October 12th 2014: World Arthritis Day

World Arthritis Day, which is held on 12 October every year, is aimed at raising awareness among the general public, health professions and public authorities, about the size of the burden generated by this disease.

A leading cause of disability in the over 40s, rheumatic diseases are, for the most part, chronic inflammatory disorders. Collectively known under the generic term “arthritis,” the latter affect the joints, but can also affect the spine, pelvis, skin, small blood vessels or vital organs.

To mark this day, Inserm and Aviesan have organised for Monday 13 October at the Pavillon de l’Eau (Water Pavilion) in Paris, in partnership with the French Society for Rheumatology and the Courtin Arthritis Foundation, the 1st meeting of the Foundations and Associations for Research on Rheumatic and Musculoskeletal Diseases, “Healthy Ageing and Rheumatic/Musculoskeletal Diseases.”

See all the information concerning this colloquium on the dedicated website.

Our last communication on this topic:
Serotonin and bones – February 2012

October 11th 2014: National “Dys” Day

National “Dys” Day, held on 11 October, has for the last 8 years been enlisting the non-profit organisations to raise awareness about problems related to an individual cognitive dysfunction (language, attention, movement, numeracy, etc.), without an overall intellectual deficiency. The latter affect 4-8% of the French population. They comprise dyslexia (specific for reading), dysorthographia (for written expression) and dyscalculia (for numeracy).
This event is aimed at raising awareness among the public, in order to improve detection and diagnosis of these learning disabilities.

Inserm team 1028, “Neurosciences, Cognitive Sciences, Neurology and Psychiatry,” led by Olivier Bertrand, is aimed at developing new methods for the evaluation and cognitive management of these “dys” disabilities. Their work, which is focused on the period prior to the development of these disorders, explores a set of processes in the human brain, at different levels of cognition, from the mechanisms of sensory integration to the higher cognitive functions.

Bubble Babies: a new gene therapy

9 children with X-linked severe combined immunodeficiency have received a new form of gene therapy. Alain Fischer, Marina Cavazzana-Calvo and Salima Hacein-Bey-Abina, together with their teams at Inserm Unit 1163 and AP-HP, have just published these results in the New England Journal of Medicine.

In 1999, these researchers pioneered the treatment by gene therapy of children with a disease that left them without any immune defences. However, some of these children developed leukaemia after therapy. Following the development of safer therapeutic vectors, it was possible to start a new clinical trial in 2010.

4 years later, the results obtained and described in this scientific article are encouraging. 7 children treated using this method are now in good health.

For more information, see the press release “Les “bébés-bulle” ont 11 ans: L’efficacité de la thérapie génique est démontrée (“Bubble babies” are 11 years old: the efficacy of gene therapy is demonstrated),” published in July 2010

Colon cancer: Two genetic alterations that generate metastases

With approximately 42,000 estimated new cases in France in 2012, colon cancer is, for both sexes combined, the third most common type of cancer, and the second most common cause of cancer deaths after lung cancer. One of the challenges is to succeed in treating the cancer when metastases are present. Researchers at Institut Curie, Inserm and CNRS describe—theoretically and experimentally—in the journal Nature Communications, the combination of two genetic alterations responsible for tumour dissemination. As well as contributing knowledge on tumour progression, the cancer colon model thus developed offers the possibility of testing new therapies for eliminating metastases.

At the time colon cancer is diagnosed, 25% of patients already show metastases, and 25-35% of patients will develop metastases as their disease progresses. If the starting point of any tumour process is the alteration of the DNA in one cell, metastases occur as a result of a series of genetic accidents. Not all alterations are associated with the same risk. So what are the essential steps in the occurrence of metastases? This question is crucial for researchers and caregivers in oncology, since, as long as the cancer remains localised, a combination of surgery and radiotherapy can eliminate it. Conversely, once it has begun to spread, its treatment becomes more difficult. The development of effective therapies, targeting the flaws in the cell, calls for an understanding of tumour biology.

In order to better understand this long and extremely complex process, and to discover new therapeutic possibilities, it is crucial to elucidate all stages of tumour progression, from the initial mutation until the development of metastases.


