Huntington’s, Alzheimer’s, ALS, and multiple other neurodegenerative diseases have a commonality: they are all characterized by proteins (different ones for each disease) aggregating in neurons within the brain and nervous system. Now, Technion scientists have found that the cells have the mechanisms to clear those aggregates – they just fail to activate them. Their study was recently published in Nature Communications.
Proteins are the building blocks and the functioning units of our body. Any time the body needs something done, specific proteins are generated to accomplish it. To do this, the code for the particular protein is read from the DNA, and the protein is built from sub-units called amino acids. It is then folded into the 3D shape it needs to assume. Other proteins, called “chaperones,” assist in this folding process.
Aggregates form when certain proteins form incorrectly. Instead of performing the function they were supposed to perform, they attach to each other, creating sizeable clusters that not only are useless, but also disrupt the cells’ normal functionality. Ph.D. student Kinneret Rozales and M.D./Ph.D. student Amal Younis, working as part of the research group of Professor Reut Shalgi, examined how the cells respond to the aggregates building up inside them.
Prof. Reut Shalgi
How can we know how a cell feels? We cannot ask it whether it is happy or in pain. But we can examine which genes the cell expresses. We know the cell would activate certain genes when it feels stress. On the other hand, if everything is fine, those genes would not be activated.
Some of what the cell does in response to stress is activating specific chaperones, in an attempt to correct or remove misfolded proteins. But which chaperones are activated? And which ones are needed to solve the problem? A great many different chaperones are encoded in the human DNA. Rozales and Younis examined 66 of them in cells with Huntington or ALS-associated protein aggregates. Some chaperones, they found, only make things worse. But quite surprisingly, they also found chaperones that could eliminate the aggregates, curing the cell. The tools to cure the disease are already within us, encoded by our own DNA!
Kinneret Rozales
Why then, if the necessary chaperones exist, do they not cure patients’ cells before neurons degenerate? “It is not enough that the tools exist in the cell’s toolbox,” said Prof. Shalgi. “The cell needs to realize there is a problem, and then it needs to know which out of the many tools available to it, it should use to solve the problem.”
Unfortunately, the group found, this is where the bottleneck lies. In cells with Huntington-associated protein aggregates, the cells sensed there was a problem, and activated some stress-response chaperones, but not the correct ones. The cells did not know what was causing the stress, or what they should do to correct the situation. With ALS-associated aggregates, things were even worse; the cells did not realize that they need to activate chaperones at all and displayed no signs of stress.
Amal Younis
“The cell is a complicated system,” said Prof. Shalgi in explaining the surprising findings. “Think of your computer: when something is wrong, sometimes you do not realize it at first. It just responds a bit slower than it used to, perhaps, or it throws an error message that you ignore and forget. When you do realize something wrong – in the way of a blue screen or a refusal to start, you, or a technician on your behalf, attempt to diagnose and solve the problem. Sometimes the solution is found straight away, but other times it is something that you never encountered before, and you don’t know which driver needs to be installed, or piece of hardware needs to be replaced. It is the same with our cells: they do not always realize there is a problem, or know how to solve it, even when they do in fact have the tools to do so. The good news is that since the ability is there, we hope future treatments can be developed to activate it and employ the body’s own tools to cure these debilitating neurodegenerative diseases.”
Cells expressing the protein FUS with an ALS-causative mutation (green). This protein generates aggregates within the cells (white arrows). When the chaperone DNAJB14 is co-expressed together with mutant FUS (pink, right panel), cells generate remarkably less FUS aggregates
The study was done in collaboration with the Berlin Lab at the Rappaport Faculty of Medicine and supported by the Israeli Science Foundation (ISF), the ERC, the Prince Center for Neurodegenerative Disorders, and the Rappaport Institute.
For the full article in Nature Communications click here
Ahead of the International Day of Women and Girls in Science, we sat down for an interview with Technion Professor Asya Rolls, a trailblazing scientist who leads a predominantly female research group that studies the effect of the brain on our body
Soul, spirit, mind, consciousness – that something inside us that calls itself “me” – what power does it have over the inner workings of our body? Is it separate from the body, or part of it? Our body has shape, it occupies space. But what shape or form does our thought take? And if it is not a “thing” that exists in space, can it affect the physical?
If the mind is, to use Gilbert Ryle’s words, “the ghost in the machine,” the body being a machine whose nuts and bolts we study, then surely our thoughts, our state of mind, cannot affect its workings. And yet, the placebo effect – belief in the efficacy of a treatment alone causing it to have a positive effect – is taken into account in every medical study, and psychosomatic illnesses, while not fully understood, are well documented. How is that possible?
