Tel Aviv University – Latest Israeli Medical Research
For the first time under laboratory conditions
New study at Tel Aviv University:
Medicinal cannabis oil found effective for treating autism
Prof. Daniel Offen
Researchers at Tel Aviv University, led by PhD student Shani Poleg and Prof. Daniel Offen of the Sackler Faculty of Medicine, Felsenstein Medical Research Center and Sagol School of Neuroscience, have successfully treated autism in animal models with medical cannabis oil. The researchers found that this treatment improves both behavioral and biochemical parameters of autism. The results of the surprising study were published in Translational Psychology published by Nature.
“The usual process for testing new medications involves research in petri dishes, followed by animal models and finally a clinical study in humans,” explains Prof. Offen. “With medicinal cannabis the process has been reversed: treatments began in humans. 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.”
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. In about 1% of all autism cases, a mutation in a single gene, called Shank3, is associated. In the current study researchers at TAU used animal models with a mutation in Shank3 to test the effectiveness of cannabis oil for alleviating symptoms of autism.
“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 overarousal 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.”
Attempting to determine which components of cannabis oil alleviate symptoms of autism, the researchers found that THC, which is responsible for the euphoric sensation associated with the use of cannabis, 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,” says 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.”
“This is of course 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.”
Is ALS Reversible?
Researchers from Tel Aviv University identified the biological mechanism causing nerve destruction in the Motor Neuron disease ALS
A research group from the Sackler Faculty of Medicine and the Sagol School of Neuroscience at Tel Aviv University uncovered, for the first time, the biological mechanism causing nerve destruction in the neurodegenerative disease ALS. The groundbreaking study, led by Prof. Eran Perlson and the doctoral students Topaz Altman and Ariel Ionescu, suggests that the course of this fatal disease can be delayed and even reversed in its early stages. It was conducted in collaboration with Dr. Amir Dori, director of the clinic for neuro-muscular diseases at Sheba Medical Center. The results of the study were published in the prestigious Nature Communication journal.
ALS is the most common type of motor neuron disease, causing paralysis and muscle atrophy. One out of every 400 people will have the disease, and yet it has no effective cure. ALS patients gradually lose their ability to control their voluntary muscle movements, leading to complete paralysis and eventually lose the ability to breathe independently. The average life expectancy of ALS patients is currently only about three years.
“To this day it is unclear what causes the disease”, explains Prof. Perlson. “Only about 10% of the patients carry a familial background with known genetic mutations, but the remaining 90% are a mystery. The paralysis caused by the disease results from damage to the motor neurons, which leads to the degeneration nerve endings and to the loss of muscle innervation. This consequently leads to the degeneration of the nerve and the death of motor neurons in the spinal cord, however until now we could not understand the basic biological mechanism causing the initial damage behind this vicious cascade”.
To solve the mystery, the Tel Aviv University researchers focused on a protein called TDP-43, which had been shown in earlier studies to accumulate in unusual amounts and localization in the brains of about 95% of all ALS patients. Prof. Perlson and his team revealed a novel biological link between the protein’s accumulation and the degeneration of the synapses between the motor neuron endings and the muscles, called neuromuscular junctions, which translate neural commands into physical movements. In muscle biopsies taken from ALS patients the researchers found that the toxic protein accumulates also in high proximity to these neuromuscular junctions during the early stages of the disease and before patients develop any serious symptoms. In a series of experiments performed by the researchers, both in cells of ALS patients and in genetically modified model animals, they discovered that the accumulation of the TDP-43 protein in the neuromuscular junction inhibits the ability to locally synthesize proteins that are essential to mitochondrial activity, which provides the power of fundamental cellular processes. The dysfunction of mitochondria in nerve terminals leads to neuromuscular junction disruption and ultimately to the death of the motor neurons. “It’s important first to understand the spatial complexity of motor neurons”, says Prof. Perlson.
“The motor neurons are found in the spinal cord and need to reach every muscle in the body in order to operate it. One can imagine, for example, an extension cable coming out of the spinal cord and reaching the muscles in the little toe in our foot. These extensions can be as long as one meter in adults and are called axons. In earlier studies, we have shown that to maintain this complex organization motor neuron axons require an increased amount of energy, particularly in the most remote parts, the neuromuscular junctions. In our current study, we focused on a pathological change in TDP-43 protein that takes place in these axons and at neuromuscular junctions. In a normal motor neuron, this protein is mainly found in the nucleus. We showed that in ALS this protein exits the nucleus and accumulates throughout the entire cell and particularly in the neuromuscular junction. As the function of motor neurons depends on these neuromuscular junctions located on the remote end of the “extension cable”, we realized that this finding could be of critical importance. We discovered that the accumulations formed by the TDP-43 protein in neuromuscular junctions trap RNA molecules and prevent the synthesis of essential proteins to mitochondrial function. Mitochondria are organelles found in cells and are the main energy providers for numerous cellular processes, including neural transmission. The condensation of TDP-43 protein in neuromuscular junctions results in a severe energy depletion, prevents mitochondrial repair, and consequently leads to the disruption of these junctions, degeneration of the entire ‘extension cable’ and to the death of motor neurons in the spinal cord.”
In order to confirm their findings, the Tel Aviv University researchers decided to use an experimental molecule recently published by a group of researchers from the US for developed for another purpose – enhancing neural regeneration after injury by the disassembly of protein condensates in neural extensions. The researchers proved that this molecule could also disassemble the axonal TDP-43 protein condensates in cells from ALS patients, and that this process improved the ability to produce essential proteins, enhanced mitochondrial activity, and prevented neuromuscular junction degeneration. Additionally, in the model animals, the researchers showed that by reversing TDP-43 accumulation in nerves and neuromuscular junction enabled recovery of degenerated neuromuscular junctions – and to rehabilitate the diseased model animals almost completely.
