Genomics & proteomics for Drug discovery & development
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" 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 http://www.stanford.edu/class/siw198q/websites/genomics/finalrpt.htm
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. http://www.cid.harvard.edu/cidbiotech/events/henderson.htm
The systematic study of the complete DNA sequences (GENOME) of organisms. MeSH, 2001
How does genomics differ from
Access Excellence, National Health Museum, US http://www.accessexcellence.org/ 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
Cold Spring Harbor, DNA Learning Center, http://vector.cshl.org/ 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, http://doegenomestolife.org/
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 http://www.ebi.ac.uk/microarray/biology_intro.htm 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 http://www.genome.gov/10506367
NCBI, NLM, NIH: Science Primer http://www.ncbi.nlm.nih.gov/About/primer/index.html 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 http://www.nature.com/genomics/post-genomics/index.html
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.
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 http://bioinfo.mbb.yale.edu/e-print/omes-genomeres/text.pdf.
Information resources Genomics
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 http://www.sciencemag.org/cgi/content/full/291/5507/1221
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.
ExPASy, Human Proteomics http://expasy.org/sprot/hpi/
VIB, the Flanders Interuniversity Institute for Biotechnology Research, Proteomics Core Facility http://www.vib.be/Research/EN/Service+Facilities/Proteomics+-+Facility/Introduction/
Harvard Extension School, Introduction to Proteomics, 2004 http://www.extension.harvard.edu/2003-04/courses/12066.jsp
Technologies overviews & introductions
Industry Canada, Life Sciences Gateway http://strategis.ic.gc.ca/epic/internet/inlsg-pdsv.nsf/en/Home
National Research Council, Canada, Biotechnology http://www.nrc-cnrc.gc.ca/randd/areas/biotechnology_e...l
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.
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.
Overviews & introductions
Stanford University, Pat Brown's Lab HomePage, Dept of Biochemistry, http://cmgm.stanford.edu/pbrown/
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
Drug Discovery and Development
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, http://www.genomicsontarget.com/pdf-cog.asp
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
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 http://www.roche.com/home/science/sci_gengen/sci_gengen_med.htm
Drug discovery and development Overviews
Molecules to Medicine http://www.nigms.nih.gov/medbydesign/molecules/ part of Medicines by Design, NIGMS http://www.nigms.nih.gov/medbydesign/
personalized/ individualized medicine
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 http://www.ornl.gov/hgmis/publicat/primer2001/6.html
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.
Dept. of Energy, Oak Ridge National Lab, Pharmacogenomics, 2003 http://www.ornl.gov/sci/techresources/Human_Genome/medicine/pharma.shtml
Promise of pharmacogenomics http://www.ncbi.nlm.nih.gov/About/primer/pharm.html 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', http://www.phgu.org.uk/about_phgu/pharmacogenetics.html Funded by the Wellcome Trust
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 http://ehp.niehs.nih.gov/txg/docs/2003/111-1T/eds/eds.html
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.
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.
See also Redefining diagnosis
Molecular Medicine Introductions & overviews
DOE Dept. of Energy, Oak Ridge National Lab, Medicine and the New Genetics http://www.ornl.gov/TechResources/Human_Genome/medicine/medicine.html
NCBI National Center for Biotechnology Information, Genes and Disease http://www.ncbi.nlm.nih.gov/disease/
NHGRI National Human Genome Research Institute, Exploring our Molecular Selves http://www.nhgri.nih.gov/educationkit/
NIGMS National Institute of General Medical Sciences, From Molecules to Medicine http://www.nigms.nih.gov/moleculestomeds/
Sanger Centre, UK Your Genome.org Beginner http://www.yourgenome.org/primer/
and public health
"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 &
Our Genes, Our Choices, PBS http://www.pbs.org/fredfriendly/ourgenes/
Your genes, your choices: Exploring the choices raised by genetic research, Catherine Baker, part of the AAAS Science + Literacy for Health Project http://ehrweb.aaas.org/ehr/books/index.html
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.
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
we know now?
Are we really post-genomic yet?
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)
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
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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