An international research team, headed by Dr. Tali Ilovitsh from the Biomedical Engineering Department at Tel Aviv University, developed a noninvasive technology platform for gene delivery into cancer cells (breast cancer). The technique combines ultrasound together with tumor-targeted microbubbles. Once the ultrasound is activated, the microbubbles explode like smart and targeted warheads, creating holes in cancer cells’ membranes, and enabling the gene delivery. The two-year research was recently published in the prestigious journal Proceedings of the National Academy of Sciences (PNAS).
Dr. Ilovitsh developed this breakthrough technology during her post doctorate research at the lab of Prof. Katherine Ferrara at Stanford University. The technique utilizes low frequency ultrasound (250 kHz) to detonate microscopic tumor-targeted bubbles. In vivo, cell destruction reached 80% of tumor cells.
Dr. Ilovitsh explains: “Microbubbles are microscopic bubbles filled with gas, with a diameter as small as one tenth of a blood vessel. At certain frequencies and pressures, sound waves cause the microbubbles to act like balloons: they expand and contract periodically. This process increases the transfer of substances from the blood vessels into the surrounding tissue. We discovered that using lower frequencies than those applied previously, microbubbles can significantly expand, until they explode violently. We realized that this discovery could be used as a platform for cancer treatment and started to inject microbubbles into tumors directly.”
Dr. Ilovitsh and the rest of the team used tumor-targeted microbubbles, that were attached to tumor cells’ membranes at the moment of the explosion, and injected them directly into tumors in a mouse model. “About 80% of tumor cells were destroyed in the explosion, which was positive on its own,” says Dr. Ilovitsh. “The targeted treatment, which is safe and cost effective, was able to destroy most of the tumor. However, it is not enough. In order to prevent the remaining cancer cells to spread, we needed to destroy all of the tumor cells. That is why we injected an immunotherapy gene alongside the microbubbles, which acts as a Trojan horse, and signaled the immune system to attack the cancer cell.”
On its own, the gene cannot enter into the cancer cells. However, this gene aimed to enhance the immune system was co-injected together with the microbubbles. Membrane pores were formed in the remaining 20% of the cancer cells that survived the initial explosion, allowing the entry of the gene into the cells. This triggered an immune response that destroyed the cancer cell.
“The majority of cancer cells were destroyed by the explosion, and the remaining cells consumed the immunotherapy gene through the holes that were created in their membranes. The gene caused the cells to produce a substance that triggered the immune system to attack the cancer cell. In fact, our mice had tumors on both sides of their bodies. Despite the fact that we conducted the treatment only on one side, the immune system attacked the distant side as well.”
Dr. Ilovitsh says that in the future she intends to attempt using this technology as a noninvasive treatment for brain related diseases such as brain tumors and other neurodegenerative conditions such as Alzheimer’s and Parkinson’s disease. “The Blood-Brain barrier does not allow for medications to penetrate through, but microbubbles can temporarily open the barrier, enabling the arrival of the treatment to the target area without the need for an invasive surgical intervention.”
Photo: Dr. Tali Ilovitsh
Two scientists from Tel Aviv University – Professor Neta Erez, head of the Department of Pathology at Tel Aviv University’s Sackler School of Medicine, and Professor Tal Pupko, head of the Shmunis School of Biomedicine and Cancer Research at the Life Sciences Faculty, have won the 2020 Nature Research Awards for Mentoring in Science, given by the Springer Nature Group, which is the home of the leading journal Nature.
The prestigious award (which is given in a different country each year), was given in Israel this year, with Tel Aviv University sweeping all the honors for mid-career mentoring. The award is given to scientists who excel in mentoring research students in their laboratories, thus contributing to the development of the future of science — in Israel in particular and in the world in general. Both winners will share the $10,000 prize. They said that the prize was especially moving for them because the ones who had nominated them for it were the very ones whom they mentored — the students and graduates of their laboratories.
