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Tiny Molecule Makes Big Impact on Cancer Treatment

Research

Aug 10th, 2022
Tiny Molecule Makes Big Impact on Cancer Treatment

Newly discovered molecule may allow for more accessible and effective cancer immunotherapies
 

  • Medicine

 

Researchers at Tel Aviv University and the University of Lisbon have discovered a potentially new immunotherapy, which may lead to more affordable and effective treatments. Immunotherapy activates the patient’s immune system to fight cancer cells.

 

In this significant step in the fight against cancer, the researchers used computational and bioinformatic systems to discover a tiny molecule which can enter a solid tumor. Thanks to its low molecular weight, the molecule outperforms existing antibodies that are used as the key component in many cancer immunotherapies today. The molecule is also small enough that it may one day be administered in a pill form, saving stressful and time-consuming trips to the hospital.

 

Behind the groundbreaking development is an international team of researchers led by 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. 

4th Covid-19 Vaccine Reduces Risk of Death by 72% Amongst Elderly

Research

Jul 21st, 2022
4th Covid-19 Vaccine Reduces Risk of Death by 72% Amongst Elderly

Study by Tel Aviv University, Ben Gurion University, and Israeli Ministry of Health included 40K Israelis

  • Medicine

A new study by Tel Aviv University and Ben Gurion University of the Negev, in collaboration with the Israeli Ministry of Health, found that the fourth COVID-19 vaccine is effective in protecting the elderly from the Omicron variant.

 

The groundbreaking study included approximately 40,000 elderly Israelis living in institutions supervised by the Ministry of Health's “Senior Shield” program, a task force launched by Israel’s government to oversee the prevention and control of COVID-19 in the country’s geriatric facilities. According to its results, elderly at-risk individuals vaccinated with the fourth dose of the Pfizer vaccine have a 34% reduced risk of contracting the Omicron variant, a 64-67% reduced risk of requiring hospitalization due to COVID, and a 72% reduced risk of death from the virus.

 

The study was led by Prof. Khitam Muhsen and Prof. Dani Cohen of the School of Public Health at Tel Aviv University, Prof. Ron Dagan of Ben Gurion University, Prof. Nimrod Maimon, director of the Internal Medicine Department at Soroka Medical Center and until recently head of the Ministry of Health’s Senior Shield program, as well as program staff members Ami Mizrahi, Omri Bodenheimer, and Boris Boltyansky, in collaboration with Lea Gaon and Zafrira Hillel-Diamant of the Ministry’s Department of Geriatrics. The study was published in the prestigious journal JAMA Internal Medicine.

 

 

Particularly Vulnerable Population

“Our study compared 24,088 residents of Senior Shield facilities who received a fourth dose of the Pfizer vaccine – that is, the second booster shot – with 19,687 residents who were vaccinated with the first three doses four months or more prior to the follow-up, but who chose not to get the second booster,” explains Prof. Muhsen.

 

“These are residents of geriatric institutions, nursing homes and assisted living facilities that are part of the Ministry of Health’s Senior Shield system – a total of about 1,000 institutions across the country. This population is particularly vulnerable to infection, morbidity, and mortality from the coronavirus, due to the nature and living conditions of the institutions, the fact that many residents need help with daily activities, and the previous health issues that many of the residents suffer from.”

 

When the Omicron wave spread throughout Israel between January and March of this year, there was no registered and available vaccine for this variant, which underwent significant mutations in the spike protein that allows the virus to attach to and penetrate human cells. Because the existing COVID-19 vaccines target the spike protein, there has been much discussion in Israel and the rest of the world about the effectiveness of existing vaccines against the Omicron variant in general, and with regards to a second booster shot. Israel was the first country to approve the second booster (the fourth dose of the vaccine) for those aged 60 and above. The present study is based on data from the Senior Shield population database, which constituted the first large group to receive the second booster. Prof. Muhsen points out that this new study was conducted on a national scale, and that it successfully addressed the methodological problems that characterize observational epidemiological studies on the effectiveness of COVID vaccines.

 

Fourth Dose Saved Many Lives

“We monitored the infections, hospitalizations and mortality rates in these two groups throughout the Omicron wave, and found that the members of the group that received the fourth vaccine were infected at a rate that was 34% less than the control group; were hospitalized for mild-to-moderate illness 64% less, and for severe illness 67% less than the control group; and had a mortality rate that was 72% less than the group vaccinated with only the first three doses," says Prof. Muhsen.

