What makes it possible for cancer cells to spread and flourish despite radiotherapy, surgery to remove the initial tumor, chemotherapy and immunotherapy?

Cancer cells may be brainless, but they are as clever as chess players who want to win. They know how to spread (metastasize) to other parts of the body. It is this “skill” that makes malignant tumors the most common cause of death in Israel.

But what makes it possible for such cells to spread and flourish despite radiotherapy, surgery to remove the initial tumor, chemotherapy and immunotherapy?

A novel explanation 

Researchers at the Technion-Israel Institute of Technology in Haifa have just published an article on the subject in iScience, an interdisciplinary open-access journal with continuous publication of research across the life, physical, and earth sciences, titled “Cancer progression as a learning process.”

Aseel Shomar, a Nazareth-born doctoral student in biochemical engineering who is on an Adams Fellowship, together with Prof. Omri Barak and Prof. Naama Brenner, suggested a novel explanation in the hope that better understanding should lead to better treatment. 

They propounded the idea that cancer cells are able to learn and adapt to changing environments by actively searching for solutions that would enable them to survive. Studying cancer using this approach and tools of learning theory will advance our understanding of these phenomena, they said.

It is commonly thought that both drug resistance and the ability to metastasize appear in cancer cells as random mutations. Since such a mutation gives cancer cells an advantage, making it possible for them to survive in an environment that struggles to fight them, these mutations become dominant. 

However, mounting evidence from research groups around the world does not seem to match this hypothesis, and treatment plans based on it did not significantly increase patients’ life expectancy.

But now, the Technion team members have proposed a new hypothesis that matches the evidence at hand: cancer cells learn and adapt to their environment, enabling them to develop drug resistances and conform to the new environments of metastasis locations.

How does a cell learn without a brain? Brenner explained that when sensing stress, the cell seeks to reduce that pressure and launches a trial-and-error process within the gene regulatory network, changing the way existing genes are expressed. An interaction that reduces the stress gets strengthened.

Even so, considering the number of possible configurations the cell can try, it seems unlikely that the process would work. However, using computer simulations based on learning theory, the group showed that cells could in fact learn and adapt in this fashion. 

One element of what makes this feasible is that more than one solution can be found to solve the same problem faced by the cell. Another element is the way the gene regulatory network is structured, with regulatory “hubs” that control parts of it.

Malignant cells are not unique in their learning ability, they said. Brenner, Prof. Erez Braun and others have shown in the past that yeast cells can adapt to new environments and develop abilities they did not initially possess.

Few other labs around the world have demonstrated this effect in simple organisms.

A rare type of discovery

Learning theory – a process that brings together personal and environmental experiences and influences for acquiring, enriching or modifying one’s knowledge, skills, values and behavior – develops hypotheses that describe how this process takes place and provides the mathematical tools to study these phenomena.

The Technion’s Network Biology Research Lab studies the way various biological systems adapt, which is a process that is not fully understood.

Its researchers – who come from a variety of faculties including physics, electrical and computer engineering, chemical engineering and medicine – seek to connect theoretical models to complex and dynamic biological systems.

While tumors that learn and adapt might sound alarming, the Haifa authors were optimistic. While cancer cells have the capacity for learning, normally something holds it back. 

In fact, the same mutations found to promote cancer in our body can be carried by cells that still remain healthy. Even cells from active tumors that wander into healthy tissue were in some experiments “cured,” reverting to their non-cancerous state.

“There is an interaction between the individual cell and the tissue,” Brenner noted. “The cell has the capacity to explore, but the tissue imposes order and stability. We propose that using the approach and methods of learning theory will help investigate this interaction in greater depth. 

“Cancer could perhaps be treated through strengthening the tissue’s ability to calm and control the pre-cancerous cell.”

Most scientific studies add a brick to build the wall of discovery, but this finding is one of a rare type that reexamines existing data and proposes a new framework, offering answers to questions that had until now remained unanswered and opening up new avenues of exploration, they concluded.

