The European Food Safety Authority (EFSA) has just announced that consumption of more than 400 milligrams of caffeine per day (i.e. 4 espressos) may be harmful for health. Caffeine consumed in high doses may be involved in cardiovascular disorders and problems of the nervous system (sleep, anxiety, etc.).
Below this threshold of 400 mg per day, there is no risk to adults from coffee.
EFSA recalls that coffee is not the only source of caffeine, and that other liquids, such as cola-type carbonated drinks and energy drinks are other sources that need to be taken into account.
This reminder is especially important since in the thirteen countries studied, one-seventh of the adult population consumes more than the recommended dose.
Furthermore, for pregnant women and children, the recommended limit is reduced to 200 mg per day and 3 mg/kg, respectively.
In 2014, Christophe Bernard, Inserm Research Director, and his team first described the harmful effects of coffee consumption during pregnancy on the brains of mouse progeny. [1]
Throughout the year, this team from Inserm Unit 1106, “Institute of Systems Neuroscience,” works to investigate the role of caffeine in the development of metabolic and brain diseases.
Another step forward has just been taken in the area of synthetic biology. Research teams from Inserm and CNRS (French National Centre for Scientific Research) Montpellier, in association with Montpellier Regional University Hospital and Stanford University, have transformed bacteria into “secret agents” that can give warning of a disease based solely on the presence of characteristic molecules in the urine or blood. To perform this feat, the researchers inserted the equivalent of a computer programme into the DNA of the bacterial cells. The bacteria thus programmed detect the abnormal presence of glucose in the urine of diabetic patients. This work, published in the journal ScienceTranslational Medicine, is the first step in the use of programmable cells for medical diagnosis.
Bacteria have a bad reputation, and are often considered to be our enemies, causing many diseases such as tuberculosis or cholera. However, they can also be allies, as witnessed by the growing numbers of research studies on our bacterial flora, or microbiota, which plays a key role in the working of the body. Since the advent of biotechnology, researchers have modified bacteria to produce therapeutic drugs or antibiotics. In this novel study, they have actually become a diagnostic tool.
Medical diagnosis is a major challenge for the early detection and subsequent monitoring of diseases. “In vitro” diagnosis is based on the presence in physiological fluids (blood and urine, for example) of molecules characteristic for a particular disease. Because of its noninvasiveness and ease of use, in vitro diagnosis is of great interest. However, in vitro tests are sometimes complex, and require sophisticated technologies that are often available only in hospitals.
This is where biological systems come into play. Living cells are real nano-machines that can detect and process many signals and respond to them. They are therefore obvious candidates for the development of powerful new diagnostic tests. However, they have to be provided with the appropriate “programme” for them to successfully accomplish the required tasks.
To do this, Jérôme Bonnet’s team in Montpellier’s Centre for Structural Biochemistry (CBS) had the idea of using concepts from synthetic biology[1] derived from electronics to construct genetic systems making it possible to “programme” living cells like a computer.
The transcriptor: the cornerstone of genetic programming
The transistor is the central component of modern electronic systems. It acts both as a switch and as a signal amplifier. In informatics, by combining several transistors, it is possible to construct “logic gates,” i.e. systems that respond to different signal combinations according to a predetermined logic. For example, a dual input “AND” logic gate will produce a signal only if two input signals are present. All calculations completed by the electronic instruments we use every day, such as smartphones, rely on the use of transistors and logic gates.
During his postdoctoral fellowship at Stanford University in the United States, Jérôme Bonnet invented a genetic transistor, the transcriptor.
The insertion of one or more transcriptors into bacteria transforms them into microscopic calculators. The electrical signals used in electronics are replaced by molecular signals that control gene expression. It is thus now possible to implant simple genetic “programmes” into living cells in response to different combinations of molecules[2].
In this new work, the teams led by Jérôme Bonnet (CBS, Inserm U1054, CNRS UMR5048, Montpellier University), Franck Molina (SysDiag, CNRS FRE 3690), in association with Professor Eric Renard (Montpellier Regional University Hospital) and Drew Endy (Stanford University), applied this new technology to the detection of disease signals in clinical samples.
Clinical samples are complex environments, in which it is difficult to detect signals. The authors used the transcriptor’s amplification abilities to detect disease markers, even if present in very small amounts. They also succeeded in storing the results of the test in the bacterial DNA for several months.
The cells thus acquire the ability to perform different functions based on the presence of several markers, opening the way to more accurate diagnostic tests that rely on detection of molecular “signatures” using different markers.
