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The cause of uncombable hair syndrome identified

Surprised disheveled preschooler girl with long hair

In 1973, the rare syndrome of uncombable hair or ‘pili trianguli et canaliculi‘ was described by a Toulouse dermatologist. More than 40 years later, Michel Simon, Inserm research director his colleagues at the ‘Epidermal Differentiation and Rheumatoid Autoimmunity’ Unit [UDEAR] (Inserm/CNRS/Toulouse III – Paul Sabatier University) have identified its genetic cause. These results are published in The American Journal of Human Genetics.

Uncombable hair syndrome is a rare disease of the hair, the prevalence of which is unknown. It generally begins during childhood between 3 months and 12 years. Dry and unruly, the hair of affected children becomes gradually silver-blond or straw coloured. Hairs stand up on the scalp and grow in all directions. It is impossible to comb it or to flatten it with a comb. In detail, scanning electron microscopy reveals a longitudinal groove running their entire length, with a triangular or kidney-shaped cross-section. However, this syndrome is not disabling and undergoes spontaneous at the end of childhood.



he researchers, working with a team from the Human Genetics Institute at Bonn University and dermatologists or geneticists from 7 different countries, have discovered that the disease is due to recessive mutations of a trio of genes that contribute to forming the hair: the gene coding for one of its structural components, trichohyalin (TCHH); or two genes coding for enzymes that take it in turns as target: peptidyl-arginine deiminase 3 (Pad3) and transglutaminase 3 (TGase3).

Furthermore, the researchers have also shown, in mice, that inactivating the Pad3 gene alters the shape of the fur and whiskers of animals, as had already been reported in TGase3-deficient mice.

In conclusion, the absence of TCHH or failure of the biochemical cascade that results in stiffening the hair stem are responsible for the hair formation abnormalities characteristic of uncombable hair syndrome or ‘pili trianguli et canaliculi‘.

These results, as well as describing the molecular cause of the disease and enabling better diagnosis, provide knew knowledge about the hair and the mechanisms of its formation£ concludes Michel Simon, Inserm research director.

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Although extremely rare, the syndrome has long been known. It was brought to public awareness by the famous literary figure ‘Struwwelpeter’ created by children’s author Heinrich Hoffmann in 1845. The book was subsequently translated into English by Mark Twain as ‘Slovenly Peter’. Although he never said so, one might even think that it inspired director Tim Burton to make his film Edward Scissorhands.

Functional human intestine grown from stem cells


Cross-section of human intestinal organoid with enteric nervous system after transplantation in mice.*

(Copyright CCHMC – Wells/Helmrath labs)

American researchers at the Cincinnati Children’s Hospital Medical Center and French researchers from Inserm (joint research Unit 913 “Neuropathies of Enteric Nervous System and Digestive Diseases”, Nantes) have succeeded in generating a functional human intestine using pluripotent human stem cells. This significant breakthrough was achieved by cultivating human intestinal tissue using nerve cells. Details of their work are published online on 21 November 2016 in Nature Medicine.


The gut is an essential organ of the human body. It is the main interface for exchanges with the external environment and has a surface area equivalent to two tennis courts. Given its importance, the gut has its own nervous system and has been commonly known as “the second brain”. The enteric nervous system controls many functions, which include mixing and propelling food along the digestive tract, hormone secretion and epithelial permeability. Disruptions of this system are the cause of many diseases. Poor gut function can actually affect intestinal muscle contraction. This plays a role in triggering abdominal pain, diarrhoea, constipation and, in serious cases, leads to functional obstruction (intestinal occlusion) that requires surgery.

Researchers have developed an innovative approach to engineering tissue involving the use of stem cells to create a functional human intestine that can be used to study intestinal diseases.

First in vitro studies — finding the right balance

To do this, the scientists successively added a cocktail of molecules designed to promote the differentiation of human pluripotent stem cells into intestinal tissue. The process was virtually the same used in 2010 and 2014 by the same laboratory that succeeded in developing the first generation of human intestinal tissue. However, the intestinal tissue did not possess an enteric nervous system through this approach alone, which is essential for absorbing nutrients and eliminating waste through the digestive tract.

At the same time and in order to develop a functional nervous system, researchers created embryonic nerve cells known as neural crest cells. These cells were manipulated to form cells that are enteric neural cell precursors. “The difficulty with this step was to identify how and when to incorporate the neural crest cells into the developing gut that was previously created in vitro”, explains Maxime Mahé, first co-author of this work and recently recruited as a junior research associate by Inserm.

The co-culture of intestinal tissue and enteric neural cell precursors resulted in human tissue that resembled a developing fetal intestine. This led to the first generation of complex and functional “mini-intestines” (known as intestinal organoids) created entirely from human pluripotent stem cells.


