Author: AUFTAU

Researchers from the School of Public Health at Tel Aviv University’s Faculty of Medicine examined the anthropometric [the scientific study of the measurements and proportions of the human body] data of about 3,000 Israeli women and men and concluded that body fat percentage is a much more reliable indicator of an individual’s overall health and cardiometabolic risk than the BMI index, widely used in clinics today. The researchers suggest that body fat percentage should become the gold standard in this respect and recommend equipping clinics all over Israel with suitable devices.

“BMI (…) is considered a standard indicator of an individual’s general health. However, despite the obvious intuitive connection between excess weight and obesity, the actual measure for obesity is the body’s fat content.” – Prof. Yftach Gepner

‘The Paradox of Obesity with Normal Weight’

The study – the largest of its kind ever conducted in Israel – was led by Prof. Yftach Gepner and PhD student Yair Lahav, in collaboration with Aviv Kfir. It was based on data from the Yair Lahav Nutrition Center in Tel Aviv.  The paper was published in Frontiers in Nutrition.

“Israel is a leader in childhood obesity and more than 60% of the country’s adults are defined as overweight,” says Prof. Gepner, adding that, “the prevailing index in this respect is BMI, based on weight and height measures, which is considered a standard indicator of an individual’s general health. However, despite the obvious intuitive connection between excess weight and obesity, the actual measure for obesity is the body’s fat content, with the maximum normal values set at 25% for males and 35% for females. Higher fat content is defined as obesity and can cause a range of potentially life-threatening cardiometabolic diseases: heart disease, diabetes, fatty liver, kidney dysfunction, and more. The disparity between the two indexes has generated a phenomenon called ‘the paradox of obesity with normal weight’ – higher than normal body fat percentage in normal-weight individuals. In this study we examined the prevalence of this phenomenon in Israel’s adult population.”

“We recommend equipping all clinics with suitable devices for measuring body fat content, and gradually turning it into the gold standard both in Israel and worldwide, to prevent disease and early mortality.” – Prof. Yftach Gepner

Body Fat Percentage – A More Reliable Indicator

The researchers analyzed the anthropometric data of 3,000 Israeli women and men, accumulated over several years: BMI scores; DXA scans (using X-rays to measure body composition, including fat content); and cardiometabolic blood markers.  About one third of the participants, 1,000 individuals, were found to be within the normal weight range.  Of these, 38.5% of the women and 26.5% of the men were identified as ‘obese with normal weight’ – having excess fat content despite their normal weight. Matching body fat percentage with blood markers for each of these individuals, the study found a significant correlation between ‘obesity with normal weight’ and high levels of sugar, fat, and cholesterol – major risk factors for a range of cardiometabolic diseases.  At the same time, 30% of the men and 10% of the women identified as overweight were found to have a normal body fat percentage.

“Our findings were somewhat alarming, indicating that obesity with normal weight is much more common in Israel than we had assumed,” warns Prof. Gepner. “Moreover, these individuals, being within the norm according to the prevailing BMI index, usually pass ‘under the radar’. Unlike people who are identified as overweight, they receive no treatment or instructions for changing their nutrition or lifestyle – which places them at an even greater risk for cardiometabolic diseases.”

Based on their findings, the researchers concluded that body fat percentage is a more reliable indicator of an individual’s general health than BMI. Consequently, they suggest that body fat percentage should become the prevailing standard of health and recommend some convenient and accessible tools for this purpose: skinfold measurements that estimate body fat based on the thickness of the fat layer under the skin; and a user-friendly device measuring the body’s electrical conductivity, already used in many fitness centers.

   Prof. Gepner: “Our study found that obesity with normal weight is very common in Israel, much more than we had previously assumed, and that it is significantly correlated with substantial health risks. And yet, people who are ‘obese with normal weight’ are not identified by today’s prevailing index, BMI. We also found that body fat percentage is a much more reliable indicator than BMI with regard to an individual’s general health. Therefore, we recommend equipping all clinics with suitable devices for measuring body fat content, and gradually turning it into the gold standard both in Israel and worldwide, to prevent disease and early mortality.”

