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adverse drug reaction ADR: ADRs may include drug interactions as one of many causes but the reverse is not true. The reader is cautioned regarding usage of drug reaction terms as multiple nearly- similar terms of varying granularity abound. .. "An adverse reaction to a drug has been defined as any noxious or unintended reaction to a drug that is administered in standard doses by the proper route for the purpose of prophylaxis, diagnosis, or treatment(2). However, WHO's original definition of ADR excluded therapeutic failures, intentional and accidental poisoning and drug abuse, as well as adverse events due to medication errors such as drug administration or non- compliance(1) ... Due to non- uniform usage of these terms, it is sometimes difficult to compare various studies and derive incidence rates, etc. for ADRs, and Drug Interactions. Saeed A Khan, "Drug Interaction or Adverse Drug Reaction? Confusing Terms", British Medical Journal 10 July, 1998 http://bmj.com/cgi/eletters/316/7149/1930 Alternatively: ADE Adverse Drug Event
adaptive clinical trials: A process for improving the efficiency of clinical trials based on interim analyses of clinical data, potentially leading to reductions in overall sample size, shorter project duration, improved quality of results, and reduced costs. Tufts Center for the Study of Drug Development, Glossary of terms, 2014 http://csdd.tufts.edu/InfoServices/Glossary.asp
The pharma industry is gradually coming to realize that the classically structured clinical trial does not offer enough flexibility to make use of continuously emerging knowledge that is generated as the trial progresses. Unacceptable levels of attrition in the clinical stage of development are driving profound changes in the architecture, design, and analysis of clinical trials. The majority of respondents to our survey said that reduction in patient numbers, less exposure to study drug, and drops in overall trial duration were key points in favor of adaptive designs; however, a majority also had specific concerns with adaptive trials―concerns that involved methodological, logistical, and regulatory uncertainties: Herman Mucke, Adaptive Clinical Trials: Innovations in clinical trial design, management and analysis, Insight Pharma Reports, 2007
Administration, Dosage, Metabolism, Elimination, Toxicology:
We know a lot about A and M, not so much about D and E.
alternative splicing: The production of two or more distinct mRNAs from RNA transcripts having the same sequence via differences in splicing (by the choice of different exons). Mouse Genome Informatics http://www.informatics.jax.org/javawi2/servlet/WIFetch?page=glossaryIndex&print=no
Recent genome- wide analyses of alternative splicing indicate that 40- 60% of human genes have alternative splice forms, suggesting that alternative splicing is one of the most significant components of the functional complexity of the human genome. Here we review these recent results from bioinformatics studies, assess their reliability and consider the impact of alternative splicing on biological functions. Although the 'big picture' of alternative splicing that is emerging from genomics is exciting, there are many challenges. High- throughput experimental verification of alternative splice forms, functional characterization, and regulation of alternative splicing are key directions for research. B. Modrek, C. Lee, "A genomic view of alternative splicing" Nature Genetics30 (1) :13- 19, Jan. 2002
analyte specific reagents: A new class of regulated product: analyte specific reagents. These products are usually a singular reagent, such as an antibody, which can be used toward developing a test by third parties, such as another company or a hospital. The manufacturer of this product is not planning to sell it as part of a kit, but only as an independent reagent. Therefore, it is of low risk to the user, it can be exempt from 501(k) [device] requirements, and by definition must be used "for identification and quantification of an individual chemical substance or ligand in biological substances." Joseph Hackett, FDA in CHI Summit Pharmacogenomics Report
antisense (molecule): An oligonucleotide or analog thereof that is complementary to a segment of RNA or DNA and that binds to it and inhibits its normal function. IUPAC Medicinal Chemistry
describing DNA sequences or referring to one of the two strands of double-
stranded DNA frequently use complementary pairs of terms, such as coding/ non-
coding, sense/ nonsense or transcribing/ non- transcribing. Unfortunately none
of these pairs is defined in a universally accepted way…Of the three pairs of
terms mentioned, NC- IUB and JCBN believe coding/ non- coding to be preferable.
Moreover, as the word 'coding' refers to the relationship between nucleic acids
and proteins, rather than the mere transcription of DNA into RNA, it is logical
to call the strand with the mRNA sequence the coding strand, as in the first
example. When DNA sequences are described by giving the sequence of only one
strand, this is usually the strand with the same sequence as the RNA (messenger,
ribosomal, transfer, etc.) and should therefore be called the coding strand.
[JCBN/ NC- IUB Newsletter, Joint Commission on Biological Nomenclature and
Nomenclature Commission of IUB 1989 http://www.chem.qmul.ac.uk/iubmb/newsletter/misc/DNA.html
antisense DNA: DNA that is complementary to the sense strand. (The sense strand has the same sequence as the mRNA transcript. The antisense strand is the template for mRNA synthesis.) Synthetic antisense DNAs are used to hybridize to complementary sequences in target RNAs or DNAs to effect the functioning of specific genes for investigative or therapeutic purposes. MeSH, 1991
antisense oligonucleotides: Short fragments of DNA or RNA that are used to alter the function of target RNAs or DNAs to which they hybridize. MeSH, 1991
An oligonucleotide that has a complementary sequence to a portion of, or to all of, an mRNA. Being complementary to a particular target mRNA, antisense oligonucleotides bind specifically to that mRNA; the proprietary chemical modifications made to the antisense molecules facilitate tight binding. When binding occurs, the ability of the mRNA to be read by the cell’s translational machinery is inhibited, and synthesis of the protein that it encodes is blocked. Unlike a gene knockout, this inhibition requires the continuous presence of the antisense molecule; thus, it is reversible. A great advantage of antisense technology is that researchers can design specific inhibitors of a gene of interest based only on knowledge of the gene sequence.
apoptosis: One of the two mechanisms by which CELL DEATH occurs (the other being the pathological process of NECROSIS). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA FRAGMENTATION) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. MeSH, 1993
If someone could figure out how to make fat cells undergo apoptosis (without harmful side effects) they could make a bundle. Related terms: programmed cell death
attrition Early attrition of poor drug candidates is central to the new drug discovery paradigm. Better to kill compounds before moving them into expensive clinical trials.
Bayesian clinical trials: In recent years, there has been an explosion in predictive technologies to help researchers select only the most promising candidates for clinical development. The need for such tools is driven by the disastrous economic consequences of late-stage failures, which account for over 60% of all drug terminations. Insight Pharma Reports, Bayesian Forecasting of Phase III Outcomes: The Next Wave in Predictive Tools, 2007
statistics is an approach for learning from evidence as it accumulates. In
clinical trials, traditional (frequentist) statistical methods may use
information from previous studies only at the design stage. Then, at the data
analysis stage, the information from these studies is considered as a complement
to, but not part of, the formal analysis. In contrast, the Bayesian approach
uses Bayes’ Theorem to formally combine prior information with current
information on a quantity of interest. The Bayesian idea is to consider the
prior information and the trial results as part of a continual data stream, in
which inferences are being updated each time new data become available.
Throughout this document we will use the terms “prior distribution”,
“prior probabilities”, or simply “prior” to refer to the mathematical
entity (the probability
distribution) that is used in these Bayesian calculations. The term
“prior information” refers to the set of all information that may be used to
construct the prior distribution. FDA, CBER, CDHR Guidance for the use of
Bayesian Statistics in Medical Device Clinical Trials Feb. 2010
Throughout this document we will use the terms “prior distribution”, “prior probabilities”, or simply “prior” to refer to the mathematical entity (the probability distribution) that is used in these Bayesian calculations. The term “prior information” refers to the set of all information that may be used to construct the prior distribution. FDA, CBER, CDHR Guidance for the use of Bayesian Statistics in Medical Device Clinical Trials Feb. 2010http://www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm071072.htm#1
big pharmas: MedAdNews publishes an annual list of the top 50 pharmaceutical companies each fall. "Biotech" companies such as Amgen are bigger than some pharmas.
play a crucial role in biomedical research. The wide array of biospecimens
including blood, saliva, plasma, and purified DNA maintained in biobanks can be
described as libraries of the human organism. They are carefully characterized
to determine the general and unique features of the continuous cell line and the
absence or presence of contaminants, therefore establishing a fundamental
understanding about the raw material from which the biological product is being
derived and maintained. Coriell
Institute for Medical Research https://www.coriell.org/research-services/biobanking/what-is-a-biobank
the field of developing medicines that use electrical impulses to modulate the body's neural circuits. Virtually all of the body's organs and functions are regulated through circuits of neurons communicating through electrical impulses. The theory is that if you can accurately map the neural signatures of certain diseases, you could then stimulate or inhibit the malfunctioning pathways with tiny electrodes in order to restore health, without having to flood the system with molecular medicines. Electroceuticals swapping drugs for devices, Wired 28 May 2013 http://www.wired.co.uk/news/archive/2013-05/28/electroceuticals Related term: electroceuticals; Genomics optogenetics
bioengineering: The application of a systematic, quantitative, and integrative way of thinking about and approaching the solutions of problems important to biology, medical research, clinical proactive, and population studies. The NIH Bioengineering Consortium agreed on the following definition for bioengineering research on biology, medicine, behavior, or health recognizing that no definition could completely eliminate overlap with other research disciplines or preclude variations in interpretation by different individuals and organizations. Integrates physical, chemical, or mathematical sciences and engineering principles for the study of biology, medicine, behavior, or health. It advances fundamental concepts, creates knowledge for the molecular to the organ systems levels, and develops innovative biologics, materials, processes, implants, devices, and informatics approaches for the prevention, diagnosis, and treatment of disease, for patient rehabilitation, and for improving health. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2227944/#!po=12.5000
bioinformatics: Roughly, bioinformatics describes any use of computers to handle biological information. In practice the definition used by most people is narrower; bioinformatics to them is a synonym for "computational molecular biology" - the use of computers to characterise the molecular components of living things. [Damian Counsell, bioinformatics.org FAQ] http://bioinformatics.org/faq/#whatIsBioinformatics See for tight and loose definitions of bioinformatics, and information on how long the term has been used. Research, development or application of computational tools and approaches for expanding the use of biological, medical, behavioral or health data, including those to acquire, store, organize, archive, analyze, or visualize such data. Biomedical Information Science and Technology Initiative BISTI Bioinformatics at the NIH, 2000 http://www.bisti.nih.gov/
We have coined the term Bioinformatics for the study of informatic processes in biotic systems. Our Bioinformatic approach typically involves spatial, multi- leveled models with many interacting entities whose behavior is determined by local information. Theoretical Biology Group, Univ. of Utrecht, Netherlands, Paulien Hogeweg Director http://www-binf.bio.uu.nl/
Original definition was “the study of informatic processes in biotic systems” Paulien Hogeweg MIRROR beyond MIRROR, puddles of LIFE, in Artificial Life, ed. C.G. Langton, Addison Wesley, 297-316, 1988 [Nick Saville's homepage, Theoretical Biology and Bioinformatics, Utrecht Univ., Netherlands, 1997 Alternatively computational biology
in contrast to drugs that are chemically synthesized, are derived from living
sources (such as humans, animals, and microorganisms). Most biologics are
complex mixtures that are not easily identified or characterized, and many
biologics are manufactured using biotechnology. Biological products often
represent the cutting- edge of biomedical research and, in time, may offer the
most effective means to treat a variety of medical illnesses and conditions that
presently have no other treatments available. About CBER, FDA, US http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CBER/ucm123340.htm
biological markers: Measurable and quantifiable biological parameters (e.g. specific enzyme concentration, specific hormone concentration, specific gene phenotype distribution in a population, presence of biological substances) which serve as indices for health - and physiology related assessments, such as disease risk, psychiatric disorders, environmental exposure and its effects, disease diagnosis, metabolic processes, substance abuse, pregnancy, cell line development, epidemiologic studies, etc. MeSH, 1989
1. Parameter that
can be used to identify a toxic effect in an individual organism and can be used
in extrapolation between species. 2. Indicator signalling an event or condition
in a biological system or sample and giving a measure of exposure, effect, or
susceptibility. IUPAC Tox
biological products: Biological products include a wide range of products such as vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins. The Center for Biologics Evaluation and Research (CBER) is responsible for ensuring the safety and efficacy of the biological products. http://www.fda.gov/BiologicsBloodVaccines/ResourcesforYou/HealthcareProviders/default.htm See also biologics, biopharmaceutical
biomarker guidelines: The National Cancer Institute (NCI) Investigational Drug Steering Committee (IDSC) charged the Biomarker Task Force to develop recommendations to improve the decisions about incorporation of biomarker studies in early investigational drug trials. The Task Force members reviewed biomarker trials, the peer-reviewed literature, NCI and U.S. Food and Drug Administration (FDA) guidance documents, and conducted a survey of investigators to determine practices and challenges to executing biomarker studies in clinical trials of new drugs in early development. This document provides standard definitions and categories of biomarkers, and lists recommendations to sponsors and investigators for biomarker incorporation into such trials. Our recommendations for sponsors focus on the identification and prioritization of biomarkers and assays, the coordination of activities for the development and use of assays, and for operational activities. We also provide recommendations for investigators developing clinical trials with biomarker studies for scientific rationale, assay criteria, trial design, and analysis. Guidelines for the Development and Incorporation of Biomarker Studies in Early Clinical Trials of Novel Agents, Dancey JE, et. al, Clin Cancer Res. 2010 Mar 9. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/20215558
biomarkers: Anatomic, physiologic, biochemical, or molecular parameters associated with the presence and severity of specific disease states. Biomarkers are detectable and measurable by a variety of methods including physical examination, laboratory assays and medical imaging. Massachusetts General Hospital, Center for Biomarkers in Imaging, 2004 http://www.biomarkers.org/NewFiles/faqs/definition.html#Anchor-What-35882
biomathematics: The application of mathematics to problems in biology and medicine. An essential tool in fields such as population genetics, cellular neurobiology, comparative genetics, biomedical imaging, pharmacokinetics, and epidemiology. It plays an increasingly vital role in the effort to understand diseases and disorders, and to improve therapies. Collection Development Manual, National Library of Medicine, US 2004 http://www.nlm.nih.gov/tsd/acquisitions/cdm/subjects14.html
BioMEMS Biological MicroElectro Mechanical Systems: Includes micro & nano drug delivery, interface of nanoscience and tissue engineering, microfluidics, and miniaturized total analysis systems (microTAS), biosensors, innovations in mass spectrometry, and nanoscale imaging.
There is a need to develop the next generation of restorative materials and medical implants. New avenues of scientific inquiry may enable the development of biomaterials that are safe, reliable, "smart", long- lasting, and perform ideally in their respective biological environments. ... Over the last few years biomimetics and tissue engineering have emerged as a new vision in the field of tissue and organ repair and restoration. Biomimetics and tissue engineering are interdisciplinary fields that combine information from the study of biological structures and their functions with physics, mathematics, chemistry and engineering for the generation of new materials, tissues and organs. These approaches can offer new ways of: (a) developing biological solutions for future design and synthesis of composite materials such as bone, cartilage, tendon, ligament, skin, dentin, enamel, cementum and periodontal ligament; (b) replacing and assembling functional tissues and organs; and (c) evaluating medical and dental implants. In the area of craniofacial, oral and dental principles from biomimetics and tissue engineering are applied to developing dental and facial implants, new polymers for guided tissue regeneration used in treating periodontal disease and bone and connective tissue defects, coral- based hydroxyapatite replicas for reconstruction of alveolar ridges and other osseous defects, temporomandibular joint (TMJ) and other joint prostheses, formation of bone matrix substitutes, and artificial replicas of bone, skin, and mucosa. [National Institute of Dental Research, NIH, US, Biomimetics and Tissue Engineering in the Restoration of Orofacial Tissues, RFA: DE-98-009, June 19, 1998] http://grants.nih.gov/grants/guide/rfa-files/RFA-DE-98-009.html
biomolecular materials: An emerging discipline, materials whose properties are abstracted from biology. They share many of the characteristics of biological materials but are not necessarily of biological origin. For example, they may be inorganic materials that are organized or processed in a biomimetic fashion. A key feature of biological and biomolecular materials is their ability to undergo self- assembly. Biomolecular self- assembling materials, National Academy of Sciences 1996 http://www.nas.edu/bpa/reports/bmm/bmm.html#PBMM
term "biomolecular screening" became widely used in the late 1980's to
broadly describe a new and rapidly adopted process for lead identification in
drug discovery. This new process involved screening natural product
extracts and/or amassed compound collections, typically from pharmaceutical
companies, in a random, unbiased manner to identify novel modulators of
biological targets ... The screens encompassed bioassays that could be
cell-based or purely biochemical in nature, and the need to screen increasing
numbers of samples as time progressed, fostered the development of many new
assay formats. IUPAC Glossary of terms in Biomolecular Screening 2011 http://iupac.org/publications/pac/83/5/1129/
biomotors: Driven by energy sources such as adenosine triphosphate (ATP) for chemical transduction and other processes. These biomotors are considered to be biomolecular and are discussed in the body of this report, but strictly speaking they do not conform to the panel's definition of self- assembly. Biomolecular self- assembling materials, National Academy of Sciences 1996 http://www.nas.edu/bpa/reports/bmm/bmm.html#PBMM
biopharmaceutical: Any therapeutic biological compound, including recombinant proteins, monoclonal and polyclonal antibodies, antisense oligonucleotides, therapeutic genes, and recombinant and DNA vaccines. Tufts Center for the Study of Drug Development, Glossary, 2014 http://csdd.tufts.edu/InfoServices/Glossary.asp See also biologics, biological products
biopolymers: Macromolecules (including proteins, nucleic acids and polysaccharides) formed by living organisms. [IUPAC Compendium] Broader term: polymers
A material transfer technique used for assembling biological material or cells
into a prescribed organization to create functional structures such as MICROCHIP
ANALYTICAL DEVICES, cell microarrays, or three dimensional anatomical
structures. MeSH 2013
New manufacturing technologies under the banner of rapid prototyping enable the fabrication of structures close in architecture to biological tissue. In their simplest form, these technologies allow the manufacture of scaffolds upon which cells can grow for later implantation into the body. A more exciting prospect is the printing and patterning in three dimensions of all the components that make up a tissue (cells and matrix materials) to generate structures analogous to tissues; this has been termed bioprinting. Printing and prototyping of tissues and scaffolds. Derby B. Science. 2012 Nov 16;338(6109):921-6. doi: 10.1126/science.1226340 http://www.ncbi.nlm.nih.gov/pubmed/23161993
biorobotics: Our research focuses on the role of sensing and mechanical design in motor control, in both robots and humans. This work draws upon diverse disciplines, including biomechanics, systems analysis, and neurophysiology. The main approach is experimental, although analysis and simulation play important parts. In conjunction with industrial partners, we are developing applications of this research in biomedical instrumentation, teleoperated robots, and intelligent sensors. Harvard Biorobotics Laboratory, 2004. http://biorobotics.harvard.edu/
biotechnology: The integration of natural sciences and engineering sciences in order to achieve the application of organisms, cells, parts thereof and molecular analogues for products and services. IUPAC Compendium
biotechnology firms: The congressional Office of Technology concluded in its pathbreaking 1984 report, and emphasized even more strongly in another 1991 report, that "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
The biotechnological innovations of the 1970’s took
until the 1990’s to integrate. "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
Biotechnology started as a means for producing biopharmaceuticals. It has only relatively recently begun to be more integrated into the drug discovery and development process.
US$1 billion in annual sales in 1987, the first global “blockbuster”
pharmaceutical product was born. Today, there are 116 so-called blockbuster
medicines, providing 36% of the global pharmaceutical market’s 2011 value, up
from 51 products and 25% of the global pharmaceutical market value in 2001.
