The study was led by Prof. Ruth Ashery-Padan and Prof. Ran Elkon and their research teams, Mazal Cohen Gulkar, Naama Mesika, Ahuvit David, and May Eshel, from the Department of Human Molecular Genetics and Biochemistry at the Sackler Faculty of Medicine and the Sagol School of Neuroscience at Tel Aviv University. The paper was published in PLOS Biology.

Prof. Ashery-Padan explains that "one of the greater challenges in genetic research today is decoding the genetic mechanisms of complex diseases caused by a combination of several different genetic and environmental factors (rather than an identifiable defect in a single gene). Diabetes, bowel diseases, and various mental illnesses are just a few examples. In our study we chose to focus on AMD, which causes degeneration of the central retina - a major cause of loss of vision at an advanced age in developed countries."

Prof. Elkon adds: "AMD has a significant genetic component. Studies comparing the genomes of people with and without AMD (as well as a range of other complex genetic diseases) have found differences in several genomic regions, probably associated with risk factors for the disease. However, these differences were not detected in any specific gene, but rather in the extensive regions that stretch between the genes, whose functions and modes of operation are still largely unknown. In fact, comparative studies have identified whole genomic regions that are probably related to the disease but were unable to pinpoint any specific feature in these regions and define it as a risk factor. Our study addressed this problem."

The study focused on the cells of a layer of tissue called retinal pigmented epithelium (RPE), which supports photoreceptors in the retina, and is essential for their initial development as well as their survival throughout an individual's lifetime. According to the researchers, this tissue is affected right from the earliest stages of AMD.

Prof. Ruth Ashery-Padan

"Our findings provide new insight into a previously unsolved issue: the functions and mode of operation of genomic sequences located outside the genes, and how they are involved in complex genetic diseases." Prof. Ruth Ashery-Padan

Novel Research Methodology

"First, we wanted to understand the genetic mechanism that activates and regulates the specific activity of pigmented epithelium cells," says Prof. Ashery-Padan. "Through a series of experiments, knocking down different proteins in both a mouse model and human cells, we identified two key proteins, LHX2 and OTX2, which together dictate the expression of many genes unique to this tissue. The proteins act as transcriptional activators - binding to specific regulatory sites in the genome to determine which genes will be expressed in a particular cell."

The next challenge was mapping the precise locations of the two proteins in the genome. The researchers used the innovative technology ChIP-seq – a DNA sequencing method that identifies binding sites where proteins bind to the DNA.

"We found that the binding sites of the two proteins were quite close to each other," explains Prof. Elkon. "Moreover, these same sites had previously been identified as related to risk factors for AMD (namely, sequences that showed differences between people with and without AMD). We assume that due to changes in DNA sequences in these genomic regions, transcriptional proteins cannot easily find and bind with their binding sites. This reduces the expression of the nearby gene regulated by the transcriptional proteins, which encodes an ion channel known as important to eye function. The decrease in the gene's activity affects the entire tissue, increasing the risk for development of AMD."

Prof. Ashery-Padan sums up the study: "In our study we identified two proteins related to risk factors for the complex genetic eye disease AMD. In addition, for the first time, we were able to map the exact genomic sites of these proteins and found that they operate in a region previously identified as related to risk factors for AMD. Our findings provide new insight into a previously unsolved issue: the functions and mode of operation of genomic sequences located outside the genes, and how they are involved in complex genetic diseases. We believe that our novel research methodology will enable the identification and mapping of many other genetic mechanisms related to AMD and other complex genetic diseases."

The study was funded by the Israel Science Foundation and was led by four researchers: Dr. Tami Bar-Shalita of the Sackler Faculty of Medicine at Tel Aviv University who initiated the study, Dr. Yelena Granovsky of the Technion and Rambam Medical Center, and Prof. Irit Weissman-Fogel and Prof. Eynat Gal of the University of Haifa. This study constitutes a framework for the theses of PhD students Tzeela Hofmann and Mary Klingel-Levy, and three articles based on it have already been published or approved for publishing. The present study has been published in the prestigious PAIN journal.

"We know that self-harm could stem from attempts to suppress pain, and it could be that [people with autism] hurt themselves to activate, unconsciously, a physical mechanism of 'pain inhibits pain'." Dr. Tami Bar-Shalita

Self-harm Not Proof of Indifference to Pain

"Approximately 10% of the general population suffer from sensory modulation dysfunction, which means sensory hypersensitivity at a level that compromises normal daily functioning and quality of life. These people have difficulty, for example, ignoring or adapting to buzzing or flickering of fluorescent lights, humming of air conditioners or fans, or the crunching of popcorn by someone sitting next to them in the cinema," explains Dr. Bar-Shalita.

