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Category: Health technologies

A New Method for Unlocking the Mysteries of Life

Posted on by Graziella Cara

To better characterize molecular interactions, researchers must also look at molecular chirality. © Valérie Gabelica

Understanding the three-dimensional structure of DNA and RNA and how they interact with other molecules is necessary for the advancement of biomedical research and drug development. A team led by Inserm researcher Valérie Gabelica at the Nucleic acids: natural and artificial regulation laboratory (ARNA, Inserm/CNRS/Université de Bordeaux)[1] has developed an innovative method pairing mass spectrometry with circularly polarized light, enabling better characterization of these different molecular interactions. This new technique is described in a study published in the journal Science.

A technique widely used in physics and biology laboratories, and also in forensic science to analyze chemical and biological samples, mass spectrometry measures the masses of each molecule in a sample, thereby providing information on how they interact and associate with each other.

Inserm researcher Valérie Gabelica and her team at the ARNA laboratory (Inserm/CNRS/Université de Bordeaux)1 are studying how short DNA and RNA sequences fold in three dimensions and interact with other molecules. To do this, they use mass spectrometry, which gives them valuable insights into how DNA and RNA associate structurally with proteins or pharmaceutical molecules, for example.

However, to better characterize these molecular interactions, the scientists must also look at molecular chirality. A molecule is said to be “chiral” when its 3D structure cannot be superimposed onto its mirror image. Due to its helical shape, DNA is therefore a chiral molecule.

Determining the chirality of a molecule is important for understanding its biological interactions with DNA and proteins – the molecules of living organisms.

Given that measuring molecular weight provides no information on chirality, the use of another technique, circularly polarized light[2], is necessary to study the 3D structure of molecules.

In a study published in Science, the researcher and her team describe a novel tool for studying chirality and how DNA and molecules assemble: a “2-in-1” method pairing a mass spectrometer and a laser that produces circularly polarized light.

Therapeutic prospects

The use of such a technique could open up new biomedical research avenues, particularly in neurodegenerative diseases, such as Alzheimer’s.

Indeed, several studies have shown that upstream of the protein aggregation process that forms senile plaques in the brain, the proteins form small complexes known as oligomers, which could be even more toxic. Applying the method developed by the researchers would make it possible to improve our understanding of when these oligomers change their 3D structure, in order to explore the role they play in disease exacerbation and plaque formation.

Another practical application is drug development. For example, if the target of a drug is a chiral protein, it is also important to characterize the chirality of the drug in order to find out more about its potential interactions.

“In the 1960s, thalidomide, a drug taken by many pregnant women to reduce nausea, caused severe birth defects in their babies. In fact, one of the images of this molecule in the mirror was anti-nausea, the other was toxic. A more in-depth study of the molecular structure and chirality would have prevented this,” emphasizes Gabelica.

By pushing back hard on the frontiers of mass spectrometry and facilitating the study of molecule chirality, this research is particularly innovative and opens up very broad prospects in the field of biomedical research.

 

[1] The IECB research support unit (CNRS/Université de Bordeaux/Inserm) also participated in this work.

[2]Light is a wave. It is described by signals that oscillate in space and time: electric and magnetic fields. These two fields have a direction, the magnetic field is perpendicular to the electric field. When light is circularly polarized, the electric field changes orientation along the beam and describes a spiral. The magnetic field is always perpendicular to the electric field

Music or Speech? The Brain is Divided…

Posted on by Graziella Cara

Photo by Thanos Pal on Unsplash

When it comes to recognizing a melody or understanding a spoken sentence, the human brain does not mobilize its hemispheres in an equivalent way. Although the concept is recognized by scientists, there had been no physiological or neural explanation for the phenomenon until now. A team co-led by Inserm researcher Benjamin Morillon at the Institute of Systems Neuroscience (Inserm/Aix-Marseille Université) in collaboration with researchers at Montreal Neurological Institute and Hospital of McGill University has been able to show that, due to different receptivities to the components of sound, the left auditory cortex neurons participate in the recognition of speech, whereas the right auditory cortex neurons participate in that of music. These findings, to be published in the journal Science, suggest that the respective specializations of the brain hemispheres for music and speech enable the nervous system to optimize the processing of sound signals for communication purposes.

