Human Health

Haitham Amal, 36

Haitham Amal

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Researchers – 40/40

Haitham Amal, 36

The Institute for Drug Research, the School of Pharmacy – the Hebrew University’s Faculty of Medicine | Lives in Haifa, married with two children.

Original Hebrew article by Efrat Neuman appeared here. Translation by HUJI staff.

Dr. Haitham Amal has developed an innovative method that can help identify therapeutic targets. He has used this method to identify significant changes in the brains of patients with neurological disorders such as autism and Alzheimer’s disease. His most significant finding came during his time at MIT, when he was the first to document a connection between high levels of nitric oxide (NO) in the brain with autism. Nitric oxide molecules regulate the activity of numerous organs, including the brain. Dr. Haitham also discovered that NO can affect key proteins, which may alter their neural function. The next step for his lab is developing a drug for altering protein function, which would cure or improve autistic behavior. The lab also aspires to identify biological markers of autism in children’s blood.

Two years ago, Dr. Amal left MIT for the Hebrew University, where he heads a research group at the Institute for Drug Research. One of his discoveries recently made headlines when he announced the identification of a joint molecular mechanism shared by Alzheimer’s patients and people with autism, which may cause neurological disorders. Dr. Amal’s discovery may help pave the way towards the development of more effective treatments.

LinkedIn | Facebook | Twitter | Dr. Amal’s Lab

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Novel Sugar Substitutes

Strawberries and Sugar
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Dr. Amiram Goldblum is a Professor Emeritus of Computational Medicinal Chemistry at the Hebrew University of Jerusalem School of Pharmacy - Institute for Drug Research. Among his many discoveries is his unique, prize-winning algorithm, Iterative Stochastic Elimination (ISE) (see box). While ISE has been used to rapidly identify potential drugs, it can also be used to identify other useful chemical substances – such as sugar substitutes.

Ah, Sugar Sugar, You’ve Got Me Wanting You

Worldwide, diabetes is on the rise. The number of diabetics nearly quadrupled between 1980 and 2014, affecting 422 million people. In addition, diabetes often causes other ailments, including kidney failure, blindness, heart attacks, strokes, and more.

As early as the late 1950s, and rapidly increasing in recent decades, artificial sweeteners appeared on the market. Generally speaking, these can be divided into three chemical “families”: peptides, sulphonamides, and saccharides/glycosides. Despite their chemical differences, they are all much sweeter than sugar, while also leaving a bitter aftertaste.

Sweets for My Sweet (Receptors)

We can taste sweetness thanks to the presence of TAS1R2/TAS1R3 proteins in our bodies, mostly on our tongue and mouth. A similar protein transmits the umami (savory) flavors, and it is entirely possible that sugar and sugar substitutes also transmit their effect through these receptors. In addition, twenty different proteins can sense bitter tastes, and it is assumed that some of them may cause the bitter aftertaste associated with substitute sugars, despite the different structures of the “bitter taste” proteins.

To solve this problem, Prof. Goldblum has constructed computational models that are capable of distinguishing between sweet, umami, and bitter tastes, and then screens millions of commercially available molecules through these models,, searching for those that will affect the sweet receptor alone (and not the bitter receptors).

"By identifying molecules that resemble sugar’s sweet taste but without its negative and dangerous impact on our health, I hope to both offer consumers a better product, while also contribute to the reduction of diabetes worldwide."

          - Prof. Goldblum

Once detecting these molecules, Prof. Goldblum will take his findings to the lab, along with a partner from the Technion. They will test the best molecules on mice, examining whether they prefer the substitute or the real thing, as well as the effect of both real and sugar substitutes on their movements, energy expenditure, and metabolism. Needless to say, mice will not have the final say – after all, they taste sweets differently than humans.

Just a Spoonful of Sugar

The first step towards FDA approval is filing an application for an investigational new drug. The molecule will be tested on a small group of healthy people to determine it is not toxic in several dose alternatives. Once approved, a panel of taste-testers will help determine the exact quantity required to obtain the same sweetness as a spoonful of sugar. The new molecule will likely be measured in milligrams, compared with the packets commonly found in restaurants and cafes, which contain 2-4 grams of sugar.

It is not hard to imagine the wide-spread market appeal of such a product. With diabetes on the rise, a reduction of sugar consumption has the potential to save and improve the lives of millions worldwide. Luckily for those with a sweet tooth, dieting may never be easier.

