Janice S. Dorman on behalf of the International Molecular
Epidemiology Task Force*
Department of Epidemiology, Graduate School of Public Health
University of Pittsburgh
Pittsburgh, PA 15261
Molecular epidemiology has recently been defined as "a science that focuses on the contribution of potential genetic and environmental risk factors, identified at the molecular level, to the etiology, distribution and prevention of disease within families and across populations".1 This new field has emerged from the integration of molecular biology into traditional epidemiologic research. The objectives of molecular epidemiology are quite broad and include: 1) descriptive and analytical studies to evaluate host/environmental interactions in disease, 2) the development of strategies for the control of bacterial, parasitic and viral disorders through molecular diagnosis, and 3) the prevention of non-communicable diseases and genetic disorders by assessing risk and identifying susceptible individuals through genetic screening.
As yet, few developing countries have a significant capability in molecular epidemiology due to a lack of trained molecular epidemiologists and a pervasive shortage of appropriate equipment and reagents. Unless these shortcomings are corrected, developing countries will be unable to realize the full benefits of molecular epidemiology. Thus, there is a great need for: 1) adequate training in methods for integrating molecular biology into epidemiologic research and public health, and 2) advanced biotechnology equipment, reagents and supplies for molecular analyses of potential genetic and environmental risk factors.1 Since training opportunities are currently limited in all nations, educational materials and short courses in molecular epidemiology must be developed across the world. Adequate laboratory facilities and advanced biotechnology equipment and supplies are also essential for molecular epidemiology and are generally unavailable in developing nations. Even when advanced technology is accessible, the problems that frequently arise due to inadequate technology transfer can appear to outweigh its possible benefits.2,3 Thus, effective plans for the transfer of advanced biotechnology and training in molecular epidemiology, as they apply to international health, are essential.
To help developing countries build up capabilities in molecular epidemiology, we propose the establishment of an International Molecular Epidemiology Task Force. The rationale for the organization of the Task Force is based upon: 1) identification of health problems in various regions of the world which may be ameliorated through molecular epidemiology, 2) establishment of the mission, membership, activities and responsibilities of the Task Force, and 3) justification for support of the Task Force from industrialized and developing countries. Each of these issues will be addressed below.
At an international conference held at Alma-Ata, in the former USSR in 1978, it was concluded that a realistic objective of the World Health Organization would be the provision of primary health care for all the world's people by the year 2000.4 Strategies for attaining this goal have been formulated, and regional and national plans are currently being implemented across the world. In the industrialized nations, health promotion initiatives have been emphasized, whereas in developing countries, activities are targeted toward the control of communicable diseases, better nutrition and improved maternal and child health.5 However, with better control of infectious disorders, non-communicable diseases are becoming a major health problem in the Third World.
These efforts can be greatly aided through molecular epidemiology by training in public health, the transfer of advanced biotechnology and the implementation of rapid methods for molecular diagnosis of infectious, inherited and chronic diseases.6 We outline below specific plans for molecular epidemiology programs in select countries in Asia, the Eastern Mediterranean Region and Latin America. Approaches for effective implementation, which will have a tremendous impact on disease prevention and the future of international public health, are also discussed.
Hepatitis B (HBV) infection is endemic in parts of China, with perinatal and early childhood infections accounting for the high rates of primary hepatocellular carcinoma in older age groups.7,8 Recombinant DNA technology, such as polymerase chain reaction (PCR), has led to the development of rapid and sensitive methods for the diagnosis of viral infections, such as HBV, that are less time consuming and labor intensive than conventional approaches.9,10 In addition, molecular methods have been utilized to develop safe, immunogenic and cost-effective recombinant HBV vaccine,8,11 which is also required for the control of the disease. With the availability of appropriate technology and the implementation of public health approaches, such as the development of vaccination strategies to reduce HBV transmission from infected mothers to their newborns12, and efficient methods for epidemiologic surveillance,13 primary and secondary prevention of HBV infection and its consequences in China can be achieved.
In terms of chronic diseases, advanced biotechnology and molecular epidemiology can be used in occupational medicine, which focuses on physical, chemical and biological factors in the workplace and their effect on human health. Molecular methods are now being used to measure exposure to genotoxic and carcinogenic substances, such as DNA and protein adducts, as well as oncogenes and tumor suppressor genes.14 Screening for these biomarkers in an occupational setting will permit early detection of substances that are potential carcinogens. This may lead to the preventive strategies, including reducing work-related exposure to carcinogenic substances, improving environmental protection measures and initiating early treatment of these disorders. Other non-communicable diseases, such as non- insulin-dependent diabetes (NIDDM), cardiovascular disease and obesity are also increasing in Asia. Recently, progress has been made in identifying potential susceptibility genes for these disorders.15,16 A number of candidate genes that are involved in control of plasma lipid levels and thrombotic potential have been determined and mutations in some of these genes have been identified.17 These genetic markers will be used in the future to identify at-risk individuals, ultimately contributing to the prevention of these and other chronic diseases. Thus, molecular epidemiology programs will contribute to the prevention of both infectious and chronic diseases in Asia.
