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Overviews: Genomics & proteomics for Drug discovery & development and Molecular Medicine 
Mary Chitty 781 972 5416
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Definitions, overviews and introductions   Biotechnology   Genomics   Proteomics   Functional genomics  Chemical genomics   Drug Discovery & Development Pharmacogenomics   Toxicogenomics      Molecular Medicine

Information Resources   Genomics   Proteomics    Combichem & chemogenomics   Technologies       Bioinformatics    Cheminformatics   Drug discovery & development   Molecular Medicine   Business 

Words and phrases in bold are [or can be] defined in the text. 

Like the web, in the short run, genomics and bioinformatics have been overhyped and subject to unrealistic expectations. But in the long run both are bringing about truly profound changes,  within the pharmaceutical industry, increasingly, to individual patients and health professionals and spillover into agriculture, food, the environment and other sectors. Progress is a mix of incremental improvements, and truly new paradigms. 

Scalability and ramping up for high throughput and automation remain challenging. It is clear that identifying genes and sequence  is not synonymous with interpretation and understanding of gene functions. Learning how to use biological insights to alter human physiology at the molecular and biochemical levels requires integrating biology,  chemistry and informatics.  

Scope: These sections focus on the use of genomics and proteomics in drug discovery and development, on current and potential uses in pre- clinical, and clinical trials, and research use in patients, and the quickly growing, but still evolving role of  molecular medicine.   Biopharmaceutical manufacturing is not a major focus, but the efforts involved in ramping up to higher throughput and scaling in going from the lab into clinical use are not inconsequential.  

Biotechnology started as a means for producing biopharmaceuticals.  It has only recently become an integral part of the drug discovery and development process. Use of genomics and proteomics is still primarily at the earliest stages of the drug discovery pipeline.

"Biotechnology" is not an industrial sector, but rather a set of methods useful in many industrial sectors (usually established ones such as drugs and biologics, devices, or agriculture), but also for some entirely new applications (e.g., DNA forensics). Many firms, almost 1500 listed by the various online services, are called "biotechnology" firms because they are largely built around technologies developed since 1980. These firms are generally competing in established markets, however, even when they compete by using novel products, services, and technical approaches. Robert Cooke- Deegan et. al., World Survey of Funding for Genomics Research: Final Report to the Global Forum for Health Research and the World Health Organization,  September 2000 

That the biotechnological innovations of the 1970’s took until the 1990’s to integrate into big pharma is outlined in "The Pharmaceutical Industry and the Revolution in Molecular Biology: Exploring the Interactions between Scientific, Institutional and Organizational Change, Iain M. Cockburn, Rebecca Henderson, Scott Stern, 1999.

More definitions of the "biotechnology industry" 

Information resources  Business

Genomics definitions
Generation of information about living things by systematic approaches that can be performed on an industrial scale. Roger Brent "Genomic biology" Cell 100: 169-183 Jan 2, 2000 

The systematic study of the complete DNA sequences (GENOME) of organisms. MeSH, 2001

More terminology Genomics  

How does genomics differ from genetics?
Genetics looks at single genes, one at a time, as a snapshot. Genomics is trying to look at all the genes as a dynamic system, over time, to determine how they interact and influence biological pathways, networks and physiology, in a much more global sense. A dynamic process, 2D vs. 3D and 4D.

Genomics overviews and introductions
AMA, Human Genome

Access Excellence, National Health Museum, US Provides high school biology and life science teachers access to their colleagues, scientists, and critical sources of new scientific information. Originally developed and launched by Genentech Inc. 

Bringing the Genome to You, NHGRI, April 2003  Webcast of celebration of the 50th anniversary of DNA and the double helix. 

Cold Spring Harbor, DNA Learning Center, A clearinghouse for information on DNA science, genetic medicine, and biotechnology, to provide an interactive learning environment for students, teachers, and nonscientists, extending the Laboratory's traditional research and postgraduate education mission to the college, precollege, and public levels

DOE Dept. of Energy, Genomes to Life,
Genomics and Its Impact on Science and Society: The Human Genome Project and Beyond, Human Genome Program, DOE  Glossary, Includes impact on medicine 

EBI European Bioinformatics Institute, UK Quick introduction to elements of biology – cells, molecules, genes, functional genomics, microarrays, Alvis Brazma, Helen Parkinson, Thomas Schlitt, Mohammadreza Shojatalab, EMBL-EBI, European Bioinformatics Institute, Oct. 2001 Intended for scientists, engineers, computer programmers, or anybody with background or strong interest in science, but without background in biology ... we have tried to distil the content down to the absolute minimum needed to make some sense of bioinformatics, while on the other to leave in enough to show why it is interesting