We sat down with Asya Rolls, Associate Professor in the Ruth and Bruce Rappaport Faculty of Medicine at the Technion, who started her career in our Faculty of Biology. Her Ph.D. was in neuroscience and immunology at the Weizmann Institute, and her postdoctoral work – in the Department of Psychiatry at Stanford University. The subject of how the mind affects the body always interested her, she says. Intuitively, it is a phenomenon observed in everyday life, and commonly accepted among medical practitioners. Good mood helps recovery, stress makes people ill. But scientifically, we didn’t really understand how that happened and what the mechanisms were. What kind of experiments can you conduct, what kind of models do you use to study this question?
Prof. Asya Rolls’ research group
The effect of the brain on the immune system
It is the emergence of new technology that made it possible to explore the connection between mind and body, and specifically, the aspect that interested Prof. Rolls most – the effect of the brain on the immune system. Recently developed methods allowed scientists to see with great precision what neurons are being activated in the brain at any given time, as well as to activate specific neurons themselves. This was the tool Prof. Rolls needed.
She made the mind-body problem the focus of her research. The results were novel, and at the same time so intuitive, that it was a wonder nobody had done this before. “I needed to see those results more than once before I believed common intuition had been right.” Asya Rolls says of her research. “I knew what we found, it seemed right, and that’s exactly why I had to doubt myself. It was very reassuring when groups started reproducing the same results.”
“I needed to see those results more than once before I believed common intuition had been right,” Prof. Rolls says.
Now, she is more confident in the direction her study is taking, and her research opens the way to therapeutic applications and potential improvement to patients suffering from many different conditions.
The placebo effect: mice whose reward system had been activated fought off bacteria considerably better
A patient receives an inert tablet, such as a sugar pill. It’s not supposed to do anything at all, but the patient reports feeling better. This is the placebo effect. What helps the patient feel better if it is not the pill itself?
Previous studies found that taking a pill with the hope it will help you, activates the reward area in the brain. This is the same area that is responsible for our wanting and enjoying such activities as eating and sex – activities necessary for the body to survive and procreate. We perform the activity and are rewarded with a sense of wellbeing. In the case of the sugar-coated pill, the expected positive effect triggers the reward system.
Prof. Asya Rolls
“Feeling better” can mean many things for a patient. “Feeling” is still in the mind. Prof. Rolls sought to see effects on the body. To examine this, her group, in collaboration with Prof. Shai Shen Orr’s research group at the Technion, directly activated the reward system in mice, and then collected blood to test the ability of the mice’s immune system to combat disease. The results, published in Nature Medicine, were undeniable – mice whose reward system had been activated fought off bacteria considerably better. A positive experience, triggered directly in the brain, activated their immune system.
Keeping a positive outlook
“I was keeping a positive outlook,” a cancer survivor recently spoke of her journey to remission in an Israel Cancer Research Fund (ICRF) webinar. “I found the humor in situations, I reminded myself every day of all the things I could be grateful for.”
There is no doubt that this positive outlook helped her mentally. But did it help her physically as well? Prof. Rolls and her research group, in collaboration with Dr. Fahed Hakim (of the Rambam Health Care Campus) and Technion’s Dr. Michal Rahat, tested this question. Once again, stimulating the reward system produced a dramatic effect; tumors were significantly smaller in mice whose reward system was activated. A positive sensation in the brain caused their body to fight cancer with greater effectiveness. These results were published in Nature Communications.
Psychosomatic illnesses: can you switch off symptoms?
In a recent study, published in November 2021 in the prestigious journal Cell, Prof. Rolls’ group explored immune memory. There is an area in the brain called the insular cortex. It is responsible for interoception – the sense of the body’s internal state. This includes feelings like hunger or the need to relieve oneself, heart rate, sexual attraction. If information about an immune response is stored somewhere in the brain, it would make sense for the insular cortex to be involved.
Prof. Rolls’ students, in collaboration with Prof. Kobi Rosenblum of Haifa University, induced bowel inflammation in mice and were able to track which neurons in the insular cortex were activated. Then, they activated those neurons themselves. The neurons acted as a switch; turn them on, inflammation appears, turn them off, inflammation goes away, regardless of whether there is a real reason for inflammation.
Patients with irritable bowel syndrome suffer from repeated digestive tract symptoms that appear to be triggered at least in part by something in the brain – by stress, rather than by some physical cause. Until now, the phenomenon has been hard to explain, and consequently the condition is hard to diagnose and sometimes treated as malingering. Prof. Rolls’ findings support the patients’ experience, and also open the way to treatment – could their symptoms be switched off just like the mice’s symptoms?
