Biomedical research [full issue]

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Cover : An electron microscope sequence showing the invasion of a red blood cell by a malaria parasite (marked with an arrow). ( Photo US National Institutes of Health) Contents The challenge of the future by T. A. Lambo 3 The biological revolution by C. de Duve . 4 Risks and rewards 12 The forgotten people by D. S. Rowe 18 New directions by M. Kaplan 24 WHO News in Brief . . 28 Young World Health . 30 World Health appears in Arabic, English, French, German, Persian, Portuguese, Rus- sian and Spanish. Articles and photographs not copyrighted may be reproduced provided credit is given to the World Health Organization. Signed articles do not necessarily reflect WHO's views. World Health, WHO, Av. Appia, 1211 Geneva 27, Switzerland. Hitherto insecticide spraying has appeared to be virtually the only way to control malaria. Now biomedical research is pursuing new paths which may make it possible to attack the malaria parasite itself in the human body. (Photo WHO/D. Henrioud) WORLD HEALTH THE ..MAGAZINE OF THE WORLD HEALTH ORGANIZATION • JUNE 7976 USA $ 1 BIOMEDICAL RESEARCH the challenge of the future BY T. ADEOYE LAMBO de he scientific and technological revolution of this age has its im-plications for our contemporary culture and civilization far beyond our imagination. The motivat- ing drive to conquer diseases and ac- quire better and more sophisticated knowledge of human biology continues unabated. The results have a great potential for improving human health but there are also unanticipated "fall out" effects, i.e. both good and bad ef- fects, which raise major moral and ethi- cal questions in the wake of the unpre- cedented progress of scientific research and discoveries. The development of biomedical research as part of a larger strategy of scientific research generally has hitherto been the monopoly of advanced nations. This monopoly has been dictated by such factors as the availability of well- trained scientists, organizational strate- gy for the development of scientific research, and the provision of material resources for such research. The rules and standards governing biomedical in- vestigation are constantly being scruti- nized. However, it is hoped that the dis- coveries that may follow these major research activities and the practical im- plementation resulting from the achieve- ments of basic scientific research may not only lead to a health revolution but may also spark off a new concept of human existence. We are duty bound to find ways of creating a balance of change that will be for the good not only of a small group of people but of mankind in every part of the world. Although the less advanced countries have benefited directly from some of the break-throughs of the past few decades, their participation in these endeavours has been unavoidably minimal. Their capacity to utilize modern scientific tools to investigate and throw light upon the major diseases which continue to devitalize the individual and cripple socio-economic development is limited. This is due to the fact that scientific "know-how", human and material re- sources, as well as organizational mea- sures are still inadequate in those coun- tries and corners of the world where medical and health problems exist in such proportions as to undermine their socio-economic development. A "unified approach" to the problems of develop- ment and to criteria for development strategies should start with the process of effective utilization of all resources— economic, scientific, technological, hu- man—for the benefit of all. The past history of WHO has shown that it has been an effective forum for scientific discussion of broad and of spe- cific aspects of research relevant to the control of major diseases. In particular, WHO has played an indispensable role in activities such as standardization and nomenclature in the fields of antibiotics, drugs, hormones and technical metho- dology. These and related activities form part of the foundation on which improved health care should be built. The supportive as well as the catalytic role of the World Health Organization is of great import. It must not only con- tinue but must also be developed at a pace commensurate with the growth of biomedical science. However, it is the active role which is now becoming a crucial question. To what extent is it possible and desirable that an international organization takes the lead in the development of certain aspects of biomedical science? Biomedi- cal science has been actively developed in relatively few countries. The process of development is complex, balancing such factors as talent against material resources, effort against need, short- term against long-term benefit, and weighing the returns to be expected for the investment made. If these are com- plex and difficult questions to resolve at a national level, they are even more so at the international level. For a truly worldwide biomedical research programme, the Human Reproduction Programme of WHO may be taken as an example. It was accepted by certain countries that there was an international need for the urgent devel- opment of methods to regulate human reproduction, that individual national resources were insufficient, and that the services of the world's best scientists in the field were required. There was also a need to deepen our knowledge of human reproductive biology. Those needs still exist. The Special Programme for Research and Training in Tropical Diseases (see page 18) is another such programme where needs and resources may logically be considered to be on a worldwide scale. This is a more complex venture. Not only is biomedical science and tech- nology to be harnessed to develop new and better remedies and prophylaxis such as vaccines, drugs and methods to control disease, including vectors, but the research has to be organized in such a way that it is problem-oriented and goal-directed. To ensure that these new remedies are economically feasible, safe, efficacious and acceptable, it seems logical to have part, if not most, of the research operation take place in ecologi- cal settings where the diseases occur. These two examples of major research programmes (the Human Reproduction Programme and the Special Programme for Research and Training in Tropical Diseases) have built in inter-disciplinary and multi-disciplinary components. The Special Programme for Research and Training in Tropical Diseases (TDR) may be regarded as a test in the field of international cooperation. It ill- ustrates some of the problems inherent in developing biomedical research on an international scale directed towards solving mankind's major health prob- lems. The danger of not moving fast enough in establishing the necessary mechanisms for coordination of research is real. A difficult and challenging task lies ahead for wHo to re-define its active role as an international health organiza- tion in an era which has been termed the coming age of biomedical science. WHO will need to develop modes of operation which favour international effort and, in this light, TDR appears as one of the most interesting and challenging models for the future. In the final analysis, any achievements in these research activities will be the property of all mankind. ■ the biological revolution Striking at the very core of life, molecular biology has finally confirmed the unity of living matter, by demonstrating the universality of the genetic code BY CHRISTIAN DE DUVE L n the past, biology was defined as the science of living beings. It has now become the science of life. Realization of the essential unity of life started already in the beginning of the last century, when it was recognized that all plants and animals are made of similar microscopic elements called cells. This unitary view was streng- thened when the theory was proposed, and progressively accepted, that plants and animals all originate from a com- mon unicellular ancestor, through the process of evolution. Recent develop- ments in biochemistry, cell biology and molecular biology have extended the monistic concept down to the most ele- mentary levels of structure and function. Life as we know it is a unique process. Behind its countless and infinitely varie- gated forms, are found the same basic mechanisms, the same molecular deter- minants. The fact that our understanding of the living process has progressed so far must be regarded as one of mankind's greatest intellectual and technical achievements, certainly the most far- reaching one in terms of its conse- quences. Much of it was accomplished in the last three decades. Until some thirty years ago, our knowledge of cell structure was limited by the resolving power of the light microscope, which is of the order of 2,500 Angstrom units (0.25 micron or one hundred-thousandth of an inch); no molecular structure greater than about one-hundredth this size was known to chemistry in any detail. Between these two boundaries, covering two orders of magnitude of linear dimension, lay a vast "terra incognita", undoubtedly replete with essential information, but quite inaccessible to the means of the day. Invasion of this territory started in the late 1940's, simultaneously from both ends of the dimension scale, that is from the side of morphology and from that of chemistry. Morphological exploration of the subcellular domain was rendered pos- sible by the invention of the electron microscope in the 1930's, and its subse- quent adaptation to the examination of biological specimens. The first electron micrograph of a cell was taken in 1945. It was a pretty poor picture by present day standards, but quite an achievement at the time, in view of the difficulties arising from the weak penetrating power of an electron beam. These difficulties were however overcome with surprising speed, so that less than ten years later, electron microscopy had already reached a high degree of perfection, revealing for the first time to our eyes the full complexity of cellular organiza- tion. In itself, this development would have brought as much frustration as delight, since there is almost no key in the sub- The cell is the fundamental and universal building-block of living systems. About a thousand cells laid side by side would measure one centimetre. The cell is enclosed in a membrane ( I ). Towards each cell's centre is the nucleus (6) which contains genetic in- formation in the form of DNA - deoxy- ribonucleic acid. The nucleus includes the nucleolus (7) where the ribo- somes (3) originate, emerging from the nucleus through pores in its lining. The ribosomes are the assembly site of protein molecules and are -programm- ed- to assemble these by instructional material (RNA or ribonucleic acid) received from the nucleus. The nucleus thus controls the chemical machinery of the cell. The ribosomes are associated with a system of fissures which are surrounded by the membranes of the endoplasmic reticulum ( 2) and through which the proteins are distributed throughout the cell. The energy required for the various cell activities is supplied by special organs, the mitochondriae (4), which obtain the glucose and oxygen needed for the energy-providing chemical processes from outside the cell. At the onset of cell duplication (not shown here) the nuclear chromatin condenses to granules, forming long entangled filaments - the chromosomes (see next page). The centrosomes (5) play an important part during cell division. ( Photo WHO) 4 cellular structures themselves to indicate their function. Only penetrating bio- chemical analyses could provide such in- formation, but for this to be accom- plished the various cell components first had to be separated from each other. This problem was solved by the devel- opment of fractionation procedures based on the application of centrifugal forces of increasing magnitude to prep- arations of tissues that had been gently disrupted in the presence of a suitable liquid medium. In this way, the nuclei and cytoplasmic particles released from the crushed cells could be partitioned