¿El aniversario de la Biología de Sistemas?

This issue of the journal Encounters in Biology honored us with its invitation to write a popular science article to celebrate the tenth anniversary of Systems Biology. However, as bad guests, we have to disagree with our host. Although Systems Biology turns one year older every year, this branch of Biology is not entering preadolescence, but is in full maturity and has already been around for several decades. Why do we say this? To clarify, we first need to understand what Systems Biology isEste número de la revista Encuentros en la Biología nos honró con su invitación a escribir un artículo de divulgación para celebrar el décimo aniversario de la Biología de Sistemas. Sin embargo, como malos invitados, nos toca discordar de nuestro huésped. Aunque cada año la Biología de Sistemas cumpla un año más, esta rama de la Biología no   está entrando en la preadolescencia, sino que se encuentra en plena madurez y cumple ya varias décadas de vida. ¿Por qué lo decimos? Para aclararlo hace falta primero que nos entendamos sobre qué es la Biología de Sistemas

Use of physiological constraints to identify quantitative design principles for gene expression in yeast adaptation to heat shock

BACKGROUND: Understanding the relationship between gene expression changes, enzyme activity shifts, and the corresponding physiological adaptive response of organisms to environmental cues is crucial in explaining how cells cope with stress. For example, adaptation of yeast to heat shock involves a characteristic profile of changes to the expression levels of genes coding for enzymes of the glycolytic pathway and some of its branches. The experimental determination of changes in gene expression profiles provides a descriptive picture of the adaptive response to stress. However, it does not explain why a particular profile is selected for any given response. RESULTS: We used mathematical models and analysis of in silico gene expression profiles (GEPs) to understand how changes in gene expression correlate to an efficient response of yeast cells to heat shock. An exhaustive set of GEPs, matched with the corresponding set of enzyme activities, was simulated and analyzed. The effectiveness of each profile in the response to heat shock was evaluated according to relevant physiological and functional criteria. The small subset of GEPs that lead to effective physiological responses after heat shock was identified as the result of the tuning of several evolutionary criteria. The experimentally observed transcriptional changes in response to heat shock belong to this set and can be explained by quantitative design principles at the physiological level that ultimately constrain changes in gene expression. CONCLUSION: Our theoretical approach suggests a method for understanding the combined effect of changes in the expression of multiple genes on the activity of metabolic pathways, and consequently on the adaptation of cellular metabolism to heat shock. This method identifies quantitative design principles that facilitate understating the response of the cell to stress

Maximization of information transmission influences selection of native phosphorelay architectures

Phosphorelays are signal transduction circuits that sense environmental changes and adjust cellular metabolism. Five different circuit architectures account for 99% of all phosphorelay operons annotated in over 9,000 fully sequenced genomes. Here we asked what biological design principles, if any, could explain selection among those architectures in nature. We began by studying kinetically well characterized phosphorelays (Spo0 of Bacillus subtilis and Sln1 of Saccharomyces cerevisiae). We find that natural circuit architecture maximizes information transmission in both cases. We use mathematical models to compare information transmission among the architectures for a realistic range of concentration and parameter values. Mapping experimentally determined phosphorelay protein concentrations onto that range reveals that the native architecture maximizes information transmission in sixteen out of seventeen analyzed phosphorelays. These results suggest that maximization of information transmission is important in the selection of native phosphorelay architectures, parameter values and protein concentrations.The travel related to this work was funded by the Ministerio de Ciencia y educación del gobierno de España (PRX18/00142 to Rui Alves) and the publication fee was funded by the Project G20010 from Universitat de Lleida. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

CAM Models: Lessons and Implications for CAM Evolution

The evolution of Crassulacean acid metabolism (CAM) by plants has been one of the most successful strategies in response to aridity. On the onset of climate change, expanding the use of water efficient crops and engineering higher water use efficiency into C3 and C4 crops constitute a plausible solution for the problems of agriculture in hotter and drier environments. A firm understanding of CAM is thus crucial for the development of agricultural responses to climate change. Computational models on CAM can contribute significantly to this understanding. Two types of models have been used so far. Early CAM models based on ordinary differential equations (ODE) reproduced the typical diel CAM features with a minimal set of components and investigated endogenous day/night rhythmicity. This line of research brought to light the preponderant role of vacuolar malate accumulation in diel rhythms. A second wave of CAM models used flux balance analysis (FBA) to better understand the role of CO2 uptake in flux distribution. They showed that flux distributions resembling CAM metabolism emerge upon constraining CO2 uptake by the system. We discuss the evolutionary implications of this and also how CAM components from unrelated pathways could have integrated along evolution