Information about Prof. Goldblum’s research on potential drugs for the Coronavirus is available here.

ISE is a generic algorithm capable of solving extremely complex combinatorial problems, such as finding the best solutions to a problem which has an enormous number of possible solutions that are not amenable to full examination by any means. The algorithm examines many possibilities and rejects possibilities in several “rounds,” until the number of combinations is small enough to be fully computed. The significant advantage of this computational tool is its ability to suggest in silico (computerized) good solutions in a very short time, which would be impossible to perform in the lab. For drug research, it has already shortened the time for discovering new candidate drugs from years to months, and even weeks. This innovation earned him the Hebrew University’s Kaye Innovation Award for 2017.
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Unraveling the Mysteries of the Brain

Shir Filo
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Shir Filo is a PhD student in computational neuroscience at the Edmond and Lily Safra Center for Brain Sciences (ELSC). She was born and raised in Tzurit, a small village in northern Israel, where she enjoyed belonging to a tight-knit, supportive community.   

Drawn to the possibility of solving some of life’s biggest mysteries, Shir studied physics and biology in high school. She eventually chose to major in these two fields as an undergraduate student at the Hebrew University and was accepted to the Etgar track for excelling students in the life sciences.

"After graduating, I realized I wanted to combine physics and biology in order to understand the most mysterious part of ourselves – the brain. Physics allows us to describe and understand the world so elegantly, and I believe that when it intersects with biology, the most interesting questions of our lives can be answered."

Developing a Quantitative MRI  

Today, Shir conducts her research in Dr. Aviv Mezer’s laboratory, developing new techniques for quantitative MRI. Currently, doctors estimate, by eye (qualitatively), whether MRI scans look normal. If they suspect a problem, the patient will undergo a painful and invasive biopsy – perhaps unnecessarily.

Yet nearly every other aspect of our healthcare is quantitative. We measure the temperature of our body in Celsius or Fahrenheit and measure the different components of our blood (red cells, white cells, platelets, etc). Why should MRI scans be any different? Shir has come up with a solution. Her biophysical models combine several MRI scans, providing quantitative information about brain tissue, including lipids and proteins.

Shir’s method can provide valuable information about the molecular changes that take place during aging, and it will be helpful for both research and clinical practice. For example, understanding what differentiates a healthily aging brain from an Alzheimer’s or Parkinson’s brain, or even to estimate the grade of a brain tumor without a biopsy.

"Not only is ELSC world-famous research center, but it also has a great sense of community, where everyone knows each other and are willing to help. Sometimes ELSC feels like a small village with a unique language and culture. It immediately draws you in and makes you feel like you belong."

Over the course of her studies, Shir has received numerous awards, including prizes from the University Rector and Dean for outstanding academic performance. She has co-published a number of articles and a book chapter.

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Taking Lethal Inflammatory Storms – By Storm

Raymond Kaempfer

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For the last three decades, Professor Raymond Kaempfer has been tackling one of medicine’s largest problems: evolving antibiotic resistance and lethality of many bacteria, including Staphylococcus aureus and Streptococcus pneumoniae.  

The mechanism by which these bacteria kill is quite straightforward: they produce toxins that our immune system would ordinarily identify, target, and neutralize. Yet these particular toxins, called superantigens, evoke our immune system to vastly over-react, resulting in severe, and often lethal, inflammation known as a cytokine storm. The potential of these toxins for ruin is compounded by the fact that they can remain active for years and are heat resistant, rendering them suitable as biological weapons. Indeed, it was the Pentagon that first approached Prof. Kaempfer, asking him to develop an antidote to this feared biological threat. 

Eureka! Deciphering the Mechanism of Cytokine Storms 

While progress had been made in the late 20th century, Prof. Kaempfer was the first to fully decipher how these toxins evoke cytokine storms, which he published in 2011 – the greatest breakthrough in this field in 22 years. Based on this novel insight, he developed unique, small protein molecules capable of attenuating excessive inflammation, and not only in infected animals (his molecules combat infections by lethal mixtures of live bacteria in mice) but especially in severe sepsis patients, specifically, those suffering from necrotizing soft tissue infection, commonly called “flesh-eating bacteria.” Rather than fighting the bacteria or toxins, Prof. Kaempfer treats the body’s self-induced inflammation, in an approach known as a Host Oriented Therapeutic strategy. Because the human immune system will not change over a single lifetime, nor over the course of a few generations, pathogens cannot become resistant through mutation. This is a major advantage over antibiotics. 