between a number of separate fractions, depending on their rate of sedimenta- tion in the centrifugal fields applied. Later,, separation techniques exploiting differences in density were also worked out. Although quite crude, these cell fractionation procedures turned out to be very rewarding, making available for biochemical analysis preparations en- riched in all the major subcellular enti- ties that could be discerned with the electron microscope. By a fortunate set of circumstances, the development of centrifugal fraction- ation coincided with that of some of the most valuable tools of biochemistry, es- pecially radio-isotopes and chromatogra- phy. Thanks to these new tools, the study of metabolic reactions and of the enzymes that catalyze them, which in half a century had moved painstakingly to the elucidation of a few simple, though quite basic, pathways such as al- coholic fermentation and the tricarb- oxylic acid cycle, suddenly blossomed in all directions. Combination of these in- vestigations with cell fractionation had a remarkable cross-fertilizing effect. Known enzymes could be assayed on subcellular fractions and their cellular localization identified in this manner. Conversely, subcellular fractions pro- vided the biochemists with structurally integrated multi-enzyme systems ca- pable of enacting in the test tube even the most complex of the vital 'processes, including the retrieval of metabolic energy, the biosynthesis of all major biological constituents, and the copying of genetic information. In less than twenty years' time, the chemical path- ways mediating these processes were largely unravelled. Two other important developments took place during the same period. One was a considerable refinement of the chemical and physical means of struc- tural analysis, resulting in the complete elucidation of the structure of a number of proteins, nucleic acids and other macromolecules. The other took its inception in genetic studies of simple microorganisms and viruses. It appeared first .as a new inconspicuous stream of rather esoteric knowledge. But in less than two decades, it had gathered on its way all the other rivulets flowing from cell biology, biochemistry and macro- molecular chemistry, emerging as the

Lower left : Thanks to the electron microscope, scientists can at last determine the shape and structure of the fundamental particles of living organisms. ( Photo WHO/T. Farkas) Left: The threadlike chromosome, part of the nucleus of living cells which transmits genetic information, assumes quite different aspects during the various phases of the division of the cell. Starting from a stretched-out state ( 1), a chromosome is shown about to coil up (2), tightened more closely (3), and tightly coiled to assume a rod-like shape (4). Underneath this rod-like exterior, strands of thin threads, also packed tightly, line the interior surface of the chromosome. Along these threads are arranged the genes, the factors of heredity, composed of DNA molecules. ( Photo WHO) Right: Two enormously complex intertwined spirals the double helix—compose the mole- cular structure of DNA, the basic particle of life. Acting through the chromosome, DNA is the physical medium in which the genetic message of reproduction is written. Even the electron microscope cannot make so tiny a particle visible: this is a diagrammatic re- presentation of what we know of the DNA structure. (Photo WHO) central mainstream of modern biology. Striking at the very core of life, molecu- lar biology has uncovered the basic mechanisms whereby genetic instruc- tions are encoded, transmitted from generation to generation, read under ap- propriate modulating signals, translated and executed. In so doing, it has also brought the final confirmation of the unity of life, by demonstrating the universality of the genetic code. To the scientists of my generation, who have witnessed this biological revo- lution and participated in its accom- plishment, it has been an unforgettable experience. While the excitement has abated, the interest remains, absorbing and fundamental to all mankind For the biological revolution, although not heralded by spectacular manifestations of the kind that announced the atomic revolution or the space revolution, is of greater significance to us than the latter since it concerns our very nature and survival. Like the other scientific revolu- tions of our times, it has evoked misgiv- ings and concerns, as well as wonder and enthusiasm. Its impact on our future has become a major issue. One prediction can safely be made. The search for knowledge will go on, whatever the cost or the risk, since nothing can stem man's curiosity. And there is much that remains to be dis- covered, immeasurably more, in fact, than is already knoWn. Revolutionary as they are, the recent advances of cellular The biological revolution and molecular biology are but a first step on what promises to be a long and increasingly arduous road. It must be realized, for instance, that our present knowledge of cellular organ- ization is still largely descriptive. We talk glibly about membranes and draw elegant diagrams illustrating their func- tions: partitioning the cell contents, transporting ions and chemicals selec- tively from one space to another, retrieving energy from electron flow, channeling secretory products from their site of synthesis to their extracellu- lar destination, walling off areas of breakdown and bringing towards them a variety of exogenous as well as endo- genous materials. But we really have no inkling of how the various types of cytomembranes are assembled, nor of what causes them to undergo the com- plex folding and fusion processes repre- sented in our schemes. Similarly, our genetic literacy is still of the most rudimentary sort. We know the alphabet and we can read a few sim- ple words. But we are still far from com- prehending even the most elementary set of instructions, let alone those incredi- bly complex programmes that direct developmental processes. In fact, the mere phenomenon of cell division is still largely a mystery and our understanding of chromosome structure and move- ments has hardly progressed since mito- sis was first described a hundred years ago. Another major challenge for the future is the problem of cell-to-cell in- teraction, especially in the nervous sys- tem. To illustrate the magnitude of this problem, there are more cells in a single human brain than there are transistors in all the world's computers put to- gether, and each cell is connected with hundreds, or even thousands, of neigh- bouring cells. It is difficult to see what instrument, aside from some sort of superbrain, could ever help us grasp such intricacy. At yet a higher level of integration, biology will branch out increasingly into population dynamics, ecology, ethology, sociology, and ultimately ethics and philosophy. The origin . of life, its evolu- tion, its possible existence elsewhere in the universe, are other fields of inquiry that are likely to attract growing atten- tion. But the search for new knowledge is only part of the scientific endeavour; its outcome is elusive and, by definition, unpredictable. What of the foreseeable applications of what is already known? Developments have been so swift that we have hardly had time to reflect on the possibilities they have opened. But it is obvious that through the biological revolution man is gaining new means of control over all living beings, including himself. These means can be of great benefit; but they could also be detrimen- tal, if used unwisely, irresponsibly, or unscrupulously for profit or for power. Here particularly is where the biological revolution has become a matter of grave concern. Spectres have been raised of major man-made ecological disasters, of deathly new species created in the labo- ratory, of sinister exploitations of biolo- gy for warfare or for the manipulation of individuals and societies. Tales of Frankenstein's monster and of the ap- prentice-sorcerer have been revived to haunt us, together with much more dis- turbing, because less fanciful, accounts of events known or purported to have taken place already. Let us face it, these threats are real, as are those posed by the development of atomic energy and by world-wide indus- trialization. But they are to be blamed on the manner science is used, not on science itself. And they will not be avert- ed by a ban on scientific research, clear- ly impossible to impose in any case. We cannot go back on knowledge. Nor can we stifle the basic human urge to search for it. On the contrary. Only more knowledge and better science can help us chart our course, point the way to survival, provide cures or antidotes against ills that are nothing but the growing pains of mankind struggling towards mastery of its own fate. Man has not awaited elucidation of the genet- ic code to plunder his environment. The skeletons of wounded mammoths trapped in the ice and the barren wastes of deserts attest to his blind capacity for destruction. At least, he is now begin- ning to acquire the means of predicting the consequences of his actions and of assuming responsibility for them. What he is most in need of now, to balance his intelligence, is wisdom. This develop- ment is becoming such a necessary con- dition for survival that we may safely predict, on evolutionary grounds, that it will take place unless man happens to be a lethal mutant. The question is: at what cost? This question is unanswer- able, but it is an encouraging sign that the biological revolution has coincided with a growing awareness of our global responsibilities. It seems almost self-evident that med- icine should be a major beneficiary of the biological revolution. Yet it has so far gained surprisingly little from the new findings of cellular and molecular biology. Even more surprising, it has done remarkably well without them. This paradox deserves to be ex- amined, not only as a point of historical interest, but also in relation to future strategy. Should medical research conti- nue along the traditional lines that have been so successful in the past? Or is there need for a change? Due to its vocation, medical research has always been primarily utilitarian and pragmatic in its approach. Its main objective is to prevent or cure, not to understand. This is not to say that it is in any way anti-intellectual or anti-scien- tific. But if it can achieve its objective without understanding how it is getting there, it does not hesitate to do so. Starting from the simple tenet that there can be no effect without a cause, it has looked in the environment for causes of disease. In this way, it has discovered microbes and viruses, noxious factors of various kinds, and, by default, the vita- mins and other essential nutrients. On the basis of these findings, it was able to devise a number of simple prophylactic measures which, in themselves, have had a profound influence on the quality of life and on life expectancy. As to the first successes of therapeutics, they were even more empirical, arising almost ex- clusively from the accumulated ex- periences of past generations and their exploitation by chemical technology. These approaches have been so rewarding that they are still applied today on a large scale. Witness the im- portance of epidemiology in clinical in- vestigation, that of mass screening in pharmaceutical research. The story of penicillin is here to remind us that mira- cle drugs can still be discovered by acci- dent. There are more cells in a single human brain >. than there are transistors in all the world's computers put together. And each cell is connected with hundreds, or even thousands, of neighbouring cells. It is difficult for us to imagine what instrument, apart from some kind of super-brain, could ever enable us to grasp such intricacy. ( Photo IBM/ WHO) 8 41116:Afre4,:'g LT .1L .J.• t. 4;5- .