Prof. Rolls (right), with graduate student Tamar Koren of her lab
‘Remembering’ previous inflammations
Our body must constantly fight various enemies – bacteria, viruses, and more, Prof. Rolls explains. The better prepared the body is to combat, the better and faster it can defeat whatever comes. So, it’s better to activate the immune system not when the infection is already there, but when the body can reasonably expect it. Activities that particularly expose us to infection include eating and sexual intercourse. These are the same activities that activate the reward system. It makes evolutionary sense for the immune system to also be activated by this trigger, to call up the reserves and prepare for battle.
It is even more effective if the body, remembering where the last attack came from, could mobilize its troops to the same place for the next attack. Like a good military commander, the body does just that – it has the capacity to remember the location of a previous inflammation and activate the immune system in that location again.
Of course, activation of the immune system might be a false alarm, causing diseases such as irritable bowel syndrome. Understanding the mechanism should give us a key to developing treatment.
Healthy mind, healthy body?
If having a positive outlook helps the body fight cancer, are patients who suffer from prolonged sadness due to their condition guilty of not improving faster? If bowel inflammation comes from the brain, is it the patient’s fault that they have recurring episodes? Should we all “think happy thoughts” to make ourselves healthy, and is not being healthy punishment for thinking the “wrong” thoughts? If illness comes from the brain, is it malingering?
It cannot be stressed enough that this is not the case. These are findings in rodents that reveal new mechanisms in biology, but there is a long way to go before we can translate them to clinical reality. Even then, the implications of the lab findings won’t be so simplistic. Understanding the intricate connections between mind and body offers a way to help patients.
A conclusion that can be drawn from these studies is already mentioned by Galen and Maimonides in their writings, and one that we know intuitively to be true. It is not enough for the doctor to prescribe the correct pill. A doctor is not a plumber, nor a car mechanic. It is equally the doctor’s task to offer empathy and encouragement – to help the patient’s mind as well as body to get well.
Fostering interdisciplinary research
In addition to being a trailblazing scientist, Prof. Rolls — who was recently chosen as one of the most influential scientists in Israel for 2021 by Globes — is also a member of the Israel Young Academy. This organization aims to strengthen the relationships among Israeli academia, policymakers and society, to develop the abilities of young scholars in Israel and to promote research and scientific capabilities.
In this capacity, Prof. Rolls is responsible for multidisciplinarity. “The way academic studies are structured,” she says, “one specializes in an increasingly narrow field. One has to, in order to know it well. But this extreme specialization is also limiting – knowledge from a different field might help me answer a question, or better yet – ask a new one. We would like to offer scientists the opportunity to broaden their horizons.”
For a scientist whose research translates René Descartes’ mind-body problem into the field of physiology, this view is hardly surprising.
Story by Tatyana Haykin
A little more about Prof. Asya Rolls…
Age: 47
Position: Associate Professor in the Ruth and Bruce Rappaport Faculty of Medicine at the Technion – Israel Institute of Technology; Head of the Rolls Lab, which is exploring brain-immune interactions
Country of Origin: Russia
Came to Israel in: 1981
What’s your greatest joy at work? The rare moments when you see a completely unexpected phenomenon that suddenly makes sense
Favorite novel:The World of Yesterday by Stefan Zweig
If you weren’t studying psychosomatic effects, what would you be doing? Sleep!
Advice to students: You can’t really plan your life, so at least if you are doing something you are passionate about, you know it will be fun
The COVID-19 pandemic, which has placed a heavy strain on health systems and medical teams, has highlighted the importance of smart technologies for continuous and real-time monitoring of people’s medical conditions. These are mainly wearable devices that monitor important physiological indicators while allowing the patient to go about his daily routine.
The journal Advanced Materials reports on a breakthrough by researchers at the Technion – Israel Institute of Technology that is expected to make a significant difference in this field. The breakthrough, which is featured as the journal’s cover story, is the result of research led by Professor Hossam Haick, postdoctoral fellow Dr. Youbin Zheng, and Ph.D. student Rawan Omar of the Wolfson Faculty of Chemical Engineering and the Russell Berrie Nanotechnology Institute. The system developed by Technion researchers is based on smart micro-needles, which are affixed to a sticker (band-aid) that attaches to the skin. The system continuously monitors the patient’s vital parameters and sends the data to the patient and his/her doctor.
The study, featured on the cover of Advanced Materials journal
Unlike standard medical needles, which are inserted through the skin, reaching blood vessels and nerves, consequently, causing pain and bleeding, the smart microneedles are short and thin and cross only the outer layer of skin. As a result, they cause only minimal discomfort. Despite their length, they monitor important physiological indicators because they reach the interstitial fluid under the skin’s surface and measure different biological and chemical components, including sodium, glucose, and pH level. The transfer of data to the doctor and the patient is done wirelessly through cloud and IoT (“Internet of Things”) technologies. This continuous monitoring, which allows the early detection of various physiological disorders, is essential for the prevention of diseases and other health complications such as heart and kidney diseases, infectious diseases, and more. It eliminates the need for conventional diagnostics such as blood tests that are currently carried out in the clinic, are painful for the patient, and do not provide online or immediate results.