Professor Erez, who established a laboratory ten years ago for researching metastasis of breast cancer and melanoma, and who has mentored 16 doctoral candidates and five master’s degree students so far, said, “For me, mentoring is a central part of my identity as a scientist. When a doctoral candidate comes to me, I tell them: ‘You are starting off as my student, and I want you to end up as my peer.’ For that reason, my role as a mentor is not only to accompany the research. My role is to teach my students to think and do research like scientists, and to find their own way in science and in life in general. I am very proud of their accomplishments. Quite a few graduates of the laboratory have been awarded prizes and grants. As of now, four of the students have completed their medical studies and are planning to combine medicine and research. One is a research fellow and a lab manager in an academic setting, another is doing post-doctoral work in the United States, and four others are working as scientists in the biotech industry. In addition, I serve as a mentor for two young researchers who recently established their own laboratories.”
Professor Pupko, who established a laboratory 17 years ago that deals with molecular evolution and bioinformatics, has mentored 18 doctoral candidates so far. “The members of the academic staff are evaluated based on a variety of parameters: research grants, publications and teaching. Another index, which I feel does not receive enough emphasis, is the success of a staff member’s laboratory graduates — the young scientists whom he taught, mentored, and ‘raised.'” I invest a great deal of thought and effort in my students in order to support, encourage, advise, and nurture them. All 12 doctoral candidates who completed their degree in my laboratory have gone on to do post-doctoral work. Four of them are staff members in academia (including three at Tel Aviv University) — a particularly high number for an academic research laboratory. Other graduates of my laboratory hold high-ranking positions in the hi-tech and bio-tech industries. As I see it, a student who excels is better than another three scientific papers. My aim is to raise up generations of researchers in Israel. I see that as my mission.”
The prize committee, which included Professor Karen Avraham of the Faculty of Medicine at Tel Aviv University, announced that it had chosen the two recipients because “it was impressed with their contagious enthusiasm of former students,” who had nominated them for the award. The committee also praised Professor Pupko for his inclusive approach and encouragement of a healthy work-life balance alongside professional excellence, and Professor Erez for her work to advance women in science and for projects that bring her influence as a mentor to wider circles, including ones outside her laboratory.
A new nanotechnology development from an international research team led by Tel Aviv University researchers will make it possible to generate electric currents and voltage within the human body itself through the activation of various organs using mechanical force. The development involves a new and very strong biological material, similar to collagen, which is non-toxic and causes no harm to the body’s tissues.
The researchers believe that this new nanotechnology has many potential applications in medicine, including harvesting clean energy to operate pacemakers and other devices implanted in the body through the body’s natural movements, eliminating the need for batteries and the surgery required to replace them.
The study was led by Professor Ehud Gazit of TAU’s Shmunis School of Biomedicine and Cancer Research at the George S. Wise Faculty of Life Sciences, the Department of Materials Science and Engineering at the Fleischman Faculty of Engineering and the Center for Nanoscience and Nanotechnology, along with his lab team, Dr. Santu Bera and Dr. Wei Ji.
Researchers from the Weizmann Institute and a number of research institutes in Ireland, China and Australia also took part in the study, which was published in Nature Communications.
“Collagen is the most prevalent protein in the human body, constituting about 30% of all of the proteins in our body,” Professor Gazit, who is also Founding Director of TAU’s Blavatnik Center for Drug Discovery, explains. “It is a biological material with a helical structure and a variety of important physical properties, such as mechanical strength and flexibility, which are useful in many applications. However, because the collagen molecule itself is large and complex, researchers have long been looking for a minimalistic, short and simple molecule that is based on collagen and exhibits similar properties.
“About a year and a half ago our group published a study in which we used nanotechnological means to engineer a new biological material that meets these requirements,” Professor Gazit continues. “It is a tripeptide — a very short molecule called Hyp-Phe-Phe consisting of only three amino acids — capable of a simple process of self-assembly of forming a collagen-like helical structure that is flexible and boasts a strength similar to that of the metal titanium.
“In the present study, we sought to examine whether the new material we developed bears piezoelectricity, another feature that characterizes collagen. Piezoelectricity is the ability of a material to generate electric currents and voltage as a result of the application of mechanical force, or vice versa, to create a mechanical force as the result of exposure to an electric field.”
The researchers created nanometric structures of the engineered material, and with the help of advanced nanotechnology tools applied mechanical pressure on them. The experiment revealed that the material does indeed produce electric currents and voltage as a result of the pressure.