Sound is produced from a complex set of air vibrations, which, when reaching the cochlea of the inner ear, are distinguished according to their speed. At any given moment, slow vibrations are being translated into deep sounds and rapid vibrations into high-pitched ones. As a result, sound can be represented according to two dimensions: spectral (frequency) and temporal (time).

These two auditory dimensions are fundamental because it is their simultaneous combination that stimulates the neurons of the auditory cortex. The latter are thought to discriminate sounds that are relevant for individuals, such as those used for communication enabling people to talk to and understand each other.

In humans, speech and music constitute the main uses of sound and the most complex on the cognitive level. The left hemisphere is primarily implicated in the recognition of speech, whereas the right hemisphere is primarily implicated in that of music. However, until now little was known about the physiological and neural reasons for this asymmetry.

A team co-led by Inserm researcher Benjamin Morillon at the Institute of Systems Neuroscience (Inserm/Aix-Marseille Université) in collaboration with researchers at Montreal Neurological Institute and Hospital of McGill University used an innovative approach to understand how speech and music are decoded within each of the human brain hemispheres.

The researchers recorded 10 sentences sung by a soprano to 10 new melodies composed especially for the experiment. These 100 recordings, in which melody and speech are dissociated, were then distorted by decreasing the amount of information present in each dimension of the sound. Forty-nine participants were asked to listen to pairs of these distorted recordings, and to determine whether they were identical in terms of speech content and melody. The experiment was conducted in French and English speakers to see whether the results were reproducible in different languages.

A demonstration of the audio test proposed to the participants is available here:

https://www.zlab.mcgill.ca/spectro temporal modulations/

The research team found that for both languages, when the temporal information was distorted, participants had trouble distinguishing the speech content, but not the melody. Conversely, when the spectral information was distorted, they had trouble distinguishing the melody, but not the speech.

Functional magnetic resonance imaging (fMRI) of the participants’ neural activity showed that in the left auditory cortex the activity varied according to the sentence presented but remained relatively stable from one melody to another, whereas in the right auditory cortex the activity varied according to the melody presented but remained relatively stable from one sentence to another.

What is more, they found that degradation of the temporal information affected only the neural activity in the left auditory cortex, whereas degradation of the spectral information only affected neural activity in the right auditory cortex. Finally, the participants’ performance in the recognition task could be predicted simply by observing the neural activity of these two areas.

Original a capella extract (bottom left) and its spectrogram (above, in blue) broken down according to the amount of spectral and temporal information (center). The right and left cerebral auditory cortexes (right) decode melody and speech respectively.

“These findings indicate that in each brain hemisphere, neural activity depends on the type of sound information, specifies Morillon. While temporal information is secondary for recognizing a melody, it is essential for the correct recognition of speech. Conversely, while spectral information is secondary for recognizing speech, it is essential for recognizing a melody. “

The neurons in the left auditory cortex are therefore considered to be primarily receptive to speech thanks to their superior temporal information processing capacity, whereas those in the right auditory cortex are considered to be receptive to music thanks to their superior spectral information processing capacity. “Hemispheric specialization could be the nervous system’s way of optimizing the respective processing of the two communication sound signals that are speech and music,” concludes Morillon.

This research was supported by a Banting fellowship to Philippe Albouy, grants from the Canadian Institutes of Health Research and the Canadian Institute for Advanced Research to Robert J. Zatorre, ANR-16-CONV-0002 (ILCB) and ANR-11-LABX-0036 (BLRI) funding and the Excellence Initiative of Aix-Marseille Université (A*MIDEX).”