The micro-needle array is attached to the body, reading, and measuring the health parameters from the interstitial fluid under the skin. The measurement results are sent immediately to the patient and doctor’s smartphone using cloud and IoT technologies
Two of the conditions that the new system monitors are hypernatremia and hyponatremia, both related to the level of sodium in the blood. The first means overly high sodium levels, while the second is sodium levels being too low. Both conditions can affect neurological function and even lead to loss of consciousness and coma. Early monitoring can prevent such deterioration. Sodium is an essential element found in blood cells and blood fluid and plays a vital role in transmitting signals in the nervous system as well as other biological functions.
“To adapt the technology to daily life,” Prof. Haick explained, “we have developed a unique band-aid made of a flexible and soft polymer that stretches and contracts along with the skin and therefore does not interfere with any action whatsoever. Since it is important for us that the system be available to everyone, we made sure to use relatively inexpensive materials, so the final product will not be expensive. The technology we’ve developed represents a leap in diagnosing clinical conditions and continuous physiological monitoring at home and in the clinic.”
Prof. Hossam Haick
Prof. Hossam Haick, head of the Nanomaterials-Based Devices Laboratories and Dean of Certification Studies at the Technion, is a leader in a variety of fields combining nanoelectronics, smart sensing, and other technologies for medical applications, some of which are adapted to the needs of the developing world.
Dr. Youbin Zheng completed all his degrees at Lanzhou University in China and came to Prof. Haick’s laboratory as a postdoctoral fellow.
Dr. Youbin Zheng
Rawan Omar is currently a doctoral student in Prof. Haick’s laboratory and a fellow in the Ariane de Rothschild Women Doctoral Program – a program that supports outstanding female doctoral students towards integrating them into key positions in academia and Israeli society.
Rawan Omar
The study was carried out in collaboration with Prof. Miaomiao Yuan and Rongjun Zhang of the Eighth Affiliated Hospital, Sun Yat-Sen University in China.
Video demonstration of the device’s stretch and return to its original size:
For the full article in Advanced Materialsclick here
The Technion – Israel Institute of Technology recently held a gala evening in honor of this year’s 27 new faculty members. Technion President Professor Uri Sivan addressed the audience and began by remarking how his own Technion journey began exactly 30 years ago when he joined the Technion Faculty.
“Most Israeli industry started here at the Technion,” the President told the new faculty members, “and support for the country — its economy and security — is part of the Technion’s DNA. The Technion has always known how to innovate and reinvent itself, and now, as we approach the Technion’s centennial year, we are asking ourselves again, how we can prepare for the next hundred years. Welcome, and I wish you all a successful integration into the Technion family.”
Technion President Prof. Uri Sivan, with new faculty members
Vice-President for Academic Affairs Professor Shimon Marom gave a moving speech, directed at his colleagues in the wider Technion community and the management, saying, “Many fruitful seeds were planted in our soil this year, and the vision of the Technion in the next ten years or so will be that of the trees that have grown from them. Much depends on the ability of the young scientists to measure, reason, doubt, dare, persevere, and strive for truth. But not less depends on us, the soil in which these seeds are planted, and on our dedication to their nourishment … I hope that we successfully face the challenge. I pray that we can provide them with a sense that the Technion is a place, a home, not an IP address but an actual space; a campus rich in academic, intellectual, and educational buzz … I hope they see in us living examples of dedication, openness, integrity, reliability, avoidance of discrimination, and respect of others.”
The new faculty members joining the Technion are: Dr. Naama Lang-Yona from the Faculty of Civil and Environmental Engineering; Dr. Shira Wilkof, Dr. Davida Schumann, Dr. Jonathan Natanian, and Dr. Guy Austern from the Faculty of Architecture and Town Planning; Dr. Michael Levy, Dr. Yitzhak Reizel, and Dr. Dan Bracha from the Faculty of Biotechnology and Food Engineering; Dr. Assaf Yosef Zinger from the Wolfson Faculty of Chemical Engineering; Dr. David Andres Gelbwaser-Klimovsky, Dr. Charlotte Vogt, and Dr. Renana Gershoni Poranne from the Shulich Faculty of Chemistry; Dr. Hila Peleg and Dr. Sarah Keren from theHenry and Marilyn Taub Faculty of Computer Science; Anna Keselman from the Faculty of Physics; Dr. Omri Ram and Dr. Christian Grussler from the Faculty of Mechanical Engineering; Dr. Ariel Rapaport, Dr. Chaim Even-Zohar, Dr. Erez Nesharim, and Dr. Nadav Dym from the Faculty of Mathematics; Dr. Ben Engelhard from the Rappaport Faculty of Medicine; Dr. Dana Harari, Dr. Yevgeni Berzak, and Dr. Atar Herziger from the Faculty of Industrial Engineering and Management; Dr. Alejandro Cohen from the Andrew and Irna Viterbi Faculty of Electrical and Computer Engineering; and Dr. Dustin Lazarovici from the Department of Humanist Studies.
