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The Microbial Pathogenesis Unit of Navarrabiomed-Public University of Navarra (UPNA) has found a new genetic organisation in bacteria that helps better understand bacterial biology. The study of this genetic architecture was published in Proceedings of the National Academy of Sciences of the United States of America (PNAS).

Research background

In 1961, François Jacob and Jacques Monod discovered that bacteria group the genes that encode the proteins for a certain metabolic pathway in a single transcription unit (which they called ‘operon’). They won the Nobel Prize in Physiology or Medicine in 1965 for their discovery.

The bacteria they chose for their study was Escherichia coli, which normally lives in the intestines of healthy people; specifically, they studied the set of genes E. coli bacteria need to transport lactose (milk sugar) and break it down. E. coli only produces the three proteins it needs to digest lactose when the sugar is available. To simplify transcription regulation, the three genes involved are adjacent in the genome and under a single regulation system. Similar transcriptional regulation systems are found in other metabolic pathways in all bacteria.

Research at Navarrabiomed

In 2018, the team of researchers at Navarrabiomed coordinated by Iñigo Lasa Uzcudun, Head of the Microbial Pathogenesis Unit and Director of the biomedical research centre, described a new way genes are organised in bacteria. This regulation system has a higher level of regulation in operon structure, which the authors of the study named ‘non-contiguous operon’.

The bacterial model analysed has a group of four genes that are transcribed as a transcription unit despite the existence of a separate gene between the second and third genes that is transcribed in the opposite direction.

This transcriptional architecture results in an antisense transcript that acts as a mutual regulation system for the expression of the genes in the operon and the gene that produces this antisense transcript. Therefore, the concept of non-contiguous operon includes not only the genes transcribed from the same transcription unit but also overlapping genes whose expression is coordinated with that of the genes in the operon.

This finding deepens the understanding of bacterial biology and may trigger novel developments in the fields of synthetic biology and bacterial biotechnology.
The study was carried out as part of the scientific activity done at the Navarra Medical Research Institute (IdiSNA).

• Paper published in PNAS.

• El estudio, financiado por el Ministerio de Economía, ha sido publicado por la prestigiosa revista Nature Communication.

Un equipo científico del centro de investigación biomédica Navarrabiomed -centro mixto del Gobierno de Navarra y la Universidad Pública de Navarra (UPNA)- ha conseguido caracterizar el sistema sensorial que las bacterias utilizan entre otras cosas para multiplicarse en el cuerpo humano y causar infección.

El avance, que ha sido publicado por la revista científica Nature Communications y cuenta con financiación del Ministerio de Economía, Industria y Competitividad, permite comprender mejor cómo las bacterias se adaptan a las diferentes condiciones ambientales y posibilitará el desarrollo de antibióticos más específicos y eficaces.
El estudio ha contado con el liderazgo del doctor Iñigo Lasa, director de Navarrabiomed e investigador responsable del Grupo de Patogénesis Microbiana del centro. Asimismo, han colaborado investigadores del Instituto de Agrobiotecnología (UPNA-CSIC-Gobierno de Navarra), del Instituto de Biomedicina de Valencia (CSIC) y del Institute of Infection, Immunity and Inflammation, University of Glasgow.

Bacterias superresistentes

Actualmente, la aparición de bacterias farmacorresistentes, que no responden a tratamientos con antibióticos, constituye uno de los problemas sanitarios a escala mundial priorizados por la Organización Mundial de la Salud (OMS).

Las bacterias detectan, responden y se adaptan a los cambios en su entorno utilizando unos elementos sensoriales denominados sistemas de dos componentes. Este tipo de sistemas sensoriales están presentes en bacterias, hongos y plantas, pero no se encuentran en células animales. En el caso de las bacterias, regulan procesos celulares tan importantes como la virulencia o su propio crecimiento, lo que los convierte en dianas para el diseño de nuevas terapias antimicrobianas.

El objetivo del trabajo ha consistido en eliminar todos los sistemas de dos componentes, es decir el sistema sensorial completo, en Staphylococcus aureus, uno de los principales patógenos humanos según la OMS y, posteriormente, en la generación de una colección de bacterias cada una de las cuales contiene un único sistema de dos-componentes. Esta estrategia ha permitido simplificar una compleja red sensorial en cada uno de sus elementos para comprender cuál es la función individual de cada uno de los sistemas y la relación existente entre ellos. 

Aplicación clínica de la investigación

En relación a la aplicación clínica, Iñigo Lasa apunta al desarrollo de nuevos antibióticos más específicos. “El hecho de que los sistemas de dos componentes estén presentes en todas las bacterias patógenas y no en las células de nuestro organismo nos puede permitir desarrollar fármacos que bloqueen estos sistemas, evitando así el desarrollo de la bacteria durante la infección, sin causar ningún efecto secundario sobre nuestras células”.