While a billion dollars may once have defined a small number of products with
truly exceptional sales, a significant expansion in the number of products
reaching this level no longer makes this an elite group. The industry must now
determine how best to define the exclusive group of drugs that are truly
exceptional in terms of their performance by establishing a new benchmark, which
accurately reflects and evolves with the current market environment. Redefining
the blockbuster model Sarah Rickwood, 2012 http://www.pharmaphorum.com/articles/redefining-the-blockbuster-model-why-the-1-billion-entry-point-is-no-longer-sufficient-part-1
90% of drugs marketed by big pharma bring in less than $180 million per year. Compare that number to the total cost of $350- 600 million for approving a single drug (including all the failures that lead up to it). Of course, one might think that the money can be made back in four years, but drugs have a huge maintenance cost in terms of regulatory compliance, marketing and sales. The margin on a drug- to- drug basis is very slim. This places the onus on the other 10% of drugs to be blockbusters – to more than make up for most of the other drugs that are earning far too little revenue. This is how the industry has structured itself around a blockbuster mentality – a reliance on drugs that bring in at least $500 million per year in revenue. Considering the odds of achieving blockbuster status, this is a very high- risk strategy. Pharmaceutical companies will have to change their ways if they are going to enter the new era of individualized medicine. Related terms: FIPCO, franchises- pharmaceutical, market fragmentation, multibusters, pharmaceutical industry
In practice, it may sometimes be
unclear whether a product is a cosmetic product in the sense of the Cosmetics
Directive or whether it falls under other sectoral legislation. This decision
is to be taken on a case-by-case basis. However, the Commission has published a
number of guidance documents to facilitate the application of
Community-legislation in these cases.
brand name drug: A
drug marketed under a proprietary, trademark- protected name. Glossary, Drugs@FDA,
CDER, 2012 http://www.fda.gov/cder/drugsatfda/glossary.htm
proprietary drug, proprietary name
cancer genomics: Cancer is a complex disease of genomic alteration, exploiting many different molecular mechanisms. Fighting cancer will ultimately require a comprehensive classification of cancers according to their genomic basis. Projects include: systematic studies of genome-wide loss and amplification; targeted resequencing to identify mutant genes in key pathways; and discovery of cancer-specific biomarkers. ... Cancer cells rely for their survival on the expression of a limited number of specific genes. Identifying these genes would yield, for the first time, a comprehensive catalog of the potential therapeutic targets for cancer. Projects include systematic use of RNA interference (RNAi) to identify such Achilles' heels of cancers. ... Genomic signatures provide a powerful way to recognize the effects of chemical compounds, both to understand cancer biology and to develop new therapeutics. Program activities include: Gene-Expression High-Throughput Screening (GE-HTS) to identify compounds that can induce specific developmental changes in cancer ... Other efforts include molecular pathology studies to map gene expression patterns to actual tumor architecture, integrating molecular signatures to predict cancer prognosis and treatment response, and developing robust computational biology tools to analyze and interpret the data generated across the large range of projects underway. Broad Institute of MIT and Harvard http://www.broadinstitute.org/scientific-community/science/programs/cancer/cancer
CBER Center for
Biologics Evaluation and Research: CBER
is the Center within FDA that regulates biological products for human use under
applicable federal laws, including the Public Health Service Act and the Federal
Food, Drug and Cosmetic Act. CBER protects and advances the public health by
ensuring that biological products are safe and effective and available to those
who need them. http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CBER/default.htm
CDER Center for Drug Evaluation and Research: http://www.fda.gov/cder/ Part of the US FDA Categories of Therapeutic Biological Products Transferred to CDER from CBER, June 30, 2003: Monoclonal antibodies for in-vivo use, Proteins intended for therapeutic use, including cytokines (e.g. interferons), enzymes (e.g. thrombolytics), and other novel proteins, except for those that are specifically assigned to CBER (e.g., vaccines and blood products). This category includes therapeutic proteins derived from plants, animals, or microorganisms, modifying a pre- existing immune response). Growth factors, cytokines, and monoclonal antibodies intended to mobilize, stimulate, decrease or otherwise alter the production of hematopoietic cells in vivo 1 Transfer of Therapeutic Products to the Center for Drug Evaluation and Research, CBER, FDA, US, 2010 http://www.fda.gov/CombinationProducts/JurisdictionalInformation/ucm136265.htm
cDNA complementary DNA: A single stranded DNA molecule with a nucleotide sequence that is complementary to an RNA molecule; cDNA is formed by the action of the enzyme reverse transcriptase on an RNA template. After conversion to the double stranded form, cDNA is used for molecular cloning or for hybridization studies. [IUPAC Biotech]
A complementary DNA for a messenger RNA molecule. Unlike an mRNA, a cDNA can be easily propagated and sequenced. [NCBI]
Single-stranded complementary DNA synthesized from an RNA template by the action of RNA- dependent DNA polymerase. cDNA (i.e., complementary DNA, not circular DNA, not cDNA) is used in a variety of molecular cloning experiments as well as serving as a specific hybridization probe. MeSH, 1994
chaperome: The goal of the "All Chaperome" project is to characterize the molecular chaperones of C. elegans. We have identified approximately 170 chaperones corresponding to the major classes of chaperones and co-chaperones conserved in S. cerevisiae, and vertebrates. Taking advantage of the lineage analysis of C. elegans, we are determining the expression pattern of each chaperone gene to establish a basis for network interactions and tissue specificity during development and aging. Morimoto Laboratory, All Chaperome Project, 2007 http://www.biochem.northwestern.edu/ibis/morimoto/research/research_chap2.html Thanks to Heike Aßmus, University of Rostock for alerting me to this -ome.
chemical genetics: A "chemistry first" approach to drug discovery. Chemical genetics strategies start with libraries of chemical compounds, and then screen these libraries to find compounds that produce differences in a disease- relevant phenotype. Once a phenotype modifying compound is found, it is used to identify the particular target protein to which it binds in the cells or small model organisms in which it had previously been studied. Sometimes used interchangeably with "chemical genomics". CHA, Cambridge Healthtech Advisors Model Animal Systems: Emerging Applications and Commercial Opportunities in Drug Discovery and Development, report, 2004
approach" first coined [by Rebecca Ward, at Harvard University] on the
inaugural cover of Chemistry and Biology nine years ago. Her term reminds us
that to understand a life process you should perturb it and determine the
consequence and that such an approach should strive to have the broad power and
generality of genetics. Stuart L. Schreiber, The Small Molecule Approach
to Biology, Chemical & Engineering News, March 3, 2003 http://www-schreiber.chem.harvard.edu/home/pdffiles/8109genomics.pdf
chemical information: Many people view chemoinformatics as an extension of chemical information, which is a well established concept covering many areas that employ chemical structures, data storage and computational methods, such as compound registration databases, on- line chemical literature, SAR analysis and molecule- property calculation. Timothy Ritchie "Chemoinformatics; manipulating chemical information to facilitate decision- making in drug discovery" Drug Discovery Today 6(16): 813-814, Aug. 2001
chemical information system: Must include registration, computed and measured properties, chemical descriptors and inventory. The primary purpose is to be able to identify a chemical substance, find compounds similar to the target compound and determine the location of the compound. To effectively build it, an object definition of the chemical sample is paramount…The hub [central database] of the chemical information system is the inventory system. Frank Brown "Chemoinformatics: What is it and How does it Impact Drug Discovery" Annual Reports in Medicinal Chemistry 33: 375-384, 1998
cheminformatics: The practice of finding the "best- fitting" compounds to address particular targets. The field encompasses diversity analysis and library design, virtual screening, rational drug design, and tools and approaches for predicting activity and other properties from structure. Going by the numbers in Google.com cheminformatics seems to be the currently most used form of this word, overtaking chemoinformatics in about 2001. Alternatively chemical informatics, chemical information, chemi-informatics
chemoinformatics: Chemoinformatics is an integral part of the discipline of knowledge management. Nicholas J. Hrib, Norton P. Peet "Chemoinformatics: are we exploiting these new science?" Drug Discovery Today 5 (11): 483- 485, Nov. 2000
Increasingly incorporates "compound registration into databases, including library enumeration; access to primary and secondary scientific literature; QSAR Quantitative Structure Activity Relationships) and similar tools for relating activity to structure; physical and chemical property calculations; chemical structure and property databases, chemical library design and analysis; structure- based design and statistical methods. Because these techniques have traditionally been considered the realms of scientists from different disciplines, differences in computer systems and terminology provide a barrier to effective communication. This is probably the single most challenging problem that chemoinformatics must solve. [M Hann and R Green "Chemoinformatics – a new name for an old problem?" Current Opinion in Chemical Biology 3:379- 383, 1999]
Mixing of information technology and management to transform data into information and information into knowledge for the intended purpose of making better decisions faster in the arena of drug lead identification and optimization. ..In Chemoinformatics there are really only two [primary] questions: 1.) what to test next and 2.) what to make next. The main processes within drug discovery are lead identification, where a lead is something that has activity in the low micromolar range, and lead optimization, which is the process of transforming a lead into a drug candidate. [Frank Brown "Chemoinformatics: What is it and How does it Impact Drug Discovery" Annual Reports in Medicinal Chemistry 33: 375-384, 1998
chemotherapy: Often refers to cancer treatments, but is also used more generally for drug therapy, particularly antimicrobial drugs. Synonyms: Drug treatment (drug therapy), medication therapy, pharmacotherapeutics, pharmacotherapy Genetics Home Reference, National Library of Medicine, NIH http://ghr.nlm.nih.gov/ghr/glossary/chemotherapy
circulating tumor cells CTCs: Molecular characterization of tumour material will become increasingly important in selecting patients for clinical trials and offering appropriate treatment for patients in clinical practice. Recent advances in the field have indicated that the molecular characteristics of a tumour can be determined from circulating tumour cells and circulating tumour DNA; thus, a simple blood sample could provide these data in a simple, convenient and efficient manner. Circulating tumour-derived predictive biomarkers in oncology, Hodgson DR, Wellings R, Orr MC, McCormack R, Malone M, Board RE, Cantarini MV., AstraZeneca, Drug Discovery Today. 2010 Feb;15(3-4):98-101. Epub 2010 Jan 4. http://www.ncbi.nlm.nih.gov/pubmed/20045486
from other informatics, clinical bioinformatics should focus more on clinical
informatics, including patient complaints, history, therapies, clinical symptoms
and signs, physician's examinations, biochemical analyses, imaging profiles,
pathologies and other measurements. It was emphasized that the simultaneous
evaluation of clinical and basic research could improve medical care, care
provision data, and data exploitation methods in disease therapy and algorithms
for the analysis of such heterogeneous data sets. Clinical bioinformatics:
a new emerging science Xiangdong Wang and
Lance Liotta, Journal
of Clinical Bioinformatics 1:1 2011http://www.ncbi.nlm.nih.gov/
application of informatics approaches to the clinical- evaluation phase of drug
development. These approaches can include clinical- trial simulations to improve
trial design and patient selection, as well as electronic capturing and storing
of clinical data and protocols. The goal is to reduce expenses and time to
Informatics News http://www.clinicalinformaticsnews.com/
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 http://www.nap.edu/books/NI000479/html/R1.html
clone: A population of genetically identical cells produced from a common ancestor. Sometimes also used to refer to a number of recombinant DNA molecules all carrying the same inserted sequence. IUPAC Medicinal Chemistry, IUPAC Compendium
Clone was coined by Herbert J. Webber in 1903 for "a colony of organisms derived asexually from a single progenitor" and was quickly adopted by botanists and cell biologists. But the popular perception of cloning can be traced to Alvin Toffler's Future Shock (1970) and was quickly popularized (and extended to items such as computers). But Lee Silver, Professor of Molecular Biology and Public Affairs, Princeton Univ. concludes that "the scientific community has lost control over Webber's pleasant sounding little word. Cloning has a popular connotation that is impossible to dislodge. We must accept that democratic debate on cloning is bereft of any meaning. Science and Scientists would be better served by choosing other words to explain advances in developmental biotechnology to the public". L. Silver "What are clones? They're not what you think they are" Nature 412 (6842): 21, 5 July 2001
cloning: Using specialized DNA technology (see cloning vector) to produce multiple, exact copies of a single gene or other segment of DNA to obtain enough material for further study. This process is used by researchers in the Human Genome Project, and is referred to as cloning DNA. The resulting cloned (copied) collections of DNA molecules are called clone libraries. A second type of cloning exploits the natural process of cell division to make many copies of an entire cell. The genetic makeup of these cloned cells, called a cell line, is identical to the original cell. A third type of cloning produces complete, genetically identical animals such as the famous Scottish sheep, Dolly. [DOE]
The process of making copies of a specific piece of DNA, usually a gene. When geneticists speak of cloning, they do not mean the process of making genetically identical copies of an entire organism. [NHGRI]
Rooting plant cuttings and having identical twins can also be considered types of cloning.
pharmaceutical outsourcing trend and economic restrictions, coupled with the
increasing attractiveness of cloud computing offerings, have created a highly
dynamic yet nascent market. Insight Pharma Reports Cloud
Computing in Life Sciences R&D 2010
be horizontal (a group of small companies), vertical (suppliers and
customers), sectoral (same industry sector) or lateral (complementary but
different sectors). From the Latin, meaning to work with.
The biomedical industry faces a crisis in productivity, with rapidly rising costs for R&D but declining results. While many other industries have found ways to enhance performance using pre-competitive collaboration, the biomedical industry has been reluctant to embrace such sharing of information, investments, risk and costs. There are, however, encouraging signs that important shifts are taking place, as evidenced by a growing number of consortia, programs for open innovation, and experiments with crowd-sourcing to find solutions outside a single company. One area ripe for collaboration is the field of neglected diseases, where the shortage of traditional profit opportunities mean that companies are forced to re-think how to achieve the most productive results.
combination products: Include (1) A product comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity; (2) Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products; (3) A drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose; or (4) Any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect. Definition of a Combination Product, FDA, Office of Combination Products, As defined in 21 CFR § 3.2(e) http://www.fda.gov/CombinationProducts/AboutCombinationProducts/ucm118332.htm
combination therapies: Today, combination products range from drug-drug combinations to drug-device combinations, such as drug-eluting stents for coronary blockages, to drug-biological products, such as monoclonal antibodies combined with a chemotherapy agent for the treatment of cancer. Each product type offers significant solutions to many of the problems plaguing healthcare. Insight Pharma Reports, Combination Therapies: Benefits and Challenges in Drug, Device and Biologicals Development, 2005 http://www.insightpharmareports.com/reports/2005/56_Combination/overview.asp
As ever more combination therapies are applied in various areas of medicine, there is a growing need for quantitative descriptions of combination effects. While most of the scientific community has agreed on a basic standard for synergy, there is no consensus on quantifying the degree to which a combination may deviate from synergy, and no predictive models are accepted to serve as benchmarks. This project will convene a working group, involving leading experts on combination effects, to (1) endorse the synergy criterion recommended at a recent meeting in Finland, (2) adopt standard measures of combination effect to quantify deviations from synergy, and (3) explore predictive combination-effect models for multiply-inhibited biological interaction networks. Quantifying the Effects of Compound Combinations Chemistry International 25 (4) July-Aug. 2004, http://www.iupac.org/publications/ci/2004/2604/pp5_2003-059-1-700.html
combinatorial chemistry: Using a combinatorial process to prepare sets of compounds from sets of building blocks. IUPAC Combinatorial Chemistry Related terms: combinatorial libraries, diversity, microtiter plates, molecular diversity, fully combinatorial, pool/ split
companion diagnostics: A trend in genetic diagnostics and therapeutics is for the two to become increasingly intertwined. Companion diagnostics identify subsets of patients who would benefit from a specific drug.
comparative effectiveness research CER: A rigorous evaluation of the impact of different options that are available for treating a given medical condition for a particular set of patients. Such a study may compare similar treatments, such as competing drugs, or it may analyze very different approaches, such as surgery and drug therapy.” Such research may include the development and use of clinical registries, clinical data networks, and other forms of electronic health data that can be used to generate or obtain outcomes data as they apply to CER. Recovery Act Limited Competition: NIH Challenge Grants in Health and Science Research (RC1), 2009 http://grants.nih.gov/grants/guide/rfa-files/RFA-OD-09-003.html
complex: It has become common to use complicated and complex interchangeably … The essence of ‘complicated’ is hard to figure out. ..Complex, on the other hand is a term reserved for systems that display properties that are not predictable from a complete description of their components, and that are generally considered to be qualitatively different from the sum of their parts. [Editorial, "Complicated is not complex" Nature Biotechnology 17: 511 June 1999]
Would it be fair to say that Mendelian genetics is linear, while genomics and polygenic diseases/traits are nonlinear?
According to the Oxford English Dictionary one of the meanings of complicated is complex, though it also means not easy to unravel or separate. Both complex and complicated are contrasted with simple. Whatever the original senses of these two words, the above distinction seems a useful one now. Related term: complexity; Narrower terms: biocomplexity, complex diseases, complex genomes; complex phenotypes, complex traits
complex diseases: Diseases characterized by risk to relatives of an affected individual which is greater than the incidence of the disorder in the population. [NHLBI]
Are complex diseases essentially the same as polygenic diseases?
complex phenotypes: Those that exhibit familial clustering, which may mean that there is some genetic component, but that do not occur in Mendelian proportions in pedigrees. Complex phenotypes may be continuous in distribution, like height or blood pressure, or they may be dichotomous, like affected and not affected. The complexity arises from the fact one cannot accurately predict the expression of the phenotype from knowledge of the individual effects of individual factors considered alone, no matter how well understood each separate component may be. Genetic Architecture, Biological Variation and Complex Phenotypes, PA-02-110, May 29, 2002- June 5, 2005 http://grants1.nih.gov/grants/guide/pa-files/PA-02-110.html
complex trait: Has a genetic component that is not strictly Mendelian (dominant, recessive, or sex linked) and may involve the interaction of two or more genes to produce a phenotype, or may involve gene environment interactions." [NHLBI] Related term: genetic architecture
complexity:: Currently there are more than 30 different mathematical descriptions of complexity. However we have yet to understand the mathematical dependency relating the number of genes with organism complexity. J. Craig Venter et. al. "The sequence of the Human Genome" Science 291 (5507): 1347, Feb. 16, 2001
An ill- defined term that means many things to many people. Complex things are neither random nor regular, but hover somewhere in between. Intuitively, complexity is a measure of how interesting something is. Other types of complexity may be well defined. Gary William Flake, Computational Beauty of Nature: Computer Explorations of Fractals, Chaos, Complex Systems, and Adaptation, MIT Press, 1998 http://www.comdig.org/
properties such as lipophilicity and molecular mass are known to have an
important influence on the absorption, distribution, metabolism, excretion
and toxicity (ADMET) profile of small-molecule drug candidates. To assess
the use of this knowledge in reducing the likelihood of compound related
attrition, the molecular properties of compounds acting at specific drug
targets described in patents from leading pharmaceutical companies during
the 2000-2010 period were analysed. ... we conclude that a
substantial sector of the pharmaceutical industry has not modified its
drug design practices and is still producing compounds with suboptimal
physicochemical profiles. Paul D. Leeson and Stephen A St-Gallay The
influence of the "organizational factor" on compound quality in
drug discovery, Nature Reviews Drug Discovery, 10:749-765, October 2011http://www.ncbi.nlm.nih.gov/pubmed/21959288
computer aided diagnosis CAD: A general term used for a variety of artificial intelligence techniques applied to medical images. CAD methods are being rapidly developed at several academic and industry sites, particularly for large-scale breast, lung, and colon cancer screening studies. X-ray imaging for breast, lung and colon cancer screening are good physical and clinical models for the development of CAD methods, related image database resources, and the development of common metrics and methods for evaluation. For large- scale screening applications CAD methods are an important for: (a) improving the sensitivity of cancer detection, (b) reducing observer variation in image interpretation, (c) increasing the efficiency of reading large image arrays, (d) improving efficiency of screening by identifying suspect lesions or identifying normal images, and (e) facilitating remote reading by experts (e.g., telemammography).