Moreover, tiny structures of mere hundreds of nanometers demonstrated one of the highest levels of piezoelectric ability ever discovered, comparable or superior to that of the piezoelectric materials commonly found in today’s market, most of which contain lead and are unsuitable for medical applications.
According to the researchers, the discovery of piezoelectricity of this magnitude in a nanometric material is of great significance, as it demonstrates the ability of the engineered material to serve as a kind of tiny motor for very small devices. Next, the researchers plan to apply crystallography and computational quantum mechanical methods (density functional theory) in order to gain an in-depth understanding of the material’s piezoelectric behavior and thereby enable the accurate engineering of crystals for the building of biomedical devices.
“Most of the piezoelectric materials that we know of today are toxic lead-based materials, or polymers, meaning they are not environmentally and human body-friendly,” Professor Gazit says. “Our new material, however, is completely biological and suitable for uses within the body.
“For example, a device made from this material may replace a battery that supplies energy to implants like pacemakers, though it should be replaced from time to time. Body movements like heartbeats, jaw movements, bowel movements, or any other movement that occurs in the body on a regular basis will charge the device with electricity, which will continuously activate the implant.”
His current focus is on the development of medical devices, but Professor Gazit emphasizes that “environmentally friendly piezoelectric materials, such as the one we have developed, have tremendous potential in a wide range of areas because they produce green energy using mechanical force that is being used anyway. For example, a car driving down the street can turn on the streetlights. These materials may also replace lead-containing piezoelectric materials that are currently in widespread use, but that raise concerns about the leakage of toxic metal into the environment.”
Walking while simultaneously carrying out a cognitive task, like talking on a cellphone or with a companion, happens frequently throughout the day for many of us. The concurrent performance of two tasks requires the ability to split attention. For older people, difficulties performing another task while walking or standing reflect an existing and/or a potential problem concerning both functions. It also means an increased risk of falling, which can have many severe and undesirable consequences for older adults.
Tel Aviv University researchers sought to examine the benefits of very low intensity, non-invasive electrical stimulation of various parts of the brain, on the capability of older adults to walk or stand while simultaneously carrying out a cognitive task, a common dual-task situation that can determine their overall functionality. They hoped that this might improve their ability to perform both tasks simultaneously in a safer manner. The researchers found that when stimulating the dorsal lateral pre-frontal cortex (DLPFC), a cognitive brain area responsible for dividing attention and executive functions, the immediate, negative impact of a dual-task on standing and walking performance was significantly reduced.
The study team under the leadership of Prof. Jeffrey Hausdorff of the Sackler Faculty of Medicine, the Sagol School of Neuroscience, and the Tel Aviv Sourasky Medical Center (Ichilov), and Dr. Brad Manor at Harvard Medical School, as well as researchers from Harvard University, research and medical institutions in the US and Spain, and the Tel Aviv Sourasky Medical Center (Ichilov). The study was published in the Annals of Neurology, the journal of the American Neurological Association. The research was funded by a grant from the US-Israel Binational Science Foundation.
The study cohort included 57 subjects over the age of 70. Each of them was tested by 4 different treatments:
Each treatment included non-invasive stimulation using a very low-intensity electric current for 20 minutes. Immediately upon the conclusion of the treatment, the walking and standing sway of each subject were evaluated, with and without the request to also perform a cognitive task.
The study showed that stimulation of the cognitive area, whether alone or together with the stimulation of the motor area, reduced the negative effects of the cognitive task on walking and standing stability by about 50%. Stimulation of the sensory-motor area alone and sham stimulation did not improve the subjects’ performance. The researchers explain that, since the stimulation is gentle, it does not activate brain neurons but only increases their excitability; in other words, it facilitates the ability of the patient to activate those neurons in his or her brain.
“In our study, we demonstrated that a low-level, gentle stimulation of a specific cognitive area of the brain can improve the performance of older adults when they carry out the double task of walking or standing in place while at the same time performing a cognitive task, at least within the immediate time range,” says Prof. Hausdorff.
“We hope that a series of treatments will lead to similar positive results over a more protracted period: to improve standing stability and walking capability, diminish the risks of falling, and perhaps also enhance cognitive function among the elderly population. This treatment is safe, and we hope that, in time, people will be able to undergo self-treatment in their own homes. Additionally, we foresee the possibility of combining this type of therapy with exercise and other modes of intervention that can help to improve walking, to enhance thinking, and to reduce the risk of falls. There is evidence that combined therapy could prove to be the most effective solution, but further research is required to examine this,” he concludes.
