Information

1.6: Model Organisms Facilitate Genetic Advances - Biology

1.6: Model Organisms Facilitate Genetic Advances - Biology


We are searching data for your request:

Forums and discussions:
Manuals and reference books:
Data from registers:
Wait the end of the search in all databases.
Upon completion, a link will appear to access the found materials.

Model organisms

Many of the great advances in genetics were made using species that are not especially important from a medical, economic, or even ecological perspective. Today, a small number of species are widely used as model organisms in genetics (Fig 1.17). chromosomes are present in pairs).

The most commonly used model organism are:

  • The prokaryote bacterium, Escherichia coli, is the simplest genetic model organism and is often used to clone DNA sequences from other model species.
  • Yeast (Saccharomyces cerevisiae) is a good general model for the basic functions of eukaryotic cells.
  • The roundworm, Caenorhabditis elegans is a useful model for the development of multicellular organisms, in part because it is transparent throughout its life cycle, and its cells undergo a well-characterized series of divisions to produce the adult body.
  • The fruit fly (Drosophila melanogaster) has been studied longer, and probably in more detail, than any of the other genetic model organisms still in use, and is a useful model for studying development as well as physiology and even behavior.
  • The mouse (Mus musculus) is the model organism most closely related to humans, however there are some practical difficulties working with mice, such as cost, slow reproductive time, and ethical considerations.
  • The zebrafish (Danio rerio) has more recently been developed by researchers as a genetic model for vertebrates.Unlike mice, zebrafish embryos develop quickly and externally to their mothers, and are transparent, making it easier to study the development of internal structures and organs.
  • Finally, a small weed, Arabidopsis thaliana, is the most widely studied plant genetic model organism. This provides knowledge that can be applied to other plant species, such as wheat, rice, and corn.

PhenoDigm: analyzing curated annotations to associate animal models with human diseases

The ultimate goal of studying model organisms is to translate what is learned into useful knowledge about normal human biology and disease to facilitate treatment and early screening for diseases. Recent advances in genomic technologies allow for rapid generation of models with a range of targeted genotypes as well as their characterization by high-throughput phenotyping. As an abundance of phenotype data become available, only systematic analysis will facilitate valid conclusions to be drawn from these data and transferred to human diseases. Owing to the volume of data, automated methods are preferable, allowing for a reliable analysis of the data and providing evidence about possible gene-disease associations. Here, we propose Phenotype comparisons for DIsease Genes and Models (PhenoDigm), as an automated method to provide evidence about gene-disease associations by analysing phenotype information. PhenoDigm integrates data from a variety of model organisms and, at the same time, uses several intermediate scoring methods to identify only strongly data-supported gene candidates for human genetic diseases. We show results of an automated evaluation as well as selected manually assessed examples that support the validity of PhenoDigm. Furthermore, we provide guidance on how to browse the data with PhenoDigm's web interface and illustrate its usefulness in supporting research. Database URL: http://www.sanger.ac.uk/resources/databases/phenodigm

Figures

Determining the phenotype similarity of…

Determining the phenotype similarity of two entities, e.g. a mouse model and a…

ROC analysis of PhenoDigm’s phenotype…

ROC analysis of PhenoDigm’s phenotype prioritization method applied to MGD’s curated mouse model–disease…

To efficiently browse the obtained…

To efficiently browse the obtained prioritisation results, a web interface was developed. As…


Humans as a Model Organism: The Time Is Now

This issue of GENETICS features an article that signals the Editorial Board’s intent for the journal to increase its presence in the human genetics arena. In its 98-year history GENETICS has featured many articles in which the subject species was Homo sapiens, but until recently those were largely in the realm of population genetics. We intend to maintain the journal as a high status, high visibility venue for communicating human population genetics research, because new sequencing technologies have made that field more important than ever.

But the journal has seldom published articles about identification of human genes and analysis of their function. We want that to change, because the depth of genetic analysis of humans is now approaching that possible with experimentally tractable organisms that have long been featured in the journal.

This is for primarily two reasons. First, remarkable advances in genomics and DNA sequence technologies enable facile identification of human genes and their DNA sequence variants that cause diseases and syndromes. Not so long ago it was a slog to map and clone a gene responsible for a phenotype (usually disease) in humans today it is almost a cakewalk. Second, decades of work on a few experimental organisms have established them as models for the function of genes and pathways that are conserved throughout the tree of life and have provided sophisticated tools for analyzing those genes and exploring the pathways they are involved in. The function of the product of a human gene can often be determined by studying its ortholog(s) in a model organism. This marriage of model organism and human genetics is bringing in-depth understanding of human gene function, and it is doing so quickly.

The paper by Brooks et al. in this issue of GENETICS is a shining example of the power of enlisting model organisms in the service of human genetics. In a Commentary, Hieter and Boycott tell how we are in the midst of an unprecedented era of human disease gene discovery, and how harnessing the analytical power of model organisms will be necessary to realize the ultimate goals of human genetics: an understanding of gene function, insights into the biology of disease, and the development of effective therapeutics.

The Editors of GENETICS want to extend the reach of the journal in the human genetics conversation. We seek submissions of papers, like Brooks et al., that provide insight into human gene function and disease. More broadly, GENETICS (and our sister journal, G3: Genes | Genomes | Genetics) seek to publish papers that describe methodological and empirical studies of humans that advance understanding of fundamental concepts of genetics, such as:

Methods for mapping loci that underlie human phenotypes.

Genome organization and structure.

Genome modification (epigenomics).

Evaluation of mutation and recombination rates and their genomic variation.

Human population genetics and genomics.

Identification of genetic variants that cause disease.

We have recruited—and will continue to recruit—well-regarded, practicing human geneticists as Associate Editors to help us choose the best papers the field has to offer for publication in the journal. I look forward to GENETICS being part of a long and productive contribution of model organism and human genetics.


Abstract

Synthetic biology aims to create functional devices, systems and organisms with novel and useful functions on the basis of catalogued and standardized biological building blocks. Although they were initially constructed to elucidate the dynamics of simple processes, designed devices now contribute to the understanding of disease mechanisms, provide novel diagnostic tools, enable economic production of therapeutics and allow the design of novel strategies for the treatment of cancer, immune diseases and metabolic disorders, such as diabetes and gout, as well as a range of infectious diseases. In this Review, we cover the impact and potential of synthetic biology for biomedical applications.

By applying engineering principles to biology, synthetic biology has become the science of reassembling catalogued and standardized biological components in a systematic and rational manner to create and engineer functional biological designer devices, systems and organisms with predictable, useful and novel functions. Synthetic biology is able to use an inventory of biomolecular parts compiled over 50 years of molecular biological and functional genomic research 1,2,3,4 , as well as technology that has made it possible to analyse 5,6 , synthesize 7,8,9 , assemble 10 , modify 11 and transfer 12,13 genetic components into living organisms.

Although it has recently become possible to reconstruct a living organism after transfer of a synthetic genome that has been assembled from chemically synthesized nucleic acid pieces 13,14 , the rational design of state-of-the-art biological circuits with predicable functions remains challenging and is apparently limited to a handful genes 15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31 .

Synthetic circuitry is composed of basic heterologous control components that fine-tune transgene expression in response to specific exogenous cues or endogenous metabolites 32 . These gene switches include trigger-inducible protein–DNA 33,34,35,36 or aptamer–transcript interactions 37,38,39 , which control transcription and translation in response to heterologous and endogenous input signals (Fig. 1). The standardized design of gene switches has improved functional compatibility 40,41 and has enabled the construction of higher-order networks — including multi-trigger inputs and sequential control 42,43 , mutual control 20,23,44,45 and feedback control 16,19,28,46 of circuit components — that are able to provide complex protein expression dynamics with high precision and predictable logic in response to external cues or physiological pathways. Because most control components function in different bacterial and eukaryotic species after minor refinements 36,47,48,49 , gene switches and network blueprints that were pioneered in bacteria or yeast are often fully functional in mammalian cells. Examples of synthetic networks with similar components and circuit topology in bacterial and mammalian cells include: regulatory cascades 42,43 , epigenetic toggle switches 15,20,23,45 , hysteretic circuits 22,50,51 , molecular timing devices 30,52 , synthetic eco-sensing systems, synthetic quorum-sensing systems, synthetic hormone systems 46,53,54 , band-pass filters 21,30,55 and different types of oscillators that program rhythmic transgene expression with a tunable frequency and amplitude 16,26,27,28,29,56,57 . Most of these first-generation synthetic circuits operated in isolation without any interface with the metabolism of the host cell, and they were used to program specific cellular functions using heterologous external input signals 58,59,60,61,62 .

a | Repression-based expression control. A repressor protein binds to its operator and thus prevents activation of the promoter and expression of the gene of interest. In response to an inducer, the repressor dissociates from the operator, the promoter is derepressed, and the gene of interest is expressed. b | Activation-based expression control. A minimal promoter (Pmin) is activated when a chimeric transcription factor that is constructed by fusing a repressor protein to a transcription activation domain binds to its operator. In the presence of an inducer, the repressor protein–transcription-activation domain complex dissociates from its operator, Pmin is no longer activated, and transcription of the gene of interest is prevented. c | mRNA transcript-based expression control. A self-cleaving ribozyme is fused to a small-molecule-binding aptamer and introduced into the 3′ untranslated region (UTR) of a gene of interest. In the absence of the inducer, the ribozyme undergoes self-cleavage, thereby eliminating the poly(A) tail (pA) from the open reading frame and preventing translation. However, in the presence of the inducer, the aptamer undergoes a conformational change, which inactivates the ribozyme and allows translation to occur.

Key challenges that often occur in the biomedical setting are the need for drug–target specificity, precise drug-dosing regimes, minimizing side effects, shortening the diagnosis-to-treatment timelines and avoiding drug-resistance of pathogens. As synthetic biology enables the engineering of complex, high-precision control devices that couple sensing and delivery mechanisms, this emerging science may be able to offer tools that are suited to meeting current biomedical challenges in new ways. A decade after the pioneering synthetic networks were reported 18,20 , the first successful therapeutic applications in animal models of prominent human diseases are starting to emerge 63,64,65 . This Review focuses on the recent progress in synthetic biology towards improving human health, including diagnostic applications, design of novel preventive care strategies, progress in drug discovery, design and delivery, and development of novel treatment strategies, such as prosthetic networks. Synthetic biology holds the promise of providing unique opportunities for major advances in the improvement of human health in the twenty-first century 4,66,67 .

Understanding disease mechanisms

Pathogen mechanisms. The availability of affordable technology for synthesizing and assembling 10 sequences for proteins or for viral 68 and bacterial 69 genomes with increased speed has dramatically improved our understanding of host–pathogen interactions and of disease mechanisms. The synthetic biology principle of 'analysis by synthesis' provides mechanistic insight by combining rapid synthesis, assembly, shuffling and mutation of individual genetic components with straightforward functional analysis. For example, the genome of the H1N1 virus that was responsible for the 1918 Spanish influenza pandemic was synthesized using sequence information from genomic pieces that were extracted from permafrost-conserved tissue samples. Functional analysis of the reconstructed virus provided new insight into the key virulence factors of the pathogen: namely, a haemagglutinin variant that induces membrane fusion without trypsin activation and a modified polymerase that enhances viral replication 68 . The same study also revealed that a combination of eight genes was responsible for the exceptional virulence of the Spanish influenza strain 68,70 . This finding may help to identify the pandemic potential of future virus variants 71,72,73 .

Synthesis and analysis of chimeric viruses have also made a substantial contribution to the understanding of coronavirus zoonoses that were responsible for the severe acute respiratory syndrome (SARS) pandemic of 2002 and 2003. The characterization of the history of the SARS coronavirus, especially its switch in tropism, was particularly challenging, as its direct ancestors could not be propagated in laboratory models. However, after a 30 kb SARS-like bat coronavirus was designed to contain the receptor-binding spike protein of its human homologue, the synthesized chimeric virus was able to replicate in culture and infect mice 74 . These in vivo studies revealed infection-enhancing mutations in the spike protein and established this surface protein as a key factor that is responsible for tropism switches in coronavirus zoonoses 74 . Reconstruction of pathogens by DNA synthesis can also be used for the production of diagnostic high-density antigen arrays 75,76 , such as those used to profile post-Lyme-disease syndrome 76 or the humoural immune responses to hepatitis C and the human immunodeficiency virus (HIV) 77 .

Immune systems. Synthetic biology has recently provided new insight into disorders that are related to deficiencies of the immune system, which is known for its particularly complex control circuits and cellular interaction networks. For example, dysfunction of B-lymphocyte activation underlies several physiological disorders 78 . Functional reconstitution and analysis of the human B cell antigen receptor (BCR) signalling cascade in insect cells revealed that BCRs are not activated by antigen-specific crosslinking, as presented in textbooks, but instead have an autoinhibitory oligomeric conformation on resting B lymphocytes that shifts to an active dissociated form when antigens bind 79 . This triggers the signalling cascade, which results in antibody production and the onset of a humoural immune response.

Also, construction of a representation of the complete human peptidome engineered for display on the surface of T7 phages enabled Church and colleagues 80 to discover new autoantigens. They used patient-derived autoantibodies to enrich autoantigenic peptides displayed on the phages they could then identify the antigens by high-throughput sequence analysis 80 . Knowledge of the antigens that are involved in autoimmune processes is important for understanding disease aetiology, developing accurate diagnostic tests and designing drugs that neutralize autoreactive immune cells 80 .

