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The Human Gut Microbiome: Implications for Future Health Care James M. Kinross, MRCS , Alexander C. von Roon, MRCS , Elaine Holmes, PhD, MRSC, Ara Darzi, FMedSci, HonFREng, KBE , and Jeremy K. Nicholson, PhD, FRSC, FRC Path Corresponding author Prof. Jeremy K. Nicholson Department of Biomolecular Medicine, Faculty of Medicine, Imperial College, 6th Floor, Sir Alexander Fleming Building, South Kensington Campus, London SW7 2AZ, United Kingdom. E-mail: [email protected] Current Gastroenterology Reports 2008, 10:396 – 403 Current Medicine Group LLC ISSN 1522-8037 Copyright © 2008 by Current Medicine Group LLC In their intestine, humans possess an “extended genome” of millions of microbial genes—the microbiome. Because this complex symbiosis influences host metabolism, physiology, and gene expression, it has been proposed that humans are complex biologic “superorganisms.” Advances in microbiologic analysis and systems biology are now beginning to implicate the gut microbiome in the etiology of localized intestinal diseases such as the irritable bowel syndrome, inflammatory bowel disease, and colon cancer. These approaches also suggest possible links between the gut and previously unassociated systemic conditions such as type 2 diabetes and obesity. The elucidation of the intestinal microbiome is therefore likely to underpin future disease prevention strategies, personalized health care regimens, and the development of novel therapeutic interventions. This review summarizes the research that is defining our understanding of the intestinal microbiome and highlights future areas of research in gastroenterology and human health in which the intestinal microbiome will play a significant role. Introduction In accordance with Koch’s postulates of the 1800s, medical science has largely held the view that one organism is associated with one infectious disease (eg, Mycobacterium tuberculosis infection). In the 1980s, the Nobel laureates Barry Marshall and Robin Warren introduced the concept that a bacterium, Helicobacter pylori, causes a seemingly noninfectious condition, peptic ulcer disease. This connection is not surprising when one considers that all vertebrates have co-evolved to a state of mutual interdepen- dence with the microbial consortia that inhabit their body surfaces and cavities. The human colonic microbiota comprises a consortium of many hundreds of bacterial species, unique to each individual host, which changes in response to diet, pharmaceutical input, age, disease, and medical or surgical intervention. Most of these bacteria are anaerobic and metabolize dietary compounds and ingested foreign compounds (xenobiotics) that escape catabolism in the upper gut. They are also essential to the enterohepatic circulation of compounds detoxified by the liver and released in bile. The resident microbiota carries out an array of enzymatic reactions, many distinct from but essential to human genome–encoded activities. In essence, therefore, mammals possess an “extended genome” of millions of microbial genes—the microbiome—located in the intestine [1]. This symbiotic condition influences host metabolism and physiology as well as host gene expression, and it has been proposed that humans are in fact a vastly complex, biologic “superorganism”[2]. Contemporary classification of human disease states derives from observed correlations between pathologic analysis and clinical syndromes. In the postgenomic era, novel systems-networking approaches are determining the complex links among previously unassociated sets of genes [3•]. However, these do not account for the role of the microbiome and its influence on the human phenotype. The notion of microbial-mammalian metabolic cooperation has therefore been defi ned through the concept of the human metabonome [4•]. This term refers to the sum of all the cellular metabolomes (the full set of metabolites within, or that can be secreted by, a given cell) and their interactions in a multicellular organism plus the products of facile chemical transformations and extragenomically generated metabolites. Such transgenomic, co-metabolic interactions greatly increase system complexity and perhaps provide the ultimate challenge to understanding the impact of intestinal microbiota modulation on the host gut and human health [5••]. Advances in bioinformatics and analytic biology are now allowing researchers to measure the influence of the intestinal ecosystem, with the implication that clinicians will no longer be restrained by inadequate culture techniques and nonspecific metabolic The Human Gut Microbiome: Implications for Future Health Care Kinross et al. tests of microbial activity. Most importantly, in the “omics” era, we may succeed in identifying and characterizing the phylogenetic makeup of the gut microbiota, and it may be possible to accurately correlate microbiome function with patient outcome. Scientific interest in the human microbiome is so intense that the US National Institutes of Health recently committed $115 million to launching the Human Microbiome Project, which