 NHGRI, National DNA Day April 25, 2003 teaching tools

NCBI, NLM, NIH: Science Primer Bioinformatics, genome mapping, molecular modeling, SNPs, ESTs, microarray technology, molecular genetics, pharmacogenomics, phylogenetics

A User's guide to the Human Genome, Nature Genetics, 32 (1): supp 2002 

more genomic overviews  See also Human genome websites

Functional genomics

The development and application of global (genome- wide or system- wide) experimental approaches to assess gene function by making use of the information and reagents provided by structural genomics [in the original more limited sense of construction of high- resolution genetic, physical and transcript maps of an organism]. It is characterized by high throughput or large- scale experimental methodologies combined with statistical and computational analysis of the results. The fundamental strategy is to expand the scope of biological investigation from studying single genes or proteins to studying all genes or proteins at once in a systematic fashion. Phil Hieter and Mark Boguski "Functional Genomics: It's All How You Read It" Science 278: 601- 602, October 24, 1997

Functional genomics' insights can be biochemical, genetic, metabolic and or physiological. Comparative genomics is the practice of uncovering the functions of human genes and other DNA regions by studying their parallels in nonhumans. 

But even defining "function" is problematic. 

"The vagueness of the term 'function' when applied to genes or proteins emerged as a particular problem, as this term is colloquially used to describe biochemical activities, biological goals and cellular structure. Gene Ontology Consortium "Gene Ontology: tool for the unification of biology Nature Genetics 25: 25-29 May 2000 

Genomics by itself cannot usually determine even the biochemical, much less the cellular or physiological functions of a protein. Structural biology can determine the shape of the protein but cannot reliably determine its function; the coupling between overall structure and function is a loose one. Given a structure, one cannot determine where on the surface of a protein the likely binding sites for ligands are located and what those ligands are likely to be. Genomewide experiments have many false positives and false negatives and often do not distinguish indirect effects from direct ones. The consequences of the expression of a given gene sequence can only be determined by integrating the results from many different types of experiments, and the best way to carry out this integration is not obvious. "From Sequence to Consequence: The Problem of Determining the Functions of Gene Products in the Age of Genomics" Dr. Gregory A. Petsko, Brandeis Univ. Cambridge Healthtech Chemogenomics/ Chemical Genomics conference, Nov. 18- 19, 2002, Boston MA

As the pressure mounts to produce validated targets and reduce late- stage attrition, functional analysis and characterization of drug targets and disease pathways is becoming key in pharmaceutical research. Understanding the role of specific genes in disease requires a highly parallelized and multidisciplinary approach. Armed with more- powerful, higher- throughput tools for gene knock- out/ knock- down, protein characterization,  metabolic profiling, high- content screening, and data management, researchers are now in a position to acquire and integrate genomic, proteomic, metabolite, phenotype, and clinical data to provide a systems- wide view of biological function and disease pathways/ mechanisms.

Comparative genomics
"We believe that the problem of the genome- phenotype connection, which, in a sense, is the central theme of biology, can be solved only through an experimental program strategically planned on the basis of comparative- genomic results. Much of the biological research of the next few decades is likely to develop along these lines. E. Koonin et al "The Impact of Comparative Genomics on our Understanding of Evolution" Cell 101:573-576 June 9, 2000 

A useful way to tackle noise and complexity of functional genomics information is to average the data from many different genes into broad 'omic categories (Jansen & Gerstein 2000. For instance, instead of looking at how the level of expression of an individual gene changes over a time- course, we can average all the genes in a functional category (e.g. glycolysis) together. This gives a more robust answer about the degree to which a functional system changes over the time- course. Dov Greenbaum, Mark Gerstein et. al. "Interrelating Different Types of  Genomic Data" Dept. of Biochemistry and Molecular Biology, Yale Univ. 2001

Information resources Genomics   


The most useful definition of proteomics is likely to be the broadest: proteomics represents the effort to establish the identities, quantities, structures and biochemical and cellular functions of all proteins in an organism, organ, or organelle, and how these properties vary in space, time and physiological state. .. A much broader field than would be apparent from early efforts, which have focused on cataloging levels of protein expression. Ideally it should encompass efforts to obtain complete functional descriptions for the gene products in a cell or organism. Defining the Mandate of Proteomics in the Post- Genomics Era, National Academy of Sciences, 2002