Image processing tools are also being developed for temporal analysis of serial images, with the aim of detecting early subtle changes that might not be obvious to the reading physician. Temporal analysis requires additional consensus on the development of reference standards (electronic ground truth), software modules for registration of serial images and related image segmentation. In addition, CAD techniques can improve the specificity of cancer detection by assigning a quantitative estimate of the probability that a detected lesion is benign or malignant. Another promising application of CAD is predicting which cases are most suitable for a particular treatment option. NEW NCI INITIATIVES IN COMPUTER AIDED DIAGNOSIS, Laurence P. Clarke, et. al. National Cancer Institute, http://imaging.cancer.gov/programsandresources/reportsandpublications/publications/newnciinitiativesincomputeraideddiagnosis
computational physiology: The International Union of Physiological Sciences (IUPS) Physiome Project is an internationally collaborative open- source project to provide a public domain framework for computational physiology, including the development of modeling standards, computational tools and web-accessible databases of models of structure and function at all spatial scales [1,2,3]. It aims to develop an infrastructure for linking models of biological structure and function across multiple levels of spatial organization and multiple time scales. The levels of biological organisation, from genes to the whole organism, includes gene regulatory networks, protein- protein and protein- ligand interactions, protein pathways, integrative cell function, tissue and whole heart structure- function relations. The whole heart models include the spatial distribution of protein expression. Keynote: Peter J. Hunter, Univ of Auckland, International Society of Computational Biology, Detroit, MI, 2005 http://www.iscb.org/ismb2005/keynotes.html
Copy Number Polymorphisms CNPs: represent a greatly underestimated aspect of human genetic variation. Recently, two landmark studies reported genome-wide analyses of CNPs in normal individuals and represent the beginning of an understanding of this type of large-scale variation. Patrick G. Buckley*, Kiran K. Mantripragada*, Arkadiusz Piotrowski, Teresita Diaz de Ståhl and Jan P. Dumanski Copy-number polymorphisms: mining the tip of an iceberg, Trends in Genetics 21 (6): 315- 317, June 2005 http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TCY-4G1PKNS-1&_user=10&_coverDate=06%2F30%2F2 Another term for CNV
Copy Number Variation CNV: We defined a CNV as a DNA segment that is 1kb or larger and present at variable copy number in comparison with a reference genome. A CNV can be simple in structure, such as tandem duplication, or may involve complex gains or losses of homologus sequences at multiple sites in the genome. Richard Redon et. al, Global Variaiton in copy number in the human genome, Nature 2006 Nov 23;444 (7118): 444- 454
Copy number variations
(CNVs) hold immense potential to explain genetic diversity, predict disease risk
and diagnose complex genomic disorders have long resisted understanding. Now
recently developed whole-genome scanning technologies have catalyzed the
appreciation of CNVs in the genomic community. Studies linking insertions,
deletions, and inversions to disease etiology continue to multiply. As
genome-wide scanning techniques become more prevalent in diagnostic
laboratories, the major challenge is how to interpret accurately which
variations are pathogenic in nature and which are benign.
data quality: A vital consideration for data analysis and interpretation. While people are still reeling from the vast amount of data becoming available, they need to brace themselves to both discard low quality data and handle much more at the same time.
developability: Drug 'developability' assessment has become an increasingly important addition to traditional drug efficacy and toxicity evaluations, as pharmaceutical scientists strive to accelerate drug discovery and development processes in a time- and cost-effective manner. D. Sun et. al, In vitro testing of drug absorption for drug 'developability' assessment: forming an interface between in vitro preclinical data and clinical outcome. Curr Opin Drug Discov Devel.; 7(1): 75- 85, Jan 2004
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 Narrower terms: companion diagnostics, molecular diagnostics
digital PCR dPCR: A new application in research and development allowing for higher sensitivity and specificity than real-time PCR. This allows researchers to closely examine rare genetic mutations (including single nucleotide polymorphisms), copy number variations, viruses, prenatal defects, and much more. National measurement institutions have also been looking into digital PCR as a reference standard as well as using its precision and accuracy to create reference standards for diagnostic labs. Digital PCR Technology Report: An Insight to Vendors, Costs & the End User Community, Insight Pharma Reports, 2013 http://www.insightpharmareports.com/digital-pcr-repor
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 http://www.sciencemag.org/cgi/content/full/293/5531/807
Collections of symptoms and signs (phenotypes) that appear to be similar … Similar clinical phenotypes may have very different underlying mechanisms. As genetic capabilities increase, we will have additional tools to subdivide disease designations that are clinically identical. Allen D. Roses “Pharmacogenetics and future drug development and delivery” Lancet 355 (9212):1358- 1361 Apr 15, 2000
disruptive technologies: Some technologies are improved in a linear fashion or incrementally. Others truly change the paradigm. Clayton Christensen writes about these in The Innovator's Dilemma. What is particularly interesting about Christensen's analysis (based on data from the disk drive industry) is that he found disruptive technologies tended to be much cheaper than existing technologies. Existing companies were quite capable of developing the technologies (and had). What they couldn't do was figure out how to market them and whether it made sense to devote sufficient resources to them (which in many cases would not have been the responsible thing to do.)
industry is mentioned only in passing, but the success of larger established
companies either partnering with smaller less established ones (clearly
happening in the pharmaceutical and biotechnology sectors) or spin- off of
promising developments as separate companies (Johnson & Johnson said to be
particularly good at this) makes a lot of sense.
DNA vaccines: DNA- mediated immunization, colloquially known as DNA vaccines. This represents a radical change in the way that antigens are delivered; it involves the direct introduction of a plasmid DNA encoding an antigenic protein which is then expressed within cells of the organism. This leads to surprisingly strong immune responses, involving both the humoral and cellular arms of the immune system. Robert G. Whelan, DNA Vaccines, Cyberspace and Self Help Programs, Intervirology 39: 120-125 (1996) DNAvaccine. com http://dnavaccine.com/
drug: Any substance which when absorbed into a living organism may modify one or more of its functions. The term is generally accepted for a substance taken for a therapeutic purpose, but is also commonly used for abused substances. Synonymous with medicine, pharmaceutical. [IUPAC Compendium]
A substance recognized by an official pharmacopoeia or formulary, a substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease. A substance (other than food) intended to affect the structure or any function of the body. A substance intended for use as a component of a medicine but not a device or a component, part or accessory of a device. Biologic products are included within this definition and are generally covered by the same laws and regulations, but differences exist regarding their manufacturing processes (chemical process vs. biological process.) CDER, FDA Glossary http://www.fda.gov/cder/drugsatfda/glossary.htm Narrower terms: specialty pharmaceuticals. Compare biologics.
drug development costs: Joseph DiMasi et. al, Tufts CSDD, 2014
drug discovery: For any given target, HTS High Throughput Synthesis remains the predominant tool for identifying leads for further drug development. Those companies that can effectively deal with the flood of large numbers of potential targets coming out of genomics are those that can gain a significant competitive advantage. However, this abundance of new targets is both an opportunity and a threat. When companies are able to prioritize and validate targets, it allows them to narrow the focus to those leads offering improved chances of success. Related terms: target validation
drug interactions: Examples of drug interaction terms include adverse drug interaction, drug- drug interaction, drug- laboratory interaction, drug- food interaction, etc. Drug interaction is defined as, "An action of a drug on the effectiveness or toxicity of another drug". .. Due to non- uniform usage of these terms, it is sometimes difficult to compare various studies and derive incidence rates, etc. for ADRs, and Drug Interactions Saeed A Khan, "Drug Interaction or Adverse Drug Reaction? Confusing Terms", British Medical Journal 10 July, 1998] http://bmj.com/cgi/eletters/316/7149/1930
Drug Safety Initiative, FDA http://www.fda.gov/cder/drugSafety.htm Related terms: idiosyncratic toxicity, pharmacovigilance
drug utilization research: was defined by WHO in 1977 as «the marketing, distribution,
prescription, and use of drugs in a society, with special emphasis on the
resulting medical, social and economic consequences». Since then, a number of
other terms have come into use and it is important to understand the
interrelationships of the different domains… Drug
utilization research may also be divided into descriptive and analytical
studies. The emphasis of the former has been to describe patterns of drug
utilization and to identify problems deserving more detailed studies. Analytical
studies try to link data on drug utilization to figures on morbidity, outcome of
treatment and quality of care with the ultimate goal of assessing whether drug
therapy is rational or not. … Drug
utilization research is thus an essential part of pharmacoepidemiology as it
describes the extent, nature and determinants of drug exposure. Over time, the
distinction between these two terms has become less sharp, and they are
sometimes used interchangeably. However, while drug utilization studies often
employ various sources of information that focus on drugs (e.g. aggregate data
from wholesale and prescription registers) the term epidemiology implies defined
populations in which drug use can be expressed in terms of incidence and
prevalence … Drug utilization research also provides insight into
the efficiency of drug use, i.e. whether a certain drug therapy provides value
for money and the results of such research can be used to help to set priorities
for the rational allocation of health care budgets. Introduction to drug
utilization research, WHO World Health Organization 2003 http://apps.who.int/medicinedocs/en/d/Js4876e/2.html
druggable: Able to be modulated by a small molecule to produce a desired phenotypic change in cell targets. Variant spelling is drugable, but druggable is more common. Alternatively/ Related terms: developability, drug-like, drug likeness, druggable, low hanging fruit, pharmaceutically tractable, privileged structure
efficacy: Describes the relative intensity with which agonists vary in the response they produce even when they occupy the same number of receptors and with the same affinity. Efficacy is not synonymous to intrinsic activity. The property that enables drugs to produce responses.
It is convenient to differentiate the properties of drugs into two groups, those which cause them to associate with the receptors (affinity) and those that produce stimulus (Efficacy). This term is often used to characterize the level of maximal responses induced by agonists. In fact, not all agonists of a receptor are capable of inducing identical levels of maximal responses. Maximal response depends on the efficiency of receptor coupling, i.e., from the cascade of events, which, from the binding of the drug to the receptor, leads to the observed biological effect. IUPAC Medicinal Chemistry
electroceuticals: The first logical step towards electroceuticals is to better map the neural circuits associated with disease and treatment. This needs to happen on two levels. On the anatomical level researchers need to map disease-associated nerves and brain areas and identify the best points for intervention. On the signalling level, the neural language at these intervention points must be decoded to develop a "dictionary" of patterns associated with health and disease states -- a project synergistic with international drives to map the human brain.
Research teams across the globe have realised that by targeting individual nerve fibres or specific brain circuits they may soon be able to treat a wide range of conditions that have formerly relied on drug-based interventions. This could include inflammatory diseases such as rheumatoid arthritis, respiratory diseases such as asthma and diabetes. In the long run you could also control neuro-psychiatric disorders like Parkinson's and epilepsy. It wouldn't be possible to treat infectious diseases, since the bacteria and viruses that cause them aren't directly connected to the nervous system, nor would you be able to treat cancer directly in this way. However, in both cases you could stimulate the relevant nerves to boost aspects of the immune system. Electroceuticals swapping drugs for devices, Wired 28 May 2013 http://www.wired.co.uk/news/archive/2013-05/28/electroceuticals Related terms: bioelectronics, Genomics: optogenetics
enabling technologies: Frequently cited examples of enabling technologies for drug discovery and development are combinatorial chemistry, high-throughput screening, microarrays, bioinformatics and computational biology, nanotechnologies, and imaging (including biosensors and biomarkers).
years scientists have known that biological fate is not regulated solely by DNA
sequence; super ordinate regulatory mechanisms exist and contribute to determine
the function of genes. Intense research has shown that these mechanisms, broadly
defined as epigenetics, are multifaceted and complex. As researchers continue to
decipher the roles of DNA, RNA, proteins, and environment in inheritance, the
increased understanding of gene regulation and cellular differentiation from
embryogenesis to aging will reveal therapeutic interventions as well as
diagnostic and prognostic tools for disease.
evidence- based toxicology: Evidence-based toxicology: a comprehensive framework for causation, Guzelian PS, Victoroff MS, Halmes NC, James RC, Guzelian CP., Hum Exp Toxicol. 2005 Apr;24(4): 161-201
expression: The cellular production of the protein encoded by a particular gene. The process includes transcription of DNA, processing of the resulting mRNA product and its translation into an active protein. N.B. A recombinant gene inserted into a host cell by means of a vector is said to be expressed if the synthesis of the encoded polypeptide can be demonstrated. IUPAC Bioinorganic, IUPAC Compendium
A description as to how a gene demonstrates a phenotype. This can range from production of a mRNA to a disease. If a disease gene carrier shows signs of the disease gene, then that gene is expressed. Note that an individual must carry the disease gene and be penetrant for it before the term expression is utilized. [NHLBI] Narrower terms: gene expression, protein expression. Related terms: expression profiling, molecular profiling
expression profiling: Expression profiling is driving the pharmaceutical R&D process. It is being used downstream of target identification, as a biological readout for target modulation. Targets first identified through genomics then need to go through validation testing, to see if a phenotypic change occurs when a target is dysregulated. These targets or pathways can be modified by using either RNAi, or the use of a chemical ligand that interacts with a target. The results are compared in order to understand a compound’s activity for on- and off- target effects.
Refers to the expression values for a single gene across many experimental conditions, or for many genes under a single condition. In the terminology of cluster format, the first case amounts to looking at a row of the data table, and the second case a column.
fail fast: Several high-quality analyses comparing the track record of smaller biotechnology companies with established pharmaceutical companies have concluded that company size is not an indicator of success in terms of R&D productivity … the strongest single correlator with success (odds ratio 3.9) was having a high termination rate in preclinical/Phase I stages. This indicates that companies have an early idea of which assets are likely to succeed, and that the companies most willing to face the hard decisions about which assets to terminate do better than companies that let assets linger. Does size matter in R&D productivity? If not, what does? Michael Ringel, Peter Tollman, Greg Hersch and Ulrik Schulze Nature Reviews Drug Discovery 12:901-902, Dec 2013 http://www.nature.com/nrd/journal/v12/n12/pdf/nrd4164.pdf
Designed to eliminate high risk compounds at an early stage to free up existing capacity for more successful compounds. The industry is faced with an increasing number of unvalidated or poorly validated candidates and targets. Companies risk decreasing their productivity rate if they end up chasing more low quality drug candidates. There isn't enough matter in the universe to make all possible compounds. A term that has tended to make people in drug discovery and development wince, but considering the costs of later failures, it looks more and more like an attractive option.
fast track: The fast track process was established in the FDA Modernization Act of 1997. Under this act, NDAs are deemed either "standard" or "priority" (fast track). With the "standard" designation, the FDA’s goal is to complete the review and make a decision on the NDA within ten months after it has been filed. With the "priority" designation, used for drugs that address unmet medical needs, the target date is six months after the filing. However, actual approval times are typically longer. In certain cases, the FDA also offers "accelerated approval" to allow the marketing of drugs for life-threatening diseases, before the benefits to patients are formally demonstrated. This approval is made on the basis of a surrogate marker (e.g., a drug’s effect on survival).
FIPCO Fully Integrated Pharmaceutical Company: Not as popular a goal in the 21st century as in the mid-late 1990's.
franchises - pharmaceutical: In the pharmaceutical industry, we tend to think of franchises as a suite of relevant drugs marketed to a specific cluster of physicians. While this definition served our needs for sales efficiency and scientific credibility, it has left too much value on the table. We encourage the industry to re-think the idea of franchise in terms of brand identity, of the images, values and ideas consumers and other stakeholders, such as pharmacists, associate with a given brand. Vimal Bahuguna and Bob Lieberman, "From Patents to Franchises, Bogart Delafield Ferrier, US http://www.bdf.com/patentstofranchises.htm
function: 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
The term "function" means many things, and its meaning changes depending on who is asking the question and what sorts of experiments are being employed to probe it. 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. Chemogenomics/ Chemical Genomics Nov. 18- 19, 2002, Boston MA Narrower terms: gene function, protein function
functional genomics: Functional genomics aims to discover the biological function of particular genes and to uncover how sets of genes and their products work together in health and disease. In its broadest definition, functional genomics encompasses many traditional molecular genetic and other biological approaches. 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 proteomics: Is yielding large databases of interacting proteins and extensive pathways maps of these interactions are being scored and deciphered by novel high throughput technologies. However, traditional methods of screening have not been very successful in identifying protein- protein interaction inhibitor
gene (cistron): Structurally, a basic unit of hereditary material; an ordered sequence of nucleotide bases that encodes one polypeptide chain (via mRNA). The gene includes, however, regions preceding and following the coding region (leader and trailer) as well as (in eukaryotes) intervening sequences (introns) between individual coding segments (exons). Functionally, the gene is defined by the cis- trans test that determines whether independent mutations of the same phenotype occur within a single gene or in several genes involved in the same function. IUPAC Compendium
There are many discussions between biologists to find a comprehensive definition of a gene, which is not easy, if possible at all. For our purposes a gene is a continuous stretch of a genomic DNA molecule, from which a complex molecular machinery can read information (encoded as a string of A, T, G, and C) and make a particular type of a protein or a few different proteins. Alvis Brazma, et. al., A quick introduction to elements of biology: 3.3 Genes and protein synthesis, European Bioinformatics Institute, Draft, 2001 http://www.ebi.ac.uk/microarray/biology_intro.html#Genomes
Specific sequences of nucleotides along a molecule of DNA (or, in the case of some viruses, RNA) which represent the functional units of heredity. The majority of eukaryotic genes contain coding regions (codons) that are interrupted by non- coding regions (introns) and are therefore labeled split genes. MeSH, 1965
is a DNA segment that contributes to phenotype/ function. In the absence of
demonstrated function a gene may be characterized by sequence, transcription or
homology. Human Gene Nomenclature, HUGO Genomics
The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein NHGRI
This definition doesn't specify that it applies only to humans - but by specifying "parents" it seems to rule out non- animal genes, and almost implies mammals, or at least warm- blooded organisms.
gene disruption: A key methodology in high- throughput gene functional analysis. Involves developing various methods for systematically disrupting genes throughout the genome of a model organism (resulting in knockouts, or null mutations of these genes) and then the phenotype (if any) of the mutant organism.
gene expression: The process by which a gene’s coded information is converted into the structures present and operating in the cell. Expressed genes include those that are transcribed into mRNA and then translated into protein and those that are transcribed into RNA but not translated into protein (e.g. transfer [tRNA] and ribosomal [rRNA] RNAs). [DOE]
The phenotypic manifestation of a gene or genes by the processes of gene action. MeSH, 1990
Our modern concept of gene expression dates back to 1961 when messenger RNA was discovered, the genetic code was deciphered, and the theory of genetic regulation of protein synthesis was described. O Ermolaeva et al “Data Management and analysis for gene expression arrays” Nature Genetics 20: 19- 23,1998
The transcription of a gene and its processing to yield a mature messenger RNA (mRNA). (Note that in proteomic studies, the same term also includes the translation of the mRNA to produce a functional protein.) In studies of differential gene expression, one looks for genes whose expression levels differ significantly under different experimental conditions, for example in normal versus diseased states or in untreated versus treated subjects. This application is perhaps the most obvious use of microarrays. Broader terms: expression, genome expression Related term: protein expression
gene expression profiling: The determination of the pattern of genes expressed i.e., transcribed, under specific circumstances or in a specific cell. MeSH, 2000
gene manipulation: The use of in vitro techniques to produce DNA molecules containing novel combinations of genes or altered sequences, and the insertion of these into vectors that can be used for their incorporation into host organisms or cells in which they are capable of continued propagation of the modified genes. [IUPAC Biotech]
gene patents: Much of the controversy surrounding patenting genes stems from a misunderstanding of the limitations of patent law. Numerous media sources often refer to "gene patents." This term is imprecise and can lead to the belief that it is possible to file for a blanket patent covering all the possible uses of a gene, or even a patent on the sequence itself. Further misunderstandings arise from the failure to differentiate between a patent that is pending and a patent that has been granted. .. [Patenting Genes, about.com] http://biotech.about.com/library/weekly/aa060900a.htm
controversy over gene patents emerged when Dr. Craig Venter, CEO of Celera
Genomics, sent 20,000 gene sequences to the PTO, claiming patents to the
sequences and to procedures that would be used to diagnose disorders with the
genes. The PTO denied these applications, suggesting that simply finding DNA
sequences and claiming their use as a research reagent was not sufficient for a
patent. The PTO thus indicated that it required the inventor of a gene to show a
level of utility beyond the gene’s use as a research tool. ¶ 6 The standard
of utility wielded by the PTO, however, has been far from clear. [THE FATE OF
GENE PATENTS UNDER THE NEW UTILITY GUIDELINES, Feb. 28 , 2001, Duke
Law and Technology Review, Cite as 2001 Duke L. & Tech. Rev. 0008] http://www.law.duke.edu/journals/dltr/ARTICLES/2001dltr0008.html
Narrower terms: cDNA
patents, disease gene patents, EST patents, gene fragments, SNP patents
gene silencing: Interruption or suppression of the expression of a gene at transcriptional or translational levels. MeSH 2000 Narrower term: RNAi RNA interference
gene therapy: Encompasses at least four types of application of genetic engineering for the insertion of genes into humans. The scientific requirements and the ethical issues associated with each type are discussed. Somatic cell gene therapy is technically the simplest and ethically the least controversial. The first clinical trials will probably be undertaken within the next year . Germ line gene therapy will require major advances in our present knowledge and it raises ethical issues that are now being debated. In order to provide guidelines for determining when germ line gene therapy would be ethical, the author presents three criteria which should be satisfied prior to the time that a clinical protocol is attempted in humans. Enhancement genetic engineering presents significant, and troubling, ethical concerns. Except where this type of therapy can be justified on the grounds of preventive medicine, enhancement engineering should not be performed. The fourth type, eugenic genetic engineering, is impossible at present and will probably remain so for the foreseeable future, despite the widespread media attention it has received. W. French Anderson "Human gene therapy: scientific and ethical considerations" J Med Philosophy 10 (3): 275- 291, Aug. 1985
human number of: The
release of the draft human genome sequence in 2001 revealed a much lower human
gene count than expected . The paper published by the public consortium
estimated 30,000 to 40,000 protein-coding genes. This number was in rough
agreement with the count in the private consortium's paper, which reported
26,588 protein-coding genes with 'strong' evidence, and an additional 12,000
computationally predicted genes with weaker evidence. Strong evidence included
similarity to previously known proteins, homology to another mammal, and EST
evidence. Weak genes were those with homology to mouse, but lack of other
supporting evidence. After 3 years of detailed finishing work, a much more
complete draft genome was published in 2004, and along with this more complete
sequence, the public consortium announced a new, much lower, estimate of human
protein-coding genes, only 20,000 to 25,000. .. Furthermore, the imprecision of
the estimate raised questions about the validity of many predicted genes.