“We have standardised our method, and confirmed the robustness of our synthetic bacterial systems in clinical samples. We have also developed a rapid technique for connecting the transcriptor to new detection systems. All this should make it easier to reuse our system,” says Alexis Courbet, a postgraduate student and first author of the article.
As a proof of concept, the authors connected the genetic transistor to a bacterial system that responds to glucose, and detected the abnormal presence of glucose in the urine of diabetic patients.
“We have deposited the genetic components used in this work in the public domain to allow their unrestricted reuse by other public or private researchers,[3]” says Jérôme Bonnet.
“Our work is presently focused on the engineering of artificial genetic systems that can be modified on demand to detect different molecular disease markers,” he adds. In future, this work might also be applied to engineering the microbial flora in order to treat various diseases, especially intestinal diseases.
This work received financial support from Inserm, CNRS, the Stanford-France Center for Interdisciplinary Studies, and Stanford University. Jérôme Bonnet is a recipient of the Atip-Avenir programme award, and is supported by the Bettencourt-Schueller Foundation.
[1] aimed at the rational engineering of artificial biological systems and functions
European Obesity Day, which will be held on Saturday 23 May, recalls the seriousness of this disease, which is affecting more and more people in France and in the world.
On a world scale, the number of obesity cases has doubled since 1980. In 2014, over 1.9 billion adults were overweight. Of this total, over 600 million were obese.
Overweight and obesity are defined as an abnormal or excessive fat accumulation. Body mass index, BMI, corresponding to the weight divided by the square of the height, expressed in kg/m2, is a quantity that makes it possible to estimate a person’s corpulence. Thus a BMI of 30 or greater is generally associated with an obese status. A person with a BMI of 25 or more is considered overweight.
According to the World Health Organisation, by 2030 most European countries are at risk of experiencing an increase, spectacular in some cases, in these diseases.[1]
As well as having an impact on peoples’ quality of life of from a social, occupational and familial point of view, obesity is a factor in cardiovascular disease, diabetes, hypertension and cancer. This serious disease, recognised as a public health priority, is the subject of much study, particularly by Inserm Units 1166, “Research Unit on Cardiovascular, Metabolic and Nutritional Diseases” (ICAN) and 1153, “Nutritional Epidemiology Research Team” (EREN).
Throughout the school year, 38 junior and senior secondary school students have been hosted each month in 9 neuroscience laboratories specialising in addiction studies. The aim: to change the views of the young “Novice Researchers” on the hidden face of drugs (alcohol, tobacco, cannabis, etc.) and addiction, and to educate them about research methods and research careers. From 1 June next, the Novice Researchers will present their research at 5 conferences organised in Marseille (1 June), Amiens (2 June), Paris (3 June), Bordeaux (4 June) and Poitiers (9 June).
The MAAD (Mechanisms of Addiction to Alcohol and Drugs) programme, launched by Inserm with the support of MILDECA (French Government Interministerial Mission for Combating Drugs and Addictive Behaviours), is based on a “scientific education” style approach, intended to increase the knowledge of young people on these substances by introducing them to the scientific method.
Nine research laboratories[1] specialising in addiction physiopathology hosted, on one Wednesday each month, two “binomes,” pairs comprising one final year junior secondary school student and one second year senior secondary school student. Mentored by a senior researcher, the adolescents conducted a research project, performed experiments and interpreted data. The conferences organised in the different research centres involved will enable these young Novice Researchers to share their results. The audience will be made up of their classmates, parents, teachers, etc.
Programme:
♦ In Paris, the conference will be held on Wednesday, 3 June 2015 at 6:00 pm, at the Ministry of Agriculture, Gambetta Room (78 rue de Varennes, Paris 5th Arrondissement) Registration required, via acmaad.tumblr.com or by contacting moc.liamg@ossa.rspa
Danièle Jourdain-Menninger, President of MILDECA, will open the event
The Novice Researchers’ presentations will be followed by a talk and discussion entitled “Nicotine et Prise de Décision” (Nicotine and Decision-Making), led by Philippe Faure, a CNRS researcher at UMR 7102.
♦ Marseille, Monday 1 June, 6:30 pm
♦ Amiens, Tuesday 2 June, 6:00 pm
♦ Bordeaux, Thursday 4 June, 6:30 pm
♦ Poitiers, Tuesday, 9 June, 6:00 pm
These conferences are open to all and admission is free.
The use of psychoactive substances (alcohol, tobacco, cannabis etc.) by young people is a constant preoccupation for the health authorities, since it is well known that early use, while the brain is still developing, is a risk factor for developing dependence during adulthood. This scheme for raising awareness about the toxicity of drugs is an attempt at innovation against a background of more traditional preventive actions (radio spots, video clips, television, newspapers and mini-conferences in schools).
