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A new study conducted at Tel Aviv University’s School of Zoology, Wise Faculty of Life Sciences and Steinhardt Museum of Natural History reveals that the Israel-Hamas war has had a severe impact on animals. The study, which focused on geckos, found that the sound of explosions from fired rockets induces stress and anxiety in these creatures, leading to a sharp increase in their metabolic rates — an energy cost that, if chronic, may be life-threatening. The researchers hypothesize that these stress responses characterize many other animals, especially those who live in the conflict zones in northern and southern Israel.

The study was led by a team of researchers from TAU’s School of Zoology and Steinhardt Museum of Natural History — Shahar Dubiner, Prof. Shai Meiri, and Prof. Eran Levin — in collaboration with Dr. Reut Vardi of the University of Oxford. The study was published in the journal Ecology.

Energy Changes in Wildlife

Prof. Shai Meiri explains: "The most tragic aspect of war is the loss of human life, among both soldiers and civilians. However, animals are also severely affected, both directly and indirectly, in ways that may threaten their survival. A few weeks before October 7, we began working on a long-term study to measure the rate of energy consumption of small ground geckos of the species Stenodactylus sthenodactylus. We obviously did not foresee the outbreak of the war, but unintentionally, we recorded the energy consumption of five geckos during the rocket barrages launched into Tel Aviv in the first month of the war".

The study’s findings showed that at the sound of the bombings, the geckos’ metabolic rate jumped to double what it was when they were at rest. Their breathing became faster, and they clearly exhibited signs of stress. The experiment lasted up to four hours after the barrages, yet even within this timeframe the geckos did not calm down and return to their resting levels. Moreover, even after a month of continuous fighting, the geckos did not acclimate to the sound of the explosions — their stress response remained unchanged.

Left to right: Prof. Shai Meiri and Prof. Eran Levin.

Prof. Levin: "A state of stress is detrimental to both humans and animals. To compensate for the increase in oxygen consumption and depletion of energy reserves, animals need to eat more. Even if they manage to find food, in the process they expose themselves to predators and lose opportunities to reproduce. In a situation of ongoing conflict, such as the current reality in Gaza, the Gaza Envelope, and along the Israeli-Lebanese border, the metabolic cost can be significant and have a real impact on the energy reserves and activity periods of reptiles and other animals. This can exacerbate their conservation status, especially for species that are already endangered".

The researchers note that the findings of this study are consistent with another experiment conducted during Operation Guardian of the Walls, in which they also observed a stress response in a small snake of the species Xerotyphlops syriacus.

Shahar Dubiner concludes: "Our research was conducted in a laboratory at Tel Aviv University and pertained to the reverberations of explosions from interceptions in the Tel Aviv area. However, given the unequivocal results showing symptoms of stress, we can infer that animals that are in the immediate conflict zones in the south and north of the country, where the intensity and frequency of fire are much higher, suffer from significantly more severe stress and anxiety symptoms that may endanger their lives".

Researchers from the Department of Industrial Engineering at TAU's Faculty of Engineering led a two-year study in which participants wore smartwatches that measured biomarkers and answered questions about their health every day. The results indicate that the wearable technology identified a change in key physiological parameters one to three whole days before the user felt the first symptom of the disease: a gap of 23 hours for COVID-19, 62 hours for group A streptococcus (GAS), and 73 hours for influenza.

The researchers: "Early diagnosis enabled by wearable technologies can be critical for inducing behavioral changes, such as reduced social contacts at an early stage, when the disease is most infectious. Potentially, this can prevent the spread of disease and even preempt global pandemics in the future".

The study was led by Prof. Dan Yamin, an expert in epidemiology and infectious disease modeling and Head of the Lab for Digital Epidemiology and Health Analytics, and Prof. Erez Shmueli, Head of the Big Data Lab, both from TAU's Department of Industrial Engineering. Other participants included: research students Shachar Snir and Matan Yechezkel from the Department of Industrial Engineering, Dr. Tal Patalon from the Kahn Sagol Maccabi Research and Innovation Center at Maccabi Healthcare Services and Yupeng Chen and Prof. Margaret Brandeau from the Department of Management Science and Engineering at Stanford University. The paper was published in Lancet Regional Health Europe.  

