Pathogenomics Pompe Et Al. 2005.Pdf 72KB Aug 20

viewpointviewpoint Future trends and challenges in pathogenomics

A Foresight study Sven Pompe, Judith Simon, Peter M. Wiedemann & Christof Tannert

he difficult thing about the future is remains an important task at the beginning review, we used both academic search that it is so hard to predict. After the of the twenty-first century. It is in this engines and direct access to scientific TSecond World War, the availability of context that we conducted our Foresight journals. The search was conducted using vaccines and antibiotics and the successes study, ‘Future Trends and Challenges in the following keywords and combinations of improved hygiene and public health Pathogenomics’, as part of the EU-funded of terms: pathogenomics, infectious policies led to such a dramatic fall in ERA-NET project PathoGenoMics, to pro- disease, public health, bacteria, fungi, mortality that in 1969 the US Surgeon vide an overview of current and future bioweapons, bioterrorism, human pathogen. General claimed that “we can close the trends and challenges in the field of From the 3,542 resulting hits, we selected book on infectious diseases.” In hindsight, genomic research on pathogenic micro- 186 review articles, abstracts and press his prediction of the future was utterly organisms. Clearly, a Foresight study is not releases, and analysed them for further wrong—infectious diseases are back with a crystal ball to peek into the future, but trends and challenges in research, threats a vengeance. Nearly 25% of the annual it does allow the identification of impor- to public health and current bottlenecks deaths worldwide are directly related to tant trends in science, as well as perceived in commercial drug and vaccine dev- pathogens (Morens et al, 2004); multidrug- gaps in research, and places them in elopment. resistant tuberculosis and HIV/AIDS are the context of future challenges for on the rise worldwide; and Staphylococcus public health. ne clear trend is that, according and Enterococcus strains in Western hospi- to Weinstock (2000), the study of tals are becoming increasingly resistant to …infectious diseases can no Opathogenic microorganisms is antibiotics. In addition, the rapid spread undergoing major changes, triggered of new pathogens, such as the SARS longer be seen as problems of by the availability of whole genome (severe acute respiratory syndrome) and developing countries, now that sequences, new screening technologies, West Nile viruses, has shown the frailty global trade and tourism enable proteomics, comparative genomics and of global public health, which is further the rapid distribution of bioinformatics. These technologies, in affected by tourism and trade. Experts in infectious organisms combination with conventional methods security and public health also worry of serology and the cultivation of strains, that publicly available scientific informa- are becoming increasingly important for tion and advanced genetic technologies We pursued a dual approach, conducting the classification and evolutionary analy- could be misused to create weapons both a survey with national and interna- sis of microorganisms (Lederberg, 2000). for bioterrorism. tional experts in the field of patho- Molecular fingerprinting, single-nucleotide To overcome these threats to human genomics and an extensive literature polymorphism analyses and molecular health, research on pathogenic microbes research. For the survey, we developed epidemiology allow the study of the mole- and the development of new diagnostics, questionnaires and emailed them to 329 cular processes during infection, includ- vaccines and therapeutic strategies experts in research on human-pathogenic ing inflammation and host immune microorganisms and related fields. We responses, and the function of cell-surface …trends and developments in received 65 replies and 40 completed proteins and bacterial secretion systems. questionnaires; an overall reply rate of In vivo expression analyses and new basic research have to be put into 19.8 % and a return rate of 12.2 %, which bioimaging techniques to measure gene context with current and future are satisfactory (Comley, 1997; Totten, expression and protein transport now challenges for public health 2002; Sheehan, 2001). For the literature enable scientists to investigate the role of