Although the near-finished human genome sequence now covers 99% of the
euchromatic (or gene-containing) genome at 99.999% accuracy, the exact number of
human genes is still unknown. … In
addition to the ongoing uncertainty about the precise number of protein-coding
genes, recent evidence has emerged that makes it clear that different humans
have slightly different individual gene sets. A major source of such differences
is variation in the number of segmental duplications scattered across the
genome. … Our personal
best guess for the total number of human genes is 22,333, which corresponds to
the current gene total at NCBI. We prefer this to the slightly higher Ensembl
gene count both because the NCBI annotation is slightly more conservative, and
because recent compelling arguments support an even lower gene total. This
number could easily shrink or grow by 1,000 genes in the near future. However,
recent analyses make it clear that even if we agree on a complete list of human
genes, any particular individual might be missing some of the genes in that
list. The genome sequence is complete enough now (although it is not yet
finished) that few new genes are likely to be discovered in the gaps, but it
seems likely that more genes remain to be discovered by sequencing more
individuals. Additional discoveries are likely to make our best estimates for
this basic fact about the human genome continue to move up and down for many
years to come. Between
a chicken and a grape: estimating the number of human genes Mihaela
Pertea and Steven
L Salzberg Genome
Biol. 2010; 11(5): 206.Published online May 5, 2010. doi: 10.1186/gb-2010-
At the 2000 Cold Spring Harbor Genome conference [May 10-14] "one of the hotly debated topics was the number of human genes. This has been estimated at anything from 35,000 to 150,000. Considering the spread of opinion, the only way to resolve was to get people to bet on it … This led to an interesting debate on the definition of a gene … and how to assess that number. A gene is a set of connected transcripts. A transcript is a set of exons via transcription followed (optionally) by pre- mRNA splicing. Two transcripts are connected if they share at least part of one exon in the genomic coordinates. At least one transcript must be expressed outside of the nucleus and one transcript must encode a protein. "Genesweep" Ensembl, European Bioinformatics Institute, UK http://www.ensembl.org/Genesweep/
With the publication of the Human Genome Project draft sequence in Feb. 2001 we learned that the number of genes (about 30,000) seems to be many fewer than expected, but the number of proteins per gene, with alternative splicing (two to three, instead of one) is greater. More surprises seem sure to be in store
genetic engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. MeSH, 1989 Related term: recombinant DNA technology
genetic enhancement: The use of genetic methodologies to improve functional capacities of an organism rather than to treat disease. MeSH, 2002
The subject of much discussion and concern over the ethics of, though new disease diagnoses, treatments (and concepts of "disease") are much closer than true genetic enhancements. The popular conception of selective breeding focuses on optimization of one or a very few traits (which produces tomatoes which ship well but have no taste, and purebred dogs with congenital hip dysplasia. Little attention has been paid to the tradeoffs (predictable and not) inevitable among polygenic traits.
"Regression to the mean" also factors in. While two tall or two bright people tend to have children who are taller or brighter than average, they are NOT usually taller or brighter than the parents are. Or as George Bernard Shaw said to the actress who told him they should have children -- "with my looks and your brain" -- what if it turned out the other way around?
Only microbes with their greatly enhanced opportunities for evolving (with such short reproductive spans) seem to quickly get reliably bigger, better (in a sense) and stronger. Biological homeostasis is incredibly powerful. We may never be able to "enhance" complex traits such as intelligence or strength. But we need to learn how to talk about these issues -- preferably before actually being able to actually implement genetic enhancement.
genetic maps: The value of the genetic map is that an inherited disease can be located on the map by following the inheritance of a DNA marker present in affected individuals (but absent in unaffected individuals), even though the molecular basis of the disease may not yet be understood nor the responsible gene identified. Genetic maps have been used to find the exact chromosomal location of several important disease genes, including cystic fibrosis, sickle cell disease, Tay- Sachs disease, fragile X syndrome, and myotonic dystrophy. Primer on Molecular Genetics, Oak Ridge National Lab, US Can be cytogenetic, linkage, or physical maps. Starting genetic maps is easier than finishing them.
genetic testing: Allen Roses, worldwide director of genetics for Glaxo Wellcome [now Glaxo SmithKline] notes "Until now, government sponsored committees convened to address ‘genetic testing’ have generally limited their definition and their reports to concerns regarding diseases caused by single gene mutations … Another class of 'genetic tests’ is related to pharmacogenetics, including ... variants or other inherited polymorphic traits that are not diagnostic of disease … Clear language and differentiation of respective ethical, legal and societal issues are required to prevent inaccurate vernacular usage creating a confused public perception. Allen Roses, Pharmacogenetics and the practice of medicine” Nature 405: 857- 865, 15 June 2000
genome: The complete set of chromosomal and extrachromosomal genes of an organism, a cell, an organelle or a virus; the complete DNA component of an organism. [IUPAC Biotech]
The fundamental concepts of genome, genotype and phenotype are not defined in a satisfactory manner within the biological literature. Not only are there inconsistencies in usage between various authors, but even individual authors do not use these concepts in a consistent manner within their own writings. We have found at least five different notions of genome, seven of genotype, and five of phenotype current in the literature. Our goal is to clarify this situation by (a) defining clearly and precisely the notions of genetic complement, genome, genotype, phenetic complement, and phenotype; (b) examining that of phenome; and (c) analysing the logical structure of this family of concepts. [M. Mahner, M. Kary "What exactly are genomes, genotypes and phenotypes? And what about phenomes?" Journal of Theoretical Biology 186 (1): 55- 63, May 1997]
All the DNA contained in an organism or a cell, which includes both the chromosomes within the nucleus and the DNA in mitochondria. [NHGRI] Size expressed by the number of base pairs. [DOE].
First used by H. Winkler in 1920, was created by elision of the words GENes and chromosOMEs, and that is what the term signifies: the complete set of chromosomes and their genes. V McKusick "Genomics: Structural and Functional studies of genomes" Genomics 45:244-249 Oct. 15 1997
development of efficient and reliable ways to make precise, targeted changes to
the genome of living cells is a long-standing goal for biomedical researchers.
Recently, a new tool based on a bacterial CRISPR-associated protein-9 nuclease
(Cas9) from Streptococcus
generated considerable excitement (1). This follows several attempts over the
years to manipulate gene function, including homologous recombination and
RNA interference (RNAi)
recent approaches to targeted genome modification – zinc-finger nucleases
[ZFNs, (7)] and transcription-activator like effector nucleases [TALENs]–
enable researchers to generate permanent mutations by introducing doublestranded
breaks to activate repair pathways. These approaches are costly and
time-consuming to engineer, limiting their widespread use, particularly for
large scale, high-throughput studies. CRISPR/Cas9
and Targeted Genome Editing: A New Era in Molecular Biology, New England BioLabs
genomic DNA gDNA: The entire length of DNA, including non coding regions. (Sometimes called gDNA.) CHI Bioinformatics report DNA which includes exons and introns, coding and noncoding regions. Compare with cDNA
genomics: 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
genotype: The genetic constitution of an organism as revealed by genetic or molecular analysis, i.e. the complete set of genes, both dominant and recessive, possessed by a particular cell or organism. [IUPAC Biotech]
The observed alleles at a genetic locus for an individual. [NHLBI]
An organism’s genetic makeup, as revealed through molecular analysis.
genotyping: The process of assessing genetic variation present in an individual. CHA Cambridge Healthtech Advisors, Clinical Genomics: The Impact of Genomics on Clinical Trials and Medical Practice report, 2004
Used for diagnosis, drug efficacy, and toxicity. Utilizes genomic DNA that, after digestion, reacts with a SNP array to obtain an individual SNP pattern. These variations can for instance provide information about the diagnosis of a certain disease, or the effectiveness or side effect of a certain drug. May refer to identifying one or more, up to the entire gene sequence of an organism. Compare phenotype Genotyping implies (though I haven't found this in print) determining known variants, as opposed to discovery of new ones.
Full DNA sequencing is the "gold standard" for genotyping.
granularity: Level of detail. As we learn more and more about biology we find that older concepts are not so much wrong, but that what we knows becomes more and more granular, and we learn more about what we don't yet know or understand.
Wide Association Sequencing: An
analysis comparing the allele frequencies of all available (or a whole GENOME
representative set of) polymorphic markers in unrelated patients with a specific
symptom or disease condition, and those of healthy controls to identify markers
associated with a specific disease or condition. MeSH 2009
The NIH is interested in advancing genome-wide association studies (GWAS) to identify common genetic factors that influence health and disease. For the purposes of this policy, a genome-wide association study is defined as any study of genetic variation across the entire human genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight), or the presence or absence of a disease or condition. Whole genome information, when combined with clinical and other phenotype data, offers the potential for increased understanding of basic biological processes affecting human health, improvement in the prediction of disease and patient care, and ultimately the realization of the promise of personalized medicine. http://grants.nih.gov/grants/gwas/ Pronounced "gee-wahs"
haplotypes: The genetic constitution of individuals with respect to one member of a pair of allelic genes, or sets of genes that are closely linked and tend to be inherited together such as those of the MAJOR HISTOCOMPATIBILITY COMPLEX. MeSH 1987
haplotyping: Somatic cells, as opposed to germ cells, have two copies of each chromosome. A given single- base position may be homozygous for the wild- type base (each chromosome has the normal allele), homozygous for a SNP base (each chromosome has the altered allele), or heterozygous for two different bases (one chromosome has the normal allele and the other has the abnormal allele). Haplotyping involves grouping subjects by haplotypes, or particular patterns of sequential SNPs, found on a single chromosome. These SNPs tend to be inherited together over time and can serve as disease- gene markers. The examination of single chromosome sets (haploid sets), as opposed to the usual chromosome pairings (diploid sets), is important because mutations in one copy of a chromosome pair can be masked by normal sequences present on the other copy. Genes tend to travel in packs. This is good news for pharmacogenomics. Broader terms genotyping, sequencing
high-content screening HTS: By using multiple fluorescent reporter systems, combined with high- resolution imaging and high- throughput image analysis, researchers can observe multiple intracellular events in individual cells. High- content screening (HCS) enables functional analysis of target and pathway modulation in living cells by potential drug compounds. Availability of high- content cellular information at early stages in drug discovery process will improve the quality of targets, hits, and leads; reduce late- stage attrition; and shorten time and cost of drug development.
high tech industry: The traditional perception of high tech - still reflected in our indicators - has been research- intensive manufacturing industries, like computers and aircraft. The penetration of technologies like information technology, biotechnology, and advanced materials throughout the economy has, however, changed the basic meaning of high tech. Rather than referring to the output of R&D intensive industries, high tech now refers to a style of work applicable to just about every business ... This change is said to have revolutionized the features of a successful technology policy. Distributed knowledge, skill, entrepreneurship, together with new forms of collaboration between firms, universities and the government, can now result in more effective products and services. Importantly for both firm and worker income, they can result in significantly differentiated products and services. In other words, technology policy must be more user- centered and demand- based than ever before. Nicholas S. Vonortas "US Policy towards Research Joint Ventures" Nov. 1999 http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.197.5598
high throughput: Although the adjective "high throughput" was originally coined in a drug screening context, high throughput strategies to accelerate and automate earlier steps in the drug discovery pipeline have already been introduced. With the introduction of genomics- based drug discovery strategies, the concept of high throughput has extended to areas like gene expression analysis, where microarrays allow the simultaneous expression profiling of thousands of genes in diseased versus normal samples. In the early stages of disease- gene research, when one wishes to identify alterations in gene expression that are associated with a disease state with significant societal impact and potential market value, a microarray- based approach provides significant acceleration over traditional methods to evaluate candidate genes one at a time.
high throughput screening: Process for rapid assessment of the activity of samples from a combinatorial library or other compound collection, often by running parallel assays in plates of 96 or more wells. IUPAC Combinatorial Chemistry
Traditionally describes the running of a large-scale assay campaign looking at the effects of a large number of compounds on a biological target. Broader term: screening Narrower terms: high content screening, ultra high throughput screening Related term: high throughput
home brews: Reagents or the combination of reagents made in a laboratory, or purchased reagents used by that laboratory for clinical tests and not for sale to other laboratories. Promoting Safe and Effective Genetic Testing in the United States Glossary, Updated 2004, Genetic Testing Report, 1997 http://www.genome.gov/10002399
housekeeping genes: In theory, expressed in all genes. Contrast with luxury genes. Genes that encode housekeeping proteins. Specific housekeeping genes can be used to normalize gene expression data. Not usually the gene of greatest interest for functional studies.
Human Genome Project HGP: Horace Freeland Judson writes in "Talking about the genome" (Nature 409:769, 15 Feb. 2001) "The language we use about genetics and the genome project at times limits and distorts our own understanding, and the public understanding. Look at the phrase - or marketing slogan - 'the human-genome project'. In reality, of course we have not just one human genome but billions. ... Then, too, the entire phrase - the human- genome project: singular, definite, with a fixed end- point, completed by 2000, packaged so it could be sold to legislative bodies, to the people, to venture capitalists. But we knew from the start the genome project would never be complete.
A coordinated effort of researchers to map (CHROMOSOME MAPPING) and sequence (SEQUENCE ANALYSIS, DNA) the human genome. MeSH, 1990
induced pluripotent stem cells hiPS: Reprogramming
differentiated human cells to induced pluripotent stem (iPS) cells
has applications in basic biology, drug development, and
transplantation. Human iPS cell derivation previously required vectors
that integrate into the genome, which can create mutations and limit
the utility of the cells in both research and clinical applications.
Here, we describe the derivation of human iPS cells using
non-integrating episomal vectors. After removal of the episome, iPS
cells completely free of vector and transgene sequences are derived
that are similar to human embryonic stem (ES) cells in proliferative
and developmental potential. Junying Yu 1*, Kejin Hu 2, Kim Smuga-Otto 1,
Shulan Tian 3, Ron Stewart 3, Igor I. Slukvin 4,
James A. Thomson 5* Human Induced Pluripotent Stem Cells Free of Vector and Transgene
Sequences, Science DOI: 10.1126/science.1172482 published online March 26, 2009
hypercompetitive: In Richard A. D'Aveni's Hypercompetitive Rivalries: Competing in Highly Dynamic Environments, (1995) he describes situations in which competitive advantages are not sustainable. Companies must be willing to cannibalize their own customers and positions, making all products obsolete including their own. The pharmaceutical industry is sometimes described as hypercompetitive.
hyphenated techniques: Usually involves a combination of chromatography and/ or mass spectrometry, NMR or other spectroscopy technologies.
idiosyncratic toxicity: Few drug development surprises can be as devastating as toxicity problems that only show up under a combination of conditions as idiosyncratic toxicity. Because of the role of variations in human drug metabolizing enzymes there may only be subtle (or no) evidence of such problems during pre-clinical safety studies. Such problems are also unlikely to show up in all but the largest clinical trials, but if the side effects are serious, it can result in product withdrawal.
ill posed problems: In the 1960s [Russian mathematician Andrei Nikolaevich] Tikhonov began to produce an important series of papers on ill- posed problems. He defined a class of regularisable ill- posed problems and introduced the concept of a regularising operator which was used in the solution of these problems. Combining his computing skills with solving problems of this type Tikhonov gave computer implementations of algorithms to compute the operators which he used in the solution of these problems.. "Andrei Nikolaevich Tikhonov", MacTutor History of Mathematics, Univ. of St. Andrews, Scotland, 1999
Problems without a unique solution, problems without any solution. Life sciences data tends to be very noisy, leading to ill-posed problems. Interpretation of microarray and gene expression data is an ill- posed problem. Compare well- posed problem
in silico: In a white paper I wrote for the European Commission in 1988 I advocated the funding of genome programs, and in particular the use of computers. In this endeavour I coined "in silico" following "in vitro" and "in vivo" I think that the first public use of the word is in the following paper: A. Danchin, C. Médigue, O. Gascuel, H. Soldano, A. Hénaut, From data banks to data bases. Res. Microbiol. (1991) 142: 913- 916. You can find a developed account of this story in my book The Delphic Boat, Harvard University Press, 2003 personal communication Antoine Danchin, Institute Pasteur, 2003
Literally "in the computer". Narrower terms: in silico biology, in silico modeling, in silico proteomics, in silico screening, in silico target discovery, virtual cells in silico Compare in vivo, in vitro
The study of the application of computer
and statistical techniques to the management of information. In genome
projects, informatics includes the development of methods to search databases
quickly, to analyse DNA sequence information, and to predict protein
sequence and structure from DNA sequence data. [ORD Office of Rare Diseases,
information overload: http://www.genomicglossaries.com/presentation/SLA_outline.asp
information silos: The cultural aspects impeding communication between different groups can be immense, are often not recognized or articulated, and greatly impede interdisciplinary research.
interdisciplinary: Terminology and ideas relevant to molecular medicine comes from a wide variety of disciplines: analytical chemistry, artificial intelligence, biochemistry, bioinformatics, biomechanics, biophysics, biotechnology, cell biology, clinical and research medicine, computer sciences, developmental and structural biology, electrochemistry, electronics, engineering, enzymology, epidemiology, genetic engineering, molecular imaging, immunology, mathematics, microbiology, molecular biology, optics, pharmacology, public health, statistics, toxicology, virology and aspects of business, chaos theory, ethics and law are all relevant. Few people (if any) can be truly interdisciplinary and expert in all of these subjects. Universities and companies are struggling with the challenge of (and need to) build bridges between departments and sectors. We all need to learn more to participate in informed public debate
International HapMap project The International HapMap Project is a partnership of scientists and funding agencies from Canada, China, Japan, Nigeria, the United Kingdom and the United States to develop a public resource that will help researchers find genes associated with human disease and response to pharmaceuticals. http://www.hapmap.org/
The goal of the International HapMap Project is to produce a resource that describes the haplotypes in the human genome and the SNPs that tag them. It is estimated that roughly 300,000 to 500,000 tag SNPs can be chosen that contain most of the information on the patterns of variation of the 10 million common SNPs in the human genome. By using the HapMap tag SNPs, researchers will be able to examine candidate regions or even the entire genome for association with a phenotype in an efficient and comprehensive way. Additional genotyping for the Human Haplotype Map, Apr. 16, 2004 RFA Number: RFA-HG-04-005 http://grants1.nih.gov/grants/guide/rfa-files/RFA-HG-04-005.html
of a system or a product to work with other systems or products without special
effort on the part of the customer. Interoperability is made possible by the
implementation of standards. IEEE, Standards Glossary 2010 http://www.ieee.org/education_careers/education/standards/standards_glossary.html
Enabling heterogeneous databases to function in an integrated way, sometimes refers to cross platform functionality and operability across relational, object- oriented, and non- standard types of databases.