Human Textiles to Repair Blood Vessels

Posted on by Graziella Cara

The researchers use extracellular matrix sheets to make yarn – a bit like that used to make clothing fabric. ©Nicolas L’Heureux

The leading cause of mortality worldwide, cardiovascular diseases claim over 17 million lives each year, according to World Health Organization estimates. To open up new research avenues into this serious public health problem, Inserm researcher Nicolas L’Heureux and his team at the Tissue Bioengineering unit (Inserm/Université de Bordeaux) are developing “human textiles” from collagen in order to repair damaged blood vessels. An innovation described in the journal Acta Biomaterialia, which still has to pass through several stages before it can be tested in humans.

What if we could replace a patient’s damaged blood vessels with brand new ones produced in a laboratory? This is the challenge set by Inserm researcher Nicolas L’Heureux, who is working on the human extracellular matrix – the structural support of human tissues that is found around practically all of the body’s cells.

In a study published in Acta Biomaterialia, L’Heureux and his colleagues at the Tissue Bioengineering unit (Inserm/Université de Bordeaux) describe how they have cultivated human cells in the laboratory to obtain extracellular matrix deposits high in collagen – a structural protein that constitutes the mechanical scaffold of the human extracellular matrix. “We have obtained thin but highly robust extracellular matrix sheets that can be used as a construction material to replace blood vessels”, explains L’Heureux.

 

Made entirely from biological material, these blood vessels would have the advantage of being well tolerated by all patients.© Nicolas L’Heureux

The researchers then cut these sheets to form yarn – a bit like that used to make fabric for clothing. “The resulting yarn can be woven, knitted or braided into various forms. Our main objective is to use this yarn to make assemblies which can replace the damaged blood vessels”, adds L’Heureux.

Made entirely from biological material, these blood vessels would also have the advantage of being well-tolerated by all patients. Given that collagen does not vary from individual to individual, it is not expected that the body will consider these vessels as foreign bodies to be rejected.

The researchers would now like to refine their techniques used to produce these “human textiles” before moving on to animal testing, in order to validate this last hypothesis. If these are conclusive, this could lead to clinical trials.

“Brain Map” paves the way for Personalized Medicine

Posted on by Graziella Cara

Adobe Stock

Using cerebral imaging, connections between the various brain regions can be visualized. These connections form a veritable “map” of its structure, specific to each individual. A team led by Christophe Bernard, Inserm researcher, and Viktor Jirsa at the Institute of Systems Neuroscience (Inserm/Aix-Marseille Université), has shown that having the knowledge of these “maps” is enough to predict not just brain function but also the potential development and treatment of neurological diseases. Their findings have been published in PNAS.

Over the previous three decades, rapid progress in brain imaging has enabled major advances in the field of neurosciences. Magnetic resonance imaging (MRI), has paved the way for a deeper understanding of the brain and of the mechanisms of certain diseases.

Using MRI, researchers can access the general organization of the brain and more particularly the map of the neural connections between its different regions – a bit like a map of the roads that link various towns. “This map is unique to each individual and is more accurate than even a fingerprint”, highlights Inserm researcher Christophe Bernard. To pursue this analogy, neurological diseases such as Alzheimer’s and epilepsy are associated with a reorganization of the “maps”: the connections between brain regions are modified and some “roads” disappear.

While it is possible to accurately visualize the brain of each individual after using MRI to obtain a map of its connections, is it also possible, just from this map, to accurately predict its function and the potential development of diseases, as well as their treatment? Is it enough just to have a knowledge of this “map” to make these types of personalized predictions for patients?

The “Virtual Brain”

These are questions that Bernard, researcher at the Institute of Systems Neuroscience (Inserm/Aix-Marseille Université) and his colleagues have tried to answer in a new study published in PNAS. They began their research by using brain imaging techniques to visualize very precisely the connections between the brain regions of several mice.

 

Mapping the brain connections of a mouse makes it possible to predict its brain activity. Results obtained following virtualization of mouse brains using The Virtual Brain platform. Credits: Christophe Bernard

Based on these “maps”, they then created virtual models of the brain of each mouse using a technology called The Virtual Brain[1], in collaboration with researchers from Technion in Israel. In each of these virtual brains, the researchers generated electrical activity, mimicking what happens in a real brain.

