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Appendix D Glossary Adhesins: Bacterial proteins that promote adherence to host-cell membranes; see http://www.nature.com/nrm/journal/v3/n10/glossary/nrm932_glossary.html (accessed August 3, 2010). Adoptive T-cell immunotherapy: A form of transfusion therapy consisting of the infusion of various mature T-cell subsets with the goal of eliminating a tumor and preventing its recurrence (Carl, H. 2007. Principles of adoptive T cell cancer therapy. Journal of Clinical Investigation 117(5):1204). Antibiotic: Class of substances that can kill or inhibit the growth of some groups of microorganisms. Originally antibiotics were derived from natural sources (e.g., penicillin from molds), but many currently used antibiotics are semisynthetic and modified with additions of man-made chemical components. See Antimicrobial. Antibody: Also known as an immunoglobulin, an antibody is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects like bacteria and viruses. Antimicrobial: In this document, the term “antimicrobial” is used inclusively to refer to any agent (including an antibiotic) used to kill or inhibit the growth of microorganisms (bacteria, viruses, fungi, or parasites). This term applies whether the agent is intended for human, veterinary, or agricultural applications. Antimicrobial resistance: Most commonly, this refers to infectious microbes that have acquired the ability to survive exposures to clinically relevant con - 501

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502 SYNTHETIC AND SYSTEMS BIOLOGY centrations of antimicrobial drugs that would kill otherwise sensitive organisms of the same strain. The phrase is also used to describe any pathogen that is less susceptible than its counterparts to a specific antimicrobial compound (or com - bination thereof). Apoptosis: A process of programmed cell death by which cells undergo an or- dered sequence of events which lead to death of the cell, as occurs during growth and development of the organism, as a part of normal cell aging, or as a response to cellular injury. Aptamer: An oligonucleotide or peptide molecule that binds to a specific target molecule. Artemisinin: Also known as qinghaosu, its derivatives are a group of drugs that possess the most rapid action of all current drugs against falciparum malaria. β-Lactam antibiotics: A broad class of antibiotics that include penicillin deriva- tives (penams), cephalosporins (cephems), monobactams, and carbapenems, that is, any antibiotic agent that contains a β-lactam nucleus in its molecular structure. They are the most widely used group of antibiotics. β-Lactamase: A type of enzyme produced by some bacteria that is responsible for their resistance to β-lactam antibiotics, such as penicillins, cephalosporins, cephamycins, and carbapenems. Bacteria: Microscopic, single-celled organisms that have some biochemical and structural features different from those of animal and plant cells. Bacteriophage: A virus that infects bacteria. BioBricks: Standard biological parts—DNA sequences of defined structure and function—that share a common interface and are designed to be composed and incorporated into living cells such as E. coli to construct new biological systems. BioBrick parts represent an effort to introduce the engineering principles of ab - straction and standardization into synthetic biology. Biocontrol: Method of controlling pests (including insects, mites, weeds, and diseases) in plants that relies on predation, parasitism, herbivory, or other natural mechanisms. Biofilms: Bacterial communities that adhere to biotic or abiotic surfaces. These microorganisms are usually encased in an extracellular polysaccharide matrix that

