Simple Model Organisms Research Articles

Silver linings: a personal memoir about Hurricane Katrina and fungal volatiles.

In the aftermath of Hurricane Katrina, the levees protecting New Orleans, Louisiana failed. Because approximately 80% of the city was under sea level, widespread flooding ensued. As a resident of New Orleans who had evacuated before the storm and a life-long researcher on filamentous fungi, I had known what to expect. After the hurricane I traveled home with a suitcase full of Petri dishes and sampling equipment so as to study the fungi that were “eating my house.” Not only were surfaces covered with fungal growth, the air itself was full of concentrated mold odor, a smell that was orders of magnitude more funky than any damp, musty basement I had ever encountered. The smell made me feel bad and I had to take regular breaks as I sampled. Being a mycotoxin expert, I knew a fair amount about “sick building syndrome” but believed that it was difficult to get enough respiratory exposure to toxins to cause the array of symptoms associated with the syndrome. So why was I feeling sick? Some Scandinavian experts had hypothesized that mold volatile organic compounds (VOCs) might be the fungal metabolites to blame for sick building syndrome and the time in my smelly, mold infested home made me think they might be right. After securing a new job and establishing a new laboratory, I endeavored to test the hypothesis that some volatile mold metabolites might be toxic. My laboratory at Rutgers University has interrogated the role of VOCs in possible interkingdom toxicity by developing controlled microcosms for exposing simple genetic model organisms to the vapor phase of growing fungi. Both Arabidopsis thaliana and Drosophila melanogaster exhibit a range of toxic symptoms that vary with the species of fungus, the duration of exposure, and other experimental parameters. Moreover, low concentrations of chemical standards of individual fungal VOCs such as 1-octen-3-ol also exhibit varying toxicity and cause neurotoxicity in a Drosophila model. Collectively, these data suggest that fungal VOCs may contribute to some of the adverse health effects reported by people exposed to damp indoor environments and that biogenic gas phase molecules deserve increased attention by the research community.

Principles of biological aging

The aging process is the substrate on which aging-associated diseases develop; therefore, the scientific discipline of gerontology aims at understanding this biological aging process, which refers to the progressive increase in the risk of death caused by a loss of body functions. Studies in simple model organisms demonstrate that pharmacological substances, genetic interventions and dietary restriction can slow down the process of aging. The cell culture model of cellular senescence gives researchers the opportunity to conduct studies in a system more closely related to the human organism; therefore, cells from different human tissues are cultured in vitro until they stop proliferating. This permanent growth arrest is called cellular senescence. Recent studies have demonstrated that senescent cells also accumulate in many tissues in vivo and contribute to age-related pathologies.

Effects of FSGS-associated mutations on the stability and function of myosin-1 in fission yeast.

ABSTRACTPoint mutations in the human MYO1E gene, encoding class I myosin Myo1e, are associated with focal segmental glomerulosclerosis (FSGS), a primary kidney disorder that leads to end-stage kidney disease. In this study, we used a simple model organism, fission yeast Schizosaccharomyces pombe, to test the effects of FSGS-associated mutations on myosin activity. Fission yeast has only one class I myosin, Myo1, which is involved in actin patch assembly at the sites of endocytosis. The amino acid residues mutated in individuals with FSGS are conserved between human Myo1e and yeast Myo1, which allowed us to introduce equivalent mutations into yeast myosin and use the resulting mutant strains for functional analysis. Yeast strains expressing mutant Myo1 exhibited defects in growth and endocytosis similar to those observed in the myo1 deletion strain. These mutations also disrupted Myo1 localization to endocytic actin patches and resulted in mis-localization of Myo1 to eisosomes, linear membrane microdomains found in yeast cells. Although both mutants examined in this study exhibited loss of function, one of these mutants was also characterized by the decreased protein stability. Thus, using the yeast model system, we were able to determine that the kidney-disease-associated mutations impair myosin functional activity and have differential effects on protein stability.

