Dr. Anna Chuprin doesn’t have much time for telephone calls in the lab, but for some calls she’ll put everything on hold. This doesn’t happen often, maybe twice or three times a week, when she is notified by one of Israel’s hospitals that a potential celiac patient is undergoing a biopsy and has agreed to donate part of it for research being conducted by Ukko, the startup company Chuprin works for as an immunologist. The samples must reach the company’s offices within two hours at a temperature of 4 degrees celsius.
Chuprin receives the biopsy in small test tubes. She extracts the blood cells (T cells) from them and grows them in a petri dish for a few weeks. When she has enough cells she moves them to a shallow dish with “wells” into which she gently drips a liquid resembling glue or wax. One liquid is gluten protein produced from wheat, while the other is gluten protein that has undergone a slight manipulation after being “redesigned” using artificial intelligence.
The T cells are the “combatants” of the immune system. When they identify foreign proteins invading the body they get activated – they multiply and attack the foreign protein in order to destroy it. Celiac patients’ T-cells mistakenly identify gluten as a foreign invader and excrete inflammatory proteins that damage the patient’s intestines. Chuprin measures the level of interferon gamma protein excreted following this encounter – and thus identifies a celiac patient whose body is incapable of digesting it.
In contrast, the cells that interact with Ukko’s gluten remain quietly in their dish. They do not multiply – an indication that they don’t identify the gluten as a threat. Last year Chuprin carried out this process on several biopsies and the results were encouraging.
Celiac patients who consume gluten over time suffer from complications and intestinal diseases. Their only solution is to completely avoid eating food products containing gluten. Gluten, “glue” in Latin, is the component that helps dough rise and preserves its firm, chewy texture. Baking without gluten is a complex task and this raises the costs of production and damages nutritional value.
Ukko, co-founded in 2017 by Professor Yanay Ofran and Dr. Anat Binur, has succeeded in engineering a gluten protein that does not contain the component that celiac patients’ immune system identifies as dangerous, while preserving all its positive attributes. Within a few years the company hopes to produce a food product that will compete with the massive gluten substitutes market - and take a cut out of its billions in revenuers. In the future the company hopes farmers will grow Ukko’s “modified” wheat from the onset and thus eliminate gluten sensitivity and provide celiac patients with healthier, tastier products.
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Ukko’s technology may also enable treating one of the most common, life threatening food allergies – peanut allergy. One of the few effective treatments today for children with peanut allergies is immunotherapy. This exposes patients to increasing amounts of the allergen itself so their bodies build up a tolerance to the allergen and their sensitivity to it is reduced. But this treatment cannot be administered to those suffering from acute allergy and could cause side effects ranging from stomach aches all the way to anaphylactic shock.
Ukko’s team hopes that their protein modifications will neutralize the protein’s ability to trigger an allergic reaction, yet preserve its positive part that leads to tolerization. That is, exposure without the risk. Ukko plans to administer the modified protein not as a food product, but as a drug.
Ukko’s approach is unique in that it learns from the patient (with blood samples and biopsies) how to treat food, and the food, in turn, can treat the patient.
Meanwhile, they succeeded in enlisting leading investors like the multinational pharmaceutical company Bayer, which led the company’s recent funding round of $40 million, and Khosla Ventures, which led the company’s previous round of some $8 million in 2017. The capital will enable Ukko to move from the initial development stage to clinical trials with human patients within the next two years.
The God of Crops
Ukko’s (In Finnish mythology, the god of crops) story started in 1997 in a shared apartment in Jerusalem. Ofran was a biology and physics student and Binur a law student, both at the Hebrew University. Over the years, their paths crossed again and again as they earned degrees and worked in New York, Boston and California.
Binur, Ukko’s CEO, was born and raised in New York until the age of 15, when she and her Israeli parents returned to Israel. She did her legal pre-internship at one of Israel’s leading law firm's high tech departments and clerked with Israel’s State Attorney, until she returned to the U.S. to study for her MA in Public Policy at Columbia University, eventually completing a doctorate in political science and behavioral economics at MIT.
During her studies she founded MEET, an organization that is still active and teaches Israeli and Palestinian high school students technology, computer science, business and leadership.
Ofran, a professor at Bar Ilan University, grew up in Jerusalem and was attracted to the overlap between computer science and biology. “When I was about to complete my BA studies, a new discipline was born based on the understanding that biological systems can be researched with the help of computer science,” he says. “In a way, they realized then that computer science will be to biology what mathematics is to physics – a theoretical framework with which it’s possible to model, predict, plan and maybe even to control biological systems.”
This was the point of origin for his research moving forward. He wrote his doctorate in molecular biophysics at Columbia, specializing in molecule interactions. His research focused on the question of how biological molecules recognize and bind to one another. On the basis of his research, which succeeded in planning molecules that connect to each other, he founded the Startup Biolojic Design, a biotech company which develops drugs.