Prof. Yamin: "Infectious diseases and pandemics pose a great threat to humanity, and we must harness our scientific and technological abilities to prevent them. Previous studies have shown that during the recent pandemic about 40% of all transmissions occurred about a day before the first symptoms appeared. In other words, the person transmitting the disease was unaware they were infected. In this study we checked whether wearable technologies could provide earlier diagnosis, to reduce contagion and prevent the spread of infectious diseases".

Tracking Key Health Changes

During the two-year study, 4,795 Israelis over 18 years of age wore a smartwatch that continuously monitored key physiological parameters, focusing on pulse rate at a 15-second resolution and HRV (Heart Rate Variability). Prof. Yamin explains: "Pulse rate and HRV provide crucial information about the two most important systems in our body – the heart and the brain. Our brain constantly consumes energy, burning oxygen provided by the cardiovascular system, and consequently, any change in our activity or condition is immediately reflected in a change in HRV. When a person becomes ill, most of the focus goes to a single system - the immune system battling the disease, keeping the heart rate relatively steady, and reducing its variability, the HRV. In this way, changes in HRV indicate physical stress".

In addition to wearing the smartwatches, participants answered a series of general questions about their condition every day: How do you feel physically? How do you feel mentally? Have you engaged in physical activity? Do you have any specific symptoms? Etc. In addition, they were provided with home test kits for three different diseases - COVID-19, influenza, and group A streptococcus – which they used at their discretion. Over two years, the researchers collected 800,000 questionnaires and this data was compared with parallel data from the smartwatch. Altogether, the data included 490 episodes of influenza, 2206 episodes of COVID-19, and 320 episodes of GAS.

Based on their abundant data, the researchers built special models that identified three critical points in time following exposure to an infectious disease. For instance, COVID-19: A. The first physiological anomaly in heart rate measures - 96 hours after exposure, an interval, which the researchers call the 'digital incubation period'; B. The first symptom noticed by the person –130 hours after exposure, an interval commonly known as the 'incubation period'; and C. Testing that ultimately diagnosed the disease - usually about 168 hours after exposure, called the 'diagnostic decision period'. The period from exposure to digital diagnosis, namely the digital incubation period, was even shorter for influenza (24 hours) and GAS (60 hours).

Getting Ahead of the Curve?

Prof. Shmueli: "Early diagnosis is extremely important for preventing the spread of the disease. Moreover, we found that even when our subjects reported first symptoms, they tended to postpone testing for a while - 53 hours for COVID-19, 39 hours for influenza, and 38 hours for GAS. Consequently, for quite a long interval, from exposure to testing, they did not change their social behavior, spreading the disease to others. We found that on average, people performed the test and changed their behavior when the disease was already past its peak, and they were much less likely to infect others. The delay between digital diagnosis and testing – 64 hours in the case of COVID-19, 68 hours for influenza, and 58 hours for GAS – is thus extremely crucial".

Prof. Yamin: "Our findings indicate that at the population level digital diagnosis can significantly reduce the spread of infectious diseases, by causing people to change their social behavior at a much earlier stage of the disease. This can even prevent the next pandemic – by bringing the basic reproduction number (R0value) to below 1.0, which means that every sick individual transmits the disease to less than one other person, and the disease soon dies out".

The researchers add that early diagnosis is also critical for effective treatment. Specifically, for COVID-19, existing treatments are very effective only when given early on, preventing severe illness, hospitalization, and even death.

A Milestone in Stopping Pandemics

Prof. Yamin: "In an ERC-funded paper published in October 2019, shortly before the outbreak of the COVID-19 pandemic, I argued that infectious diseases pose the greatest threat of a global catastrophe. The threat is especially great in the modern world, with people traveling all over the globe and potentially spreading new diseases. However, modern technology can help us combat this danger and devise more effective public health strategies. Our new method, using wearable sensors for early detection of contagious disease can potentially reduce the threat of epidemics to a minimum. Smartwatches are a relatively new technology, with enormous potential, and novel, even more sensitive and accurate wearable sensors are constantly being developed. Ultimately, this can be a high-impact tool for preempting future pandemics".