The analysis of complete complements of proteins. Proteomics includes not only the identification and quantification of proteins, but also the determination of their localization, modifications, interactions, activities, and, ultimately, their function. Initially encompassing just two- dimensional (2D) gel electrophoresis for protein separation and identification, proteomics now refers to any procedure that characterizes large sets of proteins. The explosive growth of this field is driven by multiple forces - genomics and its revelation of more and more new proteins; powerful protein technologies, such as newly developed mass spectrometry approaches, global [yeast] two- hybrid techniques, and spin-offs from DNA arrays; and innovative computational tools and methods to process, analyze, and interpret prodigious amounts of data. Stanley Fields "Proteomics in Genomeland" Science 291: 1221-1224 Feb. 16, 2001 

The systematic study of the complete complement of proteins (PROTEOME) of organisms.  MeSH 2003

A subset of genomics in a sense, but also much broader in that the function(s) of proteins change over time and in different cells and tissues. [temporal spatial localization]

The Central Dogma (DNA makes RNA makes protein(s) is still essentially valid -- except that given the unexpected prevalence of alternative splicing and our still fragmentary knowledge of post- translational modifications it is clear that DNA and RNA (singular) makes proteins (plural) and that these proteins may have multiple functions, at various times during the cell cycle and in different cellular locations.  We still have a lot to learn.

Genes are important, but proteins are what do most of the work.  Even so-called "junk DNA" seems to have important regulatory functions. 

More terminology  Proteomics

Proteomics overviews & introductions
American Medical Association, Proteomics 

ExPASy, Human Proteomics  

VIB, the Flanders Interuniversity Institute for Biotechnology Research, Proteomics Core Facility

Harvard Extension School, Introduction to Proteomics,  2004 

Information resources Proteomics

While genomics and proteomics are clearly part of the same continuum (DNA makes RNA makes protein(s)) they are two different cultures divided by instrumentation.  

Biotech Technologies overviews & introductions
BIO, Biotechnology tools in Research and Development
BIO Biotechnology: A Collection of Technologies

Industry Canada, Life Sciences Gateway 

National Research Council, Canada, Biotechnology

Genomics has flourished with PCR and automated sequencing.  Proteomics uses a variety of technologies.  Established  technologies such as mass spectrometry and NMR are more relevant to biology than ever before.  

PCR Terminology   PCR information resources

Proteomics technologies
For a field so laden with razzmatazz methods, it is striking that the number one need in proteomics may be new technology. There are simply not enough assays that are sufficiently streamlined to allow the automation necessary to perform them on a genome's worth of proteins. Those currently available barely scratch the surface of the thousands of specialized analyses biologists use every day on their favorite proteins. What we need are experimental strategies that could be termed cell biological genomics, biophysical genomics, physiological genomics, and so on, to provide clues to function. In addition, a protein contains so many types of information that each of its properties needs to be assayed on a proteome- wide scale, ideally in a quantitative manner. Stanley Fields "Proteomics in Genomeland" Science 291: 1221-1224 Feb. 16, 2001

Technologies information resources

Roger Brent compares microarrays, a technology still in its infancy  to the microscope and telescope because they "enable observation of the previous unobservable" [transcripts expressed under different conditions in cells, tissues, and organisms] Roger Brent, "Functional genomics: learning to think about gene expression data" Current Biology 9: R338-R341, May 1999.   

Microarrays, with RNA begin to bridge the chasm between DNA and protein research.

Microarrays definitions   A microscopic, ordered array of nucleic acids, proteins, small molecules, cells or other substances that enables parallel analysis of complex biochemical samples. Mark Schena et al. "Quantitative monitoring of gene expression patterns with a complementary DNA microarray" Science 270, 467-470 Oct. 20 1995

The term microarray originally referred to spotted cDNA arrays, but now we and others use it for any hybridization- based array. When the term microarray was first introduced, the prefix micro served to distinguish this new generation of arrays from their predecessors, which came to be called macroarrays. Traditionally, microarrays differ from macroarrays based on the physical size of the surface and the spots.

Numerous types of microarrays are in common use today, but they can be categorized into three main groups: spotted cDNA microarrays, spotted oligonucleotide microarrays, and Affymetrix GeneChips, which are sufficiently unique to warrant their own grouping. In the spotted- array categories, are both traditional arrays produced using contact printing in the style of Pat Brown (Stanford University), and ones produced using the newer ink- jet technology pioneered in the laboratory of  Lee Hood of the University of Washington and developed to commercial fruition by Rosetta Inpharmatics and Agilent Technologies.

Also known as DNA chips, GeneChip TM is an Affymetrix trademark.

Microarrays will be regulated by the FDA as a medical device, but are being used now in clinical oncology research. Analyte specific reagents comes into this too somehow.

Protein arrays Definitions  
Can consist of proteins themselves (e.g., for studies of protein/ protein interactions or protein/ small- molecule binding) or of probes (often antibodies) for capturing proteins so that protein levels in a sample can be gauged.  Ciphergen has trademarked ProteinChip™.  Also called protein microarrays, antibody arrays, etc.