En este sentido, las bacterias generadas en este estudio han sido patentadas y actualmente el equipo analiza diversos compuestos marinos que puedan incorporarse en el tratamiento y control de infecciones en la práctica clínica.

La investigación forma parte de la actividad científica del Instituto de Investigación Sanitaria de Navarra (IdiSNA), agrupación público-privada para el fomento de la investigación biomédica en la Comunidad Foral y de la que son miembros Navarrabiomed y la UPNA.

• Información adicional sobre el paper: Behind the paper - Nature Microbiology: "Life without sensing. Can Staphylococcus aureus live without two-component sensorial system?"

Saioa Mendaza Lainez, investigadora predoctoral en la Unidad de Patología Molecular del Cáncer de Navarrabiomed, realizará la lectura de su tesis doctoral por la Universidad Pública de Navarra el martes 30 de junio, a las 11:30, a través de videoconferencia en Navarrabiomed (solamente podrán acudir aquellas personas autorizadas previamente). 

La tesis, titulada Approaching the epigenome of triple-negative breast cancer to identify new biomarkers, ha sido desarrollada en Navarrabiomed bajo la dirección del Dr. David Guerrero Setas y la Dra. Esperanza Martín Sánchez.

El cáncer de mama es la neoplasia más frecuente en mujeres a nivel mundial y la primera causa de muerte por cáncer en este mismo sexo. La investigación aborda el cáncer de mama triple negativo (CMTN), un subtipo que a diferencia del resto carece de tratamiento dirigido, lo que conlleva consecuencias más agresivas en las personas que lo padecen. Esto hace que a día de hoy, la búsqueda de nuevos biomarcadores y dianas terapéuticas para esta enfermedad sea imprescindible.

Dado que las alteraciones epigenéticas están involucradas en la tumorigénesis, el objetivo de esta tesis ha sido caracterizar la metilación del DNA y la acetilación de histonas de este tipo de cáncer. Con ello se ha buscado identificar nuevas firmas potencialmente diagnósticas y pronósticas, así como alteraciones destinatarias de fármacos dirigidos.

Los resultados de esta caracterización han permitido concluir que el patrón epigenético está alterado en CMTN respecto a tejido mamario no neoplásico. Más importante aún, la investigación ha desvelado dos alteraciones epigenéticas específicas como potenciales biomarcadores de peor pronóstico: la acetilación de la histona H4K5 y la hipometilación del gen ADAM12, el cual se presenta también como posible diana terapéutica frente a este cáncer.

Asimismo, se ha identificado una nueva firma basada en metilación de DNA con utilidad diagnóstica. Por último, se han descrito los procesos biológicos de los distintos genes regulados por la acetilación de H4K6 en líneas celulares no neoplásicas y CMTN.

El trabajo realizado ha dado lugar a tres publicaciones científicas y ha sido difundido en dos congresos consecutivos de European Association for Cancer Research; uno celebrado en Manchester en el año 2017 y en Amsterdam en el 2018.

Para el desarrollo de la tesis Saioa Mendaza ha sido beneficiaria de dos becas: Ayudas para la formación de Personal Investigador de la Univesidad Pública de Navarra  para la realización de tesis doctorales y Beca a la excelencia de la Funcación Caja Navarra para la realización de una estancia en University of Massachussets Medical School (EEUU).

• The Carlos III Health Institute finances two projects in Navarre through Spain's COVID-19 Fund and grants the full amount applied for in both cases. 

The Spanish Ministry of Science and Innovation, through the Carlos III Health Institute (ISCIII), has awarded €232,000 to develop two public research projects within the context of the Navarre Health Research Institute (IdiSNA). David Escors Murugarren, a researcher at Navarrabiomed, and Jesús Castilla Catalán, a researcher at the Institute of Public and Occupational Health of Navarre (ISPLN), have received 100% of the amounts they applied for from the COVID-19 Fund, a mechanism approved by Royal Decree-Law 8 of 17 March 2020 on urgent extraordinary measures for dealing with the economic and social impact of COVID-19.

David Escors, the principal investigator at the Navarrabiomed Oncoimmunology Research Unit, began his scientific career working on coronaviruses at the Spanish National Biotechnology Center (CNB-CSIC), along with researcher Luis Enjuanes. He then continued his work at University College London (UCL) by applying lentiviral vectors and gene therapy in immunotherapy. He is a coronavirus specialist and the positive evaluation received from the ISCIII will enable him to obtain the €115,000 he applied for to develop the project “Platforms for developing biosafe SARS-CoV-2 vaccines.”

