Despite the biomedical advances of the last century, infectious diseases remain a leading cause of mortality and morbidity, particularly within the developing world (Fig. 1) (World Health Organization, 2008). Many of the available health technologies, including vaccines and anti-microbial drugs, fail to reach the most vulnerable, at-risk populations. Emerging and re-emerging infectious diseases exert additional pressures and strains on already struggling health systems in resource-limited settings (Seib et al., 2009). Furthermore, research funding, which is often dictated by donors from industrialized nations, does not always prioritize those non-infectious and infectious health issues of greatest importance to developing countries, the so-called ‘10/90’ gap (Global Forum for Health Research, 2004). These and many more factors expand the existing ‘North-South’ health gap. The United Nation’s Millennium Development Goals (MDGs) outline several target areas to redress many of the health inequities found between developed and developing nations (Fig. 2). In addition to building and strengthening health systems, science and technology innovation play a vital role to limit maternal and child mortality from infectious agents (MDG 4 and 5), and to effectively control major global pathogens (i.e. HIV/AIDS, tuberculosis and malaria, among others) (MDG 6).
As SARS (severe acute respiratory syndrome) and influenza H1N1 have shown us, infectious diseases are constrained by neither national borders nor geographic distance. Without timely and equitable distribution of information, technology and other resources, all global citizens become at-risk to these and future pathogens, independent of their nationality or location. Understanding that the diffusion of science and technology may not occur effortlessly in all directions (i.e. North to South), it is vital that policymakers, funding agencies, researchers and health care professionals promote collaborative research programs and lobby for the appropriate translation of this knowledge into practice. Experience shows that concerted efforts toward universal access to effective health technologies, such as expanded vaccination coverage in children or increased access to affordable anti-retroviral drugs, create significant gains toward global health equity. The development of simple, easy-to-use, low-cost, reliable prevention and treatment modalities that are adapted for resource-limited settings not only benefits developing countries, but may also curb the rising health care costs being experienced in developed countries.
Health technologies developed from the computational analysis of genomic and other genome-scale data possess great potential to impact our approach to control infectious diseases (World Health Organization, 2002). Genomics, the study of the structure and function of an organism’s genome, and its related technologies (i.e. proteomics, transcriptomics, metabolomics) can enhance our understanding of disease pathogenesis; reveal underlying mechanisms of host susceptibility; create well-defined epidemiological disease profiles; and identify pathogen-specific molecular targets that are suitable for further development as recombinant vaccines, therapeutics and molecular diagnostics. As described by Daar et al., three of the ten most promising biotechnologies to significantly impact global health are directly related to genomic technologies (Daar et al., 2002; Acharya et al., 2004).
In order to harness the power of genomics to control infectious diseases, it is essential to have access to genomic data, interdisciplinary collaborations and continual investment in genomic capacity, including personnel and research facilities for data analysis. As genomic knowledge is considered a ‘public good’, much of the data generated, as well as many of the analysis tools developed, are freely available on several public databases. Furthermore, recent advances in sequencing methodologies have resulted in the development of ‘next-generation sequencing technologies’ that have drastically decreased sequencing costs, while considerably increasing the rate at which data is generated and deposited in open-access databases.
Open access to genomic data and analysis tools allows researchers in developing countries to use this information to address local health issues. Using available and region-specific sequences, trained researchers in developing countries can begin to address and develop effective strategies to control infections of regional importance, with the majority of the work, apart from the actual sequencing, occurring on site. The H1N1 diagnostic test, the OptiMAL rapid malaria test, and other PCR-based techniques for the detection and classification of infectious agents are just a few examples of molecular diagnostics that have been developed through the use of genomic data with application value in developing countries. Properly adapted molecular diagnostics are often more cost-effective, sensitive and specific, and less complicated to use, than non-molecular based diagnostics in resource-limited settings (Coloma and Harris, 2009). New molecular tests developed using genomic data are allowing public health officials to more effectively track disease incidence and understand the patterns of pathogen drug resistance. Recombinant vaccines developed from analyzing the genomes of the pathogens that cause meningitis, pneumonia and sepsis are in various stages of preclinical and clinical evaluation for efficacy. The use of genomic data significantly decreases the length of the discovery phase and hastens the initiation of clinical testing of new vaccines (Muzzi et al., 2007). In global health research, where resources are often limited, genomics research is a cost-effective and promising investment that will produce biotechnologies that are capable of making significant short- and long-term contributions to health.