This enabled them to study which brain regions communicate together – findings that were compared with the experimental data obtained using functional imaging from each mouse in a resting state. The researchers were thus able to show that having a knowledge of the “map” of each mouse is sufficient to explain the brain activity of that same mouse as seen using functional imaging. They were also able to show which connections make each brain unique.

Although these findings remain to be validated in humans, they are already paving the way for the personalized medicine of the future. “Our research validates the strategy of patient brain virtualization in order to explore, using a computer, the optimal therapeutic strategies prior to their personalized transfer. We can imagine that the ability to predict the development of certain diseases in an individual based on the unique map of their brain will enable us to envisage prevention strategies and personalized therapeutic options”, Bernard highlights.

[1] The Virtual Brain, a neuroinformatics platform developed by Viktor Jirsa at the Institute of Systems Neuroscience (Inserm/Aix-Marseille Université) in collaboration with Randy McIntosh (Baycrest Centre, Toronto) and Petra Ritter (Charité, Berlin), is used to create individual brain models. Currently being evaluated in patients with drug-resistant epilepsy, it can, for example – following virtualization of the patient’s brain – explore and predict the best form of neurosurgery to cure such epilepsy.

Restoring Sight: the Artificial Retina Shows Growing Promise

Posted on by Léa Surugue

Adobe/Stock

Restoring sight to patients with age-related macular degeneration (AMD) or retinitis pigmentosa has become an increasingly likely prospect over recent years, with many researchers working to develop an artificial retina. In a new study, a team from Institut de la Vision (Inserm-CNRS- Sorbonne Université) led by Inserm researcher Serge Picaud has used animal models to show that a device made by the firm Pixium Vision could induce high-resolution visual perception. Their findings, published in Nature Biomedical Engineering, have paved the way for clinical trials in humans.

Age-related macular degeneration (AMD) is characterized by deterioration of the retina that can lead to central vision loss. This highly incapacitating condition is thought to affect up to 30% of people over the age of 75. For years, several groups of researchers have been working on the development of an artificial retina that could restore eyesight – not just to these patients but also to those with retinitis pigmentosa. 

The retina is made up of light-sensitive cells (photoreceptors) whose purpose is to transform the light signals received by the eye into electrical signals sent to the brain. It is these cells that are destroyed during the course of the aforementioned diseases, the outcome of which can be blindness. The principle of the artificial retina – which is implanted beneath the patient’s own retina – is simple: to act as a substitute for these photoreceptors. Its electrodes stimulate the retinal neurons to send messages to the brain.

Two devices of this type, Argus II (Second sight, USA) and Retina Implant (AG, Germany), are already in widespread use. “Nevertheless, these companies are gradually withdrawing from the market, particularly because the results seen in patients have been insufficient for targeting the device at those with AMD. The patients managed to see light signals but those able to distinguish letters were very much in the minority”, emphasizes Serge Picaud. 

Implantation in patients 

Reinventing the device to increase its performance: this is the aim of the Picaud and his colleagues. Supported by Pixium Vision, their artificial retina is wireless and less complex, unlike previous devices. In addition, this implant introduces a local return of the current, thereby enabling better resolution of the images perceived by the eye. Finally, the image is projected onto the implant by infrared stimulation that activates photodiodes connected to electrodes, enabling more direct stimulation of the retinal neurons.

In a study published in Nature Biomedical Engineering, Picaud and his colleagues tested this device on non-human primates, demonstrating that it can restore significant visual acuity. In vitro tests showed first of all that each pixel activates different cells in the retina. This selectivity is expressed in the form of very high resolution, such that implanted animals can perceive the activation of just one of the implant’s pixels in a behavior test.

The high resolution of these implants led to the device being fitted in five French patients with AMD, for whom initial results show a gradual restoration of central vision. They are able to perceive light signals and some can even identify sequences of letters, with growing rapidity over time.

