CRISPR for Precision Medicine Developing Accuracy, Speed and Efficiency in Gene Editing and Repair MARCH 14-15, 2019 San Francisco CA Gene editing, particularly using the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas system, has very rapidly established itself as an important tool in drug discovery and is now being exploited for therapeutic purposes as well. http://www.triconference.com/Gene-Editing

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.  

data science: also known as data-driven science, is an interdisciplinary field of scientific methods, processes, and systems to extract knowledge or insights from data in various forms, either structured or unstructured,[1][2]similar to data mining.  … It employs techniques and theories drawn from many fields within the broad areas of mathematics, statistics, information science, and computer science, in particular from the subdomains of machine learning, classification, cluster analysis, data mining, databases, and visualization. … is now often applied to business analytics,[7] or even arbitrary use of data, or used as a sexed-up term for statistics.[8] While many university programs now offer a data science degree, there exists no consensus on a definition or curriculum contents.[7   Wikipedia accessed 2018 Jan 23 https://en.wikipedia.org/wiki/Data_science

data scientist: a high-ranking professional with the training and curiosity to make discoveries in the world of big data. The title has been around for only a few years. (It was coined in 2008 by one of us, D.J. Patil, and Jeff Hammerbacher, then the respective leads of data and analytics efforts at LinkedIn and FaceBook.) … More than anything, what data scientists do is make discoveries while swimming in data. It’s their preferred method of navigating the world around them. At ease in the digital realm, they are able to bring structure to large quantities of formless data and make analysis possible. They identify rich data sources, join them with other, potentially incomplete data sources, and clean the resulting set.. … As they make discoveries, they communicate what they’ve learned and suggest its implications for new business directions. Often they are creative in displaying information visually and making the patterns they find clear and compelling. … Data scientists’ most basic, universal skill is the ability to write code. ..More enduring will be the need for data scientists to communicate in language that all their stakeholders understand—and to demonstrate the special skills involved in storytelling with data, whether verbally, visually, or—ideally—both. … Data scientists want to be in the thick of a developing situation, with real-time awareness of the evolving set of choices it presents. Data Scientist: The Sexiest Job of the 21st Century Thomas H. Davenport and D.J. Patil, Harvard Business Review Oct 2012  http://hbr.org/2012/10/data-scientist-the-sexiest-job-of-the-21st-century/ar/5

data stewardship: Beyond proper collection, annotation, and archival, data stewardship includes the notion of ‘long-term care’ of valuable digital assets, with the goal that they should be discovered and re-used for downstream investigations, either alone, or in combination with newly generated data. The outcomes from good data management and stewardship, therefore, are high quality digital publications that facilitate and simplify this ongoing process of discovery, evaluation, and reuse in downstream studies.: The FAIR Guiding Principles for Scientific Data Management and Stewardship  Mark D Wilkinson, Madrid, Spain; Michel Dumontier, Stanford CA, Berend Mons, Leiden Univ, Utrecht, Netherlands,  https://www.nature.com/articles/sdata201618

deep learning:  another hot topic buzzword – is simply machine learning which is derived from “deep” neural nets. These are built by layering many networks on top of each other, passing information down through a tangled web of algorithms to enable a more complex simulation of human learning. Due to the increasing power and falling price of computer processors, machines with enough grunt to run these networks are becoming increasingly affordable. What is Machine Learning: A complete beginner’s guide in 2017, Bernard Marr, Forbes 2017 May   https://www.forbes.com/sites/bernardmarr/2017/05/04/what-is-machine-learning-a-complete-beginners-guide-in-2017/#722a8489578f

deep machine learning: Deep machine learning (DML) holds the potential to revolutionize machine learning by automating rich feature extraction, which has become the primary bottleneck of human engineering in pattern recognition systems. However, the heavy computational burden renders DML systems implemented on conventional digital processors impractical for large-scale problems. The highly parallel computations required to implement large-scale deep learning systems are well suited to custom hardware. Analog computation has demonstrated power efficiency advantages of multiple orders of magnitude relative to digital systems while performing nonideal computations. In this paper, we investigate typical error sources introduced by analog computational elements and their impact on system-level performance in DeSTIN--a compositional deep learning architecture. On the impact of approximate computation in an analog DeSTIN architecture.  Young S, Lu J, Holleman J, Arel I. IEEE Trans Neural Netw Learn Syst. 2014 May;25(5):934-46. doi: 10.1109/TNNLS.2013.2283730.  https://www.ncbi.nlm.nih.gov/pubmed/24808039