[1] The 9 participating laboratories are as follows:Amiens: Inserm ERI 24, Prof. Mickaël Naassila; Bordeaux: Inserm U862 Neurosciences Magendie, Véronique Deroche; CNRS UMR 5287, Martine Cador / Stéphanie Caillé-Garnier; Marseille: Mediterranean Institute of Neurobiology (INMED), Olivier Manzoni; UMR 7289 CNRS Cognitive Neurobiology Laboratory, Christelle Baunez; Paris: Inserm UMR 894, Laurence Lanfumey, Nicolas Ramoz; Inserm UMR-S 839 Institut du Fer à Moulin, Denis Hervé, Marika Nosten-Bertrand, Manuel Mameli; CNRS UMR 7102, Philippe Faure; Poitiers: Inserm U1084 Experimental and Clinical Neurosciences Laboratory, Marcello Solinas.
Following regional heats and a Masterclass at CERN, the European Organisation for Nuclear Research, the ten finalists in the FameLab competition will display their oratory skills at Cité des Sciences et de l’Industrie on Friday 22 May, at 6:30 pm.
Each candidate will have three minutes on stage to explain a scientific concept. Using the aids of their choice, they must convince the jury of their ability to communicate their research work while remaining accessible to non-specialists.
Florence Porcel, presenter, actress and author, will compere the event, with the support of professionals working in science, communication and the media:
Claudie Haigneré, Advisor to the Director General of the European Space Agency (ESA), and former Chairperson of Universcience,
Cécile Lestienne, Managing Editor of Pour la Science magazine,
Roland Lehoucq, Astrophysicist, French Alternative Energies and Atomic Energy Commission (CEA).
The public may vote for its favourite candidate. The winner, chosen by the jury, will have the opportunity to participate in the International Grand Final, held on 4 June in Cheltenham, United Kingdom.
The FameLab France finalists
They are PhD students, research assistants, assistant engineers and students, and come from all over France to share their passion for science.
Their subjects of study relate to a variety of areas in scientific research: physics, chemistry, biology and even history. At the final, the candidates will speak to you about saving animal species, the hydrophobia of water lilies, psychiatric disorders, and even mediaeval money.
They participate in FameLab to:
Take on the challenge of the 3 Cs: content, clarity, charisma
Make their research work known.
Quentin Vincent, epidemiologist and member of the Laboratory of Human Genetics of Infectious Diseases at the Imagine Institute, Paris, will represent Inserm during this final.
According to this young physician specialising in public health, sharing advances in science with non-specialists is both essential and entertaining.
To find out more
This year, under the impetus of the British Council, the second French edition of FameLab brings together many partners from institutions, academia and associations: Amcsti (French association of museums and centres for the development of scientific, technical and industrial culture), Inserm (French National Institute of Health and Medical Research), CNES (French National Centre for Space Studies), CEA, CERN and Ifremer (French Research Institute for Exploitation of the Sea).
Created in 2005 by the Cheltenham Festival in partnership with the British innovation agency NESTA, FameLab supports young scientists and engineers in the scientific communication process.
A growing tumour exerts considerable ongoing abnormal pressure on the healthy neighbouring cells. The CNRS/UPMC/Institut Curie team directed by Emmanuel Farge, Inserm Research Director at Institut Curie, has just discovered that this force can induce tumour gene expression. The physical stress induced by tumour growth might even trigger the initial phases of malignant transformation in the adjacent tissues. This major discovery is published in the 11 May 2015 issue of Nature.
While a tumour is actively growing, it gradually induces an abnormal and permanent pressure on the healthy neighbouring cells. Could this stress transform compressed healthy cells into tumour cells and affect the development of the tumour? This is the novel approach adopted by the Mechanics and Genetics of Embryonic and Tumoral Development[1] team led Emmanuel Farge, Inserm Research Director.
First, using experimental models, the researchers measured the pressure exerted by the growth of a colon tumour on the adjacent tissues. In doing so, they demonstrated that this mechanical stress activates the beta-catenin signalling pathway in the healthy tissues adjacent to the tumour, leading to the activation of tumour genes. “Beta-catenin is well known to activate tumorigenesis in many cancers,” notes Emmanuel Farge.