Put together Israel’s vast agricultural and technological knowhow, and you’ve got breakthroughs on a global scale.

What is the recipe for meat and dairy without cows? Snacks and sauces with less sugar and salt? Long-lasting fresh produce and compostable food wrappers?

A fast-growing, climate-threatened world is hungry for such recipes. Appropriately enough, the search began in the kitchen — or rather, The Kitchen.

The world’s first food-tech hub was launched in 2015 by The Strauss Group, one of Israel’s largest food producers, as part of the Israeli Innovation Authority’s Technological Incubators Program.

“This doesn’t exist elsewhere,” said The Kitchen’s vice president of business development, Amir Zaidman, in 2016.

Today, The Kitchen has 22 portfolio companies cooking up innovations to feed the world more efficiently, sustainably and securely.

But The Kitchen is no longer alone: Governmental, corporate and academic food-tech labs and incubators are opening across Israel. The number of food-tech startups has risen to approximately 400.

Food-tech (increasingly referred to as agri-food-tech) combines two of Israel’s best assets, says Nisan Zeevi, head of business development at Margalit Startup City #Galilee.

“Our agricultural knowhow, which is one of the wonders of the world, and our technological knowhow that we have built in the past 40 to 50 years. Put them together and you’ve got breakthroughs on a global scale.”

Success is sticky

The Israeli Economy and Industry Ministry reports that food-tech investment nearly doubled between 2013 ($52 million) and 2018 ($100 million) with input from multinationals including Coca-Cola, Mars, Tyson Foods, Nestle, Danone, AB inBev, Starbucks, PepsiCo, McDonalds, Heineken and Unilever.

Tel Aviv research firm IVC found food-tech garnered $432 million in investments in 2020, less than sectors such as cyber and fintech, but growing fast.

“Success stories attract more entrepreneurs into the field,” says The Kitchen’s Zaidman, who was scheduled to speak at the Food Biotech CongressNovember 8-11 and at the first global virtual food trade show, November 21-24.

“Israel is a very entrepreneurial country and both new and serial entrepreneurs are always thinking about the next big thing. They see food-tech is an impact area on environment and health,” says Zaidman.

“Maybe they were hesitant before when looking at the money going into sectors like cyber, but now they see they can get capital investment in food-tech that can be game-changing.”

Zaidman predicts major financing rounds for Israeli food-tech in 2022.

“Startups like [cultivated steak pioneer] Aleph Farms don’t even have products in the market yet. But what they are doing is so amazing they get a lot of attention.”

Indeed, Aleph Farms got a recent investment from Leonardo DiCaprio,  while Ashton Kutcher put money into MeaTech.

Breakthroughs on a global scale

One of the Israeli companies already making inroads in the global market is InnovoPro. Its proprietary process transforms chickpeas – the humble nourishing basis of hummus — into a neutral-tasting protein concentrate for foods and beverages.

InnovoPro has factories in Canada and Germany, and a new subsidiary in Chicago as it launches a chickpea TVP (texturized vegetable protein) for plant-based burgers, nuggets and meatballs. Migros, Switzerland’s largest retailer and supermarket chain, uses InnovoPro’s product in a dairy-free yogurt.

“Hummus is a Middle East product. You take the technology and combine it with Israeli knowhow and – boom — you’ve got a successful food-tech company,” says Zeevi.

Hoping to create similar successes, Jerusalem-based Margalit Startup City inaugurated its Galilee branch in September.

The Kiryat Shmona campus encompasses a food-tech accelerator, institute, executive park and Fresh Start early-stage incubator supported by food giants Tnuva and Tempo along with Finistere Ventures and OurCrowd.

“Five years ago we came to the Galilee and wrote a plan to transform this area into a food-tech and ag-tech center with the involvement of municipalities, service providers, investors, academies and research institutes across the Galilee. The government gave it a budget of 500 million shekels,” says Zeevi.