•fts Clearly, however, modern medicine is much more than the product of empiri- cism. It owes a great deal also to basic research, partly in the form of "post hoc" explanations of earlier findings, partly in the form of genuine new prac- tical developments. Immunology and endocrinology are good examples of this, but there are many others. Similar- ly, some new drugs have been designed "de novo", on the basis of rational con- siderations, for instance the antihista- mines and certain antimitotic agents (i.e. drugs to counteract specific organic chemicals or functions). Even in these developments, however, the cell itself has been treated largely as a black box. If we look at modern clini- cal research, for example, we see that it is still essentially environmental, at least from the point of view of the cells. It explores in great detail and with sophis- ticated technology all possible physical and chemical properties of the blood and other humours. But it hardly ever looks into the cells and tissues them- selves, except with morphological tools whose informative value is very limited. Under the circumstances, it is hardly surprising that a number of major medi- cal problems should still be awaiting a solution. Prominent among these prob- lems are the degenerative conditions, such as cancer, athero-sclerosis, poly- arthritis, even aging itself, which proba- bly cannot be ascribed to a single well- defined cause, but rather represent com- plex cellular reactions to a variety of in- sults and solicitations, many of which may be inseparable from the simple business of living. As long as we knew little about normal cellular mechanisms, there was little we could do to try and understand their pathological derange- ments. But the situation has changed. Even in the field of communicable diseases, identification of the causal agent is not necessarily a sufficient con- dition of successful prevention or cure. We need only think in this respect of the parasitic diseases which still devastate large parts of the world. Unlike many bacterial infections, these diseases have not yet yielded to the combined assaults of sanitation, immunization and chemo- therapy, partly for practical reasons, but partly also for lack of sufficiently effec- tive means. In spite of considerable ef- forts, the empirical approach has met with limited success so far. Greater focus 10 The biological revolution We cannot go back on knowledge. .Nor can we stifle the basic human urge to search for it. On the contrary. Only more knowledge and better science can help us chart our course, point the way to survival, provide cures or antidotes against ills that are nothing but the growing pains of mankind struggling towards mastery of its own fate. The barren wastes of deserts attest to man's blind capacity for destroying and plundering his environment. ( Photo Len Sirman (0) Among the challenges for the future is the search for the origin of life, its evolution, its possible existence elsewhere in the universe. (Photo Metro-Goldwyn-Mayer ) on the parasites themselves is likely to be more rewarding. Surely there must be many chinks, at the subcellular and molecular level, in the armour of these fragile organisms, most of which depend for survival on complex life-cycles and on passage through at least one, and usually two or more, specific hosts. The conclusion is obvious. The bio- logical revolution can spawn a second medical revolution. But for this, the gap must be bridged between basic biology and medicine, which on a short term basis can be achieved only if those who by training and competence hold the key to the subcellular and molecular domains can be induced to turn their attention to the health problems of the world. There are many encouraging signs that this evolution is taking place. ■ risks and rewards Dr Martin Kaplan, who heads WHO's Office of Research Promotion and Development, was the moderator at a special round table dis- cussion on biomedical research arranged by World Health. With him were Professor B. 0. Osuntokun, Dean of the Medical School of Ibaclan, Nigeria; Professor Joshua Lederberg, Professor of Genet- ics at Stanford University, Palo Alto, California, USA, a Nobel laureate; and Professor Jacques Monod, Director of the Institut Pasteur in Paris and also a Nobel laureate. KAPLAN: Professor Osuntokun, in which fields of public health do you feel that research is most important for the diseases that you encounter in West Africa? OSUNTOKUN : In the developing coun- tries, particularly in the tropics, we face severe problems from communicable diseases aggravated by malnutrition. These are the areas in which research into public health can contribute tre- mendously towards ameliorating mor- bidity and mortality in these countries. It has been calculated that if we can eradicate or limit the morbidity and mortality imposed by 12 named dis- eases, we can reduce the mortality and morbidity in these developing countries by 95 per cent. KAPLAN: Here is a group of diseases in which research has been going on for many years, and yet it is apparent that we are far behind in having the available tools to combat them effectively. We have been attacking malaria, for exam- ple, for the last 10 or 15 years with in- sect control and have made great in- roads, but we have come up against a very difficult problem in Africa where social and economic conditions preclude using such means. If we had a vaccine against malaria, it would be a very marked improvement. How can we go about developing such a vaccine? LEDERBERG : I would not want it taken for granted that vector control is not part of our strategy. The situation requires much more careful examination to determine just what measures might be used. However, it is true we have tended to place almost excessive reliance on one simple technological solution. DDT was going to be the miracle that would solve this problem once and for all, and while it did for a time have nearly miraculous results in some parts of the world, it is now apparent that a much more complex approach is neces- sary. I would agree that until we can be sure that we have alternative approaches by vector control, a direct attack on a malarial parasite and an understanding of its biologies is an extremely impor- tant step to take. One reason for the relative neglect of the biology of para- sites during the past 20 years has been the temporary success of methods based on vector control. Only now when we see these have not worked out effective- ly do we realize that we must go back to much more fundamental approaches. KAPLAN : Professor Monod, your work in the field of molecular biology won you the Nobel Prize, yet it is difficult for many people to see how this can be directly related, or what promise it might hold for solving such fundamen- tal biological problems as parasitic dis- eases. MONOD : Let me begin with a field that is not mine, namely parasitic diseases again. I think all approaches must be used at the same time and I agree with Dr Lederberg that, for instance, vector control might be sought for or achieved by means other than chemicals. There is much more work to be done in develop- ing preventive means, such as vaccines, but recent work in our Institute suggests 12 Round Table discussion on biomedical research at WHO headquarters in Geneva. From left to right: Professor Jacques Monod, Dr Martin Kaplan, Professor B.O. Osuntokun, Professor Joshua Lederberg. (Photo WHO) that parasites have very special ways of defending themselves against the immu- nological defences or organisms which are successful for, say, viral diseases or microbial diseases. Some very important advances may be made in this field in the next five years. KAPLAN : Suppose we did have effective vaccines : the problem is how to apply our knowledge under difficult local con- ditions such as one finds, for example, on the African continent. OSUNTOKUN : The greatest constraints in applying knowledge and improving the delivery of health care, as far as the Afri- can continent is concerned, are con- straints dealing with the availability of manpower, and of course, ignorance which can be corrected by health educa- tion. In most of the developing coun- tries, you just don't have the manpower to go around and apply things like im- munization. This is an area in which we have to do something fairly quickly if we are going to benefit from the rapid advances in medical knowledge. KAPLAN : Lack of manpower is certainly one of the most severe constraints, and particularly the lack of research man- power. That is one of the reasons why we in the World Health Organization have launched a special programme of research in tropical diseases (see article by Dr D.S. Rowe in this issue) to try to build up a research manpower base in the developing countries. LEDERBERG : Very much depends on the time scale that you feel is important to achieve significant progress, and all these problems are interconnected. The health status of the country influences its eco- nomic productivity which in turn in- fluences the availability of capital for in- vestment, in human resources as well as other industrial resources. These matters are all completely interlinked. Now you can view parasitism with malaria as a well-established ecological equilibrium. It is not a very satisfactory equilibrium from the human standpoint, but we have the mosquito, we have the parasite, we have people; they have found them- selves in a particular circumstance which will be stable (to the human detriment) over a considerable period of time, unless we do something about it. Any large-scale disturbance that we make of that equilibrium involves some risk. It is hard to think of any method of altering the situation which might not have some side-effects. Certain side- effects followed the introduction of DDT, for example, but I am sure the hazards to human health of DDT are much less than the benefits in those zones where it has been effective as a public health pro- gramme. KAPLAN : Your point about possible risks recalls one of the most heated con- troversies of recent years, concerning the so-called genetic manipulation of micro-organisms; there have been some 13 Risks and rewards <Student nurses at a training school in Gabon, West Africa. Unfortunately, in most of the developing countries of Africa, there is simply not enough manpower to meet the health needs of the people. (Photo WHO) A patient being treated in a Sudanese hospital Jr sleeping sickness. The disease is caused by one of the parasites whose life-cycles we need to understand better if we are to control them. (Photo WHO/D. Henrioud) horror stories thrown around that this has untold dangers for mankind. We would like to know more about this procedure and how you view its future possibilities. MONOD: These hazards exist. Whenever a new powerful tool is developed in fun- damental science, new knowledge is new power, and new power can be put to good use or to ill use. But there is nothing specific about this particular development, in fact I think that it is far less hazardous than many that we have seen or will be seeing in the next few years. Microbiologists around the world have learned over the past 100 years or so since Pasteur's work to handle ex- tremely dangerous pathogenes in com- plete safety. The kind of hysteria that has developed recently—simply because the public has been poorly informed— reminds me of what happened when the Pasteur Institute was first built in Paris. A number of articles appeared at that time treating Pasteur as a sort of Fran- kenstein monster who was going to spread horrible foreign diseases around the city. It's the same story today. Frankly, there is much less danger in most of the research programmes now under way in this field than there was at the time microbiology began, and we have only to look at the benefits of microbiology. These new techniques of genetic engineering have a wide variety of application, not only in medical therapy, or prevention, but also in zoo- logical technology and agronomy; they may contribute considerably to solving some of our nutritional problems. KAPLAN: Professor Lederberg, you are a geneticist. Can you give as simple an ex- planation as possible of what is genetic manipulation? LEDERBERG: All the findings of molecu- lar biologists