Tag: Medicine

Phages are viruses that attack bacteria. Many phages can exist in one of two states: active (lysis), in which the phages attack and destroy bacteria, or dormant, in which they remain passive within the bacteria, replicating themselves but doing no damage (lysogeny). Phages of this type must decide whether to be active or dormant every time they infect a new host. If they decide to be dormant for a time, they must also decide when to ‘wake up’ and attack. As in all dilemmas, it’s important to base the decision upon solid, reliable information.

Researchers at Tel Aviv University have discovered that just like humans with Game Theory, phages weigh all their options and make an informed decision on whether it is time to exit the dormant state and attack their bacterial host. The study was led by Prof. Avigdor Eldar of The Shmunis School of Biomedicine and Cancer Research at Tel Aviv University, together with his students and partners from the Weizmann Institute of Science. The paper was published in December 2021 in the journal Nature Microbiology.

According to the researchers, it has been assumed for some time that a phage bases its decision to exit the dormant state on information regarding the condition of its bacterial host: when the host shows signs of substantial DNA damage (death throes, so to speak), it is in the phage’s interest to leave it and try to infect other bacteria.

The new study discovered an additional mechanism of communication between bacteria and phages: apparently, some phage families have developed a more complex decision-making strategy, a kind of ‘phage game theory’, in which the phage receives information not only from its own host but also from neighboring bacteria.

What’s Going On in The Neighborhood?

Prof. Eldar explains: “When a phage is dormant within a bacterial cell, it forces its host to constantly produce small communication molecules called arbitrium, to which the phage listens via a special receptor. Thus, the presence of high levels of these molecules indicates that neighboring bacteria also contain phages. When this happens, even if its own host exhibits DNA damage, the phage refrains from becoming active. Since every bacterium can only host one dormant phage, the phage makes an informed decision: it’s better to let the host try to repair itself than to ‘betray’ it, since all neighboring bacteria are already taken.”

Prof. Eldar and his team used a range of genetic and biomolecular methods to track the biochemical communication signals passing between the bacteria and phages. In a former study they used a fluorescent marker to show that communication methods used by phages, as well as a large family of similar communication systems (know generally as ‘quorum sensing’) are used only to get signals from close neighbors. “Essentially, the bacteria have developed two separate communication systems – one for long-range communication, and the other for short distances only, used to sense the state of their immediate neighbors,” says Prof. Eldar. “In the phage’s case, it controls communication, and is only interested to know whether its close neighbors, which it might easily infect, are already occupied.”

Prof. Eldar concludes: “Several years ago, Prof. Rotem Sorek and his team at the Weizmann Institute identified communication between phages for the first time. Such systems had been known to exist between other molecular parasites hosted by bacteria (called plasmids). Our new discovery is the fact that phages use communication even in their dormant state. We have identified components critical for understanding how phages combine information about their host’s condition with information about their neighbors. This is one more important step on the way to deciphering the communication and ‘behavioral economics’ of viruses. Phages have an excellent ability to process information and make the right decision to ensure optimal survival. It will be interesting to see whether viruses residing in more complex organisms but facing similar decisions have also developed comparable systems of communication.”

Our brain has a large amount of G protein-coupled receptors (GPCR). Activation of these proteins causes a chain of chemical reactions within the cell. These proteins are very common in the brain and are involved in almost every brain activity, such as learning and memory. The nerve cells in which GPCRs are common, experience changes in their electrical voltage.

20 years ago, it was unexpectedly discovered that GPCRs are voltage-dependent, meaning that they sense the changes in the electrical voltage of nerve cells and change their function. However, to date, it has not been clarified whether the voltage dependence of GPCR proteins has a physiological significance that affects brain activity, our perception, and behavior. In fact, the scientific mindset was that this voltage dependence has no physiological significance.

The study, published recently in the prestigious journal Nature Communications, was conducted by Dr. Moshe Parnas and his team from the Sackler Faculty of Medicine and the Sagol School of Neuroscience at Tel Aviv University.

The Protein that Influences our Sense of Smell

Dr. Parnas and his team investigated, by means of the olfactory system of the fruit fly, whether the voltage dependence of GPCRs is important for brain function. To this end, the researchers decided to focus on one receptor from the G protein-coupled receptor family called “Muscarinic Type A”. This protein is involved, among other things, in habituation to an odor, a process in which the intensity of the reaction to the odor decreases as a result of continuous exposure to it. Thanks to this mechanism, a few minutes after entering a room containing a distinct odor – we stop smelling it.

Dr. Parnas explains: “Nerve cells are able to communicate with each other and brain flexibility is expressed in the ability of nerve cells to set up new connections with each other and change existing connections – and thus influence behavior. Muscarinic Type A protein is involved in strengthening the bond between nerve cells, and strengthening of this bond causes fruit flies to get used to the odor and indicates normal brain flexibility.”