Vaccines. High-throughput and high-precision assembly and engineering of entire genomes from well-defined genetic components using synthetic biology principles has provided new opportunities for the design of attenuated pathogens for use as vaccines. For example, primates immunized with virus-like particles that were produced by selective expression of particular chikungunya virus (CHIKV) structural proteins were protected against viraemia after a high-dose challenge even immunodeficient mice that were treated with monkey-derived antibodies survived subsequent lethal doses of CHIKV 81 . DNA synthesis and assembly has also played an essential part in pioneering a safe live vaccine against the poliovirus 82 . The poliovirus was attenuated by systematic genome-scale changes of adjacent pairs of codons from over- to underrepresented codon sets in viral capsid genes (for example, GCC|GAA is strongly under-represented compared with GCA|GAG, although both encode Ala–Glu). These changes reduced translation and impaired the replication competence and infectivity of the virus. This attenuated poliovirus provides protective immunization in mice and offers a high safety standard given the low probability that all 631 individual changes will revert and thus reconstitute infectious wild-type viruses. The genome-engineering approach used here could represent a general strategy for designing live vaccines against infectious diseases. Other promising vaccination concepts include using antigen-producing immunostimulatory liposomes as genetically programmable synthetic vaccines 83 and the production of heat-stable oral algae-based vaccines to protect against Staphylococcus aureus infections 84,85 .

Vector control. Suppression of insect vector populations using transgenic viral strains that harbour conditional dominant-lethal synthetic circuitry may control the transmission of malaria parasites and dengue viruses and could eventually control the spread of untreatable diseases 86,87,88 . Mosquitoes that are transgenic for a tetracycline-dependent transactivator (tTA) that is exclusively expressed in the female's indirect flight muscle can only be propagated in the presence of tetracycline, which represses the transcription of this gene. However, the absence of tetracycline leads to the development of a female-specific flightless phenotype 87,88 . Putting the eggs of this transgenic mosquito into the ecosystem results in male-only releases female mosquitoes remain grounded and cannot feed, mate or take blood meals, which effectively represents a lethal phenotype. Males do not transmit the disease, but they disseminate the synthetic circuit across the resident wild-type mosquito population 87,88 (Fig. 2a).

a | A female-specific dominant-lethal gene network for mosquito control. Mosquitoes were engineered to express an intron-containing variant of the tetracycline (TET) transactivator (tTA) under the control of a flight-muscle-specific promoter (PFM). In male mosquitoes, the intron is not spliced out, which prevents correct tTA translation. In female progeny, however, functional tTA translation is restored by sex-specific mRNA splicing. This results in the activation of the tTA-responsive promoter PTET and the expression of a toxic gene that triggers a flightless phenotype. If mosquitoes are raised in the presence of tetracycline (TET), tTA is prevented from activating PTET, which results in a normal phenotype. However, following their release into the TET-free environment, engineered males mate with wild-type females. This transmits the female-specific dominant flightless phenotype and should eventually result in the reduction or extinction of the wild-type population. b | Propagation of a selfish gene converting a heterozygous into a homozygous host. The homing endonuclease I-SceI is expressed and cleaves its cognate restriction site (RS) on the homologous chromosome. Following end resection and repair, the I-SceI expression cassette is inserted into the second chromosome. pA, poly(A) tail.

Similarly, a synthetic homing endonuclease-based gene drive system could be used to spread genetic modification, such as malaria resistance, from engineered mosquitoes to the field population. Homing endonucleases typically produce a single sequence-specific double-strand break in the host genome that is repaired by homologous recombination using the homing endonuclease gene (HEG) as a template. Consequently, the selfish HEG is copied to the broken chromosome in a gene conversion process referred to as 'homing'. Expressing the HEG I-SceI under the control of a male germline promoter enabled efficient homing in transheterozygous males and rapid genetic drive, which led to HEG invasion in caged mosquito populations 89 (Fig. 2b). By engineering the sequence specificity of other HEGs (for example, I-AniI or I-CreI), the gene drive concept could, in principle, be used to knock in or knock out gene functions that target the mosquito's ability to serve as a disease vector 89 .

Field tests of release of insects carrying dominant lethals (RIDL) technology using first-generation tTA-transgenic mosquitoes have already been conducted in Grand Cayman. First, a small-scale release confirmed that transgenic males could survive, mate with wild females and produce transgenic larvae, and then the full field trial showed an 80% reduction in the numbers of wild mosquitoes about 11 weeks after release. As the study site was not isolated and the surrounding areas contained high densities of wild-type mosquitoes, scoring the actual suppression efficiency remains challenging 90 .

Drug discovery. Synthetic mammalian transcription circuits consisting of a chimeric small-molecule-responsive transcription factor and a cognate synthetic promoter were originally designed for future gene-based therapies, and the aim was to adjust therapeutic transgene expression in mammalian cells in response to a pharmacologically active substance 34,47,49,91 . As most chimeric transcription factors are derived from repressors that manage drug resistance in bacteria (for example, resistance to antibiotics 92 ) and are promiscuous for structurally related compounds, mammalian cells containing such circuitry could also be used in 'reverse mode', as integrated screening devices for the class-specific discovery of new drug candidates 33,93 (for example, new antibiotics 92 ) (Fig. 3a). When mammalian cells that are transgenic for the screening circuit are exposed to a compound library, they detect and modulate reporter gene expression in the presence of a non-toxic, cell-permeable and bioavailable molecule that has a class-specific core structure and corresponding drug activity (for example, antibiotic activity) (Fig. 3b). Using the same screening setup, compounds have been detected that lock the transcription factor onto the DNA, which may block induction of antibiotic resistance in pathogens and render them drug-sensitive 94 (for example, see Bioversys). Using such compounds alongside the specific antibiotic may offer novel anti-infective treatment opportunities and a new life cycle for established antibiotics (Fig. 3c). Other trigger-inducible transcription control systems can be used in this manner as well, such as those that are responsive to streptogramin 47 , tetracycline or macrolide antibiotics 91 , anti-diabetes drugs 95 or immunosuppressive lactones 96,97 .

a | Identification of antibiotics. In Chinese hamster ovary (CHO-K1) cells, the streptogramin-responsive repressor (PIP) was expressed by a constitutive promoter (Pconst). PIP binds to its multimeric operator (PIR3) and represses expression of the reporter gene secreted alkaline phosphatase (SEAP). Exposing this screening cell line to a small molecule library only resulted in SEAP production for compounds that were streptogramin-like, cell-permeable and non-toxic (indicated by the brown star). b | Discovery of small molecules that are able to overcome antibiotic resistance. The Mycobacterium tuberculosis antibiotic resistance regulator (EthR) was fused to the herpes-simplex-derived transcriptional activator (VP16) and expressed in human embryonic kidney cells (HEK293-T) under the control of a constitutive promoter (Pconst). When EthR–VP16 binds to its cognate operator (OEthR), the minimal promoter (Pmin) is activated, which results in expression of the reporter gene SEAP. A screen is performed to identify a cell-permeable, non-toxic molecule (indicated by the yellow star) that prevents EthR binding to OEthR, stopping SEAP expression. c | Overcoming resistance to ethionamide in M. tuberculosis. In M. tuberculosis, EthR represses transcription of both the Baeyer–Villiger monooxygenase (EthA) and itself in a negative feedback loop. When 2-phenylethylbutyrate (indicated by the pink star) is added, it prevents EthR binding its target promoter (labelled 'P' in the figure). This derepresses EthA production, thereby turning ethionamide into a cytotoxic compound that kills the mycobacterium. pA, poly(A) tail.

One example of the efficacy of a transcription circuit system involves the bacterial transcriptional repressor EthR. EthR represses transcription of ethA and so prevents EthA-mediated conversion of the last-line-defence antibiotic ethionamide into a pathogen-killing metabolite 94 . The chemical 2-phenyethylbutyrate, best known for its strawberry flavour, was the first compound found that specifically inactivated EthR and so triggered ethA expression and re-established the sensitivity of Mycobacterium tuberculosis to ethionamide (Fig. 3d). Further work revealed other EthR-inactivating ethionamide booster compounds these have also been successfully tested in a mouse model of human tuberculosis 98 . Restoring drug sensitivity by pharmacological inhibition of master resistance regulators may be widely applicable 94 .

A further example of the use of synthetic circuitry for drug discovery is provided by mammalian cells that are conditionally arrested in the G1 phase of the cell cycle by circuitry controlling the expression of the cycline-dependent kinase inhibitor p27. These cells reproducibly formed a mixture of isogenic subpopulations of proliferation-inhibited cells and proliferating cells that had spontaneously escaped the synthetic cell cycle block 99 . These cells could be used as a cell-based cancer model and could be used to screen for anticancer compounds that selectively eliminate proliferating cells while leaving arrested ones intact 100,101 .

Drug production and drug delivery. The synthetic pathways that are created by assembling enzymatic cascades or networks in bacteria, yeast and plants have been instrumental for the large-scale economic production of high-value drug and drug precursor compounds, as well as for the biosynthesis of new secondary metabolites with novel therapeutic activities. Examples include complex polyketides 102,103 , halogenated alkaloids 104,105,106 and the precursors of the anti-malaria drug artemisinin (which is produced by the company Amyris, for example) 107 and of the anti-cancer compound taxol 108 . For production of these compounds, it was necessary to overcome several challenges, including the functional expression of complex biosynthetic enzymes (such as cytochrome P450 monooxygenases 109 ) and the overall orchestration of the multistep pathway to avoid accumulation of (toxic) intermediate products and to ensure metabolic channelling 60 .

Small-molecule-responsive protein–protein and protein–DNA interactions that are used to pioneer gene switches in mammalian cells 36,49,110 have also been successfully re-engineered in the design of trigger-inducible biohybrid materials for drug delivery 111,112,113,114,115 . Using synthetic protein–polyacrylamide and DNA–polyacrylamide monomers, hydrogels can be produced that dissolve when specific ligands are supplied (Fig. 4). Biopharmaceuticals (for example, vascular endothelial growth factor (VEGF)) supplied during gel formation are loaded into the hydrogel and can be released in a dose-dependent manner after subcutaneous implantation into mice and oral administration of the trigger compound 115 . It is thought that any trigger-inducible protein–protein and protein–DNA interactions could be used to produce drug-sensing and drug-releasing hydrogels 114,116,117 .

Interactive biohybrid material based on the interaction of a repressor protein with its cognate DNA operator motif. Homodimeric tetracycline repressor (TetR) is converted into a single-chain repressor (scTetR) by connecting two TetR subunits through a flexible peptide linker, and it is tagged with six histidines (scTetR–His6). This molecule is coupled to a polymer and is mixed with a polyacrylamide that has copies of a tetracycline operator (tetO) attached to it. scTetR binds to tetO so crosslinks are formed, making a hydrogel. When tetracycline is added, scTetR releases tetO, and the gel is dissolved. This can be used to release another molecule that was attached to the polymer — in this case, the cytokine interleukin 4 (IL-4).

Novel treatments for infections

Breaking bacterial resistance by designer phages. Biofilms are surface-associated bacterial communities that are encased in a hydrated extracellular polymeric substance (EPS) matrix that is composed of polysaccharides, proteins, nucleic acids and lipids. They are crucial to the pathogenesis of many clinically important bacteria and exhibit resistance both to the immune system and to antimicrobial treatments, making them difficult to eradicate 118,119 . Collins and colleagues 120 successfully engineered bacteriophage T7 to constitutively express DspB: an enzyme that hydrolyses β-1,6-N-acetyl- D -glucosamine, which is an adhesin that is required for biofilm formation and integrity in Staphylococcus spp. and Escherichia coli clinical isolates. The initial infection of a bacterial biofilm with this bacteriophage (known as T7DspB) results in rapid multiplication of the phage and expression of DspB. Following lysis, T7DspB and DspB are released into the biofilm, which leads to re-infection and degradation of β-1,6-N-acetyl- D -glucosamine. During the process of T7DspB infection, bacterial biofilm cell counts are reduced by 99.997% — over two orders of magnitude greater than when a non-enzymatic phage is used 120 .

In a follow-up study, bacteriophage M13 was engineered to express LexA3, which suppresses the SOS DNA repair system that bacteria require to counteract antibiotic-induced oxidative stress 121,122,123 . Infection by this designer phage sensitizes E. coli to quinolone antibiotics. Use of this phage increases the survival of mice that are infected with E. coli, decreases the survival of antibiotic-resistant bacteria, persister cells and biofilm cells and reduces the number of antibiotic-resistant bacteria that arise from an antibiotic-treated population. It also acts as a strong adjuvant for other bactericidal antibiotics 124 . The designer phage platform can be used to produce other antibiotic adjuvants 124 .

Although it was once abandoned after the introduction of antibiotics, phage therapy is currently being revisited in several clinical trials around the world as the prevalence of multidrug-resistant pathogens is dramatically increasing. Although phage therapy may face clinical challenges associated with development of bacterial phage resistance, phage neutralization by the immune system and pharmacokinetics, the field will certainly receive an impetus from designer phages 125 .