In the Eastern Mediterranean Region, many countries are undergoing the epidemiologic transition. Despite the high prevalence of communicable disorders in these areas, the burden of chronic diseases is rapidly increasing. In addition, the magnitude of the health problems posed by genetic disorders, such as sickle cell anemia18 and beta thalassemia,19 contribute significantly to the psychosocial burden on relevant communities, and imposes additional strain on the existing health care systems. These genetic diseases are very common in the Eastern Mediterranean Region, due to the high degree of consanguinity in this area of the world.
DNA technology is now being utilized for diagnosis of genetic disorders; and genetic screening will permit the detection of the presence of mutant alleles in carriers. Progress with the Human Genome Project will eventually lead to the availability of DNA markers for all disorders with an underlying genetic susceptibility,20 including non-communicable diseases, which are becoming increasingly prevalent in countries undergoing transition. Thus, in the Eastern Mediterranean Region, there is a great need for the application of advanced biotechnology, with an emphasis on the development of clinical molecular laboratories to provide rapid, accurate and inexpensive methods for diagnosing disorders prenatally, conducting newborn and pre-marital screening, and identifying individuals at-risk or with early stages of disease. Countries, including Tunisia and Saudi Arabia, are in the process of initiating such activities, which will ultimately be incorporated into health care services. However, to effectively utilize relevant technology for improving health care delivery and achieving health goals, planning strategies need to be formulated. The development of national programs using molecular epidemiology will provide models for such advancements in the Eastern Mediterranean Region.
In Latin America, bacterial, viral, as well as parasitic diseases, such as malaria and leishmaniasis, remain important health problems. Strategies for controlling these disorders include improvements in laboratory facilities for rapid diagnosis and treatment.9,21 For parasitic disorders, for example, nucleic acid probes are now available for the specific species or sub-species that cause these diseases; they can be used to diagnose disorders, such as malaria, directly from finger-stick blood samples. This permits rapid detection of the organisms at a much more sensitive and specific level than existing clinical methods. Moreover, this technology has been simplified so that large numbers of specimens can be processed quickly, allowing appropriate treatment to be promptly initiated. Continued research into methods for vector control, chemotherapy, and the development of recombinant vaccines are required for lowering the prevalence of parasitic diseases.22 Molecular epidemiology provides the basis for these efforts in Latin America.
Recombinant DNA technology has also been instrumental in the development of very rapid and specific methods for diagnosing bacterial diseases. With PCR, the detection of Shigella,23 E. coli and Vibrio cholerae,24 for example, is greatly simplified and far more accurate than conventional methods. In January, 1991, an outbreak of cholera began in Peru and spread throughout many Latin American countries. By January 1, 1993, over 730,000 cases and 6,300 deaths were reported.25 PCR has been, and remains an enormously helpful diagnostic tool for the detection of the specific toxin genes associated with this disease.
Acquired immune deficiency syndrome (AIDS) has become a leading international health problem in many regions of the world.26 Once it was determined that HIV was the cause of AIDS, serological tests to detect HIV antibody were rapidly developed, and HIV can now be detected at the molecular level. In M‚xico, for example, HIV studies are being undertaken at the Instituto Nacional de Diagn¢stico y Referencia Epidemiol¢gicos (INDRE). The amplification of target DNA sequences permits screening of donated blood, as well as early identification, treatment and possible prevention of these disorders. The control of AIDS and other viral diseases will require active research, the transfer of DNA technology, and the implementation of molecular epidemiology for primary and secondary prevention.
Although communicable diseases are still highly prevalent in Latin America, life expectancy is also increasing, resulting in an aging population and a rise in the occurrence of non-communicable diseases.27 Moreover, new environmental exposures and changes in lifestyle habits, such as smoking, obesity and hypertension, are contributing to a higher prevalence of potential risk factors. As mentioned previously, molecular methods will soon be available for genetic screening of high-risk individuals. With appropriate technology transfer to Latin America in the future, prevention programs can be approached from a molecular epidemiologic perspective.