Margalit Startup City #Galilee has attracted satellite offices of Jerusalem Venture Partners, Cisco, Tel Hai College and the Migal Galilee Research Institute of the Israeli Science and Technology Ministry.

One portfolio company, DynaFresh, was established by Migal post-harvest experts to optimize the shelf life of fresh produce.

“Margalit Startup City is where everything converges at a physical hub and meets the international and business sector,” says Zeevi.

Unlike cyber and fintech, a food-tech company not only needs skilled scientists and technicians but also, after scaleup, factory workers.

This makes food-tech a promising equal-opportunity employment driver for Israel’s northern and southern periphery, says Zeevi.

Hearty investments

Not only existing VCs are investing in food-tech. Israel also has Millennium Food-Tech, an R&D partnership started in June 2020 and traded on the Tel Aviv Stock Exchange.

“There was no specialized vehicle in Israel for the post-seed food-tech startup with proven technology waiting to be piloted and commercialized,” VP Business Development Yossi Halevy tells ISRAEL21c.

“So we built a VC dedicated to food-tech. This is a sector that is untouched.”

Among Millennium’s portfolio companies are SavorEat(alternative protein), Tipa (compostable packaging), TripleW(lactic acid and other upcycled products from food waste), Aleph Farms, and Phytolon (natural food colors).

Halevy, a certified public accountant formerly with E&Y in Tel Aviv, became interested in venture creation in food and agriculture four years ago, when “the ecosystem was in diapers,” he says.

So he jumped at the chance to join his old friend, former Fresh Start director Chanan Schneider, in Millennium Food-Tech.

‘We work with Nestlé and other major food companies,” Halevy tells ISRAEL21c. “It’s a triangle relationship: We use their knowledge for our due diligence, and they use ours for investment and proof of concept.”

Halevy sees ingredient development as one of Israel’s strongest capabilities because it maximizes the country’s well-honed, well-connected multidisciplinary talents.

“Israel is unique from many aspects, but most significant is that everyone knows everyone,” he points out.

“That’s very helpful in food-tech because it has so many disciplines that need to be combined — innovation, entrepreneurship, biotech, physics, chemistry, robotics, computer vision, artificial intelligence. You can easily assemble a team and cross-mine ideas and development.”

Corporations get in onfood-tech 

The food-tech scene in Israel is expanding like a yeasty bread dough into many sectors, from corporate to academic to nonprofit, with governmental participation sprinkled in.

International Flavors & Fragrances, a US-based multinational with operations in Migdal HaEmek in northern Israel, runs the FoodNxt incubator in partnership with the Israel Innovation Authority.

IFF shares its knowledge about industry processes and technologies, international regulations and general food science expertise. The incubator also provides funding and helps portfolio startups build business plans, develop patent strategies and test products.

Salt of The Earth, a global Israeli company in the North founded in 1922, has teamed up with Tel-Hai College for multiple projects, such as testing ingredients at the college’s analytical lab.

Tel-Hai students recently were challenged to create innovations emphasizing sodium reduction and flavor enhancement. They were guided by Salt of The Earth R&D technologist and application manager Rakefet Rosenblatt, a food science graduate of Tel-Hai. 

“We always think about what we can make better,” she tells ISRAEL21c. “Salt is a known product; how can we help the industry use it in a smarter way? Students have great ideas and it’s good to invest in them.”

One group proposed a salt product enhanced with mineral-rich seaweed, using a special process to neutralize the seaweed’s strong flavor and color. Another group developed a savory vegan snack based on chickpea flour and Salt of the Earth’s Mediterranean Umami Bold flavor enhancer.

At the opposite end of Israel, down south in the Negev town of Rahat, seven major companies with a regional presence, such as SodaStream, Netafim and Dolav Plastic Products, joined with academic and VC partners in the IIA’s InNegev incubator for food-tech, ag-tech, clean-tech and Industry 4.0.

“This is our first year of operation. We’re mostly doing venture creation now, utilizing the capabilities of our partners in the Negev,” says Amir Tzach, InNegev’s VP Business Development & Investments.