The mechanics of cancer: propagation strategies
Using magnets and healthy tissues loaded with magnetic liposomes, the team then mimicked the mechanical forces induced by a tumour in the surrounding tissues, and observed the consequences. “After two weeks of such mechanical stress, we observe an increase in phosphorylation (i.e. activation) of beta-catenin, together with its translocation to the cell nucleus,” observe the scientists. Under the effect of the stress, the beta-catenin protein detaches from the cell membrane to enter the nucleus, where it then activates oncogenes that promote tumour growth.
After a month, overexpression of the c-Myc oncogene, a target for beta-catenin, is then detected, which causes uncontrolled division of healthy cells, as well as overexpression of the target gene Zeb-1, which is responsible for the loss of cell adhesion that leads to invasiveness and metastasis.
After 2-3 months, aberrant crypt foci form in the colon (enlargement of the crypts and alteration of their structure), which corresponds to the initial steps in malignant transformation. “Activation by mechanical stress of the beta-catenin signalling pathway in the healthy tissues surrounding the tumour indicates a new way for a tumour to spread,” says Emmanuel Farge. “It creates an amplificatory autoregulation loop, a chain reaction, a real ‘domino effect:’ malignant changes mechanically induced by the tumour in the genetically healthy neighbouring cells cause abnormal growth of these cells, which itself applies abnormal stress to the as yet non-malignant neighbouring cells, and so on, in a process likely to considerably amplify tumour growth and spread.”
In addition, it might contribute to tumour heterogeneity: the tumorigenic processes triggered in the adjacent cells might generate tumour cells with characteristics that are distinct from those at the core of the tumour and different in their type of response to treatment. This method of proliferation might thus constitute a factor in resistance to therapeutic treatments.
Everything is therefore not purely biochemical in the development of colon cancer. Abnormal mechanical stresses, activating tumour biomolecules, thus appear to be a potential new engine for tumour progression and invasion.
This discovery reveals that mechanical stresses caused by growth of the tumour are likely to modify the healthy cells adjacent to it, activating the malignant transformations that boost its development.
These data should therefore be incorporated into therapeutic approaches, since the complete elimination of tumours should include action on all mechanisms used by the tumour in order to grow.
[1] “PhysicalChemistry Curie” Unit, CNRS/UPMC/Institut Curie Joint Research Unit 168
By increasing the stiffness of erythrocytes infected by the causal agent of malaria, Viagra favors their elimination from the blood circulation and may therefore reduce transmission of the parasite from humans to mosquitoes. This astonishing discovery, made by scientists from the CNRS, INSERM, Université Paris Descartes – at the Institut Cochin – and the Institut Pasteur, working in collaboration with a team from the London School of Hygiene and Tropical Medicine, could lead to a treatment to reduce the spread of malaria within a population. Their work is published in PLOS Pathogens on 7 May 2015.
Plasmodium falciparum, the parasite that causes malaria, has a complex developmental cycle that is partially completed in humans and partially in the anopheline mosquito. Treatments for malaria target the asexual forms of this parasite that cause symptoms, but not the sexual forms transmitted from a human to a mosquito when it bites. Eradication of this disease thus necessitates the development of new types of treatments against sexual forms of the parasite in order to block transmission and thus prevent dissemination of the disease within the population.
The sexual forms of the parasite develop in human erythrocytes sequestered in the bone marrow before they are released into the blood. They are then accessible to mosquitoes, which can ingest them when they bite (see the top of the image on page 2). But circulating erythrocytes — whether they are gametocyte-infected or not — are deformable, thus preventing their clearance via the spleen, which constantly filters the blood and only retains stiff, old or abnormal erythrocytes. However, gametocyte-infected erythrocytes can easily pass through the spleen and persist for several days in the blood circulation.
During a new study, the scientists thus sought to stiffen the infected erythrocytes. They showed that the deformability of gametocyte-infected erythrocytes is regulated by a signaling pathway that involves cAMP. When the cAMP molecules accumulate, the erythrocyte becomes stiffer. cAMP is degraded by the enzyme phosphodiesterase, whose action thus promotes erythrocyte deformability.
Using an in vitro model reproducing filtration by the spleen, the scientists were able to identify several pharmacological agents that inhibit phosophodiesterases and can therefore increase the stiffness of infected erythrocytes. One of these agents is sildenafil citrate, better known under its brand name of Viagra. The authors showed that this agent, used at a standard dose, had the potential to increase the stiffness of sexual forms of the parasite and thus favor the elimination of infected erythrocytes by the spleen.
This discovery could help find new ways to stop the spread of malaria in a population.
Modifying the active substance in Viagra to block its erectile effect, or testing similar agents devoid of this adverse effect, could indeed result in a treatment to prevent transmission of the parasite from humans to mosquitoes.