for at least the past 25 years focus on the way in which genetic information is represented in a chemical substance at the centre of a cell. This chemical substance is DNA. And while we have had a revolution in our biological understanding of the nature of life, the cell, reproduction and the mechanism of evolution, up to now this has had very little actual medical application. DNA, deoxyribonucleic acid, is the substance in which the genet- ic information is represented and forms the material basis of the gene. It is a chemically defined structure of consider- able complexity, the blue-print of the cell. If you put DNA into an animal, or inject it into a man's veins, unless there were some very special circumstances where the DNA was taken directly from an infectious virus, it would have no biological activity whatsoever. Only in experiments with micro-organisms, with bacteria and with certain curious parti- cles found in bacteria called plasmids, have we found operationally effective ways of demonstrating that DNA does have biological specificity in revealing the information which is present in that DNA. This means that the focus of technical application of our basic scien- tific knowledge about the structure of DNA is still limited to those cases where DNA can be used as a reagent, having some effect on the biological outcome of the system into which it is introduced. KAPLAN: What benefit has medicine had 14 so far from this molecular engineering in terms of prevention of disease? LEDERBERG: So far, very little. MONOD : As Professor Lederberg says; there are still few ways of applying the basic knowledge and concepts of molec- ular genetics, of molecular biology. On the other hand, great benefits have been derived from technical advances stemm- ing from this work, for instance, most of what we know and understand about virus replication structure and so forth comes from this work and it has been very important in the development of modern viral vaccines. LEDERBERG: What are being devel- oped—which in the long run will totally transform the picture—are methods whereby DNA from one cell, from one source, can be implanted into the genetic structure of a totally different kind of cell. Thus it has been possible to move DNA not only from one strain of a common bacterium escherichia coli, into another of the same species, but even very different strains of bacteria, and even totally unrelated organisms. For example, one can take DNA from the cells of a toad, and certain special kinds of DNA in such cells can be implanted into a bacterium and used there in order to manufacture large quantities of prod- ucts that originally came from the toad. This opens possibilities for very impor- tant applications in just the sphere that we are talking about. Many of the para- sites against which we are trying to pro- duce vaccines, whose life-cycle we need to understand in order to control them, are very difficult to deal with in the lab- oratory, precisely because they are hard to cultivate. It has been a major obstacle in the study of malaria that we do not have a pure chemically defined system in which the malaria parasite can be grown in the way that we can grow bacteria. We have to grow it inside the living red cells of certain hosts, and even then, there are severe problems. One possible method of producing purified vaccines, which I am sure will be attempted in the very near future, would be to isolate fragments of DNA from the malaria parasite and implant portions of that DNA into bacterial clones. Those clones (identical progeny of a single cell) would then be examined to see whether any of them produce products that can be used as vaccines against malaria. This would be a prototype of a wide variety of ex- periments that are available to us now and simply could not have been done two years ago. KAPLAN: One of the hazards that has frequently been mentioned is that, for example, by taking a cancer virus that is known to produce a cancer in animals and then isolating the component of the DNA responsible for producing the tumor and putting it into a cell, we could reproduce large amounts of the virus. If it escaped from a laboratory, it could be spread widely among the pub- lic. Is this a matter for concern? MONOD : This is just the kind of specula- tion that has tended to frighten people. In fact, while the remote possibility of something of that kind happening has to be borne in mind, the techniques and security measures to prevent such an event or to contain any dangerous or- ganism that might turn up are well 15 known and can easily be built in at rela- tively little cost. The risks involved in the use of these techniques have been greatly exaggerated. LEDERBERG : I agree with Professor Monod and would like to add that the very term cancer virus scare is a mis- nomer. The public would be misled if they thought a wide variety of infectious agents existed which were known to produce cancer in man, in the sense that there is a virus for influenza, and a virus for measles, and so on. That kind of a virus for cancer in man does not exist. We have evidence that certain viruses, when inoculated under very restricted experimental conditions into newborn mice or newborn hamsters at a time when they have no immunological pro- tection whatsoever, can induce wide- spread tumours. This is a very interesting biological phenomenon and is expected to shed light on the problem of cancer formation. But the viruses capable of having this effect are already very com- mon in nature—one or two per cent of all wild rodents already carry the polio- ma viruses, a large fraction of wild monkeys carry the S.V. 40, and some very common viruses of the adenal virus group, which cause respiratory and in- testinal infection in man, have been shown to have cancer virus-like proper- ties and are present in perfectly healthy people. KAPLAN : And there has been no evi- dence as yet for the transfer of tumour viruses from animals to man : they seem to be quite species specific? LEDERBERG : They do, and we may in- deed be thankful that this is the case, because of our daily exposure to agents of that kind. Many viruses may contrib- ute to the possibility of cancer develop- ing in the individual, which makes it all the more important that we understand their mechanism. The risks are there. For example, as an approach to dealing with the problem of cholera, one might wish to undertake new combinations of genes, including those for the toxin of cholera, and to put it in a different bio- logical framework, like that of an other- wise harmless escherichia coli. It is quite possible that such things could be pro- duced and that, if they were, they would multiply the cholera problem because there would be a variety of kinds of or- ganisms capable of giving the sympto- mology of this disease. But as Monod said, such a level of hazard is already an important part of medical microbiologi- cal research, and it would be madness to 16 Above: Louis Pasteur ( 1822-1895) was widely considered as some kind of Frankenstein monster who was going to spread horrible foreign diseases when he opened a research institute in the centre of Paris. Below: Today, the Pasteur Institute in Paris is one of the most respected research centres in the world. (Photos Institut Pasteur and P. Almasy) Right: Rehydration fluids being administered to a baby with marasmus, whose mother has another deficiency disease, goitre. New techniques of genetic engineering may contribute to solving some of the world's nutritional problems. ( Photo WHO/E. Mandelmann) put a stop to such research. It would be folly to allow it to continue if there were not reasonable precautions connected with the circumstances in which it was done. A large part of the public outcry about research which is labelled DNA recombinant research arises because a new community of investigators are now working in this area. These are people whose prior training has been in fields other than medical microbiology and, in a certain sense, they have now discovered it for the first time. This is a very fortunate circumstance. It brings in enormous additional intellectual re- sources, but there is also a certain element of enthusiasm when they first encounter the kind of risks we are discussing. OSUNTOKUN : Could there be some reli- gious tone to the fears that maybe scien- tists these days are now creating life out of nothing? MONOD : I am sure that is so. In the years since the great discoveries in molecular biology, there have been dis- cussions in the press about the possibili- ty of manipulating the genetic structure of man, and creating a monster, or what not. Of course, what we are talking about now has absolutely nothing to do with that, and I think it is important to point it out. Even the word genetic manipulation is unfortunate. There is something ominous about it. The ex- pression genetic engineering is prefer- able. LEDERBERG : This is not to say that there are no risks to the microbiologists them- selves. There are heroes in the field. And again, there have been unfortunate inci- dents which we can trace to sloppy tech- niques. We have to be careful that microbiological research is done to a high standard of care and concern, so that we don't have a repetition of such incidents. The risk is if we neglect ele- mentary precautions. If we stop research in this direction, we shall pay a heavy cost. The enormous benefits from microbiological research are already very well established. Hundreds of mil- lions of deaths have been prevented by the knowledge that has accumulated during the past century, and there are prospects of being able to do the same by continuing this research. And those are benefits of such magnitude that I think no-one who examines the situa- tion will want to forgo them in the face of the very speculative and hypothetical risks that have been suggested about research in this area. ■ MIL 40., re' the forgotten people BY DAVID S. ROWE he poor who live in the rural areas of the tropical developing world have, with justification, been called the forgotten peo- ple. Many of them are sick, plagued by one or more chronic infectious or para- sitic diseases often unknown to those who live in more prosperous conditions in temperate climates. By any standard, these diseases are of major world impor- tance. Malaria, filariasis and schistosomiasis each now affect about two hundred mil- lion or more people, numbers compar- able to the entire population of the United States or the USSR, or one in twenty of the world's inhabitants. In Africa alone, malaria kills one million children every year. In some parts of the same continent, one person in ten is blind as a result of filarial worms caus- ing river blindness, or onchocerciasis. Schistosomiasis or bilharziasis is an in- sidious disease, also caused by worms, which undermines health by damage to many organs of the body, and which sometimes kills. Among other infections, gut parasites are ubiquitous, while intestinal infec- tions including cholera and typhoid and the more common diarrhoeal diseases present major threats to life especially to young children. Millions of people are infected with trypanosomiasis. Chagas' disease, the South American form of trypanosomia- sis, damages the heart and may be fatal. Sleeping sickness, the African form of the infection, threatens epidemics of brain damage, causing a lingering and degrading death. This listing could continue of diseases that bring death, suffering or long-term disability to many of the world's peo- ples. These diseases are not new and the huge numbers of people infected tend almost to overwhelm rather than to stimulate our concern. Perhaps it is only when they are con- sidered as problems for individuals that the realities begin to strike home. For example, if you are born to live in the African bush, you are liable to harbour four or more different disease-producing parasites simultaneously. And yet, as a parent, you must be fit enough to work, or your family will starve. In your vil- lage every child at times suffers the paroxysms of malaria fever and