Conclusive in vivo trials

The next challenge was to transplant these functional organoids into a living organism, in this instance, lab mice that lacked an immune system. This step allowed scientists to observe tissue development and function in vivo. Data from this study show that the tissues function and are structured in a way that is remarkably similar to the human intestine. They develop and ensure intestinal functions, such as the treatment of nutrients. Finally, these tissues exhibit motor functions similar to peristalsis, i.e. the series of muscle contractions that move food through the digestive tract.

Researchers then used this technology to study a rare bowel disease — Hirschsprung Disease — a disorder where the rectum and colon do not develop a nervous system, which leads to constipation and intestinal occlusion. A lethal form of Hirschsprung disease is caused by a mutation of the PHOX2B gene. In vitro tests in mice have made it possible for researchers to show that the mutated PHOX2B gene causes significant deleterious changes in the innervated intestinal tissues.

“Our work marks an essential step in understanding human digestive diseases where few models exist. This new technology offers a screening platform for new intestinal treatments. This technology is still in its infancy. However, an approach towards regenerative and personalised medicine is possible, particularly with regards to patient-specific intestinal transplantation”, explains Maxime Mahé.

This discovery yields two significant research possibilities. Firstly, intestinal disorders can be modelled and studied using three-dimensional and functional human tissue involving patient-specific cells. Secondly, new treatments can be tested using this functional human intestine before proposing clinical trials in humans.


In this image we can see the intestinal epithelium in red (E-cadherin) with lumen opening. The tissue underlying the epithelium is rich in blood vessels (green, CD31) and has neurons (yellow, TUBB3) that are also derived from human pluripotent stem cells. The observed tissue is incredibly similar to normal human tissue.

Mitochondria are essential to memory

visuel-marsicano-newsroomMitochondria develop our memory by providing brain cells with energy (c) Charlie Padgett

Numerous studies have shown that using cannabis can lead to short- and long-term memory loss. These effects on memory may be related to the presence of specific receptors on several types of brain cells (glial cells as well as neurons). Inserm researchers led by Giovanni Marsicano (Neurocentre Magendie, U1215) have shown that these effects on memory are related to the presence of these same receptors on the mitochondria, the energy centre of the cell. This is the first time that the direct involvement of mitochondria in higher brain functions, such as learning and memory, has been shown. This work is published in the journal Nature.


Mitochondria are the energy centre of the animal cell. They are present within cells to produce the energy (in the form of ATP) needed for all biochemical processes. To do this, they use oxygen to transform nutrients into ATP. These functions are obviously necessary for the survival of all the cells in the body, but in the brain the impact of mitochondria goes beyond simple cell survival. Although the brain represents only 2% of the weight of the body, it actually consumes up to 25% of its energy. As a result, the energy balance of the brain is highly important for its functions, and is therefore tightly regulated. We know very well that chronic impairment of mitochondrial functions (e.g. in mitochondrial diseases) produces serious neurological and neuropsychiatric symptoms.

However, the direct functional involvement of mitochondria in higher brain functions, such as learning and memory, was not known before now.

In other terms, do we use the mitochondria in our brain when we are learning or remembering something?

This study, which is based on the discovery that the cannabinoid receptor CB1 is also present on the brain mitochondria (where it is known as mtCB1), reveals that this is indeed the case. With the help of innovative tools, the Inserm researchers showed that the active component of cannabis, THC (delta-9-tetrahydrocannabinol), causes amnesia in mice by activating mtCB1 receptors in the hippocampus.

“The impairment in memory induced by cannabis in the mouse requires activation of these hippocampal mtCB1 receptors,” explains Giovanni Marsicano. Conversely, “Genetically deleting them prevents this effect induced by the active drug in cannabis. We therefore think that mitochondria develop our memory by providing the brain cells with energy.”

This study is important not only because it reveals a new mechanism underlying the effects of cannabis on the memory, but also because it shows that mitochondrial activity is an integral part of the functions of the brain.

Jean-Laurent Casanova, specialist in infectious disease genetics, awarded the Inserm Grand Prix 2016


On Thursday 8 December, at Collège de France, the annual Inserm Awards ceremony will honour eight researchers and engineers whose work has contributed to the Institute’s scientific excellence. The Inserm Grand Prix 2016 will be awarded to Jean-Laurent Casanova, for his work on the human genetics of infectious diseases, in the presence of Marisol Touraine, Minister of Social Affairs and Health, Thierry Mandon, Secretary of State for Higher Education and Research, and Professor Yves Lévy, Chairman and Chief Executive Officer of Inserm.


Jean-Laurent Casanova, Inserm Grand Prix 

In the 19th century, Louis Pasteur demonstrated that microbes are responsible for infectious disease, thus revolutionising medicine. However, when exposed to the same microbe, only a minority of infected children and adults develop a serious illness. When confronted by this enigma, Jean-Laurent Casanova, paediatrician and immunologist, suspected a genetic cause. He then devoted his work to research on infectious diseases of children: tuberculosis, invasive pneumococcal infection, herpetic encephalitis, etc.