"In previous studies in the lab we found that these people suffer from pain more than those without sensory modulation dysfunction. Since it is known that sensory modulation dysfunction occurs in   people with autism at a rate of 70-90%, it constitutes a criterion for diagnosing autism, and is associated with its severity. We were interested in exploring pain perception in autism, so we asked: do people with autism hurt more than the general population? This question was hardly studied in the lab before we got started."

According to the researchers, for many years the prevalent opinion was that 'people with autism hurt less' or that they were 'indifferent to pain'. Actually, 'indifference to pain' is one of the characteristics presented in the current diagnostic criteria of autism.

The proof of this was, supposedly, their tendency to inflict pain on themselves by self-harm. 

Dr. Bar-Shalita: "this assumption is not necessarily true. We know that self-harm could stem from attempts to suppress pain, and it could be that they hurt themselves to activate, unconsciously, a physical mechanism of 'pain inhibits pain'."

"The results of our study indicate that in most cases, the sensitivity to pain of people with autism is higher than that of most of the population, while at the same time they are unsuccessful at effectively suppressing painful stimuli." Dr. Tami Bar-Shalita

Dr. Tami Bar-Shalita

Contributing to Advancement of Personalized Treatment

This study is a laboratory pain study approved by the ethics committee of the academic institutions and Rambam Medical Center. The study included 52 adults with high-functioning autism (HFA) and normal intelligence – hitherto the largest reported sample in the world in studies on pain among people with autism. The study made use of psychophysical tests to evaluate pain, commonly used in the area of pain study. These methods examine the link between stimulus and response, while the researcher, using a computer, controls the duration and intensity of stimulus and the examinee is asked to rank the intensity of the pain felt by him on a scale of 0 to 100.

The findings have proven beyond doubt that people with autism hurt more. Furthermore, their pain suppression mechanism is less effective.

The researchers conducted a variety of measurements, aimed among other things at examining whether the hypersensitivity to pain derives from a sensitized nervous system or from suppression of mechanisms that are supposed to enable adjustment and, over time, reduce the response to the stimulus. They found that in the case of people with autism, it is a combination of the two: an increase of the pain signal along with a less effective pain inhibition mechanism.

Dr. Bar-Shalita concludes: "our study constituted a comprehensive, in-depth study of the intensity of pain experienced by people with autism. The prevalent belief was that they are supposedly 'indifferent to pain', and there are reports that medical and other professional staff treated them accordingly. The results of our study indicate that in most cases, the sensitivity to pain of people with autism is higher than that of most of the population, while at the same time they are unsuccessful at effectively suppressing painful stimuli. We hope that our findings will benefit the professionals and practitioners handling this population and contribute to the advancement of personalized treatment."

In additional articles soon to be published, the researchers have examined the brain activity of people with autism during pain stimuli, and sub-groups within this population concerning their perception of pain.

After having developed a robot that hears through the ear of a locust, researchers from Tel Aviv University have succeeded in equipping a robot with the sense of smell, using a biological sensor. The sensor sends electrical signals as a response to the presence of a nearby odor, which the robot can detect and interpret. The researchers successfully connected the biological sensor to an electronic system and using a machine learning algorithm, were able to identify odors with a level of sensitivity 10,000 times higher than that of a commonly used electronic device. The researchers say "The sky's the limit," and believe that this technology may also be used in the future to identify explosives, drugs, diseases, and more.

WATCH: The first robot with a biological nose. Only at Tel Aviv University.

“Man-made technologies still can’t compete with millions of years of evolution. One area in which we particularly lag behind the animal world is that of smell perception (…) When they want to check if a passenger is smuggling drugs [at the airport], they bring in a dog to sniff him." Dr. Ben Maoz and Prof. Amir Ayali

Technology Lags Behind Evolution

The biological and technological breakthrough was led by doctoral student Neta Shvil of Tel Aviv University’s Sagol School of Neuroscience, Dr. Ben Maoz of the Fleischman Faculty of Engineering and the Sagol School of Neuroscience, and Prof. Yossi Yovel and Prof. Amir Ayali of the School of Zoology and the Sagol School of Neuroscience. The results of the study were published in the prestigious journal Biosensor and Bioelectronics.