Prof. Eran Perlson
“The moment we induced the disassembly of TDP-43 protein condensates, the nerves’ ability to produce proteins was recovered, particularly the synthesis of proteins essential to mitochondrial activity. All this made it possible for the nerves to regenerate”, summarizes Prof. Perlson. “We were able to prove, through pharmacological as well as genetic means, that motor nerves can regenerate – and that patients can have hope. In fact, we located the basic mechanism, as well as the proteins responsible for the disruption of the nerves from the muscles and for their degeneration. This discovery can lead to the development of new therapies that could either dissolve the TDP-43 protein condensates or increase the production of proteins essential to mitochondrial function, and thereby heal the nerve cells before the irreversible damage that occurs in the spinal cord. We are tackling the problem on the other end – in the neuromuscular junction. And if in the future we could diagnose and intervene early enough, maybe it will be possible to inhibit the destructive degeneration in ALS patients’ muscles”.
The study is an international collaboration with leading scientists from Germany, France, England and the US, with the assistance of Tal Gardus Perry and Amjad Ibraheem from Prof. Perlson’s laboratory.
An illustration showing the TDP-43 protein destructively accumulating in motor nerve extensions, specifically in the neuromuscular junctions of ALS patients, where it traps messenger RNA molecules and prevents the synthesis of proteins essential to mitochondrial function.
Representative images of neuromuscular junctions in model animals used in the experiment. Motor nerves are colored in green and receptors on muscul fibers are colored in purple. The picture on the right was taken at low magnification (100x) whereas the left picture was taken at high magnification (600x).
Representative images showing the neuromuscular junctions of model animals used in the study. Right: healthy neuromuscular junction characterized by complete innervation of the receptors on the muscle (green) by the motor nerve (in red). Center: degenerated neuromuscular junction in diseased model mice, showing the disruption of the motor nerve (red) and the reduction in the receptor area on the muscle in response to the disruption (green). Left: neuromuscular junction in diseased model mice after clearing the TDP-43 protein from nerve extensions. Image demonstrated the renewed innervation the receptors on the muscle (green) by the motor nerve extension (red).
Saving lives with artificial intelligence
State-of-the-art technology will allow physicians to identify patients who are at risk for serious illness ahead of time
Portrait of genomics researcher Noam Shomron in his lab where he displays his paintings and other inspirational objects, such as collected antiques, at the Faculty of Medicine, Tel Aviv University, September 24, 2019.
A new technology developed at Tel Aviv University will make it possible, using artificial intelligence, to identify patients who are at risk of serious illness as a result of blood infections. The researchers trained the AI program to study the electronic medical records of about 8,000 patients at Tel Aviv’s Ichilov Hospital who were found to be positive for blood infections. These records included demographic data, blood test results, medical history and diagnosis. After studying each patient’s data and medical history, the program was able to automatically identify medical files’ risk factors with an accuracy of 82%. According to the researchers, in the future this model could even serve as an early warning system for doctors, by enabling them to rank patients based on their risk of serious disease.
Behind this groundbreaking research with the potential to save many lives are students Yazeed Zoabi and Dan Lahav from the laboratory of Prof. Noam Shomron of Tel Aviv University’s Sackler Faculty of Medicine, in collaboration with Dr. Ahuva Weiss Meilik, head of the I-Medata AI Center at Ichilov Hospital, Prof. Amos Adler, and Dr. Orli Kehat. The results of the study were published in the journal Scientific Reports.
The researchers explain that blood infections are one of the leading causes of morbidity and mortality in the world, so it is very important to identify the risk factors for developing serious illness at the early stage of infection with a bacterium or fungus. Most of the time, the blood system is a sterile one, but infection with a bacterium or fungus can occur during surgery, or as the result of complications from other infections, such as pneumonia or meningitis. The diagnosis of infection is made by taking a blood culture and transferring it to a growth medium for bacteria and fungi. The body’s immunological response to the infection can cause sepsis or shock, dangerous conditions that have high mortality rates.
“We worked with the medical files of about 8,000 Ichilov Hospital patients who were found to be positive for blood infections between the years 2014 and 2020, during their hospitalization and up to 30 days after, whether the patient died or not,” explains Prof. Noam Shomron. “We entered the medical files into software based on artificial intelligence; we wanted to see if the AI would identify patterns of information in the files that would allow us to automatically predict which patients would develop serious illness, or even death, as a result of the infection.”
To the researchers’ satisfaction, following their training the AI reached an accuracy level of 82% in predicting the course of the disease, even when ignoring obvious factors such as the age of the patients and the number of hospitalizations they had endured. After the researchers entered the patient’s data, the algorithm knew how to predict the course of the disease, which suggests that in the future it will be possible to rank patients in terms of the danger posed to their health – ahead of time.
“Using artificial intelligence, the algorithm was able to find patterns that surprised us, parameters in the blood that we hadn’t even thought about taking into account,” says Prof. Shomron. “We are now working with medical staff to understand how this information can be used to rank patients in terms of the severity of the infection. We can use the software to help doctors detect the patients who are at maximum risk.”
Since the study’s success, Ramot, Tel Aviv University’s technology transfer company, is working to register a global patent for the groundbreaking technology. Keren Primor Cohen, CEO of Ramot, says, “Ramot believes in this innovative technology’s ability to bring about a significant change in the early identification of patients at risk and help hospitals reduce costs. This is an example of effective cooperation between the university’s researchers and hospitals, which improves the quality of medical care in Israel and around the world.”