aims to characterize the microbial components of the human genetic and metabolic landscape using molecular techniques [6]. Part of this project aims to identify a “core human microbiome,” a set of microbial genes, common to all humans, without which humans cannot survive. Metagenomic and metabonomic strategies are already beginning to confi rm links to localized intestinal diseases such as the irritable bowel syndrome (IBS) [7•], inflammatory bowel disease (IBD) [8], and colon cancer [9]. These approaches also suggest possible links between the gut and previously unassociated systemic diseases such as type 2 diabetes [5••]. This review summarizes the research defi ning our understanding of the intestinal microbiome and highlights future areas of research in gastroenterology and human health in which the intestinal microbiome will play a significant role. The Intestinal Ecosystem The human intestine carries about 100 trillion microorganisms representing up to 1000 separate bacteria, yeasts, and parasites. The upper gastrointestinal tract has a sparse population as a result of the luminal medium and propulsive forces, but the large bowel contains about 1 × 1013 to 1 × 1014 microbes, weighing around 1.5 kg and carrying at least 100 times as many genes as our own genome [10•]. This impressive bacterial load is turned over every 3 days and possesses an active biomass similar to a major human organ [11•]. There is wide spatial and temporal variation within the same intestine and between individuals, ages, cultures, and sexes [12]. Although four phyla (Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria) dominate the human microbiota and are relatively constant across individuals, the makeup of a person’s microbiota at the species and strain levels can be as individual as a fingerprint; we may share as little as 1% of the same species [13]. Each host thus has a unique, genetically determined response to both aggressive and protective bacterial species. The gut flora is vital for intestinal growth and development and for the health of the host in general. Through resource competition, established symbionts protect the host from colonization by potential pathogenic microorganisms. The gut microflora not only makes otherwise inaccessible nutrients available; it is intimately involved with mammalian metabolism. Experiments comparing conventional mice with germ-free animals colonized by human bowel flora show that the gut flora appears to 397 modulate both the enterohepatic circulation of bile acids and lipid metabolism in the host [14]. The intestinal epithelium is composed of three barriers in one: a physical barrier, an innate immune barrier, and an adaptive immune barrier. The relationship between commensal gut flora and the intestinal barrier is complex and occurs at all levels. Commensal microbes such as bifi dobacteria not only maintain the mucosal barrier; they also facilitate interkingdom signaling across it. The human gastrointestinal mucosa is uniquely adapted to the proximity of a massive load of potentially antigenic microbes. Specialized mucosal immune cells continually sample intestinal microbes and initiate local immune responses without inducing a systemic response [15] by inhibiting nuclear factor (NF)-κ B activation. If inappropriately activated, floral immune-mediated cytokines have multiple actions, including altered epithelial secretion, exaggerated nociceptive signaling, and abnormal motility. The commensal flora uses a large repertoire of molecular processes to exert its beneficial health effects on the host. In vitro, many commensal strains can produce antimicrobial substances such as hydrogen peroxide, cresols, organic acids, bacteriocins, or bacteriocin-like molecules. They also block adhesion of certain pathogenic bacteria, modulate the host immune response via upregulation of phagocytic activity, and stimulate the production of nonspecific and specific secretory IgA. Further stabilization of the intestinal barrier is promoted by the stimulation of mucus production and the attenuation of the inflammatory response. The bifi dobacteria (Bifi dobacterium longum in particular) appear to play key roles within the gastrointestinal microbial ecosystem. Bifi dobacteria ferment oligosaccharides, often liberated from more complex polysaccharides by the Bacteroides, to produce short-chain fatty acids such as acetate and lactate, which in turn are converted into butyrate, the main energy source for the colonic mucosa, by other dominant members of the gut microflora. Bifi dobacterium longum downregulates inflammatory cytokine secretion in inflamed mucosal tissues from ulcerative colitis patients ex vivo [16]. Metabonomic and Metagenomic Techniques About 70% of the human microbiota cannot be identified or cultured by conventional microbiologic analyses that rely on growing colonies of organisms on agars [17 ]. Metagenomic and metabonomic techniques have completely revolutionized the study of the microbiota. The most important of these techniques are summarized below. 