From genomics to proteomics

An integrated pathway approach, i.e. investigating response at the level of both the genome and proteome, provide the opportunity to put genetic findings into biological context and give a more comprehensive picture of neuron function and pathology (Haab 2001; Gmuender 2002; Guzey et al. 2002). One obvious consideration for biomarker and proteomic research in psychiatry is access to relevant tissues, and whether information obtained from the most readily available tissues, namely blood or skin tissue samples, is relevant for what is happening in the brain. Further work may provide greater understanding to answer this latter question.

It has to be remembered, however, that there are more than 100,000 proteins in the human body and most, if not all, act on a variety of biological process. The proteomic approach is thus exposed to even greater complexity than genomics. Identifying proteins and their functions using genomic information, i.e. proteomics, presents the potential opportunity for more rapid identification of new biomarkers (Ledley 1999) that can in turn, act as a guide to find, evaluate, and support validation of genes and biomarker gene products for target diseases (Collburn 2003). This complimentary approach of genomics and proteomics in psychiatric genetics should also happen in pharmacogenetics.

The SSH (suppression subtractive hybridisation) technique, for example, has helped to identify new genes of interest, an important step before the identification of novel therapeutic targets. In this technique cDNA is generated from mRNA extracted from two types of tissues or cells, one tissue being collected from affected patients, and the other from healthy controls. For example, a group analysed genes induced by BRCA1 (an already known vulnerability gene in breast cancer) in order to find other potentially involved genes. The study thus compared control breast carcinoma cells (driver) with cells ectopically expressing BRCA1 (tester), and found that a new set of 30 genes might be involved in the risk of breast cancer (Atalay et al. 2002).

Other related techniques are also available that may have specific advantages for psychopharmacogenomics. These include differential hybridisation, subtraction cDNA libraries (Hedrick et al. 1984), mRNA differential display (Liang et al. 1992), serial analysis of gene expression (SAGE) (Velculescu et al. 1995) and microarrays for gene profiling (Schena et al. 1998).

Although these techniques are easier to apply for diseases with clear-cut lesions, such as ischemia following focal stroke (Wang et al. 2000), their potential interest and application in many psychiatric disorders is important now that large collections of brains from patients who have died are being made in different countries. These will provide samples for applying these techniques. Other developments in proteomics may be of considerable value in the development of new pharmaceutical targets through pharmacogenomics. Gene expression arrays are used to define the mechanism of action for new compounds, or to screen for direct influence of an agent on a specific pathway. Some new techniques may be specifically relevant for psychopharmacogenomics. For example, voxelation, using high-throughput analyses of spatially registered voxels harvested from the brain followed by three dimensions reconstruction, is performed before a Gene Expression Tomography (GET) which employs analyses of sets of parallel slices obtained from the brain by progressive rotation about multiple independent axes (Singh et al. 2003). Tomographic image reconstruction can then be employed for reconstructtion of gene expression patterns. This has been elegantly done for Alzheimer disease (Brown et al. 2002). Looking at the genes that are the most strongly differentially expressed between human brains from normal controls compared to patients with autism or schizophrenia, for example, could help to identify currently unknown genes. Such powerful techniques must, however, as for all scientific clinical research, be developed whilst paying close attention to the associated ethical, social and legal aspects.

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