Partial Control of Infectious Disease

The control of communicable disease has been the major advance of the 20th century in scientific medicine. It reflects the combination of improved environmental conditions and public health together with the development of immunization, antimicrobial chemotherapy, and the increasing ability to identify new pathogenic organisms. Currently, live or killed viral or bacterial vaccines—or those based on bacterial polysaccharides or bacterial toxoids—are licensed for the control of 29 common communicable diseases worldwide. The highlight of the field was the eradication of smallpox by 1977. The next target of the World Health Organization (WHO) is the global eradication of poliomyelitis. In 1998, the disease was endemic in more than 125 countries. After a resurgence in 2002, when the number of cases rose to 1,918, the numbers dropped again in 2003 to 748; by March 2004, only 32 cases had been confirmed (Roberts 2004).

The Expanded Program on Immunization (EPI), launched in 1974, which has been taken up by many countries with slight modification, includes Bacillus Calmette-Guérin (BCG) and oral polio vaccine at birth; diphtheria, tetanus, and pertussis at 6, 10, and 14 weeks; measles; and, where relevant, yellow fever at 9 months. Hepatitis B is added at different times in different communities. By 1998, hepatitis B vaccine had been incorporated into the national programs of 90 countries, but an estimated 70 percent of the world's hepatitis B carriers still live in countries without programs (Nossal 1999). Indeed, among 12 million childhood deaths analyzed in 1998, almost 4 million were the result of diseases for which adequate vaccines are available (WHO 2002a).

The development of sulfonamides and penicillin in the period preceding World War II was followed by a remarkable period of progress in the discovery of antimicrobial agents effective against bacteria, fungi, viruses, protozoa, and helminths. Overall, knowledge of the pharmacological mode of action of these agents is best established for antibacterial and antiviral drugs. Antibacterial agents may affect cell wall or protein synthesis, nucleic acid formation, or critical metabolic pathways. Because viruses live and replicate in host cells, antiviral chemotherapy has presented a much greater challenge. However, particularly with the challenge posed by HIV/AIDS, a wide range of antiviral agents has been developed, most of which are nucleoside analogues, nucleoside or nonnucleoside reverse-transcriptase inhibitors, or protease inhibitors. Essentially, those agents interfere with critical self-copying or assembly functions of viruses or retroviruses. Knowledge of the modes of action of antifungal and antiparasitic agents is increasing as well.

Resistance to antimicrobial agents has been recognized since the introduction of effective antibiotics; within a few years, penicillin-resistant strains of Staphylococcus aureus became widespread and penicillin-susceptible strains are now very uncommon (Finch and Williams 1999). At least in part caused by the indiscriminate use of antibiotics in medical practice, animal husbandry, and agriculture, multiple-antibiotic-resistant bacteria are now widespread. Resistance to antiviral agents is also occurring with increasing frequency (Perrin and Telenti 1998), and drug resistance to malaria has gradually increased in frequency and distribution across continents (Noedl, Wongsrichanalai, and Wernsdorfer 2003). The critical issue of drug resistance to infectious agents is covered in detail in chapter 55.

In summary, although the 20th century witnessed remarkable advances in the control of communicable disease, the current position is uncertain. The emergence of new infectious agents, as evidenced by the severe acute respiratory syndrome (SARS) epidemic in 2002, is a reminder of the constant danger posed by the appearance of novel organisms; more than 30 new infective agents have been identified since 1970. Effective vaccines have not yet been developed for some of the most common infections—notably tuberculosis, malaria, and HIV—and rapidly increasing populations of organisms are resistant to antibacterial and antiviral agents. Furthermore, development of new antibiotics and effective antiviral agents with which to control such agents has declined. The indiscriminate use of antibiotics, both in the community and in the hospital populations of the industrial countries, has encouraged the emergence of resistance, a phenomenon exacerbated in some of the developing countries by the use of single antimicrobial agents when combinations would have been less likely to produce resistant strains. Finally, public health measures have been hampered by the rapid movement of populations and by war, famine, and similar social disruptions in developing countries. In short, the war against communicable disease is far from over.

