Abstract
“Omics” technologies are making inroads into all aspects of biology and medicine and the new textbook Surrogate Tissue Analysis: Genomic, Proteomic and Metabolomic Approaches captures many important features of the field. Surrogate tissue markers serve to alert the investigator to the condition of the body and have been around for many years. What has changed is the sophistication of the measurement and hence the insight that may be gained; the advent of omics tools promises to offer important advantages. The three principal areas in which new surrogate markers are being developed, i.e., genomic, proteomic, and metabolomic approaches, promise not only an understanding of normal and disease, but a means to understand the mechanisms responsible. Already the academic and pharmaceutical industry science community has grasped the importance this will bring to medical practice and this book very nicely summarizes the status of that effort.
The literature on each of the various “omic” approaches has expanded exponentially in the last 10 years as methods for analysis have improved. The publication of genomic sequences for the human and a variety of surrogate species used in biological research has fostered a penetrating search for common pathways and the availability of the improved analytical tools has led to many advances in understanding gene structure and control of expression, which is now at the center of surrogate marker analysis. Soon, measurement of a single constituent such as creatinine or a single enzyme such as alanine aminotransferase (ALT) will not provide sufficient power to identify the cause of disease or distinguish healthy conditions. The compilation of approaches summarized in this book offers to the reader an opportunity to sample the breadth of the field and see the power of multi–end point evaluation. The range of specific examples and the wide array of technical backgrounds of the authors of the various chapters reflect well the diversity that is involved in this expanding field.
Starting from a very careful analysis (Chapter 2) of sample handling for the use of blood in genomic analysis, the editors by choice of topics have covered many practical areas that influence success as well as the more scientifically advanced methods. The sections of the book (genomics, proteomics, and metabolomics) focus on blood as a source of surrogate markers to a large extent because this is typically an accessible biotissue. However, as appropriate, other sources of tissue that can inform (sperm, urine, cerebrospinal fluid, lipid compartments, nipple aspirate, etc.) that can be sampled are included. In short, this book represents a cross section of the kinds of exploration of biomarker development that is currently under very active investigation.
Gene expression analysis is the holy grail of the omics analysis and this potentially powerful tool was explored for the diagnosis of neurological and psychiatric disorders as well as its potential use in evaluating effectiveness of therapy. Clearly the use of neurological tissue for direct evaluation of biomarkers is not useful for a variety of practical as well as ethical reasons; however, accessible tissues such as blood could be developed as a tool for disease management and diagnosis as the authors correctly point out. Careful analysis of “normal” healthy volunteers and patients with a variety of disorders are described in this book. However, the difficulties of identifying novel biomarkers are well illustrated by the failure to identify a unique gene expression pattern differentiator in familial Tourette syndrome by the authors; a possible linkage (in a subgroup of patients) to genes related to immune function is intriguing. As they point out, larger studies involving more patients must be carried out and cross validation from genomic to more traditional methods of diagnosis will still be needed. Importantly, the authors suggest that more robust analysis will probably occur when blood cell subsets are analyzed an important point for thorough analysis with many of the omics approaches. Similar conclusions were noted in the chapter on use of genomic methods in cancer diagnosis and treatment.
Genomic approaches for monitoring toxic effects using the easily accessible blood biospecimens are gaining in popularity and scientific understanding. Dr. Rockett summarized data gathered in an effort to identify blood “fingerprints” of toxic insult using rodents. This is likely to be the most fertile use of these technologies in the short run because sampling of tissues and surrogates such as blood offer direct comparison that is really needed to formulate hypothesis of causation or mechanism. Blood markers are certainly an appealing surrogate for disease as well as therapy and the potential exists for revolutionizing toxicology. The author identifies several hurdles that are important to progress in the field, including the identification of sensitive indicators and the development and systematic updating of databases to keep track of what is coming out of the research. Both these later issues are pivotal for more widespread use of these techniques in toxicology.