Prof. Ehud Gazit from The Shmunis School of Biomedicine and Cancer Research at The George S. Wise Faculty of Life Sciences and The Department of Materials Science and Engineering at The Iby and Aladar Fleischman Faculty of Engineering, was selected as the International Solvay Chair in Chemistry for 2023. Prof. Gazit, who also heads TAU’s Blavatnik Center for Drug Discovery, is the first Israeli to receive this annually awarded honor and the first scientist to be appointed to the position outside of the United States and Europe.
The Solvay International Institute was founded in Belgium about a century ago and is designed to develop and support creative and groundbreaking research in physics, chemistry and related fields, in order to increase and deepen the understanding of natural phenomena. The Institute organizes annual conferences on physics and chemistry, as well as international workshops for the training of doctoral students and selected topics.
As part of Gazit’s new appointment, he will spend a month or two in Brussels, the capital of Belgium, during which he will give lectures on his field of research. The prestigious nomination has previously been awarded to 15 of the world’s top scientists, including three Nobel laureates in chemistry, the Wolf Prize winner and laureates of other prestigious awards, all from leading institutions in the US and Europe, who are now joined by Gazit.
Gazit is a biophysicist, biochemist and nanotechnologist. His main area of expertise is “Solid State Biology”, an innovative field of study that combines disciplines from physics, chemistry, synthetic and structural biology and materials engineering. He is a world-renowned expert in nanotechnology and biological chemistry, a highly cited researcher who has published more than 350 scientific articles and inventor of more than 100 patents.
Previously, he served as Vice President for Research and Development of the University, as the Chairman of Ramot, Tel Aviv University’s Tech Transfer Company, and as the Chief Scientist of Israel’s Ministry of Science and Technology.
Over the years, Gazit has won a number of prestigious awards and prizes in Israel and around the world, including The Kadar Family Award for Outstanding Research, the Landau Prize in Science and Arts and the Rapaport Prize for Excellence in Biomedical Research. He is a Fellow of the Royal Society of Chemistry in the UK, a Foreign Fellow of the National Academy of Sciences in India and a Member of the European Organization for Molecular Biology.
Gazit stated: “I thank the Solvay Institute for selecting me, a great honor and excitement for me. It is a great privilege for me to join such a prestigious and impressive list of leading researchers. Today I am reminded of the former President of Israel, Prof. Ephraim Katzir, one of Israel’s greatest scientists, and of whom I am one of his academic ‘great grandchildren’ and who organized the Solvay Institute’s Chemistry Conference about 40 years ago. Apart from the personal honor, I am happy and proud to represent Tel Aviv University and the State of Israel in this appointment.”
In the first global-scale study of its kind, researchers used wide-scale data to correlate between the “Green Revolution” in agriculture and the dramatic reduction in infant mortality in the developing world. The Green Revolution was a global effort to increase the global crop yield during the second half of the twentieth century.
“In our study, we sought to use empirical methods based on our hypothesis that larger crop larger yields could improve the level of nutrition of pregnant women and young children, and also increase household income, thus contributing indirectly to improved health,” explained Dr. Fishman, of the TAU Department of Public Policy and the Boris Mints Institute for Strategic Policy Solutions to Global Challenges, who contributed to the research. “During the Green Revolution, there was support for international public agricultural R&D with a focus on developing higher-yielding strains of common staple crops, such as wheat, rice, and corn. By the end of the 20th century, approximately 60% of the developing world’s agricultural lands were using these varieties.”
At the same time, between 1960 and 2000, there was a dramatic improvement in health in the developing world- the percentage of children who died before the age of one was reduced from 20% to 10%. The cause of this improvement has been long-contested and attributed to various public health improvements but the contribution of individual factors, including the impacts of the Green Revolution, has been poorly quantified until now.
The correlation in the study suggests that the Green Revolution was responsible for a decline of some 2.5- 5% in the rate of infant mortality. This represents between 25% to 50% of the overall reduction of infant mortality during that time period.