Microarrays Overviews & introductions 
NCBI, Microarrays

Stanford University, Pat Brown's Lab HomePage, Dept of Biochemistry,   

Microarrays information resources

Combichem &  chemogenomics
Combinatorial chemistry
Using a combinatorial process to prepare sets of  compounds from sets of  building blocks. IUPAC Combinatorial Chemistry  

In the early 1990's it was believed that combinatorial chemistry would revolutionize the drug discovery industry. Ten years later the route from design and synthesis of compound libraries to identification of lead structures is still long and costly. Synthesis of an almost unlimited number of organic compounds covering as much of chemistry space as possible is no longer the most cost effective and time saving approach to hit identification. Creating libraries, using biological target structure to inform chemical design, facilitated by quantum advances in structural genomics and computational capabilities, is a smarter, more efficient way to produce good initial leads. Considering solubility, permeability and other drug- like properties early in library design and introducing both target and lead structural constraints in lead development are further ways to ensure more compounds make it to trial.  

Note that there is not enough matter in the universe to prepare all possible combinatorial variations

Chemical genomics

Uses libraries of small molecules (natural compounds, aptamers or the products of combinatorial chemistry) and high throughput screening to advance understanding  of biological pathways and to identify compounds that act as positive or negative regulators of individual gene products, pathways or cellular phenotypes. Francis C. Collins, Eric. D. Green et. al, A Vision for the Future of Genomics Research, Nature (6934): 835- 847 April  24, 2003 

Google =
"chemical genomics about 3,920 Dec. 11, 2003; about 62,500 Oct. 14, 2005
chemogenomics  about 2,170 Dec. 11, 2003, about  35,100 Oct. 14, 2005
"chemical genetics" about 3,840 Dec 11, 2003, about 55,200 Oct. 14, 2005

More on defining chemical genomics

Information resources Combichem & chemogenomics

Cheminformatics   Definitions and overviews  Information Resources

Drug Discovery and Development
New ways (both automated and human) of dealing with the tidal waves of multi- disciplinary structured and unstructured data, integrating this data into drug discovery, in response to the target glut are needed. Pharmaceutical Research & Development needs to focus on target validation and moving better candidates more quickly into pre-clinical and clinical development. Leveraging existing knowledge (text mining and other knowledge extraction techniques) may offer hope for real competitive advantages – but pushes the envelope on existing computational techniques and the interpersonal and soft people skills needed to forge strategic partnerships and cross- departmental alliances.

Linear handoffs along the pipeline need to be replaced by parallel processing and more integration. The proprietary cultures of industry are slowly evolving (at varying rates and degrees of success) into ones which encourage (and reward) information sharing.

A fair amount of today’s biopharmaceutical R&D is still at the pre- competitive stage.  But reaching agreement on what pre- competitive really means (and agreeing on how best to protect future intellectual property rights) is challenging, and much remains to be tested in the courtroom.

Big Pharmas cannot continue to spend more and more on R&D to bring fewer truly new drugs into use. Biotechnology and biopharmaceutical companies cannot survive indefinitely without bringing products to market. 

Capitalizing on genomics, Phillips Kuhl, CHI Insights, 

Target validation
While genomics has yielded a wealth of potential new targets, for the vast majority of them very little is known about their function, role in cellular pathways, or connection to disease. Target validation thus becomes the central issue in the success or failure of large- scale drug discovery. With steadily growing drug development costs, depleted pipelines, and no prospective blockbusters on the horizon, many companies are relying on novel targets to reach or maintain profitability. Researchers must find the means to choose the best among these drug targets early in the process to reduce costly attrition rates, underscoring the urgent need for target validation technologies that will allow for more efficient drug discovery and development.

Lead optimization
Pharmaceutical companies are eager to assuage the innovation deficit by using new approaches to drug discovery and development. Performing lead optimization earlier, and paralleling lead optimization and target validation, are two key goals. In vitro metabolic screens have a key role to play in early attrition.  Assays to reveal drugs that act by many pathways, as well as drug -drug interactions, are gaining in popularity.  Toxicity prediction is an especially complex problem, and getting intense attention.

The emerging drug discovery paradigm emphasizes in vitro and in silico [virtual screening] methods to predict in vivo ADMET (administration/ dosage/ metabolism/ excretion/ toxicity parameters.  These methods are being applied as early as possible to enable early attrition of compounds that will eventually fail. 