A New Drug is Born? 

Prof. Kaempfer’s first-generation molecule successfully underwent all three phases of FDA clinical trials. This month, he will be submitting his FDA application for a new drug for treating flesh-eating bacteria, the first of its kind. His second-generation molecules are proving to be up to 300 times more potent in treating wound infections in animals. Indeed, per the Pentagon’s request, Prof. Kaempfer is now testing his molecules upon wounds infected by antibiotic-resistant bacteria. 

Not only did Prof. Kaempfer succeed at deciphering a mechanism that had stumped scientists for decades, but his molecules are noteworthy for another reason: they counter the body’s excessive, harmful immune reaction while leaving the basal response intact, enabling the body to continue fighting infections on its own and developing protective immunity. 

A Call from Pandemic-Stricken New York  

In February, Prof. Kaempfer received a phone call from a large New York hospital, asking for his molecules in order to treat severely ill COVID-19 patients suffering from pulmonary cytokine storms, which closely resemble those resulting from superantigen toxins or bacteria. Yet he couldn’t just go to the post office and send a package of un-approved molecules.

With no end to the pandemic in sight, Prof. Kaempfer is hopeful that his FDA application will soon be successful. Although his application specifies the first molecule be used to combat necrotizing soft tissue infection, once approved it can be used in controlled trials on COVID-19 patients. This is especially pertinent, as many COVID-19 fatalities are due to cytokine storm. In addition, recovered patients often continue to suffer from varying degrees of multi-organ failure, also due to Coronavirus-induced inflammation.    

Throughout the pandemic, Prof. Kaempfer’s lab has been running non-stop, including during the countrywide lockdown and holidays, testing his molecules against viral and cellular components, released once the coronavirus kills infected cells, that over-activate human immune cells and evoke a cytokine storm. His entire career has prepared him for this moment: his groundbreaking research has the potential to save millions of lives worldwide, and he cannot afford to take a single day – or minute – off.

"My lab has been very lucky – if you define luck as the result of decades of hard work. One of my passions is ’survival science’ – applying my scientific knowledge, encompassing chemistry and microbiology, to creating a better world."

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Two Birds with One Stone: Combatting Smoking and the Coronavirus

Image of Woman Smoking
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Dr. Yael Bar-Zeev is on a mission: to eliminate tobacco and smoking from Israel. As a public health physician, behavioral scientist, epidemiologist, and tobacco treatment specialist, Yael is well-equipped to tackle smoking.

She is a faculty member at the Braun School of Public Health and Community Medicine, helped found and currently chairs the Israeli Medical Association for Smoking Cessation and Prevention, and is a regular participant in Knesset meetings, Ministry of Health Committees, and the media. 

Smoking in the Age of a Global Pandemic 

As the Coronavirus introduced new buzzwords such as ‘social distancing’ and ‘flattening the curve,’ Dr. Bar-Zeev’s mind was somewhere else entirely: how would the pandemic, and the looming shutdown, affect Israelis’ smoking habits? 

She identified two contradictory forces: On one hand, stress levels were skyrocketing, possibly leading to increased smoking rates. On the other hand, widespread unemployment and financial woes, coupled with a heightened awareness of pulmonary vulnerability, might lead to a reduction in smoking. An additional concern was exposure to secondhand smoke, which might become more prevalent during a shutdown or quarantine.

"Smoking kills 8,000 Israelis each year and is damaging our ability to deal with the Coronavirus pandemic. The Ministry of Health and health-care providers must not neglect the fight against smoking, which continues to be the leading risk factor for mortality and morbidity in Israel."

An Exploratory Survey 

Dr. Bar-Zeev and Prof. Yehuda Neumark designed a survey targeting smokers and ex-smokers. It was disseminated through social media, reaching 660 participants, and revealed interesting data: 

First, 45% of respondents reported an increase in their motivation to quit. Yet only 7% of respondents actually stopped smoking and another 16% were unsuccessful in their attempts. Taken together, these 24% are an improvement; during ordinary times, this number hovers around 20%. Of those who attempted to quit, nearly 16% used some form of behavioral and/or medical support.  

On the flip side, 44% of respondents reported upping their intake by an average of 3 cigarettes per day. While they may have been motivated to quit, they felt incapable of doing so. 