you will mourn the death of one or two children from this disease. The snails in the vil- lage pond carry schistosomiasis, and you do not consider it unusual when your children pass blood in their urine. You take for granted the disfigured faces and fingerless hands of the beggars in the village street suffering from lepro- sy. If you live near a river where black- flies breed, one in ten be your friends and neighbours will e blind in the prime of life from onchocerciasis, or riv- er blindness. You know that waves of killing diseases like measles and menin- gitis and perhaps sleeping sickness are liable to strike your village. But, lacking effective remedies, you tend to respond with fatalism in the face of sickness. You may make the effort to walk the ten miles to the nearest dispensary when you or your child is ill, but there may be no remedies, and it may be too late. Your experience of the quality of life is that of two hundred million Africans, and the story differs only in detail for some.five hundred million people living elsewhere in the tropics. The plight of such people has often been described (see World Health, April 1975). So what can be done? In that same WHO's new special programme for research and training in tropical diseases focuses on six diseases which have hitherto been comparatively ignored by medical research issue of World Health, it was pointed out that there is no single solution to the problems of rural health. Great im- provements would result, however, from bringing health services to the people by helping to apply what is known in a way which is appropriate for their environ- ment, their economic circumstances and their culture. Both reason and humanity prompt the belief that this essentially practical approach, if adequately devel- oped, could achieve notable success. But would that be enough? Clearly not : for example, let us take malaria. By the control of vector mosquitos, the prevalence of malaria in India was reduced from 75 million cases in 1935 to 60,000 in 1962 and in Sri Lanka the dis- ease was practically eradicated. But vec- tor control is not a panacea. In much of Africa, there is so much malaria that present methods of vector control are totally inadequate to affect the disease. In South-East Asia mosquitos have developed resistance to some insecti- cides. In India and Sri Lanka, where the resources were not available to continue the control of mosquitos, malaria is resurgent. In India the incidence of cases rose to two and one-half million in 1974, an object lesson on the risks of relying on a single method of attack. What about drugs? They are used pri- marily to treat an individual's illness. They can also be used to prevent infec- tion, as when anti-malaria tablets are taken by visitors in the tropics. The drugs for malaria are usually highly ef- fective, but in parts of South America and South-East Asia the parasite has become resistant to them and so new drugs are required. The drugs which are now available must be administrated for days or weeks to cure an attack, or, if used to prevent infection, must be taken whenever a person is liable to be bitten by infected mosquitos. These limitations prevent the general use of drugs to con- trol malaria by treatment of whole pop- ulations. Other parasitic diseases are less well served by drugs than is malaria. Many drugs, while poisonous to parasites, also tend to be harmful to man and to be of limited effectiveness. Leprosy is a dif- ferent matter. The drug dapsone is cheap and effective and harmful effects are not common, but treatment must be continued for up to five years, and the disease may recur even in those taking the drug. There is also concern since the bacterium causing the disease has on oc- casion been found to be resistant to this drug, which is the only effective agent. In summary, it has been said that many of today's tools used for the con- trol of tropical parasitic diseases are blunt, brutal, cumbersome and costly. What is needed are new methods which are safe, effective and cheap. How could such tools be obtained? How could research be organized to provide the new remedies which are needed? To begin with, let us clear away one misconception. A popular view is that the highest products of medical technology are procedures such as trans- plantation, intensive care units, treat- ment of cancer by surgery, irradiation and chemotherapy. Clearly such expen- sive and sophisticated treatment is total- 19 ly irrelevant to the control of diseases affecting millions of people. Lewis Thomas has called this stage of develop- ment a "half way" technology. Thomas also distinguishes another type of tech- nology, a "high technology" which is usually simple, cheap and effective. In this category he includes immunization, antibiotics, some chemotherapeutic agents and suppression of haemolytic disease of the new-born by the use of immune gammaglobulin. Such technolo- gy may be developed empirically as were many vaccines but it is increasingly like- ly that future advances will be based on knowledge of disease processes, as was the development of using anti-Rh gam- ma-globulin for the suppression of hae- molytic disease of the new-born. How then can medical technology be applied to improve tropical disease control by the development of the safe, effective and cheap remedies which are so greatly needed? It is necessary to in- crease the effort. Many countries both in the tropics and elsewhere have research programmes on tropical dis- eases, but their scale is inadequate. It has been estimated that the worldwide research budget is of the order of US $30 million per annum; the US alone spends more than this amount on cancer research. Because of low funding and the frequent isolation of workers in tropical diseases, it is difficult to bring major new concepts in biomedical sciences to bear. No new major reme- dies for these diseases have appeared over the past 30 years during a period when the technology of many other as- pects of medical care have been revolu- tionized through research. In these terms, it is true to say that research in tropical diseases has not yet got off the ground. And it is precisely to ensure this that WHO has set up a new Special Pro- gramme for Research and Training in Tropical Diseases. There is no illusion that the tasks to be undertaken will be quickly and easily accomplished or, for example, that the establishment of large international research institutes staffed by the best possible scientists could do the job. What is needed is a long-term collabora- tive effort involving workers in many countries. The baseline is knowledge of the diseases as they occur in countries and regions. Many questions must be asked. What types of remedies are feasible? If a drug, how effective must it be? How long must if act for? What side effects could be tolerated? How stable must it be in tropical conditions and, of great impor- 20 Health workers engaged in mosquito control, and a young patient being checked for possible enlargement of the spleen caused by malaria. Over much of Africa, there is so much malaria that present methods of vector control are inadequate to check the disease. (Photos WHO/J. Mohr/P. Pittet) tance, what is its economic cost? These and other questions concerning drugs, vaccines and agents for vector control must be asked and answered by people informed about local disease problems. Then, given such specifications, what are the most likely scientific leads? For development of a vaccine, is there evi- . dence of protective immunity in man? How could this be induced and how could enough vaccine be produced con- sidering that many pathogenic parasites cannot yet be cultivated in vitro? When and if the stage were reached of demon- strating the effectiveness of a drug vac- cine or vector control agent on a pilot scale, how could this be scaled up for production and mass application at eco- nomic cost and with adequate quality control? These are some of the ques- tions which a programme of research must answer. What is the basis for saying that there are new opportunities to develop better remedies? In the years following the Second World War, several industria- lized countries thought fit to make large investments of money and talent in biomedical research. The result has been an explosive increase of knowledge. Some of the highlights are well known — the unravelling of the genetic code, the full description of a protein mole- cule in all its complexity. In recent years more has been demanded of this type of research than acquisition of knowledge for its own sake, and part of the endea- vour has been directed towards such practical problems as the control of cancer and of heart disease. The new knowledge has already revolutionized medical care through such advances as new drugs for the treatment of high blood pressure, a new range of antibiot- ics, and a series of vaccines against dis- eases such as poliomyelitis and measles. But, since application lags behind fund- amental discovery,. even in the indus- trialized countries the full impact on the health of the people has yet to be rea- lized. What advances could reasonably be foreseen for research on tropical dis- eases between now and the end of the century? Here are a few examples: Professor de Duve describes else- where in this issue of World Health (page 10) the research being done on the subcellular and molecular structure of micro-organisms, which is clearly of great potential for the treatment of parasitic diseases. Reliable long-acting vaccines could revolutionize the control of malaria. In- fection has long been known to produce a certain degree of immunity and the way in which immunity works is begin- ning to be understood. Experimental vaccines have been produced that pro- tect animals and man. No one claims that a practical vaccine for human use is round the corner but recent results war- rant a major effort to develop one. For schistosomiasis, filariasis, trypa- nosomiasis and leishmaniasis, there is less information. But there is a prospect of vaccine for some of these diseases within the next ten to twenty years if work were intensified. Work on a vac- cine for leprosy is the most advanced: a plan is now under way to obtain and assess a leprosy vaccine within the next five years. In the past, drugs to treat parasitic infections were often selected on an em- pirical basis by the large-scale screening of possible compounds. More know- ledge of parasite function can be the basis for developing new and better drugs and for improving the best of the old ones. For example, parasites must possess surface recognition systems to enable them to identify their preferred location in the body. Malaria parasites are able to recognize the right sort of red cell and then to penetrate into it. Clues to the chemistry of this system al- ready exist, and compounds can be en- visaged which would interfere with the systems and, in effect, blindfold the parasite. Drugs based on this principle would act powerfully against malaria and could be innocuous to the human host. How could all this be done? There are few precedents for an enterprise of this scale and importance, and no single guide- line. WHO does have the unique ad- vantage of close cooperation with mem- ber countries, both in the tropics where the remedies are needed and where they may be specified, developed and tested, and with the industrialized countries where there, is much of the required scientific knowledge. The number of tropical diseases is too great to propose a single plan, however ambitious, that will encompass them all from the beginning. Six diseases — malaria, schistosomiasis, filariasis, try- panosomiasis, leprosy and leishmaniasis — constitute the crux of the problem. 