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

directed evolution: an iterative process scientists use to design biological molecules like enzymes. It requires inducing some randomness in the target enzyme within an organism like bacteria. The resulting mutated bacteria are screened to see which ones do the intended job the best. The winners are then cultured, and from their offspring, the best are selected, and then cultured, and so on. https://www.vox.com/science-and-health/2018/10/3/17931612/nobel-prize-2018-chemistry-directed-evolution-enzymes-antibodies

a method used in protein engineering that mimics the process of natural selection to evolve proteins or nucleic acids toward a user-defined goal.^[1] It consists of subjecting a gene to iterative rounds of mutagenesis (creating a library of  variants), selection (expressing the variants and isolating members with the desired function), and amplification (generating a template for the next round). It can be performed in vivo (in living cells), or in vitro (free in solution or microdroplet). Directed evolution is used both for protein engineering as an alternative to rationally designing modified proteins, as well as studies of fundamental evolutionary principles in a controlled, laboratory environment. Wikipedia accessed Sept 3 2018 https://en.wikipedia.org/wiki/Directed_evolution

directed protein evolution:  Systematic approaches to directed evolution of proteins have been documented since the 1970s. The ability to recruit new protein functions arises from the considerable substrate ambiguity of many proteins. The substrate ambiguity of a protein can be interpreted as the evolutionary potential that allows a protein to acquire new specificities through mutation or to regain function via mutations that differ from the original protein sequence. All organisms have evolutionarily exploited this substrate ambiguity. When exploited in a laboratory under controlled mutagenesis and selection, it enables a protein to "evolve" in desired directions. http://cat.inist.fr/?aModele=afficheN&cpsidt=17092756  Related term: phage display 

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.)  

The pharmaceutical 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.  
Related term: nonlinear.

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: Developing a drug is a risky and hugely expensive undertaking. Some 90% of publicly traded biopharmaceutical companies are not expected to make a profit this year, and, profitable or not, such companies require massive investments in research and development. How massive? The most thorough study of what it costs to a develop single new drug was conducted by three PhD economists: Joseph A. DiMasi, director of economic analysis at the Tufts Center for the Study of Drug Development, Henry G. Grabowski of Duke, and Ronald W. Hansen of the University of Rochester. Their papers on the subject go back to 1979 and have been cited by other researchers, including those of the U.S. government, to analyze policy questions. DiMasi and Grabowski wrote the chapter, “R&D Costs and Returns to New Drug Development: A Review of the Evidence,” in The Oxford Handbook of the Economics of the Biopharmaceutical Industry.  Tufts Research, Published in 2016, Examined 106 Drugs at Random  The most recent estimates of the three researchers were published in the May 2016 issue of the Journal of Health Economics. They looked at the research and development costs of 106 randomly selected drugs from a survey of 10 pharmaceutical firms. These data were used to estimate the average pre-tax cost of new drug and biologics development. The costs of compounds abandoned during testing were linked to the costs of compounds that obtained marketing approval.  The researchers determined that the average out-of-pocket cost per new compound approved by the Food & Drug Administration was $1.4 billion. http://www.cost-of-health-carenews.com/our-blog/issue-no-21-what-it-costs-to-make-a-pill 

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, FDA https://www.fda.gov/news-events/fda-voices-perspectives-fda-leadership-and-experts/new-cder-report-highlights-ongoing-drug-safety-initiatives-and-priorities  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).

epigenetics: For 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.  

ethical drugs: The old term ethical drugs signified drugs advertised only to doctors. The expression refers to the original 1847 code of ethics of the AMA, which deemed advertising directly to the public to be unethical. Over time, the term came to mean legal drugs. FDAReview.org, Independent Institute http://www.fdareview.org/glossary.shtml#ethical 

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.