From tumour to metastases, a multitude of events
© Eléonore Lamoglia/Institut Curie

A blend of theory and experiment
With the help of a mathematical model compiling the data from over 200 scientific publications, we first identified two vital components in the epithelial-mesenchymal transition of intestinal cells,” explains Inna Kuperstein, a researcher from Emmanuel Barillot’s team. This transition converts the epithelial cells into a form known as mesenchymal[1]. These less specialised and more plastic cells lose their capacity to adhere to one another, and acquire properties that enable them to migrate and “blend” into their immediate environment. The epithelial-mesenchymal transition may represent the first step for tumour cells towards dissemination.

For this to happen, our model shows that two events must occur in the intestinal cells: the Notch receptor must be activated, and the p53 gene must be lost,” comments Andrei Zinovyev, coordinator of the mathematical study at Institute Curie.

The researchers subsequently developed an animal model carrying these two alterations in the intestinal tissue. “This model makes it possible to study tumour cells throughout their development and thus better understand the modifications required for metastases to form,” explains Sylvie Robine, an Inserm Research Director at Institut Curie.

First observation: these mice developed numerous metastases, in several organs. The combination of alterations in Notch and p53 provides the starting ground needed for the development of metastatic colon cancer.

When colon cancer cells begin to disseminate, they progressively lose the features of epithelial cells, the tissue from which they originate, to acquire the specific features of mesenchymal cells,” she continues.

In addition, the hallmarks of mesenchymal tissue are uniquely present in the cells of the invasive front of the tumour, cells that are moving towards the “exit” from the intestinal tissue (the stroma). The cells that escape from the original tissue are therefore cells that have begun the epithelio-mesenchymal transition. “This result has been corroborated by analysing samples from invasive colon cancers and metastases taken from patients,” states Prof. Daniel Louvard[2], CNRS Research Director at Institut Curie. “The cells present in these specimens have the characteristic features of mesenchyme, not of epithelia.

Thanks to research carried out jointly by bioinformaticians from Emmanuel Barillot’s team and biologists from Prof. Daniel Louvard’s team, the stages in tumour progression and the various pathways leading to colon cancer are gradually yielding up their secrets.

The combination of alterations in p53 and Notch creates the most conducive conditions for the development of metastases in colon cancers” explains Prof. Daniel Louvard.

The mice developed constitute an excellent preclinical model, and as such they may provide the basis of a search for new therapeutic targets. By knowing the specific alterations of the tumour from an individual, better targeted and more effective personalised treatments can be created.

[1] Mesenchyme is an embryonic connective tissue that gives rise to various types of connective tissue in the adult.

[2] Prof. Daniel Louvard is the Honorary Director of the Institut Curie Research Centre, and is currently advisor to the President on international relations of Institut Curie. Maia Chanrion, a member of Daniel Louvard’s team, contributed to the experimental work, Inna Kuperstein and David Cohen, members of Emmanuel Barrillot’s team, participated in the bioinformatics study.

Nobel Prize in Chemistry 2014

The 2014 Nobel Prize in Chemistry was awarded to two Americans, Eric Betzig and William Moerner, and a German, Stefan Hell, on Wednesday 8 October “for the development of super-resolved fluorescence microscopy,” nanoscopy, as the jury said in its press release.

The laureates developed two methods enabling microscopy on a nanometric scale, and hence the study of living cells in the finest detail.

Stefan Hell, 51 years old, discovered “stimulated emission depletion (STED)” microscopy. Eric Betzig, 54 years old, and William Moerner, 61 years old, each working separately, created the method known as “single-molecule microscopy.”

Work useful in understanding, in particular, diseases such as Parkinson’s, Alzheimer’s and Huntington’s diseases.

Further information in the Nobel Prize official press release
See also the diagrams explaining STED microscopy, and single-molecule microscopy

Anorexia / bulimia: a bacterial protein implicated

Eating disorders (ED) such as anorexia nervosa, bulimia, and binge eating disorder affect approximately 5-10% of the general population, but the biological mechanisms involved are unknown. Researchers at Inserm Unit 1073, “Nutrition, inflammation and dysfunction of the gut-brain axis” (Inserm/University of Rouen) have demonstrated the involvement of a protein produced by some intestinal bacteria that may be the source of these disorders. Antibodies produced by the body against this protein also react with the main satiety hormone, which is similar in structure. According to the researchers, it may ultimately be possible to correct this mechanism that causes variations in food intake.

These results are published in the journal Translational Psychiatry, in the online issue of 7 October 2014. See the video of the discovery (English subtitles) :

Anorexia nervosa, bulimia and binge eating disorder are all eating disorders (ED). If the less well defined and atypical forms are included, ED affect 15-20% of the population, particularly adolescents and young adults. Despite various psychiatric, genetic and neurobiological studies, the molecular mechanism responsible for these disorders remains mysterious. The common characteristic of the different forms of ED is dysregulation of food intake, which is decreased or increased, depending on the situation.