Pathogenesis, Control, and Management of Non-communicable Disease

The second half of the 20th century also yielded major advances in understanding pathophysiology and in managing many common noncommunicable diseases. This phase of development of the medical sciences has been characterized by a remarkable increase in the acquisition of knowledge about the biochemical and physiological basis of disease, information that, combined with some remarkable developments in the pharmaceutical industry, has led to a situation in which few noncommunicable diseases exist for which there is no treatment and many, although not curable, can be controlled over long periods of time.

Many of these advances have stemmed from medical research rather than improved environmental conditions. In 1980, Beeson published an analysis of the changes that occurred in the management of important diseases between the years 1927 and 1975, based on a comparison of methods for treating these conditions in the 1st and 14th editions of a leading American medical textbook. He found that of 181 conditions for which little effective prevention or treatment had existed in 1927, at least 50 had been managed satisfactorily by 1975. Furthermore, most of these advances seem to have stemmed from the fruits of basic and clinical research directed at the understanding of disease mechanisms (Beeson 1980; Comroe and Dripps 1976).

Modern cardiology is a good example of the evolution of scientific medicine. The major technical advances leading to a better appreciation of the physiology and pathology of the heart and circulation included studies of its electrical activity by electrocardiography; the ability to catheterize both sides of the heart; the development of echocardiography; and, more recently, the development of sophisticated ways of visualizing the heart by computerized axial tomography, nuclear magnetic resonance, and isotope scanning. These valuable tools and the development of specialized units to use them have led to a much better understanding of the physiology of the failing heart and of the effects of coronary artery disease and have revolutionized the management of congenital heart disease. Those advances have been backed by the development of effective drugs for the management of heart disease, including diuretics, beta-blockers, a wide variety of antihypertensive agents, calcium-channel blockers, and anticoagulants.

By the late 1960s, surgical techniques were developed to relieve obstruction of the coronary arteries. Coronary bypass surgery and, later, balloon angioplasty became major tools. Progress also occurred in treatment of abnormalities of cardiac rhythm, both pharmacologically and by the implantation of artificial pacemakers. More recently, the development of microelectronic circuits has made it possible to construct implantable pacemakers. Following the success of renal transplantation, cardiac transplantation and, later, heart and lung transplantation also became feasible.

Much of this work has been backed up by large-scale controlled clinical trials. These studies, for example, showed that the early use of clot-dissolving drugs together with aspirin had a major effect on reducing the likelihood of recurrences after an episode of myocardial infarction (figure 5.1). The large number of trials and observational studies of the effects of coronary bypass surgery and dilatation of the coronary arteries with balloons have given somewhat mixed results, although overall little doubt exists that, at least in some forms of coronary artery disease, surgery is able to reduce pain from angina and probably prolong life. Similar positive results have been obtained in trials that set out to evaluate the effect of the control of hypertension (Warrell and others 2003).

Figure 5.1

Effects of a One-Hour Streptokinase Infusion Together with Aspirin for One Month on the 35-Day Mortality in the Second International Study of Infarct Survival Trial among 17,187 Patients with Acute Myocardial Infarction Who Would Not Normally Have Received (more...)

The management of other chronic diseases, notably those of the gastrointestinal tract, lung, and blood has followed along similar lines. Advances in the understanding of their pathophysiology, combined with advances in analysis at the structural and biochemical levels, have enabled many of these diseases to be managed much more effectively. The pharmaceutical industry has helped enormously by developing agents such as the H2-receptor antagonists and a wide range of drugs directed at bronchospasm. There have been some surprises—the discovery that peptic ulceration is almost certainly caused by a bacterial agent has transformed the management of this disease, dramatically reducing the frequency of surgical intervention. Neurology has benefited greatly from modern diagnostic tools, while psychiatry, though little has been learned about the cause of the major psychoses, has also benefited enormously from the development of drugs for the control of both schizophrenia and the depressive disorders and from the emergence of cognitive-behavior therapy and dynamic psychotherapy.

The second half of the 20th century has witnessed major progress in the diagnosis and management of cancer (reviewed by Souhami and others 2001). Again, this progress has followed from more sophisticated diagnostic technology combined with improvements in radiotherapy and the development of powerful anticancer drugs. This approach has led to remarkable improvements in the outlook for particular cancers, including childhood leukemia, some forms of lymphoma, testicular tumors, and—more recently—tumors of the breast. Progress in managing other cancers has been slower and reflects the results of more accurate staging and assessment of the extent and spread of the tumor; the management of many common cancers still remains unsatisfactory, however. Similarly, although much progress has been made toward the prevention of common cancers—cervix and breast, for example—by population screening programs, the cost-effectiveness of screening for other common cancers—prostate, for example—remains controversial.