FAIR data Principles : Findable, accessible, interoperable, reproducible  In the eScience ecosystem, the challenge of enabling optimal use of research data and methods is a complex one with multiple stakeholders: Researchers wanting to share their data and interpretations; Professional data publishers offering their services, software and tool-builders providing data analysis and processing services; Funding agencies (private and public) increasingly concerned with proper Data Stewardship; and a Data Science community mining, integrating and analysing the output to advance discovery. Computational analysis to discover meaningful patterns in massive, interlinked datasets is rapidly becoming a routine research activity. Providing machine-readable data as the main substrate for Knowledge Discovery and for these eScientific processes to run smoothly and sustainably is one of the Grand Challenges of eScience. https://www.force11.org/group/fairgroup/fairprinciples

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).

FDA US Food and Drug Administration http://www.fda.gov/default.htm 
FDA Drug Approvals and Databases  http://www.fda.gov/cder/rdmt/default.htm

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

A gene 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 79(4):464-470 (2002)   http://www.genenames.org/guidelines.html 

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 editing: Gene editing, particularly using the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas system, has gained importance both as a research tool in drug discovery and for drug therapy. Cambridge Healthtech Institute’s fourth annual symposium on New Frontiers in CRISPR-Based Gene Editing will bring together experts from research and clinical laboratories to talk about the recent progress in gene editing and its growing applications. However, the technology is not without limitations. What is being done to overcome some of the inherent challenges in guide RNA design, delivery and off-target effects associated with CRISPR/Cas and what are some of the alternatives being developed? Experts from pharma/biotech, academic and government labs, and technology companies will share their experiences leveraging the utility of CRISPR-based gene editing for creating cell lines and disease models, for functional in vitro, in vivo and ex vivo screening, for target and cellular pathway identification, and for therapeutic use.  New Frontiers in CRISPR based Gene Editing 2018 Feb  San Francisco CA  Program   http://www.triconference.com/gene-editing/  |

gene editing: Genetic engineering techniques that involve DNA REPAIR mechanisms for incorporating site-specific modifications into a cell's genome. MeSH Year introduced: 2017

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  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 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 [1986]. 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  

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 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

genome editing: Genome editing (also called gene editing) is a group of technologies that give scientists the ability to change an organism's DNA. These technologies allow genetic material to be added, removed, or altered at particular locations in the genome What are genome editing and CRISPR-Cas9?  Genetics Home Reference, NIH, NLM https://ghr.nlm.nih.gov/primer/genomicresearch/genomeediting    

Genome editing, or genome editing with engineered nucleases (GEEN) is a type of genetic engineering in which DNA is inserted, deleted or replaced in the genome of a living organism using engineered nucleases, or "molecular scissors." These nucleases create site-specific double-strand breaks (DSBs) at desired locations in the genome. The induced double-strand breaks are repaired through nonhomologous end-joining (NHEJ) or homologous recombination (HR), resulting in targeted mutations ('edits'). As of 2015 there were four families of engineered nucleases being used: meganucleases, zinc finger nucleases (ZFNs), transcription activator-like effector-based nucleases (TALEN), and the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas system.^[1][2][3][4]  https://en.wikipedia.org/wiki/Genome_editing  Accessed 2017 Oct 18

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: 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.

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. 

GWAS Genome 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

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. 

human 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 http://www.sciencemag.org/cgi/content/abstract/1172482

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

immunotherapy: A type of biological therapy that uses substances to stimulate or suppress the immune system to help the body fight cancer, infection, and other diseases. Some types of immunotherapy only target certain cells of the immune system. Others affect the immune system in a general way. Types of immunotherapy include cytokines, vaccines, bacillus Calmette-Guerin (BCG), and some monoclonal antibodies. NCI Dictionary of Cancer terms https://www.cancer.gov/publications/dictionaries/cancer-terms/def/immunotherapy 