The event was also attended by two faculty members who joined in the spring semester of 2001 – Dr. Luai Khoury and Dr. Yonatan Calahorra, both from the Faculty of Materials Science and Engineering.
Six students – five women and one man – won top honors in the “Jacobs Research Day”, which showcases selected studies of graduate students. This year the research day took place in an online format.
The Dean of the Graduate school, Prof. Dan Givoli, said “All the presentations were of the highest standard, and despite the online format the participation was impressive.”
The research day was attended by students who previously won top honors for their research in their department. The ranking of the winners is divided into two categories: Masters and PhD.
In the PhD category, Yonit Maroudas from the Faculty of Physics won first place for her study on “Topological defects in the nematic order of actin fibers as organization centers of Hydra morphogenesis” under the supervision of Prof. Kinneret Keren and Prof. Erez Braun.
Yonit Maroudas
Lotan Portal from the Faculty of Materials Science and Engineering took second place for her research on “Self-Catalytic Growth of 1D Materials within Dislocations in Gold” under the supervision of Prof. Boaz Fokroy and Dr. Maria Kaufman-Christosov.
Sofia Kuperman from the Faculty of Mechanical Engineering was awarded third place for “Fluid mechanics in single flow batteries with an adjacent channel for improved reactant transport” under the supervision of Prof. Amir Gat.
In the M.Sc. category, Amit Shemaiahfrom the Faculty of Mechanical Engineering won first place for his research on “Adaptable Canopy-like Structure for Underwater Sensing” under the supervision of Prof. Eyal Sussman.
Amit Shemaiah
In second place, was Stav Peled from the Faculty of Biotechnology and Food Engineering for her research on “Oligosaccharide-Lactoferrin (OS-LFH) conjugate particles for selective targeting of proteins to probiotic bacteria in the colon” under the supervision of Prof. Yoav Livni.
Anna Pshenichny-Mamo from the Faculty of Science and Technology Education took third place, for her study of “Natural History Museums Educators’ Conceptions on the Integration of Nature of Science in Guidance” under the guidance of Dr. Dina Cybulski.
Congratulations to all winners!
Technion students will soon create Hebrew Wikipedia entries as part of their coursework.
The Technion’s Social Hub and the Center for the Promotion of Learning and Teaching have teamed up with the NGO Wikimedia to encourage students to write Hebrew Wikipedia articles, with the aim of sharing knowledge with the public and expanding the free knowledge in the fields of science and engineering.
Today, there are more than 300,000 entries on the Israeli Wikipedia site, but there is a shortage of quality and quantity when it comes to STEM subjects – science, technology, engineering, and mathematics.
On January 12, an introductory meeting was held for Technion professors to promote the writing of scientific and technological entries for Wikipedia by Technion students, as part of their academic studies. Hebrew Wikipedia is the fifth largest site in Israel in terms of views, with about 2,000 page views per minute.
Dr. Keren Shatzman, coordinator of academic projects at Wikimedia, explained that the organization is working to expand Wikipedia’s free knowledge base.
“In this framework, we seek to encourage students to write entries in their fields of study, which will increase the quantity and quality of free information,” she said. “Although Wikipedia is not an academic source, about 85% of students in Israel use it as ‘pre-search’ – to understand basic terms and gain background on the subject before turning to academic articles – so it is important that the information is good quality and reliable.”
The meeting was attended by the Head of the Center for the Promotion of Learning and Teaching at the Technion, Dr. Olga Chuntonov; academic chairman of the Technion’s Social Hub Dr. Meirav Aharon Gutman; Social Hub Director Ronit Piso; students and faculty members. According to Dr. Aharon Gutman, the collaboration with Wikimedia is part of the social involvement the Hub is trying to encourage at the Technion. “Writing entries in Wikipedia is an effective way of disseminating knowledge to teachers, students, and anyone who wishes to do independent learning, outside the confines of the campus.”
Dafna Levin, a doctoral student and teaching assistant of the “Issues in Urban Sociology” course – one of the courses that form part of the project – spoke about working with the students. “This is meticulous work,” she said. “Trying to find out what our added value is compared to the English entry.”