Sergueï Fetissov’s team in Inserm Joint Research Unit 1073, “Nutrition, inflammation and dysfunction of the gut-brain axis” (Inserm/University of Rouen), led by Pierre Déchelotte, studies the relationships between the gut and the brain that might explain this dysregulation.

The mimic of the satiety hormone

In this new study, the researchers have identified a protein that happens to be a mimic of the satiety hormone (melanotropin). This protein (ClpB) is produced by certain bacteria, such as Escherichia coli, which are naturally present in the intestinal flora. Where this protein is present, antibodies are produced against it by the body. These will also bind to the satiety hormone because of its structural homology to ClpB, and thereby modify the satietogenic effect of the hormone. The sensation of satiety is reached (anorexia) or not reached (bulimia or overeating). Moreover, the bacterial protein itself seems to have anorexigenic properties.

Variations in food intake in the presence of the bacterial protein

To obtain these results, the researchers modified the composition of the intestinal flora of mice to study their immunological and behavioural response. Food intake and level of antibodies against melanotropin in the 1st group of mice, which were given mutant E. coli bacteria (not producing ClpB) did not change. In contrast, antibody level and food intake did vary in the 2nd group of animals, which received E. coli producing ClpB protein.

The likely involvement of this bacterial protein in disordered eating behaviour in humans was established by analysing data from 60 patients.

The standardised scale “Eating Disorders Inventory-2” was used to diagnose these patients and evaluate of the severity of their disorders, based on a questionnaire regarding their behaviour and emotions (wish to lose weight, bulimia, maturity fears, etc.). Plasma levels of antibodies to ClpB and melanotropin were higher in these patients. Furthermore, their immunological response determined the development of eating disorders in the direction of anorexia or bulimia.

These data thus confirm the involvement of the bacterial protein in the regulation of appetite, and open up new perspectives for the diagnosis and specific treatment of eating disorders.

Correcting the action of the protein mimicking the satiety hormone

“We are presently working to develop a blood test based on detection of the bacterial protein ClpB. If we are successful in this, we will be able to establish specific and individualised treatments for eating disorders,” say Pierre Déchelotte and Sergueï Fetissov, authors of this study.

At the same time, the researchers are using mice to study how to correct the action of the bacterial protein in order to prevent the dysregulation of food intake that it generates. “According to our initial observations, it would indeed be possible to neutralise this bacterial protein using specific antibodies, without affecting the satiety hormone,” they conclude.

This study was carried out in collaboration with other teams and platforms of the Institute for Research and Innovation in Biomedicine (IRIB) Normandy Rouen, and with the University of Tartu (Estonia). It extends other work published by the research team in 2013, which demonstrated molecular mechanisms for increasing the appetite by immunoglobulins that protect the hunger hormone (ghrelin) in obese people.

These works were the object of two demands of patents deposited by Inserm Transfert.

October 9th 2014 : World Sight Day

World Sight Day, which is held on 9 October each year, is aimed at raising public awareness of problems related to blindness and visual impairment.

Worldwide, nearly 285 million people are visually impaired, including 39 million who are blind and 246 million who have low vision. According to the World Health Organization, 80% of all these disabilities can be prevented or cured.1

To mark this day, many events have been organised by public and private institutions: screening for sight problems, spectacle collections, and information on diseases that can affect sight.

1 Source: Visual impairment and blindness, World Health Organization (WHO)

Each year, researchers at Inserm are enlisted to develop new treatments to combat these disabilities.

Cystic fibrosis: how a bacterium manipulates its host to eradicate an opponent

The main cause of death in patients suffering from cystic fibrosis is respiratory infection caused by different bacterial populations, which vary according to the age of the patient. Scientists at the Institut Pasteur and Inserm have identified a novel mechanism used by the Pseudomonas aeruginosa bacterium to hijack the immune system of its host in order to eradicate another bacterium, Staphylococcus aureus (“golden staph”), and take its place in airways. These results were published in Nature Communications on October 7, 2014, and shed light on a phenomenon involved in the regulation of bacterial composition in the airways of patients suffering from cystic fibrosis. They could also have an impact on our understanding of how intestinal microbiota evolves.