16S ribosomal RNA gene sequencing The 16S ribosomal RNA (rRNA) gene is found in all microorganisms, and its hypervariable sections make it ideal for microbe identification down to the species and strain level. Following extraction, microbial rRNA is amplified using 398 Gastrointestinal Infections Figure 1. Transgenomic human microbiome–metabonome linkage. By using computational multivariate analytic techniques such as orthogonal–partial least squares (O-PLS) analysis, it is possible to correlate metabonomic responses with those of the intestinal microbiome. DGGE—denaturing gradient gel electrophoresis; NMR—nuclear magnetic resonance; PCR—polymerase chain reaction. (Adapted from Li et al. [20•], with permission.) polymerase chain reaction (PCR), fragments are aligned, and the full sequence is compared with a publicly available database for species identification [17 ]. Fluorescent in situ hybridization Fluorescent in situ hybridization (FISH) uses DNA probes that bind to species-specific rRNA gene sequences in microorganisms. The DNA probe is tagged with a compound that will fluoresce only if the probe has attached to the microbial rRNA. This allows enumeration of specific microbial taxa under an ordinary light microscope and quantitative comparisons between experimental groups. Denaturing gradient gel electrophoresis Denaturing gradient gel electrophoresis (DGGE) allows analysis of rapid comparative shifts in microbial populations between experimental groups. As a first step, microbial rRNA is amplified with PCR. The amplified RNA fragments are then placed on a gel, which is run on a denaturing agent, usually urea. RNA fragments of different lengths separate out as discrete bands. Bands that account for variation between experimental groups may then be sampled from the gel, re-amplified using PCR, sequenced, and identified using the technique described above. Metabonomics Metabonomics, a rapidly evolving field of biomedical science, is defi ned as “the quantitative measurement of time-related multiparametric metabolic responses of multicellular systems to pathophysiological stimuli or genetic modification” [18]. In practice, it involves the use of spectroscopic metabolic profiling methods applied to various body compartments, including urine, plasma, stool, and tissue [19], coupled with multivariate statistical analysis of the data. Metabonomics provides a systems approach for studying in vivo metabolic profi les. High-throughput methods such as high-resolution 1H nuclear magnetic resonance (NMR) spectroscopy or mass spectrometry (MS) can be used to generate a metabolic “fingerprint” of biologic fluids or tissues reflecting the levels of hundreds or thousands of metabolites (molecular weight < 1000 Da). By using chemometric tools to analyze these complex metabolic data sets, latent information of prognostic and diagnostic use can be extracted and panels of biomarkers can be associated with specific pathologies. A number of urinary metabolites are of microbial origin, so urinalysis provides a window into the microbial activity in the gut. Using multivariate statistical approaches, it is now possible to establish correlation or covariance patterns between the metabonomic and metagenomic data (Fig. 1) and in this way to generate hypotheses relating to the influence of particular bacterial species on biofluid metabolite profiles and vice versa [20•]. Evidence for the Influence of the Gut Microbiome on Gastrointestinal Diseases Inflammatory bowel disease The resident bacterial flora has been suggested as an important factor that drives the inflammatory process in IBD [21]. The mechanism by which the human gut immune system discriminates between commensals and pathogens is complex, involving ingestion of luminal organisms by M cells, the presentation of bacterial antigens via dendritic cells to intestinal B cells, and production and secretion of IgA into the intestinal lumen. The NOD2/CARD15 gene, which is mutated in 17% to 25% of patients with Crohn’s disease, partly controls this process [22]. Patients The Human Gut Microbiome: Implications for Future Health Care Kinross et al. with IBD also have increased intestinal mucosal secretion of IgG against a wide spectrum of commensals. IgG, which activates the complement cascade, is much more damaging to the intestinal mucosa than IgA. Patients with IBD also have more bacteria from diverse genera attached to their gut epithelial surfaces than do healthy controls. Some of these, particularly bacteroides, were found to penetrate into the epithelial layer, at times intracellularly [23]. Some anaerobes, particularly Bacteroides fragilis and Clostridium ramosum, can induce fibrogenic responses when invading the intestinal wall. Fecal stream diversion has been shown to prevent recurrence in Crohn’s disease, whereas infusion of bowel contents into excluded ileal segments can re-activate mucosal lesions. Similarly, patients with ulcerative colitis rarely have terminal ileitis, whereas up to 50% develop pouchitis after proctocolectomy and ileal pouch formation. One of the proposed mechanisms is increased fecal stasis and increased contact time of intestinal contents with the ileal pouch