Advances in the “Omics” for Diagnosis, Pathogenesis, and Therapeutic Development

The advent of the data-intense “omic” techniques has brought wonderful new techniques and insights into biomedical science but has raised questions regarding the use and role of these technologies. The proper balance between exploratory and directed studies in science is a difficult and old subject, harkening back the formation of the scientific method in which the observation step is critical, but in which we are also instructed to observe in order to test a specific hypothesis. However, the “omic” revolution has now allowed the determination of a large amount of data with often near-similar ease as measuring one or several analytes that by themselves could address the question at hand. So the order of events, hypothesis, experimental model, data gathering and analysis, followed by successive cycles, has for some been upended in a sense in that large amounts of data can be obtained and themselves used to form the hypotheses and model construction for experimental testing. The challenge of the “omics” relies on synthesizing the old and the new. While hypotheses can be generated out of the large amount of data already existing, gathering more data to see what is out there is an endless and unproductive strategy. How to use “omics” to examine the hypothesis in question while keeping an open mind toward integrating the other information is obtained can be key to new insights. However, recognizing the value of the unexpected can be difficult both within the context of focusing on the question at hand and within the realm of exceedingly large amounts of information. The “omics” have the capability to define the limits, but even if every gene, protein, and metabolite was analyzed, being able to put these in context of a model with a testable hypothesis remains the challenge. The collection of articles in the “omics” section of this issue illustrates the analytical and scientific power of these technologies. Transcriptomics of coding and non-coding RNA, proteomics using directed and untargeted strategies, and recent advances in metabolomics including their clinical applications combine to yield a bevy of topical information for neuroscience, pharmacology, and biomedical science in general. The first three papers cover the exciting, growing field of metabolomics. The measurement of metabolites certainly precedes the “omics” and is fundamental in everything from basic biochemistry to standard tests in clinical medicine. Nordstrom and Lewensohn (2010) describe this well in the lead review on the translation of metabolomics findings to the clinic. The development of biomarkers to predict and track the development of a disease and determine prognosis and response to therapy is invaluable. Furthermore, biomarkers have great utility in studies of disease pathogenesis and can significantly facilitate drug development in terms of drug targets and beneficial and adverse effects of candidate therapeutics. The analytic challenges in metabolomics are not trivial, and the successes, challenges, and future promise of metabolomics are well described in this article. While the genome has been sequenced and proteins identified and predicted, one of the distinct challenges in metabolomics is the identification of the putative metabolites found in experimentation as the great degree of chemical diversity of metabolites dwarfs those in other fields. Fortunately, significant effort is being put into the development of comprehensive metabolite databases, and Eden Go provides a wonderful current review of these will be of great use to current researchers as well as those entering this growing field (Go 2010). Next, Sugiura and Setou (2010) provide a review on an exciting application of metabolomics, the ability to image metabolites within tissue sections. While there are many potential uses for this technological advancement, drug discovery is highlighted here. The ability to image and localize the drug and its metabolites, as well as endogenous metabolites, allows the simultaneous evaluation of drug delivery to target organs, its metabolic alterations, and the resulting metabolic changes in the host. Techniques, pitfalls, challenges, and successes are well illustrated in this article. Recognition of the power of the “omics” became widespread with the availability of gene expression profiling of transcripts. Three papers cover aspects of transcriptomics, all with a focus on central nervous system (CNS) diseases. Borjabad et al. (2010) first review transcriptomics and then focus on studies on the effects of HIV on the CNS. This has been a complex and challenging field as HIV does not infect neurons in the brain; rather, the primary target of the virus is cells of the myeloid lineage (macrophages and microglia). Thus, neurons are damaged through indirect effects. They then present new data on astrocytes, the most abundant cell type in the brain, and the effects of their exposure to HIV or its component proteins. Correlating these data with that of others reveals new insights into the participation of astrocytes in the untoward effects of HIV on the brain. While the ability to perform expression profiling of mRNA has generated a great deal of excitement and led to an immense amount of data, the recognition that non-coding RNA can play a major role in biology and disease has led to a more recent growth in methods and findings on these transcripts. This is reviewed in the article by Yelamanchili and Fox (2010) who focus on microRNAs, small regulatory RNAs that control the levels and translation of the coding mRNAs. The molecular biology of microRNAs and techniques for their measurement are first described, followed by review of studies showing their role in the nervous system and neurodegenerative diseases. Challenges in the field, and special challenges as they relate to the brain, are emphasized and help provide a road map for these studies and their potential translatability. The next paper then transitions into proteomics, revealing the strength in combining information gathered from different “omic” technologies. Scott Hemby (2010) reviews a quite difficult problem, discerning the effects of drug abuse on the brain. The focus here is on cocaine, with studies reviewed pointing out that it is important not only to appreciate the effects of drugs on the brain but also to obtain insight into harmful addictions and the molecular mechanisms that underlie these and thus lead to means to treat addiction This paper examines the realm of experimentation including transcriptomics and proteomics, covering studies from rodents to humans. In doing this, insights as to our current knowledge and important issues are raised. This article provides not only a synthesis of information on the effects of cocaine but also useful lessons for approaches to other neurological and neurodegenerative disorders. The final two papers cover proteomics, each with a different targeting strategy. Achur et al. (2010) provide a review of a second additive disorder, alcoholism, and here cover possible blood-derived protein biomarkers. As alterations in inflammatory responses have been documented in alcoholism, their focus is on the cytokine system. The utility of biomarkers for alcoholism, the rationale for targeting cytokines, and their pathophysiological importance are emphasized in this article. Finally, Gelman and Nguyen (2010) present exciting new primary data in a research article, and HIV and the brain is again the focus. While an untargeted approach was taken to the proteins in order to enrich the starting sample to functionally important areas, synaptosomes (a subcellular fraction of nerve terminals and the synaptic region) were isolated from human brain postmortem specimens. Interesting and potentially functionally important alterations were found in synaptic proteins. Furthermore, changes in the proteasomal proteins were found. As protein turnover and clearance of abnormal proteins is exceedingly important in neurons and disruption of this process is linked to a number of neurodegenerative disorders, these findings raise important insights into how HIV can affect neurons in the brain while not infecting them. In summary, these papers provide not only a snapshot of current capabilities in the “omics” but also topical information for those using or considering using similar technologies. The ability of “omics” to yield important information not obtainable by more traditional means is illustrated, and the natural flow, in addressing the hypothesis at hand while leading to new exciting hypotheses to be tested, reveals how the promise of the “omics” is being met.