A mathematical model for strigolactone biosynthesis in plants

Strigolactones mediate plant development, trigger symbiosis with arbuscular mycorrhizal fungi, are abundant in 80% of the plant kingdom and help plants gain resistance to environmental stressors. They also induce germination of parasitic plant seeds that are endemic to various continents, such as Orobanche in Europe or Asia and Striga in Africa. The genes involved in the early stages of strigolactones biosynthesis are known in several plants. The regulatory structure and the latter parts of the pathway, where flux branching occurs to produce alternative strigolactones, are less well-understood. Here we present a computational study that collects the available experimental evidence and proposes alternative biosynthetic pathways that are consistent with that evidence. Then, we test the alternative pathways through in silico simulation experiments and compare those experiments to experimental information. Our results predict the differences in dynamic behavior between alternative pathway designs. Independent of design, the analysis suggests that feedback regulation is unlikely to exist in strigolactone biosynthesis. In addition, our experiments suggest that engineering the pathway to modulate the production of strigolactones could be most easily achieved by increasing the flux of b-carotenes going into the biosynthetic pathway. Finally, we find that changing the ratio of alternative strigolactones produced by the pathway can be done by changing the activity of the enzymes after the flux branching points.This work was partially funded by PROSTRIG, an ERANET project from FACEJPI (PCI2019-103382, MICIUN) and project PI20/00377 (FIS). AL received funding from the European Union’s H2020 research and innovation programme under Marie Skłodowska-Curie grant agreement No. 801586

Competing risks to breast cancer mortality in Catalonia

Background: Breast cancer mortality has experienced important changes over the last century. Breast cancer occurs in the presence of other competing risks which can influence breast cancer incidence and mortality trends. The aim of the present work is: 1) to assess the impact of breast cancer deaths among mortality from all causes in Catalonia (Spain), by age and birth cohort and 2) to estimate the risk of death from other causes than breast cancer, one of the inputs needed to model breast cancer mortality reduction due to screening or therapeutic interventions. Methods: The multi-decrement life table methodology was used. First, all-cause mortality probabilities were obtained by age and cohort. Then mortality probability for breast cancer was subtracted from the all-cause mortality probabilities to obtain cohort life tables for causes other than breast cancer. These life tables, on one hand, provide an estimate of the risk of dying from competing risks, and on the other hand, permit to assess the impact of breast cancer deaths on all-cause mortality using the ratio of the probability of death for causes other than breast cancer by the all-cause probability of death. Results: There was an increasing impact of breast cancer on mortality in the first part of the 20(th) century, with a peak for cohorts born in 1945-54 in the 40-49 age groups (for which approximately 24% of mortality was due to breast cancer). Even though for cohorts born after 1955 there was only information for women under 50, it is also important to note that the impact of breast cancer on all-cause mortality decreased for those cohorts. Conclusion: We have quantified the effect of removing breast cancer mortality in different age groups and birth cohorts. Our results are consistent with US findings. We also have obtained an estimate of the risk of dying from competing-causes mortality, which will be used in the assessment of the effect of mammography screening on breast cancer mortality in Catalonia

Budget impact analysis of switching to digital mammography in a population-based breast cancer screening program: a discrete event simulation model

Objective: To assess the budgetary impact of switching from screen-film mammography to full-field digital mammography in a population-based breast cancer screening program. Methods: A discrete-event simulation model was built to reproduce the breast cancer screening process (biennial mammographic screening of women aged 50 to 69 years) combined with the natural history of breast cancer. The simulation started with 100,000 women and, during a 20-year simulation horizon, new women were dynamically entered according to the aging of the Spanish population. Data on screening were obtained from Spanish breast cancer screening programs. Data on the natural history of breast cancer were based on US data adapted to our population. A budget impact analysis comparing digital with screen-film screening mammography was performed in a sample of 2,000 simulation runs. A sensitivity analysis was performed for crucial screening-related parameters. Distinct scenarios for recall and detection rates were compared. Results: Statistically significant savings were found for overall costs, treatment costs and the costs of additional tests in the long term. The overall cost saving was 1,115,857J (95%CI from 932,147 to 1,299,567) in the 10th year and 2,866,124J (95%CI from 2,492,610 to 3,239,638) in the 20th year, representing 4.5% and 8.1% of the overall cost associated with screenfilm mammography. The sensitivity analysis showed net savings in the long term. Conclusions: Switching to digital mammography in a population-based breast cancer screening program saves long-term budget expense, in addition to providing technical advantages. Our results were consistent across distinct scenarios representing the different results obtained in European breast cancer screening programs.This was supported by grants from the Health Ministry of Spain (Fondo de Investigación Sanitaria PI07/90357)