"junk DNA": A general term that encompasses many different types of DNA sequences. These sequences run the gamut from introns, the parts of genes that are edited out during protein synthesis; transposable elements, repeated DNA sequences that, like parasites, duplicate themselves, adding nothing to the genome except more redundant sequence; and pseudo genes, fossils of one- time genes…all of the regulatory elements – promoters and inhibitors - required for gene transcription are spelled out somewhere between the genes. The same is true of other elements deemed junk, such as introns and RNA genes, which clearly hold important clues to understanding alternative splicing … the term junk DNA is frequently used incorrectly. Numerous articles in the medical literature use junk and non- coding DNA interchangeably. B. Kuska "Bring in Da Noise, Bring in Da Junk" JNCI 90(15): 1125-1127 Aug. 5, 1998
Dr. Susumu Ohno, writing in the Brookhaven Symposium on Biology in 1972 in the article "So Much ‘Junk DNA" in our Genome’ is credited with originating the term. But his paper was focused "mainly on the fossilized genes, called pseudo genes, that are strewn like tombstones throughout our DNA. But as the term caught on in the 1980’s, its meaning was extended to all non- coding sequences, the vast stretches of DNA that are not genes and do not produce proteins" (about 95% of the genome) … some [scientists] have begun the scrap the notion that all non- coding DNA is junk … "I don't think people take the term very seriously anymore" says Eric Green [NHGRI] whose group is mapping chromosome 7. B. Kuska "Should Scientists Scrap the Notion of Junk DNA?" JNCI 90(14): 1032-1033 July 15 1998 Narrower terms intron, non- coding, repetitive sequences.
knockdowns: Altering the function of a gene so that it can be conditionally expressed. This is necessary when complete knockout of the gene would be lethal to the organism. Related terms: antisense, embryonic lethal trait, knockin, knockout, RNAI RNA Interference Narrower term: genomewide knockdowns
knockins: Gain of function through addition/ substitution of genetic material. One example of a knockin is deletion of a coding sequence of a gene in a mouse and then replacing it with human coding sequences.
knockouts: Inactivation of specific genes. Knockouts are often created in laboratory organisms such as yeast or mice so that scientists can study the knockout organism as a model for a particular disease. [NHGRI]
Use of particular techniques to "knock out" the function of a gene in a model organism. Studying the effects of the gene knockout can help researchers understand the function of the gene that has been inhibited. Narrower terms: conditional knockout, random homozygous knockout Related terms gene knockout, knockdown, knockin, protein knockouts
knockouts -- protein: Our proteomics efforts are focused largely on developing new techniques to probe protein- protein interactions and to construct devices that allow one to monitor the levels and post- translational modification states of hundreds or even thousands of proteins simultaneously. A third major goal is to develop “protein knockout” methods that would allow researchers to rapidly develop reagents to block one or more functions of a newly discovered protein to facilitate studies of its role in cellular metabolism. [Thomas J. Kodadek, Internal Medicine and Molecular Biology, Univ. of Texas Southwestern Graduate Biomedical School, 2001] http://www2.utsouthwestern.edu/gradschool/webrib/kodadek.htm
lead optimization: The synthetic modification of a biologically active compound, to fulfill all stereoelectronic, physicochemical, pharmacokinetic and toxicologic required for clinical usefulness. IUPAC Medicinal Chemistry
Fueled by the need to bring down the cost of drug discovery and development, a major shift is occurring in how pharmaceutical companies evaluate drug leads. Whereas researchers used to begin by looking at affinity and potency, a genomics/informatics- based research culture is growing and starting to impinge on the classical mode. Companies are now concentrating on determining potential drugs leads' ADMET (absorption, distribution, metabolism, excretion, and toxicological) properties and manufacturability. Insight Pharma Advances in Lead Optimization report, 2003
Related terms: ADME, ADMETox, drug development. Narrower terms: lead discovery, lead prioritization, lead selection, lead validation, toxicogenomics, parallel optimization
An unordered collection of clones (i.e., cloned DNA from a particular organism),
whose relationship to each other can be established by physical mapping.
life cycle management: Successful drugs follow a typical pattern of heavy up- front investment in development, followed by market penetration and peaking sales, followed by a decline in the face of follow- on drugs or generics. A number of approaches can be used to alter the shape of this revenue curve, including second- generation follow- on compounds, extended life through formulation and drug delivery enhancements, outcome studies and management of the generification process. Some steps can be taken early to maximize the benefits of drug life cycle management.
life sciences informatics: Informatics are essential at every step of genomics-based drug discovery and development. The commercial landscape of life sciences information technology has changed dramatically in the last few years. Bioinformatics, in particular, has gone through a dramatic boom/bust. While IT companies are looking to the drug discovery and development arena as a new market opportunity, pharmaceutical companies are faced with rising pressure to reduce (or at least control) costs, and have a growing need for new informatics tools to help manage the influx of data from genomics, and turn that data into tomorrow's drugs. Key IT tools, such as high- performance computing, Web services, and grids, are being used to improve the speed and efficiency of drug discovery and development. True breakthroughs are still lacking, particularly in key areas such as gene prediction, data mining, protein structure modeling and prediction, and modeling of complex biological systems. However, most experts agree that IT and bioinformatics are essential to reaching the improved productivity the pharmaceutical industry craves.
life style drugs: Drugs treating conditions such as obesity, erectile dysfunction, baldness, aging. The attraction is a steady market for which consumers may well be willing to pay for.
low hanging fruit: The easiest drugs to identify and gain approval for. The big question these days is how much (if any) "low hanging fruit" is left.
market forecasting- pharmaceutical: Accurately forecasting the market potential for new compounds is becoming an essential tool in long- term strategic planning, as it aids in various decisions that are pivotal to the survival and success of a biotech or pharmaceutical company. Forecasting is used in many situations: to evaluate a licensing opportunity, to assess a particular lead compound and even in pipeline and R&D portfolio analyses. Forecasting is also essential in understanding how the dynamics of a market are changing, and in raising awareness of a company's current and future competitors. .. Top- down forecasting extrapolates from available sales data, using algorithms of how a particular drug class or market has previously performed. Bottom- up forecasting involves reconstructing the market from its components, which allows the analyst to model how particular changes over the forecast period will affect the base- year assumptions. John Earl "What makes a good forecaster?" Nature Reviews Drug Discovery 2(1): 83, Jan. 2003 http://www.nature.com/drugdisc/nj/articles/nrd1005.html
market fragmentation - pharmaceutical industry: Currently, the percentage of patients that react favorably to a drug ranges from 20-80%. The market segments itself as patients and doctors switch between medications in order to find the one that works. In fact, market share may erode further, even in the absence of significant competition, as physicians avoid prescribing a drug if a subset of patients suffer toxic side effects. By defining the population that responds well to a drug, pharmacogenomics can help secure market share. Blockbusters are still possible if the defined population is large.
mass spectrometry: This technique can be used to both measure and analyze molecules under study. It involves introducing enough energy into a target molecule to cause its ionization and disintegration. The resulting fragments are then analyzed, based on the mass/ charge ratio to produce a "molecular fingerprint."
A significant technology behind progress in proteomics
medical informatics: The field of information science concerned with the analysis and dissemination of medical data through the application of computers to various aspects of health care and medicine. MeSH, 1987
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. American Medical Association, "Proteomics" How can proteomics be applied to medicine? http://www.ama-assn.org/ama/pub/physician-resources/medical-science/genetics-molecular-medicine/current-topics/proteomics.page?
medicinal chemistry: A chemistry based discipline, also involving aspects of biological, medical and pharmaceutical sciences. It is concerned with the invention, discovery, design, identification and preparation of biologically active compounds, the study of their metabolism, the interpretation of their mode of action at the molecular level and the construction of structure- activity relationships IUPAC Medicinal Chemistry
drugs that post sales of $1 billion in more than 50 countries within two years
of their launch. IMS Reviews Pharma Growth and Outlines Future Trends
ICS Chemical Business 2000 http://www.icis.com/resources/news/2000/03/27/108823/ims-reviews-pharma-growth-and-outlines-future-trends/
Mendelian genetics: Classical genetics, focuses on monogenic genes with high penetrance, the tip of the iceberg of genetics. Genomics is both a narrower and broader term than genetics
Metabolic Engineering ME: An approach to the understanding and utilization of metabolic processes. As the name implies, ME is the targeted and purposeful alteration of metabolic pathways found in an organism in order to better understand and utilize cellular pathways for chemical transformation, energy transduction, and supramolecular assembly. ME typically involves the redirection of cellular activities by the rearrangement of the enzymatic, transport, and regulatory functions of the cell through the use of recombinant DNA and other techniques. Much of this effort has focused on microbial organisms, but important work is being done in cell cultures derived from plants, insects, and animals. National Science Foundation, Interagency Opportunities in Metabolic Engineering, Program Solicitation NSF 05-502, 2004 http://www.nsf.gov/pubs/2005/nsf05502/nsf05502.htm
metabolic profiling: For investigators of selected biochemical pathways, it is also often not necessary to view the effects of perturbation on all branches of metabolism. Instead, the analytical procedure can be focused on a smaller number of pre- defined metabolites. Sample preparation and data acquisition can be focused on the chemical properties of these compounds with the chance to reduce matrix effects. This process is called metabolite profiling (or sometimes metabolic profiling). Oliver Fiehn "Combining genomics, metabolome analysis, and biochemical modelling to understand metabolic networks" Comparative and Functional Genomics 2: 155-168, 2001 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2447208/
metabolism: In case of heterotrophic organisms, the energy evolving from catabolic processes is made available for use by the organism. IUPAC Medicinal Chemistry
The sum of chemical changes that occur within the tissues of an organism consisting of anabolism (BIOSYNTHESIS) and catabolism; the buildup and breakdown of molecules for utilization by the body. MeSH
The total fate of a xenobiotic, which includes: absorption, distribution, biotransformation, metabolism and elimination (ADME). Metabolism and biotransformation are often used interchangeably, but the latter term does not encompass absorption, distribution and elimination. Glossary, XenoTech LLC http://xenotechllc.com/Knowledge/Glossary/
Metabolism, Wikipedia, accessed May 27, 2004 http://en.wikipedia.org/wiki/Metabolism distinguishes between total metabolism, specific metabolism, cell metabolism and other types of metabolism.
metabolite: A compound derived from the parent drug through Phase I and/or Phase II metabolic pathways, Glossary, Guidance for Industry, Safety testing of drug metabolites, FDA, 2008 http://www.fda.gov/OHRMS/DOCKETS/98fr/FDA-2008-D-0065-GDL.pdf
Any intermediate or product resulting from metabolism. IUPAC International Union of Pure and Applied Chemistry, Glossary for Chemists of terms used in biotechnology. Recommendations, Pure & Applied Chemistry 64 (1): 143-168, 1992
metabolomics: The study of the metabolite profiles in biological samples, is growing amidst the current shift toward translational research. Although there is some debate over what the field should actually be called, scientists are pushing forward to find uses for metabolomic profiling, a clinical option that is comparatively cheap and noninvasive. Charles W. Schmidt, Metabolomics: What's happening downstream of DNA, EHP online Environmental Health Perspectives, Toxicogenomics, 2004 http://ehp.niehs.nih.gov/txg/members/2004/112-7/focus.html?section=toxicogenomics
The general aim of metabolomics is to
identify, measure and interpret the complex time-related concentration,
activity and flux of endogenous metabolites in cells, tissues, and other
biosamples such as blood, urine, and saliva.
For the purposes of this solicitation, metabolites include small
molecules that are the products and intermediates of metabolism, but also
carbohydrates, peptides, and lipids… It is expected that the technologies
developed under this initiative will play a major role in transferring
capabilities to laboratories and research institutes that are investigating
the underlying pathways involved in cellular homeostasis, perturbation,
development, and aging.
Due to pleiotropic effects, the effect of a single mutation may lead to the alteration of metabolite levels of seemingly unrelated biochemical pathways. This is especially liable to happen if genes are constitutively overexpressed or anti- sense inhibited. A comprehensive and quantitative analysis of all metabolites could help researchers understand such systems. Since such an analysis reveals the metabolome of the biological system under study, this approach should be called metabolomics. Analogous to proteins and proteomics, metabolomics, or metabonomics, is the study of all the metabolites of a cell or organism. Identifying and quantifying these components helps to reveal cellular regulation, pathways, activity, and response under normal and other conditions. Brush up on your 'omics, Chemical & Engineering News, 81(49): 20, Dec. 2003 http://pubs.acs.org/cen/coverstory/8149/8149genomics1.html
For functional genomic or plant breeding programmes, as well as for diagnostic usage in industrial or clinical routines, it might not be necessary to determine the levels of all metabolites individually. Instead, a rapid classification of samples according to their origin or their biological relevance might be more adequate in order to maintain a high through- put. This process can be called metabolic finger- printing. Such approaches have occasionally been termed metabonomics, which on the one hand could be mixed up with the completely different goal of metabolomics, and on the other hand with the earlier defined concept of the metabolon, the coordinated channelling of substrates through tightly connected enzyme complexes. Oliver Fiehn, "Combining genomics, metabolome analysis and biochemical modelling to understand metabolic networks" Comparative and Functional Genomics 2:155-168 April, 2001 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2447208/
metabonome, metabonomics: The quantitative measurement of the dynamic multiparametric metabolic response of living systems to pathophysiological stimuli or genetic modification. This concept has arisen from work on the application of 1H-NMR spectroscopy to study the multicomponent measurement of biofluids, cells, and tissues. [J.K. Nicholson, J.C. Lindon & E. Holmes, "Metabonomics" understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica 29, 1181-1189, 1999]
Total small molecule complement of a cell. [Jeremy K. Nicholson, J.C. Lindon & E. Holmes. "Metabonomics": understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica 29, 1181-1189, 1999]
microarrays: Tool for studying how large numbers of genes interact with each other and how a cell’s regulatory networks control vast batteries of genes simultaneously. Uses a robot to precisely apply tiny droplets containing functional DNA to glass slides. Researchers then attach fluorescent labels to DNA from the cell they are studying. The labeled probes are allowed to bind to cDNA strands on the slides. The slides are put into a scanning microscope to measure … how much of a specific DNA fragment is present. [NHGRI]
Roger Brent has compared microarrays to the telescope or microscope because they enable the observer to see what was previously unobservable. Alternatively: arrays, gene chips, SNP chips Related terms: antibody arrays, protein chips
microdosing: The concept of microdosing calls for the administration of an investigational compound to healthy human volunteers in doses at least two orders of magnitude lower than those that, based on animal studies, would have a pharmacological effect in humans. There is also a fixed ceiling dose (100 μg) that must not be exceeded. CHA Advances Report , Microdosing in Translational Medicine: Pros and Cons, Hermann A.M. Mucke, 2006
Almost half of new drugs fail at the transition from animal to human trials. Human microdosing points the way to smarter drug development and may be the answer to what has been perceived as a productivity crisis in the industry. By testing only 1% of a pharmacological dose in humans, failures can be identified much earlier in the development process – at Phase 0. This approach has proven to be successful in ADME prediction, helping scientists identify which candidates merit further development. Microdosing technology can also be used to determine absolute bioavailability, thus aiding drug developers to assess pharmacodynamics and physiological activity. Gathering scientists together to discuss this new and important tool certainly seems needed in order to promote faster, more efficacious drug development. Using microdosing shows promise of reducing time spent on drugs destined to fail, and also cutting down on the costs associated with testing. In addition, human microdosing at Phase 0 will mitigate the need for testing in animals, and can also help to determine the best animal models to use. Microdosing studies have become possible due in large part to the technical advances of detection instruments.
miniaturization: Desirable for many technologies for overall cost reduction (including reduction in the amount of reagents and analytes needed). Important to remember that building space is often the least available and most expensive component of a laboratory budget.
molecular diagnostics: 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. CHI Molecular Diagnostics: Technological Advances fueling Market Expansion report 2003
molecular diagnostics techniques: MOLECULAR BIOLOGY techniques used in the diagnosis of disease. Included are such techniques as IN SITU HYBRIDIZATION of chromosomes for CYTOGENTIC ANALYSIS; OLIGONUCLEOTIDE ARRAY SEQUENCE ANALYSIS of gene expression patterns in disease states; identification of pathogenic organisms by analysis of species specific DNA sequences; and detection of mutations with PCR (POLYMERASE CHAIN REACTION). MeSH, 2002
molecular epidemiology: The application of molecular biology to the answering of epidemiological questions. The examination of patterns of changes in DNA to implicate particular carcinogens and the use of molecular markers to predict which individuals are at highest risk for a disease are common examples. MeSH, 1994
Looking at epidemiology from a genetic/genomic and/or biochemical viewpoint.
molecular imaging: The rapidly developing domain of molecular imaging represents the merging of current advances in the fields of molecular biology and imaging research. Despite this merger, an information gap continues to exist between the scientists who discover new gene products and the imaging scientists who can exploit this information. The Gene Ontology (GO) Consortium seeks to provide a set of structured terminologies for the conceptual annotation of gene product function, process and location in databases. However, no such structured set of concept-oriented terminology exists for the molecular imaging domain. Since the purpose of GO is to capture the information about the role of gene products, we propose that the mapping of GO's established ontological concepts to a molecular imaging terminology will provide the necessary bridge to fill the information gap between the two fields. Tulipano PK, Millar WS, Cimino JJ. "Linking molecular imaging terminology to the gene ontology (GO)" Pacific Symposium Biocomputing 613- 623, 2003
molecular medicine: The Journal of Molecular Medicine publishes reports describing major advances in the understanding, prevention, diagnosis, or treatment of human disease through the application of molecular biology and gene technology, a research discipline that has become known as molecular medicine.. Journal of Molecular Medicine, Springer, Aims and Scope http://www.springer.com/biomed/molecular/journal/109 Alternatively/related terms: clinical genomics, predictive medicine
modeling, molecular modelling: A technique for the
investigation of molecular structures and properties using computational
chemistry and graphical visualization techniques in order to provide a plausible
three- dimensional representation under a given set of circumstances.
IUPAC Medicinal Chemistry, IUPAC Computational
molecular 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.
molecular profiling: A dynamic new discipline, capable of generating a global view of mRNA, protein patterns, and DNA alterations in various cell types and disease processes. MP integrates the expanding genetic databases from the Human Genome Project with newly developed expression analysis technologies and holds great promise to help us: Understand the molecular anatomy of normal cells and cells in various stages of disease. Develop new diagnostic and therapeutic targets for clinical intervention. Explain the relationship between genotype and phenotype in humans, which is still largely unknown. NCI, NIH CGAP "Molecular Profiling" http://cgap-mf.nih.gov/index.html
molecular therapeutics: Current Opinion in Molecular Therapeutics "about this journal" gives the scope as "viral and non-viral gene therapy, oligonucleotides, peptide therapeutics, antibody approaches, molecular vaccines, and the technologies underlying genomics and proteomics." http://www.biomedcentral.com/curropinmolther/ accessed Dec 27, 2010
monoclonal antibodies: A single species of immunoglobulin molecules produced by culturing a single clone of a hybridoma cell. MAbs recognize only one chemical structure, i.e., they are directed against a single epitope of the antigenic substance used to raise the antibody. IUPAC Biotech
Antibodies produced by
clones of cells such as those isolated after hybridization of activated B
lymphocytes with neoplastic cells. These hybrids are often referred to as
hybridomas. MeSH, 1982
multibusters: Multiple drugs for a single indication, efficacious in identifiable sub- populations. Related term: blockbuster drugs
multiplex: A sequencing approach that uses several pooled samples, greatly increasing sequencing speed. [DOE]
Simultaneous amplification of multiple gene products within the same reaction. Chamberlain, J.S. et al. Nucleic Acids Research 16, 11141, 1988
In general, primer- extension technologies are amenable to high- throughput applications and automation, yet only very low levels of multiplexing are possible. Higher multiplexing can be accomplished by combining primer- extension technology with microarray technology.