Among food-tech innovations under consideration at InNegev are post-harvest sensors – one that detects bacteria and another that detects soft rot in potatoes early enough so that the bad potato(es) can be removed before the rot spreads.

In the hot field of alternative protein, InNegev is looking at companies in the South engaged in algae production, and may assist local meat-processing facilities in converting space for alt-protein production.

Academic and nonprofit food-tech

Going back up north, the Carasso FoodTech Innovation Center was inaugurated in September at the Technion-Israel Institute of Technology in Haifa.

The center will house R&D for industrial production, a startup hub, packaging laboratory, industrial kitchen, tasting and evaluation units, and an educational visitor area.

Prof. Marcelle Machluf, dean of the Technion Faculty of Biotechnology and Food Engineering, said that the Covid-19 pandemic “has only emphasized the importance of food and biotechnology in maintaining our existence and meeting future existential challenges. To address the many challenges in this field, including access to healthy, affordable food and innovative medical treatments, we need advanced infrastructure that will enable the integration of new engineering and scientific tools.”

In Tel Aviv, the Israeli not-for-profit Start-Up Nation Central joined forces with global entrepreneur network TiE to advance Israeli and Indian food- and ag-tech solutions for novel foods, post-harvest storage, alternative protein, food safety and packaging.

Israeli startups selected for the mentorship program so far include multiple award-winning grasshopper protein company Hargol, automated cooking manufacturer Kitchen Robotics, vision-based robotic controller Deep Learning Robotics and produce storage humidity control solution UmiGo.

Fighting food scarcity for the future

Start-Up Nation Central CEO Avi Hasson noted that farmers face increasingly harsher weather conditions, environmental pollutants and soil depletion.

Coupled with population growth and increased product demand, these issues increase global concerns about food security.

“Technologies that have the potential to either improve crop yields or transform, preserve, and tailor foods with improved functional and nutritional values will ensure a stable supply of food in the future,” said Hasson.

The Kitchen’s Zaidman predicts that as the sector matures, we’ll see more segmentation.

“For example, Aleph Farms started working on cultivated meat before there was any existing technology. A lot of the innovation we’ll see in the next two to three years will be much more specialized in certain aspects that support this industry,” he explains.

“In terms of global trends, alternative proteins will continue as a strong trend because we’re just scratching the surface of consumer interest. There’s a lot of potential in alternative dairy, seafood and eggs.”

Aviv Oren, business engagement and innovation director of the Israeli branch of the Good Food Institute, says Israel hosts about 100 alt-protein startups and 28 alt-protein research labs in academic institutions.

One of the newest ones, Alfred’s, offers an innovative platform for producing plant-based whole cuts for the meat, poultry, meat analog and cultivated meat industry.

“Israel now ranks second in the world behind the United States in its total number of fermentation and cultivated meat companies,” Oren notes.

GFI Israel Managing Director Nir Goldstein sees Israel’s role as potentially monumental.

“With governmental support in this industry, Israel, which currently exports only five percent of the food it produces, could become a global supplier of raw materials and advanced production technologies for alternative proteins,” he says.

Inexpensive, fast method to make freeform optics could benefit applications from eyewear to telescopes.

Researchers have developed a way to create freeform optical components by shaping a volume of curable liquid polymer. The new method is poised to enable faster prototyping of customized optical components for a variety of applications including corrective lenses, augmented and virtual reality, autonomous vehicles, medical imaging, and astronomy.

Common devices such as eyeglasses or cameras rely on lenses – optical components with spherical or cylindrical surfaces, or slight deviations from such shapes. However, more advanced optical functionalities can be obtained from surfaces with complex topographies. Currently, fabricating such freeform optics is very difficult and expensive because of the specialized equipment required to mechanically process and polish their surfaces.