Engineered probiotic bacteria decrease pathogen virulence. Bacteria can communicate with each other using a chemical language known as quorum sensing. Individual bacteria produce and secrete signalling molecules (called autoinducers) that are common to multiple species or are species-specific. These molecules accumulate as the population grows and can bind to receptors that coordinate colony-wide gene expression or manipulate the behaviour of other bacterial populations. For example, Vibrio cholerae produces cholera autoinducer 1 (CAI-1) and autoinducer 2 (AI-2), which trigger repression of key virulence factors. Feeding infant mice with a probiotic E. coli that naturally produces AI-2 and has been engineered to constitutively synthesize CAI-1 significantly increased the animals' survival rate after ingesting V. cholerae 126 . This suggests that such an approach could be an economic strategy to prevent infectious diseases. Unlike antibiotics, quorum-sensing-based interventions do not kill pathogens but reprogram their behaviour this strategy may be free of selection pressure and therefore may be less prone to develop resistance. In another study, commensal bacteria were equipped with synthetic circuitry to stimulate glucose-dependent insulin production in intestinal epithelial cells 127 .

Despite decades of progress in cancer therapy, a major challenge remains: how to specifically target and selectively kill neoplastic cells that develop within native and implanted tissue and relocate within the organism to form metastasis. Therefore, therapeutic strategies that are designed to eliminate cancer cells must be extremely precise to exclusively target diseased tissue while leaving normal tissue intact. Although native cytotoxicity or the constitutive expression of anticancer compounds have demonstrated some potential in animal studies and human clinical trials 128 , trigger-inducible drug expression circuits delivered by tumour-invasive bacteria or tumour-transducing viral particles may improve cancer therapy. Synthetic biologists have recently designed a few anti-cancer devices that provide precise timing, location and dosing of drug production by external cues and could provide greater intra-tumoural effects while minimizing systemic toxicity.

Bacterial synthetic devices. After intravenous injection or oral administration, many bacterial species (for example, E. coli and Salmonella spp.) naturally sense and self-propel towards tumours. These bacteria have also been engineered to selectively invade and proliferate in tumour tissues and to produce cytotoxic compounds as well as reporter proteins for non-invasive follow-up monitoring of tumour regression 128 . These bacteria express flagella to penetrate tissue and chemotactic receptors to promote migration towards aspartate produced by viable cancer cells, ribose released by necrotic tissue or hypoxic regions generated by the hyper-metabolic activities of neoplastic cells. After they have reached the tumour site, the bacteria then either proliferate in the extracellular space or invade the tumour cells. In either situation, selective cytotoxicity was engineered by expressing toxins, cytokines, tumour antigens, pro-apoptotic factors or prodrug-converting enzymes 128 . Non-invasive E. coli has successfully been programmed to invade cultured tumour cells in a hypoxia-responsive or population-density-dependent manner. The corresponding circuitries consist of the anaerobically induced formate dehydrogenase promoter driving the Yersinia pseudotuberculosis invasin gene (inv), which mediates invasion using specific integrin receptors that are typically expressed on tumour cells. Population-density-dependent invasion requires an engineered quorum-sensing circuit that triggers inv expression after the bacterial population has reached a threshold size at the tumour site. This circuitry consists of quorum-sensing receptor LuxR that co-induces luxI (which encodes the enzyme producing the quorum-sensing messenger autoinducer 1 (AI-1)), and inv. AI-1-triggered, LuxR-mediated expression of luxI represents a positive feedback loop that amplifies inv expression and AI-1 production this coordinates and broadcasts the invasion order across the entire population 129 (Fig. 5a).

a | Population-density-dependent invasion of cancer cells. After intravenous injection, Escherichia coli accumulates in cancer tissue, where it reaches high population densities. E. coli is engineered to link the quorum-sensing receptor LuxR to an autoinducer 1 (AI-1)-inducible promoter (Plux). Plux is also used to drive luxI and the invasin gene inv. LuxI produces AI-1, generating a positive feedback loop that coordinates invasion throughout the population. b | Acetylsalicylic acid (Aspirin)-triggered killing of cancer cells after invasion of Salmonella spp. Salmonella spp. naturally invade cancer cells after intravenous injection. Salmonella spp. were engineered with a Pseudomonas putida-derived signal-amplifying two-level cascade in which NahR controls salicylate promoter (Psal)-driven xylS2 expression and XylS2 then triggers a XylS2-dependent promoter (Pm)-driven expression of the cytosine deaminase (labelled CD in the figure). Salicylate induces both NahR-based Psal and XylS2-mediated Pm activation. Mammalian cells are resistant to 5-fluorocytosine because they lack cytosine deaminase, which converts 5-fluorocytosine into the toxic cancer therapeutic 5-fluorouracil. c | Invasive bacteria suppress oncogene expression. E. coli is engineered to constitutively co-express a catenin β-1-specific short hairpin RNA (shRNA), Listeria monocytogenes listeriolysin (LLO*) and inv under control of the bacteriophage T7 promoter (PT7). They invade cancer cells (using the Inv protein), escape from the phagosome (using LLO*) and knock down the catenin β-1 oncogene (using shRNA). d | Therapeutic protein transduction. Lentiviral particles are produced using an integrase-negative helper vector (designated 'helper' in the figure) and a constitutive expression vector encoding the protein of interest (designated 'protein' in the figure) fused to viral protein R (VPR) and a protease cleavage site (PC). This can be delivered to any target cell in the absence of viral nucleic acids and proteins. An example application is described in the main text. pA, poly(A) tail. PEF1α, elongation factor 1 alpha (EF1α) promoter.

Tumour-invading bacteria have also been engineered for trigger-inducible drug expression after entering tumour cells. In addition to L -arabinose- 130 and γ-irradiation-induced 131 drug expression, a synthetic salicylate-triggered expression device has been used to control expression of drug components following systemic administration of the trigger molecule in mice in tumour cells that have been invaded by Salmonella spp. 132 . The device is based on a circuit that is derived from Pseudomonas putida, which controls expression of cytosine deaminase in a salicylate-inducible manner 132 . Mammalian cells normally lack cytosine deaminase, which means that they are resistant to 5-fluorocytosine because this enzyme is needed to convert 5-fluorocytosine into the cytotoxic molecule 5-fluorouracil. Tumour-bearing mice were injected with attenuated Salmonella enterica engineered with the P. putida-derived circuit and then treated with 5-fluorocytosine. The mice showed significant tumour regression when fed with acetylsalicylic acid (Aspirin) 132 , which is rapidly converted to salicylate after intake by the animal (Fig. 5b).

RNAi is a potent and highly conserved mechanism for the targeted knockdown of mRNA translation by small RNAs. Non-pathogenic E. coli was engineered to express a short RNA hairpin that triggers RNAi against catenin β-1, which is a colon-cancer-specific oncogene 133 . These bacteria, which were also engineered to express proteins to mediate cellular invasion and escape from the phagosome, were administered orally or intravenously and significantly reduced catenin β-1 levels in the intestinal epithelium and in human colon cancer xenografts in mice 133 (Fig. 5c). Combining various bacterial anti-cancer treatment strategies may increase safety, specificity and efficiency in future clinical trials.

Viral synthetic devices. Viruses have also been successfully engineered to transduce specific cells by expressing epitopes that are recognized by particular cell-surface receptors and to express prodrug convertases and cytokines for use in cancer therapy 134 . Most of these oncolytic viruses carry coding viral nucleic acids, which may cause side effects owing to recombination with the host chromosome or proviral elements that are already in the host cell. Recently, synthetic viral particles have been designed that lack coding nucleic acids and that exclusively package therapeutic proteins, which can be released in a dose-dependent manner 135 . For example, viral particles carrying linamarase from Manihot esculenta were injected into human breast cancer xenografts in mice that had been treated with the non-toxic natural product linamarin these viruses triggered efficient tumour regression owing to the cyanide produced by linamarase-mediated conversion of linamarin 135 (Fig. 5d). Similarly, protein-carrying viral nanoparticles have been used to deliver site-specific DNA recombinases, such as FLP, to precisely integrate or excise genetic components on the host chromosome 136 . They might also be used to deliver native or chimeric transcription factors that could transiently control the expression of target genes that are involved in therapeutic interventions, lineage control or induction of pluripotency 137 .

A transformation sensor for cancer therapy. Gene therapy advances for cancer include virus-mediated delivery of cytotoxic effector genes controlled by cancer-specific promoters 138,139 or delivery of chimeric adaptor proteins to link tyrosine kinase signalling to the apoptosis-inducing caspase machinery 140 . Most promoters and control circuits that coordinate simple reactions such as these are inherently noisy and only allow linear responses, which means limited control of specificity and efficacy. However, using two internal input signals can improve fidelity, mediate sharp response profiles and ensure robust biochemical processes 141 . Using decision-making circuits as blueprints, Nissim and Bar-Ziv 142 designed a tunable dual promoter integrator (DPI) to target cancer cells precisely. The DPI consists of two native promoters that are concurrently activated by two independent transcription factors. Each cancer-sensing promoter produces a different fusion protein in proportion to its activity, and these two proteins assemble together as a chimeric transcription factor. This transcription factor then activates a synthetic promoter that controls expression of the herpes simplex virus type 1 thymidine kinase (TK1), which is cytotoxic in the presence of nucleotide analogues, such as ganciclovir (Fig. 6a). The DPI could be optimized for a specific cancer cell type by using different combinations of input promoters and effector genes, as well as by modulating the assembly efficiency and half life of the chimeric transactivator components. So far, a set of three promoters have been characterized in detail, but the DPI design may accommodate other suitable promoters.

a | A transformation-sensing cancer kill switch can consist of a two-input, transformation-sensing device with 'AND' logic. The device constantly monitors the transformation state of a cell and produces a kill signal when two malignancy markers occur. Two independent malignancy-sensitive promoters drive expression of two chimeric proteins (DocS–VP16 and Gal4BD–Coh2). When they are simultaneously expressed, both proteins dimerize to form a synthetic transcription factor that binds Gal4 operator sites (OGal4), induces downstream minimal promoters (Pmin) and triggers expression of the herpes simplex virus type 1 thymidine kinase (TK1). In the presence of ganciclovir, the system is cytotoxic. b | A microRNA (miRNA)-based cancer classifier that discriminates cancer cells from non-transformed cells by scoring high and low expression profiles of a set of cancer-specific miRNAs. The classifier consists of high and low miRNA sensors that exclusively promote output gene expression if the specific input miRNAs are expressed at high or low levels, respectively. In the high miRNA sensor, high-target miRNA concentrations prevent translation of mRNAs encoding the reverse tetracycline-dependent transactivator (rtTA) and the repressor of the lactose operon (LacI). This results in derepression of transcription of the output gene (labelled 'Output' in the figure). In the low miRNA sensor, the output-gene-encoding mRNA is only translated when low-target miRNA concentrations are present. c | By combining different high and low miRNA sensors, the classifier can be customized to sense predetermined profiles of high and low miRNA levels, such as the ones that are typically produced by cancer cells and respond with expression of the apoptosis-inducing human BCL2-associated X protein (BAX). pA, poly(A) tail.

The recently developed 'cell-type classifier' is conceptually similar to the DPI, as it can also be programmed to destroy cells that express a specific set of neoplastic markers 31 . The cell-type classifier combines transcription and translation control components in a single scalable synthetic circuit that senses expression levels of a set of (currently up to six) endogenous microRNAs (miRNAs) it triggers an apoptosis-inducing response only if those levels match a preset profile. The cell-type classifier combines sensor modules for the detection of highly and lowly expressed miRNAs (Fig. 6b). For clinical implementation, both the DPI and the cell-type classifier must either be delivered to the cancer tissue, or they must provide a fail-safe mechanism that constantly eliminates transforming cells from engineered tissue implants.

Other emerging tools for biomedicine

Novel treatment strategies will require new technologies to sense and control disease. Synthetic biologists have designed new devices that could sense key physiological activities and have found new ways to dose therapeutic interventions precisely in response to external physical cues. Such synthetic devices could have wide-ranging biomedical applications.

RNA controllers of cell proliferation. Thus far, synthetic control devices that are designed to interface with host metabolism and to reprogram cellular behaviour have largely been limited to heterologous transcription factors. RNA controllers may represent an alternative. They are straightforward to design and can be integrated into a single expression unit containing sensors (aptamers), gene-regulatory components (ribozymes) and effector transgenes 39,143,144 . The inherent modularity and compatibility of RNA-based control components enables them to be independently optimized or exchanged. For example, an RNA control device consisting of a drug-responsive aptamer linked to a ribozyme in the 3′ untranslated region (UTR) of a cytokine expression unit enabled trigger-inducible inactivation of ribozyme-mediated transcript cleavage and full transgene expression in the presence of the input signal 145 . This synthetic RNA control device was applied to control proliferation of engineered primary human T cells and enabled external control of the expansion of transgenic T cells that are implanted into mice. Synthetic RNA control devices could provide the advance that is necessary to enable T cell therapy 145 by contrast, state-of-the-art, trigger-inducible expansion of engineered T cells using chimeric antigen receptors has only led to moderate proliferation and poor survival of T cells in clinical trials 146,147 .

