The New Frontier Systems Biology

Systems biology focuses on the study of emergent properties, defined as important features of biologic systems that are often discerned only by examination of the system as a whole. Until recently, the study of the genetic component in the etiology of disease was limited to the study of single genes, their message, and/or its protein. The advent of high throughput methods made possible by both advances in data analysis and technology allows for the interrogation of entire genomes and their expression (i.e. the transcriptome, the proteome). Such systems-level approaches are being applied in ever-evolving and innovative ways, to the study of organisms, tissues, cells, and even organelles. Of particular interest is the growing focus on systems biology, where the findings from several lines of inquiry (e.g. a genome search and a gene expression analysis) are integrated to gain further insight into a biologic process, be it physiologic or pathophysiologic. A goal of this approach is to construct networks of genes, proteins, even metabolites, that act in concert to create a biological process. For an in-depth review, see Ref. 32.

Despite the challenges in the measurement of pain, the discovery of genes and gene variations involved in pain sensitivity is advancing. Clinical characteristics, population frequency, and methods of measurement for specific trait(s) continue to play important roles in the research design of studies of pain (Table 4.1). For example, an estimate of the heritability of pain sensitivity in humans was recently explored by studying a group of 51 mono-zygotic and 47 dizygotic female twins.33 Evidence for a genetic component for a range of painful stimuli (e.g. heat pain threshold, the pain rating during induction of a thermal burn) was observed with estimates ranging between 22 and 55 percent. Of note, not all phenotypic measurements of pain provided evidence of a genetic component. The area of skin flare following thermal burn induction did not have a significant genetic component. This finding indicates that careful assessment of the painful phenotype is critical for any genetic study.

A striking demonstration of the role of genetics in the control of human pain was demonstrated by Cox and colleagues.34 Three distinct mutations in the sodium channel N9A (SCN9A) gene that encodes the alpha subunit of the voltage-gates sodium channel (Nav1.7) result in a rare and complete inability to sense pain and exhibit an autosomal recessive pattern of inheritance.34 Nav1.7 is highly expressed in nociceptive neurons.

Of note, genetic modulation of pain is not limited to the nuclear genome. Several human diseases (e.g. cardi-omyopathy, neuropathy, deafness) are caused by mito-chondrial gene mutations. In addition, acquired deficiencies in mitochondrial function are thought to lead to some forms of neuropathy.

The elegant control of a gene's expression is also fertile ground for the characterization of the mechanisms that control pain. For example, the mu opioid receptor, the endogenous receptor for opioid drugs, has several functional splice variants in mammals.35,36 Of note, each splice variant displays a different affinity for exogenous opioid ligands (e.g. mu, kappa, delta opioids).

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