“The objective now is to conduct a Phase 3 trial in a larger group of patients with AMD. If the artificial retina works for them, there is no reason why it should not work in patients with retinitis pigmentosa – a disease also related to photoreceptor degeneration”, concludes Picaud.

How People with Autism Might Avoid Socio-Emotional Situations

Posted on by Graziella Cara

One hypothesis put forward to explain the repetitive behaviors of people with Autism Spectrum Disorder is a lack of cognitive flexibility. However, this may well not be the case. A recent study by a team of researchers from Inserm and Université de Tours used MRI to track the brain activity of autistic and non-autistic subjects faced with situations similar to those that cause problems in the daily lives of people with the disorder. Their findings, published in Brain and Cognition, suggest that the inflexibility of autistic individuals is actually the result of a strategy used to avoid socio-emotional situations. This research, which suggests now considering the cognitive and socio-emotional domains as closely linked rather than dissociated, opens up new avenues in the understanding and management of autism.

In their daily activities, people with Autism Spectrum Disorder (ASD) experience difficulty adapting their behavior to environmental changes. ASD is characterized by two main diagnostic criteria: the individual experiences persistent difficulties in social communication and is locked into repetitive behavioral patterns, restricted interests and/or activities. But while both criteria need to be present in order to diagnose ASD, little attention has been paid to how they interact.

In a study led by Marie Gomot, Inserm researcher at the Imaging and Brain laboratory (Inserm/Université de Tours), this question was explored by comparing the cognitive management of socio-emotional information and that of non-social information in people with ASD.

While the processes responsible for ASD symptoms have not yet been fully elucidated, one current hypothesis is a lack of cognitive flexibility – in other words, difficulty in alternating between multiple tasks and in analyzing one’s environment in order to adapt to these changes.

To evaluate this flexibility, the researchers used MRI to track the brain activity of ASD and non-ASD participants who underwent a test simulating situations similar to those that cause problems in the daily lives of people with the disorder.

The research team used a modified version of a test traditionally used in neuropsychology in order to test cognitive flexibility while processing non-social or socio-emotional information. Five cards were presented, each illustrated with a different face. The participants were asked to match the central card with one of four surrounding cards, according to one of the following three rules: frame color (non-social information), facial identity (social information) or facial expression (socio-emotional information). In order to evaluate their cognitive flexibility, the participants were asked throughout the test to make different matches (same color, same identity or same facial expression) by changing or maintaining one of the three rules.

The research team saw no significant difference between the ASD and non-ASD participants when it came to the behavioral parameters measuring cognitive flexibility alone – namely the capacity to adopt a new rule. However, the study did reveal the importance of information type for these cognitive flexibility processes in ASD. While the ASD participants needed more attempts than the non-ASD participants in order to adopt the rule linked to socio-emotional information, they had no particular difficulty in adopting those involving the processing of non-emotional information.

In parallel, the MRI revealed a significantly higher level of brain activity in the ASD participants when they were required to demonstrate cognitive flexibility. This brain activity only stabilized when the ASD participants received confirmation that they had found the correct rule to apply, thereby suggesting that people with ASD require a higher level of certainty in order to adapt to a new situation.

“These findings are important because they suggest that the implementation of routines and repetitive behaviors by people with ASD might not be due to a genuine lack of cognitive flexibility but rather to avoid being confronted with certain socio-emotional situations, specifies Gomot. The need for a high level of certainty combined with a poor understanding of the codes that govern socio-emotional interactions would thereby lead to the avoidance of tasks with a socio-emotional component.” And to conclude, “this research confirms the close link between cognitive and emotional dysfunction in ASD and the need for future studies to take them into joint consideration more often.

Human Adipose Tissue Reproduced in the Lab

Posted on by Graziella Cara

©STROMALab

Can human adipose tissue be reproduced in a laboratory? It can now, thanks to a research team with members from Inserm, CNRS, Université Toulouse III-Paul-Sabatier, the French Blood Establishment (EFS) and the National Veterinary School of Toulouse (ENVT) working together at STROMALab. This team used 3D culture to develop adipose tissue organoids (or adipospheres) – small cellular units that mimic the characteristics and organization of adipose tissue as it presents in vivo. In their article, published in Scientific Reports, the researchers describe the various stages of the experimental conditions needed to obtain these adipospheres from human cells. An innovation that could make it possible not just to study diseases related to the impaired functioning of this tissue, such as obesity and type 2 diabetes, but also to develop new drugs to treat them.