Another use for synthetic RNA is the design of programmable sensor–actuator devices that convert levels of an intracellular protein into a discrete high or low transgene-expression state 148 . The RNA devices consist of a three-exon, two-intron minigene followed by the transgene. The introns contain protein-sensing aptamers, and the central exon includes a stop codon. Binding of the protein to the aptamers controls splicing of the minigene when the central exon is spliced out, the transgene is expressed at high levels, and when it remains unspliced, the transgene is expressed at low levels. Such a device was configured to sense subunits of nuclear factor kappa B (NFκB) or β-catenin (which are neoplastic markers) and to express the herpes simplex virus thymidine kinase. Thymidine kinase renders cells susceptible to ganciclovir, so this device only operated as a cancer kill switch in the presence of the cancer markers and gangcicolvir 148 . The modular configuration of the RNA sensor–actuator device allows it to be tailored to different intracellular proteins and even to multi-protein input using specific intronic aptamers. Also, responsiveness and performance can be tuned by placing the aptamers at different locations within the introns. The availability of compact RNA sensor–actuators that are easy to design and to alter and that control transgene expression in response to intracellular levels of key proteins may also improve the ability to link metabolic disease states with gene-based therapeutic interventions.

Optogenetic devices in blood glucose homeostasis. Light is becoming increasingly popular as a traceless, molecule-free input signal for triggering transgene expression in living systems. Bacteria have been engineered to record projected images with gigapixel resolution 149,150,151 and to adjust transgene expression in response to multi-chromatic input 150 , and now genetic light switches have also been designed to control gene expression 152 and shape of mammalian cells 153 .

Devices that convert light pulses into transcription may foster novel therapeutic opportunities in future gene- and cell-based therapies and may improve the manufacturing of difficult-to-produce protein pharmaceuticals, such as cancer therapeutics. An illustrative example is light-controlled expression of the glucagon-like peptide 1 (GLP1), which is a promising drug candidate for the treatment of type 2 diabetes 65 (Fig. 7a). An optogenetic device that enables light-triggered gene expression in human cells was designed. This involves ectopic expression of melanopsin in human embryonic kidney cells and functional rewiring of signalling downstream of melanopsin the cascade integrates blue-light-pulse-triggered photoreception and produces a reversible and sustained intensity-dependent transcription response. When placed in hollow fibre containers and implanted into mice, transgene expression in the engineered light-sensitive cells could be controlled remotely by an optical fibre 65 . Illuminating mice that carried subcutaneous implants of microencapsulated photo-responsive cells also enabled transdermal control of transgene expression and of corresponding protein levels in the blood of treated animals. This system was able to attenuate glycaemic excursions and to control glucose homeostasis in a mouse model of human type 2 diabetes 65 .

a | Light-triggered transcription control of blood glucose homeostasis. The synthetic phototransduction cascade consists of rewired melanopsin and nuclear factor of activated T cells (NFAT) control circuits. Photo-isomerization of the 11-cis-retinal chromophore (R) by blue light (

480 nm) activates melanopsin. This sequentially turns on Gaq-type G protein (GAQ), phospholipase C (PLC) and phosphokinase C (PKC) and triggers Ca 2+ ion influx via transient receptor potential channels (TRPCs) and possibly also from the endoplasmic reticulum. This Ca 2+ ion surge activates calmodulin (CaM) to calcineurin (CaN), which dephosphorylates NFAT. NFAT then translocates into the nucleus, where it binds to specific promoters (PNFAT) and coordinates transgene transcription. When linked to the glucagon-like peptide (GLP1), this mechanism allowed light-controlled blood glucose homeostasis to be achieved in a mouse model of type 2 diabetes. b | Prosthetic network for the treatment of tumour lysis syndrome and gout. Implanted sensor–effector cells are used to monitor serum urate levels constantly: they import urate via a transgenic human uric acid transporter (URAT1). Urate prevents binding of the uric acid-sensitive transsilencer (KRAB–HucR, which is the uricase regulator linked to a KRAB domain) to its operator (hucO8). This operator controls expression of secretion-engineered urate oxidase (smUOX), so smUOX is expressed when urate concentration reaches pathological levels. smUOX mediates conversion of urate into allantoin. Expression of smUOX stops when urate concentration reaches oxidative-stress-protective urate levels. pA, poly(A) tail. Part a is modified, with permission, from Ref. 65 © (2011) American Academy for the Advancement of Science.

Prosthetic networks. Prosthetic networks are synthetic sensor–effector devices that act as molecular prostheses. When engineered into cells and functionally connected to host metabolism, they sense, monitor and score disease-relevant metabolites, process off-level concentrations and coordinate adjusted diagnostic, preventive or therapeutic responses in a seamless, automatic and self-sufficient manner.

An example of the use of a prosthetic network is the sensing of metabolites to improve control of urate homeostasis (Fig. 7b). Moderate levels of uric acid, which scavenges radicals, are deemed to be beneficial. However, a transient surge in uric acid that is released by dying cells during cancer therapy leads to tumour lysis syndrome, and chronic hyperuricaemia can result in gout. Humans are particularly sensitive to imbalances of urate homeostasis because they lack uricolytic activity. A prosthetic network that constantly monitors blood urate concentrations and restores urate homeostasis by controlled expression of a urate oxidase — which reduces excessive urate concentration while preserving levels that are suitable for radical scavenging — could represent a treatment strategy for hyperuricaemic disorders 64 . In brief, human cells that contain such a prosthetic network have recently been designed by combining: the uric acid sensor HucR 154 , which manages oxidative stress protection in Deinococcus radiodurans the human uric acid transporter URAT1 (also known as SLC22A12), which increases the intracellular uric acid levels and thus the sensitivity of the prosthetic circuit and a secretion-engineered urate oxidase (smUOX) that is clinically licensed for the treatment of the tumour lysis syndrome 155 . The prosthetic uric-acid-responsive expression network (UREX) was able to sense uric acid concentrations precisely and to activate secretion of smUOX when the uric acid concentration was at pathologic levels. Secretion of smUOX is stopped as soon as the uric acid concentration has returned to the homeostasis level. This was impressively demonstrated when UREX-transgenic cells were implanted into urate-oxidase-deficient mice, which develop acute hyperuricaemia with symptoms that are similar to human gout. UREX was able to degrade urate and restore urate homeostasis in the blood, resulting in the dissolution of uric acid crystal deposits in the kidney of treated animals 64 . Its straightforward design may allow UREX to serve as a blueprint for the assembly of other prosthetic networks that sense metabolic disturbances and circulating pathologic metabolites.

An artificial insemination device. Artificial insemination is standard practice to facilitate both human reproduction and livestock breeding. Because of broad variations in oestrus expression and ovulation timing, coordinating sperm delivery with female oestrus is still a major challenge. Ovulation is triggered at a specific time when the pituitary gland releases luteinizing hormone, which binds to the luteinizing hormone receptor (LHR) and coordinates the release of the oocyte. By integrating synthetic signalling cascades with advanced biomaterials, Kemmer and colleagues 63 designed an artificial insemination device that coordinates sperm delivery with oestrus control. The artificial insemination device consists of cellulose sulphate capsules containing bull sperm and sensor cells 63,156,157 . The sensor cells are engineered to express LHR constitutively so that when it is activated, it triggers expression of cellulase that can be secreted. After implantation into the cow's uterus, the sensor cell line constantly monitors the animal's luteinizing hormone levels, and the oestrus-triggered surge in luteinizing hormone levels leads to the production of secreted cellulase, which degrades the implanted capsule and results in the timely delivery of the sperm and successful conception. Fine tuning of the designer cascade could enable its use in other species, including in humans.

Perspectives and conclusions

In recent years, synthetic biology has substantially advanced strategies for classical biomedical applications, such as pathogen characterization 68,70,74 , disease analysis 78,79,80 , diagnostics 75,76,77 , screening assays 33,92,94,100,101 , drug production 105,106,107,108,158 and vaccination 81,82,85 . This progress may imminently develop into shorter drug discovery 94,98 and drug development timelines, increased precision of drug delivery 112,114 and production of new and more affordable medicines 104,105,106,107,108,109 . Ultimately, sophisticated therapeutic sensor–effector devices that can sense disturbances, seek out pathological conditions and restore function are on the roadmap. Such therapeutic networks that connect diagnostic input with therapeutic output may provide all-in-one diagnostic, preventive and therapeutic solutions in future gene- and cell-based therapies. Matching diagnostic outcome with high-end therapies has recently become a focus of the pharmaceutical industry, which has declared personalized medicine as the treatment strategy of the future. Tools that will have a tremendous impact in future biomedical applications include: using light-activated triggers to bring about a precise therapeutic response in cells 65 , programming bacteria to seek and destroy cancer cells 128,132,133 and using synthetic circuitry to keep crucial metabolites at homeostatic levels 64,65 , to manage disease-controlled expansion 145 or to eliminate specific cell populations 31,148,159 . Recent work has shown that this is, in principle, possible and that some devices are working as expected and are producing a therapeutic impact in animal models of human diseases 64,65 . Implants consisting of engineered microencapsulated cells represent a way of introducing prosthetic networks with a predefined function instead of directly targeting the host cells with the genetic material. Although implants containing cells with engineered prosthetic networks are certainly the most promising way forward, they will limit biomedical applications to extracellular disease metabolites that can be therapeutically addressed through the vascular system.

However, there is still a long way to go until synthetic-biology-based biomedical devices will be a clinical reality. Placing therapeutic circuits in specific cells of a patient and making sure that there will be no interference with human metabolism are the most important challenges. Therefore, clinical use of synthetic-biology-based devices and therapeutic scenarios will face the same scientific, ethical and legal issues as any gene- and cell-based therapy, but they may offer more complex control dynamics and are therefore expected to have a higher therapeutic impact. Although none of the synthetic devices, prosthetic networks and related products that are pioneered by synthetic biologists have yet been used in the clinics or in clinical trials, the stage is set — with novel treatment strategies available and the commitment of the pharmaceutical industry in place — for synthetic biology to deliver the biomedicines of the twenty-first century.


Many of the major biological discoveries of the 20th century were made using just six species: Escherichia coli bacteria, Saccharomyces cerevisiae and Schizosaccharomyces pombe yeast, Caenorhabditis elegans nematodes, Drosophila melanogaster flies and Mus musculus mice. Our molecular understanding of the cell division cycle, embryonic development, biological clocks and metabolism were all obtained through genetic analysis using these species. Yet the ‘big 6’ did not start out as genetic model organisms (hereafter ‘model organisms’), so how did they mature into such powerful systems? First, these model organisms are abundant human commensals: they are the bacteria in our gut, the yeast in our beer and bread, the nematodes in our compost pile, the flies in our kitchen and the mice in our walls. Because of this, they are cheaply, easily and rapidly bred in the laboratory and in addition were amenable to genetic analysis. How and why should we add additional species to this roster? We argue that specialist species will reveal new secrets in important areas of biology and that with modern technological innovations like next-generation sequencing and CRISPR-Cas9 genome editing, the time is ripe to move beyond the big 6. In this review, we chart a 10-step path to this goal, using our own experience with the Aedes aegypti mosquito, which we built into a model organism for neurobiology in one decade. Insights into the biology of this deadly disease vector require that we work with the mosquito itself rather than modeling its biology in another species.

Progress in the experimental biological sciences is driven by work in simple systems, from carefully controlled in vitro approaches that utilize purified biological material outside its natural context to in vivo studies in model organisms from microbes to primates. These organisms provide opportunities to ‘model’ complex biological processes relevant to human health or provide a powerful window into fundamental biological principles shared across the tree of life. For instance, the components of the cell division cycle were identified using the humble yeast Schizosaccharomycespombe and Saccharomyces cerevisiae (Nurse, 2017), while S.cerevisiae was the first eukaryotic organism to have its genome sequenced (Goffeau et al., 1996). Many of the genetic rules governing embryonic development were discovered through the pioneering work of Christiane Nüsslein-Volhard and Eric Wieschaus working in Drosophilamelanogaster flies (Nüsslein-Volhard and Wieschaus, 1980). The genetic basis of biological rhythms, a fundamental principle of plant and animal life organized around the circadian rhythm of the sun, was also worked out in flies (Bargiello et al., 1984 Hardin et al., 1990 Konopka and Benzer, 1971). Major insights into the endocrine signaling that links hunger, metabolism and body weight came from analysis of leptin and leptin receptors in ob and db mutant mice (Friedman, 1998). These are but a few of the many examples from the last century of the power of model organisms in producing important basic and clinical insights.

Model organisms are relatively easy and inexpensive to culture in the laboratory, have fast generation times that facilitate genetic analysis, and can be readily manipulated using increasingly comprehensive and powerful experimental genetic tools to visualize and manipulate specified cells across developmental time and space. For neuroscientists, access to behaviors that can be genetically dissected has driven interest in flies and worms (Brenner, 2009 Vosshall, 2007), and there are now thousands of laboratories around the world that generate, maintain and openly share thousands of distinct strains to understand the workings of these invertebrate nervous systems. The success of these organisms is self-perpetuating: the community of researchers working with them continues to grow, new methodologies and resources are developed and shared, and the body of specific knowledge and access to powerful tools to manipulate, observe and experiment upon these model organisms further lowers the bar to entry so that the cycle can repeat. Model organisms are irreplaceable for studying fundamental aspects of biology but fall short in their ability to address biological specializations that arise in specific branches of the evolutionary tree. Migration of monarch butterflies, vocal learning in songbirds and camouflage in cuttlefish are examples of fascinating biological problems that can only be fully understood by moving these non-traditional species toward model organism status.