Many aspects of maternal and child health have improved significantly. A better understanding of the physiology and disorders of pregnancy together with improved prenatal care and obstetric skills has led to a steady reduction in maternal mortality. In an industrial country, few children now die of childhood infection; the major pediatric problems are genetic and congenital disorders, which account for about 40 percent of admissions in pediatric wards, and behavioral problems (Scriver and others 1973). Until the advent of the molecular era, little progress was made toward an understanding of the cause of these conditions. It is now known that a considerable proportion of cases of mental retardation result from definable chromosomal abnormalities or monogenic diseases, although at least 30 percent of cases remain unexplained. Major improvements have occurred in the surgical management of congenital malformation, but only limited progress has been made toward the treatment of genetic disease. Although a few factors, such as parental age and folate deficiency, have been incriminated, little is known about the reasons for the occurrence of congenital abnormalities.

In summary, the development of scientific medical practice in the 20th century led to a much greater understanding of deranged physiology and has enabled many of the common killers in Western society to be controlled, though few to be cured. However, although epidemiological studies of these conditions have defined a number of risk factors and although a great deal is understood about the pathophysiology of established disease, a major gap remains in our knowledge about how environmental factors actually cause these diseases at the cellular and molecular levels (Weatherall 1995).

Consequences of the Demographic and Epidemiological Transitions of the 20th Century

The period of development of modern scientific medicine has been accompanied by major demographic change (Chen 1996; Feachem and others 1992). The results of increasing urbanization, war and political unrest, famine, massive population movements, and similar issues must have had a major effect on the health of communities during the 20th century, but there has been a steady fall in childhood mortality throughout the New World, Europe, the Middle East, the Indian subcontinent, and many parts of Asia during this period, although unfortunately there has been much less progress in many parts of Sub-Saharan Africa. Although much of the improvement can be ascribed to improving public health and social conditions, the advent of scientific medicine—particularly the control of many infectious diseases of childhood—seems likely to be playing an increasingly important part in this epidemiological transition. Although surveys of the health of adults in the developing world carried out in the 1980s suggested that many people between the ages of 20 and 50 were still suffering mainly from diseases of poverty, many countries have now gone through an epidemiological transition such that the global pattern of disease will change dramatically by 2020, with cardiorespiratory disease, depression, and the results of accidents replacing communicable disease as their major health problems.

Countries undergoing the epidemiological transition are increasingly caught between the two worlds of malnutrition and infectious disease on the one hand and the diseases of industrial countries, particularly cardiac disease, obesity, and diabetes, on the other. The increasing epidemic of tobacco-related diseases in developing countries exacerbates this problem. The global epidemic of obesity and type 2 diabetes is a prime example of this problem (Alberti 2001). An estimated 150 million people are affected with diabetes worldwide, and that number is expected to double by 2025. Furthermore, diabetes is associated with greatly increased risk of cardiovascular disease and hypertension; in some developing countries the rate of stroke is already four to five times that in industrial countries. These frightening figures raise the questions whether, when developing countries have gone through the epidemiological transition, they may face the same pattern of diseases that are affecting industrial countries and whether such diseases may occur much more frequently and be more difficult to control.

Partly because of advances in scientific medicine, industrial countries have to face another large drain on health resources in the new millennium (Olshansky, Carnes, and Cassel 1990). In the United Kingdom, for example, between 1981 and 1989, the number of people ages 75 to 84 rose by 16 percent, and that of people age 85 and over by 39 percent; the current population of males age 85 or over is expected to reach nearly 0.5 million by 2026, at which time close to 1 million females will be in this age group. Those figures reflect the situation for many industrial countries, and a similar trend will occur in every country that passes through the epidemiological transition. Although data about the quality of life of the aged are limited, studies such as the 1986 General Household Survey in the United States indicate that restricted activity per year among people over the age of 65 was 43 days in men and 53 days in women; those data say little about the loneliness and isolation of old age. It is estimated that 20 percent of all people over age 80 will suffer from some degree of dementia, a loss of intellectual function sufficient to render it impossible for them to care for themselves. Scientific medicine in the 20th century has provided highly effective technology for partially correcting the diseases of aging while, at the same time, making little progress toward understanding the biological basis of the aging process. Furthermore, the problems of aging and its effect on health care have received little attention from the international public health community; these problems are not restricted to industrial countries but are becoming increasingly important in middle-income and, to a lesser extent, some low-income countries.