Systems biology is helping researchers to know more about drug mechanisms and life sciences informatics is pushing the envelope in computing.  Demand for new algorithms, new methods of organizing and interpreting data, new computing platforms (such as grid computing) and new business models promise both opportunities -- and pitfalls -- for many. More on systems biology

Clinical genomics
The linkage of clinical medical information to molecular information represents one of the primary challenges for bioinformatics in the next century. As the genome sequencing projects mature and complete, we will have the genetic DNA sequences of both humans and a host of human pathogens, and informatics tools will be necessary to deliver this information in appropriate ways to medical decision makers. This information will impact decisions about diagnosis, prognosis, treatment and epidemiology. ... [these] data sources are extremely valuable independently, but may contain valuable information when properly combined. This becomes the challenge of what some have termed "clinical genomics" or the marriage of clinical investigation with genomic science. Russ Altman "Bioinformatics in support of molecular medicine" American Medical Informatics Association Symposium 1998

Clinical proteomics
Clinical proteomics aims to discovery proteins with medical relevance said Alan Sachs, a director of R&D at Merck. Such discoveries can be defined broadly as those that identify a potential target for pharmaceutical development, a marker(s) for disease diagnosis or staging and risk assessment, both for medical and environmental studies. (Note that there is a difference between developing biological insight and identifying clinically important diagnostic and prognostic protein- based assays.) Defining the Mandate of Proteomics in the Post- Genomics Era, Board on International Scientific Organizations, National Academy of Sciences, 2002

Medical genomics: The mission of the Roche Centre for Medical Genomics (RCMG) is to apply genetic and genomic knowledge to the understanding of the molecular pathology of major human disease leading to the discovery of new and more effective therapies. Research at the centre for medical genomics will focus on: Genetics, as a basis for understanding gene functions and the role of genes in disease; Bioinformatics and computer- aided biology, for efficient use of new scientific data and findings; Functional genomics, as a basis for developing medicines and diagnostic tests that are individually tailored to patients' needs.  Roche Centre for Medical Genomics, F. Hoffman LaRoche, Ltd. 1996- 2005  

Medical proteomics
Proteomic technologies will play an important role in drug discovery, diagnostics and molecular medicine because is the link between genes, proteins and disease. As researchers study defective proteins that cause particular diseases, their findings will help develop new drugs that either alter the shape of a defective protein or mimic a missing one. Already, many of the best-selling drugs today either act by targeting proteins or are proteins themselves. Advances in proteomics may help scientists eventually create medications that are "personalized" for different individuals to be more effective and have fewer side effects. Current research is looking at protein families linked to diseases including cancer, diabetes and heart disease. American Medical Association, "Proteomics" How can proteomics be applied to medicine?

Drug discovery and development Overviews & introductions
About Pharmacology, American Society for Pharmacology and Experimental Therapeutics

Molecules to Medicine  part of Medicines by Design, NIGMS

Information resources  Drug discovery & development   

Pharmacogenomics, pharmacogenetics,  personalized/ individualized medicine
The Human Genome will need to be sequenced only once, but it will be resequenced thousands of times … Eric Lander, Whitehead Institute "The New Genomics" Science 274: 536, 25 Oct. 1996

Can be construed as the study of the entire complement of pharmacologically relevant genes, how they manifest their variations, how these variations interact to produce phenotypes, and how these phenotypes affect drug response. A key element of pharmacogenomics is, not surprisingly, the large- scale and high throughput collection of data, including DNA sequence variations, mRNA expression analysis, enzyme kinetic assays, and cellular  localization experiments. Russ Altman "Challenges for Biomedical Informatics and Pharmacogenomics, Stanford Medical Informatics, c.2001

More than 100,000 people die each year from adverse responses to medications that are beneficial to others. Another 2.2 million experience serious reactions, while others fail to respond at all. ... Genomic data and technologies also are expected to make drug development faster, cheaper, and more effective. Most drugs today are based on about 500 molecular targets; genomic knowledge of the genes involved in diseases, disease pathways, and drug- response sites will lead to the discovery of thousands of new targets. New drugs, aimed at specific sites in the body and at particular biochemical events leading to disease, probably will cause fewer side effects than many current medicines. Ideally, the new genomic drugs could be given earlier in the disease process. As knowledge becomes available to select patients most likely to benefit from a potential drug, pharmacogenomics will speed the design of clinical trials to bring the drugs to market sooner. Medicine and the New Genetics: Genomic and its impact on Medicine and Society, A 2001 primer, Oak Ridge National Lab, US

Genomics is beginning to offer the possibility of more precise patient stratification and segmentation, as well as the opportunity to revive some failed candidates, as appropriate patients can be identified and adverse reactors can be screened out. While pharmacogenomics has always threatened to further fragment an already fragmented pharmaceutical industry, the possibility of real savings by more selective use of expensive therapies and identification of non- responders is quite real.

