Researchers at the Technion’s Ruth and Bruce Rappaport Faculty of Medicine and the Rappaport Family Institute for Research in the Medical Sciences have discovered a subset of blood cells that predict the success of immunotherapy treatment. These findings are expected to streamline the process of matching an immunotherapy treatment to a specific patient, since it is very important to identify in advance those patients who will react to a given treatment.

The research published in Cancer Cell was led by doctoral student Madeleine Benguigui and post-doctoral fellow Dr. Tim J. Cooper, under the supervision of Professor Yuval Shaked of the Rappaport Faculty of Medicine. They contributed equally to the research and to the article. The translational research is based on RNA sequencing (scRNA-seq), analysis of existing data, pre-clinical models of cancer, and the corroboration of the findings in humans.

Background

Immunotherapy, which is considered one of the most important breakthroughs in the treatment of cancer, is based on the understanding that the natural immune system excels at attacking cancer cells in a selective and precise manner. The problem is that, in many cases, the cancerous tumor tricks the immune system and prevents it from identifying the cells as enemies. Immunotherapy is based on the concept that, instead of attacking the cancer with chemotherapy drugs that also harm healthy tissue, it is preferable to boost the immune system with the goal to identify cancer cells as enemies and let it do the rest of the work on its own.

Despite the remarkable success of the immunotherapy approach for treating cancer, its effectiveness is still limited to around 40% of all patients. This means that many patients receive this harsh treatment without positive results. Consequently, it is crucial to attain a deep understanding of biological reactions to these treatments and to identify biomarkers that can predict the treatment’s future success.

Biomarkers are an important component of personalized medicine, which help physicians make educated medical decisions and formulate optimal treatment protocols adapted to the specific patient and their medical profile. Biomarkers are already being used for immunotherapy treatments, but they are obtained through biopsies – an invasive procedure that can endanger the patient. Moreover, this approach fails to sufficiently take into account the specific patient’s immune profile and its predictive capability is limited. For this reason, a great deal of research in this field – both in industry and in academia – strives to find new ways to predict which patients will respond to immunotherapy treatments.

The research itself

Technion researchers who focused on antibody-based immunotherapy discovered biomarkers that predict a specific patient’s response to the treatment. Since these biomarkers are in the bloodstream, they don’t require taking biopsies from the tumor – an invasive procedure that is not always feasible and, as mentioned, can sometimes endanger the patient.

In brief, the researchers discovered that a protein called STING, that activates the immune system, is triggered by cancerous growths, and is especially pronounced in cancer cells that will respond to immunotherapy treatment. This protein is manifested in interferon protein, which in turn stimulates neutrophils to be differentiated to a specific type (which expresses the protein Ly6E^hi). These neutrophils act directly on the immune system and stimulate it to target the cancerous tumor. Indeed, the researchers discovered that, these neutrophils may help the actual treatment, as their presence in the tumor prompts greater sensitivity to immunotherapy treatment.

The researchers inferred that testing the levels of Ly6E^hi neutrophils in the patient’s blood could serve as an efficient biomarker for predicting the response to immunotherapy treatment. The researchers tested these findings, which were based on pre-clinical studies, on patients with lung cancer and melanoma. These findings are consistent with the analysis of existing data on 1,237 cancer patients who underwent antibody-based immunotherapy treatments. Therefore, they demonstrated the neutrophils’ ability to predict with a high degree of precision, response to immunotherapy in humans.

The technology developed by Prof. Yuval Shaked’s research group was registered as a patent and it is currently in the midst of a tech transfer process with the company OncoHost, in order to continue its development. Prof. Shaked points out that the technology can be used with the ubiquitous flow cytometry device, which can be found in almost every hospital and is approved by the regulatory agencies.

Various research groups from Israel and around the world took part in the research, including physicians and researchers from the Hadassah, Rambam, and Sheba Medical Centers, as well as from the University of Haifa, Heidelberg University (Germany), and Yale University (USA).

The research was supported by a European Research Council (ERC) grant, the Bruce & Ruth Rappaport Cancer Research Center, Israel Science Foundation, National Institutes of Health (USA), Ariane de Rothschild Foundation (Ariane de Rothschild Women’s Doctoral Program scholarship), and the Rappaport Technion Integrated Cancer Center (RTICC) as part of the Steven & Beverly Rubenstein Charitable Foundation Fellowship Fund for Cancer Research.