Technion students have already participated in writing articles for Wikipedia. The entry “Public Space,” written as part of Dr. Aharon-Gutman’s course, has already received 5,000 views, and “Porosity,” written as part of one of Professor Uri Shavit’s courses, has received about 6,000.
At the January meeting, Zohar Weiss, a graduate student in the urban planning track in the Faculty of Architecture and Town Planning, said that writing the entry on “cooperative housing” combined her personal interest with the professional knowledge she acquired in her studies. “At the end of the day people use Wikipedia to find out about everything, but its impact is even greater because the information reaches a really wide audience, which is really exciting.”
Zohar Weiss
A study carried out at the Rappaport Faculty of Medicine sheds light on the mechanisms that sometimes result in successful chemotherapy, but that lead to the development of cancer metastasis – the main cause of cancer mortality. The article, published recently in Cancer Research, was selected to feature as the cover story and written about in an opinion piece by the magazine’s editors.
Professor Yuval Shaked and doctoral student Jozafina Haj-Shomaly, who led the study, explain that the existing cancer treatments are highly effective and in many cases save lives, as demonstrated in clinical studies and data accumulated over the years. However, they say there are patients who do not respond to this treatment, and in whom the disease breaks out more aggressively afterwards, including metastases in other organs such as the lungs. The article explains the mechanism that causes metastasis after treatment even in cases where it successfully inhibits the initial tumor. The researchers focused on the development of metastases in the lung tissue following chemotherapy for breast cancer.
Breast cancer is the most common malignancy in women; it also occurs in men, albeit at a low rate. The survival rates of Israeli breast cancer patients are increasing thanks to early detection of the disease and the improvement of treatment technologies. However, when the tumor metastasizes to other organs, the chances of recovery plummet. According to the statistics, about 30% of patients diagnosed with early stage breast cancer who are treated conventionally are expected to develop metastases within a few months or years. Metastases from breast cancer are due in part to the breast’s proximity to the lymph nodes in the armpits. This proximity makes it easy for cancer cells to make their way from the breast to the lymphatic system, which is a branched tubular system very similar to the circulatory system. Through the lymph fluid, the cancer cells migrate to other organs such as the lungs, liver, and bones, where they produce metastases.
The question that preoccupies many cancer researchers, in this context, is what conditions encourage the metastatic process and which medical interventions might contain it. According to Prof. Shaked: “Today we know that the metastatic process is not completely random. The metastases thrive in tissues where they find mechanical support and a supportive cell environment.”
Professor Yuval Shaked
Prof. Shaked’s research group discovered in previous studies that LOX, a common enzyme that affects tissue configuration, may alter lung tissue in a way that makes it easier for cancer cells to stick to it and develop metastases. When the researchers inhibited the activity of the same enzyme, a significant reduction in the ability of the cancer cells to attach to the lung tissue was achieved, thus reducing the formation of cancerous metastases.
In the current study, the researchers also focused on the LOX enzyme but this time in a different context – its involvement in the development of metastases following its secretion from specific immune cells: T cells classified as CD8+. The LOX enzyme can also be found in high doses in lung tissue in healthy individuals, however this dose increases rapidly and dramatically in response to chemotherapy. Contrary to popular belief that this enzyme manifests itself in mesenchymal cells, the Technion researchers were surprised to discover that the increased concentration of LOX was due to its increased secretion by the immune cells – those T cells classified as CD8+. The increase in the presence of this enzyme affects the properties of the lung tissue and transforms it into an environment that benefits cancer cells. This phenomenon can explain why some patients undergoing chemotherapy develop metastases even following successful primary care. In brief, chemotherapy affects the lung tissue in a way that makes it more comfortable for cancer cells.
“When we talk about the lung environment in this study,” explained Prof. Shaked, “we refer to the ECM, the extracellular environment within which the cells are located. This is a complex network of proteins that supports the cell structurally and mechanically as well as in terms of various functional aspects. In the current study, we found that LOX’s activity harnesses the extracellular environment in favor of the cancer cells. Following the changes that the T cells and the LOX enzyme cause in this medium, it begins to help the cancer cells grow, survive, move, divide, and cling to each other. Moreover, it can block the entry of normal immune cells and even anti-cancer drugs into the malignant region.”
The study was conducted in a breast cancer model in mice and the anti-cancer drug Paclitixel, but the researchers assume their findings will be relevant to other drugs and cancers, which are expected to be tested in future studies. “We were surprised to find that the mechanisms of action we discovered, which encourage the development of cancerous metastases, are activated not only in response to surgeries as previously found, but also in response to chemotherapy and other drugs that we are currently investigating,” said doctoral student Jozafina Haj-Shomaly.