Since the 1990s, and thanks to his work, a paradigm shift has occurred. Jean-Laurent Casanova has provided proof that serious infectious diseases are also genetic diseases that make children susceptible to one microbe or another. A pioneer in this area, he has contributed to the identification of several hundred genetic mutations involved in immune deficiencies that predispose to infection.

Today his discoveries make it possible to offer the children affected, and their families, a molecular and genetic diagnosis, together with preventive measures or even therapeutic strategies.

Director of the Laboratory of Human Genetics in Infectious Diseases, which he founded with Laurent Abel, jointly hosted by the Imagine Institute at the Necker Hospital for Sick Children, Paris and The Rockefeller University, New York, Jean-Laurent Casanova, at 53 years of age, is being awarded the Inserm Grand Prix for his entire body of work.

Molecular and genetic diagnosis, made possible by the research carried out by Jean-Laurent Casanova, illustrates the need for an effective implementation of the measures contained in the Aviesan Alliance’s French Plan for Genomic Medicine 2025.


Linda Fried, International Prize

The International Prize honours Linda Fried, Dean and DeLamar Professor at the Columbia University Mailman School of Public Health (New York). Dr Fried is a public health leader in the fields of epidemiology and geriatrics, renowned worldwide for having identified the age-related frailty syndrome. She has also designed an intergenerational tutoring programme, having demonstrated its efficacy in preventing cognitive impairment and dementia.



Catherine Barthélémy, Honorary Prize

The Honorary Prize is awarded to Catherine Barthélémy, Emeritus Professor of the Tours Faculty of Medicine, and former Director of the “Autism” team at Inserm Unit 930, “Imaging and Brain,” for her work on the brain mechanisms involved in autism. With a long history of working toward the early recognition of children with autism, she is currently pursuing her research to enable further advances with these children.


The Opecst-Inserm Prize is awarded to Martine Bungener, researcher, economist and sociologist, President of Inserm’s patients’ association liaison group, GRAM – Groupe de Réflexion avec les Associations de Malades – for her work in support of the dialogue between patients, those close to patients, and researchers. Her work has also contributed to developing the key role of friends and families in the patient pathway.

The Research Prizes are awarded to Rosa Cossart, Research Director at Unit 901, “Mediterranean Institute of Neurobiology” (Inserm/Aix-Marseille University), in recognition of her studies on the synchronisation mechanisms of neural networks, and to Xavier Jouven, researcher, cardiologist and statistician at Unit 970, “Paris – Cardiovascular Research Center” (Inserm/Paris-Descartes University), whose achievements include the discovery of a new form of renal transplant rejection, using mathematical models.

The Innovation Prizes distinguish Benjamin Mathieu, Research Engineer at Unit 1024, “Biology Institute, École Normale Supérieure” (Inserm/CNRS/École Normale Supérieure, Paris), whose work has led to the development of a microscope that allows optical measurement of the activity of the neurons in a living animal, and Céline Tomkiewicz-Raulet, Design Engineer at Unit 1124, “Toxicology, Pharmacology and Cell Signaling” (Inserm/Paris Descartes University), in recognition for her work on the influence of pollutants on breast cancer.

Attacks and risks of post-traumatic stress

In a traumatic event, such as the attacks on Paris on 13 November 2015, and on Nice on 14 July 2016, the risk for victims and witnesses of developing post-traumatic stress disorder (PTSD) is high.

PTSD is characterised by several symptoms: the person relives the event in the form of recurrent memories, nightmares or flashbacks, avoids anything that reminds him/her of the moment, is in a constant state of alert, and shows difficulty in concentrating. Changes in mood may also occur.

At Inserm, there is ongoing active research to better identify the people most at risk of developing post-traumatic stress disorder, and thereby improve their care.

In the Phoenix study, which evaluates the impact of a trauma or chronic stress on the physical and mental health of 123 patients for a one-year period, work carried out by Isabelle Chaudieu, Inserm Unit 1061 “Neuropsychiatry: Epidemiological and Clinical Research,” is aimed at identifying biomarkers to predict PTSD. Her team is trying to determine whether the allostatic load might make it possible to predict the development of PTSD.

By collecting and analysing personal accounts from 1,000 volunteers over a ten-year period, the 13 Novembre programme (CNRS – Inserm), codirected by historian Denis Peschanski and neuropsychologist Francis Eustache, is aimed at studying the construction and evolution of memory after the attacks of 13 November 2015, and the interaction between individual and collective memory. The researchers will try to better understand the impact of traumatic shocks on the memory, and identify brain markers associated with resilience to trauma.

Read the press release “Attacks: 13-Novembre, a novel research program on traumatic memories.”

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