Researchers at Tel Aviv University, among other institutions, have developed an innovative gene therapy that may help children suffering from Dravet syndrome (DS), a severe developmental epilepsy caused by a random mutation in the SCN1A gene during fetal development. DS is characterized by uncontrollable epilepsy, developmental delays, cognitive impairment, and a high risk of early death. The team’s innovative gene therapy not only improved epilepsy but also protected against early death and enhanced cognitive abilities in DS lab models.

Breakthrough Gene Therapy

The researchers are hopeful that their genetic therapy can be adapted for other genetic epilepsies and may lead to the development of similar treatments for rare diseases. The study involved injecting a virus carrying a normal SCN1A gene into the brains of DS mice. The treatment demonstrated effectiveness in various critical aspects, even after the onset of severe epilepsy. The researchers express optimism that their laboratory technique will eventually reach clinical settings and provide help to children wit this debilitating disease. They also believe that the tools developed during this research will pave the way for similar treatments for other rare diseases.  

The study was led by Dr. Moran Rubinstein and graduate student Saja Fadila, along with Anat Mavashov, Marina Brusel and Karen Anderson, all from the Sackler Faculty of Medicine and the Sagol School of Neuroscience at Tel Aviv University, and Dr. Eric Kremer, from the University of Montpellier in France. Also participating in the study were Bertrand Beucher and Iria González-Dopeso Reyes from Montpellier and other researchers from France, the USA and Spain. The research was published in the Journal of Clinical Investigation.

Dr. Moran Rubinstein

Dravet syndrome affects approximately one in 16,000 births and is considered relatively common among rare genetic diseases. Currently, there are around 70 affected children in Israel. The syndrome presents as thermally-induced seizures around six months of age, with progress to frequent spontaneous epileptic seizures and motor and cognitive developmental delays after one year.

Dr. Rubinstein highlights that existing epilepsy drugs are insufficient for children with DS, who face a significant risk of early death. The syndrome results from a genetic mutation that occurs randomly during fetal development in a gene called SCN1A and is not inherited from the parents. Unfortunately, the disease cannot be predicted or discovered during pregnancy, making early diagnosis challenging.

According to the researchers, it is customary nowadays to perform a genetic analysis for children who suffer from complex thermally-induced seizures around the age of six months. However, even if the test detects that the problem is in the SCN1A gene, the final diagnosis is often given after the epilepsy worsens, with the appearance of severe spontaneous convulsions and developmental delays. Although it is important to have an early diagnosis, diagnosis is often delayed, and most children are diagnosed only at the age of one or two years and sometimes even later.

Promising Results in Lab Models

Although genetic therapies have shown promise in DS mice and some of them are undergoing clinical trials in humans, they have only been effective when administered at very early stages, prior to symptom onset. Given the complex and invasive nature of gene therapy, it cannot be administered without a confirmed diagnosis of DS. Hence, the researchers focused on developing a treatment that could be effective after seizure onset, even at a relatively late age. Additionally, since DS involves cognitive impairments, the team aimed to alleviate both epilepsy and cognitive symptoms.

Dr. Rubinstein explains that viruses are commony used as carriers in genetic therapies to introduce normal genetic material into patients, enabling normal cellular function. For this purpose, the virus is engineered: its original genetic material is removed so it cannot cause disease or replicate itself, and instead, the relevant normal gene is packed inside. In the case of Dravet syndrome, since the SCN1A gene is very large, it was not possible to use common viruses that are usually used for this purpose and a virus capable of carrying and transferring large genes was needed. The team solved this problem by using a virus called Canine adeno virus type 2, as a carrier of the normal gene.

The carrier virus was directly injected into the brains of DS mice since its properties prevent it from crossing the blood-brain barrier. The treatment was administered to 31 mice at three weeks of age,  after spontaneous convulsions had commenced (equivalent to one to two years of age in children), and to 13 mice at five weeks of age (equivalent to approximately six to eight years of age in children). The injection was performed in multiple brain areas, while an empty virus was injected into the brains of 48 control mice.

Potential for Rare Diseases

Promising results followed, with the highest efficacy observed when the treatment was administered at three weeks of age. In these mice, seizures ceased entirely within 60 hours of injection, life expectancy significantly increased, and cognitive impairment, assessed through spatial memory tests, was completely restored. Even in mice treated at five weeks of age, there was notable improvement, characterized by reduced epileptic activity and protection against thermally-induced seizures. In the control group that received the empty virus, no improvement was observed, and the mice experienced symptoms akin to untreated mice, with approximately 50% succumbing to early death due to severe epilepsy. The treatment was also applied to healthy mice without any adverse effects, demonstrating its safety.