Argentina, Brazil and M‚xico represent ideal countries for national programs for molecular epidemiology and advanced biotechnology transfer. The basic scientific infrastructure in these countries is sufficiently strong to support the implementation of such programs for national public health. Moreover, Buenos Aires, Argentina, Sao Paulo, Brazil and M‚xico City, M‚xico were among the initial participating centers in the WHO Multinational Project for Childhood Diabetes, known as the DIAMOND Project.28 This long-standing collaboration has provided a foundation for the development of studies of the molecular epidemiology of insulin-dependent diabetes mellitus (IDDM), which will serve as the basis for similar efforts for other chronic and infectious diseases.
To implement the programs described above, an International Molecular Epidemiology Task Force* will be established in 1993. The mission of the Task Force is to facilitate the development and implementation of national programs in molecular epidemiology and to promote advanced biotechnology transfer for disease prevention in various regions of the world. Members of the Task Force will include internationally recognized scientists and representatives of:
* Ministries of Health
* World Health Organization
* WHO Collaborating Centers
* World Bank
* Pan American Health Organization
* International Centre for Genetic Engineering and
Biotechnology
* Fogarty International Center
* National and International Experts on Molecular Biology, Genetics and
Epidemiology
* Biotechnology Industry
Within each country, a National Scientific Committee with Government Advisors will also be established to interact with the international representatives and to direct the activities of that nation. The first meeting of members of the Task Force will be in 1993.
We believe that effective advanced biotechnology transfer to developing countries will be based upon: 1) the provision of relevant scientific information to key officials, 2) training in molecular epidemiology and approaches for disease prevention, 3) obtaining financial support for the operation and maintenance of laboratory equipment, 4) the evaluation of advanced biotechnology transfer, and 5) the development of national and international scientific networks. These will represent the primary activities and responsibilities of the members of the Task Force.
The Task Force will provide relevant scientific information to key officials in the national government, academia, industry and the health care profession. Presentations will be made at individual and group meetings, as well as at national and international scientific conferences, such as this NATO Advanced Research Workshop, and an upcoming meeting in Saudi Arabia on the epidemiologic transition and health in developing countries, to be held in 1994. Brochures, journal articles, and technical information concerning the potential contribution of advanced biotechnology transfer to the health, research and economic goals of developing countries will be prepared and distributed.
Initial efforts will also be directed towards conducting a survey of each region to determine the availability, utilization and need for recombinant DNA technology in various areas of the country. This will be based upon the recent international questionnaire on DNA technology and molecular epidemiology that was distributed to scientists from across the world (Annex A). These efforts will contribute to the infrastructure necessary for effective transfer of advanced biotechnology.
The Task Force will develop plans for short regional training courses in molecular epidemiology for 1994. This will provide additional opportunities to local scientists and clinicians in developing countries to receive training in molecular epidemiology and its application to public health. In Latin America, the training program will be based upon an existing course in molecular genetics that is held at INDRE in M‚xico City each year. In 1993, the molecular genetics course will, for the first time, include lectures on molecular epidemiology and its applications in M‚xico. Full training courses in molecular epidemiology are being planned for 1994 in Saudi Arabia and China, and will include laboratory experiments, instruction in basic epidemiologic methods, such as defining cases of disease, assessing incidence and prevalence, and evaluating disease associations with potential risk factors. Development of specific disease prevention programs using advanced biotechnology will be outlined during the courses, such that they will be ready for immediate implementation. Training in minor repairs on equipment will also be provided. This will enhance effective technology transfer and increase its potential utilization for a variety of research and clinical activities.
One of the major problems with technology transfer to developing countries has been the lack of financial support for the purchase of laboratory equipment and its continued operation and maintenance. Reagents, enzymes and the other chemicals required for molecular analyses are also expensive, limiting effective advanced biotechnology transfer. The Task Force will determine what resources are required to develop molecular epidemiology in these areas. Members of the biotechnology industry will be particular helpful in dealing with these issues. The Task Force will also assess how funds to purchase items can be obtained. Proposals, grants and requests for funding will be submitted by the Task Force to national and international organizations and funding agencies to obtain sufficient financial support for equipment and supplies.
The Task Force will outline strategies for evaluating advanced biotechnology transfer to developing countries to determine its effectiveness, assess potential barriers, and increase its utilization in the future. Such evaluations will include details about prevention programs, research projects, grants and/or scientific publications that were initiated since the technology became available. The level of funding obtained from various sources will also be determined. Barriers to effective technology transfer, including inefficient utilization and operation of laboratory equipment, the high costs of supporting the technology, difficulties with access to supplies, etc., will also be assessed. The Task Force will review this evaluation with the key officials mentioned above. This will contribute to the formulation of future technology applications in clinical medicine, public health, industry, and agriculture.