Synthetic lethal screening in the mammalian central nervous system identifies Gpx6 as a modulator of Huntington’s disease

Huntington's disease, the most common inherited neurodegenerative disease, is characterized by a dramatic loss of deep-layer cortical and striatal neurons, as well as morbidity in midlife. Human genetic studies led to the identification of the causative gene, huntingtin. Recent genomic advances have also led to the identification of hundreds of potential interacting partners for huntingtin protein and many hypotheses as to the molecular mechanisms whereby mutant huntingtin leads to cellular dysfunction and death. However, the multitude of possible interacting partners and cellular pathways affected by mutant huntingtin has complicated efforts to understand the etiology of this disease, and to date no curative therapeutic exists. To address the general problem of identifying the disease-phenotype contributing genes from a large number of correlative studies, here we develop a synthetic lethal screening methodology for the mammalian central nervous system, called SLIC, for synthetic lethal in the central nervous system. Applying SLIC to the study of Huntington's disease, we identify the age-regulated glutathione peroxidase 6 (Gpx6) gene as a modulator of mutant huntingtin toxicity and show that overexpression of Gpx6 can dramatically alleviate both behavioral and molecular phenotypes associated with a mouse model of Huntington's disease. SLIC can, in principle, be used in the study of any neurodegenerative disease for which a mouse model exists, promising to reveal modulators of neurodegenerative disease in an unbiased fashion, akin to screens in simpler model organisms.

Engineering recombinant Orsay virus directly in the metazoan host Caenorhabditis elegans.

The recent identification of Orsay virus, the first virus that is capable of naturally infecting Caenorhabditis elegans, provides a unique opportunity to explore host-virus interaction studies in this invaluable model organism. A key feature of this system is the robust genetic tractability of the host, C. elegans, which would ideally be complemented by the ability to genetically manipulate Orsay virus in parallel. To this end, we developed a plasmid-based reverse genetics system for Orsay virus by creating transgenic C. elegans strains harboring Orsay virus cDNAs. Both wild-type and mutant Orsay viruses, including a FLAG epitope-tagged recombinant Orsay virus, were generated by use of the reverse genetics system. This is the first plasmid-based virus reverse genetics system in the metazoan C. elegans. The Orsay virus reverse genetics we established will serve as a fundamental tool in host-virus interaction studies in the model organism C. elegans. Importance: To date, Orsay virus is the first and the only identified virus capable of naturally infecting Caenorhabditis elegans. C. elegans is a simple multicellular model organism that mimics many fundamental features of human biology and has been used to define many biological properties conserved through evolution. Thus, the Orsay virus-C. elegans infection system provides a unique opportunity to study host-virus interactions. In order to take maximal advantage of this system, the ability to genetically engineer mutant forms of Orsay virus would be highly desirable. Most efforts to engineer viruses have been done with cultured cells. Here we describe the creation of mutant viruses directly in the multicellular organism C. elegans without the use of cell culture. We engineered a virus expressing a genetically tagged protein that could be detected in C. elegans. This provides proof of concept for modifying Orsay virus, which will greatly facilitate studies in this experimental system.

Drug elucidation: invertebrate genetics sheds new light on the molecular targets of CNS drugs.

Many important drugs approved to treat common human diseases were discovered by serendipity, without a firm understanding of their modes of action. As a result, the side effects and interactions of these medications are often unpredictable, and there is limited guidance for improving the design of next-generation drugs. Here, we review the innovative use of simple model organisms, especially Caenorhabditis elegans, to gain fresh insights into the complex biological effects of approved CNS medications. Whereas drug discovery involves the identification of new drug targets and lead compounds/biologics, and drug development spans preclinical testing to FDA approval, drug elucidation refers to the process of understanding the mechanisms of action of marketed drugs by studying their novel effects in model organisms. Drug elucidation studies have revealed new pathways affected by antipsychotic drugs, e.g., the insulin signaling pathway, a trace amine receptor and a nicotinic acetylcholine receptor. Similarly, novel targets of antidepressant drugs and lithium have been identified in C. elegans, including lipid-binding/transport proteins and the SGK-1 signaling pathway, respectively. Elucidation of the mode of action of anesthetic agents has shown that anesthesia can involve mitochondrial targets, leak currents, and gap junctions. The general approach reviewed in this article has advanced our knowledge about important drugs for CNS disorders and can guide future drug discovery efforts.