During the course of the study, the researchers were able to neutralize the voltage sensor of the “Type A” Muscarinic protein by means of genetic editing, and thus eliminate its dependence on the electrical voltage of the nerve cell. The researchers found, by applying molecular, genetic and physiological methods, that disabling the voltage sensor actually causes uncontrolled brain flexibility and consequently the process of excessive and uncontrolled habituating to an odor.

Dr. Moshe Parnas

Control Mechanism Uncovered

Dr. Parnas adds: “We found that the receptor in question is very much involved in strengthening the intercellular bond in the brain, much more than what we thought. When we turned off its voltage sensor, the connection between the nerve cells became too strong.”

According to Dr. Parnas, “These findings change our perception of G-protein-coupled receptors. To date, no reference has been made to the effect of electrical voltage on their function and its implications on brain flexibility and conduct. These receptors are involved in many systems and brain diseases and we have now discovered a control mechanism upon which an attempt at drug treatment can be based.”

“Following this, we are continuing to investigate additional receptors. It is reasonable to assume that their dependence on the electrical voltage is important in other systems and not only in the olfactory system [i.e. the bodily structures that serve the sense of smell].”

This study by Dr. Parnas is a follow-up to a study conducted by his parents about two decades ago, which focused solely on the protein level. The current study by Dr. Parnas and his team advances to the next stage, connecting molecules, brain and conduct and indicating, for the first time, that eliminating their ability to sense electrical voltage affects brain activity and our ability to optimally adapt to the environment.

Autism is a neurodevelopmental disease, and its main symptoms are social deficiencies and compulsive behaviors. Cases range from mild to severe, and causes are both genetic and environmental. Researchers at Tel Aviv University have successfully treated autism in animal models with medical cannabis oil, improving behavioral and biochemical parameters.

Advancing in Reverse Order

In about 1% of all autism cases, a mutation in a single gene, called Shank3, is associated. While testing of medicinal cannabis traditionally begins with humans, in the current study PhD student Shani Poleg and Prof. Daniel Offen of TAU’s Sackler Faculty of Medicine, Felsenstein Medical Research Center and Sagol School of Neuroscience used animal models with a mutation in Shank3 to test the effectiveness of cannabis oil for alleviating symptoms of autism. The results of the surprising study were published in Translational Psychology published by Nature.

“We saw that cannabis oil has a favorable effect on compulsive and anxious behaviors in model animals,” says Shani Poleg. “According to the prevailing theory, autism involves over arousal of the brain which causes compulsive behavior. In the lab, in addition to the behavioral results, we saw a significant decrease in the concentration of the arousing neurotransmitter glutamate in the spinal fluid – which can explain the reduction in behavioral symptoms.”

A Little Euphoria Makes All the Difference

Attempting to determine which components of cannabis oil alleviate symptoms of autism, the researchers found that THC, the main psychoactive compound in cannabis which is responsible for the euphoric sensation associated with its use, is effective in treating autism, possibly even in small quantities.

“Clinical trials testing cannabis treatments for autism usually involve strains containing very large amounts of CBD – due to this substance’s anti-inflammatory properties, and because it does not produce a sense of euphoria,” explains Poleg. “Moreover, the strains used for treating autism usually contain very little THC, due to apprehension regarding both the euphoria and possible long-term effects.”

“In the second stage of our study we inquired which active substance in cannabis causes the behavioral improvement, and were surprised to discover that treatment with cannabis oil that contains THC but does not contain CBD produces equal or even better effects – both behavioral and biochemical. Moreover, our results suggest that CBD alone has no impact on the behavior of model animals.”

Addressing Existing Misinformation

Prof. Daniel Offen says, “Since cannabis is not defined as a medication, trials have already been conducted in children and adolescents with autism – without any preliminary studies addressing issues like the effect of cannabis on biochemical processes in the brain, spinal fluid or blood, and who can benefit from which type of cannabis oil. There is a great deal of misinformation on the subject of medicinal cannabis and autism, and Shani Peleg’s doctoral project represents pioneering basic research with regard to treating autism with cannabis oil.”

“This is an initial study,” concludes Poleg. “But we hope that through our basic research we will be able to improve clinical treatments. Our study shows that when treating autism with medicinal cannabis oil there is no need for high contents of either CBD or THC. We observed significant improvement in behavioral tests following treatments with cannabis oil containing small amounts of THC and observed no long-term effects in cognitive or emotional tests conducted a month and a half after the treatment began.”