 

"These are significant data, because the Senior Shield population is one of the groups who suffer the most severe morbidity from the coronavirus, at a much higher rate than the general population. We assume that the fourth dose of the vaccine boosted the level of neutralizing antibodies, which conferred cross-protection against the Omicron variant. Our study points to the significant benefit of administering the fourth dose of the vaccine and confirms that the policy adopted by the State of Israel was the correct one. The decision to vaccinate at-risk populations with the fourth dose was a wise choice that saved a lot of human lives.”

 

Prof. Muhsen adds: “This is a groundbreaking and innovative study based on a database of the elderly population in care facilities. Previous studies have been conducted in the general population, and therefore also among relatively young populations with an average age of around 72, whereas the average age in our study was 80. Moreover, in general, people who go to be tested or vaccinated against COVID tend to exhibit positive health behaviors, so it is very difficult to compare their morbidity levels to those of unvaccinated people or those who have been vaccinated with three doses. We have no information as to why some of the residents chose not to receive the fourth vaccine dose, but both groups in our study underwent routine and ‘blind’ COVID tests according to uniform Senior Shield protocol, regardless of whether they received the vaccine. Therefore, our study was less affected by the ‘healthy vaccinee effect,’ and its results can also be applied to other populations, in Israel and around the world.”

 

According to Prof. Dani Cohen, “The study indicates that giving booster shots and raising the level of antibodies through a vaccine based on the original COVID-19 strain provides significant protection against the onset of serious illness even after infection with new variants, including those that are very different from the original, such as Omicron.”

 

Prof. Nimrod Maimon adds that “The task of protecting institutions for people living outside of the home is a very important aspect of the Ministry of Health’s Senior Shield program. The database that the project has built and accumulated about the institutions and their residents has allowed for rapid and effective vaccination campaigns, which have yielded dramatic results in curbing illness from the coronavirus amongst these populations. The impressive results of the program have received widespread international praise, with health authorities from many countries around the world seeking to learn from the Senior Shield program.”

 

Prof. Ron Dagan concludes that the results presented in the study demonstrate once again the critical role of vaccines and the use of structured and effective systems in curbing waves of severe morbidity and mortality in at-risk populations.

Going to the Beach? Sun Exposure Makes Men Hungrier than Women

Research

Jul 19th, 2022
Going to the Beach? Sun Exposure Makes Men Hungrier than Women

TAU researchers find surprising connection between sun exposure and men's appetite

  • Medicine

A new study from Tel Aviv University reveals that solar exposure increases appetite in males, but not in females. It is the first gender-dependent medical study ever conducted on UV exposure, and for the first time, the molecular connection between UV exposure and appetite was deciphered.

 

Skin as Regulator of Appetite

The groundbreaking study was led by Prof. Carmit Levy and PhD student Shivang Parikh of the Department of Human Molecular Genetics and Biochemistry at TAU's Sackler Faculty of Medicine. It was conducted in collaboration with many researchers in Israel and worldwide, including contributors from Tel Aviv Sourasky (Ichilov), Assuta, Meir, and Sheba Medical Centers, along with Dr. Yiftach Gepner and Dr. Lior Bikovski from TAU's Sackler Faculty of Medicine, and Prof. Aron Weller of Bar-Ilan University. The paper was published in the prestigious journal Nature Metabolism.

 

The study was based on epidemiological data collected in a year-long survey about the eating habits of approximately 3,000 Israelis of both sexes, including self-reports from students who had spent time in the sun, combined with the results of a genetic study in a lab model. The findings identify the skin as a primary regulator of energy and appetite (metabolism) in both lab models and humans.

 

Prof. Carmit Levy

 

Estrogen Hormone Blocks Urge to Eat in Women

The study unravels the differences between males and females in the activation of the metabolic mechanism. The researchers explain that in males of both animal species and humans, sun exposure activates a protein called p53, to repair any DNA damage in the skin that might have been caused by the exposure. The activation of p53 signals the body to produce a hormone called ghrelin, which stimulates the appetite.

 

In females, the hormone estrogen blocks the interaction between p53 and ghrelin, and consequently does not catalyze the urge to eat following exposure to the sun.

 

The researchers explain that there is a dramatic metabolic difference between males and females, impacting both their health and their behavior. However, so far it has not been established whether the two sexes respond differently to environmental triggers such as exposures to the sun's UV radiation.