individual genes during infection in real sidebar titled ‘Important challenges for time (Doyle et al, 2004). All these techno- basic research’). IMPORTANT CHALLENGES FOR logical advances and their application in In general, these new technologies are BASIC RESEARCH microbiology contribute to a better under- needed to understand more clearly the standing of host–microbe interactions and nature of infection, so as to devise new Methods immune responses on the molecular and strategies against infectious organisms. An •Automated high-throughput methods physiological level. important goal will be the identification of (microarray technology) •Genomics, transcriptomics, metabolomics specific target genes for DNA chips used and proteomics in clinical diagnostics and for the develop- There are also many aspects in •Improvement of serology, spectroscopy, the medical system itself that ment of new antibiotics and vaccines. chromatography and microscopy According to Weinstock (2000), the dis- pose a threat to public health •In vivo approaches (animal models, covery of such target genes will not be a bioimaging, real-time PCR) major problem, rather the development of •Novel technologies (for example, microfluids, According to Hatfull & Jacobs (2000) high-throughput methods to test the effi- siRNA, multiplex assays) there has also been much progress in cacy of new therapeutics. Furthermore, he •Whole-genome sequencing and studying the genetics of infection and forecasts that candidate genes will be bioinformatics pathogenesis, as well as the communica- identified and will be in commercial use Understanding ways of infection tion between microorganisms. But much long before scientists are able to under- •Comparative and functional genomics more needs to be known; Parsek & Fuqua stand fully the molecular mechanisms of •Factors of virulence and resistance (mobile (2004) highlight the importance of infection and pathogenesis. pathogenic elements) research on surface-associated pathogens, •Host switching and antigen diversity (genome such as biofilms or planktonic cultures, nother important research area, plasticity) which has so far been neglected. Such particularly in light of new and •Immune response (defensins, inflammation) knowledge will help researchers to under- Are-emerging diseases, concerns the •Role of surface proteins stand the complex interactions between dynamics of microbe populations and microbes, whereas modelling of stress the effects of environmental factors on Understanding pathogenesis factors in the environment can elucidate these populations. These include the nat- •Communication between species (biofilm, intestinal linings) interactions between microbes and host ural reservoirs of pathogens and their •Effects of DNA methylation and identification factors. In this context, the identification geographical distributions, differentiation of conserved DNA regions of virulence factors and secreted effectors between generalists and specialists among •Factors and mechanisms of pathogenicity that modulate the human immune system, human-pathogenic agents, and microbe– (secretion systems) such as exotoxins, small molecules or environment interactions (Cleaveland et al, •Host–microbe interaction extracellular enzymes, is another impor- 2001). According to Woolhouse and col- •In-host competition tant goal. To meet the increasing problem leagues (2001), population biology will •SNP analysis and molecular epidemiology of antibiotic resistance, basic research explain the evolutionary dynamics of path- should also concentrate on the detection ogenic specialization and the stress Diagnostics and analysis of mobile pathogenic ele- responses of microbes. Woolhouse (2002) •Chronic infections and chronic inflammation ments and resistance transfer through also emphasizes the importance of study- •Development of specific antibodies genomic islands (Hacker & Carniel, ing routes of pathogen transmission •Identification and classification of human- 2001). Another important development is through vectors (such as arthropods) and pathogenic bacteria and fungi the fusion of cell biology with microbiology, direct (for example, physical contact) or •Identification of toxins, small molecules and which will be of great importance for indirect contact (such as through food). allergenic compounds studying the in situ expression of genes Ultimately, this epidemiological research •Specific DNA arrays to identify species in (Roux et al, 2004). Denning and col- will contribute to the early identification of polymicrobial cultures leagues (2003) note recent advances in novel and re-emerging diseases caused by microscopy, such as multidimensional bacteria, fungi and multi-resistant bacterial Clinical importance imaging, laser-scanning microscopy, epi- strains. In this context, the understanding •Development of new diagnostic and therapeutic agents fluorescence microscopy and fluorescent of immune selection and the impact of •Evaluation of effects of chemotherapeutics light-based imaging, while stressing the vaccination and antibiotic intervention (such as antibiotics) importance of microscopy and histo- on microbial populations are future •Creation and extension of databases pathology. The need for better coopera- challenges for research (Grenfell et al, •Link between diagnostics and therapy tion between basic and clinical research, 2004). So far, such studies have mostly (individualized medicine) particularly when collecting epidemio- used pure bacterial cultures, which of •Rapid, sensitive, cheap and standardized logical data or devising new or more effi- course do not reflect reality. DeLong diagnostics cient therapies, is also a related concern. (2004) therefore stresses the need for •Validation of diagnostics and molecular Here, nanobiotechnology will also gain microbial population genomics to charac- methods importance for analytical approaches in terize uncultivatable bacterial and fungal •Target identification (new vaccines, antimicrobial targets) chip technology, as will systems biology species, and the interactions between for the analysis of experimental data (see various microbial populations.