In terms of secondhand smoke, over 80% of respondents noted no change in their home smoking rules. This may be good news, as nearly 88% already restricted smoking in their homes, including nearly 70% who limited smoking to the balcony or outdoors. At the same time, 6.6% (equaling roughly 80,000 smokers) reported that their home smoking rules worsened during the shutdown, exposing their loved ones to more secondhand smoke. 

A Missed Opportunity? 

Dr. Bar-Zeev’s data, along with similar surveys conducted worldwide, indicate that the pandemic might be an ideal time to reach out to smokers and actively offer guidance and support for quitting or reducing one’s cigarette intake.

"The pandemic has presented a golden opportunity to leverage smokers’ heightened motivation to quit and provide them with free, effective support, all while taking specific, immediate steps that could aid also in the management of the Coronavirus pandemic."

Yet despite the immense potential, reality was sobering. During the period of severe restrictions in Israel, group counseling workshops already in progress transitioned to one-on-one telephone consultations, and all scheduled cessation workshops were cancelled. The two health-care providers that routinely provide quit-line phone services require that patients must first obtain a referral from their primary care physician – posing an additional logistical hurdle. Only now, over six months into the Coronavirus pandemic, these providers have begun offering scant online group workshops. 

In January, the Israeli Ministry of Health opened a national quit-line – with little fanfare and even less advertising. As a result, when the pandemic struck, very few Israelis, including medical practitioners, were aware of the quit-line’s existence.  

In addition, it took the Ministry of Health until June to create two Coronavirus-themed anti-smoking ads, which are published on alternate months. These ads were the first to feature the national quit-line number. 

Don't Double Your Risk

The two Ministry of Health Coronavirus-themed anti-smoking advertisements. The first ad (right) came out in June 2020.

Translating Findings to Policy Recommendations  

Dr. Ben-Zeev has plenty of ideas how to leverage the Coronavirus crisis to help combat smoking. These range from requiring the health-care providers to actively reach out to smokers to training cessation counselors to help smokers reduce or maintain their intake, to prevent increases. In addition, she was a signatory on a policy paper issued by a variety of medical, health, and anti-smoking organizations, submitted to the Ministry of Health this May. 

Among their recommendations:

  1. Gather accurate smoking data and history of all Coronavirus patients.
  2. Run public awareness campaigns on ways to quit and reducing exposure to secondhand smoke, including adding a specific insert and the national quit-line number on all tobacco products packaging.
  3. Create a national, proactive plan to support people who wish to quit, including staffing the phone lines, planning workshops in accordance to the Ministry’s Coronavirus guidelines, and foster interorganizational cooperation.
  4. Limit smoking in public and include anti-smoking policies within the Ministry’s guidelines; specifically, banning outdoor smoking in public places such as restaurants and coffee-shops, so people do not have to choose between reducing their exposure to the Coronavirus and exposure to secondhand smoke.
  5. Continue expanding the ban on advertising tobacco products to include the print media.
  6. Continue implementing the WHO Framework Convention on Tobacco Control, which Israel has ratified.
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An Innovative Coating for Creating Anti-Viral Surfaces

Meital Reches
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Prof. Meital Reches’s research groups is focused on saving lives: 6,000 lives in Israel, 100,000 lives in the United States – and many, many more worldwide. Infectious “superbugs” kill this many hospitalized patients a year, a number that dwarfs the Coronavirus death toll. 

Leading her team within the Institute of Chemistry, Prof. Reches has developed a unique coating that can be sprayed onto glass, metal, and plastic surfaces, rendering them resistant to fungus, yeast, and bacteria. The patented spray comprises three amino acids: One of DOPA, which is an extremely strong adhesive that naturally occurs in many forms, including enabling mussels “glue” themselves to any surface; and two of phenylalanine, which is one of the two amino acids that make up aspartame. 

DOPA enables Prof. Reches’s spray to stick, while the two phenylalanine amino acids self-assemble on the surface. The phenylalanine is modified with fluorine atoms, resulting in a non-stick surface that resembles Teflon©. Once applied, fungus, yeast, or bacteria are unable to stick or grow on treated surfaces. 

What About Viruses? 

Until now, Prof. Reches had primarily focused on bacteria, since their interactions and combinations may lead to their development of antibiotic resistance – turning them into “superbugs.” 

Then came the Coronavirus. Studies have shown that SARS-CoV-2 can remain on metal and glass for up to 5 days, plastic and stainless steel for 2-3 days, and cardboard for one day. Hence an anti-viral coating would serve as a barrier to transmission.  