At the present time, programs sponsored by WHO are targeted towards conditions such as AIDS, malaria, leishmaniasis, leprosy, tuberculosis and other communicable diseases.29 Emphasis is placed upon the application of research to disease prevention, the development of immunization programs, the delivery of effective chemotherapy, and the utilization of rapid diagnostic methods which can be standardized across populations. In addition, adequate laboratory technology has been promoted and training courses for the prevention and control of disease have been organized in developing nations. International laboratory standards, methods and reference preparations, which have been very effective in stimulating collaborative research, have also been developed. Members of the Task Force are directly involved with these efforts; their experience will be invaluable for the development of programs for molecular epidemiology.
International collaborative studies, such as the WHO DIAMOND Project, are also working towards the achievement of global health. Such international efforts require the development and implementation of standards, which can be applied across populations to assure that accurate comparisons can be made. For example, the identification of HLA-DQ locus polymorphisms, which are highly associated with IDDM,30 led to the development of a DIAMOND Sub-Project to test the hypothesis that population variation in the frequency of HLA class II alleles is the primary determinant of the worldwide patterns of disease.1,31 The implementation of standards for this international study in developing countries, for example, where studies of IDDM are urgently needed, is difficult due to the lack of resources and technology. This DIAMOND Sub-Project presents a unique opportunity to promote molecular epidemiology and the transfer of advanced biotechnology and molecular epidemiology through collaborative grants. One such proposal will be submitted to the NIH in 1993 to investigate the molecular epidemiology of IDDM in Latin America, where such studies have been recently initiated.32-34 The existence of the strong international DIAMOND network and the support of WHO and PAHO will provide an infrastructure for effective transfer of technology and training, and will encourage scientific collaboration between developing and industrialized nations.
CONCLUSIONS The attainment of "health for all" is a goal which all nations are actively pursuing. While international efforts must continue to be directed towards improving the social and economic conditions of many areas, and providing education and health care to under-served populations, the attainment of international health can also be realized by the development of molecular epidemiology and the transfer of advanced biotechnology. Increasing capabilities in molecular epidemiology, if effective, will greatly contribute to a reduction in the morbidity and mortality associated with the most prevalent diseases in both developing and industrialized countries.
In this manuscript, we outlined plans for molecular epidemiology programs in Asia, the Eastern Mediterranean Region and Latin America. Similar approaches can be adopted by other regions of the world. However, the implementation of molecular epidemiology programs and achieving effective biotechnology transfer to developing countries can only be accomplished with careful planning, coordination and organization at the national and international level. This requires discussions between members of the government, the scientific community, industry and the health professions. Thus, an International Molecular Epidemiology Task Force has been established, with its membership reflecting various areas of expertise and representing many nations across the world. National scientific committees, with government advisors, are also being organized to interact with the international representatives and to direct the programs of individual countries.
The mission of the Task Force is to assist in the development and implementation of national programs in molecular epidemiology and to promote advanced biotechnology transfer for disease prevention in various regions of the world. This will be accomplished by: 1) the provision of relevant scientific information to key officials, 2) training in molecular epidemiology and approaches for disease prevention, 3) obtaining financial support for the operation and maintenance of laboratory equipment, 4) the evaluation of advanced biotechnology transfer, and 5) the development of national and international scientific networks. The development of national molecular epidemiology programs in one country will serve as a basis for additional programs in other countries and regions of the world. Thus, international support is vital to the success of this mission. Through collaboration and communication, the development of molecular epidemiology and effective biotechnology transfer will have a tremendous impact on the prevention of infectious and chronic diseases and the attainment of "health for all by the year 2000".