Abstract 316: Cell-Matrix Contacts Regulate Age-Associated Cardiac Function

An increased deposition of ECM is observed in all advanced age heart failure patients. Therefore, it is necessary to investigate the effect of extracellular remodeling on mechanical function in genetically tractable, rapidly aging, and simple model organisms such as Drosophila melanogaster . The bilayered design of the Drosophila heart-tube makes it an easier model in which to study the interplay between ECM and cardiomyocytes as they regulate contraction. Here we present data from two common wildtype strains of Drosophila exhibiting different aging profiles in terms of cytoskeletal and ECM regulation and remodeling. Using a recently developed nanoindentation method to measure cardiomyocyte stiffness of intact Drosophila hearts, we have found that while yellow-white ( yw ) flies show midline stiffening at the intercalated discs (ICD) presenting a clear diastolic dysfunction with age, the white-1118 ( w1118 ) flies exhibit no ICD stiffening, but show an increase in thickness of the ECM layer between the ventral muscle (VM) and cardiomyocytes (CM). Paired with increased expression of ECM proteins, the w1118 Drosophila line may provide a good model for exploring the effect of cell-ECM contacts on regulating cardiac function with age. Knock-down of integral ECM genes LamininA and Viking (Collagen IV) result in no effect on cardiac performance in juvenile flies but causes a decrease in underlying cardiomyocyte stiffness and an increase in the contractile irregularity of heart beats. This suggests that the cell-ECM contacts in the basement membrane are intimately tied to coupling of the cardiomyocytes of the Drosophila heart-tube, which may have larger implications for elderly patients suffering from myocardial fibrosis and experiencing cardiomyocyte decoupling and resultant arrhythmias.

At neutral pH the chronological lifespan of Hansenula polymorpha increases upon enhancing the carbon source concentrations.

Dietary restriction is generally assumed to increase the lifespan in most eukaryotes, including the simple model organism Saccharomyces cerevisiae. However, recent data questioned whether this phenomenon is indeed true for yeast. We studied the effect of reduction of the carbon source concentration on the chronological lifespan of the yeast Hansenula polymorpha using four different carbon sources. Our data indicate that reduction of the carbon source concentration has a negative (glucose, ethanol, methanol) or positive (glycerol) effect on the chronological lifespan. We show that the actual effect of carbon source concentrations largely depends on extracellular factor(s). We provide evidence that H. polymorpha acidifies the medium and that a low pH of the medium alone is sufficient to significantly decrease the chronological lifespan. However, glucose-grown cells are less sensitive to low pH compared to glycerol-grown cells, explaining why only the reduction of the glycerol-concentration (which leads to less medium acidification) has a positive effect on the chronological lifespan. Instead, the positive effect of enhancing the glucose concentrations is much larger than the negative effect of the medium acidification at these conditions, explaining the increased lifespan with increasing glucose concentrations. Importantly, at neutral pH, the chronological lifespan also decreases with a reduction in glycerol concentrations. We show that for glycerol cultures this effect is related to acidification independent changes in the composition of the spent medium. Altogether, our data indicate that in H. polymorpha at neutral pH the chronological lifespan invariably extends upon increasing the carbon source concentration.

Emerging models for DNA repair: Dictyostelium discoideum as a model for nonhomologous end-joining

DNA double strand breaks (DSBs) are a particularly cytotoxic variety of DNA lesion that can be repaired by homologous recombination (HR) or nonhomologous end-joining (NHEJ). HR utilises sequences homologous to the damage DNA template to facilitate repair. In contrast, NHEJ does not require homologous sequences for repair but instead functions by directly re-joining DNA ends. These pathways are critical to resolve DSBs generated intentionally during processes such as meiotic and site-specific recombination. However, they are also utilised to resolve potentially pathological DSBs generated by mutagens and errors during DNA replication. The importance of DSB repair is underscored by the findings that defects in these pathways results in chromosome instability that contributes to a variety of disease states including malignancy. The general principles of NHEJ are conserved in eukaryotes. As such, relatively simple model organisms have been instrumental in identifying components of these pathways and providing a mechanistic understanding of repair that has subsequently been applied to vertebrates. However, certain components of the NHEJ pathway are absent or show limited conservation in the most commonly used invertebrate models exploited to study DNA repair. Recently, however, it has become apparent that vertebrate DNA repair pathway components, including those involved in NHEJ, are unusually conserved in the amoeba Dictyostelium discoideum. Traditionally, this genetically tractable organism has been exploited to study the molecular basis of cell type specification, cell motility and chemotaxis. Here we discuss the use of this organism as an additional model to study DNA repair, with specific reference to NHEJ.