mucosa. In rodent models, IBD does not occur in germ-free animals, in contrast to their naturally colonized littermates [8]. Colorectal cancer Evidence suggests that the gut microbiota may play an important role in modulating the effects of diet as an environmental risk factor for colorectal cancer. High dietary consumption of fat and red meat (especially processed meat) is associated with increased risk of colorectal cancer, an effect thought to be modulated by N-nitroso compounds and heterocyclic aromatic amines [24]. Heterocyclic amines induce damage to DNA in colonocytes; some intestinal microbes substantially increase this damage, whereas other bacteria can take up and detoxify such compounds. In animal studies, bacteria of the bacteroides and clostridium genera increase the growth rate of colonic tumors, whereas lactobacilli and bifidobacteria prevent tumorigenesis [25,26]. Superoxide-producing Enterococcus faecalis has conclusively been shown to produce epithelial cell damage. Sulfate-reducing bacteria are also thought to be implicated, with a similar mechanism, but conclusive evidence is lacking [9]. These findings are supported by a human study, which found higher levels of Bacteroides vulgatus and Bacteroides stercoris in people with a high risk of colon cancer, and higher levels of Lactobacillus acidophilus and Lactobacillus S06 in people at low risk of colon cancer [27]. 399 Several studies have suggested the presence of qualitative changes in the colonic flora in IBS patients; the most consistent fi nding is a relative decrease in the population of bifi dobacteria. Recently, the fecal microbiota of patients with IBS symptoms was compared by 16S rRNA gene analysis with that of age- and sex-matched asymptomatic volunteers [7•]. Significant differences were demonstrated, as were differences between the clone libraries in several bacterial species belonging to the genera Coprococcus, Collinsella, and Coprobacillus. IBS is often linked to extensive gas production in the colon, and some bacterial groups are more prone to gas production than others. Therefore the composition and activity of clostridial species has been specifically investigated using similar techniques [29]. The Clostridium coccoides–Eubacterium rectale group was the dominant subgroup of clostridia, contributing a mean of 43% of the total bacteria in control subjects and 30% (constipation type) to 50% (diarrhea type) in IBS subjects. The DGGE profi les of IBS patients also indicated greater instability of bacterial populations compared with controls. A small percentage (6%–17%) of patients develop postinfective IBS, with symptoms appearing for the fi rst time after an acute episode of infective gastroenteritis, which appears to be directly responsible for low-grade immune activation [30]. Postinfective IBS appears to be a nonspecific response to injury and has been reported after Salmonella, Campylobacter, and Shigella infections. Although IBS has generally been considered a motility disorder, it seems likely that the condition may involve changes in epithelial fluid and electrolyte transport. Bile acid malabsorption has been observed in 33% of patients with diarrhea-predominant IBS. An NMRbased metabonomic strategy was employed in a mouse model of postinfective IBS to study the metabolic effects of Lactobacillus paracasei on gut dysfunction. Plasma metabolic profi les of animals infected with Trichinella spiralis showed increased energy metabolism, fat mobilization, and a disruption of amino acid metabolism due to increased protein breakdown; these effects were related to intestinal hypercontractility [31]. L. paracasei treatment normalized the muscular activity and the disturbed energy metabolism, suggesting that it may be possible to create a noninvasive, metabolic, prognostic profi le to determine which patients are at risk of developing postinfective IBS. Irritable bowel syndrome Although current defi nitions of IBS specify that there are no structural or biochemical abnormalities to account for the symptoms, there is growing evidence that floralmucosal interactions, the enteric nervous system, and the brain-gut axis are directly involved in its pathogenesis. This idea is based partly on fi ndings that antibiotic use may predispose to IBS or exacerbate symptoms [28], and that manipulation of the gut flora by prebiotics or probiotics may ameliorate them. Evidence for the Influence of the Gut Microbiome on Systemic Disease States Obesity and the metabolic syndrome Between 1980 and 2004, the prevalence of obesity in the United States increased from 15% to 33% in adults and from 6% to 19% in children [32]. Type 2 diabetes mellitus is the most significant cause of morbidity in obese patients; it is often referred to as “diabesity.” This metabolic syndrome is thought to occur by a progressive defect 400 Gastrointestinal Infections in insulin secretion coupled with a progressive rise in insulin resistance. Numerous mechanisms contribute to insulin sensitivity regulation throughout disparate tissue groups (skeletal muscles, fat, liver). Genomic strategies have now begun to