Click here for the full article: https://www.cell.com/cancer-cell/pdf/S1535-6108(23)00433-6.pdf

From the moment we are born, and even before that, we interact with the world through movement. We move our lips to smile or to talk. We extend our hand to touch. We move our eyes to see. We wiggle, we walk, we gesture, we dance. How does our brain remember this wide range of motions? How does it learn new ones? How does it make the calculations necessary for us to grab a glass of water, neither dropping it, nor squashing it, nor missing it?

Technion Prof. Jackie Schiller and her team examined the brain at a single-neuron level to shed light on this mystery. They found that computation happens not just in the interaction between neurons (nerve cells), but within each individual neuron. Each of these cells, it turns out, is not a simple switch, but a complicated calculating machine. This discovery promises changes not only to our understanding of how the brain works, but better understanding of conditions ranging from Parkinson’s disease to autism. And if that weren’t enough, these same findings are expected to advance machine learning, offering inspiration for new architectures.

Movement is controlled by the primary motor cortex of the brain. In this area, researchers are able to pinpoint exactly which neuron(s) fire at any given moment to produce the movement we see. Prof. Schiller’s team was the first to get even closer, examining the activity not of the whole neuron as a single unit, but of its parts.

Every neuron has branched extensions called dendrites. These dendrites are in close contact with the terminals (called axons) of other nerve cells, allowing the communication between them. A signal travels from the dendrites to the cell’s body, and then transferred onwards through the axon. The number and structure of dendrites varies greatly between nerve cells, like the crown of one tree differs from the crown of another.

The particular neurons Prof. Schiller’s team focused on were the pyramidal neurons. These cells, known to be heavily involved in movement, have a large dendritic tree, with many branches, sub-branches, and sub-sub-branches. What the team discovered is that these branches do not merely pass information onwards. Each sub-sub-branch performs a calculation on the information it receives, and passes the result to the bigger sub-branch. The sub-branch than performs a calculation on the information received from all its subsidiaries, and passes that on. The result is a complex calculation performed within each individual neuron. For the first time, Prof. Schiller’s team showed that the neuron is compartmentalised, and that its branches perform calculations independently.

“We used to think of each neuron as a sort of whistle, which either toots, or doesn’t,” Prof. Schiller explains. “Instead, we are looking at a piano. Its keys can be struck simultaneously, or in sequence, producing an infinity of different tunes.” This complex symphony playing in our brains is what enables us to learn and perform an infinity of different, complex and precise movements.

Multiple neurodegenerative and neurodevelopmental disorders are likely to be linked to alterations in the neuron’s ability to process data. In Parkinson’s disease, it has been observed that the dendritic tree loses branches. In light of the new discoveries by the Technion team, we understand that as a result of that loss, the neuron’s ability to perform parallel computation is reduced. In autism, it appears the excitability of the dendritic branches is altered, resulting in the numerous effects associated with the condition. The novel understanding of how neurons work opens new research pathways with regards to these and other disorders, with the hope of their alleviation.

These same findings can also serve as an inspiration for the machine learning community. Deep neural networks, as their name suggests, attempt to create software that learns and functions somewhat similarly to a human brain. Although their advances constantly make the news, these networks are primitive compared to a living brain. A better understanding of how our brain actually works can help in designing more complex neural networks, enabling them to perform more complex tasks.

This study was led by two of Prof. Schiller’s students: Yara Otor, and Shay Achvat. Yara, an MD-PhD candidate focusing on neuroscience, was in charge of performing the experiments. Shay did the mathematical analysis of the results.

The study was partially supported by the Israeli Science Foundation, Prince funds, the Rappaport Foundation and the Zuckerman Postdoctoral Fellowship.

In peacetime, aside from his research, Professor Aviv Censor has a large following in Israel for his ultra-helpful videos explaining complex math problems for high schoolers.

Since October 7^th, he’s helped Israelis down South navigate the complex logistical and other challenges after the horrific attack.

Likewise active in the Achim LeNeshek (Brothers-in-Arms) organization protesting judicial reform, Aviv took a drastic pivot just 2 days after the attacks on Gaza Envelope kibbutzes.

He took his family and moved in with friends temporarily in Le Havin, 10 minutes north of Beer Sheva, so he could help in the massive Home Front effort.

The local Achim LeNeshek headquarters were quickly converted into a logistical coordination center and Aviv and other volunteers got quickly to work.

The aftermath of the attack, aside from being beyond devastating and totally unprecedented, required a lot of help with even simple things, like armed convoys to evacuate families, bringing medicines and equipment to just-arrived army units, baby food to families who needed it.

There is a strong need to pick vegetables and fruits to prevent them going to waste.

Cows and other domestic animals need to be evacuated or cared for in difficult conditions (army equipment noise, among others).

