Health data cooperatives - citizen empowerment.

INTRODUCTION: This article is part of a Focus Theme of Methods of Information in Medicine on Health Record Banking. BACKGROUND: Healthcare is often ineffective and costs are steadily rising. This is in a large part due to the inaccessibility of medical and health data stored in multiple silos. Furthermore, in most cases molecular differences between individuals that result in different susceptibilities to drugs and diseases as well as targeted interventions cannot be taken into account. Technological advances in genome sequencing and the interaction of 'omics' data with environmental data on one hand and mobile health on the other, promise to generate the longitudinal health data that will form the basis for a more personalized, precision medicine. OBJECTIVES: For this new medicine to become a reality, however, millions of personal health data sets have to be aggregated. The value of such aggregated personal data has been recognized as a new asset class and many commercial entities are competing for this new asset (e.g. Google, Facebook, 23andMe, PatientsLikeMe). The primary source and beneficiary of personal health data is the individual. As a collective, society should be the beneficiary of both the economic and health value of these aggregated data and (health) information. METHODS: We posit that empowering citizens by providing them with a platform to safely store, manage and share their health-related data will be a necessary element in the transformation towards a more effective and efficient precision medicine. Such health data platforms should be organized as cooperatives that are solely owned and controlled by their members and not by shareholders. Members determine which data they want to share for example with doctors or to contribute to research for the benefit of their health and that of society. Members will also decide how the revenues generated by granting third parties access to the anonymized data that they agreed to share, should be invested in research, information or education. RESULTS: Currently no functional Health Data Cooperatives exist yet. The relative success of health data repositories such as 23andme and PatientsLikeMe indicates that citizens are willing to participate in research even if - and in contrast to the cooperative model - the commercial value of these data does not go back to the collective of users. CONCLUSIONS: In the Health Data Cooperative model, the citizens with their data would take the center stage in the healthcare system and society would benefit from the health-related and financial benefits that aggregation of these data brings.

The IGFBP7 homolog Imp-L2 promotes insulin signaling in distinct neurons of the Drosophila brain.

In Drosophila, Insulin-like peptide 2 (Dilp-2) is expressed by insulin-producing cells in the brain, and is secreted into the hemolymph to activate insulin signaling systemically. Within the brain, however, a more local activation of insulin signaling may be required to couple behavioral and physiological traits to nutritional inputs. We show that a small subset of neurons in the larval brain has high Dilp-2-mediated insulin signaling activity. This local insulin signaling activation is accompanied by selective Dilp-2 uptake and depends on the expression of the Imaginal morphogenesis protein-late 2 (Imp-L2) in the target neurons. We suggest that Imp-L2 acts as a licensing factor for neuronal IIS activation through Dilp-2 to further increase the precision of insulin activity in the brain.

Experiences of early users of direct-to-consumer genomics in Switzerland: an exploratory study.

AIMS: This study explores attitudes, motivations and self-reported impact in connection with direct-to-consumer (DTC) genomic testing amongst a group of life scientists in Switzerland. METHODS: Data were collected through: (1) a self-completion online questionnaire, and (2) semi-structured qualitative interviews. Forty participants completed the questionnaire and 10 were interviewed. RESULTS: Curiosity was mentioned as the primary reason for undergoing testing, while less significance was attributed to receiving actionable health information. The opportunity to contribute to research ranked high as a motive for testing. Overall, participants assessed their experience with the test as positive and were willing to recommend it to others. Some reported that the testing had an impact on how they view their health, but only a third of participants planned on showing the results to health practitioners. Participants consistently referred to 'fun' when describing several aspects of the testing experience. The 'fun factor' manifested itself in different phases of the process, including the motivation for taking the test, receiving the information and putting the test results to use (including sharing and discussing it with others). This finding suggests the need to further explore the concept of personal utility in DTC genomics. CONCLUSIONS: Although this group is not representative of the broader population due to both their scientific expertise and their willingness to try out a controversial new technology, their experiences provide valuable insights into the role of personal curiosity and altruism (fostering medical research) as motivations for testing and the utility attributed to both.