Automation Highlights from the Literature

Automation Highlights from the Literature

Synthesis of a novel series of thiazole-based histone acetyltransferase inhibitors

Acetylation, which targets a broad range of histone and non-histone proteins, is a reversible mechanism and plays a critical role in eukaryotic genes activation/deactivation. Acetyltransferases are very well conserved through evolution. This allows the use of a simple model organism, such as budding yeast, for the study of their related processes and to discover specific inhibitors. Following a simple yeast-based chemogenetic approach, we have identified a novel HAT (histone acetyltransferase) inhibitor active both in vitro and in vivo. This new synthetic compound, 1-(4-(4-chlorophenyl)thiazol-2-yl)-2-(propan-2-ylidene)hydrazine, named BF1, showed substrate selectivity for histone H3 acetylation and inhibitory activity in vitro on recombinant HAT Gcn5 and p300. Finally, we tested BF1 on human cells, HeLa as control and two aggressive cancer cell lines: a neuroblastoma from neuronal tissue and glioblastoma from brain tumour. Both global acetylation of histone H3 and specific acetylation at lysine 18 (H3AcK18) were lowered by BF1 treatment. Collectively, our results show the efficacy of this novel HAT inhibitor and propose the utilization of BF1 as a new, promising tool for future pharmacological studies.

The emerging synthesis of development and evolution: A new biology for psychoanalysis

Significant transformations have taken place in our understanding of evolution and development since the late nineteenth century, when the two seemed so closely related; at that time, the ideas of Charles Darwin, Ernst Haeckel, and other biologists played a prominent role in Freud's creation of psychoanalysis. During the twentieth century, as biological research reached the molecular level, biological concepts of development and of evolution veered progressively further from each other and further away from psychoanalysis. Then most recently, in response to a flood of discoveries in the last two decades, the long-separated fields of developmental and evolutionary biology have come together in the creation of a new field, informally referred to as “Evo–Devo.” In this paper, I trace these remarkable changes, and discuss how these recent advances have returned biological concepts to a closer alignment with psychoanalytic principles regarding the role of early experience in long-term developmental change and the importance of the role that early parent-infant interactions play in shaping our lives and those of our children. I have illustrated the changes in our thinking that have taken place over the past half century by describing the different ways that I have thought about, puzzled over, and been enlightened by these changing concepts in the course of my psychobiological research on the roles of the mother-infant relationship in the development of a relatively simple model organism, the laboratory rat.

Using fluorescence to study actomyosin in yeasts.

This year marks the 30th anniversary of the first description of the cellular distribution of actin within a yeast cell. Since then advances in both molecular genetics and imaging technologies have ensured research within these simple model organisms has blazed a trail in the field of actomyosin research. Many yeast proteins and their functions are functionally conserved in human cells. This, combined with experimental speed, minimal cost and ease of use make the yeasts extremely attractive model organisms for researching diverse cellular processes, including those involving actomyosin. In this chapter, current state-of-the-art fluorescence methodologies being applied to yeast actomyosin research, together with an honest appraisal of their limitations, such as the pitfalls that should be considered when fluorescently labelling proteins interacting within a dynamic cytoskeleton, will be discussed. Papers describing the established techniques developed for yeast localisation studies will be highlighted. This will provide the reader with an informed overview of the arsenal of imaging techniques available to the yeast actomyosin researcher and encourage them to consider novel ways these simple unicellular eukaryotes could be used to address their own research questions.

Bioactivity of nanosilver in Caenorhabditis elegans: Effects of size, coat, and shape

The in vivo toxicity to eukaryotes of nanosilver (AgNP) spheres and plates in two sizes each was assessed using the simple model organism Caenorhabditis elegans. For each shape, smaller AgNP size correlated with higher toxicity, as indicated by reduced larval growth. Smaller size also correlated with significant increases in silver uptake for silver nanospheres. Citrate coated silver spheres of 20 nm diameter induced an innate immune response that increased or held steady over 24 h, while regulation of genes involved in metal metabolism peaked at 4 h and subsequently decreased. For AgNP spheres, coating altered bioactivity, with a toxicity ranking of polyethylene glycol (PEG) > polyvinylpyrrolidone (PVP) ≅ branched polyethyleneimine (BPEI) > citrate, but silver uptake ranking of PEG > PVP > citrate > BPEI. Our findings in C. elegans correlate well with findings in rodents for AgNP size vs. uptake and toxicity, as well as for induction of immune effectors, while using methods that are faster and far less expensive, supporting the use of C. elegans as an alternative model for early toxicity screening.