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503 APPENDIX D they themselves synthesize and may be found on essentially any environmental surface in which sufficient moisture is present. Cephalosporins: A class of β-lactam antibiotics originally derived from Acremo- nium, which was previously known as “Cephalosporium.” They have the same mode of action as other β-lactam antibiotics (such as penicillins) but are less susceptible to enzymes that break down penicillin (penicillinases). Chassis: In the context of synthetic biology, chassis refers to the cell or organ - ism in which the engineered DNA or biopart is embedded in order to produce the desired device or system (Royal Academy of Engineering, 2009). Cytokine: A category of signaling molecules that mediate and regulate immunity, inflammation and hematopoiesis, and many other cellular processes. Cytokines were initially identified as products of immune cells that act as mediators and regulators of immune processes but many cytokines are now known to be pro- duced by cells other than immune cells and they can have effects on nonimmune cells as well. Dendritic cells: Dendritic cells are a type of immune system cell known as antigen presenting cells; when antigens enter the body, dendritic cells communi - cate that information to T-cells. Toll-like receptors (TLRs) are innate receptors expressed by dendritic cells. TLRs have evolved to sense highly conserved mo - lecular patterns within microbes and viruses. Deoxyribonucleic acid (DNA): A nucleic acid that contains the genetic instruc- tions used in the development and functioning of all known living organisms with the exception of some viruses. The main role of DNA molecules is the long-term storage of information. Disease: In medicine, disease is often viewed as an observable change of the normal network structure of a system resulting in damage to the system. DispersinB® (DspB): An antibiofilm enzyme, which has been shown to inhibit and disperse biofilms. DNA synthesis: A technology that enables the de novo generation of genetic sequences that specifically program cells for the expression of a given protein. Enterobacter: A genus of common Gram-negative, rod-shaped bacteria of the family Enterobacteriaceae. Several strains of these bacteria are pathogenic and cause opportunistic infections in immunocompromised (usually hospitalized)

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504 SYNTHETIC AND SYSTEMS BIOLOGY hosts and in those who are on mechanical ventilation. The urinary and respiratory tracts are the most common sites of infection. Feedback loop: Feedback is a mechanism, process, or signal that is looped back to control a system within itself. Such a loop is called a feedback loop. In systems containing an input and output, feeding back part of the output so as to increase the input is positive feedback (regeneration); feeding back part of the output in such a way as to partially oppose the input is negative feedback (degeneration). Gene regulation: The process through which a cell determines—through interac- tions among DNA, RNA, proteins, and other substances—when and where genes will be activated and how much gene product will be produced; see http://pubs. niaaa.nih.gov/publications/arh26-3/165-171.htm (accessed July 19, 2010). Genome: The complete genetic composition of an organism (e.g., human, bac - terium, protozoan, helminth, fungus), contained in a chromosome or set of chro - mosomes or in a DNA or RNA molecule (e.g., a virus). Genome metastructure: Organization of the genome with respect to where the various structural and functional components are located. Gram-negative bacteria: Refers to the inability of a microorganism to accept a certain stain. This inability is related to the cell wall composition of the microor- ganism and has been useful in classifying bacteria. Gram-positive bacteria: Refers to the ability of a microorganism to retain a cer- tain stain. This ability is related to the cell wall composition of the microorganism and has been useful in classifying bacteria. Half-life (biological): The time it takes for a substance to lose half of its phar- macologic, physiologic, or radiologic activity. Hemagglutination inhibition (HAI): The HAI tests measure the amount of serum antibodies directed against a hemagglutinating virus, with higher levels, or titers, being associated with greater protection. Human Genome Project: An international scientific research project with a primary goal of determining the sequence of chemical base pairs which make up DNA, and of identifying and mapping the approximately 20,000–25,000 genes of the human genome from both a physical and functional standpoint. A working draft of the genome was announced in 2000 and a complete one in 2003, with further, more detailed analysis still being published.

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505 APPENDIX D Immunoglobulins: A class of proteins produced in lymph tissue in vertebrates and that function as antibodies in the immune response; see http://wordnetweb. princeton.edu/perl/webwn?s=immunoglobulin (accessed August 2, 2010). Integrative conjugative elements (ICEs): Chromosomally located gene clusters that encode phage-linked integrases and conjugation proteins as well as other genes associated with an observable phenotype, such as virulence or symbiosis. They can be transferred between cells and have some phage-like genes, but they do not lyse the cell or form extracellular particles; see http://www.nature.com/ nrmicro/journal/v3/n9/glossary/nrmicro1235_glossary.html (accessed June 16, 2010). Integron: A mobile DNA element that can capture and carry genes, particularly those responsible for antibiotic resistance. It does this by site-specific recombi - nation; see http://www.medterms.com/script/main/art.asp?articlekey=32273 (ac - cessed June 14, 2010). Intrinsic resistance gene: A gene that codes for traits that reduce an organism’s sensitivity to antibiotics, such as efflux pumps, but is not specifically a resistance gene. Lysogenic: The state of a bacterial cell that has an integrated phage (pro- phage) in its chromosome; see http://www.everythingbio.com/glos/definition. php?word=lysogenic (accessed June 18, 2010). Lysogenic bacteriophage: A lysogenic phage is a “temperate” bacteriophage (such as lambda phage) that integrates its genome into the genome of the host without immediately transcribing and making new virus particles. However, at a later time, the integrated genome can be excised and begin to be actively tran - scribed, producing virus particles that eventually burst the cell. This is opposite to the “lytic” variety of bacteriophage (T4 phage) that immediately transcribe and make new virus after infecting the host cell, causing rapid lysis; see http://wiki. answers.com/Q/What_is_a_lysogenic_bacteriophage (accessed June, 23 2010). Macrolides: Family of bacteriostatic antibiotics that inhibit protein synthesis by binding to the large subunit of the bacterial ribosome; includes erythromycin, clindamycin, and the newer drugs clarithromycin and azithromycin. Metabolism: The organic processes (in a cell or organism) that are necessary for life; see http://wordnetweb.princeton.edu/perl/webwn?s=metabolism (accessed July 20, 2010).