Dr. Maoz and Prof. Ayali explain: “Man-made technologies still can’t compete with millions of years of evolution. One area in which we particularly lag behind the animal world is that of smell perception (…) When they want to check if a passenger is smuggling drugs [at the airport], they bring in a dog to sniff him."

"In the animal world, insects excel at receiving and processing sensory signals. A mosquito, for example, can detect a 0.01 percent difference in the level of carbon dioxide in the air. Today, we are far from producing sensors whose capabilities come close to those of insects.”

The researchers point out that, in general, our sensory organs, such as the eye, ear and nose – as well as those of all other animals – use receptors that identify and distinguish between different signals. Then, the sensory organ translates these findings into electrical signals, which the brain decodes as information. The challenge of biosensors is in the connection of a sensory organ, like the nose, to an electronic system that knows how to decode the electrical signals received from the receptors.

Dr. Ben Maoz and doctoral student Neta Shvil

“Nature is much more advanced than we are, so we should take advantage of that." Dr. Ben Maoz. 

10,000 Times More Sensitive to Smell

“We connected the biological sensor [to the electronic system] and let it smell different odors while we measured the electrical activity that each odor induced," explains Prof. Yovel. "The system allowed us to detect each odor at the level of the insect’s primary sensory organ."

"Then, in the second step, we used machine learning to create a ‘library’ of smells. In the study, we were able to characterize 8 odors, such as geranium, lemon and marzipan, in a way that allowed us to know when the smell of lemon or marzipan was presented. In fact, after the experiment was over, we continued to identify additional different and unusual smells, such as various types of Scotch whiskey. A comparison with standard measuring devices showed that the sensitivity of the insect’s nose in our system is about 10,000 times higher than the devices that are in use today.”

“Nature is much more advanced than we are, so we should take advantage of that," says Dr. Maoz. "The principle we have demonstrated can be used and applied to other senses, such as sight and touch. For example, some animals have amazing abilities to detect explosives or drugs; the creation of a robot with a biological nose could help us preserve human life and identify criminals in a way that is not possible today. Some animals can detect diseases. Others sense earthquakes. The sky is the limit.”

What's next? The researchers plan to give the robot a navigation ability to allow it to localize the odor source and later, its identity. 

Will he be able to retire soon? A working dog searches for hazardous materials at the airport

The research was carried out by PhD student Matan Yechezkel under the supervision of Prof. Dan Yamin, Head of the Laboratory for Epidemic Research and led in collaboration with Prof. Erez Shmueli, Head of the Big Data Laboratory, all from The Iby and Aladar Fleischman Faculty of Engineering at Tel Aviv University. Other collaborators were Dr. Tal Patalon and Dr. Sivan Gazit, Director and Deputy Director, respectively, of KSM, as well as Dr. Amichai Painsky and Ms. Merav Mofaz from Tel Aviv University. The results of the research were published in the prestigious journal, Lancet Respiratory Medicine.

As Prof. Yamin explains: "We wanted to test the safety of booster vaccines against the coronavirus. We conducted a large-scale, two-year clinical study during which we equipped 4,698 Israelis with smartwatches. The smartwatches were used to monitor several parameters such as heart rate, variation in heart activity, quality of sleep, number of daily steps taken, and more. In addition, the participants were asked to fill out daily questionnaires about their health status in a customized application that we developed. Finally, we analyzed data on potential unusual events from the medical files of a quarter of a million randomly selected, anonymous, insured members of the Maccabi Health Services."

Since the medical file contains the date the booster vaccine was administered, researchers were able to compare the condition of the vaccinated patient with his/her baseline condition from 42 days before receiving the vaccine to the condition of 42 days after receiving the vaccine. The data was obtained from the questionnaires, smartwatches, and records of the Maccabi Health Fund.

Prof. Dan Yamin

"We saw clear and significant changes after administration of the vaccine, such as an increase in heart rate compared to the pulse rate measured before vaccination," says Prof. Yamin, "and then we saw a return to the participant’s baseline, i.e., the pulse levels after vaccination returned to their previous levels after six days. Hence, our study confirms the safety of the vaccine."

"The research also allowed us to compare subjective and objective indicators and medical diagnosis of the same participant who received the first booster and a few months later the second booster," explains Prof. Yamin and adds, "We found no difference in the physiological response recorded by the smartwatches and that reported by the participant in the app."