In 2009, we began a journey to build Aedesaegypti into a model organism for neurobiology. After decades of working in ‘the fly’, D. melanogaster, we were ready for the challenge of moving into a new species to ask questions that could not be addressed in the traditional model organisms. Some species of mosquito are the deadliest animals on the planet, driven by anthropophilic species that bite humans to take their blood and simultaneously act as a vector for disease-causing pathogens such as the Plasmodium malaria parasites and arboviruses including chikungunya, dengue, eastern equine encephalitis, yellow fever, Zika and others. The elements of mosquito biology most relevant to disease transmission are specialized and thus elude comprehensive study in model organisms. Mosquitoes possess unique anatomical appendages that facilitate piercing skin and sucking blood, and have exquisitely sensitive sensory systems that are tuned to help them locate vertebrate hosts in their environment. Drosophila, by contrast, feed on yeast and lay eggs in rotting fruit, uninterested in many of the cues that lure mosquitoes. While many of the gene families involved in these processes are relatively conserved, an estimated 260 million years of evolution separates mosquitoes from Drosophila (Arensburger et al., 2010) and many critically important genes do not share one-to-one orthology. Thus, understanding how mosquitoes operate in their environment requires studying mosquitoes themselves.

This review will focus on the practical challenges and recent opportunities available to those seeking to establish a new model organism, drawing on our experiences with the mosquito Ae. aegypti. The review is organized into 10 steps that we followed in our own work (see Box 1). While we focus on the tools and approaches required to perform rigorous and reproducible science on the genes and neural circuits that generate behavior, many of the lessons and approaches are generalizable to other areas of biology as well. Not all steps are required – or even feasible – in a given species, but the more steps that can be accomplished, the more progress that can be made in working with the species in a mechanistic framework.


Lead Guest Editor Dr. Nelson S. Yee

Dr. Nelson S. Yee is an Assistant Professor of Medicine in Hematology-Oncology at Pennsylvania State University. He completed his MD and PhD at Cornell University and Memorial Sloan-Kettering Cancer Center, and he has previously worked at University of Pennsylvania and University of Iowa. He now works primarily on ion channels in cancer using zebrafish and mouse models as well as developing therapeutics and biomarkers in patients with malignant diseases. Dr. Yee is the author or co-author of 40 published papers and has presented at 30 conferences, and holds editorial appointments at Clinical Cancer Drugs, Molecular & Cellular Oncology, Annals of Hematology & Oncology, Biomarkers & Diagnosis, International Scholarly Research Notices, Cloning & Transgenesis, Advances in Biology, and Genetic Disorders & Gene Therapy.


Biological Sciences (BIO_SC)

Selected topics not covered in current offerings. May not be used in partial fulfillment of requirements for a biological science in general education. May be graded on A-F or S/U basis.

Credit Hour: 1-3

BIO_SC�: Topics in Biological Sciences - Biological Sciences

Selected topics not in regularly offered courses. Selected sections of this course may be graded either on A-F or S/U basis only.

Credit Hour: 1-3

BIO_SC�: Topics in Biological Sciences - Mathematical Sciences

Selected topics not in regularly offered courses. Selected sections of this course may be graded either on A-F or S/U basis only.

Credit Hour: 1-31

BIO_SC�: Topics in Biological Sciences - Physical Sciences

Selected topics not in regularly offered courses. Selected sections of this course may be graded either on A-F or S/U basis only.

Credit Hour: 1-3

BIO_SC�: General Principles and Concepts of Biology

Emphasizes connections and applications to society and the human condition, science literacy, and critical thinking skills. A discussion of general principles and fundamental concepts of living things. This course is intended for non-science majors. No more than 5 credits for BIO_SC�, BIO_SC�, and BIO_SC�.

Credit Hours: 3
Recommended: MATH�

BIO_SC�: General Biology Laboratory

Laboratory exercises dealing with representative organisms and methods of modern biological sciences. This course is intended for non-science majors. No more than 5 credits for BIO_SC�, BIO_SC�, and BIO_SC�.

Credit Hours: 2
Prerequisites or Corequisites: BIO_SC�

BIO_SC�: General Principles and Concepts of Biology with Laboratory

Survey of general principles and basic concepts of life science, emphasizing applications to society and the human condition. Lectures address science literacy and critical thinking and laboratory exercises use representative organisms to complement lecture topics. This course is intended for non-science majors. No more than 5 credits for BIO_SC�, BIO_SC�, and BIO_SC�.

Credit Hours: 5
Recommended: MATH� or concurrent enrollment

BIO_SC�: Basic Environmental Studies

Considers the ecosystem, energy and biogeochemical cycles and population dynamics relation of the environment to agriculture and technology, pollution, power and food production politico-economic considerations moral and ethical issues. For non-science majors.

Credit Hours: 3

BIO_SC�: General Botany with Laboratory

Introduction to study of plants. Emphasis on structure, growth, physiology, genetics and reproduction of plants.

Credit Hours: 5

BIO_SC�: Evolution for Everyone

This course will explore the application of evolutionary theory to modern human affairs. We will study the processes involved in evolution and investigate evolutionary interpretations of human social behavior (e.g., psychology, mate choice, economics, religion, and morality). No credit if student has received credit for BIO_SC� or BIO_SC�.

Credit Hours: 3

BIO_SC�: Introduction to Biological Systems with Laboratory

Basic concepts and principles of the structure and function of living systems, from cells to populations. Foundation course for science students intending to complete a 3-semester sequence that also includes genetics and cell biology.

Credit Hours: 5
Recommended: MATH� or sufficient ALEKS score

BIO_SC�H: Introduction to Biological Systems with Laboratory Honors

Basic concepts and principles of the structure and function of living systems, from cells to populations. Foundation course for science students intending to complete a 3-semester sequence that also includes genetics and cell biology.

Credit Hour: 3-5
Prerequisites: MATH� and high school chemistry. Honors eligibility required

BIO_SC�: Topics in Biological Sciences - General

Selected topics not covered in current offerings. May not be used in partial fulfillment of requirements for a biological science in general education. May be graded on A-F or S/U basis.

Credit Hour: 1-3
Recommended: One course in Biology

BIO_SC�: Topics in Biological Sciences- Biological Sciences

Selected topics not covered in regularly offered courses. Selected sections of this course may be graded either on A-F or S/U basis only.

Credit Hour: 1-3
Recommended: a course in general biology

BIO_SC�H: Topics in Biological Sciences- Biological Science - Honors

Selected topics not covered in regularly offered courses. Recommended: a course in biology

Credit Hour: 1-3
Prerequisites: Honors eligibility required

BIO_SC�: Topics in Biological Sciences- Mathematical Sciences

Selected topics not covered in regularly offered courses. Selected sections of this course may be graded either on A-F or S/U basis only.

Credit Hour: 1-3
Recommended: a course in general biology

BIO_SC�H: Topics in Biological Sciences- Mathematical Science - Honors

Selected topics not covered in regularly offered courses. Recommended: a course in biology

Credit Hour: 1-3
Prerequisites: Honors eligibility required

BIO_SC�: Topics in Biological Sciences- Physical Sciences

Selected topics not covered in regularly offered courses. Selected sections of this course may be graded either on A-F or S/U basis only.

Credit Hour: 1-3
Recommended: a course in general biology

BIO_SC�H: Topics in Biological Sciences- Physical Science - Honors

Selected topics not covered in regularly offered courses. Recommended: a course in biology

Credit Hour: 1-3
Prerequisites: Honors eligibility required

BIO_SC�: Undergraduate Seminar in Biological Sciences

Discussion and critical evaluation of current topics in biological sciences for intermediate-level students. Some sections may be graded on either A-F or S/U basis only.

Credit Hour: 1-3
Prerequisites: sophomore standing

BIO_SC�: Biological Career Explorations

Students will learn about career options and choices, construct career portfolios, and interact with current biological professionals. Graded on S/U basis only.

Credit Hour: 1
Prerequisites: Departmental consent
Recommended: Sophomore standing

BIO_SC�: World of Neuroscience

(same as PSYCH�, CMP_SC�, ECE�, BIOL_EN�, BME�). This course will introduce undergraduates to the growing area of neuroscience from the perspectives of 3 disciplines: engineering, biology and psychology. May not be used to satisfy degree requirements for the major or minor in biological sciences.

Credit Hour: 1
Prerequisites: Sophomore standing

BIO_SC�: How the Brain Works

Basic structure and function of the brain left and right brain studies gender differences learning and memory brain disorders..

Credit Hour: 1
Prerequisites: C- or above in BIO_SC� or BIO_SC�

BIO_SC�: Life of the Cell

This course will help students understand basic concepts of biomolecular structure, cell organization, cell membranes, energy and metabolism, cellular communication, and cell division. This course is intended for non-science majors and may not be used to satisfy requirements for either a major or a minor in biological sciences.

Credit Hours: 3
Prerequisites: BIO_SC�

BIO_SC�: Community Biology

Principles of population biology, ecology, and evolution, including consideration of human impacts on biological communities and ecosystems.

Credit Hours: 3
Prerequisites: BIO_SC� or equivalent. Not open to biology majors

BIO_SC�: Infectious Diseases

An introduction to the basic science of bacterial, viral, protozoan, fungal and helminth infections, including discussions of how illness has influenced or been affected by public policy and culture.

Credit Hours: 3
Prerequisites: BIO_SC�, BIO_SC� or BIO_SC�. Not open to Biology Majors

BIO_SC�: Genetic Diseases

This course will discuss the biological basis for genetic diseases, including inherited diseases and non-inherited diseases such as cancer. The units will include an introduction providing necessary background information, as section studying the technology used to study genetic diseases and several units discussing specific diseases and their impact on history and society. This course is intended for non-science majors. Cannot be used to satisfy degree requirements for biology major or biology minor.

Credit Hours: 3
Prerequisites: BIO_SC�

BIO_SC�: General Genetics

Principles of inheritance in plants and animals structure and use of genetic material, transmission of genetic information, linkage, modification of genetic information, regulation of genetic activity, population genetics.

Credit Hours: 4
Prerequisites: BIO_SC 1100, BIO_SC� or BIO_SC� and CHEM� (or concurrent enrollment)

BIO_SC�H: General Genetics - Honors

Principles of inheritance in plants and animals structure and use of genetic material, transmission of genetic information, linkage, modification of genetic information, regulation of genetic activity, population genetics. Prerequisites:

Credit Hours: 4
Prerequisites: BIO_SC 1100, BIO_SC� or BIO_SC� and CHEM� (or concurrent enrollment). Honors eligibility required

BIO_SC�: Introduction to Cell Biology

Analysis of cellular organization and function at the molecular level. The mechanisms underlying cellular trafficking, cell motility, and signaling within cells and between cells and their environment will be emphasized.

Credit Hours: 4
Prerequisites: BIO_SC�

BIO_SC�H: Introduction to Cell Biology- Honors

Analysis of cellular organization and function at the molecular level. The mechanisms underlying cellular trafficking, cell motility, and signaling within cells and between cells and their environment will be emphasized.

Credit Hours: 5
Prerequisites: BIO_SC� or BIO_SC�H. Honors eligibility required

BIO_SC�HW: Introduction to Cell Biology - Honors/Writing Intensive

Analysis of cellular organization and function at the molecular level. The mechanisms underlying cellular trafficking, cell motility, and signaling within cells and between cells and their environment will be emphasized.

Credit Hours: 5
Prerequisites: BIO_SC� or BIO_SC�H. Honors eligibility required

BIO_SC�: Internship in Biological Science

Work experience in a non-profit, for profit, or governmental organization relevant to the biological sciences. Intended for students doing internships in which independent research is less than 50% of the experience. Graded on S/U basis only.

Credit Hour: 1-3
Prerequisites: instructor's consent
Recommended: junior standing, 12 hours of biological science and 2.70 GPA

BIO_SC�: Directed Independent Research

Participation in faculty research activities. May not be used to satisfy degree requirements for BA or BS in biological sciences or the minor in biological sciences.

Credit Hour: 1-3
Prerequisites: Departmental consent

BIO_SC�: Readings in Biological Science

Supervised reading in biological literature. May be repeated up to six hours total credit. Selected sections of this course may be graded either on A-F or S/U basis only. May not be used in partial fulfillment of Arts and Science foundation requirement.

Credit Hour: 1-3
Prerequisites: instructor's consent

BIO_SC�H: Honors Readings in Biological Literature

Selected readings in biological literature for Honors, in consultation with instructor. May not be used in partial fulfillment of Arts and Science foundation requirement.

Credit Hour: 1-3
Prerequisites: overall 3.3 GPA instructor's consent. Honors eligibility required

BIO_SC�: Topics in Biological Sciences - Biological Sciences

Selected topics not in regularly offered courses. Selected sections of this course may be graded either on A-F or S/U basis only.

Credit Hour: 1-3
Recommended: Junior Standing

BIO_SC�H: Topics in Biological Sciences- Biological Sciences - Honors

Selected topics not offered in regular curriculum.

Credit Hour: 1-3
Prerequisites: Honors eligibility required

BIO_SC�W: Topics in Biological Sciences- Biological Sciences - Writing Intensive

Selected topics not in regularly offered courses. Selected sections of this course may be graded either on A-F or S/U basis only.

Credit Hour: 1-3
Recommended: Junior Standing

BIO_SC�: Topics in Biological Sciences - Mathematical Sciences

Selected topics not in regularly offered courses. Selected sections of this course may be graded either on A-F or S/U basis only.

Credit Hour: 1-3
Recommended: Junior Standing

BIO_SC�H: Topics in Biological Sciences- Mathematical Sciences - Honors

Selected topics not offered in regular curriculum.