 

"We examined the differences between men and women after sun exposure and found that men eat more than women because their appetite has increased. Our study was the first gender-dependent medical study ever conducted on UV exposure, and for the first time, the molecular connection between UV exposure and appetite was deciphered. Gender-dependent medical studies are particularly complex, since twice the number of participants is required to find statistically significant differences," explains Prof. Levy.

 

"As humans, we have cast off our fur and consequently, our skin, the largest organ in our body, is exposed to signals from the environment. The protein p53, found in the skin, repairs damage to the DNA caused by sun exposure, but it does more than that. It signals to our bodies that winter is over, and we are out in the sun, possibly in preparation for the mating season. Our results provide an encouraging basis for more research, on both human metabolism and potential UV-based therapies for metabolic diseases and appetite disorders," Prof. Levy concludes.

While You Were Sleeping

Research

Jul 13th, 2022
While You Were Sleeping

Could we be one step closer to verifying whether a seemingly unconscious person is truly unaware of his or her surroundings?

  • Medicine
  • Engineering

A new TAU discovery may provide a key to a great scientific enigma: How does the awake brain transform sensory input into a conscious experience? The researchers were surprised to discover that the brain's response to sound remains powerful during sleep in all parameters but one: the level of alpha-beta waves associated with attention to the auditory input and related expectations. This means that during sleep, the brain analyzes the auditory input but is unable to focus on the sound or identify it, and therefore no conscious awareness ensues.

 

The study was led by Dr. Hanna Hayat and with major contribution from Dr. Amit Marmelshtein, at the lab of Prof. Yuval Nir from the School of Medicine of the Sackler Faculty of Medicine, the Sagol School of Neuroscience, and the Department of Biomedical Engineering, and co-supervised by Prof. Itzhak Fried from the UCLA Medical Center. Other participants included: Dr. Aaron Krom and Dr. Yaniv Sela from Prof. Nir's group, and Dr. Ido Strauss and Dr. Firas Fahoum from the Tel Aviv Sourasky Medical Center (Ichilov). The paper was published in the prestigious journal Nature Neuroscience.

 

A Deep Dive into the Human Brain

Prof. Nir explains that this study is unique in that it builds upon rare data from electrodes implanted deep inside the human brain, enabling high-resolution monitoring, down to the level of individual neurons, of the brain's electrical activity.

 

While electrodes cannot be implanted in the brain of living humans just for the sake of scientific research, in this case the researchers were able to utilize a special medical procedure in which electrodes were implanted in the brains of epilepsy patients, monitoring activity in different parts of their brain for purposes of diagnosis and treatment. The patients volunteered to help examine the brain's response to auditory stimulation in wakefulness versus sleep.

 

The researchers placed speakers emitting various sounds at the patients’ bedside and compared data from the implanted electrodes – neural activity and electrical waves in different areas of the brain – during wakefulness and during various stages of sleep. Altogether, the team collected data from over 700 neurons (about 50 neurons in each patient) over the course of 8 years.

 

Dr. Hanna Hayat

 

Measuring the Strength of Alpha-beta Waves

“After sounds are received in the ear, the signals are relayed from one station to the next within the brain," explains Dr. Hayat. "Until recently it was believed that during sleep these signals decay rapidly once they reach the cerebral cortex.  But looking at the data from the electrodes, we were surprised to discover that the brain's response during sleep was much stronger and richer than we had expected. Moreover, this powerful response spread to many regions of the cerebral cortex. The strength of brain response during sleep was similar to the response observed during wakefulness, in all but one specific feature: the level of activity of alpha-beta waves.”

 

The researchers explain that alpha-beta waves (10-30Hz) are linked to processes of attention and expectation that are controlled by feedback from higher regions in the brain. As signals travel 'bottom-up' from the sensory organs to higher regions, a 'top-down' motion also occurs: the higher regions, relying on prior information that had accumulated in the brain, act as a guide, sending down signals to instruct the sensory regions as to which input to focus on, which should be ignored, etc. Thus, for example, when a certain sound is received in the ear, the higher regions can tell whether it is new or familiar, and whether it deserves attention or not.

 

"We hope that our findings will serve as a basis for developing effective new methods for measuring the level of awareness of individuals who are supposedly in various states of unconsciousness."

