Monday, November 28, 2011

P4 infectious diseases medicine

The XXI century has brought a new concept to Medicine, the P4 medicine, term coined by Leroy Hood. More than a new concept, P4 medicine should be considered as a new way to approach medical care. The vision of P4 medicine —shorthand for predictive, preventive, personalized and participatory medicine— is that instead of waiting until the patient is sick before responding, physicians will be able to detect early warnings of disease to take early action and people may even be able to adjust their lifestyles to prevent disease. To make P4 medicine true it is essential a broad interdisciplinary approach including methods for personalized genome sequencing and new computational techniques for building dynamic and disease‐predictive networks from massive amounts of data from a variety of OMICs. In other words, the heart of P4 medicine is to define new methods for interrogating and understanding the interaction between the environment and the genome of the individual. 

There are already P4 medicine successful stories. An excellent example of the effectiveness of this approach is the change in cancer treatments. Nowadays, emphasis is placed on early detection, followed by genotyping of the patient to use the most adequate treatment according to the genetic background. Cardiovascular diseases and perhaps even neurodegenerative disorders will be the next targets for P4 medicine. However, what about infections? Can we apply the P4 medicine approach to infectious diseases? In my view, yes.

* Recently I have published a review based on this blogpost in the June 2012 issue of International Microbiology, the flagship journal from the Spanish Microbiology Socitey (SEM).

The premise of P4 medicine is that diseases result from perturbations of biological networks. These disease-perturbed networks both cause and reflect the progression of a disease. Thus, diseases can be diagnosed, treated and prevented by understanding and intervening in the networks that underlie health and illness. And this is exactly the prevailing view on infectious diseases. Infections can be viewed as the result of the interplay between two complex biological networks: the host and the pathogen. The understanding of this interaction requires large scale analysis of the host-pathogen interface. This knowlege should help to identify host pathways important for infection as well as pathogen determinants involved in disease progresion. The identified host and pathogen targets may help to develop innovative therapies based on the modulation of the host-pathogen interface.

Let´s consider the four "P" of P4 medicine in the context of infections:

Preventive: General methods to prevent transmission of pathogens include disinfection and pest control. Vaccination can be considered the most efficient method to prevent disease progression and even may lead to erradication of the infection. Epidemiological studies also help to decrease the transmission rate of infectious diseases.
Predictive: There are certain gene deficiencies that predispose to recurrent infections (for a review see Clinical Microbiology Reviews, 2011). These are extreme cases but it is evident that not all of us are equally susceptible to infections.  On average, each human differs from another by less than one percent of their genetic makeup. But these genetic differences give rise to our physical differences, including our potential predisposition to various diseases. It is tempting to speculate that health will be the combination of two types of defence mechanisms against infections: resistance and tolerance. Immunology has largely focused on the identification of  mechanisms of resistance but the molecular bases of tolerance are largely unknown. Nevertheless, plotting health (cytokine levels, biomarkers, fever,...) versus pathogen loads over the course of an infection may help to predict recovery and point out bifurcations (failure of treatment). The slope of this plot defines the tolerance of the individual.
Personalized: It is possible to sequence not only our genome but also that of the pathogen. But this is not of much help without functional studies. For example, recently Lalita Ramakrishnan and co-workers identifed a locus associated to differential production of an anti-inflammatory product leading to hypersusceptibility to tuberculosis and leprosy (Cell, 2010). On the other hand, it is technologically feasible to analyze host responses to different infections ex vivo by challenging blood cells in a test tube. These data could be compared to those obtained from infected patients and even connected to different genotypes. Altogether, this information will help to predict susceptibility to certain infections or whether the defense response will be enough to clear the pathogen. The pathogen side is easier to tackle. There are platforms allowing the identification of the pathogen without culturing, the detection of virulence factors associated to bad prognosis and even the characterization of the antibiotic resistance markers. And all this, in  no more than 3-4 h!. This information will lead to rational treatments.
Participatory: This includes a variety of aspects of participation including sharing data, education of patients and physicians and engaging patients in personal choices about illness and well-being. However, there are still technical problems for mining, comparing and analyzing data sets from thousands-millions of individuals. The issues of data ownership (by scientists and by institutions) and a reluctance to believe in open-source and open-data policies will have to be overcome if we are to mine the incredible potential of the exploding opportunities of patient data accumulation.
On the whole, despite the fascinating technical poblems ahead, P4 infectious diseases medicine shows great promises to maximize wellness for each individual rather than simply to treat infections. The future is just around the corner! 

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