In a breakthrough study by an international team of scientists led by researchers from Tel Aviv and Glasgow Universities, the 'cat parasite' Toxoplasma gondii was engineered to deliver drugs to the human brain. The study was led by Prof. Oded Rechavi from the Department of Neurobiology and the Sagol School of Neuroscience at Tel Aviv University, together with his PhD student Dr. Shahar Bracha, and with Prof. Lilach Sheiner, an Israeli scientist and toxoplasma expert from the University of Glasgow in Scotland. The results were published in the leading scientific journal Nature Microbiology.

"One of the biggest challenges in treating neurological diseases is getting through the blood-brain barrier (BBB)," explains Prof. Rechavi. "It is tough to deliver drugs to the brain via the bloodstream, and this is especially true for large molecules such as proteins, the critical 'machines' that carry out many important functions inside the cell".

Toxoplasma gondii - the 'cat parasite'

The creative solution proposed by the TAU team utilizes the unicellular parasite Toxoplasma gondii, which can infect a vast variety of organisms, but reproduces only in the guts of cats. The parasite is very effective in infecting humans, with an estimated third of the global population infected at some point in their lives. Prof. Rechavi explains: "Most people don't even feel the infection or only experience mild flu-like symptoms.

Dormant Parasite Sparks New Treatment

The parasite is, however, dangerous for people with immune failure due to conditions like AIDS, and for fetuses whose immune system has not yet developed. This is why pregnant women are advised not to eat raw meat which might contain the parasite, and to stay away from cats, which might deliver it through their feces. While ridding the body of the parasite, a healthy immune system has only limited access to the brain, and the parasite remains in the brain throughout the carrier's lifetime".

The parasite's ability to penetrate the human brain and survive there in a dormant state, without reproducing, made it a perfect candidate for the researchers' novel approach: genetically engineering Toxoplasma gondii to secrete therapeutic proteins.

Can Parasites Deliver Medications to the Brain?

"The parasite has three distinct secretion systems and we 'hitched a ride' on two of them", says Prof. Rechavi. "We did not intervene with the first system, which secretes proteins outside the neurons. The second system 'shoots' a 'harpoon' into the neuron, to enable penetration. Once inside, the parasite forms a kind of cyst that continues to secrete proteins permanently. We engineered the parasite's DNA to make it produce and secrete the proteins we want, which have therapeutic potential".

"The parasite's ability to pass through the BBB and communicate with the neurons, combined with our ability to engineer the parasite, generate a golden opportunity for solving the great therapeutic challenge of delivering medications to the brain", says Prof. Sheiner.

Illustration of the activity of neurons

In this study, the team used transgenic model animals that were injected with parasites genetically engineered to produce and secrete proteins that travel into cell nuclei. Several lines of evidence proved that the proteins had been delivered to the target area and remained active in the neurons' nuclei. One of these was especially eye-catching: a protein that, delivered by the parasite, entered the nuclei and cut out specific DNA segments, causing the transgenic animals’ brains to glow in the dark.

New Method for Rett Syndrome

This breakthrough can have far-reaching implications for a series of severe diseases. In the present study, the researchers specifically demonstrated the delivery of a protein called MeCP2, whose deficiency is associated with Rett syndrome. "This is a deadly syndrome caused by a deficiency in a single gene called MePC2 in brain cells, and our engineered Toxoplasma gondii was able to deliver it to the target cells", says Prof. Rechavi. "But this is just one example. There are many other diseases caused by deficiency or abnormal expression of a certain protein". To ensure the method's safe and effective therapeutic implementation, for both drug delivery and genetic editing, a company named Epeius was established in collaboration with Ramot – the technology transfer company of Tel Aviv University, and with the University of Glasgow's research and innovation services.