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

in vitro diagnostics: The process of developing a successful in vitro diagnostic (IVD) relies on the expertise of a diverse group of individuals, including the scientists who identify the biomarkers of significance, engineers and assay developers who translate those ideas into a tangible product, and the sales and marketing staff who get the product into the market. Global and regional trends have a tremendous effect on the IVD industry. Rising healthcare costs have led to a greater emphasis on evidence-based medicine and a focus on improved patient outcomes. An aging population along with the growing epidemic of chronic diseases and (re)emergence of infectious diseases are creating a demand for diagnostic devices for a variety of conditions. The growth of emerging economies and the push for decentralized healthcare are opening the IVD market to a wider audience. Healthcare delivery systems are changing, with growing numbers of integrated delivery networks and accountable care organizations, while smaller physician and hospital networks are being acquired by larger corporations and/or are aligning themselves with other small groups. Commercializing Novel IVDs , Harry Glorikian, Insight Pharma Reports http://www.insightpharmareports.com/Commercializing-Novel-IVDs-Report/\   Executive Summary http://www.insightpharmareports.com/Commercializing-Novel-IVDs-Executive-Summary/ 

informatics: 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, NIH glossary] 
Narrower terms: bioinformatics; cheminformatics; clinical informatics, molecular informatics, pharmacoinformatics, protein informatics, research informatics  

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

interoperability:  Ability 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.  Related term: FAIR Data

"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

Laboratory Developed Tests LDTs: A laboratory developed test (LDT) is a type of in vitro diagnostic test that is designed, manufactured and used within a single laboratory. ... For example, sometests can detect many DNA variations from a single blood sample, which can be used to help diagnose a genetic disease.  FDA, LDTshttps://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/LaboratoryDevelopedTests/default.htm

The Coverage and Analysis Group at the Centers for Medicare & Medicaid Services (CMS) requested from The Technology Assessment Program (TAP) at the Agency for Healthcare Research and Quality (AHRQ) a horizon scan to summarize the available scientific evidence on the quality of laboratory-developed ("home brew" or "in-house") molecular tests, which are currently not actively regulated by the U.S. Food and Drug Administration (FDA). CMS has concerns about the quality of laboratory-developed tests and the validation currently being performed on these tests . AHRQ assigned this report to the following Evidence-based Practice Center (EPC): ECRI EPC (Contract Number: 290 2007 10063 I). To help CMS to address its concerns, this horizon scan is intended to: 1) identify types of laboratory-developed molecular tests (LDMTs) currently available for conditions relevant to the Medicare over-65-year-old population, 2) identify the methodologies and the processes that have been developed for the assessment of analytical and clinical performance of molecular tests, 3) summarize the role of Federal agencies in regulating LDMTs, and 4) identify the quality standards that have been developed for molecular tests by regulatory bodies, the industry, and the medical community. http://www.cms.gov/medicare-coverage-database/details/technology-assessments-details.aspx?TAId=72&bc=BAAgAAAAAAAA&   See also Analyte Specific Reagents

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.
Related terms: ADME, ADMETox, drug development. Narrower terms:  lead discovery, lead prioritization, lead selection, lead validation, toxicogenomics, parallel optimization

library: An unordered collection of clones (i.e., cloned DNA from a particular organism), whose relationship to each other can be established by physical mapping. [DOE] 
Narrower terms: cDNA libraries, chemical libraries, combinatorial library, compound libraries, DNA library, gene library, genomic library, hit optimization library, lead discovery library,  biased libraries, combinatorial antibody libraries, directed libraries, focused libraries, pool, pool/ split libraries, sub- library, random libraries, unbiased libraries; 

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. 

machine learning: At its most simple, machine learning is about teaching computers to learn in the same way we do, by interpreting data from the world around us, classifying it and learning from its successes and failures. In fact, machine learning is a subset, or better, the leading edge of artificial intelligence. How did machine learning come about?  Building algorithms capable of doing this, using the binary “yes” and “no” logic of computers, is the foundation of machine learning – a phrase which was probably first used during serious research by Arthur Samuel at IBM during the 1950s. Samuel’s earliest experiments involved teaching machines to learn to play checkers.  … For example, in medicine, machine learning is being applied to genomic data to help doctors understand, and predict, how cancer spreads, meaning more effective treatments can be developed.  What is Machine Learning: A complete beginner’s guide in 2017, Bernard Marr, Forbes 2017 May  
https://www.forbes.com/sites/bernardmarr/2017/05/04/what-is-machine-learning-a-complete-beginners-guide-in-2017/#33c58c2f578f