highlight candidate single nucleotide polymorphisms (SNPs) responsible for insulin resistance through genome-wide association studies. However, the biocomplexity of the diabetes/obesity axis is significantly influenced by sociologic, cultural, and environmental factors not accounted for by the human genome. Although “infectobesity” arising from viral infection has been previously described in numerous animal models, there is increasing evidence that the intestinal microbiome is one of the most significant environmental factors associated with obesity and the metabolic syndrome. Conventionalized animals have 40% more body fat than germ-free animals and diet is known to modulate gut-microbial composition [33]. Bacteroides thetaiotaomicron, a dominant member of the normal distal intestinal microbiota, hydrolyzes otherwise indigestible dietary polysaccharides and supplies humans with 10% to 15% of their caloric requirement [34]. Lactobacillus species are responsible for a significant proportion of bile acid deconjugation, a process that efficiently reduces lipid absorption in the gut [35]. Mice that are genetically obese (ob/ob) have 50% fewer Bacteroidetes (and correspondingly more Firmicutes) than their lean (+/+) siblings [36•]. Other animal studies have confi rmed that gut microbiota in these ob/ob mice are more effective at releasing calories from food during digestion than are the +/+ microbiota. Most importantly, this trait is transmissible: colonization of germ-free mice with an “obese microbiota” results in a significantly greater increase in total body fat than colonization with a “lean microbiota”[37••]. Germ-free mice are protected against the obesity that develops after consuming a Westernstyle, high-fat, sugar-rich diet [38]. As in animal models, two groups of beneficial bacteria, the Bacteroidetes and the Firmicutes, are also dominant in the human gut. Ley et al. [39••] recently studied 12 obese patients randomized to either carbohydrate-restricted or fat-restricted diets and monitored them over the course of 1 year by sequencing 16S rRNA genes from stool samples. The relative proportion of Bacteroidetes was lower in obese people than in lean people, and this proportion increased with weight loss. Several mechanisms determine how the microbiome influences the host. Peroxisome proliferator-activated receptor (PPAR)- γ, an intranuclear receptor highly expressed in adipose tissue, is linked with insulin resistance. B. thetaiotaomicron attenuates proinflammatory cytokine expression by promoting nuclear export of the NF-κ B subunit RelA through a PPAR- γ –dependent pathway in Caco-2 cells exposed to Salmonella enteritidis [40]. The role of the microbiome has therefore been further investigated by metabonomic studies. In addition to the suppression of the inflammatory response and the regulation of fat storage by microbiota [41], a diet-induced mechanism of steatosis triggered by symbiotic microbiota has been described [42•]. Nonalcoholic fatty liver disease (NAFLD) was induced in mice given a high-fat diet. They demonstrated low plasma phosphatidylcholine concentrations and high levels of urinary methylamines as detected by 1H NMR. Methylamines are coprocessed by gut microbiota, resulting in the observed reduction of choline bioavailability and NAFLD. Hierarchical metabonomic clustering derived from 1H NMR plasma spectral data in a mouse model has also provided a phylometabonomic classification of strain-specific metabolic features and differential responses to a high-fat diet that closely match SNP-based phylogenetic relationships among strains [43]. The microbiome also influences the host obesity phenotype via the gut-brain axis. There is evidence that the intestinal flora or dietary components trigger the production of autoantibodies that cross-react with regulatory peptides via a mechanism of molecular mimicry [44]. Germ-free rats maintain relatively lower levels of IgA autoantibodies directed against hormones (eg, corticotropin-releasing hormone) because of the absence of intestinal antigens. However, in the presence of selected pathologic flora, the production of IgG autoantibodies directed against ghrelin is upregulated, suggesting a complex mechanism of interaction between microbial antigens and autoantibody levels. Peptide fragments identical to leptin were found in proteins belonging to Lactococcus lactis, Escherichia coli, Lactobacillus bacteriophage, Yarrowia lipolytica, and Candida and Aspergillus species. Sequence homology was also demonstrated in Lactobacilli and their phages, Bacteroides, and commensal strains of E. coli, which displayed molecular mimicry with leptin, insulin, ghrelin, and other hormones. It is therefore possible that under normal conditions, not a single regulatory peptide may escape this microbe-derived, immune-mediated control. Hypertension and cardiovascular risk The International Study of Macronutrients and Blood Pressure (INTERMAP) used a 1H NMR–based metabonomic approach to investigate differences in urine metabolic profiles across 17 large populations, with 4630 participants from China, Japan, the United