Disease related tissues, which now seem very indistinguishable (even to pathologists) may be quite identifiable at the molecular level. Technologies for measuring differential gene and protein expression levels in healthy and diseased cells and tissue are emerging and interpretation of the results is beginning to move into clinical research work.  Researchers at the National Cancer Institute (US) and elsewhere are working on obtaining more reproducible results and interpreting very noisy biological data.  Discussions on standards are evolving, higher throughput, more automation and expense are among the challenges. Greater knowledge of population genetics and population genomics should also be useful.

From pharmacology + genomics.

Pharmacogenomics overviews & introductions
American Medical Association, Pharmacogenomics

Dept. of Energy, Oak Ridge National Lab, Pharmacogenomics, 2003 

Promise of pharmacogenomics  National Center for Biotechnology Information, US, 2001. Part of NCBI's Science Primer

Public Health Genetics Unit, UK,  2003 'My Very Own Medicine: What Must I Know? Information Policy for Pharmacogenetics', Funded by the Wellcome Trust

Redefining Genetics  
Clearly defined terminology should form the basis for informative discussions so that the word ‘genetics’ is not demonized. For example, tests that are specific to disease genes can help diagnose disease, determine the carrier status of an individual or predict the occurrence of disease. These are quite distinct from profiles ... which provide information on how a medicine will be metabolized in an individual. … Language needs to be more precise so that there can be clarity, especially for public policy debates. Allen D. Roses "Pharmacogenetics and the practice of medicine" Nature 405: 857- 865 June 15 2000

The key role of diagnostic, efficacy, and toxicity biomarkers in drug development is clearly accepted. Biomarkers provide the basis for developing new diagnostic products, accelerating clinical trials, predicting disease progression, and enhancing the drug safety profiles by assessing toxicity and efficacy at the pre- clinical stage

Once you have identified a number of proteins secreted in sera or urine, you can segregate the proteins by which are linked to early disease, the onset of metastasis, who does and does not tolerate treatment, toxic effects, and who is prone to resistance or relapse." Fundamentally, you establish a pharmacoproteomic profile of an individual. Like pharmacogenomics, which allows researchers and clinicians to predict the response of an individual to drug treatment on the basis of his or her genetic profile, the evolving field of pharmacoproteomics allows drug developers and clinicians to further subdivide the treated population. Randall C. Willis, ":The Matching Game" Modern Drug Discovery, 5(5): 26-35, May 2002

Information resources  Pharmacogenomics   

The study of the structure and output of the genome as it responds to adverse xenobiotic exposure. Ulrich RG. The toxicogenomics of nuclear receptor agonists. Current Opinion in Chemical Biology 7(4) 505- 510, August 2003 [and personal communication]

An emerging discipline that combines expertise in toxicology, genetics, molecular biology, and environmental health to elucidate the response of living organisms to stressful environments. Of particular interest to scientists in the field is the advancement of high- throughput and computational methodologies to study gene and protein expression at all levels, and the application of this knowledge to enhance our understanding and therapeutic management of human illnesses. The promise of toxicogenomics will become a reality as we begin to fully understand how subtle variations in the environment give rise to altered phenotypes that compromise organ and system functions. NIEHS, EHP Toxicogenomics, Jan. 2003

Both legal departments and funding sources see the possibilities of reduced costs as patients susceptible to toxic side effects may be screened out before receiving a drug and patients now being unnecessarily over- treated can offset some of the costs of more expensive new drugs.

Toxicogenomics Overviews & introductions
Concept Statement
, National Center for Toxicogenomics, NIEHS

The use of global protein expression technologies to better understand environmental and genetic factors, both in episodes of acute exposure to toxicants and in the long-term development of disease. Integrating transcript, protein, and toxicology data is a major objective of the field of toxicogenomics. KB Tomer, DB Merrick, Toxicoproteomics: a parallel approach to identifying biomarkers Environmental Health Perspectives 2003 Aug;111(11): A578- 579.

Identification of patients likely to incur adverse and toxic reactions is a more complicated situation. Certainly earlier identification of and knowledge about toxicities will ultimately be useful. But in the short run, when information will be incomplete it seems less valued.