To conduct the study, the researchers collected detailed data about the mortality rates of 600,000 infants born in 37 developing countries between 1961 and 2000, and cross-referenced them with information about the diffusion of the improved Green Revolution seeds in the place and year of birth of each of these infants. Using sophisticated statistical methods, they estimated the association between these two variables. The analysis found a statistically significant causal link between the two data sets. In locations where improved varieties diffused earlier – in part because of the types of crops grown, there was also a more rapid decrease in mortality rates.
“Our study proves the historical importance of agricultural R&D for the health of the rural populations in the developing world. We showed that improved crop varieties, which thus improved nutrition and income and reduced hunger, saved the lives of tens of millions of children in the second half of the twentieth century, and have most likely also brought about improved health for tens of millions of other individuals not directly visible in the data,” said Dr. Fishman.
According to Dr. Fishman, these findings highlight the continued need to address public health. “Israel, as a global leader in agriculture R&D, has much to offer to the developing world,” he says.
The study was conducted by an international team of researchers from Tel Aviv University, the Indian School of Business, the World Bank, the University of California San Diego, Michigan State University, and Colorado State University. The paper was published in the Journal of Health Economics.
Featured images: TAU Prof. Ram Fishman and agricultural expert Omar Zaidan explain seedling use to farmers in India. Credit: the Nitzan Lab
A new study at Tel Aviv University presents an innovative treatment for deafness, based on the delivery of genetic material into the cells of the inner ear. The genetic material ‘replaces’ the genetic defect and enables the cell to continue functioning normally.
The scientists were able to prevent the gradual deterioration of hearing in mice with a genetic mutation for deafness. They maintain that this novel therapy could lead to a breakthrough in treating children born with various mutations that eventually cause deafness.
The study was led by Prof. Karen Avraham and Shahar Taiber, a student in the combined MD-PhD track, from the Department of Human Molecular Genetics and Biochemistry at the Sackler Faculty of Medicine, and the Sagol School of Neuroscience, and Prof. Jeffrey Holt from Boston Children’s Hospital and Harvard Medical School. Additional contributors included Prof. David Sprinzak from the School of Neurobiology, Biochemistry and Biophysics at the George S. Wise Faculty of Life Sciences at Tel Aviv University. The paper was published in EMBO Molecular Medicine.
Deafness is the most common sensory disability worldwide. According to the World Health Organization there are about half a billion people with hearing loss around the world today, and this figure is expected to double in the coming decades. One in every 200 children is born with a hearing impairment, and one in every 1,000 is born deaf. In about half of these cases, deafness is caused by a genetic mutation. There are currently about 100 different genes associated with hereditary deafness.
Prof. Avraham: “In this study we focused on genetic deafness caused by a mutation in the gene SYNE4 – a rare deafness discovered by our lab several years ago in two Israeli families, and since then identified in Turkey and the UK as well. Children inheriting the defective gene from both parents are born with normal hearing, but gradually lose their hearing during childhood. This happens because the mutation causes mislocalization of cell nuclei in the hair cells inside the cochlea of the inner ear, which serve as soundwave receptors and are thus essential for hearing. This defect leads to the degeneration and eventual death of hair cells.”
Shahar Taiber: “We implemented an innovative gene therapy technology: we created a harmless synthetic virus and used it to deliver genetic material – a normal version of the gene that is defective in both the mouse model and the affected human families. We injected the virus into the inner ear of the mice, so that it entered the hair cells and released its genetic payload. By so, we repaired the defect in the hair cells, and enabled them to mature and function normally.”
The treatment was administered soon after birth and the mice’s hearing was then monitored using both physiological and behavioral tests. Prof. Holt: “The findings are most promising: Treated mice developed normal hearing, with sensitivity almost identical to that of healthy mice who do not have the mutation”. Following the successful study, the scientists are currently developing similar therapies for other mutations that cause deafness.
Prof. Wade Chien, MD, from the NIDCD/NIH Inner Ear Gene Therapy Program and Johns Hopkins School of Medicine, who was not involved in the study, illuminates its significance: This is an important study that shows that inner ear gene therapy can be effectively applied to a mouse model of SYNE4 deafness to rescue hearing. The magnitude of hearing recovery is impressive. This study is a part of a growing body of literature showing that gene therapy can be successfully applied to mouse models of hereditary hearing loss, and it illustrates the enormous potential of gene therapy as a treatment for deafness.