“Our achievement – the detection of the mechanism that causes a structural change in health by the immune system – may enable the development of combined drugs and treatments that prevent this phenomenon and reduce the chances of developing metastases,” said Prof. Shaked. “We are now working on developing barriers to the different proteins that cause the same structural change in lung tissue. We believe the findings of the studies will lead to an updated definition of the therapeutic bank targets and the use of LOX inhibitors to inhibit metastatic developments.”
The study was supported by the BSF (US-Israel Binational Science Foundation), the ERC (European Research Council), and the ISF (Israel Science Foundation). Doctoral student Jozafina Haj-Shomaly is a fellow in the Ariane de Rothschild Women Doctoral Program – a program that supports outstanding doctoral students towards their integration into key positions in academia and Israeli society.
For the full article in Cancer Researchclick here.
Jozafina Haj-Shomaly (front) and Prof. Yuval Shaked
A collaboration between researchers from the Technion – Israel Institute of Technology and the University of Debrecen, Hungary has led to the development of a novel experimental method that makes it possible to track the motion of a twin boundary at nanometer size scales and microsecond time scales. The paper, published in Advanced Functional Materials, was led by Professor Doron Shilo and the Ph.D. candidate Emil Bronstein of the Faculty of Mechanical Engineering, and Professor Ronen Talmon of the Andrew and Erna Viterbi Faculty of Electrical & Computer Engineering.
Twin boundary motion governs a highly prevalent deformation mechanism called “twinning.” This mechanism is found in a variety of materials (e.g., magnesium, titanium) and material classes (e.g., shape memory alloys, minerals, ferroelectrics). Because of this, understanding the behavior of twin boundaries has a crucial scientific significance and a direct influence on the comprehension of electro/magneto/thermo-mechanical responses of the aforementioned materials, and many more.
It has long been thought that when a material is rapidly loaded (e.g., by a strong, rapid electric impulse), a twin boundary propagates continuously at a velocity determined by the external loading. Contrarily, when a material is slowly loaded (e.g., by slow compression), twin boundary motion is discrete (discontinuous), and is characterized by short durations at which the twin boundary rapidly propagates separated by long durations at which the twin boundary is static. Despite being the same process, the link between the different behaviors (i.e., the responses to slow and rapid loading) has not previously been considered.
The researchers, however, developed a novel experimental method that enables direct tracking of the twin boundary motion by measuring the magnetic dipole changes of the material. The developed method can track the twin boundary during events that last a few microseconds (a millionth of a second) and have a characteristic size of nanometers. As a result, they provide direct measurements of the motion at unprecedented length and time scales. Analysis of the experimental results indicated, for the first time, that twin boundary motion under both slow and rapid loading can be explained by the same theory. The findings of this research have fundamental scientific importance, as well as a potential to improve actuators (motors) that rely on this process and are used in automobiles, aircraft, spacecraft, and biomedical applications.
Now, the researchers work on the development of data-driven, machine learning methods for the analysis of measured signals that will allow similar studies in a variety of materials and phenomena at short analysis times.
An experiment planned and built in the Faculty of Physics at the Technion will be launched to the International Space Station. Called GALI (Gamma-ray Burst Localizing Instrument), the experiment is an innovative gamma-ray (γ-ray) detection system. Placing the system on the space station will help identify the γ-ray radiation that originates from high-energy eruptions in distant galaxies.
It is widely assumed that short γ-ray bursts come from the fusion of two neutron stars, an event that also produces gravitational waves. However, to date, only one such event has been identified (in2017), hence the importance of the development of new detection tools. The detector developed in the Faculty of Physics is based on hundreds of small crystals arranged in a unique 3D pattern. Based on the relative signal received in each crystal, it is possible to reconstruct the location of the eruption with high accuracy.
Led by Professor Shlomit Tarem and Professor Ehud Behar, the research team also includes Ph.D. student Roi Rahin, master’s student Julia Salah, undergraduate Solomon Margolin, research assistants Alex Vdovin and Amir Feigenboim, systems engineer Avner Kaidar, and Hovhannes Agalarian from the Asher Space Research Institute.
L-R: Prof. Shlomit Tarem, Prof. Ehud Behar and Roi Rahin
“The main innovation in our system is in accurately identifying the location of the eruption,” Prof. Tarem said. “Such identification would allow astronomers around the world to direct telescopes to the event, study the eruption and link it to other events such as gravitational waves. Thanks to this unique arrangement, GALI will provide more accurate results than existing detectors, even though its dimensions are much smaller.”