Information resources  Toxicogenomics   

Clinical Trials

Redefining diseases
The human genome sequence will dramatically alter how we define, prevent, and treat disease. As more and more genetic variations among individuals are discovered, there will be a rush to label many of these variations as disease- associated. We need to define the term disease so that it incorporates our expanding genetic knowledge, taking into account the possible risks and adverse consequences associated with certain genetic variations, while acknowledging that a definition of disease cannot be based solely on one genetic abnormality. Disease is a fluid concept influenced by societal and cultural attitudes that change with time and in response to new scientific and medical discoveries. Historically, doctors defined a disease according to a cluster of symptoms. As their clinical descriptions became more sophisticated, they started to classify diseases into separate groups, and from this medical taxonomy came new insights into disease etiology. K Larissa et. al. "Defining Disease in the Genomics Era" Science 293 (5531): 807- 808, Aug. 3, 2001

See also Redefining diagnosis

Molecular Medicine
Definitions Molecular Medicine
Recent advances in molecular and cell biology have enormous potential for medical research and practice. Initially they were most successfully exploited for determining the causes of genetic diseases and how to control them. However, it is now clear that recombinant DNA technology is finding applications in almost every branch of medical practice. It is revolutionising cancer research, offers new approaches to vaccines, has spawned a biotechnology industry that is already producing a wide range of diagnostic and therapeutic agents and, in the longer term, promises to play a major role in clarifying the causes of some of the unsolved mysteries of modern medicine: heart disease, hypertension, major psychiatric illness, rheumatic disease and many others. It should also help us gain insights into broader aspects of human biology, including development, ageing and evolution. Wetherall Institute of Molecular Medicine, Univ. of Oxford, UK

More molecular medicine terminology

Molecular Medicine Introductions & overviews
AMA, Genetics 101, 

DOE Dept. of Energy, Oak Ridge National Lab, Medicine and the New Genetics

NCBI National Center for Biotechnology Information, Genes and Disease 

NHGRI National Human Genome Research Institute, Exploring our Molecular Selves

NIGMS National Institute of General Medical Sciences, From Molecules to Medicine

Sanger Centre, UK Your Beginner

Molecular medicine information resources

Emerging medical genomics specialties

Genomics and public health
Genomics will cut across virtually all areas of public health. Public health activities traditionally associated with genetics include newborn screening, reproductive health, and genetic services. As genomics advances, related public health activities will include chronic diseases, infectious diseases, environmental health, and epidemiology.

Public health information resources

Molecular Diagnostics
Molecular diagnostics definitions
The scope note of the Journal of Molecular Diagnostics mentions "translation and validation of molecular discoveries in medicine into the clinical diagnostic setting, and the description and application of technological advances in the field of molecular diagnostic medicine.  The editors welcome for review articles that contain: novel discoveries with direct application to clinical diagnostics or clinicopathologic correlations including studies in oncology, infectious diseases, inherited diseases, predisposition to disease, or the description of polymorphisms linked to disease states or normal variations; the application of diagnostic methodologies in clinical trials; or the development of new or improved molecular methods for diagnosis or monitoring of disease predisposition." Journal of Molecular Diagnostics, Association for Molecular Pathology  

"The term molecular diagnostics has a relatively narrow clinical definition, namely, the use of nucleic acids as analytes in assays designed to investigate given disease states." Review by Charles P. Cartwright of Molecular Diagnosis of Infectious Diseases by U. Reischl, Humana Press, 1998, American Journal of Clinical Pathology Archive.  Is this changing?

Molecular Diagnostics Overviews & introductions
Understanding Gene Testing
, National Cancer Institute, US, 2001

Our Genes, Our Choices, PBS

Your genes, your choices: Exploring the choices raised by genetic research,  Catherine Baker, part of the AAAS Science + Literacy for Health Project

Redefining "diagnosis"
Allen Roses, worldwide director of genetics for Glaxo Wellcome [now Glaxo SmithKline] notes that "precise diagnoses leading to universal specific treatments are, for many illnesses, myths... for many diseases there is no accurate, single diagnostic test" . A.D. Roses "Pharmacogenetics and future drug development and delivery" Lancet 355 (9212):1358-61 Apr 15, 2000

See also Redefining diseases

Traditionally, diagnostics has been quite distinct from therapeutic development. Molecular medicine is changing that paradigm, as molecular markers become increasingly important for understanding disease biology, selecting and validating targets, and assessing the efficacy and safety of compounds under development. Such molecular diagnostics have a much greater role, only one of which involves commercialization and use in patient care. Pharmaceutical companies are making use of molecular diagnostics within the drug development process.  Strategic Implications of Therapeutically Specific Molecular Diagnostics, CHI report, 2003

Molecular diagnostic technologies are likely to have a strong impact on the drug treatment of many major illnesses. The first molecular diagnostic products to reach the market included tests for detection for viral RNA or DNA, genetic tests, and tests to determine risk for developing certain cancers, such as breast or colon cancer. Now, a wealth of genomic data is enabling researchers to predict a patient's response to therapy based on the genetic make- up of a tumor (in the case of cancer), or the viral genotype.. 