Autophagy in Drosophila ovaries is induced by starvation and is required for oogenesis.

Autophagy, an evolutionarily conserved lysosome-mediated degradation, promotes cell survival under starvation and is controlled by insulin/target of rapamycin (TOR) signaling. In Drosophila, nutrient depletion induces autophagy in the fat body. Interestingly, nutrient availability and insulin/TOR signaling also influence the size and structure of Drosophila ovaries, however, the role of nutrient signaling and autophagy during this process remains to be elucidated. Here, we show that starvation induces autophagy in germline cells (GCs) and in follicle cells (FCs) in Drosophila ovaries. This process is mediated by the ATG machinery and involves the upregulation of Atg genes. We further demonstrate that insulin/TOR signaling controls autophagy in FCs and GCs. The analysis of chimeric females reveals that autophagy in FCs, but not in GCs, is required for egg development. Strikingly, when animals lack Atg gene function in both cell types, ovaries develop normally, suggesting that the incompatibility between autophagy-competent GCs and autophagy-deficient FCs leads to defective egg development. As egg morphogenesis depends on a tightly linked signaling between FCs and GCs, we propose a model in which autophagy is required for the communication between these two cell types. Our data establish an important function for autophagy during oogenesis and contributes to the understanding of the role of autophagy in animal development.

Cancer, type 2 diabetes, and ageing: news from flies and worms.

The tumour suppressor gene PTEN is, next to p53, the second most frequently mutated gene in human cancers. The genes TSC1 and TSC2 are mutated in the severe human syndrome called Tuberous Sclerosis. Patients with this disease have large benign tumours composed of large cells in the brain. The genetic dissection of pathways controlling the growth of cells, organs, and the entire organism in Drosophila has contributed to the understanding of the signalling pathways that are controlled by these two tumour suppressors. Together with studies on nutrient regulation of growth and ageing in the nematode Caenorhabditis elegans, evidence from these model organisms has moved the Insulin/IGF (IIS) and the Target Rapamycin (TOR) signalling pathway onto the centre stage of cellular growth control and made them attractive novel targets for cancer therapy. In this review, I will outline the contributions of model organism genetics to the understanding of these disease relevant pathways and highlight the evolutionary conservation of nutrient-dependent growth regulation.

Interplay between growth factor and nutrient signaling: lessons from Drosophila TOR.

During normal development, cellular and organismal growth is coordinately regulated. Each cell and each individual organ integrates information about nutrient availability, hormonal signals, and intrinsic growth programs. Describing the signaling pathways involved in these processes and how they are integrated is important to understand how growth is controlled during development and may also permit the development of means to curb uncontrolled growth in disease. In recent years, the biochemical analysis of cellular growth in cultured cells and the genetic dissection of growth control in model organisms has identified two conserved signaling pathways dedicated to cellular growth. The target of rapamycin (TOR) pathway regulates growth in response to nutrients, and the insulin/IGF pathways are involved in coordinating cellular growth in response to endocrine signals. This review discusses recent advances in the understanding of the interaction between these pathways, with a special focus on the contribution of the genetic analysis of these pathways in Drosophila.

PDK1 regulates growth through Akt and S6K in Drosophila.

The insulin/insulin-like growth factor-1 signaling pathway promotes growth in invertebrates and vertebrates by increasing the levels of phosphatidylinositol 3,4,5-triphosphate through the activation of p110 phosphatidylinositol 3-kinase. Two key effectors of this pathway are the phosphoinositide-dependent protein kinase 1 (PDK1) and Akt/PKB. Although genetic analysis in Caenorhabditis elegans has implicated Akt as the only relevant PDK1 substrate, cell culture studies have suggested that PDK1 has additional targets. Here we show that, in Drosophila, dPDK1 controls cellular and organism growth by activating dAkt and S6 kinase, dS6K. Furthermore, dPDK1 genetically interacts with dRSK but not with dPKN, encoding two substrates of PDK1 in vitro. Thus, the results suggest that dPDK1 is required for dRSK but not dPKN activation and that it regulates insulin-mediated growth through two main effector branches, dAkt and dS6K.

Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein.

The Drosophila melanogaster gene chico encodes an insulin receptor substrate that functions in an insulin/insulin-like growth factor (IGF) signaling pathway. In the nematode Caenorhabditis elegans, insulin/IGF signaling regulates adult longevity. We found that mutation of chico extends fruit fly median life-span by up to 48% in homozygotes and 36% in heterozygotes. Extension of life-span was not a result of impaired oogenesis in chico females, nor was it consistently correlated with increased stress resistance. The dwarf phenotype of chico homozygotes was also unnecessary for extension of life-span. The role of insulin/IGF signaling in regulating animal aging is therefore evolutionarily conserved.

Ras controls growth, survival and differentiation in the Drosophila eye by different thresholds of MAP kinase activity.

Ras mediates a plethora of cellular functions during development. In the developing eye of Drosophila, Ras performs three temporally separate functions. In dividing cells, it is required for growth but is not essential for cell cycle progression. In postmitotic cells, it promotes survival and subsequent differentiation of ommatidial cells. In the present paper, we have analyzed the different roles of Ras during eye development by using molecularly defined complete and partial loss-of-function mutations of Ras. We show that the three different functions of Ras are mediated by distinct thresholds of MAPK activity. Low MAPK activity prolongs cell survival and permits differentiation of R8 photoreceptor cells while high or persistent MAPK activity is sufficient to precociously induce R1-R7 photoreceptor differentiation in dividing cells.

An evolutionarily conserved function of the Drosophila insulin receptor and insulin-like peptides in growth control.

BACKGROUND: Size regulation is fundamental in developing multicellular organisms and occurs through the control of cell number and cell size. Studies in Drosophila have identified an evolutionarily conserved signaling pathway that regulates organismal size and that includes the Drosophila insulin receptor substrate homolog Chico, the lipid kinase PI(3)K (Dp110), DAkt1/dPKB, and dS6K. RESULTS: We demonstrate that varying the activity of the Drosophila insulin receptor homolog (DInr) during development regulates organ size by changing cell size and cell number in a cell-autonomous manner. An amino acid substitution at the corresponding position in the kinase domain of the human and Drosophila insulin receptors causes severe growth retardation. Furthermore, we show that the Drosophila genome contains seven insulin-like genes that are expressed in a highly tissue- and stage-specific pattern. Overexpression of one of these insulin-like genes alters growth control in a DInr-dependent manner. CONCLUSIONS: This study shows that the Drosophila insulin receptor autonomously controls cell and organ size, and that overexpression of a gene encoding an insulin-like peptide is sufficient to increase body size.

Lilliputian: an AF4/FMR2-related protein that controls cell identity and cell growth.

Members of the AF4/FMR2 family of nuclear proteins are involved in human diseases such as acute lymphoblastic leukemia and mental retardation. Here we report the identification and characterization of the Drosophila lilliputian (lilli) gene, which encodes a nuclear protein related to mammalian AF4 and FMR2. Mutations in lilli suppress excessive neuronal differentiation in response to a constitutively active form of Raf in the eye. In the wild type, Lilli has a partially redundant function in the Ras/MAPK pathway in differentiation but it is essential for normal growth. Loss of Lilli function causes an autonomous reduction in cell size and partially suppresses the increased growth associated with loss of PTEN function. These results suggest that Lilli acts in parallel with the Ras/MAPK and the PI3K/PKB pathways in the control of cell identity and cellular growth.

Modulation of the Ras/MAPK signalling pathway by the redox function of selenoproteins in Drosophila melanogaster.