Argentina:
Dr. Julio Libman, Universidad Nacional de Rosario,
Facultad de Ciencias Medicas, Santa Fe 3100, 2000 Rosario, Argentina
Dr. Jorge R. Palazzi, Instituto de Estudios Bioquþmicos,
Mendoza 1180, 2000 Rosario, Argentina
Brazil:
Dr. Laercio Joel Franco, Departamento de Medicina Preventiva,
Escola Paulista de Medicina, Rua Botucatu, 740 04023 Sþo Paulo-SP, Brazil
China:
Dr. Wang Ke-An, Vice President, Chinese Academy of Preventive
Medicine,
10 Tian Tan XiLi, Beijing 100050, People's Republic of China
Dr. Shen Yi-E, Vice Director, Department of Preventive Medicine,
WHO Collaborating Center for Occupational Health, Shanghai Medical
University, Shanghai 200032, People's Republic of China
Egypt:
Dr. Ala'din A.S. Alwan, WHO Regional Office for the Eastern
Mediterranean Region, P.O. Box 1517, Alexandria, Egypt 21511
Germany:
Dr. Winfried Albert, Boehringer Mannheim, GMBH Research Center,
Tutzing, Bahnhofstrasse 9-15, D-8132, Tutzing, Germany
Italy:
Dr. Arturo Falaschi, Director, International Centre for Genetic
Engineering and Biotechnology, Padriciano 99, I-34012 Trieste, Italy
Japan:
Dr. Shigeaki Baba, Hyogo Institute for Research in Adult
Diseases, 13-70 Kitaoji-cho, Akashi 673, Japan
Dr. Naoko Tajima, Jikei University School of Medicine, Third
Department of Internal Medicine, 3-25-8 Nishi-shibashi, Minatoku,
Tokyo, Japan
Me‚xico
Dr. Luis Cabrera Coello, Enfermedades Transmisibles Hpt,
Organizacion Pan Americana de la Salud, Organizacion Mundial de la
Salud, Av. Paseo de las Palmas 530, Delegacion Miguel Hidalgo,
M‚xico,, D.F., C.P 11000, Me‚xico>
Dr. Clara Gorodezky, Chief, Department of Immunogenetics, Instituto
Nacionale de Diagn¢stico Y Referencia Epidemiol¢gicos, SSA Carpio
470-1, Me‚xico D.F. 11340 Me‚xico
Dr. Juan Manuel Sotelo Figueiredo, Representante Organizacion Pan
Americana de la Salud, Organizacion Mundial de la Salud, Av. Paseo
de las Palmas 530, Delegacion Miguel Hidalgo, M‚xico,, D.F., C.P11000,
Me‚xio
Saudi Arabia:
Dr. Moshen El-Hazmi, Director, WHO Collaborating Centre for
Haemoglobinopathies, Thalassaemias and Enzymopathies, King Saud
University, Riyadh, Saudi Arabia
Spain:
Dr. Manuel Serrano Rios, Hospital Clinico San Carlos, Department of
Internal Medicine, Ala Norte 6th., c/Martin Lagos s.n., Madrid 28040,
Spain
U.K.:
Dr. Steve Humphries, University College London Medical School,
Department of Medicine, Division of Cardiovascular Genetics and
Centre for Genetics of Cardiovascular Disorders, Rayne Institute,
5 University Street, London WC1E 6JJ, UK
U.S.A.:
Dr. Paul Basch, Department of Health Research and Policy, School of
Medicine, Stanford University, Stanford CA 94305
Dr. Peter Bennett, Chief, Phoenix Epidemiology and Clinical Research
Branch, NIDDK, 1550 East Indian School Road, Building 1, Phoenix,
Arizona 85014
Dr. Janice S. Dorman*, Director, Molecular Epidemiology, WHO
Collaborating
Center for Diabetes Registries and Training, University of Pittsburgh,
Pittsburgh, PA 15261 and Director of IME Task Force
Dr. Josefa Ippolito-Shepherd / Dr. Arlene Fonaroff, Office of the
Director, Program Officer for the Americas and WHO, Fogarty
International
Center, National Institutes of Health, Bethesda, MD 20892
Dr. Thomas Calloway, Director, Scientific Affairs, Roche Molecular
Systems, Inc., 1080 US Highway 202, Branchburg, NJ 08876
Dr. Massimo Trucco, Department of Pediatrics, Division of
Immunogenetics,
Rangos Research Center, Children's Hospital of Pittsburgh,
Pittsburgh, PA 15213
Mr. Michael Uhrin, Molecular Diagnostics Reference Laboratory,
Central Blood Bank, 812 Fifth Avenue, Pittsburgh, PA 15219
Dr. Raymond A. Zilinskas, Center for Public Issues in Biotechnology,
University of Maryland Baltimore County, Catonsville, MD 21228
OBSERVERS:
Dr. V. Boulyjenkov, Hereditary Disease Programme, World Health
Organization, CH-1211, Geneva 27, Switzerland
Dr. Claus C. Heuck, Health Laboratory Technology and Blood Safety,
World Health Organization, CH-1211, Geneva 27, Switzerland
Dr. Gabriel Schmunis, Pan American Health Organization, 525
Twenty-Third Street, NW, Washington, D.C. 20037
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