Vets and cattle ranchers and farm volunteers need transport and other help.

Lots of other non-military needs arise each day.

Just today, he went to sit shiva with various families, to provide comfort to mourners.

The volunteer effort is a truly massive one in the South, just as in the North and Center, a testament to the resilient and helpful spirit of Israel.

The Technion community is immensely proud and supportive of Aviv and our many other volunteers, as well as reservists and soldiers on active duty.

We pray for their safety and for better times very soon.

On the morning of October 7th, Neta Portal and Santiago Perez woke up in their small apartment in Kfar Aza to the sound of warning sirens. They locked themselves in their safe room but were injured by the bullets that penetrated the door. When Santiago realized that the terrorists had thrown a grenade at the safe room door, he pushed Neta out of the window and followed her. While escaping from the apartment, they faced more gunfire from terrorists but managed to evade it and hide under one of the nearby buildings in the kibbutz. Santiago was hit in the back by a bullet, and Neta suffered seven gunshot wounds to her legs.

Both Neta and Santiago survived, injured but hidden, until they were rescued by Neta’s father, Deputy Chief Superintendent Shimon Portal. During her rehabilitation period at the Loewenstein Rehabilitation Center, Neta received a unique orthotic device tailored especially for her. The device will help her to walk while her severely injured ankle is unable to bear weight. The device was developed at the Technion and tailored to Neta based on a three-dimensional scan of her leg. The personalized device was built thanks to a long-standing collaboration between Dr. Dana Solav from the Technion’s Faculty of Mechanical Engineering and Dr. Amir Haim from the Loewenstein Rehabilitation Center. Both were doctoral students at the Technion under the guidance of Prof. Alon Wolf, currently dean of the Faculty of Mechanical Engineering, and have maintained a fruitful professional relationship ever since.

From left to right: Dr. Dana Solav, Neta Portal and Dr. Amir Haim

According to Dr. Solav, the purpose of the device is to enable the recovery of mobility while practicing natural and symmetrical walking under the requirement that the ankle is entirely or partially offloaded. The device effectively transfers weight to the healthy part of the leg above the injured part, allowing walking without causing pain. Moreover, it features an adjustment mechanism that facilitates a gradual and measured increase of weight-bearing of the affected part, according to the level permitted by the clinical condition.

Dr. Solav added that while walking with the device, the knee and hip joints can move and function normally, which helps prevent muscle atrophy and bone density reduction, especially in long-term rehabilitation processes. The three-dimensional scan eliminates the need for a plaster cast, and the computational design process facilitates the fabrication process, which combines a lightweight aluminum frame and 3D-printed parts.

Dr. Solav stated that in peacetime, injuries like Neta’s are uncommon. Unfortunately, in recent months, she has encountered other cases of soldiers with similar injuries. Sometimes, the injuries lead to amputation, but in many cases, doctors try to save the foot and ankle with complex surgeries, and the orthosis can improve the effectiveness of long-term rehabilitation after surgery. Additionally, they believe the orthosis can assist many diabetes patients who cannot walk due to pressure ulcers on the soles of their feet.

Dr. Solav’s research team, which consists of students and engineers, continues to develop and improve the orthosis while exploring its impact on walking. Simultaneously, the team is planning clinical trials in collaboration with Loewenstein Rehabilitation Center, and hoping to see many people improve their walking rehabilitation by using the innovative orthosis in the near future.

Dr. Dana Solav, a faculty member in the Faculty of Mechanical Engineering at the Technion, completed her MSc and PhD under the guidance of Prof. Alon Wolf and Prof. Miles Rubin, and returned to the Technion as a faculty member after completing a post-doctorate at MIT. Her laboratory focuses on biomechanical interfaces, developing medical devices that connect to the body, such as prosthetics and braces, using 3D scans, medical imaging, and computer simulations.

Dr. Amir Haim is the director of the Biomechanical Rehabilitation Unit, the chairman of the Research Authority and a senior physician in the Department of Orthopedic Rehabilitation at the Loewenstein Rehabilitation Medical Center. He is a senior lecturer at the Faculty of Medicine at Tel Aviv University and an outstanding graduate of the combined MD/PhD track at the Technion – a track where participants complete a degree in medicine and a doctorate in philosophy.

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Nanopowders are the basis of many nanotechnologies; Technion researchers coin a new term in the field of nanomechanics: “pseudo-elasticity”

 “In the scientific world today, there are two central schools of thought regarding the way nanocrystals come into contact,” says Prof. Eugene Rabkin of the Faculty of Materials Engineering at the Technion. “One school asserts that the crystals homogenously stretch in order to stick together (elastic deformation), but once they adhere, they return to their original shape. According to the other school of thought, as they approach, the inter-atom forces are strong enough to overcome the individual nanocrystals’ strength and compel them to change shape irreversibly (plastic deformation).”