HIV genotyping is an early example of how treatment decisions are made based on the genotype of the virus. Genetic polymorphisms of certain cytochrome P450 enzymes can affect how a patient metabolizes certain drugs, and thus can affect effectiveness or toxicity of these drugs in certain patients. Potential applications for emerging molecular diagnostics tests include viral genotyping for drug resistance, cancer diagnosis and prognosis, disease susceptibility and prediction, diagnosis of inherited genetic disorders, prediction of drug response, and identity/forensic testing.

Molecular pathology
The collection and analysis of tissue samples is a long- established technique in pathology. What is new in "molecular pathology" is the emphasis on assessing gene expression in addition to morphology, and the use of gene expression analysis to validate large numbers of targets. (However, histochemistry and immunohistochemistry have been used, for specific proteins, since before the advent of genomics.) Corporate genomic researchers are increasingly seeking access to human tissue samples via collaborations with pathology departments at clinical research institutions 

Genomics related diagnostics are apt to precede therapeutics for some time to come.  A trickle of approved drugs (mostly for fairly rare conditions) has begun. Look for progress to be difficult to predict and nonlinear for some time -- but physicians and patients are apt to be surprised by the speed with which medical decisions are affected. That doesn't mean the decisions will necessarily be easy. They will almost certainly involve balancing various tradeoffs.

Genetic and Genomic testing
Extensive media coverage of genomic discoveries has fueled the public appetite for personalized medicine and a rush to develop and market new genomic tests, often without the necessary intervening research. Public health sciences have an important role in evaluating the validity and utility of genomic tests, which include not only DNA- based tests for single gene variants, but complex genotypes, tests for acquired mutations, and measures of gene expression, from RNA microarrays to biochemical assays. Before a genomic test can be used for epidemiologic research or clinical practice, laboratory comparison with a gold standard must demonstrate analytic validity. Epidemiologic studies are needed to establish clinical validity (sensitivity, specificity, and predictive value). Research Priorities for Public Health Sciences in the Post- Genomic Era, Marta Gwinn and Muin J. Khoury, Centers for Disease Control, US Genetics in Medicine 4(6): 410- 411, 2002

Molecular diagnostics information resources

What do we know now?
Weather may be a good metaphor for what we can hope to do with genomics, proteomics and informatics. We can predict and track hurricanes a lot better than we could 100 (and even 25) years ago. Modern building codes have reduced property damage and mortality rates. But we are still far from being able to stop storms (or earthquakes) or prevent them.

Are we really post-genomic yet?
We know something about monogenic diseases, with high penetrance. Do we really know anything about polygenic diseases with varying penetrance?

We are just starting to learn about genetic trade-offs (such as heterozygotes for sickle cell trait being more resistant to malaria).

We are post-Mendelian. The more we know, the more we realize we still have to understand.

Nobody can be experts in all the disciplines relevant to biopharmaceuticals today. We need people who are good at communicating across information silos. Artificial intelligence has been struggling to agree on unambiguous, mutually exclusive, disjoint definitions for medical terms for 30 years. A combination of automation and human interventions seems likely to produce the best results.

Multi-disciplinary and inter-disciplinary challenges

Genomic success stories (still being written)

Antimicrobials: MD DeBacker , P Van Dijck, Progress in functional genomics approaches to antifungal drug target discovery, Johnson & Johnson Pharmaceuticals Group, Trends in Microbiology 11(10): 470-478, Oct. 2003
As traditional drug screening on existing targets is not delivering the long- awaited potent antifungals, efforts to use novel genetics and genomics- based strategies to aid in the discovery of novel drug targets are gaining increased importance. The current paradigm in antifungal drug target discovery focuses on basically two main classes of targets to evaluate: genes essential for viability and virulence or pathogenicity factors. Here we report on recent advances in genetics and genomics- based technologies that will allow us not only to identify and validate novel fungal drug targets, but hopefully in the longer run also to discover potent novel therapeutic agents. Fungal pathogens have typically presented significant obstacles when subjected to genetics, but the creativity of scientists in the anti- infectives field and the cross- talk with scientists in other areas is now yielding exciting new tools and technologies to tackle the problem of finding potent, specific and non- toxic antifungal therapeutics.

There are exciting signs of progress -- but only for a limited number of patients and conditions right now. 

As Cohen wrote in Science, use of the term "new paradigm" has grown exponentially.  How many changes are truly new is questionable.  But mixed in with incremental changes are the truly new and profoundly different approaches.  J Cohen "The March of Paradigms" Science 283 : 1998-1999 Mar 26, 1999

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