A new study from Tel Aviv University found that mothers devote only 25% of their attention to their toddlers while using smartphones, a practice which may impair child development. The researchers believe the findings are applicable to fathers as well.

To conduct the study, researchers monitored dozens of mothers who were asked to perform three tasks alongside their toddlers, aged two to three: Browse a specific Facebook page and like videos and articles that interest them; read printed magazines and mark articles that interest them; and finally, play with the child while the smartphone and magazines were outside the room (uninterrupted free play).

The goal was to simulate situations in real life where the mother has to take care of her child, while at the same time devoting some of her attention to her smartphone. To encourage natural behavior, the mothers were unaware of the purpose of the experiment when browsing a smartphone or reading a printed magazine compared to periods of uninterrupted free play.

The results of the new study, which was led by Dr. Katy Borodkin of the Department of Communication Disorders at The Stanley Steyer School of Health Professions, Sackler Faculty of Medicine of Tel Aviv University, were published in the top-tier Journal of Child Development.

When Mom Reads a Really Good Post

“The mothers talked up to four times less with their children while they were on their smartphones,” said Dr. Borodkin. Not only did they exchange fewer conversational turns with the toddler, the quality of the interactions was also poorer, as the mothers provided less immediate and content-tailored responses, and more often ignored explicit child bids. “Even when they were able to respond while browsing Facebook, the quality of the response was reduced – the mothers kept their responsiveness to a bare minimum to avoid a complete breakdown in communication with the toddler.”

While the researchers did not find that one medium distracted the mothers more than the other between smartphones and magazines, Borodkin noted that: “It is clear that we use smartphones much more than any other media, so they pose a significant developmental threat.

While the study focused on the mothers, the researchers believe the findings characterize communication interferences between fathers and their toddlers as well, since the smartphone usage patterns are similar between men and women.

WATCH: Dr. Katy Borodkin explains how extensive use of smartphones by parents might damage toddlers’ development

Parents, Put Your Phones Away! 

As the mothers performed the tasks, the researchers assessed three components of mother-child interaction: They first examined maternal linguistic input, the spoken content that the mother conveys to the child, regarded as an important predictor of a child’s speech development. Previous studies revealed that reduced linguistic input leads to decreased vocabulary in children, a shortcoming that may extend to adulthood.

Next, the researchers examined how interactive the discourse was. Known as “conversational turns,” the back-and-forth discourse between parent and child is a predictor of language and social development, as the child learns that he or she has something to contribute to the interaction as well as the basic social norms of social interactions.

Finally, maternal responsiveness was examined through the extent the mother responded to their child’s speech. This was measured by the immediacy of the response and its contingency on what the child said. For example, when the child says “look, a truck”, there is no comparison between a response such as “yes, that’s great” and a response such as “correct, this is a red truck, like the one we saw yesterday”. This measure is the basis for almost every aspect of child development: linguistic, social, emotional, and cognitive.

“We currently have no evidence suggesting an actual effect on child development related to the parental use of smartphones, as this is a relatively new phenomenon. However, our findings indicate an adverse impact on the foundation of child development. The consequences of inadequate mother-child interaction can be far-reaching.”

A Tel Aviv University-led research team has uncovered a core mechanism that causes ALS and has succeeded in reversing its effects. While the root cause of ALS remains unknown, the discovery reveals the basic biological mechanism that leads to nerve destruction in the early stages of the incurable disease that afflicts an estimated one out of every 400 people. 

To date, there is no effective treatment to prevent or halt disease progression. The average life expectancy of ALS patients is approximately three years from diagnosis. “This discovery can lead to the development of new therapies that could enable nerve cells to heal before irreversible damage occurs in the spinal cord,” said lead investigator Prof. Eran Perlson of the Sackler Faculty of Medicine and the Sagol School of Neuroscience at TAU. 

New Tool for Combating the Disease 

The team discovered that an abnormal buildup of a protein called TDP-43 in neuromuscular junctions, which translate brain signals into physical movements, leads to the degeneration and death of nerve cells (motor neurons). They found that this hinders the activity of mitochondria, which are critical for cells to function.  

The researchers found that this process occurs during the early stages of ALS, initiating damage to motor neurons before patients develop serious symptoms. Eventually, the deterioration of nerve cells in the brain and spinal cord causes ALS patients to gradually lose voluntary muscle ability, leading to complete paralysis including the inability to breathe independently. 

Reversing the Domino Effect  

Using an experimental molecule (originally developed to enhance neural regeneration after injury), the team demonstrated its success in dismantling the toxic protein buildup found in ALS patients. Additionally, in lab models, the researchers showed that this approach actives the process of nerve regeneration, leading to almost complete rehabilitation from the disease. 