 

This kind of brain activity is manifested in the suppression of alpha-beta waves, and indeed, previous studies have shown a high level of these waves in states of rest and anesthesia. According to the current study, the strength of alpha-beta waves is the main difference between the brain's response to auditory inputs in states of wakefulness vs. sleep.

 

Decoding Consciousness

Prof Nir summarizes: “Our findings have wide implications beyond this specific experiment. First, they provide an important key to an ancient, fascinating enigma: What is the secret of consciousness? What is the ‘X-factor’, the brain activity that is unique to consciousness, allowing us to be aware of things happening around us when we are awake, and disappearing when we sleep? In this study we discovered a new lead, and in future research we intend to further explore the mechanisms responsible for this difference. 

 

"In addition, having identified a specific brain feature that is different between states of consciousness and unconsciousness, we now have a distinct quantitative measure – the first of its kind - for assessing an individual’s awareness of incoming sounds. We hope that in the future, with improved techniques for measuring alpha-beta brain waves, and non-invasive monitoring methods such as EEG, it will be possible to accurately assess a person's state of consciousness in various situations: verifying that patients remain unconscious throughout a surgical procedure, monitoring the awareness of people with dementia, or determining whether an allegedly comatose individual, unable to communicate, is truly unaware of his/her surroundings. In such cases, low levels of alpha-beta waves in response to sound could suggest that a person considered unconscious may in fact perceive and understand the words being said around him. We hope that our findings will serve as a basis for developing effective new methods for measuring the level of awareness of individuals who are supposedly in various states of unconsciousness. “

 

Two New Planets Found in Milky Way

Research

Jul 11th, 2022
Two New Planets Found in Milky Way

TAU team leads discovery of giant planets, similar in size to Jupiter, in remote corner of the galaxy

  • Life Sciences
  • Astronomy

Tel Aviv University researchers led the recent discovery of two new planets in remote solar systems within the Milky Way galaxy. They identified the giant planets, named Gaia-1b and Gaia-2b, as part of a study in collaboration with teams from the European Space Agency (ESA) and the body’s Gaia spacecraft.

 

The development marks the first time that the Gaia spacecraft successfully detected new planets. Gaia is a star-surveying satellite on a mission to chart a 3D map of the Milky Way with unprecedented accuracy comparable to standing on Earth and identifying a 10-shekel coin (roughly the size of a U.S. nickel) on the Moon.  

 

TAU’s Prof. Shay Zucker, Head of the Porter School of the Environment and Earth Sciences, and doctoral student Aviad Panahi from the Raymond and Beverly Sackler School of Physics & Astronomy led the initiative. The findings were published in the scientific journal Astronomy & Astrophysics. 

 

More Discoveries on the Horizon

“The discovery of the two new planets was made in the wake of precise searches, using methods of artificial intelligence," said Prof. Zucker. "We have also published 40 more candidates we detected by Gaia. The astronomical community will now have to try to corroborate their planetary nature, like we did for the first two candidates."

 

The two new planets are referred to as "Hot Jupiters" due to their size and proximity to their host star: "The measurements we made with the telescope in the U.S. confirmed that these were in fact two giant planets, similar in size to the planet Jupiter in our solar system, and located so close to their suns that they complete an orbit in less than four days, meaning that each Earth year is comparable to 90 years of that planet,” he adds.  

 

Giant Leaps for Astronomy 

There are eight planets in our solar system. Less known are the hundreds of thousands of other planets in the Milky Way, which contains an untold number of solar systems. Planets in remote solar systems were first discovered in 1995 and have been an ongoing subject of astronomers' research ever since, in hopes of using them to learn more about our own solar system.  

 

To fulfill its mission, Gaia scans the skies while rotating around an axis, tracking the locations of about 2 billion suns, stars at the center of a solar system, in our galaxy with precision of up to a millionth of a degree. While tracking the location of the stars, Gaia also measures their brightness -- an incomparably important feature in observational astronomy, since it relays significant information about the physical characteristics of celestial bodies around them. Changes documented in the brightness of the two remote stars were what led to the discovery. Aviad Panahi explains: "The planets were discovered thanks to the fact that they partially hide their suns every time they complete an orbit, and thus cause a cyclical drop in the intensity of the light reaching us from that distant sun."

 

To confirm that the celestial bodies were in fact planets, the researchers performed tracking measurements with the Large Binocular Telescope, in Arizona, one of the largest telescopes in the world today. The telescope makes it possible to track small fluctuations in a star's movement which are caused by the presence of an orbiting planet.