“Our approach to making freeform optics achieves extremely smooth surfaces and can be implemented using basic equipment that can be found in most labs,” said research team leader Moran Bercovici from the Technion – Israel Institute of Technology. “This makes the technology very accessible, even in low resource settings.”

In Optica, Optica Publishing Group’s journal for high-impact research, Bercovici and colleagues show that their new technique can be used to fabricate freeform components with sub-nanometer surface roughness in just minutes. Unlike other prototyping methods such as 3D printing, the fabrication time remains short even if the volume of the manufactured component increases.

“Currently, optical engineers pay tens of thousands of dollars for specially designed freeform components and wait months for them to arrive,” said Omer Luria, one of the contributors to the paper. “Our technology is poised to radically decrease both the waiting time and the cost of complex optical prototypes, which could greatly speed up the development of new optical designs.”

From eyeglasses to complex optics

The researchers decided to develop the new method after learning that 2.5 billion people around the world don’t have access to corrective eyewear. “We set out to find a simple method for fabricating high quality optical components that does not rely on mechanical processing or complex and expensive infrastructure,” said Valeri Frumkin, who first developed the method in Bercovici’s lab. “We then discovered that we could expand our method to produce much more complex and interesting optical topographies.”

One of the primary challenges in making optics by curing a liquid polymer is that for optics larger than about 2 millimeters, gravity dominates over surface forces, which causes the liquid to flatten into a puddle. To overcome this, the researchers developed a way to fabricate lenses using liquid polymer that is submerged in another liquid. The buoyancy counteracts gravity, allowing surface tension to dominate.

With gravity out of the picture, the researchers could fabricate smooth optical surfaces by controlling the surface topography of the lens liquid. This entails injecting the lens liquid into a supportive frame so that the lens liquid wets the inside of the frame and then relaxes into a stable configuration. Once the required topography is achieved, the lens liquid can be solidified by UV exposure or other methods to complete the fabrication process.

After using the liquid fabrication method to make simple spherical lenses, the researchers expanded to optical components with various geometries — including toroid and trefoil shapes — and sizes up to 200 mm. They show that the resulting lenses exhibited surface qualities similar to the best polishing technologies available while being orders of magnitude quicker and simpler to make. In the work published in Optica, they further expanded the method to create freeform surfaces, by modifying the shape of the supportive frame.

Infinite possibilities

“We identified an infinite range of possible optical topographies that can be fabricated using our approach,” said Mor Elgarisi, the paper’s lead author. “The method can be used to make components of any size, and because liquid surfaces are naturally smooth, no polishing is required. The approach is also compatible with any liquid that can be solidified and has the advantage of not producing any waste.”

The researchers are now working to automate the fabrication process so that various optical topographies can be made in a precise and repeatable way. They are also experimenting with various optical polymers to find out which ones produce the best optical components.

Reference: “Fabrication of freeform optical components by fluidic shaping” by M. Elgarisi, V. Frumkin, O. Luria, M. Bercovici, 18 November 2021, Optica.
DOI: 10.1364/OPTICA.438763

In mice with active inflammation, suppressing the neurons that remembered it produced an immediate reduction in the inflammation.

Your phone pings. It’s a message from a friend you met for drinks last night, who just tested positive for Covid-19.

Your throat starts feeling scratchy. A short cough sputters out. Is your body temperature rising? You run to take a PCR test. When the results come back negative, you realize it was all in your head — a psychosomatic response.

Researchers from the Technion – Israel Institute of Technology in Haifa wanted to explore the connection between the brain’s perception of illness and the real thing.

They induced inflammation in mice, and after the inflammation subsided, the researchers triggered the neurons in the mice’s brains that were active during the initial inflammation.

The result was dramatic: The inflammation re-emerged in the same area as before. Simply “remembering” the inflammation was enough to reactivate it.

The researchers then wondered: If the brain can generate disease, can the brain also turn it off?

The answer was a resounding yes. In mice with active inflammation, suppressing the neurons that remembered it produced an immediate reduction in the inflammation.