Although dire poverty is self-evident as one of the major causes of ill health in developing countries, this phenomenon is emphatically not confined to those populations. For example, in the United Kingdom, where health care is available to all through a government health service, a major discrepancy in morbidity and mortality exists between different social classes (Black 1980). Clearly this phenomenon is not related to the accessibility of care, and more detailed analyses indicate that it cannot be ascribed wholly to different exposure to risk factors. Undoubtedly social strain, isolation, mild depression, and lack of social support play a role. However, the reasons for these important discrepancies, which occur in every industrial country, remain unclear.

Genomics, Proteomics, and Cell Biology

Without question the fields of molecular and cell biology were the major developments in the biological sciences in the second half of the 20th century. The announcement of the partial completion of the human genome project in 2001 was accompanied by claims that knowledge gained from this field would revolutionize medical practice over the next 20 years. After further reflection, some doubts have been raised about this claim, not in the least the time involved; nevertheless, considerable reason for optimism still exists. Although the majority of common diseases clearly do not result from the dysfunction of a single gene, most diseases can ultimately be defined at the biochemical level; because genes regulate an organism's biochemical pathways, their study must ultimately tell us a great deal about pathological mechanisms.

The genome project is not restricted to the human genome but encompasses many infectious agents, animals that are extremely valuable models of human disease, disease vectors, and a wide variety of plants. However, obtaining a complete nucleotide sequence is one thing; working out the regulation and function of all the genes that it contains and how they interact with each other at the level of cells and complete organisms presents a much greater challenge. The human genome, for example, will require the identification and determination of the function of the protein products of 25,000 genes (proteomics) and the mechanisms whereby genes are maintained in active or inactive states during development (methylomics). It will also involve the exploration of the roles of the family of regulatory ribonucleic acid (RNA) molecules that have been discovered recently (Mattick 2003). All this information will have to be integrated by developments in information technology and systems biology. These tasks may take the rest of this century to carry out. In the process, however, valuable fallout from this field is likely to occur for a wide variety of medical applications. Many of these are outlined in a recent WHO report, Genomics and World Health 2002 (WHO 2002a).

The first applications of DNA technology in clinical practice were for isolating the genes for monogenic diseases. Either by using the candidate gene approach or by using DNA markers for linkage studies, researchers have defined the genes for many monogenic diseases. This information is being used in clinical practice for carrier detection, for prenatal diagnosis, and for defining of the mechanisms of phenotypic variability. It has been particularly successful in the case of the commonest monogenic diseases, the inherited disorders of hemoglobin, which affect hundreds of thousands of children in developing countries (Weatherall and Clegg 2001a, 2001b). Through North-South collaborations, it has been possible to set up screening and prenatal diagnosis programs for these conditions in many countries, resulting in a marked decline in their frequency, particularly in Mediterranean populations (figure 5.2). Gene therapy, that is, the specific correction of monogenic diseases, has been fraught with difficulties, but these are slowly being overcome and this approach seems likely to be successful for at least some genetic diseases in the future.

Figure 5.2

Decline in Serious Forms of Thalassemia in Different Populations after the Initiation of Prenatal Diagnosis in 1972 following the Development of North-South Partnerships.

From the global perspective, one of the most exciting prospects for the medical applications of DNA technology is in the field of communicable disease. Remarkable progress has been made in sequencing the genomes of bacteria, viruses, and other infective agents, and it will not be long before the genome sequence of most of the major infectious agents is available. Information obtained in this way should provide opportunities for the development of new forms of chemotherapy (Joët and others 2003) and will be a major aid to vaccine development (Letvin, Bloom, and Hoffman 2001). In the latter case, DNA technology will be combined with studies of the basic immune mechanisms involved in individual infections in an attempt to find the most effective and economic approach. Recombinant DNA technology was used years ago to produce pure antigens of hepatitis B in other organisms for the development of safe vaccines. More recently, and with knowledge obtained from the various genome projects, interest has centered on the utility of DNA itself as a vaccine antigen. This interest is based on the chance observation that the direct injection of DNA into mammalian cells could induce them to manufacture—that is, to express—the protein encoded by a particular gene that had been injected. Early experiences have been disappointing, but a variety of techniques are being developed to improve the antigens of potential DNA-based vaccines.