Originally a math term meaning multiple, later a 19th century telecommunications term, dating from the telegraph. Oxford English Dictionary
nanomedicine: The monitoring, repair, construction and control of human biological systems at the molecular level, using engineered nanodevices and nanostructures. [Robert A. Freitas, Nanomedicine, Foresight Institute, 1998- 2002] http://www.foresight.org/Nanomedicine/
A rapidly expanding field that includes many potential technologies and approaches. The key to this definition is that phenomena and materials at the nanometer scale are known to have properties that are uniquely attributable to that scale length. Nanomedicine could similarly be defined [as nanotechnology] as the design, synthesis, or application of materials, devices, or technologies in the nanometer-scale for the basic understanding, diagnosis, and / or treatment of disease. Canadian Institute of Health Research, Regenerative Medicine and Nanomedicine, RFA, 2003 http://www.cihr-irsc.gc.ca/e/services/16044.shtml
Obtaining thorough, reliable measures of quantity is the vital first step of nanomedicine. … Research conducted over the first few years will be spent gathering extensive information about how molecular machines are built. A key activity during this time will be the development of a new kind of vocabulary —lexicon — to define biological parts and processes in engineering terms. …Once researchers have completely catalogued the interactions between and within molecules, they can begin to look for patterns and a higher order of connectedness than is possible to identify with current experimental methods. Mapping these networks and understanding how they change over time will be a crucial step toward helping scientists understand nature’s rules of biological design. Understanding these rules will, in many years’ time, enable researchers to use this information to address biological issues in unhealthy cells. The availability of innovative, body-friendly nanotools will help scientists figure out how to build synthetic biological devices, such as miniature, implantable pumps for drug delivery or tiny sensors to scan for the presence of infectious agents or metabolic imbalances that could spell trouble for the body. NHGRI, Nanomedicine, 2007 http://www.genome.gov/11508736
The goal of the Common Fund's Nanomedicine program is to determine how cellular machines operate at the nanoscale level and then use these design principles to develop and engineer new technologies and devices for repairing tissue or preventing and curing disease. Nanomedicine, NIH Common Fund http://commonfund.nih.gov/nanomedicine/
Nanomedicine Taxonomy, Canadian NanoBusiness Alliance, 2003 http://www.pain.cz/nanomedicina/files/taxanomy.pdf
The study of phenomena and manipulation of materials at atomic,
molecular and macromolecular scales, where properties differ significantly from
those at a larger scale. Draft definitions, Royal Society, Royal Academy of
Engineering Nanotechnology and Nanoscience, 2003 http://www.nanotec.org.uk/draftdefinition.htm
NCE New Chemical Entity A compound not previously described in the literature. IUPAC Medicinal Chemistry
Any new molecular compound not previously approved for human use, excluding diagnostic agents, vaccines and other biologic compounds not approved by the FDA's Centers for Drug Evaluation and Research (CDER). Also excluded are new salts, esters and dosage forms of previously approved compounds. Tufts Center for the Study of Drug Development, Glossary, 2004 http://csdd.tufts.edu/InfoServices/Glossary.asp Compare: me too drug
NDA New Drug Application: For decades, the regulation and control of new drugs in the United States has been based on the New Drug Application (NDA). Since 1938, every new drug has been the subject of an approved NDA before U.S. commercialization. The NDA application is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the U.S. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/NewDrugApplicationNDA/
networks: Although there is no consensus definition of "program" or "networks", these terms are most often encountered and understood in the context of the regulatory interactions that link groups of genes and gene products in developmental processes. Many of these linkages have recently been elucidated in considerable detail for key events in a variety of species. Sean Carroll "Communications breakdown?" (book review) Science 291: 1264-1265, Feb. 16, 2001
There are three bottlenecks in the numerical analysis of biochemical reaction networks. The first is the multiple time scales involved. Since the time between biochemical reactions decreases exponentially with the total probability of a reaction per unit time, the number of computational steps to simulate a unit of biological time increases roughly exponentially as reactions are added to the system or rate constants are increased. The second bottleneck derives from the necessity to collect sufficient statistics from many runs of the Monte- Carlo simulation to predict the phenomenon of interest. The third bottleneck is a practical one of model building and testing: hypothesis exploration, sensitivity analyses, and back calculations, will also be computationally intensive. [Lawrence Berkeley Lab "Advanced Computational Structural Genomics" Glossary] Narrower terms: biochemical networks, molecular networks. Related terms: network models, pathways
new paradigms: An investigation by Science revealed that use of the term "new paradigm" in MEDLINE and the ISI database of leading journals increased steadily during the 1990’s, as did its use in NIH and NSF databases of new grants. J Cohen "The March of Paradigms" Science 283 : 1998-1999 Mar 26, 1999
While many advances are unlikely to be truly new paradigms, a few developments show signs of being more than incremental improvements. Roger Brent compares microarrays to the microscope and telescope because they "enable observation of the previous unobservable" [transcripts expressed under different conditions in cells, tissues, and organisms] [R. Brent, "Functional genomics: learning to think about gene expression data" Current Biology 9: R338-R341, May 1999] This is no overstatement.
next generation sequencing technologies: Next-generation sequencing (NGS) has taken the worldwide biomedical research community by storm. Funding is relatively abundant for the moment, collaborative programs and consortia abound, and early results in many cases appear to justify all the activity. Many observers sense imminent new revelations and even paradigm shifts offering significant improvements in the understanding and treatment of disease. Insight Pharma Reports Next-Generation Sequencing Technologies: Applications and Markets 2010
Up-to-date information on the newest options for DNA sequencing, and the tools to manage the data. The major new advantages will be showcased in the latest platforms, and strategies for managing the data to turn it into useful information will be demonstrated. Next generation sequencing technologies DVD 2010 Molecular Medicine short course http://www.triconference.com/SC1_DVD.asp
NME New Molecular Entity: A New Molecular Entity is an active ingredient that has never before been marketed in the United States in any form. FDA, Glossary Drugs@FDA, 2012, http://www.fda.gov/cder/drugsatfda/glossary.htm
NMR Nuclear Magnetic Resonance: A technology for protein structure determination. NMR generally gives a lower- resolution structure than X-ray crystallography does, but it does not require crystallization. .
nonlinear: Advances in biopharmaceutical technologies are a mix of incremental improvements to existing technologies (linear) and occasionally, a truly new paradigm or breakthrough. Related terms: disruptive technologies, emerging technologies, biocomplexity, complex
nutraceuticals: Foods with specific health or medical benefits. Differentiate from supplements, which supplies missing nutrients. Examples include folic acid (to prevent birth defects) or pectin (to lower cholesterol) and fiber (to reduce the risk of color cancer). Sometimes spelled nutriceutical.
off label: The use of an FDA- approved drug or device for a purpose other than that intended by the manufacturer and described on the label. FDA only approves drugs or devices for their intended use as described on the label. Neal Holtzman, Michael Watson "Promoting Safe and Effective Genetic Testing in the United States: Final Report" glossary, 1997 http://www.nhgri.nih.gov/ELSI/TFGT_final/glossary.html
-omes: A key approach in genomic research is to divide the cellular contents into distinct sub- population, each given an -omic term. Broadly, these 'omes can be divided into those that represent a population of molecules, and those that define their actions. ... Once the individual sub- populations are defined and analyzed, we can then try to reconstruct the full organism by interrelating them, eventually allowing for a full and dynamic view of the cell. ... A problem in comparing the different 'omes' is that each represents a different set of genes. Mark Gerstein "What is Bioinformatics?" Molecular Biology & Biochemistry 474b3, Yale Univ. 2001 http://bioinfo.mbb.yale.edu/what-is-it.html
In physics, probably starting with Faraday's ion, cation, anion, the -on suffix has tended to signify an elementary particle, later materially focused on the photon, electron, proton, meson, etc., whereas -ome in biology has the opposite intellectual function, of directing attention to a holistic abstraction, an eventual goal, of which only a few parts may be initially at hand. Joshua Lederberg and Alexa T. McCray "'Ome Sweet 'Omics: A Genealogical Treasury of Words" Scientist 15 (7): 8 April 2, 2001 http://www.the-scientist.com/yr2001/apr/comm_010402.html
According to the Oxford English Dictionary this is an Anglicized version of the suffix "oma", primarily found in botanical terms and usually meaning normal, in contrast to the pathology implied by "oma".
ontologies: What is an ontology?, W3C, Requirements for a web ontology language, [work in progress] http://www.w3.org/TR/webont-req/#onto-def
optogenetics: A rapidly evolving field of technology that allows optical control of genetically targeted biological systems at high temporal and spatial resolution. By heterologous expression of light-sensitive microbial membrane proteins, opsins, cell type-specific depolarization or silencing can be optically induced on a millisecond time scale. … Although recent developments in optogenetics have largely focused on neuroscience it has lately been extended to other targets, including stem cell research and regenerative medicine. The optogenetic (r)evolution, Martin L Rein, Jan M. Deussing, Mol Genet Genomics. 2012 February; 287(2): 95–109, Published online 2011 December 20. doi: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266495/
organization of pharmaceutical R&D: By far the most common organizational structure within pharmaceutical R&D is based on therapeutic indications. As target pathways and target families become better recognized as opportunities for synergistic development that cut across disease indications, what are the implications for how best to capture this synergy? As molecular tools are increasingly applied beyond target biology to more of the entire development process, how can expertise in specific tools best be leveraged across different departments? As chemistry and biology become more intertwined, how can researchers trained in one discipline or the other learn to better communicate with each other? As researchers trained in reductionist techniques and used to working on small projects become involved in much larger systems biology and high throughput chemistry projects, how does this change the nature of the work they do? What organizational structures and policies may facilitate optimal performance under these changing conditions?
I have hoped drug companies which encouraged open sharing of scientific information would prosper in the long run, without finding much evidence (even anecdotal) until I read this report, which quantified the positive correlation between companies encouraging peer reviewed scientific publication and productivity (patents issued to company scientists and articles published in peer- reviewed journals by company scientists). Diffusion of Science Driven Drug Discovery Organizational Change in Pharmaceutical Research, Iain M. Cockburn, Rebecca Henderson and Scott Stern, NBER, Sept. 1999 http://www.cid.harvard.edu/cidbiotech/events/henderson.htm
orphan drug: Drugs developed for rare diseases and conditions which, in the U.S., affect fewer than 200,000 people or, in the European Union, affect 5 or fewer per 10,000 people. Because sales of orphan drugs are likely to be small compared to their development costs, pharmaceutical companies are awarded exclusive rights to market these medicines for a period of time as an incentive to develop them. Tufts Center for the Study of Drug Development, Glossary, 2004 http://csdd.tufts.edu/InfoServices/Glossary.asp
orphan genes: Putative ORFs without any resemblance to previously determined protein- coding sequences…While theoretical evolutionary arguments support the reality of genes when homologues are found in a variety of distant species, this is not the case for orphan genes … Our results suggest that a vast majority of E. coli ORFs presently annotated as “hypothetical” correspond to bona fide genes. J Alimi et al “RT-PCR validation of 25 “orphan” genes” Genome Research 2000 Jul; 10 (7): 959- 966 Related terms: deorphaning, deorphanizing, orphan proteins
orphan designation: Committee for Orphan Medicinal Products COMP, EMA, European Union http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000029.jsp
orphan products: The Orphan Drug Act (ODA) provides for granting special status to a product /indication combination upon request of a sponsor, and if the product/indication combination meets certain criteria. This status is referred to as orphan designation. Orphan designation qualifies the sponsor of the product for the tax credit and marketing exclusivity incentives of the ODA. [FDA, US Orphan Product Designation, 2001] http://www.fda.gov/orphan/designat/index.htm
outcomes research: The terms "outcomes research" and "effectiveness research" have been used to refer to a wide range of studies, and there is no single definition for either that has gained widespread acceptance. As these fields evolved, it appears that "outcomes research" emerged from a new emphasis on measuring a greater variety of impacts on patients and patient care (function, quality of life, satisfaction, readmissions, costs, etc). The term "effectiveness research" was used to emphasize the contrast with efficacy studies, and highlighted the goal of learning how medical interventions affected real patients in "typical" practice settings (OTA, 1994). Effectiveness studies sought to understand the impact of health care on patients with diverse characteristics, rather than highly homogeneous study populations. While the terms may have different initial roots, there does not appear to be much value in distinguishing these activities, and the field is generally referred to as OER. .. OER evaluates the impact of health care (including discrete interventions such as particular drugs, medical devices, and procedures as well as broader programmatic or system interventions) on the health outcomes of patients and populations. OER may include evaluation of economic impacts linked to health outcomes, such as cost- effectiveness and cost utility. OER emphasizes health problem- (or disease-) oriented evaluations of care delivered in general, real- world settings; multidisciplinary teams; and a wide range of outcomes, including mortality, morbidity, functional status, mental well- being, and other aspects of health-related quality of life. [Outcome of Outcomes Research at AHCPR: Final Report, Agency for Health Care Policy and Research, AHCPR Publication No. 99-R044] http://www.ahrq.gov/clinic/out2res/outcom1.htm
Pan Assay Interference Compounds: A
true drug inhibits or activates a protein by fitting into a binding site on the
protein. Artefacts have subversive reactivity that masquerades as
drug-like binding and yields false signals across a variety of assays.
These molecules. have defined structures, covering several classes of compounds.
… But biologists and inexperienced chemists rarely recognize them. .. Time and
research money are consequently wasted in attempts to optimize the activity of
these compounds. Chemical con artists foil drug discovery, Jonathan Baell,
Michael A. Walters, Nature 513: 481-483, 25 Sept 2014 doi:
colloquialism to denote the potential sharp decline in revenues upon patent
expiry of one or more leading products of a firm. http://www.investopedia.com/terms/p/patent-cliff.asp#ixzz2Esh3BTKi
“Investors are increasingly willing to accept that pharma companies can navigate the patent cliff through factors including growth in emerging markets, cost management, diversification and in some cases new drug launches,” said Deutsche Bank analyst Mark Clark “ Big pharma approaching bottom of patent cliff,, Nature Blog Oct 2012 http://blogs.nature.com/news/2012/10/big-pharma-approaching-bottom-of-patent-cliff.html
patent pooling: A patent pool is an agreement between two or more patent owners to license one or more of their patents to one another or third parties. A patent pool allows interested parties to gather all the necessary tools to practice a certain technology in one place, e.g, "one- stop shopping," rather than obtaining licenses from each patent owner individually. US Patent and Trademark Office "USPTO issues white paper on patent pooling" Jan. 19, 2001 http://www.uspto.gov/web/offices/com/speeches/01-06.htm
stacking: Taking out many patents
for different aspects of a single innovation, thus forcing several royalty
applications and payments. Aaron Cosbey , Sustainable Development Effects of the
WTO TRIPS Agreement: A Focus on Developing Countries, International Institute
for Sustainable Development, Canada, 2000 http://www.iisd.org/trade/trips.htm#_Toc364270391
patent thickets: An overlapping set of patent rights requiring those seeking to commercialize new technology obtain licensees from multiple patentees. Navigating the patent thicket, Carl Shapiro, Univ. of California, Berkeley, Mar. 2001 http://faculty.haas.berkeley.edu/shapiro/thicket.pdf
pathways: A general term meant to include all forms of molecular transactions and processes that are part of biochemical systems. Some of these pathways may involve linear processing, but many involve complex branches, convergences, and even cycles. .... There are several different classes of biochemical pathways: metabolic pathways, signal transduction cascades, genetic networks, and drug metabolism pathways. In addition, protein interaction data links protein data objects, and can therefore also be conceptualized as graphs. Although the relationship of protein- interaction maps with biochemical pathways is undeniable, it is not obvious. ... the design of adequate models for bio- process representation, manipulation and simulation is still a very open field of research. In conclusion, we will need to examine and discuss the relationships between all pathway information, protein interaction data, and biological process information in order to successfully produce informatics specifications for any of these kinds of data. Biopathways Consortium "Definition" http://www.biopathways.org/
Pathway elucidation is critical, in order to both identify the biochemical components in a pathway associated with disease, and the affect of a chemical entity on this pathway. This synergistic approach will help to identify ways to validate and prioritize targets, and enable us to understand the molecular mechanism of therapeutics. The term biochemical pathways has principally referred to metabolic pathways, which are the pathways by which a cell converts compounds that enter it into cellular components (e.g., small molecules and macromolecules including proteins, nucleic acids, storage carbohydrates, and fatty acids) and by which the cell derives energy. Signaling pathways are biochemical pathways that regulate cellular characteristics and processes such as physiology, proliferation, changes in shape and motility, differentiation, adhesion, and intercellular interactions. High- content screening approaches can be used to help elucidate pathways.
PCR Polymerase Chain Reaction: A laboratory technique to rapidly amplify pre- determined regions of double- stranded DNA. Generally involves the use of a heat stranded DNA polymerase. IUPAC Bioinorganic
In vitro method for producing large amounts of specific DNA or RNA fragments of defined length and sequence from small amounts of short oligonucleotide flanking sequences (primers). The essential steps include thermal denaturation of the double- stranded target molecules, annealing of the primers to their complementary sequences, and extension of the annealed primers by enzymatic synthesis with DNA polymerase. The reaction is efficient, specific, and extremely sensitive. Uses for the reaction include disease diagnosis, detection of difficult to isolate pathogens, mutation analysis, genetic testing, DNA sequencing, and analyzing evolutionary relationships. [MeSH, 1991]
Originally described in 1984 by Kary B. Mullis, who shared the Nobel Prize for Chemistry for this invention in 1993, PCR enables the amplification of specific nucleotide sequences through the use of a DNA polymerase. The sequence to be amplified is identified through the use of synthetic oligonucleotides that are complementary to the two terminal regions of the targeted sequence. Related terms: branched DNA, gene amplification, LCR Ligase Chain Reaction, NASBA. Narrower terms: nested PCR, OLA, PNA Q-PCR, real time PCR, RT-PCR.
personalized medicine: The ability to offer the appropriate treatment to the right person, only when needed. CHA Cambridge Healthtech Advisors, Clinical Genomics: The Impact of Genomics on Clinical Trials and Medical Practice report, 2004
Pgx: Collective use of pharmacogenetics and pharmacogenomics. NIH comments on FDA's draft guidance for Industry Pharmacogenomic Data Submission, Docket No. 2003D-0497, Feb. 2004 http://www.fda.gov/ohrms/dockets/dailys/04/feb04/021104/03D-0497_emc-000009-01.pdf
epidemiological methods to studies of the clinical use of drugs in populations.
A modern definition of pharmacoepidemiology is: «the study of the use and
effects/side-effects of drugs in large numbers of people with the purpose of
supporting the rational and cost-effective use of drugs in the population
thereby improving health outcomes… Pharmacoepidemiology may be drug-oriented,
emphasizing the safety and effectiveness of individual drugs or groups of drugs,
or utilization-oriented aiming to improve the quality of drug therapy through
pedagogic (educational) …
Sophisticated utilization-oriented pharmacoepidemiology may focus on the drug
(e.g. dose-effect and concentration-effect relationships), the prescriber (e.g.
quality indices of the prescription), or the patient (e.g. selection of drug and
dose, and comparisons of kidney function, drug metabolic phenotype/genotype,
age, etc.). intervention. …
The initial focus of pharmacoepidemiology was on the safety of individual drug
products (pharmacosurveillance), but it now also includes studies of their
beneficial effects. … Pharmacoepidemiological studies often make useful
contributions to our knowledge about effectiveness and safety, because, unlike
clinical trials, they assess drug effects in large, heterogeneous populations of
patients over longer periods. Introduction
to drug utilization research, WHO World Health Organization 2003
pharmacogenetics: The study of existing genetic knowledge, and the generation of new genetic data, to understand and thus avoid DRUG TOXICITY and adverse effects from toxic substances from the environment. MeSH 2004
The terms "pharmacogenomics" and "pharmacogenetics" are often interchanged and used without clear definition. For the purpose of this meeting, I will use working definitions. Pharmacogenetics refers to people including gene identification and "right medicine for right patient." Pharmacogenomics refers to the application of tools including, but not limited to, the functional genomics toolbox of differential gene expression (DGE), proteomics, yeast 2- hybrid (Y2H) analyses, tissue immuno- and histopathology, etc. There are two applications of pharmacogenetics that may use similar techniques but are quite distinct: a) susceptibility gene identification and b) "right medicine for right patient" . Allen D. Roses "Pharmacogenetics and pharmacogenomics in the discovery and development of medicines " Pharmacogenetique et Pharmacogenetique, Institut Pasteur, Paris [France], 12-13 Octobre 2000, Institut Pasteur] http://www.pasteur.fr/applications/euroconf/pharmaco/pharmaco-prog.html
A subset of pharmacogenomics encompassing the study of genetic variation underlying differential response to drugs, particularly genes involved in drug metabolism. With the implementation of pharmacogenetics, diseases will be evaluated by mechanisms, rather than just symptoms, and early response will be based on prognosis and susceptibility rather than just diagnosis. It will introduce a bottom- up approach to disease, which will be defined in terms of its heterogeneity, and not "averaged out" to conform to a uniform model.
pharmacogenomics: Comprises the study of variations in targets or target pathways, variation in metabolizing enzymes (pharmacogenetics) or, in the case of infectious organisms, genetic variations in the pathogen. CHI Drug Discovery Map http://www.healthtech.com/drugdiscoverymap.asp
Pharmacogenomics is the analysis of the effect of genomics — in particular, genetic variation (polymorphisms) — on drug response. This practice can potentially help clinicians administer more tailored treatment. The term pharmacogenetics is often used to refer specifically to tests that predict drug response; however, the terms pharmacogenetics and pharmacogenomics are often used interchangeably.
