Category: Medicine

An Israeli research group says its artificially intelligent antibiotic-prescribing algorithm can cut the risk of antibiotic resistance by half.

Antibiotics are essential to curing bacterial infections, but their overuse promotes the appearance and proliferation of antibiotic-resistant bacteria.

“We wanted to understand how antibiotic resistance emerges during treatment and find ways to better tailor antibiotic treatment for each patient to not only correctly match the patient’s current infection susceptibility but also to minimize their risk of infection recurrence and … resistance to treatment,” said Roy Kishony from the Technion – Israel Institute of Technology.

The group focused on two common bacterial infections — urinary tract infections and wound infections — to show how each patient’s past infection history can be used to choose the best antibiotic to reduce the chance of antibiotic resistance emerging.

“As most infections are seeded from a patient’s own microbiota, these resistance-gaining recurrences can be predicted using the patient’s past infection history and minimized by machine learning [with] personalized antibiotic recommendations, offering a means to reduce the emergence and spread of resistant pathogens,” the researchers said.

They used genomic sequencing techniques and machine learning analysis of patient records to develop this approach, described in the journal Science.

“We found that the antibiotic susceptibility of the patient’s past infections could be used to predict their risk of returning with a resistant infection following antibiotic treatment,” said lead author Mathew Stracy.

“Using this data, together with the patient’s demographics like age and gender, allowed us to develop the algorithm.”

The study was a collaboration involving Kishony and physicians Varda Shalev, Gabriel Chodick and Jacob Kuint at Maccabi KSM Research and Innovation Center. Maccabi is one of Israel’s four national health maintenance organizations.

The hope is that this algorithm could be used at the point of care to improve treatment and minimize the spread of resistant bacteria.

The CDC describes antibiotic resistance as “one of the world’s most urgent public health problems,” noting that it “has the potential to affect people at any stage of life, as well as the healthcare, veterinary and agriculture industries.”

In its 2019 Antibiotic Resistance Threats Report, it said more than 2.8 million antibiotic-resistant infections occur each year in the United States, resulting in the deaths of more than 35,000 people.

When Clostridioides difficile — a bacterium associated with antibiotic use that is not typically resistant but can cause deadly bouts of diarrhea — is added to these figures, the reported U.S. toll exceeds 3 million infections and 48,000 deaths.

Cells contain certain chaperone proteins that can break down the protein clumps found in amyotrophic lateral sclerosis (ALS) and Huntington’s disease, but don’t always activate the right proteins at the right time, a recent study shows.

“[The cells] 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,” Reut Shalgi, PhD, a professor at Technion Israel Institute of Technology and the study’s principal investigator, said in a press release.

“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,” Shalgi said.

The study, “Differential roles for DNAJ isoforms in HTT-polyQ and FUS aggregation modulation revealed by chaperone screens,” was published in Nature Communications. 

Neurodegenerative diseases, including ALS and Huntington’s, are characterized by protein aggregation (clumping) in the nerves’ cells, impairing their function.

Normally, when a protein is made in the body, it is folded into the 3D shape it needs to perform its function. In neurodegenerative diseases, however, certain proteins fail to fold properly, and instead stick to each other, forming aggregates.

Chaperone proteins help other proteins fold into the correct shape. Sometimes, when proteins aggregate, chaperones are activated to correct the mistake.

The researchers sought to investigate the ability of specific chaperones to break down ALS or Huntington’s-associated aggregates. To do so, they tested 66 chaperones in cultures with either aggregates of the Huntington’s-related Huntingtin protein, or with FUS protein aggregates, which are found in many cases of familial ALS.

Overall, eight individual chaperones were able to prevent ALS aggregate formation, and four provided significant protection against Huntington’s aggregates, although there was no overlap between the two diseases, the researchers noted.

One chaperone that protected against ALS aggregates — DNAJB14 — exists in two versions, called isoforms. The isoforms are similar, but one is shorter and lacks some important protein domains that are present on the longer version.

The researchers found that, contrary to the long version, the short version could not break down the FUS aggregates. According to the researchers, this could be because the long isoform contains a region responsible for interacting with HSP70 proteins — an important family of chaperones — that the researchers hypothesized may be important for the protein’s ability to break down aggregates.

Indeed, when the researchers blocked the HSP70-binding domain on the long version, it also lost its ability to prevent aggregates.

In Huntington’s aggregates, another chaperone, DNAJB12, significantly worsened aggregate formation in its long isoform, but was protective in its short isoform, which also lacked the HSP70 binding domain.

Although DNAJB12 did not independently influence ALS aggregates, a physical interaction was sometimes observed between DNAJB14 and DNAJB12. When the team prevented this interaction, DNAJB14 no longer was able to clear FUS aggregates, suggesting that the interaction between the two proteins likely contributes to DNAJB14’s ability to remove aggregates.

Overall, “these results collectively support the notion that the DNAJB14–DNAJB12–HSP70 complex is essential for providing substantial protection from [ALS-associated aggregates],” the researchers wrote.

Furthermore, when DNAJB14’s long version was added to cell cultures containing FUS aggregates, the expression of more chaperones and other proteins important for maintaining protein function — which had been diminished by aggregate formation — was restored.

“This represented a fine-tuned, apparently well-suited response to address the challenges of [FUS aggregate-containing] cells,” the researchers wrote.

However, when the team compared overall production of chaperone proteins in cells with and without the protein clumps, they found that the cells with FUS aggregates failed to naturally increase levels of the protective chaperones in response to the aggregates. In fact, many chaperones, including those in the HSP70 family, were repressed.

Overall, this suggests that while cells have the tools to break down ALS aggregates, they don’t always respond properly, and may fail to activate the right chaperones at the right time.

“It is not enough that the tools exist in the cell’s toolbox. 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,” said Shalgi.

The team noted, however, that identifying the key chaperones involved provides a target for the development of future therapeutic interventions. 

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.