Genomic approaches to control infectious diseases rely heavily upon the formation of interdisciplinary collaborations connecting genome-centric research centers with health professionals possessing clinical expertise in the management and treatment of these infectious agents in developing countries (Okeke and Wain, 2008). On-site researchers and clinicians are best able to articulate clinical observations, identify appropriate samples for sequencing, and translate the generated knowledge into practice. Researchers with genomic expertise are able to assess the appropriateness and applicability of various genomic tools to the problem at hand. These collaborations, when developed as equitable partnerships, increase the strength and relevance of the data to address local health concerns in developing countries. As the ultimate goal of such research is a reduction in the burden of infectious diseases, all major stakeholders, including the populations under study, must in the end be beneficiaries of any knowledge accrued. Including health care providers and researchers from developing countries in project development, implementation and analysis helps to ensure that the pathogen-specific data generated benefits the most-affected populations. Furthermore, these collaborations serve to build local genomic capacity, which contributes to the continued application of genomic technologies to health issues within developing countries.
One example of applying genomics to the problem of infectious diseases is my dissertation project at Baylor College of Medicine in the Translational Biology and Molecular Medicine graduate program. Under the direction of George Weinstock and Wendy Keitel, my work focuses on global differences in the pathogenesis of Streptococcus pneumoniae serotype 1 infection.
Each year, approximately one million children under the age of five, mostly living in developing countries, die from invasive S. pneumoniae infections. In developing countries, S. pneumoniae serotype 1 is commonly isolated from lethal cases of invasive pneumococcal disease (IPD) in children as well as adults. This serotype has caused meningitis outbreaks throughout Western Africa, and a significant proportion of pneumococcal-associated mortality and morbidity in developing countries can be attributed to serotype 1 infections. By contrast, within developed countries, S. pneumoniae serotype 1 infections rarely result in mortality and are strongly associated with pneumonia and empyema, which are milder forms of IPD, in children. The molecular epidemiology of serotype 1 shows that isolates from developing and developed countries form distinct clonal complexes. Working with colleagues at the Medical Research Council Laboratories The Gambia (MRC-TG) (Banjul, The Gambia), University of Birmingham (Birmingham, UK), Baylor College of Medicine Genome Center (Houston, TX) and the Genome Center at Washington University in Saint Louis (St Louis, MO), we analyzed how the genomic backgrounds of clinical serotype 1 isolates from developed (European and North American) and developing (African) countries influence the observed differences in virulence.
Our genomic analysis is supplemented by research with murine models of IPD. This approach allows for a direct comparison of virulence between isolates from distinct settings, with populations that have varying genetic backgrounds and biases in their basic health status. The combination of genomics and animal models, along with other molecular biology techniques, allows us to identify potential molecular targets that are likely to curb serotype 1 infections and the associated mortality through prevention, early diagnosis and effective treatment.
The molecular targets suggested by our research for therapeutic intervention may be accessed by our Gambian collaborators for their potential use as molecular diagnostics and for their further development as effective vaccines and/or therapeutics. It is common and easy to assume that many of the health problems facing developing countries are because of a lack of resources and/or access to health care. However, as our research has shown in certain cases, the pathogens themselves can contribute to the observed difference in clinical outcomes between developed and developing settings, independent of population health status. This knowledge should further help to inform policy decisions targeting serotype 1 infections within developing countries, as well as provide a data resource to begin to develop effective strategies to prevent and treat this disease.
The success of this project is testament to the synergy of our international collaboration. The field and epidemiological foundation work of our Gambian collaborators provided us with a clear and focused scientific question, and provided access to a well-cataloged sample repository. After spending several months at the MRC-TG facilities and seeing first-hand the extensive research network that they have developed for epidemiological and clinical studies, I have a true appreciation for the pain-staking effort involved in sample and data collection by the dedicated field team at the MRC-TG. This work also highlights the absolute necessity of a ‘field-to-bench’ approach to translate genomic knowledge into application and evidence-based policy (i.e. ‘bench to bedside’). Bolstered by our pneumococcal project and other on-going genomics-based projects, our Gambian collaborators hosted the first ever genomics-focused scientific meeting in The Gambia during December 2008. A pivotal component of this conference was a session in which local researchers and visiting scientists, including members of our pneumococcal genome project, engaged in a productive dialogue on how to build genomic capacity (including technology, personnel, computing infrastructure and the continued development of appropriate collaborations) in order to locally address the pressing health concerns of the regions.
After being introduced to this idea of using genomics to combat infectious diseases, my time as a graduate student has been a fulfilling experience demonstrating the real-world application of this concept in a feasible time scale. It is encouraging as a student to know that someone’s level of training does not limit their ability to contribute to the promotion of health equity throughout the world.