Human adipose tissue, highly vascularized by a network of capillaries, is made up of fat cells known as adipocytes. Until now, laboratory researchers used 2D models that did not take into account the 3D architecture of this tissue as found in the human body.

Mini organs, which are known as organoids and capable of reproducing the cellular organization of a specific organ, have already been developed for some tissues, such as that of the intestine. However, none had been able to reproduce in 3D the cellular and vascular organization of the adipose tissue in a laboratory setting.

However, this is now possible thanks to researchers from Inserm, CNRS, Université Toulouse III-Paul-Sabatier, the French Blood Establishment (EFS) and the National Veterinary School of Toulouse (ENVT) working together at STROMALab. Thanks to the advent of the new 3D cell culture methods, the control of the selection and characterization of adipose tissue stromal cells (support cells), the team was able to develop organoids of this tissue, called adipospheres.

Generating organoids in 3D

From these stromal cells of the human adipose tissue, the researchers developed new 2D – followed by 3D – culture conditions, making it possible to obtain both adipocytes and endothelial cells from this tissue. The adipospheres obtained contained an intact vascular network organized around adipocytes in the same way as in actual human tissue. Better still, the adipocytes obtained were capable of differentiating into those of brown or white tissue (the two types of human adipose tissue) in the same way as those encountered in the human body.

Transplantation in mice

The research team then transplanted these adipospheres into mice in order to verify the functionality of their vascular network. They observed that not only was this network maintained in the body but also that it extended itself by establishing connections with the host’s circulatory system.

The researchers also observed so-called chimeric vessels, constituted of both mouse and human cells. “These are all signs that the host tolerates the transplanted organoids well, explain Isabelle Ader, Inserm researcher, and Frédéric Deschaseaux, from the French Blood Establishment (EFS), authors of the study. From this we can conclude that not only are these small structures faithful to the organization of human tissue, but also that they are capable of staying alive by establishing connections with the host circulatory system that provides them with the necessary oxygen and nutrients.“

According to the researchers, this innovation will enable continued study of the functioning and properties of human adipose tissue. By working directly on this tissue, the use of animals will be reduced.

“This innovation will also make it possible to test various drugs that could be used to treat certain diseases related to a pathology of adipose tissue, such as obesity or type 2 diabetes“, conclude Isabelle Ader and Frédéric Deschaseaux.

Read the article (in french) published in Magazine de l’Inserm, n°43, Juin 2019.

Wound Dressings to Regenerate Joints

Posted on by Graziella Cara

Cartilage articulaire © Inserm/Chappard, Daniel

Researchers from Inserm and Université de Strasbourg at Unit 1260 “Regenerative Nanomedicine” have developed an implant which, when applied like a wound dressing, regenerates cartilage in the event of major joint lesions and incipient osteoarthritis. The details of this innovation, which has been validated in the preclinical setting, have been published today in Nature communication.

Increases in life expectancy and the number of accidental traumas call for the development of new types of surgery to replace defective joints. Among the chronic diseases, osteoarthritis – described as destruction of the cartilage affecting the various joint structures, including the bone and synovial tissue that lines the inside of the joints – represents a genuine public health issue. Depending on the clinical diagnosis, various therapeutic options are possible – ranging from microtransplant to joint replacement. Nevertheless, these procedures are all invasive, potentially painful, limited in efficacy and not without side effects. In reality, apart from joint replacement, current treatment strategies are limited to temporary cartilage repair and pain relief. Treatments mainly involve the injection of anti-inflammatories as well as hyaluronic acid to improve joint viscosity. Stem cells can also be used, particularly because they secrete molecules able to control the inflammation.