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506 SYNTHETIC AND SYSTEMS BIOLOGY Microbe: A microorganism or biologic agent that can replicate in humans (in- cluding bacteria, viruses, protozoa, fungi, and prions). Microbiome: Term used to describe the collective genome of our indigenous microbes (microflora); see Hooper, L. V., and J. I. Gordon. 2001. Commensal host bacterial relationships in the gut. Science 292(5519):1115-1118. Monoclonal antibodies: Antibodies produced against a single antigen in cells that are clones of a single parent (germ) cell. Mutation: Genetic change that can occur either randomly or at an accelerated rate through exposure to radiation or certain chemicals (mutagens) and may lead to change in structure of the protein coded by the mutated gene. Nomogram: A graphical calculating device, a two-dimensional diagram designed to allow the approximate graphical computation of a function; it uses a coordinate system other than Cartesian coordinates. Pathogen: An organism capable of causing disease. Penicillins: Any of the various antibiotics derived from Penicillium fungi. All penicillins are β-lactam antibiotics and are used in the treatment of bacterial infections caused by susceptible, usually Gram-positive, organisms. They are historically significant because they are the first drugs that were effective against many previously serious diseases and are still widely used today, though many types of bacteria are now resistant. Persister cells: Cells produced by bacterial populations that neither grow nor die in the presence of antibiotics. These cells are largely responsible for the high levels of tolerance to antimicrobial agents often observed in biofilms. Plasmid: A small cellular inclusion consisting of a ring of DNA that is not in a chromosome but is capable of autonomous replication. Polymerase chain reaction (PCR): A scientific technique in molecular biol- ogy to amplify a single or a few copies of a piece of DNA across several orders of magnitude, generating thousands to millions of copies of a particular DNA sequence. Polypeptide antibiotics: A class of antibiotics used for eye, ear, or bladder infec- tions in addition to aminoglycosides. They are toxic and are therefore not suitable for systemic administration. They are usually applied directly to the eye or skin

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507 APPENDIX D or are inhaled into the lungs. Examples include actinomycin, bacitracin, colistin, and polymyxin B. Positron emission tomography (PET) scan: The PET scan is a nuclear medi- cine imaging technique that produces a three-dimensional image or picture of functional processes in the body. Principal component analysis (PCA): A mathematical procedure that uses an orthogonal transformation to convert a set of observations of possibly cor- related variables into a set of values of uncorrelated variables called principal components. Prodrug: A pharmaceutical substance that is inactive at the time of adminis- tration and activates once it diffuses into a cell and is modified into a reactive product by a specific enzyme. Pseudomonas aeruginosa: A common bacterium that can cause disease in hu- mans and animals. It is found in soil, water, skin flora, and most man-made environments throughout the world. It uses a wide range of organic material for food; in animals, this enables the organism to infect damaged tissues or people with reduced immunity. These infections cause generalized inflammation and sepsis and can be fatal if they occur in critical organs, such as the lungs, the urinary tract, and kidneys. Quinolones: Class of purely synthetic antibiotics that inhibit the replication of bacterial DNA; includes ciprofloxacin and fluoroquinolone. Reactive oxygen species (ROS): Chemically reactive molecules containing oxy- gen. Examples include oxygen ions and peroxides. They can be either inorganic or organic. Recombinant DNA: Genetically engineered DNA prepared by transplanting or splicing genes from one species into the cells of a host organism of a different species. Such DNA becomes part of the host’s genetic makeup and is replicated. Recombination: A combining of genes or characters different from what they were in the parents; see http://wordnetweb.princeton.edu/perl/webwn?s=recombination (accessed July 19, 2010). Resistome: The collection of all genes that directly or indirectly result in anti - microbial resistance.

