A critical review of the Royal Society's report on personalized medicine.
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Biomedical subjects
Publications and source records attributed to Kewal K Jain.
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The application of nanotechnology in life sciences, nanobiotechnology, is already having an impact on diagnostics and drug delivery. Now, researchers are starting to use nanotechnology in the field of drug discovery. This review explains how several technologies, including nanoparticles and nanodevices such as nanobiosensors and nanobiochips, are used to improve drug discovery and development. Nanoscale assays can contribute significantly to cost-saving in screening campaigns. In addition, some nanosubstances (such as fullerenes) could be potential drugs for the future. Although there might be some safety concerns with respect to the in vivo use of nanoparticles, studies are in place to determine the nature and extent of adverse events. Future prospects for the application of nanotechnology in healthcare and for the development of personalized medicine appear to be excellent.
Nanotechnology-the creation and utilization of materials, devices, and systems through the control of matter on the nanometer-has been applied to molecular diagnostics. This article reviews nanobiotechnologies that are clinically relevant and have the potential to be incorporated in clinical laboratory diagnosis. Nanotechnologies enable the diagnosis at single cell and molecule level and some of these can be incorporated in the current molecular diagnostics such as biochips. Nanoparticles, such as gold nanoparticles and quantum dots, are the most widely used but various other nanotechnologies for manipulation at nanoscale as well as nanobiosensors are reviewed. These technologies will extend the limits of current molecular diagnostics and enable point-of-care diagnosis as well as the development of personalized medicine. Although the potential diagnostic applications are unlimited, most important current applications are foreseen in the areas of biomarker research, cancer diagnosis and detection of infectious microorganisms.
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Pharmacogenetics has assumed increasing importance with the developing concepts of personalized medicine. There is a need to determine the metabolic status of an individual when using drugs, the actions of which are influenced by drug-metabolizing enzymes. Cytochrome P450 (CYP) and its variants, particularly CYP2D6 and CYP2C19, play a role in the metabolism of approximately 25% of all prescription drugs. This review covers the role of the CYP system not only in the metabolism of drugs but also in the pathophysiology of disease. Various technologies for the assessment of CYP status are described, with the focus on AmpliChip CYP450 (Roche Molecular Diagnostics, Alameda, CA, USA), the first approved microarray molecular diagnostic test for the analysis of 29 polymorphisms and mutations of the CYP2D6 gene, and two polymorphisms of the CYP2C19 gene. It combines Roche's PCR technology with the GeneChip microarray system (Affymetrix, Santa Clara, CA, USA). Examples of numerous drugs that are metabolized by the CYP system are listed, and categories of antidepressants, antipsychotics, immunosuppressive and anticancer drugs are described to illustrate the role of testing for CYP polymorphisms in the therapeutic use of these drugs. CYP testing has applications in toxicology and absorption, distribution, metabolism and excretion (ADME) profiling as a guide to drug development. AmpliChip CYP450 may be used in conjunction with pharmacotherapy to guide decision making about selection of drugs and dosage. The test is not a solitary tool to determine optimum drug dosage, but is meant for use along with clinical evaluation and other methods for the selection of the treatment that is best suited for an individual patient. AmpliChip CYP450 is the first DNA microarray test to be cleared by the US FDA, and its clearance paves the way for similar microarray-based diagnostic tests to be developed in the future. This will facilitate the development of personalized medicine.
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Oncoproteomics is the term used to describe the application of proteomic technologies in oncology and parallels the related field of oncogenomics. It is now contributing to the development of personalized management of cancer. Proteomic technologies are used for the identification of biomarkers in cancer, which will facilitate the integration of diagnosis and therapy of cancer. Molecular diagnostics, laser capture microdissection and protein biochips are among the technologies that are having an important impact on oncoproteomics. The discovery of protein patterns developed by the US Food and Drug Administration/National Cancer Institute Clinical Proteomics Program is capable of distinguishing cancer and disease-free states with high sensitivity and specificity and will also facilitate the development of personalized therapy of cancer. Examples of application are given for breast and prostate cancer and a selection of companies and their collaborations that are developing application of proteomics to personalized treatment of cancer are discussed. Continued refinement of techniques and methods to determine the abundance and status of proteins in vivo holds great promise for the future study of normal cells and the pathology of associated neoplasms. Personalized cancer therapy is expected to be in the clinic by the end of the first decade of the 21st century.