A literature review by Cleaveland and diseases due to environmental factors and colleagues (2001) identified 1,415 species CHALLENGES FOR recent man-made interventions. This of organisms known to be pathogenic to INTERDISCIPLINARY RESEARCH trend is further accelerated by antibiotic humans, including 538 bacteria and rick- ON HUMAN-PATHOGENIC overuse in agriculture, which may ettsia and 307 fungi, and according to MICROORGANISMS increase the proliferation of bacterial and Rappuoli (2004), “dozens of new infec- Epidemiology fungal diseases. tious diseases are expected to emerge in •Commensal bacterial flora and opportunistic The rapid spread of SARS in 2003 from the coming decade.” Viruses, particularly infections China to the rest of the world showed that RNA viruses, seem to emerge most rapidly. •Lifestyle of humans infectious diseases can no longer be seen In this context, Lederberg (2000) stresses •Routes of transmission as problems of developing countries, now the need to understand evolutionary •Spread of pathogens that global trade and tourism enable the strategies of pathogenic microbes that •Transmission bottlenecks rapid distribution of infectious organisms. facilitate their re-emergence and the emer- •Vector analysis Mangili & Gendreau (2005) thus predict gence of new, unknown pathogens due to an increase in airborne, food-borne, vector- Ecology and environment their rapid reproduction and enormous borne and zoonotic diseases caused by •Ecological niches and natural reservoirs potential for genetic variation. Mutation, •Geographical distribution the increasing ease and affordability of genetic variation, recombination and hori- •Host range air travel. Cleaveland and colleagues zontal gene transfer of pathogenic islands •Microbe–environment interaction (2001) therefore stress human behaviour are keys to the evolution of pathogens as the main factor for the spread of (Hacker & Carniel, 2001), which still have Evolution and taxonomy infectious diseases. to be understood. •Identification and classification of clinical species •Intra-host evolution here are also many aspects in the f course, these trends and devel- •Phylogenetic derivation medical system itself that pose a opments in basic research have to threat to public health. The most Population dynamics and selection pressure T be put into context with current important problem is the lack of hygiene O •Cultivation-independent genome analyses and future challenges for public health •Dynamics of antibiotic resistance in hospitals and the resulting increase (see sidebar titled ‘Challenges for inter- •Immune selection of so-called nosocomial, or hospital- disciplinary research on human-pathogenic •Impact of vaccination and antibiotic intervention acquired, diseases (Burke, 2003). New microorganisms’). These encompass demo- •Interaction between clonal communities technologies, such as transplantation graphic changes in ageing populations, •Understanding mechanisms of generalists and medicine, immunosuppressive therapies and the effects of globalization, popula- specialists and prosthetic devices, have also raised tion growth and migration—whose social, •Understanding microbial diversity the prevalence of chronic or polymicro- ecological and economic factors and their bial infections (Donlan & Costerton, interplay are still poorly understood (Pang 2002). Their increasing number (Brogden & Guindon, 2004). Most experts in our et al, 2005), and the deaths caused by survey identified HIV and the spread of health (Wilson, 1995). Man-made ecolog- mycoses (McNeil et al, 2001), should be multidrug-resistant tuberculosis in Eastern ical changes, such as deforestation and taken very seriously. Further problems in Europe as major problems for public pollution, and the effects of land use or the public-health system itself include a health—some experts estimate that about water storage, also influence the biologi- decreasing number of effective anti- one-third of the world is infected with cal diversity and distribution of parasitic biotics, insufficient guidelines and surveil- Mycobacterium tuberculosis (Fauci et al, and infectious diseases (Guernier et al, lance methods for antibiotic resistance, 2005). Other problems mentioned in the 2004). Chan and colleagues (1999) esti- and a general decrease in research on expert survey included malaria, SARS, mate that global climatic conditions in anti-infectives (Denning et al, 2003). monkey pox and sexually transmitted, res- particular are the most important determi- Lederberg (2000) criticizes especially the piratory and diarrhoeal diseases. The nants for pathogen distribution, but so far misuse of antibiotics and the popularity of greatest challenge is what Chan and col- few studies of this phenomenon are avail- antibacterial products, which further con- leagues (1999) describe as the substantial able. Irrespective of global climatic contribute to the spread of multi-drug anti- differences between developed and devel- ditions, simple weather changes influence microbial resistance (Goossens et al, oping countries with respect to the burden the emergence of infectious diseases and 2005), particularly among Mycobacterium of infectious diseases. The authors esti- their vectors (Sutherst, 2004), for example tuberculosis and Staphylococcus aureus. mate that about 40% of the population of the El Niño phenomenon in the Southern Methicillin-resistant S. aureus, vancomycin- the developing world are infected with at Pacific, or floods that cause outbreaks of resistant Enterococci and drug-resistant least one pathogenic organism compared malaria or waterborne disease such as Gram-negative bacteria such as Klebsiella with only 2% in the developed world. cholera (Morens et al, 2004). Altekruse and Enterobacter spp. have already In many developing countries, socio- and colleagues (1997) therefore identify become major problems in many hospital economic factors, such as poverty, crowd- food-borne and water-borne diseases as settings (Levy, 2001; Kipp et al, 2004), ing and poor hygiene, represent major major threats to public health. Morens which has led Cars & Nordberg (2004) risks for the transmission of infectious dis- and colleagues (2004) also describe an to speculate about the possibility of a eases and accordingly for global public increase in zoonotic and vector-borne post-antibiotic era.