The clinical applications of genomics for the control of communicable disease are not restricted to infective agents. Recently, the mosquito genome was sequenced, leading to the notion that it may be possible to genetically engineer disease vectors to make them unable to transmit particular organisms (Land 2003). A great deal is also being learned about genetic resistance to particular infections in human beings (Weatherall and Clegg 2002), information that will become increasingly important when potential vaccines go to trial in populations with a high frequency of genetically resistant individuals.

The other extremely important application of DNA technology for the control of communicable disease—one of particular importance to developing countries—is its increasing place in diagnostics. Rapid diagnostic methods are being developed that are based on the polymerase chain reaction (PCR) technique to identify pathogen sequences in blood or tissues. These approaches are being further refined for identifying organisms that exhibit drug resistance and also for subtyping many classes of bacteria and viruses. Although much remains to be learned about the cost-effectiveness of these approaches compared with more conventional diagnostic procedures, some promising results have already been obtained, particularly for identification of organisms that are difficult to grow or in cases that require a very early diagnosis (Harris and Tanner 2000). This type of technology is being widely applied for the identification of new organisms and is gaining a place in monitoring vaccine trials (Felger and others 2003). The remarkable speed with which a new corona virus and its different subtypes were identified as the causative agent of SARS and the way this information could be applied to tracing the putative origins of the infection are an example of the power of this technology (Ruan and others 2003).

Genomics is likely to play an increasingly important role in the control and management of cancer (Livingston and Shivdasani 2001). It is now well established that malignant transformation of cell populations usually results from acquired mutations in two main classes of genes:

• First are oncogenes—genes that are involved in the major regulatory processes whereby cells interact with one another, respond to environmental signals, regulate how and when they will divide, and control the other intricate processes of cell biology (box 5.1).
• Second are tumor suppressor genes; loss of function by mutation may lead to a neoplastic phenotype.

Box 5.1

Chronic Myeloid Leukemia: The Path from Basic Science to the Clinic. 1960 An abnormal chromosome, named the Philadelphia chromosome, was found in the white cells of most patients with chronic myeloid leukemia (CML). 1973 By the use of specific dyes to (more...)

In the rare familial cancers, individuals are born with one defective gene of this type, but in the vast majority of cases, cancer seems to result from the acquisition during a person's lifetime of one or more mutations of oncogenes. For example, in the case of the common colon cancers, perhaps up to six different mutations are required to produce a metastasizing tumor. The likelihood of the occurrence of these mutations is increased by the action of environmental or endogenous carcinogens.

Array technology, which examines the pattern of expression of many different genes at the same time, is already providing valuable prognostic data for cancers of the breast, blood, and lymphatic system. This technology will become an integral part of diagnostic pathology in the future, and genomic approaches to the early diagnosis of cancer and to the identification of high-risk individuals will become part of clinical practice. It is also becoming possible to interfere with the function or products of oncogenes as a more direct approach to the treatment of cancer (box 5.1), although early experience indicates that drug resistance may be caused by mutation, as it is in more conventional forms of cancer therapy.

The genomic approach to the study of common diseases of middle life—coronary artery disease, hypertension, diabetes, and the major psychoses, for example—has been widely publicized (Collins and McKusick 2001). Except in rare cases, none of them is caused by a defective single gene; rather, they appear to be the result of multiple environmental factors combined with variation in individual susceptibility attributable to the action of several different genes. The hope is that if these susceptibility genes can be identified, an analysis of their products will lead to a better understanding of the pathology of these diseases and will offer the possibility of producing more definitive therapeutic agents. Better still, this research could provide the opportunity to focus public health measures for prevention on genetically defined subsets of populations.

Pharmacogenomics is another potential development from the genomics revolution (Bumol and Watanabe 2001) (table 5.1). Considerable individual variability exists in the metabolism of drugs; hence, clinical medicine could reach a stage at which every person's genetic profile for the metabolism of common drugs will be worked out and become part of their physicians' toolkit. This information will also be of considerable value to the pharmaceutical industry for designing more effective and safer therapeutic agents.