Prof. Reches is currently testing her coating in the lab, using a surrogate for the Coronavirus. Given the similarities between bacteria and virus surfaces (both contain coat proteins) there is reason to hope that her spray will be effective against the Coronavirus as well. If successful, Prof. Reches hopes to market it and gain FDA approval per intended use.

"This innovative spray will be capable of preventing various infections, proving especially valuable as we cope with the current global pandemic."

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Understanding How Human Cells Work – By Studying Animal Evolution

Mice Image
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What can we learn by comparing our genes to those of a giant squid, a frog, or a blind mole? Turns out, a lot. Especially if you throw in 1,600 other species whose full genomes have been decoded in recent years. This is the specialty of Dr. Yuval Tabach at the Hebrew University’s Faculty of Medicine – taking apart the genes of thousands of animals, comparing them to one another, and extracting important conclusions about what human genes do, how they influence cancer and other diseases, and how they can be targeted by drugs.

Thanks to exponential developments in genomics, Dr. Tabach now has access to the genomes of 1,600+ species. This is Big Data: the ability to compare millions of genes, representing hundreds of millions of years of evolution. (For comparison, Dr. Tabach’s first paper, published in 2013, was based on 87 species, and in 2019 he had access to 600 species). 

Mining such vast amounts of data to benefit humans is far from simple. Dr. Tabach’s lab develops artificial intelligence algorithms that can search and compare these genomes for evolutionary patterns – identifying distinct networks of genes that execute a particular function. 

Co-Evolving Genes: An Indicator of Mutual Reliance (and Significance) 

How is this done? A guiding principle is that if two genes co-evolve closely together across many species, they are likely to play a similar role and even work together. Co-evolution means that these genes are always found together within a given species, and both absent in other species. In other words, if two genes have evolved together and changed at a similar rate across species, they may rely on each other to execute their tasks.

For example, Dr. Tabach’s algorithms can identify the genes that enable most animals (but not humans) to biosynthesize vitamin C or the genes involved in eyesight. His computational tools can highlight entire gene networks, including genes that might not have been thought to play a role in a given function.

Using his powerful methods, Dr. Tabach recently discovered new functions of genes involved in human breast cancer. By tracking the co-evolution of genes associated with DNA repair (genes that maintain the integrity of our genome) he discovered new genes involved in this important function. When these “repair” genes mutate in cancer, this contributes to the disease. 

Nature’s Superpowers 

Another passion of Dr. Tabach’s is studying nature’s “superpowers”: outliers in the animal kingdom. In particular, he is interested in animals that do not develop cancer and whose aging is slow – including elephants, whales, and naked mole rats. Often these are larger animals, with significantly more cells than humans, and thus have a higher potential for incurring mutations. And yet, these animals have substantially less cancer than other creatures, including humans.

"My team has identified 101 such genes that may play a role in these species’ resistance to cancer. Laboratory tests have shown that one of these genes was capable of reducing cancer potential by 10-20% in human cells, through improving the mechanism of repairing damaged DNA. It is easy to imagine the exciting, vast potential of the other 100 genes, which can be translated into dozens of new anti-cancer mechanisms."

Will We Grow Tusks?

If we begin replacing our genes with elephant DNA, will we become elephants? No. The genetic signatures and genes identified by Dr. Tabach are associated with cancer resistance and can increase life expectancy across species. Having survived millions of years of evolution, these universal, anti-cancer mechanisms may play an extremely valuable role without being highly specific to one organism or another. 

What’s Next?

Computational tools are predictive: they can scan and process large amounts of data and identify patterns. However, the findings and predictions must be tested through laboratory work – first with human cells and tissues, then with live animals. One of Dr. Tabach’s goals is to genetically engineer a cancer-resistant and potentially long-lived mouse. Another direction he is actively pursuing is the development of medications that mimic or replace genes. These may serve as preventative or curative measures.

Dr. Tabach’s work is both broad and specific – and offers hope of a healthier future for people worldwide.

"It is really exciting for us to look back through hundreds of millions of years of genetic evolution, and extract information that can impact human health in the present."

To read about Dr. Tabach’s Coronavirus research, click here.

Photo credit: "Mouse ENCODE" by Darryl Leja, NHGRI. Accessed on Flickr, used under a CC BY 2.0 license. The image has been cropped

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Applying Computational Tools to Curing Cancer

Yotam Drier
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Dr. Yotam Drier, from the Lautenberg Center for Immunology and Cancer Research at the Hebrew University, has set out to cure cancer. Using sophisticated computational methods, he is able to decipher the complex mechanisms that regulate the activity of thousands of genes and show how these mechanisms go awry in cancer. 