A type of ARTIFICIAL INTELLIGENCE that enable COMPUTERS to independently initiate and execute LEARNING when exposed to new data.  Year introduced: MeSH  2016

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

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

megabrands: 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: 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. NIH Guide Metabolomics Technology 2004  http://grants.nih.gov/grants/guide/rfa-files/RFA-RM-04-002.html 

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: 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 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 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

molecular 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  
Related terms: CADD Computer Assisted Drug Design, in silico, molecular graphics, molecular dynamics, virtual screening

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.

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
Broader term: antibody  Related terms: cloning, hybridoma, fully humanized antibodies, therapeutic antibodies, polyclonal antibodies

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 19^th 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/

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 www.ifm.liu.se/physchem/courses/NKEC18/Nanomedicinetaxonomy.pdf

nanoscience:  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 
Narrower terms: nanobiology, nanobiotechnology, nanochemistry, nanoengineering, nanophysics. Alternatively nanotechnology Related terms: quantum physics

NCE New Chemical Entity A compound not previously described in the literature. IUPAC Medicinal Chemistry   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: 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  

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  

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 drugs: The Orphan Drug Designation program provides orphan status to drugs and biologics which are defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases/disorders that affect fewer than 200,000 people in the U.S., or that affect more than 200,000 persons but are not expected to recover the costs of developing and marketing a treatment drug. FDA https://www.fda.gov/forindustry/developingproductsforrarediseasesconditions/default.htm

may be defined as Drugs that are not developed by the pharmaceutical industry for economic reasons but which respond to public health need.  Actually, the indications of a drug may also be considered as ' orphan ' since a substance may be used in the treatment of a frequent disease but may not have been developed for another, more rare indication. In fact, three cases may arise :  Products intended to treat rare diseases : These products are developed to treat patients suffering from very serious diseases for which no treatment, or at least a satisfactory one, has so far been available. These diseases affect only a small proportion of the population (less than one person per 2,000 in Europe), most often at birth or in infancy. The number of rare diseases for which no treatment is currently available is estimated to be between 4,000 and 5,000 world-wide. Twenty-five to 30 million people are reported to be affected by these diseases in Europe. Products withdrawn from the market for economic or therapeutic reasons : For example, thalidomide widely much used as a hypnotic drug some years ago and was then withdrawn from the market when its high teratogenic (triggering fetal malformations) risk was discovered. However this drug showed very interesting analgesic proprieties in diseases such as leprosy or lupus erythematosus. They are diseases for which no satisfactory treatment has been available. Products that have not been developed :either because they are derived from a research process that cannot be patented ; or because they concern important markets which are, however, not creditworthy (see the text Orphan drugs for Third-World countries). Orphanet About orphan drugs https://www.orpha.net/consor/cgi-bin/Education_AboutOrphanDrugs.php?lng=EN  Related term: rare diseases

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 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 

PAINS 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: 10.1038/513481a https://www.nature.com/news/chemistry-chemical-con-artists-foil-drug-discovery-1.15991 

patent cliff: A 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

patent 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 
Related term: royalty stacking

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.

PGx: may be pharmacogenomics or pharmacogenetics.

pharmacoepidemiology: applies 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  http://apps.who.int/medicinedocs/en/d/Js4876e/2.html

