Behind the groundbreaking development is an international team of researchers led by 2020 Kadar Family Award recipient Prof. Ronit Sachi-Fainaro, Director of the Center for Cancer Biology Research and Head of the Laboratory for Cancer Research and Nanomedicine at the Sackler Faculty of Medicine at Tel Aviv University, along with Prof. Helena Florindo and Prof. Rita Guedes from the Research Institute for Medicines at the Faculty of Pharmacy, University of Lisbon. The results of the study were published in the Journal for ImmunoTherapy of Cancer.

Making Effective Immunotherapy Accessible

Immunotherapies can significantly improve patient recovery rates, without the severe side effects that accompany treatments such as chemotherapy. Immunotherapies often make use of antibodies, which are similar to proteins produced by the immune system to destroy infection-causing organisms. However, while lab-grown antibodies created to fight cancer have demonstrated some success, they are costly and not always effective.

“I believe that in the future, the small molecule will be commercially available and will make immunotherapy affordable for cancer patients."

Considering these challenges, TAU and University of Lisbon researchers used computational, bioinformatics and data analysis tools to evaluate thousands of molecular structures. They discovered a list of potential candidates and used the best structure they found to synthesize the new, small molecule which has successfully activated immune cells against cancer cells in lab models, including patient-derived ones. 

The creation of this small molecule builds on the research of Nobel Prize winners James Allison and Tasuku Honjo, who originally developed the CTLA-4 and PD-1 antibodies, respectively, which are used in today's cancer immunotherapies. The two discovered that immune cells are essentially disabled by particular proteins found in cancer and immune cells. The protein called PD-L1 is found in cancer cells, and paralyzes immune cells by binding to a protein on these cells called PD-1. Honjo's antibodies neutralize the PD-1/PD-L1 protein bond, allowing the immune system to attack the cancer. 

“Patients will probably be able to take it at home, orally, without the need for IV administration in the hospital."

Prof. Satchi-Fainaro, head of the TAU research team and a 2020 Kadar Family Award winner, explains that whereas lab-grown antibodies have complex structures and are expensive to produce, the new molecule was synthesized with simple equipment at a low cost. “I believe that in the future, the small molecule will be commercially available and will make immunotherapy affordable for cancer patients." 

The small molecule is also better equipped to penetrate a solid tumor than previous treatments. The antibodies used for current treatments enter a tumor via its blood vessels. "If there are fewer blood vessels in a particular area of ​​the tumor, the antibody will not be able to get inside. The small molecule, on the other hand, diffuses, and is therefore not entirely dependent on the tumor's blood vessels or on its hyper-permeability,” says Prof. Satchi-Fainaro. “Another advantage of the small molecule is that it may be available in a format that patients will probably be able to take at home, orally, without the need for intravenous injections in the hospital."

This work was supported by Fundação para a Ciência e a Tecnologia, Ministério da Ciência, Tecnologia e Ensino Superior (FCT-MCTES) and by The Israeli Ministry of Health under the frame of EuroNanoMed-II, “La Caixa” Foundation, Liga Portuguesa Contra o Cancro, the European Research Council (ERC), The Israel Science Foundation, The Melanoma Research Alliance (MRA), the Israel Cancer Research Fund (ICRF) Professorship award and the Morris Kahn Foundation. 

The study was conducted by doctoral student Shira Klorfeld-Auslender and Prof. Nitzan Censor from the School of Psychological Sciences and the Sagol School of Neuroscience at Tel Aviv University, in collaboration with Prof. Ilan Dinstein and his team from Ben-Gurion University. The study was published in the journal Current Biology.

"A large part of learning does not happen in formal training settings but afterwards, through processes of assimilation and reinforcement of memory that occur in an 'offline' state; for example, when our brain is asleep."

Longer Not Necessarily Better

The new method proposed by the researchers is based on utilizing "memory flashes," by exposing a person for just a few seconds to a task that has already been learned. While standard teaching practice reinforce length and repetition of new skills, the new method improved both visual perception capabilities and the generalization of learning through helping the subjects excel in the same tasks, under different conditions.

"In my laboratory, we focus on the study of learning in humans, and we know that a large part of learning does not happen in formal training settings but afterwards, through processes of assimilation and reinforcement of memory that occur in an 'offline' state; for example, when our brain is asleep," explains Prof. Censor.

"However, standard teaching methods still advocate an approach where longer practice equals better learning: if you want to play the piano, you should practice playing the piano for many hours every day until the playing becomes second nature to you. We have identified an alternative learning mechanism that uses 'memory flashes' – a brief exposure to a task that has already been learned –to assimilate and generalize skill developed."

Prof. Nitzan Censor

Effective with Added Value

In the study, 30 high-functioning adults with autism were asked to learn a visual task (for example, identifying the direction of lines that appear for a few milliseconds on the screen). However, instead of repeating the task for a long time each day, the examinees in the main experimental group learned the task in depth on the first day, and in the following days they were exposed to the visual stimulus for only a few seconds. At the end of the process, although the study participants studied the task for a minimal amount of time, their performance improved significantly, by about 20–25%, which was a similar result to those subjected to multiple-repetition learning and to the achievements of subjects without autism.