Within this area and with the aim of regenerating this supple and often elastic connective tissue that covers our joints and enables the bones to move and slide in relation to each other, a team of researchers from Inserm and Université de Strasbourg has recently developed a dressing for cartilage – inspired by the new-generation wound dressings that act as a second skin. With the dressings developed by Ms. Benkirane-Jessel and her team, the therapeutic response reaches a new milestone. We are no longer talking about repair but the actual regeneration of the joint tissue.

What Ms. Benkirane-Jessel’s team has developed is an innovative osteoarticular implant technique, able to reconstitute a damaged joint and whose application can be likened to that of wound dressings. “The implant we’ve developed is intended for two cases in particular: major cartilage lesions and incipient osteoarthritis.” she explains.

These dressings comprise two layers. The first – which acts as a support (reminiscent of everyday wound dressings) – is a membrane comprised of polymer nanofibers and supplied with small vesicles containing growth factors in quantities similar to those secreted by our own cells. The second is a layer of hydrogel loaded with hyaluronic acid and stem cells from the patient’s own bone marrow. It is these cells that – by differentiating into chondrocytes (cells that form the cartilage) – will regenerate the joint cartilage.

The scientists envision a promising future for their “cartilage dressing” which, in addition to the shoulder and knee joints, could also be used for the temporomandibular joint that connects the jawbone to the skull. Quite incapacitating, disorders in this area can cause pain, joint sounds and above all the inability to open and close the jaw completely. The research team has already conducted studies on cartilage lesions in small and large animals (mice, rats, sheep and goats), which are highly suitable models with cartilage comparable with that of humans. The objective is to launch a study in humans with a small cohort of 15 patients.

This project has received the support of Satt Conectus, ANR and the Grand Est region.

Miniaturized Chemical Sensors to Monitor Brain Function

Posted on by Priscille Rivière

©Stéphane Marinesco / Inserm, Photograph of an implantable chemical sensor (bottom right) made with platinized carbon fiber and coated with a recognition enzyme, placed next to a human hair (top).

A team of Inserm and CNRS researchers has succeeded in developing new-generation chemical sensors to monitor the brain’s metabolism, particularly during stroke, trauma or epileptic seizure. Measuring less than 15 µm in diameter, these minimally-invasive tools monitor what is happening in the brain in order to obtain data that are much more reliable and representative of the neurochemical exchanges. This research has been published in ACS Central Science.

Analyzing the interstitial fluid of the brain can reveal important chemical information about the state of the latter. In the clinic or in laboratory animals, the ability to detect, over time, the levels of metabolites characteristic of brain energy (such as glucose) can help detect the onset of brain lesions, enabling doctors to act before it is too late. In addition, the activation of neuronal networks leading to a release of neurotransmitters can be detected in interstitial fluid. However, up until now the size of the probes and the local injury caused by their implantation were parameters which disrupted the quality of the measurements obtained. In particular, the rupture of small cerebral blood vessels during implantation represents a major trigger for inflammation. Within the first hour after implantation, local chemical brain tissue composition can be affected.

The first innovation presented by the scientists in this research consisted of developing miniature sensors.

Invisible to the naked eye, they measure less than 15 microns in diameter (compared with 50 to 250 microns, currently), making them narrower than a strand of hair. The major advantage of being able to miniaturize the sensors to this extent is that implanting them no longer causes lesions in the nervous tissues. “Their size is smaller than the average distance between two brain capillaries, meaning that they are not damaged by the device” explains Stéphane Marinesco, Inserm researcher in charge of the study.

The second innovation was to coat the carbon fibers with platinum followed by a very thin layer of enzyme.

Up until then, electrochemical analysis using carbon fiber microelectrodes was limited to a highly-restrictive number of so-called “oxidable” molecules. Coating them with platinum makes it possible to attach enzymes and detect a potentially unlimited number of molecules. For Marinesco, “while platinum deposition is a commonly used technique in the field of microelectronics, it is usually performed with flat silicon substrates. Our results show that, despite their unusual cylindrical geometry, carbon fibers could be successfully covered with a platinum layer. The sensitivity achieved is similar or better than that of the thicker solid platinum wires which are commercially available.”