There’s no guarantee this experiment would work in human beings. But it raises the possibility of a new therapeutic avenue for treating chronic inflammatory conditions such as Crohn’s disease and psoriasis.

The brain’s ability to bring on illness psychosomatically is more a feature than a bug, explained Prof. Asya Rolls, of the Technion’s Faculty of Medicine.

“The body needs to respond to infection as quickly as possible before the attacking bacteria or viruses can multiply,” she said.

“If certain activity – for example consuming particular foods – has exposed the body to infection and inflammation once, there is an advantage to gearing up for battle when one is about to engage in the same activity again. A shorter response time would allow the body to defeat the infection faster and with less effort.”

The research was led by Tamar Koren, an MD-PhD student in Rolls’ lab. Other participants included Dr. Kobi Rosenblum of the University of Haifa and Dr. Fahed Hakim of EMMS Hospital in Nazareth.

The study was supported by the European Research Council (ERC) Starting Grant, the Allen and Jewel Prince Center for Neurodegenerative Disorders of the Brain, the Howard Hughes Medical Institute (HHMI) and the Wellcome Trust.

SOURCE

Can our brain make our body sick? Likely yes, Israeli research shows

Technion scientists uncovered how neurons can trigger physiological responses in the body that translate in real illnesses but might also help treat them.

Can our brain trigger an actual illness in the body? New research by Technion-Israel Institute of Technology scientists conducted on mice suggests that the answer is likely yes.

Over the years, the intuitive idea that the brain exercises a significant influence on people’s physical well-being has been supported by increasing scientific evidence.

“Several years ago, we studied the mechanism behind the placebo effect, demonstrating that when people experience a positive expectation, their conditions improve in many ways,” Technion Prof. Asya Rolls said.

“We were able to show that by activating brain areas that are related to positive expectations, we would boost the immune response,” she said. “What amazed us was how precise this response was, and therefore we thought that the brain could not have such an exact control of the system without knowing what its status is.”

The researchers started to examine whether the brain is able to represent the status of the immune system.

The new study was led by Rolls and her MD/PhD student Tamar Koren and was conducted in cooperation with Dr. Kobi Rosenblum of the University of Haifa and Dr. Fahed Hakim of EMMS Nazareth Hospital. The results were published in the journal Cell on Monday.

The scientists checked which areas of the brain would be activated when mice experienced genetically induced colon inflammation. Among others, the insular cortex – which is responsible for sensations such as thirst, hunger and pain and other manifestations of the body’s physiological state – presented increased neurological activity.

“When we reactivated the same neurons afterward, we recorded the same inflammatory response,” Rolls said. “It was quite shocking.”

The results offer evidence that the brain contains a representation of the immune system, and it can reactivate it when presented with specific stimuli and possibly other forms of memories, the researchers said.

The brain does not cause the body to be reinfected by a pathogen, but it might potentially trigger a reaction in the body similar to the one caused by the original infection, they said.

“We have to remember that, many times, the damage to the body is not caused by the pathogen itself but, rather, by the immune system’s reaction to it,” Rolls said.

The mechanism may help explain what triggers psychosomatic disorders, which are health problems that appear without any apparent biological cause, the researchers found. Autoimmune diseases or other conditions, such as Crohn’s disease, could also be based on a similar process.

It would be wrong to assume that the results obtained from the study on mice will translate in humans in the exact same way, Rolls said.

However, there is hope that the research can contribute to understanding better how certain diseases work and how to treat them, possibly by inhibiting the neurons from activating and triggering the inflammation.

“There are many ways we can control neuronal activities in the human brain, for example, through magnetic or electrical stimulation or by neurofeedback when a person learns how to control their neurons on their own,” Rolls said.

“We know that we can do it because we know the power of a psychosomatic effect,” she said. “For example, during the clinical trial of the COVID vaccine, many people who received the placebo experienced very similar side effects to those who received the actual vaccine. Clearly, this was caused by some mental process resulting in a physiological response.”