An ancestral non-proteolytic role for presenilin proteins in multicellular development of the social amoeba Dictyostelium discoideum.

Mutations in either of two presenilin genes can cause familial Alzheimer's disease. Presenilins have both proteolysis-dependent functions, as components of the γ-secretase complex, and proteolysis-independent functions in signalling. In this study, we investigate a conserved function of human presenilins in the development of the simple model organism Dictyostelium discoideum. We show that the block in Dictyostelium development caused by the ablation of both Dictyostelium presenilins is rescued by the expression of human presenilin 1, restoring the terminal differentiation of multiple cell types. This developmental role is independent of proteolytic activity, because the mutation of both catalytic aspartates does not affect presenilin ability to rescue development, and the ablation of nicastrin, a γ-secretase component that is crucial for proteolytic activity, does not block development. The role of presenilins during Dictyostelium development is therefore independent of their proteolytic activity. However, presenilin loss in Dictyostelium results in elevated cyclic AMP (cAMP) levels and enhanced stimulation-induced calcium release, suggesting that presenilins regulate these intracellular signalling pathways. Our data suggest that presenilin proteins perform an ancient non-proteolytic role in regulating intracellular signalling and development, and that Dictyostelium is a useful model for analysing human presenilin function.

Composition of agarose substrate affects behavioral output of Drosophila larvae

In the last decade the Drosophila larva has evolved into a simple model organism offering the opportunity to integrate molecular genetics with systems neuroscience. This led to a detailed understanding of the neuronal networks for a number of sensory functions and behaviors including olfaction, vision, gustation and learning and memory. Typically, behavioral assays in use exploit simple Petri dish setups with either agarose or agar as a substrate. However, neither the quality nor the concentration of the substrate is generally standardized across these experiments and there is no data available on how larval behavior is affected by such different substrates. Here, we have investigated the effects of different agarose concentrations on several larval behaviors. We demonstrate that agarose concentration is an important parameter, which affects all behaviors tested: preference, feeding, learning and locomotion. Larvae can discriminate between different agarose concentrations, they feed differently on them, they can learn to associate an agarose concentration with an odor stimulus and change locomotion on a substrate of higher agarose concentration. Additionally, we have investigated the effect of agarose concentration on three quinine based behaviors: preference, feeding and learning. We show that in all cases examined the behavioral output changes in an agarose concentration-dependent manner. Our results suggest that comparisons between experiments performed on substrates differing in agarose concentration should be done with caution. It should be taken into consideration that the agarose concentration can affect the behavioral output and thereby the experimental outcomes per se potentially due to the initiation of an escape response or changes in foraging behavior on more rigid substrates.

Integrated omics study delineates the dynamics of lipid droplets in Rhodococcus opacus PD630

Rhodococcus opacus strain PD630 (R. opacus PD630), is an oleaginous bacterium, and also is one of few prokaryotic organisms that contain lipid droplets (LDs). LD is an important organelle for lipid storage but also intercellular communication regarding energy metabolism, and yet is a poorly understood cellular organelle. To understand the dynamics of LD using a simple model organism, we conducted a series of comprehensive omics studies of R. opacus PD630 including complete genome, transcriptome and proteome analysis. The genome of R. opacus PD630 encodes 8947 genes that are significantly enriched in the lipid transport, synthesis and metabolic, indicating a super ability of carbon source biosynthesis and catabolism. The comparative transcriptome analysis from three culture conditions revealed the landscape of gene-altered expressions responsible for lipid accumulation. The LD proteomes further identified the proteins that mediate lipid synthesis, storage and other biological functions. Integrating these three omics uncovered 177 proteins that may be involved in lipid metabolism and LD dynamics. A LD structure-like protein LPD06283 was further verified to affect the LD morphology. Our omics studies provide not only a first integrated omics study of prokaryotic LD organelle, but also a systematic platform for facilitating further prokaryotic LD research and biofuel development.

Will calorie restriction work in humans?