This study involved the teams led by Catherine Lavazec and Gordon Langsley at the Institut Cochin and Institut Pasteur and David Baker’s team at the London School of Hygiene and Tropical Medicine. It received support from the CNRS ATIP-Avenir program, INSERM, the Labex Gr-EX and Parafrap, the Fondation Inkermann and the Bill and Melinda Gates Foundation, in the context of a project in collaboration with Pierre Buffet’s team at Université Pierre et Marie Curie.
Metabolic complications of obesity and overweight, such as type 2 diabetes, are an important challenge to public health. Teams led by Nicolas Venteclef, Dominique Langin, Karine Clément and Irina Udalova (Kennedy Institute of Rheumatology, University of Oxford, UK) in collaboration with several teams[1], have succeeded in elucidating part of the mechanisms involved in the development of these metabolic complications associated with obesity. Results of these studies are published online in the journal Nature Medicine.
Currently, over one and a half billion people worldwide suffer from overweight or obesity. We have known for about a decade that a chronic state of inflammation is present in obese patients. This state might play a fundamental role in the development of associated metabolic diseases. This inflammation results from abnormal activity of the immune system observed both systemically (bloodstream) and locally (in metabolic organs such as the liver, muscles, pancreas and especially the adipose tissue).
Following excessive weight gain, the adipose tissue develops in an abnormal manner in the intra-abdominal region (android obesity), and becomes an important source of pro-inflammatory mediators, the “chemical messengers” that activate inflammation, with harmful metabolic consequences. This phenomenon is particularly provoked by the accumulation of pro-inflammatory macrophages in this tissue. Paradoxically, some obese subjects do not develop metabolic alterations. Indeed, when adipose tissue expansion occurs in the more superficial deposits, such as the subcutaneous adipose tissue (gynoid obesity), the risk of developing metabolic complications is reduced.
In an earlier study (Dalmas et al. Diabetes 2014), the team led by Karine Clément (Guerre-Millo and coll., UMR_S 1166, Paris, France), in collaboration with Nicolas Venteclef, had observed the importance of inflammatory and prodiabetogenic cross-talk between macrophages and lymphocytes in the visceral adipose tissue of obese patients.
By characterising these macrophages, they were able to identify transcription factor IRF5 (Interferon Regulatory Factor 5) as the orchestral conductor of macrophage activation in adipose tissue in obesity.
In order to demonstrate the importance of IRF5 in obesity and type 2 diabetes, the authors generated mice lacking this factor, and then subjected them to a high-fat diet that usually induces obesity and type 2 diabetes. Surprisingly, mice deficient in IRF5 did develop obesity, but without metabolic complications, in contrast to wild-type mice expressing IRF5. This beneficial adaptation by IRF5-deficient mice can be explained by preferential storage of fat in the subcutaneous (protective) and not the intra-abdominal (harmful) region. Decoding of molecular and cellular mechanisms made it possible to show a substantial reprogramming of inflammation in the visceral adipose tissue when IRF5 is absent, which helps to limit its expansion. Indeed, in the absence of IRF5, obesity induces an immune response characterised by the presence of anti-inflammatory macrophages and reduced immune response activation. This modification induces tissue remodelling that limits the expansion of intra-abdominal adipose tissue. This allows the redistribution of lipids in the intra-abdominal cavity to the subcutaneous deposits, a less harmful form of storage for the body.
Data obtained with mice were confirmed in overweight, obese or massively obese patients, by showing significant correlation between IRF5 expression in the visceral adipose tissue and metabolic dysfunctions associated with obesity.
This pioneering study suggests that the immune system (in this case the macrophages of the adipose tissue) directly influences the accumulation of fatty matter in the visceral region, a likely target in the prevention of type 2 diabetes. For the researchers, “It is therefore crucial to decipher the different aspects of inflammation in order to better understand the multifactorial diseases associated with obesity, such as type 2 diabetes.”
The approach implemented in this study encapsulates translational research, which is aimed at developing effective therapies for patients by establishing a fruitful dialogue between clinicians and researchers, in order to produce robust results that are supported by mouse models while being relevant to humans.
This work received financial support from the French National Research Agency (ANR), Inserm, Pierre and Marie Curie University (UPMC), the French Medical Research Foundation (FRM), ICAN and the Ile de France Region (CORDDIM).
[1] This study was carried out in collaboration with researchers from the French National Centre for Scientific Research (CNRS), the Institute of Cardiometabolism and Nutrition (ICAN), Paul Sabatier University, Toulouse, and Charles University, Prague (Czech Republic).
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