EPIDEMIOLOGY

New trends in the epidemiology of emerging diseases

This text summarises a lecture given at the European Action On Global Life Sciences (EAGLES) Food Workshop, 4-5 december 2006, Hangzhou, China, following the SARS episode that developed from the Metropole Hotel in Hong Kong
欧洲全球生命科学计划粮食研讨会

Languages and an evolved culture are specific to humanity. They separate human beings from their environment. In early attempts to place man in context, culture perceives nature as a fragile entity, which must be protected from human action (Lévy-Strauss 1955). However, nature is often hostile, and plants and animals had to be placed in the context of human behavior. This is how the process of domestication was born, starting in the Neolithic period. Animals (and plants, in fact), when domesticated, bring with them a variety of commensals, parasites, symbionts and pathogens. In this context, human behaviour (urbanization in particular) creates new entry points for many pathogens. The risk of transmission from one host to another one increases with phylogenetic proximity; thus, contrary to popular opinion, what is more natural (i.e. closer to our biological nature) is more dangerous than what is artificial. The clear message is that emerging diseases are the result of human behaviour.

How to understand (and then control) emerging diseases? Life results from the combination of two entities, a molecular machine, compartmentalized and operating on the chemical flows forming metabolism, and an information transfer process that behaves like a recipe book that would be replicated when the organism multiplies. This particular organization is strongly reminiscent of the way computers are made, separating a machine from the data/programs organized in strings of symbols belonging to a finite alphabet. The three domains of life, prokaryotes (cells without a nucleus), split into Archaea and Bacteria, and eukaryotes (cells with a nucleus and organelles such as chloroplasts, hydrogenosomes or mitochondria), Eukarya correspond, in the metaphor of the genetic program, to computers with different operating systems (OSs). In this metaphor, there would be three different operating systems. As is well known, many programs are impossible to run when switching from one OS to another. The OS of the Eukarya is special in that these organisms have integrated, first as symbionts and then as organelles, organisms from the domain of Bacteria. This implies some kind of interoperability and could explain the remarkable observation that Bacteria, but not Archaea, can become pathogens for plants and animals. This metaphor is also remarkable in that it is so consistent with the behavior of viruses (pieces of program designed to self-replicate, but entirely dependent on the existence of a host system) that the metaphor has moved from biology to computer science, i.e., in the opposite way that the concept of program has moved from computer science to biology.

With this view in mind, it becomes fairly obvious that compatibility is the core question when considering pathogenic behaviour. And the nearer organisms are to each other the more compatible they are, accounting for example for the potential hazards of human blood, as it is preadapted to all human pathogens. In contrast, artificial constructs, unless purposely meant to be harmful, generally show considerable incompatibility with humans and are therefore less dangerous (they would be more dangerous for those organisms they derive from).

As control elements, genes are at the root of pathogenic behaviour, and it is therefore of interest to investigate the sources of genes. Genome programs have uncovered an evergrowing source of genes, which started in 1991 when it was found that at least half of the newly-discovered genes had no significant counterpart in anything known. The core genes of life combine growth and maintenance (which drives survival), while life in context explores and exploits specific niches. Analysis of gene persistence in a large number of genomes shows that the former constitutes a highly conserved set of genes, the paleome which recapitulates the three phases of the origin of life; metabolism of small molecules on surfaces, substitution of surfaces by an RNA-world where transfer RNA played a central role, and invention of template-mediated information transfer. Colonisation of the niche is performed using an unlimited set of genes, forming the cenome. Pathogenicity of living organisms often results from discovery of a novel niche, using genes that have been previously used in another context. Indeed, biological systems, which are submitted to the trio variation/selection/amplification, evolve by creating functions which recruit pre-existing structures, as do handymen with the material they collect in a more or less haphazard way.

Changes in lifestyle, and in particular in the way patients are treated in hospitals, facilitate several commensals to occupy new niches. Acinetobacter baumanii and Staphylococcus epidermidis illustrate this situation (Quinn 1998, Foster 2005, Massey et al. 2006). Analysis of the single nucleotide polymorphism in the genome of the latter shows that, in addition to genes of the cenome, adaptation involves genes of the core genome, in particular genes involved in stress adaptation, maintenance and repair (Wei et al. 2006). This is so general that it seems likely that many bacteria may become emerging pathogens in patient care units.

The case of viruses is somewhat different, and unfortunately more likely to be successful in making diseases emerge. Indeed, viruses are pieces of genetic program that can readily be expressed in many cell types, and they often need simply to find an entry door to a new cell type to be successful. Many emerging viruses, therefore, are variants of existing viruses. In particular, shifting from a host to a new one can happen when mutations modify the virus envelope so that it can bind to a new receptor and then is internalized in a host’s cell type. The influenza virus is a paradigm in the domain as it is usually a mild parasite of Anatidae (ducks, geese and the like) which can infect humans, often after having infected pigs as an intermediate host (Kaleta et al. 2005). The structure of the small farm in China, with its pond and its pig under a roof (as in the Chinese character for ‘family’ 家) is remarkably adapted to this type of transition. In the same way, we can see pox viruses (infecting buffaloes, sheep and monkeys) as possible sources of emerging pox infections in the future.

Many viruses causing zoonoses are of great concern (De Clercq and Goris 2004). SARS, whose exact origin is still not entirely traced back (bats may be a reservoir of the original coronavirus (Wong et al. 2007)), is a case in point. An epidemic in pigs (Laude et al. 1998), where there was a tropism shift of a coronavirus between gut and lungs, illustrates what happened in 2002-2004 in humans. The spread of the disease is not easy to understand with simple epidemiological models (why almost no cases in Shanghai and many in Beijing?) and a model suggested a double epidemic where two viruses with different tropisms and/or virulence overlapped (Ng et al. 2003). This type of situation should, in any event, be explored further.

In the case of genetically modified organisms (GMOs), while the dangers of plant GMOs looks fairly limited (artifice is less dangerous than nature), the potential dangers of some animal GMOs are evident. In particular, humanization of organs from animals carrying a wealth of retroviruses is a matter of extreme concern. In this domain, epidemiological studies of the morbidity and mortality of butchers, slaughterhouse personnel, etc. would be most welcome to permit some evaluation of the potential risks associated with ordinary domestic animals.

In the case of unconventional pathogenic agents, such as prions, not much has been explored on the exact route of contamination. While contaminated food has been incriminated (but with no solid proof of contamination), the existence of affected wild animals and of contaminated pastures suggests that other ways should be explored. The possibility of a new type of vector, that of parasites multiplying intracellularly, has been investigated in a model study (Ng et al. 2007). It shows that, depending on the background previous contamination of the host by the vector, one could witness either an epidemic scenario or sporadic cases, exactly as is observed at present. Parasites such as Microsporidia would be consistent with such a scenario.

Finally, human activity, in terms of biological warfare or bioterrorism, should be considered seriously, as new means provided by synthetic biology (Heller et al. 2005) could, unfortunately, be used by the dark part of humanity.

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