 

The discovery marks another milestone in the scientific contribution of the Gaia spacecraft’s mission, which has already been credited with a true revolution in the world of astronomy. Gaia's ability to discover planets via the partial occultation method, which generally requires continuous monitoring over a long period of time, has been doubted up to now. The research team charged with this mission developed an algorithm specially adapted to Gaia's characteristics, and searched for years for these signals in the cumulative databases from the spaceship.  

 

Signs of Life?

What about the possibility of life on the surface of those remote new planets? "The new planets are very close to their suns, and therefore the temperature there is extremely high, about 1,000 degrees Celsius, so there is zero chance of life developing there," explains Panahi. Still, he says, “I'm convinced that there are countless others that do have life on them, and it's reasonable to assume that in the next few years we will discover signs of organic molecules in the atmospheres of remote planets. Most likely we will not get to visit those distant worlds any time soon, but we're just starting the journey, and it's very exciting to be part of the search." 

Diagnosing Diseases in Space

Research

Jul 6th, 2022
Diagnosing Diseases in Space

TAU researchers successfully test genetic diagnosis under microgravity conditions

  • Life Sciences
  • Astronomy

If pursuing the unknown in space is on your bucket list, you can take comfort in knowing that TAU researchers recently conducted a unique experiment at the International Space Station to test genetic diagnosis under microgravity conditions. The researchers launched a kit together with Israeli astronaut Eytan Stibbe to space and proved that an existing technology based on a bacterial immune system against viruses, 'CRISPR', can be used to identify viruses and bacteria infecting crew members during space missions.

 

The study was led by Dr. Dudu Burstein from the Shmunis School of Biomedicine and Cancer Research, Tel Aviv University and Dr. Gur Pines from the Volcani Institute. The experiment was conducted by Stibbe as part of the "Rakia" mission in April, under the leadership of the Ramon Foundation and the Israel Space Agency.

 

Suited for Astronauts

CRISPR systems are the immune systems of bacteria from viruses. Bacteria use the CRISPR-Cas systems as a sort of molecular 'search engine' to locate viral sequences and cleave them to disable viruses.

 

As part of their scientific vision, the researchers hypothesized that genetic diagnostics using this method, which requires minimal and easily operated equipment, could be suitable for long space missions: "Conditions in space are extremely problematic," explains Burstein. "Treatment methods are limited, so it is essential to identify pathogens [= a microorganism that can cause disease] in a rapid, reliable, and straightforward method." The method stands in contrast to tests like PCR (which we are now all familiar with due to Covid-19), which Burstein notes require trained personnel and relatively complex equipment."

 

Researchers discussing the experimental design. From left to right: Dan Alon, Dr. David Burstein, Dr. Gur Pines (Photo: Ella Rannon)

 

Burstein outlines the process: "First, the DNA is amplified: each targeted DNA molecule is repeatedly duplicated many times. Then the CRISPR-Cas goes into action: If it identifies the target DNA, it activates a fluorescent molecular marker. The fluorescence lets us know whether the bacteria or viruses of interest are indeed present in the sample. This whole process can be conducted in one tiny test tube, so it is well suited for the astronauts' needs."

 

Zero Gravity? No problem!

Dr. Burstein describes the preparation for the space experiment: "Doctoral student Dan Alon and Dr. Karin Mittelman planned the experiment in detail and conducted it countless times in the lab under various conditions. After reaching the desired result, they prepared a kit, including the CRISPR-Cas system and the other components required for detection. Eventually, the kit was launched with Eytan Stibbe to the International Space Station."

 

The experiments conducted by Stibbe were very successful, and proved that it is indeed possible to perform precise and sensitive CRISPR-based diagnosis - even in an environment with virtually no gravity.

 

What now? "This is the first step towards the simple and rapid diagnosis of diseases and pathogens on space missions," says Burstein, adding that there is still some work to do on the next stages, including, "simple extraction of DNA from samples, making the system more efficient, so that it will be able to test a variety of organisms in one test tube, and diagnosis of more complex samples."

 

"It was inspiring to see our test kit in Eytan's hands at the Space Station, and we're even more excited by the possibility that such kits will help future astronauts on their extraterrestrial missions," he concludes.

 

Eytan Stibbe executing the experiment on the International Space Station (Photo: the Ramon Foundation and the Israel Space Agency)

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