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508 SYNTHETIC AND SYSTEMS BIOLOGY Respiratory syncytial virus: A respiratory virus that infects the lungs and breath- ing passages. Most otherwise healthy people recover from a respiratory syncytial virus infection in 1 to 2 weeks; however, infection can be severe in some people, such as certain infants, young children, and older adults; see http://www.cdc.gov/ rsv/ (accessed June 18, 2010). Ribonucleic acid (RNA): A biologically important type of molecule that consists of a long chain of nucleotide units. Each nucleotide consists of a nitrogenous base, a ribose sugar, and a phosphate. RNA is very similar to DNA, but differs in a few important structural details: in the cell, RNA is usually single-stranded, while DNA is usually double-stranded; RNA nucleotides contain ribose while DNA contains deoxyribose (a type of ribose that lacks one oxygen atom); and RNA has the base uracil rather than thymine that is present in DNA. RNA polymerase (RNAP or RNApol): An enzyme that produces RNA. Sidephores: Low-molecular-weight compounds with a high binding affinity for insoluble iron-III; microorganisms release sidephores to scavenge iron-III and then transport it back into the cell. Signal transduction: The process by which an extracellular signaling molecule activates a membrane receptor that, in turn, alters intracellular molecules, creating a response. There are two stages in this process: a signalling molecule activates a certain receptor on the cell membrane, causing a second messenger to continue the signal into the cell and elicit a physiological response. In either step, the signal can be amplified, meaning that one signalling molecule can cause many responses. SOS response: A postreplication DNA repair system using the RecA protein that allows DNA replication to bypass lesions or errors in the DNA. It is an error- prone repair system. Staphylococcus aureus: A Gram-positive bacteria that is the most common cause of staph infections. It is frequently part of the skin flora found in the nose and on skin. About 20 percent of the human population are long-term carriers of S. aureus. Subsistome: A subset of genes in the resistome that permit microbes to degrade antibiotics and use them as an energy source. Synthetic biology: Research that combines biology with the principles of engi- neering to design, construct, or adapt existing DNA or other biological structures into standardized, interchangeable building blocks. These biological “parts” have

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509 APPENDIX D specific functions and can be joined to create engineered cells, organisms, or bio - logical systems that reliably behave in predictable ways to perform specific tasks. Systems biology: The study of the behavior of complex biological organization and processes in terms of their molecular constituents. Toll-like receptors (TLRs): A class of proteins that play a key role in the innate immune system. Transcription: The process of creating a complementary RNA copy of a se- quence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes. During transcription, a DNA sequence is read by RNA polymerase, which produces a complementary, antiparallel RNA strand. As opposed to DNA replication, transcription results in an RNA complement that includes uracil (U) in all instances where thymine (T) would have occurred in a DNA complement. Transposon: A mobile piece of DNA flanked by terminal repeat sequences that can insert into a chromosome, exit, and relocate and typically bears genes coding for these functions; see http://www.everythingbio.com/glos/definition. php?word=transposon (accessed June 14, 2010). Vaccine: A vaccine is a biological preparation that improves immunity to a par- ticular disease. A vaccine typically contains an agent that resembles a disease- causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins. Vaccinology: The science or methodology of vaccine development. Virulence factor: Intrinsic characteristic of an infectious bacteria that facili- tates its ability to cause disease; see http://www.nature.com/scitable/definition/ virulence-factor-53 (accessed August 3, 2010). Virus: A small infectious agent that can replicate only inside the living cells of organisms.

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