Competing risks to breast cancer mortality in Catalonia

Background: Breast cancer mortality has experienced important changes over the last century. Breast cancer occurs in the presence of other competing risks which can influence breast cancer incidence and mortality trends. The aim of the present work is: 1) to assess the impact of breast cancer deaths among mortality from all causes in Catalonia (Spain), by age and birth cohort and 2) to estimate the risk of death from other causes than breast cancer, one of the inputs needed to model breast cancer mortality reduction due to screening or therapeutic interventions. Methods: The multi-decrement life table methodology was used. First, all-cause mortality probabilities were obtained by age and cohort. Then mortality probability for breast cancer was subtracted from the all-cause mortality probabilities to obtain cohort life tables for causes other than breast cancer. These life tables, on one hand, provide an estimate of the risk of dying from competing risks, and on the other hand, permit to assess the impact of breast cancer deaths on all-cause mortality using the ratio of the probability of death for causes other than breast cancer by the all-cause probability of death. Results: There was an increasing impact of breast cancer on mortality in the first part of the 20th century, with a peak for cohorts born in 1945–54 in the 40–49 age groups (for which approximately 24% of mortality was due to breast cancer). Even though for cohorts born after 1955 there was only information for women under 50, it is also important to note that the impact of breast cancer on all-cause mortality decreased for those cohorts. Conclusion: We have quantified the effect of removing breast cancer mortality in different age groups and birth cohorts. Our results are consistent with US findings. We also have obtained an estimate of the risk of dying from competing-causes mortality, which will be used in the assessment of the effect of mammography screening on breast cancer mortality in Catalonia

Evolución de la mortalidad por cáncer de mama y diseminación de la mamografía de cribado en Cataluña: un análisis por regiones sanitarias

Fundamento: El descenso de las tasas de mortalidad por cáncer de mama (CM) se ha atribuido a la implantación de programas de cribado y a avances terapéuticos. El objetivo de este trabajo es comparar la evolución de su mortalidad en las regiones sanitarias de Cataluña en el periodo 1993-2007. Paralelamente, se ha analizado la diseminación de la mamografía periódica en las regiones sanitarias. Métodos: Se analizaron los datos del registro de mortalidad y encuestas de salud. Se utilizaron regresiones de Poisson y «joinpoint» para comparar las tasas de mortalidad por CM y analizar su evolución temporal. Se utilizaron modelos de efectos mixtos para comparar el nivel y la evolución de la mortalidad por regiones. Resultados. La tasa de mortalidad por CM descendió un 3% anual en Cataluña. Entre 1993 y 2007, la tasa estandarizada varió de 34,8 a 23,3 por 100.000 mujeres. Barcelona ciutat presentó unas tasas de mortalidad más elevadas que las regiones Centre (ratio de tasas (RT)=0,87), Costa de Ponent (RT=0,89), Tarragona (RT=0,9) y Lleida (RT=0,915), pero estas diferencias tendieron a desaparecer. No se observaron cambios de tendencia en la evolución de la mortalidad de las regiones, excepto en la región Centre. Durante los años 1990 Barcelona ciutat presentó unos porcentajes de utilización de mamografía periódica del 36,1% de las mujeres de 40-74 años, en la encuesta de 1994, la región Centre (23,7%) y Costa de Ponent (25,2%). Conclusiones: La progresiva utilización de mamografía periódica y la disminución de la mortalidad por CM fueron similares en las regiones sanitarias de Cataluña.Background: The decrease of breast cancer (BC) mortality rates has been attributed to early detection programs and therapeutic advances. The objective is to compare BC mortality trend in health regions of Catalonia during the period 1993-2007. In parallel, dissemination of periodic mammography in the health regions has been analyzed. Methods: Mortality and health surveys data were used. Poisson and «joinpoint» regression analyses were used to compare regional BC mortality rates and quantify their temporal evolution. Mixed effects models were used to compare the rates and their evolution by region. Results: The BC mortality rate decreased 3% annually in Cataluña. Between 1993 and 2007, the standard mortality rate changed from 34.8 to 23.3 per 100,000 women. Barcelona ciutat showed higher mortality rates than the Centre (rate ratio (RR)=0.873), Costa de Ponent (RR=0.885), Tarragona (RR=0.9) and Lleida regions (RR=0.915), but these differences tend to disappear over time. There were no observed trend changes in the evolution of the regional mortality rates, except in the Centre region. The use of periodic mammography was similar across health regions. During the 90s, Barcelona ciutat had a 36.1% utilization of periodic mammography in women aged 40-74, in the 1994 survey, the Centre 23.7 and Costa de Ponent 25.2%. Conclusions: The progressive increase in the use of periodic mammography and the decrease of BC mortality were similar in the eight health regions of Catalonia