Together with Dr. Amir Dori, director of the clinic for neuro-muscular diseases at Sheba Medical Center, and scientists from the US, UK, Germany and France, Perlson and doctoral students Topaz Altman and Ariel Ionescu conducted the study through a series of experiments. The findings were published in the peer-reviewed journal Nature Communication.

Featured image: Prof. Eran Perlson

An extensive TAU-led international study found that an experimental drug, which has already been awarded orphan drug designation by the FDA for future treatment of a rare development disorder, may also be used for treating a variety of symptoms relating to autism, intellectual disability, and Alzheimer’s disease.

The drug, NAP, was discovered in the lab of Prof. Illana Gozes of the Tel Aviv University Sackler Faculty of Medicine’s Department of Human Molecular Genetics and Biochemistry. The latest study is an important milestone on the way to developing a drug, or drugs, that will help children with autism stemming from genetic mutations, as well as Alzheimer’s patients.

Groundbreaking Technology

In recent years, the FDA has granted the experimental drug with orphan drug designation and pediatric rare disease designation for treatment of a rare developmental disorder called ADNP syndrome, which can cause a variety of symptoms, among them intellectual disability and autism spectrum disorder.

In the current study, a team of researchers led by Prof. Gozes (also from Sagol School of Neuroscience) developed an innovative lab model and found that NAP can be effective in treating a broad spectrum of symptoms of ADNP syndrome, which is caused by mutations in the ADNP gene (essential to cerebral development and protecting cerebral brain cells). Previous studies showed that ADNP syndrome is related to Alzheimer’s disease and certain types of mental disabilities, developmental delays, and autism.

The study, which is the culmination of the MD/PhD student Dr. Gideon Carmon’s doctoral research, was joined by a team of researchers from Prof. Gozes’s lab: Dr. Shlomo Sergovich, Gal Hacohen-Kleiman, Inbar Ben-Horin-Hazak, Dr. Oxana Kapitansky, Alexandra Lubincheva, and Dr. Eliezer Giladi. The team was further joined by Dr. Moran Rubinstein, Prof. Noam Shomron, and Guy Shapira of TAU’s Sackler Faculty of Medicine, and Dr. Metsada Pasmanik Chor of Tel Aviv University’s The George S. Wise Faculty of Life Sciences. Researchers from the Czech Republic, Greece, Germany, and Canada also participated. The article was published in the prestigious journal Biological Psychiatry.

Important Milestone

Prof. Gozes explained that: “NAP, in fact, comprises a short segment of the normal ADNP protein. We previously found that treatment using NAP corrects the function of human nerve cells afflicted with ADNP syndrome in a laboratory test-tube. In this study, we sought to examine the efficacy of NAP in treating various aspects of the syndrome using a model with the most harmful mutation, which allowed us to view brain development and facilitate remedying of behavioral problems.”

The researchers found that mice suffering from ADNP syndrome demonstrated a broad spectrum of symptoms, including increased rates of neonatal death immediately after birth, slowed development and abnormal stride, primarily among females, as well as poor voice communication.

Cerebral examinations demonstrated additional findings: A relatively small number of synapses (the points of contact between nerve cells), impaired electrophysiological activity demonstrating a low potential for normal cerebral arousal, as well as excessive buildup of the Tau protein in young mice, similar to those in the brains of elderly Alzheimer’s disease patients.

Prof. Gozes: “In the past, we have found that NAP corrects impaired functioning of ADNP that has mutated in the nerve cell model in the culture. We now examined its effect in vivo – in animals modeling the syndrome (ADNP mutation). To our amazement and joy, we discovered that treatment using NAP normalizes the functioning of these mice for most of the symptoms indicated above!”

Prof. Gozes summarized: “In this study, we examined the effect of the ADNP gene’s most prevalent mutation in a broad spectrum of aspects and found extensive impairment in physical and cerebral functioning parallel to the symptoms of autism, developmental delay, mental disability, and Alzheimer’s disease in humans. Similarly, we examined the potential use of the NAP drug for treating these diseases, and discovered that it is effective against most of these symptoms in lab models. This study is an important milestone on the way to developing a drug, or drugs, that will help children with autism stemming from genetic mutations, as well as Alzheimer’s patients.”

Ramot – Tel Aviv University Tech Transfer Company filed a number of patent applications to protect the technology and its implementation and, in collaboration with Prof. Gozes, is raising funds to finance further clinical research. Similarly, Ramot is in discussions regarding commercial collaboration with pharmaceutical companies. “We’re excited by this new discovery and believe that this is groundbreaking technology that will remedy a variety of symptoms and disabilities in a broad spectrum of orphan diseases,” said Prof. Keren Primor Cohen, CEO of Ramot.

Featured image: Prof. Illana Gozes