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 

Pharmacogenetics and pharmacogenomics are frequently interchanged terms and can therefore be confused. For the purpose of clarity in the use of the terms in this review, pharmacogenetics is defined as the study of variability in drug responses attributed to hereditary factors in different populations. Pharmacogenomics is the determination and analysis of the genome (DNA) and its products (RNA and proteins) as they relate to drug response. For example, gene expression profiling using various microarray technologies has enabled the demonstration of distinct sub-sets of genes that may be expressed differentially in disease and healthy tissues. These genomic techniques can be useful for differential diagnosis of patients, particularly for heterogeneous diseases that present with similar clinical phenotypes but differ in molecular expression. Response to treatment can sometimes be recognized at the genomic level by tissue gene expression profiles. Expression profiles, however, differ from the approach of using inherited differences in our genetic information to predict responses to medicines, pharmacogenetics. Allen D. Roses; Pharmacogenetics, Human Molecular Genetics, Volume 10, Issue 20, 1 October 2001, Pages 2261–2267, https://doi.org/10.1093/hmg/10.20.2261 https://academic.oup.com/hmg/article/10/20/2261/559355

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, Annual Review of Pharmacology & Toxicology 2002 https://www.annualreviews.org/doi/abs/10.1146/annurev.pharmtox.42.082401.140850?journalCode=pharmtox  

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

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 0 studies are exploratory studies that often use only a few small doses of a new drug in a few patients. They might test whether the drug reaches the tumor, how the drug acts in the human body, and how cancer cells in the human body respond to the drug. The patients in these studies might need extra tests such as biopsies, scans, and blood samples as part of the study process.The biggest difference between phase 0 and the later phases of clinical trials is that there’s almost no chance the volunteer will benefit by taking part in a phase 0 trial – the benefit will be for other people in the future. Because drug doses are low, there’s also less risk to the patient in phase 0 studies compared to phase I studies. Phase 0 studies help researchers find out whether the drugs do what they’re expected to do. If there are problems with the way the drug is absorbed or acts in the body, this should become clear very quickly in a phase 0 clinical trial. This process may help avoid the delay and expense of finding out years later in phase II or even phase III clinical trials that the drug doesn’t act as expected to based on lab studies. Phase 0 studies aren’t used widely, and there are some drugs for which they wouldn’t be helpful. Phase 0 studies are very small, often with fewer than 15 people, and the drug is given only for a short time. They’re not a required part of testing a new drug. American Cancer Society, Phase Zero Clinical trials https://www.cancer.org/treatment/treatments-and-side-effects/clinical-trials/what-you-need-to-know/phases-of-clinical-trials.html  Related terms: microdosing

phenotypic screens: look 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 2012 http://www.nature.com/nrd/journal/v13/n8/full/nrd4366.html  Compare 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.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.

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]

precompetitive research: Several 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.

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:  Although not suggested by natural language, and in contrast to usage in other areas, Proof of Principle and Proof of Concept are not synonymous in drug development. A third term, Proof of Mechanism, is closely related and is also described here. All of these terms lack rigorous definitions and exact usage varies between authors, between institutions and over time. The descriptions given below are intended to be informative and practically useful.^{[citation needed]} The underlying principle is related to the use of biomarkers as surrogate endpoints in early clinical trials. See for example the introductory discussion on pages 3 to 9 of Downing's Biomarkers and surrogate endpoints: clinical research and applications.^[6] In early development it is not practical to directly measure that a drug is effective in treating the desired disease, and a surrogate endpoint is used to guide whether or not it is appropriate to proceed with further testing. For example, although it cannot be determined early that a new antibiotic cures patients with pneumonia, early indicators would include that the drug is effective in killing bacteria in laboratory tests, or that it reduces temperature in infected patients - such a drug would merit further testing to determine the appropriate dose and duration of treatment. A new antihypertension drug could be shown to reduce blood pressure, indicating that it would be useful to conduct more extensive testing of long-term treatment in the expectation of showing reductions in stroke (cerebrovascular accident) or heart attack (myocardial infarction). Surrogate endpoints are often based on laboratory blood tests or imaging investigations like X-ray or CT scan.^{[citation needed]}  ...  refers to early clinical drug development, conventionally divided into Phase I and Phase IIa.  Wikipedia  accessed 2018 Feb 5 https://en.wikipedia.org/wiki/Proof_of_concept   

Compare proof of principle. Proof of concept is certainly more prevalent as a term.  Google 2018 Sept 10 Proof of concept over 21 Million, proof of principle over 6 Million, 3 ½ times as many for proof of concept.  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.