"We have shown that it does not take prolonged practice time to assimilate the task – it is enough to flash it for a few seconds to stimulate the relevant brain network, and the brain will then assimilate the material on its own."

Moreover, even when presented with the task under new conditions (for example, when the stimulus was learned in a new location), the examinees who learned with the memory flash method performed better than those in the control group - they knew how to generalize the skills learned in the first task. The participants' success in generalizing the learning to other situations is considered significant, as these are skills that people with autism tend to struggle with.

"We have already proven in previous studies that processes of learning assimilation can be improved through flashes of memory," says Prof. Censor. "We have shown that it does not take prolonged practice time to assimilate the task – it is enough to flash it for a few seconds to stimulate the relevant brain network, and the brain will then assimilate the material on its own."

"In this case, we tested people with autism. People with autism often have difficulty learning and generalizing repetitive learning, that is, using tools that have also been learned when executing new tasks. Through short flashes of visual stimulus of a task learned, we were able to produce learning that is identical to repetitive learning in terms of its effectiveness; meaning, we significantly shortened the learning time. The added value is the ability to generalize: the examinees performed a task under new conditions, as if they had fully learned it. "

According to Prof. Censor, the new method may have significant potential implications in a wide range of areas. The new study could pave the way for more meaningful approaches to learning for people with autism, and in a wide variety of tasks. Moreover, the method may contribute to shorten rehabilitation after neurological injuries.

A new Tel Aviv University study, in collaboration with the Steinhardt Museum of Natural History, and the Interuniversity Institute for Marine Sciences in Eilat, has proven for the first time that the magical phenomenon – whereby corals in deep reefs display glowing colors (fluorescence) - is intended to serve as a mechanism for attracting prey.

The study was led by Dr. Or Ben-Zvi, in collaboration with Yoav Lindemann and Dr. Gal Eyal, under the supervision of Prof. Yossi Loya from the School of Zoology and the Steinhardt Museum of Natural History at Tel Aviv University.

Chasing the Glow

The researchers first sought to determine whether plankton (small organisms that drift in the sea along with the current) are attracted to fluorescence, both in the laboratory and at sea. Then, in the lab, the researchers quantified the predatory capabilities of mesophotic corals (corals that live between the shallow coral reef area and the deep, completely dark zone of ​​the ocean), which exhibit different fluorescent appearances.

To test the planktons’ potential attraction to fluorescence, the researchers used, among other things, the crustacean Artemia salina, which is used in many experiments as well as for food for corals. The researchers noted that when the crustaceans were given a choice between a green or orange, fluorescent target versus a clear 'control' target, they showed a significant preference for the fluorescent target.

Moreover, when the crustaceans were given a choice between two clear targets, its choices were observed to be randomly distributed in the experimental setup. In all of the laboratory experiments, the crustaceans vastly exhibited a preferred attraction toward a fluorescent signal. Similar results were presented when using a native crustacean from the Red Sea. However, unlike the crustaceans, fish that are not considered coral prey did not exhibit these trends, and rather avoided the fluorescent targets.

Fluorescent Traps

The second phase of the study was carried out about 40 meters deep in the sea, where the fluorescent traps (both green and orange) attracted twice as many plankton as the clear trap.

“We conducted an experiment in the depths of the sea to examine the possible attraction of diverse and natural collections of plankton to fluorescence, under the natural currents and light conditions that exist in deep water," says Dr. Or Ben-Zvi. "Since fluorescence is ‘activated’ principally by blue light (the light of the depths of the sea), at these depths the fluorescence is naturally illuminated, and the data that emerged from the experiment were unequivocal, similar to the laboratory experiment.”

"This phenomenon may play a greater role in marine ecosystems than previously thought."

 

The "Light Trap Hypothesis"

In the last part of the study, the researchers examined the predation rates of mesophotic corals that were collected at 45 m depth in the Gulf of Eilat. They found that corals that displayed green fluorescence enjoyed predation rates that were 25 percent higher than corals exhibiting yellow fluorescence.

Prof. Loya: “Many corals display a fluorescent color pattern that highlights their mouths or tentacle tips, a fact that supports the idea that fluorescence, like bioluminescence (the production of light by a chemical reaction), acts as a mechanism to attract prey. The study proves that the glowing and colorful appearance of corals can act as a lure to attract swimming plankton to ground-dwelling predators, such as corals, and especially in habitats where corals require other energy sources in addition or as a substitute for photosynthesis (sugar production by symbiotic algae inside the coral tissue using light energy).”

Dr. Ben-Zvi concludes: “Despite the gaps in the existing knowledge regarding the visual perception of fluorescence signals by plankton, the current study presents experimental evidence for the prey-luring role of fluorescence in corals. We suggest that this hypothesis, which we term the ‘light trap hypothesis’, may also apply to other fluorescent organisms in the sea, and that this phenomenon may play a greater role in marine ecosystems than previously thought.”