Kingdom, and the United States [45]. It demonstrated that urinary metabolite excretion patterns for East Asian and Western population samples are significantly different, as are patterns for subgroups with differences in blood pressure and in dietary intake of vegetable/animal protein [46]. Increased levels of formate, a microbial co-metabolite, were significantly associated with higher blood pressure in multiple regression analyses, as were high alanine and low hippurate. The implication is that this technology can now be employed to study the metabolic perturbations effected by the microbiome that are associated with geographic variations commonly found in numerous diseases. The Human Gut Microbiome: Implications for Future Health Care Kinross et al. Future Implications of Research on Gut Microbiome Activity The concept of “bioecologic” control of the gut has recently been proposed as a novel method of improving human health [47 ]. This approach encompasses the use of “functional foods”—probiotics, prebiotics (nondigestible food ingredients that benefit the host by selectively stimulating the growth or activity of bacteria that can improve the host’s health), and synbiotics (a combination of both) [48]. There is now considerable evidence to support the efficacy of this approach, with numerous studies suggesting that functional foods improve outcome in IBS, IBD [49], and antibiotic-associated diarrhea in the critically ill. However, the mechanisms by which prebiotic bioecologic strategies exert their beneficial health effects remain largely unknown. Furthermore, considering the large variability in the human intestinal ecosystem, these approaches are unlikely to fulfill their potential until it is possible to determine the exact profile of an individual’s microbiome. Then specific biologic treatments can be tailored to an individual’s need. The result may be the development of novel therapeutic strategies for systemic conditions not typically associated with the gut, such as diabetes or cardiovascular disease. Patterns of gut microbiota, as well as specific bacterial species, that are associated with certain diseases will also constitute a new type of drug target [11•]. It is also feasible that intestinal flora will be used not only as a novel method of drug delivery but also as a bioreactor, using new cloning and biosynthetic expression strategies for the controlled secretion of biologically active molecules and vaccines. A new class of pharmaceutical compounds derived from previously uncultured commensal microorganisms in appropriate in vitro or animal models may be produced to develop long-term host immunotherapy for diseases such as IBD [11•]. Although animal studies are useful for indicating possible mechanisms of action, functional foods will be accepted in mainstream therapy only when a clear mechanistic link is established between microbiotal modulation and improvements in host health or biomarkers of disease risk. Animal gut flora may not accurately reflect human flora. However, encouraging first steps are being made through the development of a germ-free mouse model that is colonized with human baby flora [14], as well as germ-free piglets transfected with human flora, which demonstrate minimal individual variation and aging patterns similar to those observed in humans [50]. Conclusions Metagenomic and metabonomic approaches are beginning to provide us with a greater understanding of biologic function and the complex host-microfloral metabolic cross-talk of humans at a “superorganism” level. These tools permit in-depth and noninvasive analysis of intestinal ecology. The initial evidence provided by such 401 an approach suggests that the mammalian/microbiome symbiosis is vital to human health and fundamental to numerous pathologic processes. The notion that the intestine is instrumental in the development of many systemic conditions not previously associated with the gut implies that the role of the gastroenterologist is becoming increasingly important. These system-based approaches are also likely to underpin disease prevention strategies, personalized health care regimens, and the development of novel therapeutic approaches of the future. Acknowledgment James Kinross and Alexander von Roon are both funded by One-year Surgical Research Fellowships granted by the Royal College of Surgeons of England. Disclosures No potential conflicts of interest relevant to this article were reported. References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1. 2. Lederberg J: Infectious history. Science 2000, 288: 287–293. Dethlefsen L, McFall-Ngai M, Relman DA: An ecological and evolutionary perspective on human-microbe mutualism and disease. Nature 2007, 449:811– 818. 3.• Loscalzo J, Kohane I, Barabasi AL: Human disease classification in the postgenomic era: a complex systems approach to human pathobiology. Mol Syst Biol 2007, 3:124. This important paper addresses the variable phenotypic expression of human disease and the excessive reliance on Cartesian reductionism in establishing diagnoses. 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