Credit Hour: 1-3
Prerequisites: Honors eligibility required

BIO_SC�W: Topics in Biological Sciences- Mathematical Sciences - Writing Intensive

Selected topics not in regularly offered courses. Selected sections of this course may be graded either on A-F or S/U basis only.

Credit Hour: 1-3
Recommended: Junior Standing

BIO_SC�: Topics in Biological Sciences - Physical Sciences

Selected topics not in regularly offered courses. Selected sections of this course may be graded either on A-F or S/U basis only.

Credit Hour: 1-3
Recommended: Junior Standing

BIO_SC�H: Topics in Biological Sciences- Physical Sciences - Honors

Selected topics not offered in regular curriculum.

Credit Hour: 1-3
Prerequisites: Honors eligibility required

BIO_SC�W: Topics in Biological Sciences- Physical Sciences - Writing Intensive

Selected topics not in regularly offered courses. Selected sections of this course may be graded either on A-F or S/U basis only.

Credit Hour: 1-3
Recommended: Junior Standing

BIO_SC�: Professional Skills

This course will focus on application and interview skills for students interested in medical school. Graded on S/U basis only.

Credit Hour: 1
Prerequisites: instructor's consent
Recommended: junior standing 3.4 GPA, and biological sciences majors

BIO_SC�: Genetics and Society

Examines topics in human biomedical genetics from both a scientific and a social standpoint. Current topics include gene editing and gene drive, prenatal testing and genetic counseling, hemoglobin genes and gene therapy, COVID-19 and inequality, racial disparities in medicine, gender issues in STEM fields, sports federations and the intersex athlete, ancient DNA and human migrations, altitude adaptations. Students choose their own text and research subject based on personal interest.

Credit Hours: 3
Prerequisites: ENGLSH� or equivalent, BIO_SC�
Recommended: BIO_SC�

BIO_SC�W: Genetics and Society - Writing Intensive

Examines topics in human biomedical genetics from both a scientific and a social standpoint. Current topics include gene editing and gene drive, prenatal testing and genetic counseling, hemoglobin genes and gene therapy, COVID-19 and inequality, racial disparities in medicine, gender issues in STEM fields, sports federations and the intersex athlete, ancient DNA and human migrations, altitude adaptations. Students choose their own text and research subject based on personal interest.

Credit Hours: 3
Prerequisites: ENGLSH� or equivalent, BIO_SC�
Recommended: BIO_SC�

BIO_SC�: Science and Society: Past, Present and Future

This course will examine the scientific process and how it has evolved over the years, starting from the inception of the scientific method in the Middle Ages through the present day. The course will focus on the impact of advancements in technology and societal and cultural views on some of the most significant breakthroughs in biology.

Credit Hours: 3
Prerequisites: BIO_SC� or BIO_SC� or equivalent

BIO_SC�W: Science and Society: Past, Present and Future - Writing Intensive

This course will examine the scientific process and how it has evolved over the years, starting from the inception of the scientific method in the Middle Ages through the present day. The course will focus on the impact of advancements in technology and societal and cultural views on some of the most significant breakthroughs in biology.

Credit Hours: 3
Prerequisites: BIO_SC� or BIO_SC� or equivalent

BIO_SC�: The Human Microbiome

This course examines the astonishing diversity and medical significance of the microbes that inhabit our bodies. Interactive discussions explore scientific and ethical dimensions of topics ranging from probiotics and "poop transplants" to the role of microbes in asthma and obesity.

Credit Hours: 3
Prerequisites: BIO_SC�

BIO_SC�W: The Human Microbiome - Writing Intensive

This course examines the astonishing diversity and medical significance of the microbes that inhabit our bodies. Interactive discussions explore scientific and ethical dimensions of topics ranging from probiotics and "poop transplants" to the role of microbes in asthma and obesity.

Credit Hours: 3
Prerequisites: BIO_SC�

BIO_SC�: Plant Systematics

Principles of classification of plants survey of diversity in flowering plant families identification of local flora use of keys. Includes lab.

Credit Hours: 4
Recommended: 8 hours of Biological Sciences

BIO_SC�W: Plant Systematics - Writing Intensive

Principles of classification of plants survey of diversity in flowering plant families identification of local flora use of keys. Includes lab.

Credit Hours: 4
Recommended: 8 hours of Biological Sciences

BIO_SC�: Invertebrate Zoology

Structure, ecology and phylogeny of the invertebrate phyla. Includes lab.

Credit Hours: 4
Prerequisites: BIO_SC 1100 or BIO_SC�
Recommended: Junior Standing

BIO_SC�W: Invertebrate Zoology - Writing Intensive

Structure, ecology and phylogeny of the invertebrate phyla. Includes lab when offered for 4 credits.

Credit Hour: 3-4
Prerequisites: BIO_SC 1100 or BIO_SC�
Recommended: Junior Standing

BIO_SC�: Herpetology

The biology, ecology, taxonomy, and distribution of amphibians and reptiles. Some Saturday field trips.

Credit Hours: 4
Recommended: 8 hours Biological Sciences or equivalent

BIO_SC�: Evolution and Ecology

Introduction to principles of evolution and ecology. Topics include natural selection, adaptation, phylogenetic analysis, human evolution, population growth and regulation, population interactions, ecosystem ecology, and human impacts on ecological processes. No credit for this course if either BIO_SC� or BIO_SC� already completed may not co-enroll in this course and BIO_SC�.

Credit Hours: 3
Prerequisites: BIO_SC�

BIO_SC�: Biology of Fungi

(same as PLNT_SCI�). The diverse roles of fungi in the biosphere will be explored by considering fungi we eat, fungi which destroy our food, fungi in folklore and fungi as global nutrient recyclers. Includes lab.

Credit Hours: 3
Prerequisites: BIO_SC� or BIO_SC� or equivalent

BIO_SC�: General Ecology

Principles of populations, coevolution, density factors, competition physical environment concept of community, trophic structure, biotic succession characterization of biomes, man in ecosystem. Biology majors having completed BIO_SC�: 2 hours credit.

Credit Hours: 5
Prerequisites: junior standing
Recommended: 10 hours in Biology

BIO_SC�W: General Ecology - Writing Intensive

Principles of populations, coevolution, density factors, competition physical environment concept of community, trophic structure, biotic succession characterization of biomes, man in ecosystem. Biology majors having completed BIO_SC�: 2 hours credit.

Credit Hours: 5
Prerequisites: junior standing
Recommended: 10 hours in Biology

BIO_SC�: Tropical Ecology: Methods and Applications

Field study of tropical community additional fee for transportation and accommodations required.

Credit Hours: 3
Prerequisites: BIO_SC� or BIO_SC� or BIO_SC 4660

BIO_SC�: Animal Physiology

Introduces concepts of vertebrate organ function and homeostatic control emphasizing mammalian physiology. Some comparisons to function in other vertebrates and strategies for coping with environmental stresses introduced. Includes lab.

Credit Hours: 5
Prerequisites: BIO_SC�

BIO_SC�: Introductory Entomology

(same as PLNT_SCI�). Emphasizes the role insects play in the scheme of life. Topics include insect structure, development, diversity, ecology, communication and behavior, and management. Prerequisites: Completion of 60 credit hours and one of the following: BIO_SC 1100 (or F_W�) or BIO_SC�, or BIO_SC�.

Credit Hours: 3

BIO_SC�: Insect Diversity

(same as PLNT_SCI�). Laboratory exercises emphasizing external insect anatomy, classification, and identification (to family level). Preparation of an insect collection is required.

Credit Hours: 2
Prerequisites: PLNT_SCI� (or BIO_SC�) or concurrent registration

BIO_SC�: General Microbiology

Explores the diversity and adaptive capabilities of microbial life. Topics include bacterial cell structure, metabolism, genetics, and ecology.

Credit Hours: 3
Prerequisites: BIO_SC�
Recommended: grades in C range for prerequisites

BIO_SC�: Microbiology Laboratory

This is a hands-on microbiology lab course which provides students with training in microbiology techniques, data collection and analysis, writing a research proposal and completing an independent project.

Credit Hours: 2
Prerequisites or Corequisites: BIO_SC� or MICROB� or concurrent enrollment in BIO_SC�

BIO_SC�: Genetics Laboratory

Experimental genetic studies of Drosophila, corn and microorganisms.

Credit Hours: 2
Prerequisites: C range grade or better in BIO_SC� or instructor's consent

BIO_SC�: Topics in Biological Science - Biological Science

Selected topics not in regularly offered courses. May be repeated up to 2 times for credit.

Credit Hour: 1-3
Prerequisites: senior standing

BIO_SC�: Topics in Biological Science - Mathematical Science

Selected topics not in regularly offered courses. May be repeated up to 2 times for credit.

Credit Hour: 1-3
Prerequisites: senior standing

BIO_SC�: Topics in Biological Science - Physical Science

Selected topics not in regularly offered courses. May be repeated up to 2 times for credit.

Credit Hour: 1-3
Prerequisites: senior standing

BIO_SC�: Problems in Biological Sciences

Individual supervised work to supplement regularly organized courses in biology introduction to research. Selected sections of this course may be graded either on A-F or S/U basis only.

Credit Hour: 1-3
Prerequisites: instructor's consent
Recommended: Junior Standing

BIO_SC�W: Problems in Biological Sciences - Writing Intensive

Individual supervised work to supplement regularly organized courses in biology introduction to research. Selected sections of this course may be graded either on A-F or S/U basis only.

Credit Hour: 1-3
Prerequisites: instructor's consent
Recommended: Junior Standing

BIO_SC�: Molecular Plant Physiology

(same as PLNT_SCI� cross-leveled with BIO_SC�, PLNT_SCI�). Modern physiology of higher plants using common cultivated plants as examples.

Credit Hours: 3
Prerequisites: BIO_SC� or BIO_SC� and CHEM�

BIO_SC�: Introductory Radiation Biology

(same as NU_ENG�, RADIOL� cross-leveled with BIO_SC�, NU_ENG�, RADIOL 7328). Concepts of ionizing radiations, their actions on matter through effects on simple chemical systems, biological molecules, cell, organisms, man.

Credit Hours: 3
Prerequisites: junior standing, Sciences/Engineering one course in Biological Sciences and Physics/Chemistry or instructor's consent

BIO_SC�: Plant Anatomy

(same as PLNT_SCI� cross-leveled with BIO_SC�, PLNT_SCI�). Comparative structure, growth of meristems development, structure of important cell types, tissues, tissue systems comparative anatomy of stem, root, leaf. Emphasizes anatomy of gymnosperms, angiosperms. Includes lab.

Credit Hours: 4
Prerequisites: BIO_SC� or BIO_SC�

BIO_SC�: Neurobiology

(cross-leveled with BIO_SC�). Vertebrate and invertebrate neurobiology, including cell and molecular biology of the neuron, neurophysiology, neuroanatomy, neuroethology and developmental neurobiology.

Credit Hours: 3
Prerequisites: BIO_SC� or instructor's consent
Recommended: BIO_SC�

BIO_SC�: Sensory Physiology and Behavior

(cross-leveled with BIO_SC�). Basic principles of coding and integration of sensory stimuli neural correlates of animal behavior environmental influences on postnatal sensory development. Graded on A-F basis only.

Credit Hours: 3
Prerequisites: BIO_SC�

BIO_SC�: Computational Neuroscience

(same as ECE�, BIOL_EN�, BME� cross-leveled with ECE�, BIOL_EN�, BIO_SC�). An interdisciplinary course with a strong foundation in quantitative sciences for students in biological and behavioral science and an introduction to experimental methods for students from quantitative sciences.

Credit Hours: 4
Prerequisites: BIO_SC� or BIO_SC� MATH�

BIO_SC�: Evolution

Surveys various processes in organic evolution and underlying genetic mechanisms.

Credit Hours: 3
Prerequisites: BIO_SC�

BIO_SC�: Behavioral Biology

(cross-level with BIO_SC�). Comparative study of animal ethology. Principles of animal ethology illustrated in different animal phyla. May be taken with Laboratory for 4 credits.

Credit Hour: 3-4
Prerequisites: BIO_SC�
Recommended: one additional upper-level course in Biological Sciences or Psychology

BIO_SC�: Animal Communication

Physical properties of sensory stimuli, receptor mechanisms, functional significance of communication behavior, and multidisciplinary and experimental approaches to current research in animal communication.

Credit Hours: 3
Prerequisites: BIO_SC� or BIO_SC�

BIO_SC�W: Animal Communication - Writing Intensive

Physical properties of sensory stimuli, receptor mechanisms, functional significance of communication behavior, and multidisciplinary and experimental approaches to current research in animal communication.

Credit Hours: 3
Prerequisites: BIO_SC� or BIO_SC�

BIO_SC�: Avian Ecology

(cross-level with BIO_SC�). Advanced examination of ecological patterns in birds. Explores the environmental factors affecting the evolution of avian behavior, morphology, community structure and distribution.

Credit Hours: 3
Prerequisites: BIO_SC 2600 or BIO_SC�

BIO_SC�: Undergraduate Research in Biology

Individually directed field or laboratory research for upperclass students under faculty supervision. Project must be arranged by student and faculty member prior to registration. May be repeated to a maximum of 6 hours.