Finally, the potential misuse of scientific risk-assessment strategies to set national pharmaceutical companies. Spellberg information and genetic engineering for and global health priorities (Murray et al, and colleagues (2004) stress that out of bioterrorism and biowarfare is worrying 2003). Forecasting systems, computer- 506 drugs that were in late-stage clinical public health and security experts (May & modelling techniques and disease epi- testing in 2004, only six were new Silverman, 2003). It remains to be seen demiology are other measures to assess antibacterials. Similarly, there is only a whether freely available information the impact of disease outbreaks small number of biotech companies that on genetics and genomic research is (Hampton, 2004). develop vaccines or antifungal drugs sufficient for the development of biol- (Bröker, 2003; Bonn, 1997). ogical weapons (Rappert, 2003). The rom the perspective of basic research, World Health Organization (Geneva, the identification of factors leading to …rapid, sensitive and robust Switzerland; WHO, 2004) accordingly chronic and secondary diseases and F diagnostic tools are needed in addresses the need for action plans to the evolution of antibiotic resistance are counteract potential bioterrorist attacks; most fundamental challenges (Cassell & addition to improved disease- indeed, Woodall (2005) criticizes that Mekalanos, 2001). On a more practical management strategies and there is no such international body to level, rapid, sensitive and robust diagnos- infrastructures as part of an early investigate the sudden emergence of tic tools are needed in addition to response strategy to tackle infectious diseases. improved disease-management strategies and infrastructures as part of an early infectious diseases redominantly, what is needed to pre- response strategy to tackle infectious dis- vent re-emerging infectious diseases eases. This does not, however, replace the Nevertheless, there are promising and Pfrom turning into an epidemic or imperative to develop new antibiotics and commercially attractive areas of research pandemic is a global surveillance network make better use of existing ones. on anti-infectives and vaccines. Sheridan and vaccination strategy (Mabey et al, According to Bonhoeffer and colleagues (2005), for instance, describes innovative 2004), especially for childhood immu- (1997), the alternation of different anti- approaches that use recombinant DNA nization (Breiman, 2001). Both developed biotics, the evaluation of single and multi- techniques to develop new vaccines. and developing countries must therefore ple antibiotic therapies and the rational Combination vaccines to prevent complex increase their participation rates in vacci- use of antibiotics in general are necessary syndromes might be useful, along with nation programmes by improving health to reduce bacterial resistance. new methods of vaccine application and education and public policy. In addition to antibody preparation, which are often these general measures, Cangelosi and Education,sanitation and water faster and cheaper than vaccine develop- colleagues (2005) recommend more effec- ment itself (Breiman, 2001; Casadevall et al, tive monitoring of pathogens in the envi- supply in developing countries 2004). Bröker (2003) also forecasts a rising ronment, which would allow researchers must be improved to counteract market for products on the basis of reverse to understand their incidence and persis- the increasing internationalization vaccinology, genetic vaccination and tence. Regarding novel infectious dis- of health risks brought about by recombinant antigens, and for conjugate eases, Guillemot and colleagues (2001) infectious disease and therapeutic vaccines. According to address the identification of natural EFPIA (2003), outsourcing such projects sources and zoonotic reservoirs as the by subcontracting to smaller companies, basis of preventing or controlling such Although the development of new especially in the area of pre-clinical outbreaks. According to Enserink (2004), antibiotics and vaccines remains an research or toxicological analysis, could better coordination between labs and pub- important public-health imperative, phar- render antibiotic and vaccine develop- lic health organizations by global alert maceutical companies have little interest ment sufficiently beneficial for both the networks such as the Global Outbreak in this research area. The European pharmaceutical and biotech industries. Alert and Response Network (GOARN) Federation of Pharmaceutical Industries Finally, Cockerill & Smith (2004) expect would lead to earlier identification of and Associations (EFPIA; Brussels, a greater market for genomic-based novel pathogens. Belgium) notes that the European industry diagnostics and screening technologies. Education, sanitation and water supply has been undergoing radical changes dur- However, an important step towards a in developing countries must be improved ing the past decade, triggered by the better fit between industry’s interests and to counteract the increasing international- increasing costs for R&D and marketing public health needs would be more coop- ization of health risks brought about by (EFPIA, 2003). This has led to a rising eration between public-health authorities, infectious disease (Pang & Guindon, number of company mergers and clinicians, affected communities and phar- 2004). The US National Institute of Allergy takeovers and a greater focus on drugs to maceutical companies. Hence, govern- and Infectious Diseases (Bethesda, MD, treat chronic and abundant diseases in mental support such as the reduction of USA; NIAID, 1999) stresses the need for mainly affluent populations. Because the administrative barriers (EFPIA, 2004), food safety, animal-control programmes development of new antibiotics and vac- public–private partnerships as advocated and clean water and sewers, because cines is a long and costly process and will by organizations such as the WHO (Ridley, many gastrointestinal pathogens are ultimately find only a limited market 2003), partnerships with small and medium transmitted through water. Moreover, (Williams & Heymann, 1998), research in biotech companies, and new business it is essential to develop comparative this area is not very attractive for many models to encourage the development of

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