Metallic nanocrystals have an orderly atomic structure, and the way in which they can undergo plastic deformation is by creating a linear “defect” in the orderly atomic structure. These linear defects, which are called “dislocations”, were first observed under a microscope in the mid-1950s and since then they have served as an important basis for understanding the mechanical characteristics of materials. Because of the size of nanocrystals, they generally have a perfect atomic structure and do not have dislocations.

 “Justification for both schools of thought has been offered, yet without a way to resolve the contradiction between them,” adds Prof. Rabkin. “On the one hand, analytical models have shown that the stresses that are created in nanocrystals during the contact formation are large enough to create a large number of dislocations; on the other hand, in experimental observations, only isolated dislocations were observed in the nanocrystalline clusters, in contradiction to the models.”

In order to resolve the contradiction, the Technion researchers used advanced simulation tools that run on high-performance parallel computer located on campus. “The calculation is performed at the atomic level,” relates Dr. Dan Mordehai who today is a member of the Faculty of Mechanical Engineering at the Technion, but who was a post-doctoral fellow in Prof. Rabkin’s group when the research was conducted. “We describe the nanocrystals using the atoms that comprise them and the forces between these atoms, and thus, we actually allow the atoms to choose their preferred “path”. These calculations include several hundreds of thousands of atoms and we have to execute them on parallel computer – that is, execute the calculation on a number of computers simultaneously.”

The Technion researchers found, for all intents and purposes, that neither of the schools of thought described the process in its entirety. In their simulation they showed that when the nanocrystals approach each other, the force of their interaction rises to become as great as that which creates many dislocations (as predicted by the second school of thought). Nevertheless, during the adhering process between the nanocrystals, additional dislocations are created, which “repair” the defects, and by the end of the adhering process, they no longer have any dislocations, as observed during experiments.

Thus the new nanomechanical term, coined by the Technion researchers, “pseudo-elasticity” was born. This mechanism enables nanocrystals to retain their original shape, despite the forces acting upon them, which are large enough to overcome their own strength limit. This mechanism may have great importance in many additional fields in contact mechanics for each pair of bodies that gets within a few nanometers of each other.

Prof. David Srolovitz, who is the head of the Institute of High Performance Computing in Singapore, participated in this research.

Above: Pictures of the simulations that were performed in the Technion show the process of contact formation between two nanocrystals. (Left) The atomic structure of nanocrystals before contact. (Right) The pseudo-elastic mechanism in action (1 to 8). In order to demonstrate the mechanism, only some of the atoms necessary for the process are shown. One can see that during the process of adhering, many defects are created (the atoms appear in dark grey in pictures 3-7), but at the end, the nanocrystals do not exhibit any defects (8). Illustration: Technion Spokesman.

The Technion is in 42^nd place in Engineering and Technology

Computer science at the Technion was ranked as 15^th in the world (among 500 universities) by the respected Shanghai Ranking published this week. Shanghai Jiaotong University published its list of university rankings – considered especially prestigious and reliable – http://www.shanghairanking.com/index.html. Harvard University tops the list, with MIT heading the engineering and technology rankings.

The Technion is ranked 42^nd in the world in engineering and technology and among the 75 leading universities in life sciences, mathematics and chemistry.

The Shanghai Ranking debuted in 2003 and is intended to improve the level of Chinese universities by comparing them to the top 500 universities in the world. The ranking is based on objective criteria and numerous data. Among the criteria – the number of Nobel Prize and other prestigious award winners, the number of scientific papers published in the leading journals – Nature and Science and other performance relative to the size of the university. The comprehensive Chinese research examines 1000 universities, including the top 500 ones.

Technion President, Prof. Peretz Lavie, said that the high ranking of the Technion in the computer field explains high position of the state of Israel in global high tech. “Research that is now being completed shows that Technion graduates do indeed lead the high tech sector that is moving Israel’s economy forward,” he said. “It turns out that 76% of Technion graduates in the last two decades work in the country’s high tech industry, which is responsible for 51% of the state of Israel’s industrial exports. Of these graduates, 25% are CEOs or deputy general managers, 21% hold other types of management positions, 10% are team leaders and 12.6% are involved in R&D. 59 out of 121 Israeli companies whose shares are traded on NASDAQ were established or are managed by Technion graduates.”