21 The forgotten people The means presently available to control and treat them are of limited effective- ness and there is little research directed towards new remedies, compared with the research on major diseases that also occur in temperate climates such as meningitis, measles and intestinal infec- tions. The six tropical diseases hold together as a group from the point of view of research; advances in one may open up new approaches for another. Thus the development of a vaccine for leprosy could point the way to vaccines for any of the other five. Leishmaniasis, although less important numerically as a disease, is included since the parasite is easily handled in the laboratory and there are exceptional opportunities to study the relationship between this para- site and certain cells of the body. This kind of research could lead to better drugs not only for leishmaniasis, but also for leprosy, trypanosomiasis and malaria, in which the same body cells are involved. Malnutrition is a major factor related to all these diseases, and its effects on severity and on the effec- tiveness of remedies will also be studied. These diseases have been singled out on the basis of the need and opportunity to obtain new remedies, but others may be added later and, when success is achieved and effective remedies are found, some may be deleted. At the beginning the plan focuses on one continent that carries the major burden. Africa has the highest prev- alence of all the six diseases, except filariasis and South American trypano- somiasis. In Africa, multiple infection is almost the rule, and the need for control is perhaps greatest. New remedies would transform the quality of life in many African communities, and the health au- thorities welcome enthusiastically the idea that the work should begin there. But the fundamental concept of the plan is global. There is no reason, other than manageability, why the plan should be restricted to one continent. South America will be involved from the beginning through the work on try- panosomiasis and leishmaniasis. Ex- perience gained in the early stages can be used for development elsewhere and to bring into play, for example, the major resources of the Indian subcon- tinent. The plan is to enlist the support of scientists in laboratories throughout the world to carry out the work. In Africa, a framework on which to build exists already. The East African Medical 22 Research Council has seven laboratories working on tropical infectious diseases in Kenya, Tanzania and Uganda. Nai- robi is a hub of biomedical enterprise with major national and international research laboratories and institutions. The thrust of the Nigerian Medical Research Council's effort is toward bet- ter control of tropical diseases. There are 25 university medical schools in tropical Africa and several European countries support research laboratories in Africa. The Government of Zambia has provided space in a new hospital at Ndola for the development of a Research Centre. These and other labo- ratories, and such bodies as l'Organisa- tion de Coordination et de Cooperation pour la lutte contre les Grandes Ende- mies and l'Organisation de Coordina- tion pour la lutte contre les Endemics en Afrique centrale together form a basis upon which the proposed network can be built. Some of these laboratories are inade- quately staffed, equipped and funded are needed, together with others skilled in disciplines such as molecular biology, immunology, chemotherapy and clinical medicine, to help in the planning, to develop special aspects of research of the type described by Professor de Duve, and to carry out training. There is a genuine enthusiasm among young scien- tists for this work. To conduct this large programme, WHO proposes two parallel systems of organization : Task Forces and Net- works. Task forces are groups of scien- tists of the highest international stand- ing which aim to develop more effective remedies. For this, they will first define the remedies that are needed and then plan all phases of the research necessary to achieve them. Task force members are chosen for their qualifications for the work in hand, and they change ac- cording to the phases of the work. A task force to develop a diagnostic skin test and a vaccine for leprosy has been working for the past two years as a pilot operation, and expects to achieve its goals within the next five years. Studies have already been made on the feasibili- ty of new drugs and vaccines for the other five diseases. While the task forces are responsible for scientific planning and direction, the actual carrying out the research will be in the hands of a worldwide network of collaborating laboratories. The founda- tions of the network are the existing research institutes and university depart- ments. In the initial stages, those of Africa will be involved to the fullest possible extent. Laboratories in the in- dustrially developed countries will play an essential part by contributing their special skills. While the network will focus on research tasks, it will also train the new scientists needed to carry on and develop the work. So far as pos- sible, scientists will be trained in their own countries or their own regions to acquaint them with local disease prob- lems and to minimize the risk of a brain drain. and are too narrowly specialized to make an immediate effective contribu- tion. They need better training pro- grammes and adequate career structures to attract first-class scientists. They also need better communication with other scientists to break down the isolation that handicaps so many laboratories in Africa. These requirements are ultimate- ly the responsibility of governments; WHO's plan is to provide the resources and the technical cooperation needed to begin. The importance of the conduct of research in the tropical countries has been stressed. But much of the necessary knowledge and skill is chiefly to be found among the scientists of the indus- trialized world, and their involvement is crucial. There are a number of scientists with experience in tropical medicine now working outside the tropics. They Schistosomiasis (also called bilharziasis). On this page, the snail carrier of this parasitic disease. Beside it, greatly magnified, the fat male and the slender female worm which, united in a perpetual embrace, live in the bloodstream of their human hosts. Opposite : Bulinus truncatus, the snail that transmits the disease, lives in shallow strewn-beds or irriga- tion ditches. In many parts of the world, as much as 98 per cent of local populations may be infected. (Photos WHO I P. Almasy) What of the practical considerations of budget and timetable? A Special Pro- gramme on this scale adds a new dimen- sion to wHo's work and requires an annual budget to be measured in tens of millions of dollars. Its financing cannot depend on WHO's regular budget with all the present demands being made on it, but on extrabudgetary funds to be sought from governments, agencies and foundations. Equally, resources will come from the participating tropical countries willing to invest their skilled manpower and resources. The programme has already started : scientific groups have been convened to evaluate problems and propose lines of research, and a meeting was held with participating countries and agencies in October 1975. The plan is to begin oper- ations in 1977. The Special Programme is a long-term effort and, although there must be a continued assessment of effec- tiveness, the time required for real results in terms of impact on tropical disease problems must surely be mea- sured in decades. The Programme is WHO's response to a challenge to broaden its scope to include the development of new health tools as well as the now classic one of involvement in their delivery. The Programme is not to be seen in isolation from other efforts to combat these diseases. It introduces an essential aspect of research and development related to such programmes as that for onchocerciasis control in West Africa, the major international effort now being developed to control schistosomiasis, and WHO's own programmes for the improvement of rural health. While the initial effort is focused on six diseases and on Africa, the concept is global. There is a note of urgency. If better remedies are not forthcoming for these diseases during this century, then they will spread and the plight of man will become even more serious. Increasing population and the growing inadequacy of food supplies will increase disease and make control more difficult. Even agricultural development may promote diseases such as schistosomiasis and riv- er blindness by providing new breeding grounds for their vectors. There is now an exceptional opportunity to prevent this. While the plan carries no certain promises, there is every reason to believe that better remedies can be found for many of the great diseases of the tropics. In the name of humanity, of dignity and equity, since there is oppor- tunity, should we not seize it? ■ 23 • nely directions The yardstick to justify WHO's research activities will be the extent to which they strengthen national research capabilities and help to foster self-reliance BY -VIARTI KAP LA N ne of the functions of WHO, as expressed in its Constitution drawn up in 1946, is "to pro- mote and conduct research in the field of health". Until very recently, the Organization's activities in medical research have to a large extent been focused upon urgent technical prob- lems connected with the need to lay down technical principles and proce- dures in selected biomedical fields and disciplines which would be serviceable on a global basis. These include biologi- cal standards, microbiology, immunolo- gy, cancer, communicable diseases and nutrition. Headquarters technical staff have been primarily responsible for such activities which were, and still are, most- ly coordinative in nature, taking advan- tage of the resources in personnel and facilities of already existing institutions throughout the world. This ground work having been sub- stantially accomplished, it became es- sential for the emphasis in research mat- ters to move into new directions, so that VVHO could contribute as much as pos- sible towards solving present and emerg- ing problems in a rapidly changing world, with primary emphasis on deve- loping countries. Dr H. Mahler, Director-General of WHO, took this need into account in a report to the fifty-seventh session of the wHo Executive Board which met in January 1976. This required a recasting of the principal objectives of WHO's research activities, which he described as the strengthening of national research capabilities, particularly in developing countries, and the promotion and appli- cation of existing and new scientific knowledge and research methodology on problems closely related to WHO's designated priorities. He noted that, to achieve the latter objective, the Organization must seek to identify priority areas and problems for research based principally on their relative im- portance for social and economic devel- opment; other criteria would be secon- dary. The yardstick to justify all who's research activities will therefore be the extent to which they strengthen national research capabilities, and thus foster self-reliance and self-sufficiency. This displaces the primordial role hitherto as- signed to the solving of particular tech- nical problems, although such tasks are by no means being neglected. Work will continue on communicable disease problems which, while largely solved in developed countries, remain paramount in the economically poor countries. The same applies to chronic degenerative diseases such as cancer, cardiovascular diseases, rheumatoid arthritis and men- tal disorders, which affect large seg- ments of the population in all countries. The need for research in all these areas provides an endless and changing field for who's attention and action. Specifically, the new challenges and certain of their implications now facing 24 One of the most urgent problems facing WHO today is how to achieve better delivery of health care, especially in rural districts of the poarer countries. Here, a primary health worker at a West African social centre is advising mothers on the care and feeding of their children. (Photo WHO /J. Mohr) WHO can be viewed as follows : — The unexploited potentials and the need for development of research resources (manpower