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 http://www-smi.stanford.edu/pubs/SMI_Reports/SMI-2001-0898.pdf
The study of how an individual's genetic inheritance affects the body's response to drugs and holds the promise that drugs might one day be tailor- made for individuals and adapted to each person's own genetic makeup. Environment, diet, age, lifestyle, and state of health all can influence a person's response to medicines, but understanding an individual's genetic makeup is thought to be the key to creating personalized drugs with greater efficacy and safety. Pharmacogenomics combines traditional pharmaceutical sciences such as biochemistry with annotated knowledge of genes, proteins, and single nucleotide polymorphisms. Human Genome Project Information, Pharmacogenomics, Oak Ride National Lab, 2001
From pharmacology + genomics. Alternatively: individualized medicine, personalized medicine, pharmacoproteomics
pharmacologically active metabolite: A metabolite that has pharmacological activity at the target receptor. The activity may be greater than, equal to, or less than that of the patent drug. Glossary, Guidance for Industry, Safety testing of drug metabolites, FDA, 2008 http://www.fda.gov/OHRMS/DOCKETS/98fr/FDA-2008-D-0065-GDL.pdf
pharmacovigilance: The aims of pharmacovigilance are to enhance patient care and patient safety in relation to the use of medicines, especially with regard to the prevention of unintended harm from the use of drugs; to improve public health and safety in relation to the use of medicines by the provision of reliable, balanced information resulting in more rational use of drugs; and to contribute to the assessment of the risk-benefit profile of medicines, thus encouraging safer and more effective use of medicines and a resolution of the sometimes apparently conflicting interests of public health and individual patient welfare. WHO 2006 http://www.who.int/medicines/areas/quality_safety/safety_efficacy/pharmvigi/en/index.html
The process of (a) monitoring medicines as used in everyday practice to identify previously unrecognised or changes in the patterns of their adverse effects; (b) assessing the risks and benefits of medicines in order to determine what action, if any, is necessary to improve their safe use; (c) providing information to users to optimise safe and effective use of medicines; (d) monitoring the impact of any action taken. Medicines Control Agency, UK, Pilot publication scheme, Glossary of terms, 2003 http://www.mca.gov.uk/pilot/app1.htm#A Related terms: Phase IV/postmarketing surveillance
pharming: Use of transgenic animals to produce drugs in their milk, urine or eggs. Transgenic plants can also be used. (Tobacco is said to be particularly amenable to this application).
Phase IV/ postmarketing surveillance: At this stage, after a drug has been launched, pharmaceutical companies may conduct further studies of its performance, often examining long- term safety.
Phase zero, Phase O: Phase Zero is a novel pre-clinical testing service that combines a range of integrated technologies and involves the introduction of human tissue at the earliest stages of drug development. It allows target identification and validation as well as testing the viability of drug leads and candidates in human tissue before entering the clinic. This enables rationalization of the drug development process and improves the outcome at several points along the developmental path. Pharmagene signs new Phase Zero agreement with Taisho, Friday, March 09, 2001 http://www.pharmabiz.com/article/detnews.asp?articleid=6449§ionid=14 Related terms: microdosing
at the effects, or phenotypes, that compounds induce in cells, tissues or whole
organisms … Beginning in the 1980s, advances in molecular biology and genomics
led to phenotypic screens largely being replaced by screens against defined
targets implicated in disease.… some researchers have concluded that
reductionist approaches such as target-based screening are useful but may also
limit the breadth of new findings. Phenotypic
screening, take two Kotz,
J.SciBX 5(15); doi:10.1038/scibx.2012.380 Published online April 12
targeted based drug discovery, screens
pipelines: The process of drug development has evolved into an extremely complex procedure. The average drug takes 12 years and $270 million from initial discovery to public usage.(1) For every drug that is deemed marketable by the FDA, thousands of others are considered either unsafe or ineffective clinically. Beginning with preclinical research, new chemical entities (NCEs) are discovered in laboratories and tested in animals for safety and biological activity. If a compound is thought to be safe and effective as a chemical agent, a pharmaceutical company then submits an investigational new drug application (NDA) to the FDA. Once approved for clinical studies, a three-phase process begins where safety and efficacy are continually assessed with increased scrutiny and an increasing patient population. Approximately 70% of drugs entering clinical trials complete Phase I, 33% complete Phase II, and 27% complete Phase III. After Phase III is completed a company then submits a NDA to the FDA. Those drugs that are approved for marketing comprise an extremely small percentage of new chemical entities (NCEs) that are tested. In fact, from thousands only a handful of drugs undergo clinical studies, and even fewer receive market approval. C. Daniel Mullins et. al. " Projections of drug approvals, patent expirations and generic entry from 2000 to 2004" report prepared for the Dept. of Health and Human Services' Conference on Pharmaceutical Pricing Practices, Utilization and Costs August 8- 9, 2000, Washington DC, US http://aspe.hhs.gov/health/reports/Drug-papers/Mullins-Palumbo%20paper-final.htm
portfolio management: For many pharmaceutical companies, much of the focus in managing portfolio risk has focused on R&D choices for pipeline products, as well as research portfolio choices on the drug discovery side. In addition to these levers, there is significant opportunity for pharmaceutical companies to manage risk through smarter investment in life- cycle management. These investments span a variety of functions from legal to sales and marketing to R&D. In the R&D area, some of the key investments include clinical studies and investments in formulation sciences and drug delivery. Managing Product Risk through Life- Cycle Management, Dr. Philip Ma, Partner, McKinsey & Co. Intelligent Drug Discovery R&D Strategies: Managing Risk to Increase Value, May 17-19, 2003, Philadelphia PA Related term: life cycle management
post-genomic: The genome era is generally regarded to have started on 28 July 1995, with the publication of the genome of the bacterium Haemophilus influenzae. ["A point of entry into genomics" Nature Genetics 23:273 Nov. 1999] But the human mitochondrial genome was sequenced in 1981 and published in Nature 290 (5806): 457- 465, Apr. 9, 1981. Sequence and organization of the human mitochondrial genome by S. Anderson et. al.
With an increasing number of organisms for which we have (more or less) complete genomes we are beginning to see glimpses of the power of having fully mapped sequences. Still, in most contexts talk about being "post- genomic" seems a little premature. "Post Mendelian" seems more accurate as we move from an era in which genetics has been rooted in monogenic diseases with high penetrance to a greater awareness (but limited understanding) of polygenic diseases (and traits) often with relatively low penetrance.
post-translational modifications: Proteins once synthesized on the ribosomes, are subject to a multitude of modification steps. They are cleaved (thus eliminating signal sequences, transit or pro- peptides and initiator methionines); many simple chemical groups can be attached to them … as well as some more complex molecules, such as sugars and lipes. Finally they can be internally or externally cross- linked. More than a hundred different types of post- translational modifications are currently known (Aug. 1999) and many more are yet to be discovered. The complexity due to all these modifications is compounded by the high level of diversity that alternative splicing can produce at the level of sequence. Thus the number of different protein molecules expressed by the human genome is probably closer to a million than to the hundred thousand generally considered by genome scientists. Human Proteomics Initiative, Amos Bairoch, ExPaSy, Swiss Institute of Bioinformatics, 2003 http://au.expasy.org/sprot/hpi/hpi_desc.html
preclinical drug evaluations: Preclinical testing of drugs in experimental animals or in vitro for their biological and toxic effects and potential clinical applications. MeSH, 1974
preclinical investigations: Laboratory and animal studies designed to test the mechanisms, safety, and efficacy of an intervention prior to its applications to humans [IRB]
preclinical studies: Studies that test a drug on animals and other nonhuman test systems. They must comply with FDA's good laboratory practices. Data about a drug's activities and effects in animals help establish boundaries for safe use of the drug in subsequent human testing (clinical studies). Also, because animals have a much shorter lifespan than humans, valuable information can be gained about a drug's possible toxic effects over an animal's life cycle and on offspring. Drug Review Glossary, FDA Consumer Magazine, http://www.fda.gov/fdac/special/newdrug/bengloss.html
issues need to be resolved in order to establish a collaborative consortia from
the pharmaceutical company perspective. A major challenge is defining the domain
of precompetitive research. The basic biology, the understanding of disease,
biomarkers of prognosis, and even drug responses all can be areas of
precompetitive R&D, Power said. Pharmaceutical companies have recognized
that they cannot develop a full understanding of these different facets of drug
development on their own. Establishing
Precompetitive Collaborations to Stimulate Genomics-Driven Product Development:
Workshop Summary. 2011 http://www.ncbi.nlm.nih.gov/books/NBK54320/
predictive ADME: The completion of the Human Genome Project and recent advances in our understanding of the molecular mechanisms of diseases have provided increasing numbers of newly defined biological pathways and networks with potential preventive or therapeutic targets. The development of molecular diversity libraries and screening of these libraries have provided tremendous opportunities to discover new chemical and biological agents for the prevention and treatment of diseases. This created the belief that increasing numbers of new molecular entities would enter clinical testing and would receive approval from the Food and Drug Administration (FDA) to treat human disorders. However, this has not occurred. Many candidate agents are failing during clinical testing because of their unfavorable pharmacokinetic properties, unacceptable adverse effects, or major toxicities, as well as the lack of efficacy.
The safety of each new chemical entity must be demonstrated prior to its entry into clinical trials. Investigational New Drug (IND) applications to the FDA require chemistry, manufacturing, and control information and results from preclinical toxicology studies for the safety of new agents. Results of nonclinical pharmacokinetic studies for defining ADME properties, addressing important safety issues, or assisting the evaluation of toxicology data for investigational new agents are highly desirable in IND submissions. Novel preclinical tools for Predictive ADME-Toxicology RFA Number: RFA-RM-04-023, 2004 http://grants.nih.gov/grants/guide/rfa-files/RFA-RM-04-023.html#PartI
predictive safety: Unexpected toxicity is the single greatest cause of pipeline attrition. Despite the fact that a typical preclinical safety program will consume about 1,300 rats and 90 dogs, there is no guarantee that the compound will not present safety problems serious enough to warrant termination. CHA Outlook for Predictive Safety Technologies, 2006
price trends - prescription drugs: The prices of new drugs will be analyzed over time and by factors that may be associated with launch prices. Price trends for 1995 to 1999 will also be examined by therapeutic category for a number of major categories (in terms of expenditure levels or growth) with well- defined subclasses that can be analyzed individually and compared on the basis of the age of the category. The pricing of generic substitutes in these therapeutic categories will also be provided for comparative purposes. Finally, launch prices during the study period for new entrants to existing subclasses within the therapeutic categories will be examined and compared to the prices of the incumbents in the subclass.
The results show that new drugs can vary substantially in their impact on drug expenditures. Some drugs are introduced at significant discounts to existing drugs that are highly substitutable with the new drug. In addition, while entirely new classes of compounds to treat a disease or condition are often priced at a premium relative to older classes, this is not always the case. The data also suggest that new drug prices tend to reflect the degree of price sensitivity in the market and the perceived value of the product to patients. Finally, average price increases over time for the pharmacologic and chemical classes examined varied in all directions in relation to general price inflation. However, most class price increases were similar to economy- wide inflation rates. Joseph A. DiMasi, PRICE TRENDS FOR PRESCRIPTION: PHARMACEUTICALS: 1995- 1999, Aug. 8- 9, 2000 http://aspe.hhs.gov/health/reports/Drug-papers/dimassi/dimasi-final.htm
Measuring Trends in the Development of New Drugs, Joseph DiMasi, 2007 http://units.sla.org/division/dpht/meetings/spring2007/dimasi_2007s.ppt
productivity: Iain Cockburn, a professor at the Boston University School of Management who has extensively studied pharmaceutical research productivity, believes the current dearth of new drugs is merely an inevitable pause in the industry's development cycle. Today's drug deficit is often compared with a golden age of applications in the early 1990s that were spawned by advances in small- molecule chemistry 15 to 20 years earlier, he says. Now the industry is adjusting to a new era of molecular biology that will take time to produce results. The adjustment, Cockburn suggests, was side- tracked somewhat by the 1990's biotechnology boom, which confused the process of drug development as large pharmaceutical firms and biotech companies sorted out their roles as potential rivals and collaborators. Further, he says, it is simply harder to invent new drugs now, because the low- hanging fruit -- such as the once- revolutionary ace inhibitors -- has already been plucked. "Now the industry is focusing on cancer, Alzheimer, and exotic viruses. They're working on tougher problems," he says. "The way you come up with these drugs is through a lot of heavy- duty science rather than industrial chemistry, and it's just a lot more expensive." Susan Warner, Pipeline Anxiety: Scientists Pumped into New Roles, Scientist, 17 (10) May 19, 2003 http://www.the-scientist.com/?articles.view/articleNo/14772/title/Pipeline-Anxiety--Scientists-Pumped-into-New-Roles/
proof of concept: Evidence that demonstrates that a business model or idea is feasible. [Investorwords] http://www.investorwords.com/p5.htm#proofofconcept
Compare proof of principle. Proof of concept is certainly more prevalent as a term. (166,000 hits on google May 15, 2002 vs. proof of principle 13,600. These two terms are sometimes used interchangeably, though proof of concept seems generally earlier than proof of principle. While many of the above examples have a financial context these terms are also used in more basic research.
proof of principle: The lowest cost program aimed at developing an integrated and broad understanding of the basic scientific and engineering aspects of the concept which can be scaled with confidence to provide a basis for evaluating the potential of the concept for fusion energy applications. The basic prerequisite for embarking on an engineering PoP [proof of principle] stage is that (1) its scientific and engineering basis looks promising and that (2) it will lead to an attractive energy utilization embodiment. As with the concept exploration stage, the PoP stage is a combined effort involving experiments, modeling and theory. Snowmass US Fusion energy sciences program, 1999] http://www.fusion.ucla.edu/snowmass/questions/common3/common3prospectus.html
Compare proof of concept which is certainly more prevalent as a term. (166,000 hits on google May 15, 2002 vs. proof of principle 13,600. These two terms are sometimes used interchangeably, though proof of concept seems generally earlier than proof of principle. While many of the above examples have a financial context these terms are also used in more basic research.
protein expression: Just because a gene is overexpressed doesn’t necessarily mean the protein will be. Sometimes we find the accompanying protein to be downregulated even though the gene is upregulated: That is because there are a lot of steps between gene expression and protein expression. Better Understanding of Diseases and Drug Targets Through Systems Biology: An Interview with N. Stephen Ober of Beyond Genomics, CHI's GenomeLink 17.2 http://www.chidb.com/newsarticles/issue17_2.asp
Protein expression analysis is undergoing a technological revolution, which will change the fundamental nature of the data available. ... Current methods for measuring protein expression are very different from those for measuring gene expression. Typically, 2D gels are used to separate the proteins from one another, and mass spectrometry (MS) is then applied to identify the proteins. MS provides remarkably specific identification of protein fragments, based on their masses. The masses are then compared with lists of computed masses for identification. More and more groups are now seeking to bypass 2D gels, using combinations of protein chips, liquid chromatography, capillary electrophoresis, and mass spectrometry for protein analysis.
protein microarrays: In conjunction with high throughput expression and purification of recombinant proteins, we can prepare microarrays of functionally active proteins on glass slides. These arrays can then be used to identify protein- protein interactions, to identify the substrates of protein kinases, or to identify the targets of biologically active small molecules. [Harvard Center for Genomic Research, MacBeath Lab, Overview] http://www.cgr.harvard.edu/macbeath/index.html Related terms: antibody microarrays, protein arrays, protein chips. Narrower terms: high- density electrospray- fabricated protein microarrays, functional protein microarrays, protein-protein interaction chips, proteome chip
proteomics: 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
rational drug design: The input of biocomputing in drug discovery is twofold: firstly the computer may help to optimise the pharmacological profile of existing drugs by guiding the synthesis of new and "better" compounds. Secondly, as more and more structural information on possible protein targets and their biochemical role in the cell becomes available, completely new therapeutic concepts can be developed. The computer helps in both steps: to find out about possible biological functions of a protein by comparing its amino acid sequence to databases of proteins with known function, and to understand the molecular workings of a given protein structure. Understanding the biological or biochemical mechanism of a disease then often suggests the types of molecules needed for new drugs. Wolfram Altenhogen "Biocomputing and drug design, 1996 http://www.techfak.uni-bielefeld.de/bcd/ForAll/Introd/drugdesign.html Alternatively: structure based drug design
recombinant DNA technology: A body of techniques for cutting apart and splicing together different pieces of DNA. When segments of foreign DNA are transferred into another cell or organism, the substance for which they code may be produced along with substances coded for by the native genetic material of the cell or organism. Thus, these cells become "factories" for the production of the protein coded for by the inserted DNA. [NIGMS] Related terms: biotechnology, gene disruption, gene manipulation, genetic engineering
regenerative medicine: A field of medicine concerned with developing and using strategies aimed at repair or replacement of damaged, diseased, or metabolically deficient organs, tissues, and cells via TISSUE ENGINEERING, CELL TRANSPLANTATION; and ARTIFICIAL ORGANS and BIOARTIFICIAL ORGANS and tissues. MeSH 2004
research tools: We use the term "research tool" in its broadest sense to embrace the full range of resources that scientists use in the laboratory, while recognizing that from other perspectives the same resources may be viewed as "end products." For our purposes, the term may thus include cell lines, monoclonal antibodies, reagents, animal models, growth factors, combinatorial chemistry libraries, drugs and drug targets, clones and cloning tools (such as PCR), methods, laboratory equipment and machines, databases and computer software. .. NIH Working Group on Research Tools, June 4, 1998 http://www.nih.gov/news/researchtools/ Related term: pre-competitive
resourceome: Biologist users and scientists approaching the field do not have a comprehensive index of bioinformatics algorithms, databases, and literature annotated with information about their context and appropriate use. We suggest that the full set of bioinformatics resources—the “resourceome”—should be explicitly characterized and organized. A hierarchical and machine-understandable organization of the field, along with rich cross-links (an ontology!) would be a useful start. "Time to organize the bioinformatics resourceome" Nicola Cannata, Emanuela Merelli, Russ B. Altman*, PLOS Computational Biology, Dec. 2005 DOI: 10.1371/journal.pcbi.0010076 http://compbiol.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pcbi.0010076
What does it take to turn a ridiculome into a
RNAi RNA interference: A gene silencing phenomenon whereby specific dsRNAs ( RNA, DOUBLE- STRANDED) trigger the degradation of homologous mRNA ( RNA, MESSENGER). The specific dsRNAs are processed into SMALL INTERFERING RNA (siRNA) which serves as a guide for cleavage of the homologous mRNA in the RNA- INDUCED SILENCING COMPLEX (RISC). DNA METHYLATION may also be triggered during this process. MeSH 2003 Broader term: gene silencing
robust: A statistical test that yields approximately correct results despite the falsity of certain of the assumptions on which it is based Oxford English Dictionary
Hence, can refer to a process which is relatively insensitive to human foibles and variables in the way (for example, an assay) is carried out. Idiot- proof.
rules of five: Lipinski’s rules. Set of criteria for predicting the oral bioavailability of a compound on the basis of simple molecular features (molecular weight, CLogP, numbers of hydrogen- bond donors and acceptors). Often used to profile a library or virtual library with respect to the proportion of drug- like members which it contains. [IUPAC Combinatorial]
An algorithm, developed by Christopher A. Lipinski (of Pfizer) and colleagues, in which many of the cutoff numbers are five or multiples of five. There are actually four rules, and Pfizer has developed a additional number of criteria for adoption of lead candidates. Advanced Drug Delivery Research 23: 3- 25, 1997.