GALI may have applied importance in other areas. According to Prof. Behar, “We found out that the system we developed is also interesting to people outside the world of astrophysics. Our collaborators in the Nuclear Research Center Negev, for example, want reliable and accurate systems that detect radioactive sources from afar. The system we have developed will be able – with required adjustments – to help locate such sources with high accuracy. In these contexts, the system also provides information about the emitting substances; so, it may help to adapt the optimal treatment. This is the context in which we submitted a joint U.S. patent.”
GALI detection system
The GALI experiment is one of 30 Israeli experiments which are managed by the Ramon Foundation for the Rakia mission. The GALI test is scheduled to take off for the International Space Station on May 2022 with the SpX – 25 flight and will be accompanied by the Rakia Mission and supported by the Ministry of Innovation, Science and Technology.
Watch a video explaining the experiment (and others):
The development of drugs and other medical treatments usually begins with basic research, followed by experiments in the laboratory, pre-clinical trials and, finally, clinical trials that confirm both the treatment’s efficacy in humans and its safety. Clinical trials are long and expensive processes that seal the fate of the proposed treatment – whether it will receive approval from the FDA or other authorities, or be rejected. As a result, they play a central and critical role in the development of medical treatments.
A new article by researchers at the Henry and Marilyn Taub Faculty of Computer Science at the Technion – Israel Institute of Technology, in collaboration with Dr. Eric Horvitz of Microsoft Research, describes a specific bias that affects the implementation of these trials’ findings: underrepresentation of women in many clinical trials. The article, which was published in the Journal of the American Medical Informatics Association (JAMIA), depicts the bias and presents a specialized tool that can help compensate for this gender gap, thereby improving medical treatments for women.
According to Technion Ph.D. candidate Shunit Agmon, who conducted the research together with Technion alumna and visiting professor Dr. Kira Radinsky, “Nowadays, we know that different population groups react differently to a given treatment – in particular, women can have a different reaction than men to a treatment. For example, Zolpidem, a drug used to treat sleeping problems, clears more slowly in women and therefore it is important to prescribe a smaller dose for women than for men – which was discovered only after the drug was released to the market. The underrepresentation of women in clinical trials creates a problematic bias that harms the quality of women’s healthcare, including misdiagnosed diseases and adverse drug reactions.”
Dr. Kira Radinsky. Photo credit: Omer Hacohen
Gender bias in clinical trials is not new, and it has in fact worsened following traumatic events, including the Thalidomide affair – a drug that caused numerous birth defects when prescribed to pregnant women to alleviate morning sickness. That tragic episode, which took place in the early 1960s, led to a drastic decline in female participants in clinical trials.
In 1993, laws were passed in the United States that mandated the inclusion of women in these trials and the analysis of results with regards to gender. Yet, female underrepresentation remained a prevalent phenomenon, especially for trials that took place prior to 1993. Agmon points out that other population groups are also underrepresented, including certain age groups, ethnic groups, and other demographics. In some cases, there is also an underrepresentation of men, such as for diseases that are considered more “feminine,” such as fibromyalgia.
Shunit Agmon
In recent years, machine learning models have been introduced to the world of medicine, aiming to improve medical diagnosis, treatment, and prevention. However, Agmon claims that “many of these models are based on biased trials and therefore they ‘inherit’ their biases, and in some cases even amplify them.”
The researchers explored this issue using machine learning tools, including natural language programming (NLP), and vector representation of words (word embeddings) – approaches that enable computers to “understand” texts. They used these methods on 16,772 articles from the PubMed database and allotted each one a “weight” based on the percentage of women in the clinical trials described in each article. This way, they developed an algorithmic tool that enables gender-sensitive use of clinical literature. This algorithm corrects the gender bias and improves the treatments’ suitability for female patients.
The algorithm succeeded in substantially improving predictions for women in various situations, including length of hospitalization, re-hospitalization within a month, and correlation between various diseases. Although the model focused on improving predictions for women, it also significantly improved overall clinical predictions (for men as well).
The researchers expect the JAMIA article to increase awareness of the problems of underrepresentation in research in general and in clinical trials in particular, and to promote additional solutions to improve the quality of personalized medicine.
Mean absolute error for the length of stay prediction task (lower is better), analyzed by gender
Area under the ROC curve for the readmission within 30 days prediction (higher is better), analyzed by gender
Shunit Agmon grew up in the Haifa region and studied in the Technion’s Henry and Marilyn Taub Faculty of Computer Science. After completing her B.Sc. summa cum laude, she worked for Google for two years and then returned to the faculty to pursue a master’s degree under the supervision of Professor Assaf Schuster. After receiving her M.Sc., she began her doctoral studies under the supervision of Dr. Kira Radinsky and Professor Benny Kimelfeld.