Modulation of reactive oxygen species (ROS) plays a key role in signal transduction pathways. Selenoproteins act controlling the redox balance of the cell. We have studied how the alteration of the redox balance caused by patufet (selD(ptuf)), a null mutation in the Drosophila melanogaster selenophosphate synthetase 1 (sps1) gene, which codes for the SelD enzyme of the selenoprotein biosynthesis, affects the Ras/MAPK signalling pathway. The selD(ptuf) mutation dominantly suppresses the phenotypes in the eye and the wing caused by hyperactivation of the Ras/MAPK cassette and the activated forms of the Drosophila EGF receptor (DER) and Sevenless (Sev) receptor tyrosine kinases (RTKs), which signal in the eye and wing, respectively. No dominant interaction is observed with sensitized conditions in the Wnt, Notch, Insulin-Pi3K, and DPP signalling pathways. Our current hypothesis is that selenoproteins selectively modulate the Ras/MAPK signalling pathway through their antioxidant function. This is further supported by the fact that a selenoprotein-independent increase in ROS caused by the catalase amorphic Cat(n1) allele also reduces Ras/MAPK signalling. Here, we present the first evidence for the role of intracellular redox environment in signalling pathways in Drosophila as a whole organism.

Genetic control of size in Drosophila.

During the past ten years, significant progress has been made in understanding the basic mechanisms of the development of multicellular organisms. Genetic analysis of the development of Caenorhabditis elegans and Drosophila has unearthed a fruitful number of genes involved in establishing the basic body plan, patterning of limbs, specification of cell fate and regulation of programmed cell death. The genes involved in these developmental processes have been conserved throughout evolution and homologous genes are involved in the patterning of insect and human limbs. Despite these important discoveries, we have learned astonishingly little about one of the most obvious distinctions between animals: their difference in body size. The mass of the smallest mammal, the bumble-bee bat, is 2 g while that of the largest mammal, the blue whale, is 150 t or 150 million grams. Remarkably, even though they are in the same class, body size can vary up to 75-million-fold. Furthermore, this body growth can be finite in the case of most vertebrates or it can occur continuously throughout life, as for trees, molluscs and large crustaceans. Currently, we know comparatively little about the genetic control of body size. In this article we will review recent evidence from vertebrates and particularly from Drosophila that implicates insulin/insulin-like growth factor-I and other growth pathways in the control of cell, organ and body size.

Genetic and biochemical characterization of dTOR, the Drosophila homolog of the target of rapamycin.

The adaptation of growth in response to nutritional changes is essential for the proper development of all organisms. Here we describe the identification of the Drosophila homolog of the target of rapamycin (TOR), a candidate effector for nutritional sensing. Genetic and biochemical analyses indicate that dTOR impinges on the insulin signaling pathway by autonomously affecting growth through modulating the activity of dS6K. However, in contrast to other components in the insulin signaling pathway, partial loss of dTOR function preferentially reduces growth of the endoreplicating tissues. These results are consistent with dTOR residing on a parallel amino acid sensing pathway.

Genetic control of cell size.

Over the past 25 years, the genetic control of cell size has mainly been addressed in yeast, a single-celled organism. Recent insights from Drosophila have shed light on the signalling pathways responsible for adjusting and maintaining cell size in metazoans. Evidence is emerging for a signalling cascade conserved in evolution that links external nutrient sources to cell size.

PTEN affects cell size, cell proliferation and apoptosis during Drosophila eye development.

Mutations in the tumor suppressor gene PTEN (MMAC1/TEP1) are associated with a large number of human cancers and several autosomal-dominant disorders. Mice mutant for PTEN die at early embryonic stages and the mutant embryonic fibroblasts display decreased sensitivity to cell death. Overexpression of PTEN in different mammalian tissue culture cells affects various processes including cell proliferation, cell death and cell migration. We have characterized the Drosophila PTEN gene and present evidence that both inactivation and overexpression of PTEN affect cell size, while overexpression of PTEN also inhibits cell cycle progression at early mitosis and promotes cell death during eye development in a context-dependent manner. Furthermore, we have shown that PTEN acts in the insulin signaling pathway and all signals from the insulin receptor can be antagonized by either Drosophila or human PTEN, suggesting a potential means for alleviating symptoms associated with altered insulin signaling.

Drosophila S6 kinase: a regulator of cell size.