Table 5.1

Pharmacogenomics.

A word of caution is necessary: Although well-defined genetic variation is responsible for unwanted side effects of drugs, this information is still rarely used in clinical practice; a possible exception is screening for glucose-6-phosphate dehydrogenase (G6PD) deficiency for primaquine sensitivity, though the costs preclude its application in many developing countries. Furthermore, plasma levels after the administration of most common drugs follow a normal distribution, indicating that if genetic variation exists, a number of different genes must be involved. Hence, although the idea of all people having their genetic profile for handling drugs as part of their standard medical care will take a long time to achieve, if it ever happens, no doubt exists that this field will gradually impinge on medical research and clinical practice.

Many other potential applications of genomic research for medical practice wait to be developed. The role of DNA array technology for the analysis of gene expression in tumors has already been mentioned. Advances in bioengineering, with the development of biomicroelectromechanical systems, microlevel pumping, and reaction circuit systems, will revolutionize chip technology and enable routine analysis of thousands of molecules simultaneously from a single sample (Griffith and Grodzinsky 2001), with application in many other fields of research. Although somatic cell gene therapy—that is, the correction of genetic diseases by direct attack on the defective gene—has gone through long periods of slow progress and many setbacks, the signs are that it will be successful for at least a limited number of monogenic diseases in the long term (Kaji and Leiden 2001). It is also likely to play a role for shorter-term objectives—in the management of coronary artery disease and some forms of cancer, for example. DNA technology has already revolutionized forensic medicine and will play an increasingly important role in this field. Although it is too early to assess to what extent the application of DNA technology to the studies of the biology of aging will produce information of clinical value, considering the massive problem of our aging populations and the contribution of the aging process to their illnesses, expanding work in this field is vital. Current work in the field of evolution using DNA technology seems a long way from clinical practice; however, it has considerable possibilities for helping us understand the lack of adaptation of present day communities to the new environments that they have created.

Stem Cell and Organ Therapy

Stem cell therapy, or, to use its more popular if entirely inappropriate title, therapeutic cloning, is an area of research in cellular biology that is raising great expectations and bitter controversies. Transplant surgery has its limitations, and the possibility of a ready supply of cells to replace diseased tissues, even parts of the brain, is particularly exciting. Stem cells can be obtained from early embryos, from some adult and fetal tissues, and (at least theoretically) from other adult cells.

Embryonic stem cells, which retain the greatest plasticity, are present at an early stage of the developing embryo, from about the fourth to seventh day after fertilization. Although some progress has been made in persuading them to produce specific cell types, much of the potential for this field so far has come from similar studies of mouse embryonic stem cells. For example, mouse stem cells have been transplanted into mice with a similar condition to human Parkinson's disease with some therapeutic success, and they have also been used to try to restore neural function after spinal cord injuries.

Many adult tissues retain stem cell populations. Bone marrow transplantation has been applied to the treatment of a wide range of blood diseases, and human marrow clearly contains stem cells capable of differentiating into the full complement of cell types found in the blood. Preliminary evidence indicates that they can also differentiate into other cell types if given the appropriate environment; they may, for example, be a source of heart muscle or blood vessel cell populations. Although stem cells have also been found in brain, muscle, skin, and other organs in the mouse, research into characterizing similar cell populations from humans is still at a very early stage.

One of the major obstacles to stem cell therapy with cells derived from embryos or adult sources is that, unless they come from a compatible donor, they may be treated as "foreign" and rejected by a patient's immune system. Thus, much research is directed at trying to transfer cell nuclei from adult sources into an egg from which the nucleus has been removed, after which the newly created "embryo" would be used as a source of embryonic stem cells for regenerative therapy for the particular donor of the adult cells. Because this technique, called somatic cell nuclear transfer, follows similar lines to those that would be required for human reproductive cloning, this field has raised a number of controversies. Major ethical issues have also been raised because, to learn more about the regulation of differentiation of cells of this type, a great deal of work needs to be carried out on human embryonic stem cells.

If some of the formidable technical problems of this field can be overcome and, even more important, if society is able to come to terms with the ethical issues involved, this field holds considerable promise for correction of a number of different intractable human diseases, particularly those involving the nervous system (Institute of Medicine 2002).