Use of spermatozoal gene expression analysis to monitor paternal exposure to toxicants is covered. This area has added importance due to the documented drop in sperm counts and some suggestions that this phenomenon is due to environmental exposures. However, even though there is an interesting observation of a plethora of mRNA in sperm, there is only limited evidence that this tissue can act as a surrogate for exposures and hence much work remains to be done as the authors suggest.
Although a strong case can be made that change in the proteome is the true result of differences in gene expression, technical and practical difficulties in ascertainment have held back the field of proteomics. Part of the difficulty is that the proteome is the result of the cascade that occurs in disease and due to therapy. The series of chapters in the proteomic section of the book illustrate this issue very nicely. To a large extent, the view of the protein structure seen in accessible tissue samples, i.e., blood, nipple aspirate etc., is not static and much work remains to be done. Nevertheless, these authors have done a very nice job of summarizing some of the important hurdles still to be resolved in the quest for biomarkers of disease and therapeutic progress.
Metabolomic approaches are in a very exciting stage as well and are beginning to show progress in a number of important respects. Use of a diversity of tissues is producing great insight into the possible. The key strength of this methodology is that it applies powerful analytical tools to tissues and uses pattern recognition to distinguish effects that would otherwise go unrecognized. The methods described in this book range from blood to cerebrospinal fluid and others. The examination of lipid components as well as methylation pattern can be evaluated and lead to insight into the questions. This section of the book summarizes some interesting and nonmechanistically based evaluation tools.
The final section of the book on future considerations for the development and application of surrogate tissue profiling covers a very important part of the field. The acceptance of the methods covered in this book depends mightily on the resolution of a number of regulatory and practical hurdles. The use of surrogate markers in the clinical setting will require adequate proof that the disease and/or therapy under development is demonstrated in animal models, reflected in the human population and supported by sufficient data to be acceptable by regulatory agencies for example. The years since global gene expression analysis became practical have seen an expansion of the numbers of scientists taking advantage of the tools to investigate fairly narrow questions and thus importantly building the body of knowledge about gene use and expression. However, the rigorous incorporation of gene expression will require careful attention to many of the problems carefully laid out in this textbook. The logical place for existing techniques to receive maximum application is within the drug development process and indeed, we are seeing evidence of the utility of this kind of data being used for identification of mechanistic cause of disease and for following the progress of therapy. In pharmacogenomic study of disease and the use of the human subject has resulted in the recognition that collaboration serves useful purposes and some of this activity has been summarized in this book. Acceptance (in other than a safe harbor mode) of the findings is essential for more widespread use of the technology. Although there are cases of omics successes in identifying useful genes discovery science, the expectation both on the part of pharmaceutical development groups and the regulatory agencies is that more robust methods will appear. This book summarizes many interesting kinds of approaches and deserves careful scrutiny in that regard. Such issues as informed consent, chain of custody, and specimen traceability as well as the integrity of the process are carefully covered and offer significant guidance to those interested in designing and carrying out clinical trials with the goal of developing better therapies. To that end, in this section is included a list of potential standard operating procedures for use in a clinical pharmacogenomics laboratory setting that are particularly useful. Economic considerations are covered near the end of the book and deserve to be read carefully because the cost of carrying out these kinds of studies is quite substantial.
The penultimate chapter on the impact of these technologies is insightful and informative and offers perspective on the very real pressures to move the omics field out into mainstream medicine. This chapter summarizes the application of the techniques to several specific disease states and then broadens to provide both practical and regulatory guidance.
In summary, the editors and their coauthors have done a very creditable job of expressing the breadth of the field of surrogate tissue analysis and provide many concrete examples of techniques for analysis. The treatment of this arising technology is at once learned and practical with examples of success and of the need for further research. The chapters at the end with perspective setting essays on economic and regulatory needs may help some not accustomed to these issues to understand the issues. However, the lesson to take away from this text is the great possibilities that exist to sharpen our view of biology and of medicine in particular. Future progress will involve refinement of the methods describe here. There are methods that will not stand the test of time but taken as a whole, this book should be widely read. Every chapter has extensive bibliographic references and should serve as entrée into the literature even if the specific examples are of only passing interest. The editors and their coauthors are to be commended in providing a very thorough and interesting sampling of the methods being developed in the field.