When these sensors were implanted in the brains of rats during laboratory testing, no injuries to the brain tissue or blood vessels were detected.

In addition, these microelectrodes supplied more precise and reliable evaluations of glucose, lactate and oxygen concentrations compared with conventional sensors (in which one sensor per parameter is necessary by implanting a multi-microelectrode “comb”). Numerous tests were performed on these new microelectrodes, in particular on their stability over time because they were also tested after 6 months of storage (room temperature in darkness).

Marinesco clarifies that: “This minimally invasive device represents a major advance in our ability to analyze the brain interstitial fluid, paving the way for the measurement of new physiological parameters and multiple applications. This novel tool could be used to test the effect of certain medicinal products on the brain. Finally, in the longer term, monitoring the human brain could provide invaluable information to doctors in order to better understand how a patient with brain lesions recovers after a head injury or stroke. This device could also help them to take the best therapeutic decisions depending on the patient’s condition”.

Cancer under pressure: visualizing the activity of the immune system on tumor development

Posted on by Lea Roy

Cancérogenèse : Surexpression de TRF2, marqué en vert, dans les vaisseaux tumoraux, marquage rouge, dans un cancer ovarien. ©Inserm/Wagner, Nicole, 2014

As tumors develop, they evolve genetically. How does the immune system act when faced with tumor cells? How does it exert pressure on the genetic diversity of cancer cells? Scientists from the Institut Pasteur and Inserm used in vivo video techniques and cell-specific staining to visualize the action of immune cells in response to the proliferation of cancer cells. The findings have been published in the journal Science Immunology on November 23, 2018.

Over time, the uncontrolled proliferation of tumor cells results in the accumulation of new mutations and changes to their genome. This gradual process creates significant genetic diversity among the cancer cells in any given patient. And although the cells in the immune system, especially T cells, are potentially able to eliminate these abnormal cells, tumor diversity can have a harmful effect, complicating the action of the immune system and rendering some therapies ineffective. Understanding this frantic race between tumor development and the immune response is key to the success of future immunotherapy techniques.

Scientists in the Dynamics of Immune Responses Unit (Institut Pasteur/Inserm), directed by Philippe Bousso, in collaboration with Ludovic Deriano, Head of the Genome Integrity, Immunity and Cancer Unit (Institut Pasteur), investigated how spontaneous immune responses to tumors influence this tumor heterogeneity. They demonstrated that the immune system can employ mechanisms to significantly reduce tumor diversity, favoring the emergence of more genetically homogeneous tumor cells.

In their study, the scientists marked each cancer cell subclone with a separate color in a mouse model. By monitoring these different colors they were therefore able to characterize the evolution of tumor heterogeneity in time and space. They were also able to observe the contacts between T cells and cancer cells and determine how some tumor cells are destroyed. Their research highlights the drastic impact the immune system can have on tumors by reducing their heterogeneity.

 

Visualizing the action of stained immune cells.
In this video, the tumor cells are shown in gray. The tumor-specific T-cells, in purple, come into contact with the cancer cells and destroy them. The killed cells are shown in blue. In green, the control cells circulate but do not kill the tumor cells. © Institut Pasteur / Philippe Bousso

 

Visualizing different clusters of cancer cell clones.
This video illustrates how tumor subclones, each marked by a different color (blue, orange and green), develop in the bone marrow. The vessels are shown in white. © Institut Pasteur / Philippe Bousso

The same impact on the heterogeneity of tumor cells has also been observed in response to immunotherapies that release the brakes on the immune system, an approach which was awarded the Nobel Prize in Physiology or Medicine this year.

This research shows that taking into account the interaction between immunotherapies and tumor heterogeneity could contribute to the development of optimum therapeutic combinations and sequences.

In addition to the organizations mentioned above, this research was funded by the Fondation de France, the French National Cancer Institute (INCa) and the European Research Council (ERC).

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