"The smartwatch sensors 'felt' that the vaccine was safe, the vaccinee himself reported that the vaccine was safe, and finally, the doctors determined that the vaccine was safe. The results of the study have far-reaching implications regarding objective testing of vaccine safety in the future." Prof. Dan Yamin

Far-reaching Implications

In the medical literature, twenty-five unusual side effects attributed to the Corona vaccine were reported, and the researchers paid special attention to look for rare cases of inflammation of the heart muscle (myocarditis) and pericarditis. Prof. Yamin and his colleagues checked the frequency of these unusual side effects among a quarter of a million Maccabi members and found no increase in serious incidents of any kind associated with vaccination.

Prof. Yamin concludes: "If the watch reports any minor changes in the muscles, and the participant reports only significant changes he feels, the medical file tells us about unusual events diagnosed by the doctors as well as hospitalizations that may be related to vaccinations, with an emphasis on cardiac events. We did a comprehensive analysis of all those twenty-five unusual side effects, and we did not see an increase in their incidence among those receiving the booster. We found the vaccine to be safe to use. The smartwatch sensors 'felt' that the vaccine was safe, the vaccinee himself reported that the vaccine was safe, and finally, the doctors determined that the vaccine was safe. The results of the study have far-reaching implications regarding objective testing of vaccine safety in the future.”

The study was conducted under the leadership of doctoral student Yuval Werber of the Department of Evolutionary and Environmental Biology at the University of Haifa and his two supervisors, Prof. Yossi Yovel, head of Tel Aviv University’s Sagol School of Neuroscience and faculty member of the School of Zoology, and Prof. Nir Sapir, the Head of the Department of Evolutionary and Environmental Biology at the University of Haifa, and in collaboration with the company WinGo Energy and the entrepreneur Gadi Hareli. The article was published in the journal Remote Sensing in Ecology and Conservation, and the study was funded by a research grant from the Israeli Ministry of Energy.

“Wind turbines are considered a promising technology in the field of renewable energy, but their operation involves a variety of biological challenges," explains Prof. Yossi Yovel. "Today, the only solution to prevent the death of bats is to stop turbine activity at times when the bats are expected to be particularly active. But such interruptions reduce the turbines’ efficiency and the amount of energy they can produce."

"The advantage of the drone is that it is in constant motion and transmits a combination of visual and acoustic signals designed specifically for bats, warning them of danger. When signals are stationary and constant, animals tend to get used to them and eventually ignore them.”

Yuval Werber shares that, “the study, which is part of my doctoral thesis, was conducted in the Hula Valley, an area with a lot of bat activity. We operated the drone at a height of 100 meters – the average height of the center of a wind turbine, and in motion along a path of about 100 meters, back and forth."

"To track the bats’ activity, we used RADAR located on the ground, which allowed for tracking at a height of 100 meters and above, and we added a LIDAR device – a laser-based tool that is used to detect objects at short distances, mainly in the automotive industry – for tracking at a lower height. At the same time, we made acoustic recordings of the bats in flight, using receivers placed at three different heights: one meter, 150 meters, and 300 meters. We used a blimp to elevate the receivers. Importantly, our study was the first in the world to combine these technologies – RADAR, LIDAR and high-altitude acoustic recorders – to track bats.”

"On the one hand, it prevents the killing of bats, and on the other hand, it enables the operation of the turbine and the production of green energy in a safe, continuous and efficient manner." Prof. Yossi Yovel

Effective Bat Repeller

Using a variety of monitoring methods, the researchers compared the bats' normal activity with their activity in the presence of the drone carrying the deterrent device. The findings were unequivocal – the device succeeded in keeping the bats away. With the drone’s presence, the bats’ activity underneath it decreased by about 40 percent, at a distance of up to about 400 meters. On the other hand, their activity increased above the drone’s altitude of 100 meters, up to 800 meters.

“It appears that the device is effective in repelling bats from its immediate environment – the bats sense the visual and ultrasonic signals it emits and choose to fly over it, as we had hoped,” says Prof. Yovel.

“We hypothesize that if the device is activated near a turbine, it will lead the bats to fly over the turbine and out of harm’s way. This is an effective and easily-implemented solution that is reasonably priced, with great benefit to all parties: on the one hand, it prevents the killing of bats, and on the other hand, it enables the operation of the turbine and the production of green energy in a safe, continuous and efficient manner. We intend to carry out a follow-up experiment on a wind turbine site, in order to test the efficiency of the device under these conditions.”