The analgesic properties of nicotine have prompted attempts to develop compounds that specifically target nicotinic acetylcholine receptors (nAChRs) in the nervous system, with the beneficial effects of nicotine but without its side effects. Thus far, only nAChR agonists have been reported as being in development for pain, although nAChR antagonists could also have a potentially analgesic action. Various problems associated with the use of nAChR agonists as analgesics have been identified and measures suggested to overcome some of them. This review describes the nAChR agonists A-85380, tebanicline, ABT-366833, ABT-202, ABT-894, epibatidine analogs and SIB-1663, of which ABT-366833, ABT-202 and ABT-894 are currently undergoing development as pain therapeutics. In vivo studies of the pathomechanism of neuropathic pain indicate that targeting alpha3beta4 does not have a specific action on neuropathic pain, and that alpha3beta4 ligands cause side effects. On the other hand, alpha4beta2 receptors are specific for neuropathic pain, and ligands that bind preferentially to these receptors both effectively relieve pain and do not cause many adverse effects. This is the basis of the difference between the action of tebanicline, which binds with greater specificity to alpha3beta4 receptors, and ABT-366833, which binds more specifically to alpha4beta2 receptors.
This review examines the role of advances in biochip and microarray technologies in the development of personalized medicine. Biochips (eg, GeneChip, CYP450, electrochemical biochips, protein biochips, microfluidic biochips and nanotechnology-based biochips) are assuming an important role in molecular diagnostics, and their application in point-of-care diagnosis is expected to facilitate the development of personalized medicine. Gene expression profiling by microarrays should advance the progress of personalized cancer treatment based on the molecular classification of subtypes. Refinements in biochip miniaturization with the advent of nanotechnology will further contribute to molecular diagnostics and the development of personalized medicine.
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The IIR Life Sciences conference on stem cell technologies in regenerative medicine was held in London, UK on 11 - 12 July 2002. The conference covered not only technologies but also ethical/regulatory and financial aspects of embryonic stem (ES) cell therapy. An excellent introduction to embryonic stem cells was given by Prof. William Kridel (Ferghana Partners, London, UK). Details of basic technologies are not described as they are covered in a detailed report on cell therapy [1]. Due to limitation of space only a selected few of the seventeen presentations are reported here.
Ethical and regulatory issues concerning embryonic stem (ES) cell research are reviewed here a year after the controversy became a public and political issue in the US. The background of various issues are examined and the current regulations in various countries are reviewed. In the US, the debate is linked with abortion, as well as the status of a fetus as a human being, and is politically driven. Obtaining stem cells from embryonic tissues involves destruction of the embryo, to which objections are raised. Religious beliefs are examined and no serious impediments to ES cell research could be identified. Regulations vary from one country to another and it is unlikely that there will ever be any universally uniform ethical and regulatory standards for ES cell research. Currently, the most liberal and favourable environments for ES cell research are in the UK, Singapore, Sweden, India, Israel and China. Unless the US liberalises ES cell research, it may lose its lead in ES cell research and investments in this area may drift to countries with better environments for research. Suggestions are offered in this review to improve the ethical environment for ES cell research.
Advances in proteomics are contributing to the understanding of pathophysiology of cancer, cancer diagnosis and anticancer drug discovery. Laser capture microdissection (LCM) provides an ideal method for extraction of cells from specimens in which the exact morphologies of both the captured cells and the surrounding tissue are preserved. Differentially expressed proteins in tumor tissue are found by comparing the protein expression patterns generated using SELDI (surface-enhanced laser desorption/ionization)-based protein chip technology. Proteomic technologies have been used for the study of cancer of various organs. Continued refinement of techniques and methods to determine the abundance and status of proteins in vivo holds great promise for future study of cancer and development of personalized cancer therapies.
Personalized medicine simply means the prescription of specific therapeutics best suited for an individual based on pharmacogenetic and pharmacogenomic information. The basis of personalized medicine are reviewed. Several technologies are used including single nucleotide polymorphism genotyping. haplotyping, gene expression studies by biochip/microarrays and proteomics. Molecular diagnostics will play an important role in the development of personalized medicine, in which therapy and diagnosis will be integrated. There are several examples of the personalized medical approach, which include genotype-based selection of patients for effective cancer therapy, to spare those who would not respond or would suffer undesirable side effects. Personalized therapy is financially feasible, as it will reduce the costs of drug development by shortening the drug development cycle. The introduction of pharmacogenomics into clinical trials is reducing the chances of failed clinical trials and increasing the prospects of safer and more effective therapies for specific groups of patients. Several advantages, as well as challenges to the development of personalized medicine are examined. Personalized medicine is anticipated to be an acceptable part of medical practice by the year 2010.