Cell proliferation requires cell growth; that is, cells only divide after they reach a critical size. However, the mechanisms by which cells grow and maintain their appropriate size have remained elusive. Drosophila deficient in the S6 kinase gene (dS6K) exhibited an extreme delay in development and a severe reduction in body size. These flies had smaller cells rather than fewer cells. The effect was cell-autonomous, displayed throughout larval development, and distinct from that of ribosomal protein mutants (Minutes). Thus, the dS6K gene product regulates cell size in a cell-autonomous manner without impinging on cell number.

Autonomous control of cell and organ size by CHICO, a Drosophila homolog of vertebrate IRS1-4.

The control of growth is fundamental to the developing metazoan. Here, we show that CHICO, a Drosophila homolog of vertebrate IRS1-4, plays an essential role in the control of cell size and growth. Animals mutant for chico are less than half the size of wild-type flies, owing to fewer and smaller cells. In mosaic animals, chico homozygous cells grow slower than their heterozygous siblings, show an autonomous reduction in cell size, and form organs of reduced size. Although chico flies are smaller, they show an almost 2-fold increase in lipid levels. The similarities of the growth defects caused by mutations in chico and the insulin receptor gene in Drosophila and by perturbations of the insulin/IGF1 signaling pathway in vertebrates suggest that this pathway plays a conserved role in the regulation of overall growth by controling cell size, cell number, and metabolism.

The dominant mutation Glazed is a gain-of-function allele of wingless that, similar to loss of APC, interferes with normal eye development.

Dominant mutations have served as invaluable tools for Drosophila geneticists. Here we analyze the dominant eye mutation Glazed (Gla) that was described by T. H. Morgan more than 50 years ago. We show that Gla causes the loss of photoreceptor cells during pupal stages, in a process reminiscent of apoptosis, with a concomitant overproduction of eye pigment. This phenotype is very similar to that caused by the loss of D-APC, a negative regulator of Wingless (Wg) signal transduction. Genetic analyses reveal however that the Gla gain-of-function phenotype can be reverted to wild-type. By generating a P-element-induced revertant of Gla we demonstrate that Gla is allelic to wg. The molecular lesion in Gla indicates that the insertion of a roo retrotransposon leads to ectopic expression of wg during pupal stages. We show that the Gla phenotype is similar to that caused by ectopic expression of Wg driven by the sevenless (sev) enhancer. In both cases Wg exerts its effect, at least in part, by negatively regulating the expression of the Pax2 homolog sparkling (spa). Gla represents not only the first dominant allele of wg, but it may also be the first allele ever described for wg.

Control of growth and differentiation by Drosophila RasGAP, a homolog of p120 Ras-GTPase-activating protein.

Mammalian Ras GTPase-activating protein (GAP), p120 Ras-GAP, has been implicated as both a downregulator and effector of Ras proteins, but its precise role in Ras-mediated signal transduction pathways is unclear. To begin a genetic analysis of the role of p120 Ras-GAP we identified a homolog from the fruit fly Drosophila melanogaster through its ability to complement the sterility of a Schizosaccharomyces pombe (fission yeast) gap1 mutant strain. Like its mammalian homolog, Drosophila RasGAP stimulated the intrinsic GTPase activity of normal mammalian H-Ras but not that of the oncogenic Val12 mutant. RasGAP was tyrosine phosphorylated in embryos and its Src homology 2 (SH2) domains could bind in vitro to a small number of tyrosine-phosphorylated proteins expressed at various developmental stages. Ectopic expression of RasGAP in the wing imaginal disc reduced the size of the adult wing by up to 45% and suppressed ectopic wing vein formation caused by expression of activated forms of Breathless and Heartless, two Drosophila receptor tyrosine kinases of the fibroblast growth factor receptor family. The in vivo effects of RasGAP overexpression required intact SH2 domains, indicating that intracellular localization of RasGAP through SH2-phosphotyrosine interactions is important for its activity. These results show that RasGAP can function as an inhibitor of signaling pathways mediated by Ras and receptor tyrosine kinases in vivo. Genetic interactions, however, suggested a Ras-independent role for RasGAP in the regulation of growth. The system described here should enable genetic screens to be performed to identify regulators and effectors of p120 Ras-GAP.