Credit Hour: 1-3
Prerequisites: instructor's consent
Recommended: Overall GPA 2.75 20 hours of Biological Sciences and/or Chemistry

BIO_SC�H: Honors Research in Biology

Individually directed field or laboratory research for upper-level Honors students, in consultation with a faculty member. Project must be arranged by student and faculty member prior to registration. May be repeated for credit. Graded on A-F basis only.

Credit Hour: 1-3
Prerequisites: overall GPA 3.3 instructor's consent biology or microbiology major. Honors eligibility required

BIO_SC�: Undergraduate Research in Biology

Individually directed field or laboratory research for upperclass students under faculty supervision. Project must be arranged by student and faculty member prior to registration. May be repeated to a maximum of 6 hours.

Credit Hour: 1-3
Prerequisites: BIO_SC� overall GPA 2.75 instructor's consent

BIO_SC�H: Honors Research in Biology

Continuation of research program. Successful completion requires public presentation and leads to degree with Honors in biological sciences. May be repeated for credit for maximum of 6 hours. Graded on A-F basis only.

Credit Hour: 1-3
Prerequisites: BIO_SC�H overall GPA 3.3 instructor's consent. Honors eligibility required

BIO_SC�: Special Readings in Biological Sciences

Independent readings and discussions of topics in biology selected in consultation with supervising faculty member. Selected sections of this course may be graded either on A-F or S/U basis only.

Credit Hour: 1-3
Prerequisites: senior standing in Biological Sciences and instructor's consent

BIO_SC�: Developmental Biology

Analysis of the molecular, genetic, cellular, and morphological processes responsible for phenotypic changes in developing organisms. A variety of experimental systems are discussed to identify common mechanisms used by developing organisms.

Credit Hours: 3
Prerequisites: BIO_SC�, BIO_SC�, CHEM�

BIO_SC�W: Developmental Biology

Analysis of the molecular, genetic, cellular, and morphological processes responsible for phenotypic changes in developing organisms. A variety of experimental systems are discussed to identify common mechanisms used by developing organisms.

Credit Hours: 3
Prerequisites: BIO_SC�, BIO_SC�, CHEM�

BIO_SC�: Molecular Biology

(cross-leveled with BIO_SC�). Molecular mechanisms of DNA replication, mutation, recombination and gene expression in prokaryotes, eukaryotes, and their viruses gene fine structure genetic engineering.

Credit Hours: 3
Prerequisites: BIO_SC� and BIO_SC�

BIO_SC�: Cancer Biology

(same as BIOCHM� cross-leveled with BIO_SC�, BIOCHM�). The cellular and molecular basis of cancer, with emphasis on the application of genomics, proteomics, and genetic manipulations in model organisms to the study of cancer biology.

Credit Hours: 3
Prerequisites: BIO_SC� and BIO_SC�
Recommended: BIO_SC� or BIOCHM� and BIOCHM�

BIO_SC�: Human Inherited Diseases

(cross-leveled with BIO_SC�). Advances in molecular genetics have led to a revolution in our understanding of human disease. This course will examine how molecular technologies, combined with detailed information on cell biology and biochemistry, have been used to unravel the causes of human inherited disease. In addition, we will examine how this new understanding is being used to design therapies for the diseases, and we will discuss some of the ethical and moral questions that have been generated by recent scientific progress.

Credit Hours: 3
Prerequisites: BIO_SC� and BIO_SC�

BIO_SC�W: Human Inherited Diseases - Writing Intensive

(cross-leveled with BIO_SC�). Advances in molecular genetics have led to a revolution in our understanding of human disease. This course will examine how these technologies, combined with detailed information on cell biology and biochemistry, have been used to unravel the causes of human inherited disease. In addition, we will examine how this new understanding is being used to design therapies for the diseases, and we will discuss some of the ethical and moral questions that have been generated by recent scientific progress. Graded on A-F basis only.

Credit Hours: 3
Prerequisites: BIO_SC� and BIO_SC�

BIO_SC�: Molecular Ecology

Application of molecular genetic techniques to topics in ecology and population biology such as sex ratios, dispersal, mating systems, biogeography and conservation genetics.

Credit Hours: 4
Prerequisites: BIO_SC� or BIO_SC� and BIO_SC�

BIO_SC�: Mammalian Reproductive Biology

Adult reproductive anatomy, physiology and behavior gametogenesis and fertilization placentation sexual differentiation parturition maternal behavior and lactation puberty reproductive aging reproductive ecology.

Credit Hours: 3
Prerequisites: junior standing
Recommended: 15 hours of Biological Sciences

BIO_SC�: Neurology of Motor Systems

(cross-leveled with BIO_SC�). Examination of the function of neural networks at all levels, from properties of single neurons to large collections of neural elements.

Credit Hours: 3
Prerequisites: BIO_SC� or instructor's consent

BIO_SC�: Nerve Cells and Behavior

The cellular basis of behavior. Molecular and cellular properties of nerve cells, as related to behavior, will be represented and discussed.

Credit Hours: 3
Prerequisites: BIO_SC� or instructor's consent

BIO_SC�: Vertebrate Histology and Microscopic Anatomy

Microscopic anatomy of vertebrate tissues and organs. Includes lab.

Credit Hours: 5
Prerequisites: junior standing
Recommended: BIO_SC�, or equivalent

BIO_SC�: Senior Seminar

Readings and critical evaluation of selected problems and theories in biology. Offered in one or more sections, with specialized subdisciplinary emphasis.

Credit Hours: 3
Prerequisites: Biological Sciences major, senior standing

BIO_SC�H: Senior Seminar - Honors

Readings and critical evaluation of selected problems and theories in biology. Offered in one or more sections, with specialized sub disciplinary emphasis.

Credit Hours: 3
Prerequisites: Biological Sciences major, senior standing Honors eligibility required

BIO_SC�HW: Senior Seminar - Honors/Writing Intensive

Readings and critical evaluation of selected problems and theories in biology. Offered in one or more sections, with specialized sub disciplinary emphasis.

Credit Hours: 3
Prerequisites: Biological Sciences major, senior standing Honors eligibility required

BIO_SC�W: Senior Seminar - Writing Intensive

Readings and critical evaluation of selected problems and theories in biology. Offered in one or more sections, with specialized subdisciplinary emphasis.

Credit Hours: 3
Prerequisites: Biological Sciences major, senior standing

BIO_SC�: Topics in Biological Sciences

Advanced topics not in regularly offered courses. May be repeated for credit. Graded on A-F basis only.

Credit Hour: 1-6

BIO_SC�: Molecular Plant Physiology

(same as PLNT_SCI� cross-leveled with BIO_SC�, PLNT_SCI�). Modern physiology of higher plants using common cultivated plants as examples. May be taken with or without laboratory.

Credit Hours: 3
Prerequisites: BIO_SC� or BIO_SC� and 5 hours Chemistry

BIO_SC�: Introductory Radiation Biology

(same as NU_ENG�, RADIOL 7328, V_M_S� cross-leveled with BIO_SC�, NU_ENG�, RADIOL�). Concepts of ionizing radiations, their actions on matter through effects on simple chemical systems, biological molecules, cell, organisms, man.

Credit Hours: 3
Prerequisites: Sciences/Engineering one course in Biological Sciences and Physics/Chemistry or instructor's consent

BIO_SC�: Plant Anatomy

(same as PLNT_SCI� cross-leveled with BIO_SC�, PLNT_SCI�). Comparative structure, growth of meristems development, structure of important cell types, tissues systems comparative anatomy of stem root, leaf. Emphasizes anatomy of gymnosperms, angiosperms. Includes lab. Graded on A-F basis only.

Credit Hours: 4
Prerequisites: BIO_SC� or equivalent

BIO_SC�: Vertebrate Histology and Microscopic Anatomy

Microscopic anatomy of vertebrate tissues and organs. Graded on A-F basis only.

Credit Hours: 5
Prerequisites: BIO_SC� and BIO_SC�, or equivalent

BIO_SC�: Neurobiology

(cross-leveled with BIO_SC�). Vertebrate and invertebrate neurobiology, including cell and molecular biology of the neuron, neurophysiology, neuranatomy, neurothology and developmental biology. Graded on A-F basis only.

Credit Hours: 3
Prerequisites: BIO_SC� or BIO_SC�

BIO_SC�: Sensory Physiology and Behavior

(cross-leveled with BIO_SC�). Basic principles of coding and integration of sensory stimuli neural correlates of animal behavior environmental influences on postnatal sensory development.

Credit Hours: 3
Prerequisites: BIO_SC� or equivalent

BIO_SC�: Computational Neuroscience

(same as BIOL_EN�, ECE� cross-leveled with BIO_SC�, BIOL_EN�, ECE�, BME�). An interdisciplinary course with a strong foundation in quantitative sciences for students in biological and behavioral sciences and an introduction to experimental methods for students from quantitative sciences.

Credit Hours: 4
Prerequisites: BIO_SC� or BIO_SC�, MATH�

BIO_SC�: Behavioral Biology

(cross-leveled with BIO_SC�). Comparative study of animal ethology. Principles of animal ethology illustrated in different animal phyla.

Credit Hours: 3
Prerequisites: BIO_SC� and one additional upper-level course in Biological Sciences or Psychology

BIO_SC�: Avian Ecology

(cross-leveled with BIO_SC�). Advanced examination of ecological patterns in birds. Explores the environmental factors affecting the evolution of avian behavior, morphology, community structure and distribution.

Credit Hours: 3
Prerequisites: BIO_SC� or BIO_SC� BIO_SC 2600

BIO_SC�: Molecular Biology

(cross-leveled with BIO_SC�). Molecular mechanisms of DNA replication, mutation, recombination and gene expression in prokaryotes, eukaryotes, and their viruses gene fine structure genetic engineering.

Credit Hours: 3
Prerequisites: BIO_SC� and BIO_SC�

BIO_SC�: Cancer Biology

(same as BIOCHM� cross-leveled with BIO_SC�, BIOCHM�). The course will cover major molecular and cellular aspects of cancer. Students will read original research articles, present overviews and lead class discussions.

Credit Hours: 3
Prerequisites: BIOCHM�, BIO_SC� and BIO_SC� or equivalent

BIO_SC�: Human Inherited Diseases

(cross-leveled with BIO_SC�). Advances in molecular genetics have led to a revolution in our understanding of human disease. This course will examine how molecular technologies, combined with detailed information on cell biology and biochemistry, have been used to unravel the causes of human inherited disease. In addition, we will examine how this new understanding is being used to design therapies for the diseases, and we will discuss some of the ethical and moral questions that have been generated by recent scientific progress.Graded on A-F basis only.

Credit Hours: 3
Prerequisites: BIO_SC� and instructor's consent

BIO_SC�: Neurology of Motor Systems

(cross-leveled witgh BIO_SC�). Examination of the function of neural networks at all levels, from properties of single neurons to large collections of neural elements. Graded on A-F basis only.

Credit Hours: 3
Prerequisites: BIO_SC�

BIO_SC�: Non-thesis Research

Independent research not leading to a thesis. Some sections may be offered on either A-F or S/U grading basis.

Credit Hour: 1-99
Prerequisites: instructor's consent

BIO_SC�: Topics in Biological Sciences- Biological/Physical/Mathematics

Advanced topics not in regularly offered courses.

Credit Hour: 1-6

BIO_SC�: Professional Survival Skills

Introduction to resources, facilities, and communication skills for professional careers in biological sciences. Topics include computer resources, accessing scientific literature, making slides and figures, grantsmanship, resume preparation, manuscript review, and research presentation.

Credit Hours: 2

BIO_SC�: Ethical Conduct of Research

(same as BIOCHM�). Discussion of ethical issues in biological research, including the rules and conventions for appropriate research conduct. Graded on S/U basis only.

Credit Hour: 1

BIO_SC�: Professional Communication Development

The purpose of this course is to develop professional communication skills in students that are planning to attend (or are in their first year of) graduate training. Some sections may be offered with A-F or S/U grading option.

Credit Hour: 1-2

BIO_SC�: Problems in Biological Sciences

Research not expected to terminate in thesis, or individual advanced study in special subjects.

Credit Hour: 1-99
Prerequisites: instructor's consent

BIO_SC�: Seminar

Current topics in the biological sciences. Open to all graduate students. Graded S/U basis only.

Credit Hour: 1

BIO_SC�: Research in Biological Sciences

Research leading to thesis. Graded on S/U basis only.

Credit Hour: 1-99
Prerequisites: instructor's consent

BIO_SC�: Seminar in Areas of Specialization

Offered each semester in one or more specialized sections followed by the topic title of the seminar. Graded on S/U basis only.

Credit Hour: 1

BIO_SC�: Advanced Plant Genetics

Genetic approaches to molecular and biochemical studies in maize, wheat, and Arabidopsis.

Credit Hours: 3
Prerequisites: General Genetics and course in Cell Biology or Plant Physiology

BIO_SC�: Fungal Genetics and Biology

Introduction to fungal research, with an emphasis on genetics, biochemistry, cell and molecular biology, and pathogenicity of fungi. Graded A-F only.

Credit Hours: 3

BIO_SC�: Developmental Genetics

An overview of various developing systems amenable to classical and molecular genetic analysis. Specific developmental phenomena will be introduced in particular model systems, with an emphasis on experimental approaches used to address the underlying mechanisms.

Credit Hours: 3
Prerequisites: BIO_SC� and BIO_SC�

BIO_SC�: Integrative Neuroscience I

(same as NEUROSCI�). Organization, development and function of the nervous system focusing on cellular and molecular processes. Graded on A-F basis only.