Cystic fibrosis is the most common serious hereditary genetic disease in the Caucasian population, and is due to a mutation of the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) chloride channel.This mutation leads to a fatal impairment of the respiratory system, which affects one in 2,500 births in Europe and North America. Life expectancy of patients is about 30 to 40 years. CFTR mutation leads to the abundant secretion of a thick mucus by airways in the lungs, which promotes bacterial infection. These infections are treated with antibiotics and, over time, this leads to bacterial multiresistance. Bacterial infections in airways are the main cause of patient death.

In patients suffering from cystic fibrosis, bacterial populations in airways vary depending on the patient’s age. The team working under Lhousseine Touqui, a scientist in the Innate Host Defense and Inflammation Unit (Department of Infection and Epidemiology, Institut Pasteur / Inserm U874), looked at two bacteria commonly found in the airways of patients: a Gram positive bacterium, Staphylococcus aureus (“golden staph”), and a Gram negative bacterium, Pseudomonas aeruginosa. S. aureus is mainly present in the airways of young patients, and decreases with age until it becomes virtually absent at the end of life. P. aeruginosa, on the other hand, is practically absent in the airways of young patients, and then progressively increases over a lifetime, to be the most abundant bacterial type at the end of life. The scientists explained how this progressive shift of infection between the two bacteria takes place within patients’ airways over the course of a lifetime.

The scientists first of all proved that the predominance of P. aeruginosa at the end of life was not due solely to antibiotic resistance, since S. aureus presents the same resistance and nevertheless progressively disappears. They then showed that a particular enzyme produced by the airways of cystic fibrosis patients is instrumental in the elimination of S. aureus by P. aeruginosa. The latter uses the airway’s immune system to kill the S. aureus bacterium.

The Institut Pasteur and Inserm scientists have demonstrated the role played in this bacterial contest by an enzyme, type IIA phospholipase A2(sPLA2-IIA), whose ability to kill Gram positive bacteria such as S. aureus was already known. To date, sPLA2-IIA is known as the most powerful antimicrobial peptide produced by humans and able to kill S. aureus. The scientists noticed that, in animal models, P. aeruginosa stimulates the production of sPLA2-IIA in airways, which is then released by host cells and kills S. aureus.

In addition, it has emerged that sPLA2-IIA increases with patient age. This explains the fact that, with the appearance of P. aeruginosa at a certain age, secretion of sPLA2-IIA by the airways is triggered and kills S. aureus. It should also be noted that sPLA2-IIA is almost totally absent in the airways of healthy subjects. P. aeruginosa therefore manipulates its host in order to kill S. aureus, its bacterial competitor in the airways.

Scientists have therefore been able to explain a sophisticated and previously unknown mechanism implemented by a bacterium to manipulate its host and kill a competing bacterium. This discovery suggests that sPLA2-IIA probably plays a similar role in intestinal microbiota dynamics, as these microbiota populations also vary according to host age. Lastly, looking beyond cystic fibrosis patients, sPLA2-IIA could be injected into patients infected with Gram positive bacteria, which could be a useful alternative therapy to overcome bacterial resistance to antibiotics.

This study was supported by the French cystic fibrosis association Vaincre la Mucoviscidose, and the DIM Malinf research foundation (Greater Paris area).


Illustration: Pulmonary epithelium of patients suffering from cystic fibrosis

  1. Stimulation of the production of sPLA2-IIA by Pseudomonas aeruginosa.
  2. sPLA2-IIA kills Staphylococcus aureus.

    © Lhousseine Touqui, Institut Pasteur

Nobel Prize in medicine 2014

The Nobel Prize of physiology or medicine 2014 is awarded to John O’Keefe,  May-Britt and Edvard I. Moser for their work about for their discoveries of cells that constitute a positioning system in the brain.

May-Britt’s work, conducted with Edvard Moser as a long-term collaborator, includes the discovery of grid cells in the entorhinal cortex, as well as several additional space-representing cell types in the same circuit.

Read the press release

See the computer graphic

Pink October: a month of mobilisation against breast cancer

This year marks the 10th edition of Pink October, a month of national mobilisation against breast cancer. An opportunity to recall that this disease remains a major public health challenge, despite the advances in treatment.

Breast cancer is indeed the leading female cancer, and the leading cause of cancer deaths in women. In 2012, nearly 48,800 new cases and 11,886 deaths were recorded in France.

Throughout this month, many actions will be taken to raise awareness about screening, and to inform people about the management of this cancer.