Information Technology

The explosion in information technology has important implications for all forms of biomedical research, clinical practice, and teaching. The admirable desire on the part of publicly funded groups in the genomics field to make their data available to the scientific community at large is of enormous value for the medical application of genomic research. This goal has been achieved by the trio of public databases established in Europe, the United States, and Japan (European Bioinformatics Institute, GenBank, and DNA Data Bank of Japan, respectively). The entire data set is securely held in triplicate on three continents. The continued development and expansion of accessible databases will be of inestimable value to scientists, in both industrial and developing countries.

Electronic publishing of high-quality journals and related projects and the further development of telepathology will help link scientists in industrial and developing countries. The increasing availability of telemedicine education packages will help disseminate good practices. Realizing even these few examples of the huge potential of this field will require a major drive to train and recruit young information technology scientists, particularly in developing countries, and the financial support to obtain the basic equipment required.

Minimally Invasive Diagnostics and Surgery: Changes in Hospital Practice

Given the spiraling costs of hospital care in industrial countries and the likelihood of similar problems for developing countries in the future, reviewing aspects of diagnostics and treatment that may help reduce these costs in the future is important. Changes in clinical practice in the latter half of the 20th century have already made some headway on this problem. In the U.K. NHS, the number of hospital beds occupied daily halved between 1950 and 1990 even though the throughput of the service, after allowance for change of definition, increased from 3 million to 10 million inpatients per year. Remarkably, by 1996, of 11.3 million finished consultant episodes, 22 percent were single-day cases. How can this efficient trend be continued? A major development with this potential is the application of minimally invasive and robotic surgery (Mack 2001). Advances in imaging, endoscopic technology, and instrumentation have made it possible to convert many surgical procedures from an open to an endoscopic route. These procedures are now used routinely for gall bladder surgery, treatment of adhesions, removal of fibroids, nephrectomy, and many minor pediatric urological procedures. The recent announcement of successful hip replacement surgery using an endoscopic approach offers an outstanding example of its future potential. Although progress has been slower, a number of promising approaches exist for the use of these techniques in cardiac surgery and for their augmentation by the introduction of robotics into surgical practice. Transplant surgery will also become more efficient by advances in the development of selective immune tolerance (Niklason and Langer 2001).

These trends, and those in many other branches of medicine, will be greatly augmented by advances in biomedical imaging (Tempany and McNeil 2001). Major progress has already been made in the development of noninvasive diagnostic methods by the use of MRI, computer tomography, positron imaging tomography, and improved ultrasonography. Image-guided therapy and related noninvasive treatment methods are also showing considerable promise.

Human Development and Child and Maternal Health

Among the future developments in molecular and cell biology, a better understanding of the mechanisms of human development and the evolution of functions of the nervous system offer some of the most exciting, if distant, prospects (Goldenberg and Jobe 2001). In the long term, this field may well have important implications for reproductive health and birth outcomes. The role of a better understanding of the monogenic causes of congenital malformation and mental retardation was mentioned earlier in this chapter. Already thoughts are turning to the possibility of the isolation and clinical use of factors that promote plasticity of brain development, and specific modulators of lung and gut development are predicted to start to play an increasing role in obstetric practice. A better understanding of the mechanisms leading to vasoconstriction and vascular damage as a cause of preeclampsia has the potential for reducing its frequency and thus for allowing better management of this common condition. Similarly, an increasing appreciation of the different genetic and metabolic pathways that are involved in spontaneous preterm births should lead to effective prevention and treatment, targeting specific components of these pathways and leading to reduction in the frequency of premature births. An increasing knowledge of the mode of action of different growth factors and promoters of gut function will enhance growth and development of preterm infants.

Neuropsychiatry

Particularly because depression and related psychiatric conditions are predicted to be a major cause of ill health by 2020 and because of the increasing problem of dementia in the elderly, neuropsychiatry will be of increasing importance in the future (Cowan and Kandel 2001). Developments in the basic biomedical sciences will play a major role in the better diagnosis and management of these disorders. Furthermore, the application of new technologies promises to lead to increasing cooperation between neurology and psychiatry, especially for the treatment of illnesses such as mental retardation and cognitive disorders associated with Alzheimer's and Parkinson's diseases that overlap the two disciplines.