Credit Hours: 3

BIO_SC�: Integrative Neuroscience II

(same as NEUROSCI�). Organization and function of the nervous system at the systems level to examine processes of behavior and cognition. Graded on A-F basis only.

Credit Hours: 3

BIO_SC�: Advanced Cancer Biology

A study of the molecular basis of cancer, including topics in tumor cell biology, interactions between cancer cells and normal cells, mechanisms of metastasis, and novel approaches to development of new chemotherapies.

Credit Hours: 3

BIO_SC�: Plant Stress Biology

(same as PLNT_SCI�). This course will introduce the basic concepts of abiotic and biotic plant stress agents and discuss how to conduct research with plant stress agents alone or in combination. Graded on A-F basis only.

Credit Hours: 3

BIO_SC�: Design of Ecological Experiments

Principles of experimental design in the context of ecological, behavioral, and evolutionary research.

Credit Hours: 2
Prerequisites: STAT�

BIO_SC�: Current Concepts in Conservation Biology

Survey of current concepts in conservation biology literature. Discussions will provide students with an appreciation of the historical development of concepts, the interdisciplinary nature of conservation problems, and the research required for effective solutions.

Credit Hours: 2

BIO_SC�: Molecular and Network Evolution

(same as AN_SCI�). Evolution of biological macromolecules and networks, including sequence analysis algorithms and theory, phylogenetics, gene duplication, genome evolution, principles of biological networks. Development of computational skills emphasized.

Credit Hours: 3
Prerequisites: Instructor's consent required

BIO_SC�: Quantitative Methods in Life Sciences

(same as PTH_AS�). Quantitative Methods in Life Sciences is a graduate-level course in statistical analysis designed for the specific needs of students in life sciences, focusing on statistical literacy: performing, interpreting, and writing about biological data analysis. As such, the course assumes a basic understanding of some topics and little understanding of other topics. The course will cover most topics broadly and occasionally in great depth, highlighting the perils and pitfalls of different methods, while providing guidelines for a wide array of statistical approaches to data analysis. The course seeks to find the balance between really understanding all the math involved and learning to be a competent practitioner and consumer of analysis, emphasizing the practical over the theoretical, with additional focus on the communication of data (plotting, graphs, figures) and of results. Graded on A-F basis only.

Credit Hours: 3
Prerequisites: Consent of instructor

BIO_SC�: Ecological Genetics

Population genetics and evolutionary theory, with emphasis on studies of natural populations.

Credit Hours: 3
Prerequisites: BIO_SC�, BIO_SC� or BIO_SC�, and STAT� or equivalent

BIO_SC�: Speciation

Advanced discussion of species concepts and the processes of formation of species.

Credit Hours: 3
Prerequisites: BIO_SC� and BIO_SC�

BIO_SC�: College Science Teaching

(same as LTC�, PHYSCS�, ASTRON 8310). Study of learner characteristics, teaching strategies, and research findings related to teaching science at the post-secondary level.

Credit Hours: 3

BIO_SC�: Science Outreach: Public Understanding of Science

(same as AN_SCI�, PHYSCS�, LTC�). Development of presentations to adult audiences on the science underlying issues of current interest. May be repeated for credit.

Credit Hour: 1-2

BIO_SC�: Integrating Science with Outreach

(same as LTC�). This course provides an opportunity for students to earn credit for outreach activities in the community. Students will capitalize on their area of study and scientific expertise in developing, implementing, and evaluating related outreach activities. May be repeated for credit.

Credit Hour: 1-6

BIO_SC�: Plant/Animal Interactions

Discussion and lectures on herbivory, pollination biology, and dynamics of fruit and seed dispersal from ecological and evolutionary perspectives.

Credit Hours: 3
Prerequisites: BIO_SC� or BIO_SC 4660 or equivalent

BIO_SC�: Research in Biological Sciences

Research leading to dissertation.Graded on S/U basis only.

Credit Hour: 1-99
Prerequisites: instructor's consent

BIO_SC�: Molecular Biology II

(same as MICROB�, BIOCHM�) Detailed experimental analysis of eukaryotic cellular and molecular biology relevant to cellular and viral gene expression, post-transcriptional and post-translational modifications and genome replication. Models for developmental genetic analysis and genetic determinants controlling processes utilizing the current literature will be examined.

Credit Hours: 4
Prerequisites: MICROB 9430

BIO_SC�: Molecular Biology of Plant Growth and Development

(same as BIOCHM�). Molecular biology of plant hormones, signal transduction, environmental signals.

Credit Hours: 3
Prerequisites: BIO_SC�


Contents

Some of the first work with what would be considered model organisms started because Gregor Johann Mendel felt that the views of Darwin were insufficient in describing the formation of a new species and he began his work with the pea plants that are so famously known today. In his experimentation to find a method by which Darwin’s ideas could be explained he hybridized and cross-bred the peas and found that in so doing he could isolate phenotypic characteristics of the peas. These discoveries made in the 1860s lay dormant for nearly forty years until they were rediscovered in 1900. Mendel’s work was then correlated with what was being called chromosomes within the nucleus of each cell. Mendel created a practical guide to breeding and this method has successfully been applied to select for some of the first model organisms of other genus and species such as Guinea pigs, Drosophila (fruit fly), mice, and viruses like the tobacco mosaic virus. [2]

Drosophila Edit

The fruit fly Drosophila melanogaster made the jump from nature to laboratory animal in 1901. At Harvard University, Charles W. Woodworth suggested to William E. Castle that Drosophila might be used for genetical work. [3] Castle, along with his students, then first brought the fly into their labs for experimental use. By 1903 William J. Moenkhaus had brought Drosophila back to his lab at Indiana University Med School. Moenkhaus in turn convinced entomologist Frank E. Lutz that it would be a good organism for the work he was doing at Carnegie Institution’s Station for Experimental Evolution at Cold Springs Harbor, Long Island on experimental evolution. Sometime in the year 1906 Drosophila was adopted by the man who would become very well known for his work with the flies, Thomas Hunt Morgan. A man by the name of Jacques Loeb also tried experimentation in mutations of Drosophila independently of Morgan’s work during the 1st decade of the twentieth century. [4]

Thomas Hunt Morgan is considered to be one of the most influential men in experimental biology during the early twentieth century and his work with the Drosophila was extensive. He was one of the first in the field to realize the potential of mapping the chromosomes of Drosophila melanogaster and all known mutants. He would later expand his findings to a comparative study of other species. With careful and painstaking observation he and other "Drosophilists" were able to control for mutations and cross breed for new phenotypes. Through many years of work like this standards of these flies have become quite uniform and are still used in research today. [5]

Microorganisms Edit

Insects were not the only organisms entering the laboratories as test subjects. Bacteria had also been introduced and with the invention of the electron microscope in 1931 by Ernst Ruska, a whole new field of microbiology was born. [6] This invention allowed microbiologists to see objects that were far too small to be seen by any light microscope and thus viruses which had perplexed biologists of many fields for years, now came under scientific scrutiny. [7] In 1932 Wendell Stanley began a direct competition with Carl G. Vinson to be the first to completely isolate the Tobacco Mosaic Virus, a virus that had been until then invisibly killing tobacco plants across England. [8] It was Stanley who would accomplish this task first by changing the pH to one a more acidic one. In doing so he was able to conclude that the virus was either a protein or closely related to one, thus benefiting experimental research.

There are very important reasons why these new, much smaller organisms such as the Tobacco Mosaic Virus and E. coli made their way into the molecular biologists’ laboratories. Organisms like Drosophila and Tribolium were much too large and too complex for the simple quantitative experiments that men like Wendell Stanley wanted to perform. [9] Before the use of these simple organisms molecular biologist had comparatively complex organisms to work with.

Today these viruses, including bacteriophages, are used extensively in genetics. They are critical in helping researchers to produce DNA within bacteria. The Tobacco Mosaic Virus has DNA that stacks itself in a distinctive way that was influential in Watson and Cricks development of their model of the helical structure for DNA. [10]

Mice Edit

Both the community of insects and the viruses were a good start to the history of model organisms, but there are yet still more players involved. At the turn of the century much biomedical research was being done using animals and especially mammalian bodies to further biologists’ understanding of life processes. It was around this time that American humane societies became very involved with preserving the rights of animal and for the first time were beginning to gain public support for this endeavor. At this same time American biology was also going through its own internal reforms. From 1900 to 1910 thirty medical schools were forced to close. During this time of unrest a man named Clarence Cook Little, through a series of luckily timed events, became a researcher at Harvard Medical School and worked on mouse cancers. He began developing large, mutant strain, colonies of mice. Under the charge of Dr. William Castle, Little helped to expand the animal breeding habits in the Bussey laboratory at Harvard. Due to freedom in the way Castle was allowed to run the laboratory and his financial backing by the University they were able to create an extensive program in mammalian genetics. [11]

The mice turned out to be an almost perfect solution for test subjects for mammalian genetic research. The fact that they had been bred by ‘rat fanciers’ for hundreds of years allowed for diverse populations of an animal while the public held far less sentiment for these rodents than they did for dogs and cats. Because of social allowance, Little was able to take new ideas of ‘pure genetic strains’ merging from plant genetics as well as work with Drosophila and run with them. The idea of inbreeding to achieve this goal of a ‘pure strain’ in mice was one that may have created a negative response to the fertility of the mice thus discontinuing the strain. Little achieved his goal of a genetically pure strain of mice by 1911 and published his finding shortly thereafter. He would continue his work with these mice and used his research to demonstrate that inbreeding is an effective way of eliminate variation and served to preserve unique genetic variants. Around this time as well there was much work being done with these mice and cancer and tumor research. [12]

Throughout the 1920s’ work continued with these mice as model organisms for research into tumors and genetics. It was during the great depression that this field of study would take its biggest blow. With the economy at rock bottom labs were forced into selling many of their mice just to keep from shutting down. This necessity for funds all but stopped the continuation of these strains of mice. The transition for these laboratories to exporters of massive quantities of mice was one that was rather easily made if there were adequate facilities for their production on site. Eventually in the mid-1930s the market would return and genetics laboratories around the country resumed regular funding and thus continued in the areas of research they had started before the depression. As research into continued, so did the production of mice in places like Jackson Laboratory. Facilities like these were able to produce mice for research facilities around the world. These mice were bred with Mendelian breeding technique of which Little had implemented as standard practice around 1911. This meant that the mice being experimented on were not only the same within the laboratory, but in different laboratories around the world. [13]

The mouse has remained important as molecular genetics and genomics have progressed sequencing of a reference mouse genome was completed in 2002. [14] More broadly, comparative genomics has advanced our understanding and reinforced the importance of model organisms, especially ones with relatively small and nonrepetitive genomes.


An Introduction to Plant Tissue Culture: Advances and Perspectives

Plant tissue culture techniques are the most frequently used biotechnological tools for basic and applied purposes ranging from investigation on plant developmental processes, functional gene studies, commercial plant micropropagation, generation of transgenic plants with specific industrial and agronomical traits, plant breeding and crop improvement, virus elimination from infected materials to render high-quality healthy plant material, preservation and conservation of germplasm of vegetative propagated plant crops, and rescue of threatened or endangered plant species. Additionally, plant cell and organ cultures are of interest for the production of secondary metabolites of industrial and pharmaceutical interest. New technologies, such as the genome editing ones combined with tissue culture and Agrobacterium tumefaciens infection, are currently promising alternatives for the highly specific genetic manipulation of interesting agronomical or industrial traits in crop plants. Application of omics (genomics, transcriptomics, and proteomics) to plant tissue culture will certainly help to unravel complex developmental processes such as organogenesis and somatic embryogenesis, which will probably enable to improve the efficiency of regeneration protocols for recalcitrant species. Additionally, metabolomics applied to tissue culture will facilitate the extraction and characterization of complex mixtures of natural plant products of industrial interest. General and specific aspects and applications of plant tissue culture and the advances and perspectives are described in this edition.

Keywords: Aseptic culture Genetic modified organisms Large-scale propagation Metabolic engineering Plant cell culture Proteomics Transcriptomics.


Advances in RIP-chip analysis : RNA-binding protein immunoprecipitation-microarray profiling

In eukaryotic organisms, gene regulatory networks require an additional level of coordination that links transcriptional and post-transcriptional processes. Messenger RNAs have traditionally been viewed as passive molecules in the pathway from transcription to translation. However, it is now clear that RNA-binding proteins (RBPs) play a major role in regulating multiple mRNAs to facilitate gene expression patterns. On this basis, post-transcriptional and transcriptional gene expression networks appear to be very analogous. Our previous research focused on targeting RBPs to develop a better understanding of post-transcriptional gene-expression processing and the regulation of mRNA networks. We developed technologies for purifying endogenously formed RBP-mRNA complexes from cellular extracts and identifying the associated messages using genome-scale, microarray technology, a method called ribonomics or RNA-binding protein immunoprecipitation-microarray (Chip) profiling or RIP-Chip. The use of the RIP-Chip methods has provided great insight into the infrastructure of coordinated eukaryotic post-transcriptional gene expression, insights which could not have been obtained using traditional RNA expression profiling approaches (1). This chapter describes the most current RIP-Chip techniques as we presently practice them. We also discuss some of the informatic aspects that are unique to analyzing RIP-Chip data.


Watch the video: Intravenous and tail fin microinjection in zebrafish (May 2022).