and institutions) and research activities in Member coun- tries, particularly in the developing world. These involve much more active participation on the part of research workers and institutions within the Member States themselves, in collabora- tion with wHo's regional offices and as- sisted by funds to be sought outside the Organization's regular budget (i.e. in the form of voluntary contributions). —Deficient or neglected areas of urgently needed research in the desig- nated priority programme areas of wHo; delivery of health services, educa- tional techniques and other aspects of manpower development and training; and certain aspects of disease prevention and control (e.g. tropical communicable diseases coupled with malnutrition). Ob- viously, from these wide fields a careful selection of problems for attack must be made, based on a ranking of their im- portance and their solvability or poten- tial for clarification as a result of action by WHO. The untapped reservoir of research institutions, national scientific research councils and young scientists, in devel- oped and developing countries alike, with whom WHO could collaborate in furthering technical activities. The new resources thus made available can be greatly amplified by WHO's exploitation of its collaborative mechanisms. The need to develop mechanisms for the rapid and efficient application of rel- evant existing knowledge under particu- lar local conditions, as well as of new scientific knowledge as it emerges. This calls for a combination of operational research and more effective use of the exchange of bio-medical research infor- mation. Such research consists primarily of carefully observing how various fac- tors operate in a particular situation, and the design and testing of improved procedures so as to obtain maximum benefits at lowest cost. The progressive development of the Organization's capacity is to provide Member States with an integrated health alert (early warning) and health inform- ation system. This will be a long haul, requiring considerable research and de- velopment starting at the country level. Maintaining sufficient flexibility to adapt to new problems, expected and unexpected, as they emerge during the next 25 years, for example, a shift of disease priorities with the conquest of major communicable diseases, improve- ments in the quality of life, and prolon- gation of productive life. 25 In order to meet these challenges, the whole spectrum of WHO's research activ- ities is being viewed in a systems context involving Member States and WHO Regional Offices as well as technical units at WHO Headquarters; these in turn require a research management framework to ensure their harmoniza- tion and integration. This implies the application of mechanisms which will ensure the most efficient use of WHO's actual and potential resources and procedures to achieve maximum impact. The most successful mechanisms used up to now have consisted of Expert Committees, consultants and groups of scientists, and collaborating institutions. In carrying out research activities, WHO calls on panels of outside experts and scientific consultants in various health disciplines totalling more than 2000 scientists, as well as on some 550 WHO collaborating centres throughout the world. The senior peer review scientific group for the Organization is the Advi- sory Committee on Medical Research (Acw) which was established by the World Health Assembly in 1959. The ACMR consists of a rotating group of 19 distinguished scientists representing various research disciplines, which keeps under review the overall technical as- pects of research activities in all major WHO programmes. With the expansion of these activities in recent years, task forces and small peer review groups called in to formulate and guide research approaches and activities on particular problems have proved to be very successful. A good example is WHO's coordinated research on the biol- ogy of human reproduction. Similar in- itiatives are now being developed in oth- er major research programmes, such as the Special Programme for Research and Training in Tropical Diseases de- scribed elsewhere in this issue. The concept of the programme team, which uses technical expertise wherever it may exist throughout the Organization and cuts across administrative and func- tional units, is being vigorously pursued. Eventually all WHO's major research Above: A young Egyptian research worker sorts specimens of snails in a schistosomiasis laboratory in Alexandria. WHO must tap the vast reservoir of research institutions, national scientific research councils and young scientists in both developed and developing countries, and encourage international collaboratioh in technical activities. (Photo WHO/D. Henrioud) Above right: A malaria patient being tended by a medical assistant in Sudan. ( Photo WHO /E. Schwab) Lower right: Aerial view of the Ndola Hospital complex in Zambia, which will house a research centre for WHO's Special Programme for Research and Training in Tropical Diseases. (Photo WHO) programmes will adopt these flexible mechanisms. Perhaps the most urgent problem fac- ing WHO today is how to achieve better delivery of health care, especially in rural districts of the poorer countries 26 where trained manpower, facilities and funds are so deficient. Here the research component concerns the optimum appli- cation of existing knowledge and the rapid transfer of new knowledge as it emerges. There are no general rules nor magical formulae to answer such ques- tions, and each situation must be tackled in its own right. The important ingredients for success—motivation and self-help--do not follow scientific rules. But the application of operational research as a methodological tool could no doubt assist very much in achieving a rationalization of resources and health planning. This tool has achieved some measure of success when the problem has been narrowly focused, for instance in pointing up the critical question of the stability of antigens in WHO's ex- panded programme for immunization in West Africa, or in increasing the effi- cient operation of rural health clinics. As regards broader problems in the health field, however, results have not so far been very productive. But the principal new dimension in WHO's research activities is the marked extension of such activities to the coun- try level through WHO's regional offices. Responding to recent resolutions of World Health Assemblies, four of the six regional offices—Western Pacific, South-East Asia, Eastern Mediterranean and Africa—have established regional advisory committees on medical research to develop activities of impor- tance to their particular regions, with starting points established in the indi- vidual member countries. These coun- tries are giving positive encourage- ment and guidance to the establishment of medical research councils or compar- able groups where they do not already exist, to the collection of data on research institutions and facilities, and to the improvement of exchanges of biomedical research information. The Regional Office for the Americas has had its own regional advisory committee on medical research for the past 14 years and the European Regional Of- fice has established a special consulta- tive group on research in that region. All these new resources to be tapped and developed by the decentralization of WHO's research activities, and their har- monization at the various operating levels of the Organization—in the coun- tries themselves, in the Regional Offices and at Headquarters—will provide a great challenge and an opportunity for the Organization to put the tools of scientific research to the best possible use. ■ 27 WHO NEWS IN BRIEF Heavy drinking, however defined, is a public health concern. (Photo WHO /K. Brodie) Control of Alcohol "Changes in the overall consumption of alcoholic beverages have a bearing on the health of the people in any society. Alcohol control measures can be used to limit con- sumption; thus, control of alcohol avail- ability becomes a public health issue." This is the argument of a 106-page report issued jointly by the Finnish Foundation for Alcohol Studies, the Addiction Research Foundation of Ontario, and WHO's Regional Office for Europe in Copenhagen. Entitled "Alcohol Control Policies in Public Health Perspective", it was published on the occasion of the Finnish Foundation's 25th Anniversary. As early as 1947, WHO's First World Health Assembly recognized that work on alcoholism belonged to the field of mental health. The first WHO Expert Committee on Mental Health dealt with the problem. Throughout the 1950s, there was steady progress in the field of treatment methods. A change of emphasis became apparent at the Twenty-eighth World Health Assembly, in 1975, which expressed its concern over present levels of alcohol consumption and their health implications. It adopted a reso- lution indicating the need for a complemen- tary approach: any anti-alcoholism pro- gramme must be preventive as well as cura- tive; alcoholism or alcohol dependence is only a part of alcohol-related problems, which in turn cannot be tackled without a policy with regard to the agent, alcohol. Even before that, the Regional Office for Europe had designed a long-term pro- gramme in mental health under the guid- ance of the late Dr Anthony R. May. This made a correlation between the compara- tively high level of alcohol consumption in many European countries and the new dimensions of the industrial society, for in- stance the growing volume of road traffic. The present report, compiled by Dr Kettil Bruun, Director of the Finnish Foundation for Alcohol Studies, with the help of ten scientists, first examines the question wheth- er heavy alcohol consumption is related to excess mortality or morbidity, and attemps to define the adjective "heavy". Given that heavy drinking, however defined, is a public health concern, how closely will the prev- alence of such drinking be related to the mean alcohol consumption of populations? Is it possible to obtain valid data on national alcohol consumption? The report contains a number of statistical tables show- ing worldwide trends in alcohol consump- tion and production. Underlying market forces might influence such trends, and the report seeks to define their real extent. Various strategies of prevention are then discussed; but the report points out that these are relatively ineffective in the absence of international co-operation. Members of the working group which produced the report have tried to be as ob- jective as possible in analysing the available evidence. Alcohol is a drug which, in every sense, excites passions. The consumption of alcohol brings pleasure and occasionally pain : for both the individual and society there is a profit and loss account. Moderate- ly drinking members of the community may feel that concern about alcohol consump- tion reflects an invasion of their privacy or that they are in some way being exposed to a sermon. Manufacturers of alcoholic bever- ages will be equally wary, while govern- ments, which derive a large part of their revenue from liquor taxes, may well be faced with a dilemma. Assistance to Lebanon WHO's contribution towards emergency assistance to Lebanon began last October with a delivery of vaccines against cholera and TAB. In addition to US$255,000 made available from wHo funds, the United Nations High Commission for Refugees (uNHcR) contributed $200,000, making a total of $455,000; this enabled wHo to pro- vide limited quantities of the top priority emergency items required. A list of short-term and medium-term requirements to restore the country's health services was drawn up by the Lebanese Ministry of Health and was roughly esti- mated to cost $4,000,000. The United Nations system is providing assistance in the various sectors of Lebanon's emergency needs; the overriding priority is for medi- caments and medical supplies desperately needed by the hospitals. Additional priority items and quantities will be procured by wHo when funds become available from the