The researchers clarify that their treatment restored normal function to damaged neurons in the brain by introducing a complete, normal gene. This approach is crucial in treating Dravet syndrome since the mutation can occur at different locations within the gene, and administering a complete gene provides a univform treatment suitable for all DS patients. Furthermore, the chosen virus infected numerous nerve cells and spread widely beyond the injection site, enhancing its effectiveness.  

Dr. Rubinstein concludes that their treatment is the first proven to be effective for Dravet syndrome after the onset of spontaneous convulsions, offering improvement in cognitive function for DS mice. The team has already registered a patent, and hopes to see the treatment reach clinical settings to benefit children affected by this debilitating disease. They are also exploring its potential applicability to other genetic neurodevelopmental diseases. The developed platform represents a plug-and-play system for genetic therapies, with the possibility of incorporating different types of normal genetic material into the carrier virus for treating additional diseases in the future.

A new study conducted at Tel Aviv University and the Sheba Medical Center reveals how melanoma cancer cells affect their close environment to support their needs – by forming new lymph vessels in the dermis to go deeper into the skin and spread through the body. The researchers believe that the new discovery may contribute to the development of a vaccine against the deadly cancer.

The Hidden Mechanism

The scientific breakthrough was led by Prof. Carmit Levy of Tel Aviv University’s Sackler Faculty of Medicine and Prof. Shoshana Greenberger from the Sheba Medical Center. The study was funded by ICRF (the Israel Cancer Research Fund) and its results appeared in the Journal of Investigative Dermatology published by Nature.

“We demonstrated for the first time that in the first stage, in the epidermis, melanoma cells secrete extracellular vesiculas called melanosomes.” – Prof. Shoshana Greenberger

The researchers (from left): Prof. Carmit Levy and Prof. Shoshana Greenberger

Melanoma, the deadliest of all skin tumors, starts with uncontrolled division of melanocyte cells in the epidermis – the top layer of the skin. In the second stage the cancer cells penetrate the dermis and metastasize through the lymphatic and blood systems.

In previous studies a dramatic rise was observed in the density of lymph vessels in the skin around the melanoma – a mechanism that was not understood by researchers until now.

“Our main research question was how melanoma impacts the formation of lymph vessels, through which it then metastasizes,” explains Prof. Greenberger. “We demonstrated for the first time that in the first stage, in the epidermis, melanoma cells secrete extracellular vesiculas called melanosomes.”

What are these vesiculas and how do they impact their environment? Examining this in human melanomas from the Pathology Institute, the researchers demonstrated that melanosomes could penetrate lymph vessels. They then examined their behavior in the environment of actual lymph vessel cells and found that here too the melanosomes penetrate the cells and give them a signal to replicate and migrate. In other words, the primary melanoma secretes extracellular vesiculas that penetrate lymph vessels and encourage the formation of more lymph vessels near the tumor, enabling the melanoma to advance to the lethal stage of metastasis.

“If we can stop the mechanisms that generate metastases in lymph nodes, we can also stop the disease from spreading” – Prof. Shoshana Greenberger

Melanoma’s Stealth Tactics

Prof. Carmit Levy adds that, “melanoma cells secrete the extracellular vesiculas, termed melanosomes, before cancer cells reach the dermis layer of the skin. These vesicles modify the dermis environment to favor cancer cells. Therefore, melanoma cells are responsible for enriching the dermis with lymph vessels, thereby preparing the substrate for their own metastasis. We have several continuing studies underway, demonstrating that the melanosomes don’t stop at the lymph cells, as they also impact the immune system, for example.”

A Promising Vaccine Hope

Since melanoma is not dangerous at the premetastatic stage, understanding the mechanism by which the metastases spread via the lymphatic and blood systems can hopefully contribute to the development of a vaccine against this deadly cancer.

“Melanoma that remains on the skin is not dangerous,” says Prof. Greenberger. “Therefore, the most promising direction for fighting melanoma is immunotherapy: developing a vaccine that will arouse the immune system to combat the melanosomes, and specifically to attack the lymphatic endothelial cells already invaded by the melanosomes. If we can stop the mechanisms that generate metastases in lymph nodes, we can also stop the disease from spreading.”