of what could be done to improve access to information for those in DCs and to improve their opportunities to communicate what they are doing in the field. Immunologists interested in working with and for developing countries should keep all of these points in mind while developing their proposals and programmes for collaboration.