international community in response to an appeal by UN Secretary-General, Kurt Waldheim. wHo has also sent to Lebanon an epide- miologist, Dr G. Lavoipierre, to advise on measures to prevent communicable diseases, and a public health administrator, Dr G. Rifka, to assist Dr Lavoipierre in his dis- cussions with the government authorities and the UNICEF Representative in Beirut on the public health needs and the assistance required on a short-term and medium-term basis. Decade of Action ainst Blindness ? "The prevention of blindness is not just an ophthalmic sideshow: it is the sum of all the disciplines having any bearing on eye care and eye care delivery—the coordination of all actions necessary to prevent blindness in the community, in the nation, in the world. It is not isolated activity but is relat- ed to the whole movement for development within any country—health, education, wel- fare, economic advance, human relations. In the final analysis, it is part of the sense of value which is built into any culture, into any civilization." This is how Sir John Wilson, President of the International Agency for the Prevention of Blindness, summed up the task ahead for public health ophthalmology, when he ad- dressed a recent WHO-sponsored interre- gional meeting on the prevention of blind- ness, held in Baghdad. The meeting, held shortly before World Health Day, 7 April, which spotlighted the theme "Foresight Pre- vents Blindness", was attended by 53 oph- thalmologists and other eye care specialists from 31 countries. Describing the work of the Agency, which was formed last year and works through national committees in 42 countries, Sir John called for a decade of international ac- tion against needless blindness in the deve- loping world. "We agree with the WHO," he 28 Letters to the Editor said, "that the priority target in any global strategy must be the four giants—blinding infection including trachoma, blinding filaria (onchocerciasis or river blindness), cataract and blinding malnutrition. Control these and we can break the link between blindness and population growth. Neglect them and, 25 years from now, the whole rehabilitation systems of the world will be inadequate to accommodate the multitude of blind people." Sir John went on: "The great ophthalmic institutions have an essential role, particu- larly those research centres and training col- leges whose programmes are related to in- ternational needs. But behind the bricks and mortar, behind the elegant departmental structures, there must be services, big enough, mobile and flexible enough to cover whole communities and to offer eye care to millions... The task above all is to graft ophthalmic technology on to the broad structure of community health care." Emphasizing the need for a favourable climate of public opinion, internationally and nationally, he said: "Above all there must be motivation in the benefiting com- munity. The difference between a village where children go blind and one where sight is retained is not, I suspect, a question of medicine but of public attitude. At that level, the cause of blindness is not a disease, a virus, a deficiency—these are the symp- toms; the cause is lack of stimulus and com- munication, ignorance and apathy." "In the final analysis, the prevention of blind- ness is part of the sense of value which is built into any culture." (Photo WHO I A. Fisher) Sir John described a visit he had paid to a school for the blind in Iraq, in which many of the children had lost their sight through smallpox. He commented : "I thought then that the most extraordinary feature of this whole situation is that smallpox will never again destroy an eye. Obviously there are differences between the eradication of small- pox and the control of blindness, but there are also many similarities : a historic oppor- tunity to advance against an ancient scourge, the need for a total, straightfor- ward commitment and a clean thrust through the argument and clutter towards a simple, realisable objective." ■ Dear Sir, I have been receiving your magazine for the past seven or eight years, and consider it one of the best publications which I read. My two sons, one in fourth year of medical school and the other in his second year of medicine, also appre- ciate reading this magazine. In the January 1976 issue of World Health, in an article entitled "New Views", H. Tristram Engelhardt quotes Thomas Aquinas as saying : "The devel- oped plan of living according to reason comes from man; the plan of nature comes from God, and therefore a viola- tion of this plan, as by unnatural sins, is an affront to God, the ordainer of nature". But the original Latin text of Aquinas deviates considerably from that suggested by Dr Engelhardt. Aquinas speaks of order (in Latin, ordo) and not plan or developed plan, and he refers to right reason and not merely to reason. These distinctions are simple, but absolutely necessary in order to un- derstand Aquinas' real opinion. For Aquinas, there is only one plan (although he does not use this terminology) which is the plan of God, a dynamic plan, founded in the love and goodness of God towards man. When the rational order (order of right reason) and the natural order (order of nature) coincide with this plan, that is, when man's plan coincides with God's plan, then man is one with God his creator. There is no dichotomy between the two orders, rational and natural, in Aquinas as Dr Engelhardt ap- pears to believe, nor can there exist any disharmony between these two orders and the divine order. Aquinas says that the difference be- tween a sin against nature and one only against right reason is that the first goes directly against God and does not direct- ly affect other persons, only the one who commits the sin, whereas the other goes against one's neighbour, as in fornica- tion, adultery, incest and so on. For love of God, man should avoid natural sins (contraception, homosexuality, bestiality, masturbation, etc.) and for the love of man and God, such sins as fornication, adultery, incest and so on, since these lat- ter kind of sins break the bounds of friendship and love which should exist between men. Thus Aquinas' opinion, in its profun- dity, is that it is love and not merely rea- son which should guide man so that he might know and follow the "plan of God", so that this plan might also be the plan of man, a plan of true love for man and God at the same time. I believe the subject treated by Dr En- gelhardt is of the greatest importance. Naturally, it is a matter which is at the border of medicine, philosophy and reli- gion, something vital for our modern world as it always has been. Sincerely yours, David Thomson Principal of the Colegio San Fernando, Salamanca, Spain Dear Sir, In a recent issue of World Health (Oc- tober 1975), you speak of road accidents as an "epidemic". In my view, the first thing is to call a halt to the manufacture of machines capable of speeds which are simply un- controllable in an emergency. Vehicles travelling faster than 100 kilometres per hour (62 m.p.h.) are lethal weapons, yet more and more of them are entrusted to the hands of the young and inex- perienced. Moreover their owners gener- ally consider them as toys, and no amount of driving tests can determine the mentality or the mood of all drivers. Even though it was slight, the drop in the number of accidents in 1974 due to the high cost of private motoring and the lower speed limits following the oil crisis (no longer applicable in 1975) proves that the motor-car is a dangerous instrument, since the damage it causes decreases when its numbers and its speed are reduced. Timid measures to control this modern and unnecessary scourge, and jubilation over a slight and very fleeting lessening of the harm it does, will not bring us any nearer a solution to this problem. Yours faithfully, Robert Geraads 1, rue Saint-Hubert, Paris Dear Editor, We read with interest your February- March 1976 issue devoted to the vision needs of the world's people. We did, however, note that something was miss- ing. Are you aware of the world health work being done by the Volunteer Op- tometrists in Service to Humanity (VOSH) and the Student Optometrists in Service to Humanity (SOSH). Every year, these two groups visit different countries to provide vision care services to the people at no or at token cost. Oph- thalmologists, physicians, dentists, nurses and other health professions often join the VOSH teams, contributing their spe- cific skills where needed to this four-year- old humanitarian service. Yours truly, Charlotte Rancilio News Services Coordinator American Optometric Association 29 WORLD HEALTH Basic Particle of Life A Deoxyribonucleic acid, called DNA for short, is the basic building-block of all life forms on earth. It forms the medium by which the genetic mes- sage of reproduction is transmitted through the chromosome. DNA's entwined spiral structure, the Double Helix, was first deciphered in 1953 by Francis Crick (U K), James Watson (USA) and Maurice Wilkins (UK). All three shared the Nobel Prize for physiology and medicine in 1962. The illustration shows the model which they devised, showing only a few of thousands of turns in the hypothetical structure of the DNA molecule. Each of the two ribbons represents the sugar-phosphate "backbone" (S and P). The third "ingredient" consists of four bases (a base is the non-acid part of a salt) called adenine (A), guanine (G), cytosine (C) and thymine (T). For another model of the DNA double helix, turn to page 7. (Photo WHO) CARRIERS OF DISEASE Many of the worst diseases to which mankind is prey are transmitted through the medium of an animal, an insect or some other life-form. On the right we picture some of these creatures, and below we list their names and the diseases of which they are the carriers. But the diseases are not in the right order. See if you can match the diseases with the right pictures. The answers are printed at the foot of the next page. Louse 1 River blindness (onchocerciasis) Rat 2. Rabies Tsetse fly 3. Chagas' disease (American trypanosomiasis) Snail "bulinus 4. Malaria truncatus" Fox 5. Schistosomiasis (bilharziasis) Mosquito 6. Typhus "anopheles gambiae" Blackfly 7. African sleeping "simulium sickness damnosum" (trypanosomiasis) Blood-sucking 8. Plague bug "rhodnius prolixus" 30 PUZZLE PICTURE It looks like a jelly-fish or perhaps a badly tangled ball of wool. But what is it? This is a human lymphocyte as seen by a scanning electron microscope. The lym- phocyte is a white blood corpuscle responsible for our body's defence against disease. When foreign invaders—such as viruses—enter the body, the lymphocytes go into action to fight off the invasion. (Photo WHO) ANAESTHETIST H 9 a L 3 8 9 :9 :SIBAASUe D Authors of the month Dr T. ADEOYE LAMBO, Deputy Direc- tor-General of wit°, is a former Vice-Chancellor of the University of Ibadan, Nigeria. Professor CHRISTIAN DE DUVE, one of three Nobel Prizewinners contri- buting to this month's issue, is the Director of the Laboratory of Physiological Chemistry at the Cath- olic University of Louvain, Belgium. Dr JOSHUA LEDERBERG and Dr JAC- QUES MONOD, both Nobel Laureates, are respectively Professor of Genet- ics, Stanford University School of Medicine, California, USA, and Director of the Pasteur Institute in Paris. Professor B. 0. OSUNTOKUN is Dean of the Faculty of Medicine at the University of Ibadan, Nigeria. Dr DAVID S. RowE is the Senior Pro- gramme Officer for the WHO's Spe- cial Programme for Research and Training in Tropical Diseases. Dr MARTIN KAPLAN is the Director of who's Office of Research Promo- tion and Development. WORLD HEALTH for readers everywhere ORDER FORM Please enter my subscription to "World Health" as follows: US$* Sw.fr.* One year 10.— 25.— Two years 18.— 45.— Three years 24.— 60.— One year : Two years: 0 Three years: I enclose cheque/postal order in the amount of Name: Street : City : Country: or equivalent in local currency. World Health, WHO, Avenue Appia, 1211 Geneva 27, Switzerland Theforgotten people See article on page 18. .( Photo II71-101 P. Pipet)