The increasing application of functional imaging, together with a better understanding of biochemical function in the brain, is likely to lead to major advances in our understanding of many neuropsychiatric disorders and, hence, provide opportunities for their better management. Early experience with fetally derived dopaminergic neurons to treat parkinsonism has already proved to be successful in some patients and has raised the possibility that genetically manipulated stem cell treatment for this and other chronic neurological disorders may become a reality. Promising methods are being developed for limiting brain damage after stroke, and there is increasing optimism in the field of neuronal repair based on the identification of brain-derived neuronotrophic growth factors. Similarly, a combination of molecular genetic and immunological approaches is aiding progress toward an understanding of common demyelinating diseases—notably multiple sclerosis.

Strong evidence exists for a major genetic component to the common psychotic illnesses—notably bipolar depression and schizophrenia. Total genome searches should identify some of the genes involved. Although progress has been slow, there are reasonable expectations for success. If some of these genes can be identified, they should provide targets for completely new approaches to the management of these diseases by the pharmaceutical industry. Recent successes in discovering the genes involved in such critical functions as speech indicate the extraordinary potential of this field. Similarly, lessons learned from the identification of the several genes involved in familial forms of early-onset Alzheimer's disease have provided invaluable information about some of the pathophysiological mechanisms involved, work that is having a major effect on studies directed at the pathophysiology and management of the much commoner forms of the disease that occur with increasing frequency in aged populations.

Nutrition and Genetically Modified Crops

By 2030, the world's population is likely to increase by approximately 2.5 billion people, with much of this projected growth occurring in developing countries. As a consequence, food requirements are expected to double by 2025. However, the annual rate of increase in cereal production has declined; the present yield is well below the rate of population increase. About 40 percent of potential productivity in parts of Africa and Asia and about 20 percent in the industrial world are estimated to be lost to pathogens.

Given these considerations, the genetic modification (GM) of plants has considerable potential for improving the world's food supplies and, hence, the health of its communities. The main aims of GM plant technologies are to enhance the nutritional value of crop species and to confer resistance to pathogens. GM technology has already recorded several successes in both these objectives.

Controversy surrounds the relative effectiveness of GM crops as compared with those produced by conventional means, particularly with respect to economic issues of farming in the developing world. Concerns are also expressed about the safety of GM crops, and a great deal more research is required in this field. The results of biosafety trials in Europe raise some issues about the effects of GM on biodiversity (Giles 2003).

Plant genetics also has more direct potential for the control of disease in humans. By genetically modifying plants, researchers hope it will be possible to produce molecules toxic to disease-carrying insects and to produce edible vaccines that are cheaper than conventional vaccines and that can be grown or freeze dried and shipped anywhere in the world. A promising example is the production of hepatitis B surface antigen in transgenic plants for oral immunization. Work is also well advanced for the production of other vaccines by this approach (WHO 2002a).

Social and Behavioral Sciences, Health Systems, and Health Economics

As well as the mainstream biomedical sciences, research into providing health care for the future will require a major input from the social and behavioral sciences and health economics. These issues are discussed in more detail in chapter 4.

The World Health Report 2002 (WHO 2002c) emphasizes the major gaps in public perception of what is meant by health and, in particular, risk factors, in both industrial and developing countries. Epidemiological studies have indicated that morbidity and mortality may be delayed among populations that are socially integrated. Increasing evidence of this kind underlines the importance of psychosocial factors in the development of a more positive approach to human health, clearly a valuable new direction for research on the part of the social sciences.

Neither developing nor industrial countries have come to grips with the problems of the organization and delivery of health care. Learning more about how to build effective health delivery strategies for developing countries is vital. Similarly, the continuous reorganization of the U.K. NHS, based on short-term political motivation and rarely on carefully designed pilot studies, is a good example of the requirement for research into the optimal approaches to the provision of health care in industrial countries. Indeed, across the entire field of health provision and the education of health care professionals, an urgent requirement exists for research into both methodology and, in particular, development of more robust endpoints for its assessment.

Similar problems exist with respect to research in health economics. Many of the parameters for assessing the burden of disease and the cost-effectiveness of different parameters for the provision of health care are still extremely crude and controversial, and they require a great deal more research and development. These problems are particularly relevant to the health problems of the developing countries.

One of the main barriers to progress in these fields is the relative isolation of the social sciences and health care economics from the mainstreams of medical research and practice. Better integration of these fields will be a major challenge for universities and national and international health care agencies.