The aim of the initiative is to develop a platform for engineering biosafe vaccines for the virus that causes COVID-19 disease. The focus will be on the expression of viral proteins that may activate immunity. This line of research was started up specifically for COVID-19, given the current health emergency, but is based on the European ISOLDA Project - Horizon 2020 for generating more effective and safer virus vaccines (yellow fever, influenza and coronavirus) for adults over 65. Navarrabiomed has worked on this project since 2019 in coordination with professionals from the Spanish National Research Council (CSIC) and with Dutch, German and Italian collaborators.

Institute of Public and Occupational Health of Navarre

At the Institute of Public and Occupational Health of Navarre’s Group of Infectious Diseases and Vaccines, Jesús Castilla will lead the study “Infection, Hospitalization, ICU Admissions and Deaths Caused by SARS-CoV-2 in a Population Cohort.” To carry out the study, he will also receive the total amount applied for from the ISCIII: €117,000.

His proposal focuses on estimating the effect of sociodemographic characteristics, chronic diseases and other conditioning health factors on the risk of infection, hospitalization and severe forms of COVID-19. This will involve calculating the incidence of suspected cases, infections confirmed using PCR, hospitalizations, ICU admissions, assisted ventilation and mortality. The mortality rate will also be calculated in confirmed cases and hospitalizations. Antibody seroprevalence will also be evaluated in a sample of patients from the sentinel physician network and/or donors.

This is the second SARS-CoV-2 initiative for Jesús Castilla, given the ISPLN’s participation in the European project I-MOVE-COVID-19, with the involvement of 11 countries and 20 organizations. It is one of the European projects funded through the fast-track call of Horizon 2020, the European Union’s research and innovation program to promote research of different aspects of the SARS-CoV-2 virus.

Both research projects financed by the ISCIII will form part of the scientific activity of the IdiSNA, a public-private partnership for promoting biomedical research in Navarre. Both the ISPLN and Navarrabiomed are partnership members.

El Dr. Hugo Arasanz, oncólogo del Complejo Hospitalario de Navarra e investigador de la Unidad de Inmunomodulación de Navarrabiomed - IdiSNA, recibió ayer en Madrid la Ayuda Clínico Junior de la Asociación Española Contra el Cáncer (AECC). La financiación recibida (120.000 €) se destinará al proyecto "Subpoblaciones linfocitarias como biomarcador predictivo de respuesta a inmunoterapia anti-PD1/PDL1 en carcinoma no-microcítico de pulmón avanzado en 1º línea de tratamiento". Este estudio se desarrollará durante los próximos cuatro años y contará con la dirección del Dr. David Escors. 

El Museo Reina Sofía acogió ayer la entrega de las ayudas anuales de la AECC, dentro de los actos programados en el Día Mundial de la Investigación en Cáncer (WCRD en sus siglas en inglés), que se comemora cada año el 24 de septiembre. En total, la AECC ha entregado casi 21 millones de euros para financiar 171 proyectos que se suman a los 56M€ con los que hoy se están financiando 380 proyectos de investigación en desarrollo.

Asimismo, la asociación ha puesto de manifiesto la necesidad de elaborar un Plan Nacional de Investigación en Cáncer para alcanzar el 70% de supervivencia media a cinco años en el año 2030, en la actualidad se sitúa en un 53%.

Más información sobre el proyecto

La inmunoterapia antiPD1/PDL1 ha supuesto una revolución en el tratamiento del cáncer no-microcítico de pulmón, ya que ha mejorado los resultados de la quimioterapia, asociando además menor toxicidad. Por desgracia la proporción de pacientes que responden al tratamiento es reducida, son menos todavía los que mantienen la enfermedad controlada durante un periodo de tiempo prolongado, y no se dispone de biomarcadores predictivos que permitan identificar a estos pacientes con precisión.

El equipo del Dr. David Escors ha desarrollado un sistema de monitorización de poblaciones linfocitarias por citometría de flujo a partir de sangre periférica en pacientes en progresión a quimioterapia que permite predecir aquellos que van a responder a la inmunoterapia. Dada la reciente aprobación de la inmunoterapia en pacientes en primera línea, este proyecto pretende correlacionar los perfiles linfocitarios de los pacientes y su dinámica con la eficacia del tratamiento en este contexto, incorporando además el estudio de las citosinas proinmunogénicas en plasma y la posible influencia del daño genotóxico en las células inmunitarias producido por las diferentes terapias como causa de menor eficacia en segunda línea.

El proyecto del Dr. Hugo Arasanz se completará con estudios mecanísticos in vitro que permitan conocer los elementos que condicionan la respuesta al tratamiento y plantear combinaciones que puedan revertir la resistencia primaria a estas terapias.