The study was supported by the BSF – US-Israel Binational Science Foundation, the NIH – National Institutes of Health, the ERC – European Research Council, and the Israel Precision Medicine Partnership Program of the Israel Science Foundation.
Cut your finger and lost your sense of touch? There’s hope yet.
Tel Aviv University’s new and groundbreaking technology inspires hope among people who have lost their sense of touch in the nerves of a limb following amputation or injury. The technology involves a tiny sensor that is implanted in the nerve of the injured limb, for example in the finger, and is connected directly to a healthy nerve. Each time the limb touches an object, the sensor is activated and conducts an electric current to the functioning nerve, which recreates the feeling of touch. The researchers emphasize that this is a tested and safe technology that is suited to the human body and could be implanted anywhere inside of it once clinical trials will be done.
The technology was developed under the leadership of a team of experts from Tel Aviv University: Dr. Ben M. Maoz, Iftach Shlomy, Shay Divald, and Dr. Yael Leichtmann-Bardoogo from the Department of Biomedical Engineering, Fleischman Faculty of Engineering, in collaboration with Keshet Tadmor from the Sagol School of Neuroscience and Dr. Amir Arami from the Sackler School of Medicine and the Microsurgery Unit in the Department of Hand Surgery at Sheba Medical Center. The study was published in the prestigious journal ACS Nano.
The researchers say that this unique project began with a meeting between the two Tel Aviv University colleagues – biomedical engineer Dr. Maoz and surgeon Dr. Arami. “We were talking about the challenges we face in our work,” says Dr. Maoz, “and Dr. Arami shared with me the difficulty he experiences in treating people who have lost tactile sensation in one organ or another as a result of injury. It should be understood that this loss of sensation can result from a very wide range of injuries, from minor wounds – like someone chopping a salad and accidentally cutting himself with the knife – to very serious injuries. Even if the wound can be healed and the injured nerve can be sutured, in many cases the sense of touch remains damaged. We decided to tackle this challenge together, and find a solution that will restore tactile sensation to those who have lost it.”
In recent years, the field of neural prostheses has made promising developments to improve the lives of those who have lost sensation in their limbs by implanting sensors in place of the damaged nerves. But the existing technology has a number of significant drawbacks, such as complex manufacturing and use, as well as the need for an external power source, such as a battery. Now, the researchers at Tel Aviv University have used state-of-the-art technology called a triboelectric nanogenerator (TENG) to engineer and test on animal models a tiny sensor that restores tactile sensation via an electric current that comes directly from a healthy nerve and doesn’t require a complex implantation process or charging.
The researchers developed a sensor that can be implanted on a damaged nerve under the tip of the finger; the sensor connects to another nerve that functions properly and restores some of the tactile sensation to the finger. This unique development does not require an external power source such as electricity or batteries. The researchers explain that the sensor actually works on frictional force: whenever the device senses friction, it charges itself.
The device consists of two tiny plates less than half a centimeter by half a centimeter in size. When these plates come into contact with each other, they release an electric charge that is transmitted to the undamaged nerve. When the injured finger touches something, the touch releases tension corresponding to the pressure applied to the device – weak tension for a weak touch and strong tension for a strong touch – just like in a normal sense of touch.
The researchers explain that the device can be implanted anywhere in the body where tactile sensation needs to be restored, and that it actually bypasses the damaged sensory organs. Moreover, the device is made from biocompatible material that is safe for use in the human body, it does not require maintenance, the implantation is simple, and the device itself is not externally visible.
According to Dr. Maoz, after testing the new sensor in the lab (with more than half a million finger taps using the device), the researchers implanted it in the feet of the animal models. The animals walked normally, without having experienced any damage to their motor nerves, and the tests showed that the sensor allowed them to respond to sensory stimuli. “We tested our device on animal models, and the results were very encouraging,” concludes Dr. Maoz. “Next, we want to test the implant on larger models, and at a later stage implant our sensors in the fingers of people who have lost the ability to sense touch. Restoring this ability can significantly improve people’s functioning and quality of life, and more importantly, protect them from danger. People lacking tactile sensation cannot feel if their finger is being crushed, burned or frozen.”
Dr. Maoz’s laboratory:
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