Ofran says the rationale was “to take everything biology knows about molecules that take part in a certain disease, detect which one of them must be attacked in order to correct the malfunction and design using computer science the precise antibody for them - one without side effects.” That means designing the drug so that it itself becomes a biological antibody. Biolojic Design is entering clinical trials with cancer patients in the coming months. It took Ofran five more years until this idea led him to the insight behind Ukko.
In 2014 Ofran went on Sabbatical in Harvard University and asked himself a scientific question: He had already shown that he could program an antibody that would bind to a human protein in order to attack it. But was it possible to do the reverse? Was it possible to design a protein that will not bind itself to a harmful protein, and actually avoid it?
“I worked on it for some time and concluded that it was possible and was simpler than I initially thought. At that point I called Anat (Binur) and told her we have to do something with this.”
Binur wasn’t only a potential partner for a startup company due to their long acquaintance and friendship, she was also the right person to consult with. As a partner in the venture capital firm Innovation Endeavors, founded on the capital of former Google chairman Eric Schmidt, she met entrepreneurs on a daily basis, examined business models and was familiar with the innovation industry in Silicon Valley.
Brainstorming togerther, the two reached the conclusion that a correct application for Ofran’s findings was in the field of food sensitivity. Patients with food sensitivities have specific unique antibodies that detect the protein in food as a disease. Children with peanut allergies, for example, have antibodies that recognize the peanut protein, bind to it, and that connection triggers a sequence of events that ends with an acute allergic attack. If the two could redesign the food protein so that those antibodies don’t recognize it anymore and don’t bind themselves to it, then these children could enjoy peanuts with no side effects.
Didn’t anyone think of that before you?
Ofran: “We are at the historical point in which three revolutions converged, making possible something that wasn’t possible five years ago. The first is the ability to detect the problem accurately – we have good computational tools to analyze the molecular basis of the disease by analyzing blood samples from patients and medical files. Until today it was possible to tell you that you have an allergy to peanuts and maybe even to ‘this protein in the peanut.’ Today we know that the problem on the peanut’s protein is a specific nook and cranny, a micro-molecule. The second is that we can design molecules – that is to develop the solution. The third is that we can manipulate genomes, for example in plants, very effectively. That enables us to create a product on a wide scale.
“Until today we examined whole organisms – a plant, a cow, a germ – but today the tools enable us to separate it into genes and to say ‘this one’s good’ and ‘that one’s bad,’ redesign the molecular components and produce food with components that have been fixed to get rid of what was wrong with them.”
Won’t genetically modified food have new side effects?
Ofran: “When you go to the supermarket today there isn’t a single product that is sold the way it was in nature, before civilization. All the products raised by farmers – fruit and vegetables, the animals – are things people have been improving for hundreds of years by various methods.
“At times the improvement was relatively smooth, sometimes it wasn’t. Improvement processes are always being revised and corrected, and perhaps in Ukko we’ll also find we need correction, but the ability to extract the toxicity from wheat and keep its components is a blessing, at the first stage.”
Why did you start with peanuts and gluten?
Binur: “Peanuts are the holy grail of the allergy world - it’s one of the fatal allergies and is the most common and researched one. If you solve peanuts, the assumption is that the rest will be simpler. Gluten completes the allergy and sensitivity picture: peanuts are in the antibody world and gluten is the T cells.
“They in fact represent the two arms of the adaptive immune system. In addition, gluten is an enormous market with numerous substitutes. Those are also the two sensitivities with the most dramatic influence on people’s lives. Peanuts because they are lethal and gluten because it’s simply everywhere. Sensitivity to milk, for example, mostly passes with age.”
The commercial potential is indeed very big. The global gluten substitute market has a return of tens of billions a year. Gluten free products are generally seen as part of the health trend, but very frequently these products are processed and contain large amounts of sugar and vegetable fats or substitutes like empty starches. This is also the reason, apparently, that despite the many substitutes available today the substitute consumption among gluten sensitive people is extremely low compared to the consumption of pastries and bread products in the general public. Ukko’s figures show that people who are not sensitive consume 15 times more bread and six times more pastries.
Scientists are in the process of working on solutions for celiac like a pill that can be swallowed before eating to neutralize the harmful effect, or an interim solution of extracting most of the gluten from the bread. But the many substitutes and the enthusiastic consumers show that there could be more than one solution.
Yanay is Ukko’s active chairman and CEO of Biolojic Design. The two companies share a floor of 1,400 square meters in the science park. Ukko has some 35 employees. The companies do not compete with each other. One deals with agriculture and food and the other designs drugs on the basis of a reverse idea. But both share artificial intelligence for designing proteins and are happy to share expertise, technology and equipment – and even lunches.
“The companies are managed separately, but we’ve created a joint work space for eating and lectures. There are people here from the age of 22 to 60,” says Binur. “And if we need an instrument that costs a million shekels, and there are a few here that do – then we buy it together. It saves costs.”