Calorie Restriction (CR) without malnutrition slows aging and increases average and maximal lifespan in simple model organisms and rodents. In rhesus monkeys long-term CR reduces the incidence of type 2 diabetes, cardiovascular disease and cancer, and protects against age-associated sarcopenia and neurodegeneration. However, so far CR significantly increased average lifespan only in the Wisconsin, but not in the NIA monkey study. Differences in diet composition and study design between the 2 on-going trials may explain the discrepancies in survival and disease. Nevertheless, many of the metabolic and hormonal adaptations that are typical of the long-lived CR rodents did not occur in either the NIA or WNPRC CR monkeys. Whether or not CR will extend lifespan in humans is not yet known, but accumulating data indicate that moderate CR with adequate nutrition has a powerful protective effect against obesity, type 2 diabetes, inflammation, hypertension, cardiovascular disease and reduces metabolic risk factors associated with cancer. Moreover, CR in human beings improves markers of cardiovascular aging, and rejuvenates the skeletal muscle transcriptional profile. More studies are needed to understand the interactions between CR, diet composition, exercise, and other environmental and psychological factors on metabolic and molecular pathways that regulate health and longevity.

The C. elegans male exercises directional control during mating through cholinergic regulation of sex-shared command interneurons.

BackgroundMating behaviors in simple invertebrate model organisms represent tractable paradigms for understanding the neural bases of sex-specific behaviors, decision-making and sensorimotor integration. However, there are few examples where such neural circuits have been defined at high resolution or interrogated.Methodology/Principal FindingsHere we exploit the simplicity of the nematode Caenorhabditis elegans to define the neural circuits underlying the male’s decision to initiate mating in response to contact with a mate. Mate contact is sensed by male-specific sensilla of the tail, the rays, which subsequently induce and guide a contact-based search of the hermaphrodite’s surface for the vulva (the vulva search). Atypically, search locomotion has a backward directional bias so its implementation requires overcoming an intrinsic bias for forward movement, set by activity of the sex-shared locomotory system. Using optogenetics, cell-specific ablation- and mutant behavioral analyses, we show that the male makes this shift by manipulating the activity of command cells within this sex-shared locomotory system. The rays control the command interneurons through the male-specific, decision-making interneuron PVY and its auxiliary cell PVX. Unlike many sex-shared pathways, PVY/PVX regulate the command cells via cholinergic, rather than glutamatergic transmission, a feature that likely contributes to response specificity and coordinates directional movement with other cholinergic-dependent motor behaviors of the mating sequence. PVY/PVX preferentially activate the backward, and not forward, command cells because of a bias in synaptic inputs and the distribution of key cholinergic receptors (encoded by the genes acr-18, acr-16 and unc-29) in favor of the backward command cells.Conclusion/SignificanceOur interrogation of male neural circuits reveals that a sex-specific response to the opposite sex is conferred by a male-specific pathway that renders subordinate, sex-shared motor programs responsive to mate cues. Circuit modifications of these types may make prominent contributions to natural variations in behavior that ultimately bring about speciation.

Using C. elegans to Decipher the Cellular and Molecular Mechanisms Underlying Neurodevelopmental Disorders

Neurodevelopmental disorders such as epilepsy, intellectual disability (ID), and autism spectrum disorders (ASDs) occur in over 2 % of the population, as the result of genetic mutations, environmental factors, or combination of both. In the last years, use of large-scale genomic techniques allowed important advances in the identification of genes/loci associated with these disorders. Nevertheless, following association of novel genes with a given disease, interpretation of findings is often difficult due to lack of information on gene function and effect of a given mutation in the corresponding protein. This brings the need to validate genetic associations from a functional perspective in model systems in a relatively fast but effective manner. In this context, the small nematode, Caenorhabditis elegans, presents a good compromise between the simplicity of cell models and the complexity of rodent nervous systems. In this article, we review the features that make C. elegans a good model for the study of neurodevelopmental diseases. We discuss its nervous system architecture and function as well as the molecular basis of behaviors that seem important in the context of different neurodevelopmental disorders. We review methodologies used to assess memory, learning, and social behavior as well as susceptibility to seizures in this organism. We will also discuss technological progresses applied in C. elegans neurobiology research, such as use of microfluidics and optogenetic tools. Finally, we will present some interesting examples of the functional analysis of genes associated with human neurodevelopmental disorders and how we can move from genes to therapies using this simple model organism.