• JAMA Pediatrics, the journal of the American Pediatrics Association, has published the study results.

A group of researchers from Navarrabiomed and the Department of Health Sciences at the Universidad Pública de Navarra (UPNA) specializing in prescribing physical exercise to improve health and quality of life has published an article on the effects of increasing the quality and quantity of physical education (PE) classes on improving the health-related physical fitness and fundamental motor skills of young people (ages 3 to 18). The article was recently published in JAMA Pediatrics (Journal of the American Medical Association).

The study analyzed data from approximately 50,000 young people and concluded that qualitative strategies such as including games and activities involving a high level of cardiovascular and muscular work, as well as better methodological session planning could provide young people with healthy benefits in terms of fitness and fundamental motor skills.

In addition to Antonio García-Hermoso, Robinson Ramírez-Vélez, Alicia María Alonso-Martínez and Mikel Izquierdo Redín (who form part of Navarrabiomed, Idisna and UPNA), the article authors also include Miguel Ángel Pérez-Sousa (Universidad de Huelva) and Rodrigo Ramírez-Campillo (Universidad de Los Lagos, Osorno, Chile).

Exercise is necessary to improve physical fitness

The study researchers also point out that it is not always possible to increase the number of hours spent per week on exercise or PE classes during school hours and therefore recommend improving the efficiency of these sessions by using strategies such as high-intensity interval training (HIIT), and muscle strength, jumping or circuit training. However, the authors mention that, despite the benefits of these strategies during school hours, young people should also participate in more out-of-school physical activities based on their age group (i.e., 60 minutes a day of moderate to intense physical activity).

They argue that PE classes also offer other benefits not specifically related to physical activity, such as helping young people develop socialization, teamwork and body language skills, and fostering healthy habits. Above all, the authors highlight the fact that improving physical fitness among school kids is a fundamental short- and long-term aspect of good health, given the high rates of obesity and physical inactivity among young people, which the authors refer to as “a public health problem that must be addressed by schools.”

Researchers from the Public University of Navarra (UPNA), Navarrabiomed and the Education Department of the Government of Navarra participated in a research project financed by the Navarra Education Department to create the first Physical Education Observatory for 3- to 6-year-old children in Navarra. They were Alicia Alonso, Mikel Izquierdo and Alazne Antón (UPNA), Antonio García-Hermoso and Robinson Ramírez-Vélez (Navarrabiomed), and Berta Villoslada and Berta Echavarri (CIP FP Lumbier-Education Department, Government of Navarra).

The Observatory is meant to promote physical activity in schoolchildren, reducing their screen time and adding relaxation time instead, as it has been shown that developing healthy habits in childhood is crucial to preventing cardiovascular disease in adult life. In order to achieve its goal, the Observatory will conduct a series of assessments in local schools, with children and their families, testing their fitness, measuring their sleep time and analysing all this information with them. The evaluation includes physical tests (jumping with both feet, speed/agility tests, etc.), body composition analysis (waist circumference, percentage of body fat and body mass index) and the use of personal electronic devices to measure the intensity of everyday activity and rest/sleep periods. In addition, the correlation will be established between fitness and school achievements.

The study is set to begin in Colegio Santa María la Real-Maristas Pamplona in October, then moving to Colegio Público San Juan de la Cadena. Finally, there will be a special teacher training module in CIP FP Lumbier, targeted at the students in the higher education training cycles (80), who will become assessors. This will be part of the module titled ‘Fitness testing and response to accidents’.

Throughout the process, school teachers will participate in measurements and evaluations, in an effort to introduce new trends, methods and formulas in children health assessment. According to the authors of the study, ‘the results might help understand why schoolchildren are gaining weight and their performance at school is worsening, with low levels of physical activity.’

Childhood as a critical period to develop healthy habits

‘Early childhood is a critical period for physical, social and cognitive development, to establish healthy behaviour patterns that can be kept into adulthood,’ the researchers say. Studies show that ‘regular participation in physical activities by pre-schoolers is essential for normal development and growth, with immediate and long-term benefits for physical and psychological wellbeing,’ they add. However, they explain, evidence for this age group is still relatively scarce as compared to the data available for children and adolescents aged 6 to 17.

Recently, the World Health Organisation (WHO) published new guidelines on physical activity, sedentary behaviour and sleep for children under 5 years of age. According to these recommendations, children 3-5 years of age should spend at least 180 minutes in a variety of types of physical activities, of which at least 60 minutes is moderate- to vigorous-intensity activity. ‘Despite the benefits for health of regular physical activity, many pre-schoolers fail to meet these standards,’ the authors of the study state. The Observatory is aimed at improving results in this area.