Reducing the investment made in likely drug development failure. CHI's Genome Link 15.1 http://www.chidb.com/newsarticles/issue15_1.asp Christopher Lipinski on the rules of five (see section 8.4) There are actually 50+ rules now.
safety pharmacology: Pharmacology studies can be divided into three categories: primary pharmacodynamic, secondary pharmacodynamic, and safety pharmacology studies. For the purpose of this document, safety pharmacology studies are defined as those studies that investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure in the therapeutic range and above. ICH Guidance for Industry, S7A Safety Pharmacology Studies for Human Pharmaceuticals, 2001 http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm074959.pdf
sample preparation: The discussants concluded that the issue of sample preparation and purification has been sadly neglected at most meetings dealing with proteomics. There was the impression among some of the discussants that protein biochemists were developing and using methods to purify proteins that were not being adequately defined compositionally by mass spectrometrists interested in proteins. Defining the Mandate of Proteomics in the Post- Genomics Era, National Academy of Sciences, 2002 http://www.nap.edu/books/NI000479/html/R1.html
Sample prep isn't the sexiest job around, but it is one of the most critical. The quality of isolated nucleic acid and protein samples is critical to generating accurate and informative data. As genomic and proteomic technologies move in the direction of higher throughput, upstream sample preparation becomes a potential bottleneck. Sample capture, transportation, storage, and handling are as critical as extraction and purification procedures. Obtaining homogenous samples or isolating individual cells from clinical material is imperative. Standards are essential. Advances in microfluidic and microarray technologies have further amplified the need for higher throughput, miniaturized, and automated sample preparation processes.
scaffold hopping: the definition of scaffold hopping and, more importantly, the detection of what constitutes a scaffold hop, is also ill-defined and highly subjective. Essentially, it is agreed that scaffolds should be substantially different from each other, although significantly similar to each other, to constitute a hop. In the latter, the scaffolds must permit a similar geometric arrangement of functional groups to permit the mode of action. However, this leaves the paradox of how to describe both scaffold similarity and dissimilarity simultaneously. In this paper, the current statuses of scaffolds and scaffold hopping are reviewed based on published examples of scaffold hopping from the literature. An investigation of the degree to which it is possible to formulate a more rigorous definition of scaffolds and hopping in the context of molecular topologies is considered. N Brown, E Jacoby, On scaffolds and hopping in medicinal chemistry. Mini Rev Med Chem 6 (11) :1217- 1229, Nov 2006 Related term: molecular scaffold.
scalable: Capable of being industrialized and expanded for high- throughput. Analogous to recipes optimized for large groups, rather than standard recipes being quadrupled or more, with less than ideal results. Also spelled scaleable.
self-assembly: <biology> A process in which supramolecular hierarchical organization is established without external intervention.... The approaches used can be expected to fall into two general categories. The first involves directly mimicking biological systems or processes to produce materials with enhanced properties. An example of this approach is the use of molecular genetic techniques to produce polymers with unprecedentedly uniform molecular length. The second category involves studying how nature accomplishes a task or creates a structure with unusual properties, and then applying similar techniques in a completely different context or using completely different materials. [Biomolecular self- assembling materials, National Academy of Sciences 1996] http://www.nas.edu/bpa/reports/bmm/bmm.html#PBMM Narrower terms: self- assembling biomolecular materials, self-assembling peptides. Related terms: nanoscience
Sentinel Initiative: On May 22, 2008, FDA launched the Sentinel Initiative with the ultimate goal of creating and implementing the Sentinel System--a national, integrated, electronic system for monitoring medical product safety. The Sentinel System will enable FDA to query multiple, existing data sources, such as electronic health record systems and medical claims databases, for information about medical products. The system will enable FDA to query data sources at remote locations, consistent with strong privacy and security safeguards. Data sources will continue to be maintained by their owners. This historic new system will strengthen FDA's ability to monitor the performance of a product throughout its entire life cycle. FDA, US http://www.fda.gov/oc/initiatives/advance/sentinel/
sexy technologies: What makes technologies sexy? It seems to be a combination of being new, innovative and challenging, affording clever people a chance to learn new skills (and demonstrate how competitive and bright they are) and expensive (or otherwise not available to just anyone). A quick Google search identified artificial intelligence, fuel cells, high- speed computers, robotics, nanotechnology, Java, smart cards, wireless communications and biomaterials as "sexy" by some criteria. I'd be interested to hear other interpretations and nuances of this class of technologies. Are there significant differences in what biologists, businesspeople, chemists, computer scientists and others consider "sexy technologies"?
single molecule detection: Recent advances in optical imaging and biomechanical techniques have demonstrated that it is possible to make observations on the dynamic behavior of single molecules, to determine mechanisms of action at the level of an individual molecule, and to explore heterogeneity among different molecules within a population. These studies have the potential to provide fundamentally new information about biological processes and are critical for a better understanding of cellular function. ... Single molecule methods are likely to lead to significant advances in understanding molecular movement, dynamics, and function. NIGMS, NICDC, NHGRI, Single Molecule Detection and Manipulation, Feb. 12, 2001 http://grants.nih.gov/grants/guide/pa-files/PA-01-049.html Broader terms: attomole, femtomole, micromole, nanomole, picomole, ultrasensitivity, yocto, zeptomole
small molecules: Preferred for drugs as they are orally available (unlike proteins which must be administered by injection or topically). Size of small molecules is generally under 1000 Daltons, but many estimates seem to range between 300 to 700 Daltons.
SNP Single nucleotide polymorphism: SNPs are single base pair positions in genomic DNA at which different sequence alternatives (alleles) exist in normal individuals in some population(s), wherein the least frequent allele has an abundance of 1% or greater. Thus single base insertion/ deletion variants (indels) would not formally be considered to be SNPs. ... In practice, the term SNP is typically used more loosely than required by the above definition. ... Complications with the above definition also exist. Specifically, some people might not want to consider disease predisposing single base variants to be SNPs - but the above definition would encompass such things as recessively acting, low penetrance, dominant, quantitative trait loci, or risk associated alleles, since all of these will occur in some normal (non- diseased) individual. Also the 'some population' component of the definition is limited by practical challenges of attaining and surveying representative global population samples. Consequently, claims of non- polymorphic sequences should always be accompanies by statements of the actual populations and the numbers of chromosomes tested. Overall, it is therefore apparent that the term 'SNP' is being widely and imprecisely used as a catch- all label for many different types of subtle sequence variation. Anthony Brooks "The essence of SNPs" Gene 234: 177-186, 1999 .
The most common form of DNA variation, alterations to a single base. If the SNP is in a gene, it can disrupt the gene's function. Most SNPs do not occur in genes, but can be associated with other types of DNA variation and so are used effectively as markers. CHA Cambridge Healthtech Advisors, Clinical Genomics: The Impact of Genomics on Clinical Trials and Medical Practice report, 2004
A SNP is a position in the genome where some individuals have one DNA base (e.g., A), and others have a different base (e.g., C). SNPs and point mutations are structurally identical, differing only in their frequency. Variations that occur in 1% or less of a population are considered point mutations, and those occurring in more than 1% are SNPs. This distinction is pragmatic and reflects the fact that low- frequency mutations cannot be used effectively in genetic studies as genetic markers, while more common ones can.
SNPs can occur in
coding regions of the genome (cSNPs), in regulatory regions (rSNPs), or, most
commonly, in "junk DNA" regions, in which case they are referred to as
specialty pharmaceuticals: The Specialty Pharmaceutical industry includes companies that sell pharmaceuticals in niche markets, apply novel delivery technology, or use the tools of chemistry in order to improve the therapeutic value of drugs. This is a heterogeneous industry involving companies that have different strengths in technology, employ different business models such as collaborative development or self-directed, and are at different stages in their life cycle. Research Sectors: Specialty Pharmaceuticals Overview, WR Hambrecht & Co. http://www.wrhambrecht.com/ind/research/pharm/ovw.html#lwebb
stealth patents: Beware of submarine- stealth genetic patents, they can be deadly for scientific research. That was the consensus of genetic patent experts Monday at CHI's Genome Tri-Conference The biggest enemy of scientific progress, the experts said, are so- called "stealth" patents -- those which are filed on genes that researchers have located, but haven't discovered their function. They sit on the patent, sometimes for long periods of time, during which no research is done. In January , the U.S. Patent and Trademark Office finalized guidelines forbidding stealth patenting, but finding these patents will be a long process. [Kristen Philipkowski "New Quest: Mapping Gene Patents" Wired, Mar 6, 2001] http://www.wired.com/news/technology/0,1282,42214,00.html
Patents filed on genes which have been discovered but have unknown function(s). Also known as submarine patents
stem cell transplantation: The transfer of STEM CELLS from one individual to another within the same species (TRANSPLANTATION, HOMOLOGOUS) or between species (XENOTRANSPLANTATION), or transfer within the same individual (TRANSPLANTATION, AUTOLOGOUS). The source and location of the stem cells determines their potency or pluripotency to differentiate into various cell types. MeSH 2003
stem cells: Relatively
undifferentiated cells of the same lineage (family type) that retain the
ability to divide and cycle throughout postnatal life to provide cells that
can become specialized and take the place of those that die or are lost.
Includes Fibroblasts, Hematopoietic Stem Cells, Erythroid Progenitor Cells,
Tumor Stem Cell MeSH, 1984 Narrower
terms: embryonic stem cells, hematopopoietic stem
Alliances are not always as strategic as hoped.
of corporations that invest on behalf of their parent company STRATEGIC VS.
TRADITIONAL INVESTORS: THE LOWDOWN FROM A VENTURE CAPITAL VET,PAUL
H. LEE, Fast Company Oct 8 2009 http://www.fastcompany.com/
structural genomics: The discipline of determining protein structures. It adds critical information in at least two points in the drug discovery pathway: (1) target identification, or selecting a pathway in which a drug might function, and (2) medicinal chemistry, or the actual design of compounds to modulate this pathway. As traditionally defined, the term structural genomics referred to the use of sequencing and mapping technologies, with bioinformatic support, to develop complete genome maps (genetic, physical, and transcript maps) and to elucidate genomic sequences for different organisms, particularly humans. Now, however, the term is increasingly used to refer to high- throughput methods for determining protein structures.
structural variants: No two genomes are alike; instead, each displays structural variability in the form of single-nucleotide polymorphisms (SNPs), deletions or insertions of various sizes, which are collectively called copy number variants (CNVs) and inversions, which are copy number neutral structural variants. Nicole Rusk, Finding copy-number variants, Nature Methods 5(11):917 Nov 2008
Structure Activity Relationship (SAR): The relationship between chemical structure and pharmacological activity for a series of compounds. IUPAC Medicinal Chemistry
structure based design: A design strategy for new chemical entities based on the three- dimensional (3D) structure of the target obtained by X-ray or nuclear magnetic resonance (NMR) studies, or from protein homology models. IUPAC Computational
structure based drug design: Structure-based design (SBD) has been in use within the pharmaceutical industry for over twenty-five years. SBD of compound properties are still developing and growing in acceptance..
synchrotrons: Devices for accelerating protons or electrons in closed orbits where the accelerating voltage and magnetic field strength varies (the accelerating voltage is held constant for electrons) in order to keep the orbit radius constant. MeSH, 1993
An important alternative to x-ray crystallography for solving protein structures.
biology: A) the design and construction of new
biological parts, devices, and systems, and B) the re-design of existing,
natural biological systems for useful purposes. http://syntheticbiology.org/d systems, and
systems biology: There are two opinions on what systems biology is supposed to be. One group sees systems biology as another level of combining data from different levels (like DNA, RNA and protein level) (see [Leroy] HOOD). Another group wants to combine classical molecular and cell biology with systems theory and focus on the new forms of behavior that emerge when systems of genes and proteins are studied in a wholistic way. For this they need data from all those different levels as well, of course. That is why they see systems biology as a cooperative effort, with systems theory providing a theoretical framework and a new view on things for biologists, along with lots of experience with complex systems, and biology providing in-depth knowledge of the field of application as well as practical handling experience. This data is the basis for developing the kind of detailed models that are necessary for such studies of systemic properties and behavior. For both groups, the goal is to reach a new level of understanding of biological systems often referred to as 'systems level' understanding. A glossary for Systems Biology, Systems Biology Group, Stuttgart http://www.sysbio.de/projects/glossary/SYSTEMS_BIOLOGY.shtml#systems_biology
The very nature of systems biology requires integrating data from a variety of sources generated and interpreted by people skilled in different areas -- engineering, computer science, biology, physics, mathematics, and statistics. Key considerations in this process include the generation of quantitative data, barriers in communication across departments, and organizational challenges.
target: Molecules in the body that may be addressed by drugs to produce a therapeutic effect. (Also used to refer to the material -- DNA or RNA - that one exposes to the probes on a microarray so that hybridization can be measured subsequently. CHI High- Content Analysis Market Outlook report, 2004 Narrower terms: target characterization, target glut, target identification, target screening, target validation. Related terms: gene function, protein function, antisense, hit, lead
target identification: Target identification methods provide a finer degree of detail than target screening and require evidence that the gene/ protein is correlated with the disease.
target validation: Demonstrating that a molecular target is critically involved in a disease process, and that modulation of the target is likely to have a therapeutic effect. CHA, Cambridge Healthtech Advisors Model Animal Systems: Emerging Applications and Commercial Opportunities in Drug Discovery and Development, report, 2004
Determining which among genes or proteins being investigated as potential drug targets lead to phenotypic changes when modulated, suggesting that they may have value as therapeutic targets. CHI High- Content Analysis Market Outlook report, 2004
Many people would say a target is truly validated only after proven effective in human trials. The definition of target validation is clearly evolving, can be seen as "slippery" and clearly means different things to different people.
text mining: The aim of the text mining project is to research technologies to discover useful knowledge from enormous collections of documents, and to develop a system to provide this knowledge and to support the user's decisions. ... we focus on Natural Language Processing (NLP) technologies to extract such information. Using NLP technologies, documents are transformed into a collection of concepts, described using terms discovered in the text. Usually, "text mining" is used to indicate a text search technique. But, we think of text mining as having more functions. Text mining technologies extract more information than just picking up keywords from texts: facts, author's intentions, their expectations, and their claims. This knowledge is helpful to many applied tasks such as marketing, trend analysis, claim processing, generating FAQ (frequently asked questions), and so on. Text Mining, TRL, IBM, 2000 http://www.trl.ibm.com/projects/s7710/tm/index_e.htm
Using data mining on unstructured data, such as the biomedical literature.
Text Mining Glossary, ComputerWorld, 2004 http://www.computerworld.com/article/2564877/business-intelligence/sidebar--text-mining-glossary.html Includes Categorization, clustering, extraction, keyword search, natural language processing, taxonomy, and visualization.
tissue engineering: Generating tissue in vitro for clinical applications, such as replacing wounded tissues or impaired organs. A cell culture facility is required for cell harvest and expansion. MeSH, 2002
The term "tissue engineering" was coined at an NSF [National Science Foundation] -sponsored meeting in 1987. At a later NSF- sponsored workshop, tissue engineering was defined as "...the application of principles and methods of engineering and life sciences toward fundamental understanding ...and development of biological substitutes to restore, maintain and improve [human] tissue functions." This definition is intended to include procedures where the biological substitutes are cells or combinations of different cells that may be implanted on a scaffold such as natural collagen or as synthetic, biocompatible polymers to form a tissue. ["Tissue Engineering" National Science Foundation] http://www.nsf.gov/od/lpa/nsf50/nsfoutreach/htm/n50_z2/pages_z3/45_pg.htm
top-down: A systems approach, which looks at the big picture and complexity. Genomics is essentially a top- down approach, the opposite of a bottom- up approach. Our ways of thinking have been so profoundly influenced by bottom- up, reductionist approaches that we are having to learn to think in very different ways to begin to fully exploit genomic data
toxicogenetics: The study of existing genetic knowledge, and the generation of new genetic data, to understand and thus avoid DRUG TOXICITY and adverse effects from toxic substances from the environment. MeSH 2004
toxicogenomics: In its strictest definition, refers to the use of DNA microarray technology to identify patterns of gene expression that can be used to predict human toxicity of new drug candidates or other potential toxicants. The concept is based on the hypothesis, proven in only a preliminary sense, that a finite and limited set of such patterns, or signatures, exists and that these signatures are, in fact, highly predictive CHI report Toxicogenomics: The Promise of Safer, Smarter Drug Development
medicine: Recent advances in biological understanding are allowing
pharmaceutical companies to begin to develop tailored therapeutics, thereby
allowing patients to receive the right drug, at the right dose, and at the right
time. However, in order for such treatments to be developed, companies need to
be able to better link data from the laboratory to the clinic (bench to
bedside). This concept is frequently referred to as translational medicine.
Semantic Web Health Care and Life Sciences SIG Charter, 2008 http://www.w3.org/2008/05/HCLSIGCharter#translat
translatome: The cellular population of proteins expressed in the organism at a given time, explicitly weighted by their abundance. ... Our definition of the translatome is partially motivated by the ambiguities in term proteome, which has two competing definitions. First, broadly favoured by computational biologists, is a list of all the proteins encoded in the genome (Gaasterland 1999, Doolittle 2000). In this context, it is equivalent to what some refer to as the ORFeome, i.e. the set of genes excluding non- coding regions. Experimentalists, especially those involved in large- scale experiments such as expression analysis and 2D electrophoresis, favor a second definitions. Here it is used to describe the actual cellular contents of proteins, taking into account the different levels of protein concentrations (Yates 2000). We prefer the former definition for proteome, and use the term translatome for the later. Dov Greenbaum "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
truth: Making new technology work may be easier than using it to discover truth. Roger Brent, "Functional genomics: learning to think about gene expression data" Current Biology 9: R338- R341, 1999
Question from Nature column Lifelines put to Michel Brunet, palaeontologist "What is the one thing about science you wish the public understood better?" Answer "That the 'truth' is always an asymptotic ideal." Dreams of the past, Nature 423 (6939): 121, 8 May 2003
type I biomarkers: Capture the effects of an intervention in accordance with the mechanism of action of a drug , even though the mechanism may not be associated with clinical outcome. ...A priori validation of Type I biomarkers is impossible for truly novel targets without an effective positive control treatment. By definition, the more innovative the target, the less validated will be the associated biomarkers. Richard Frank, Richard Hargreaves, Clinical biomarkers in drug discovery and development. Nature Reviews Drug Discovery. 2(7): 566- 580, July 2003
type II biomarkers: Are considered surrogate endpoints because a change in that marker predicts clinical benefit. ... Type II biomarkers (or surrogate end-points) must be relevant both to the mechanism of action of the drug and to the pathophysiology of the disease. Changes in the biomarker should reflect treatment benefit and therefore effective therapy is necessary for this validation. Richard Frank, Richard Hargreaves, Clinical biomarkers in drug discovery and development. Nature Reviews Drug Discovery. 2(7): 566- 580, July 2003
uncertainty: The condition in which reasonable knowledge regarding risks, benefits, or the future is not available. MeSH 2003
The shift to a post- Mendelian view of genetics (with variable penetrance and eventually, insights into polygenic diseases) and genomics seems likely to result in more uncertainty, not less, at least for some time.
valid biomarker: A biomarker that is measured in an analytical test system with well-established performance characteristics and for which there is an established scientific framework or body of evidence that elucidates the physiologic, toxicologic, pharmacologic, or clinical significance of test results. The classification of biomarkers is context specific. Likewise, validation of a biomarker is context-specific and the criteria for validation will vary with the intended use of the biomarker. The clinical utility (e.g. predict toxicity, effectiveness or dosing) and use of epidemiology/ population data (e.g. strength of genotype- phenotype associations) are examples of approaches that can be used to determine the specific context the necessary criteria for validation. Guidance for Industry, Pharmacogenomic Data Submissions CDER, CBER, CDRH, FDA, March 2005 Non-binding recommendations. http://www.fda.gov/cber/gdlns/pharmdtasub.pdf
to build stronger social purpose organisations by providing them with both
financial and non-financial support in order to increase their societal impact.
EVPA purposely uses the word societal because the impact may be social,
environmental, medical or cultural. What is VP? European Venture
Philanthropy Association http://evpa.eu.com/knowledge-centre/what-is-vp/
Some patient advocacy groups are investing in companies working on therapeutics in their areas of interest, an d may also help recruit patients for clinical trials.
virtual molecules: It has also become clear that even the most efficient combinatorial chemistry approaches can generate only a minute fraction of the 1 x 1040 virtual drug molecules that could be prepared. Timothy Ritchie "Chemoinformatics; manipulating chemical information to facilitate decision- making in drug discovery" Drug Discovery Today 6(16): 813- 814, 16 Aug. 2001
Many more terms and definitions ... http://www.genomicglossaries.com/default.asp
IUPAC definitions are reprinted with the permission of the International Union of Pure and Applied Chemistry.
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