Cancer: The Evasive Killer  

Cancer is the number one killer in western society, and has proven a formidable disease to combat. One reason is that cancer cells are constantly changing (mutating) while also multiplying, acquiring new abilities and evading therapies. How do cancer cells do this? The key lies in mis-regulation of their genes.  

Cancer occurs when one of the trillions of cells in our body begins multiplying uncontrollably, giving rise to a tumor mass. This may be caused by gene overactivity or under-activity. For example, a gene might receive mis-repeated instructions to multiply (thus growing out of control), or a gene meant to block cell growth may become inactive. As cancer progresses, several such key genes tend to mutate, resulting in permanent changes to their activity.

Yet perfectly healthy genes can still drive cancer. How? The answer lies in the regulatory DNA, the “other” 97% of our DNA that does not contain genes. These regulatory elements dictate which genes are active within each cell, but it is not very straightforward. Their complex interactions, with each other and with multitudes of genes, make it challenging to uncover how they work.   

At the Cutting-Edge of Cancer Research  

Using advanced tools for genetic analysis and novel computational algorithms, Dr. Drier’s work has revealed several key ways in which gene regulatory elements can drive cancer:

Epigenetics: Chemical “markings” upon the regulatory DNA affect how the genes are regulated. Numerous simultaneous epigenetic changes can drastically change gene activity and drive cancer.  

3D genetic “tangles”: Each cell contains a sort of “tangled” DNA pom-pom, in which genes and their regulatory elements are in close proximity and interact. This structure is often changed in cancer cells. Without proper interactions, genes are not properly activated, driving cancer. 

Dr. Drier has successfully associated between particular changes to the regulatory DNA and specific types of cancer, including pancreatic neuroendocrine tumors, tumors of the salivary gland, and others.

"I’m aiming to systematically uncover the code of regulatory DNA and its disruption in cancer. This will allow us to both better understand how basic processes are regulated by, and encoded in, the DNA, as well as to uncover what drives various tumors we do not yet understand. We can suggest better strategies to manage these diseases and new drugs for targeting them."

At the Frontier of Computational Medicine

Dr. Drier’s lab team applies cutting-edge experimental techniques to studying and characterizing tumors in high throughput. In other words, rather than studying a specific gene or type of cancer, he studies a system: the entire cancer genome. Dr. Drier’s lab generates and analyzes a significant amount of data, including the tumor’s genetics, epigenetics, structure, gene expression, and more. 

By applying powerful algorithms, Dr. Drier integrates his findings with other databases and develops computational models capable of predicting cancer-driving events, focusing on changes to regulatory DNA elements. Such events may include changes and differences among healthy and cancerous cells and what causes the cancer to appear, keep growing, and metastasize. In other words, Dr. Drier is capable of predicting the function of observed changes to regulatory DNA and their role in driving cancer. 

Dr. Drier is currently taking a very broad approach; after identifying specific regulatory DNA alterations responsible for causing a particular form of cancer, his team will experimentally check whether indeed introducing these changes to cells causes the predicted outcome in order to establish cause and effect between regulatory DNA changes and cancer (rather than mere correlations).  

Dr. Drier’s work is at the forefront of computational medicine, both at the Hebrew University and globally. His work has greatly contributed to our understanding of how disruptions to regulatory DNA can lead to cancer, and his breakthroughs are illuminating new ways to treat cancer patients.

"I am very grateful for the opportunity to work in the diverse and stimulating environment that the Hebrew University’s Faculty of Medicine provides, where collaborations naturally form between physicians, experimental biologists, and computational biologists, an intersection that provides for very rewarding science."

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Entering Our Bodies: ACE2 Receptors as Gateway Cells

Covid Image

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The coronavirus is currently understood to enter the human body by interacting with a receptor named ACE2. This receptor is a protein that is displayed on the surface of certain cells in the lungs, nose, and oral cavity, among others. In a sense, the receptor and virus are like a keyhole and key; they must perfectly fit for the virus to enter and infect a person. 

However, which cell types present ACE2 on their surface, and what determines their presence, is unknown. Prevent ACE2 from being displayed, or blocking its interaction with the virus, would likely reduce infection rates and stymie the virus’s ability to infect additional cells in the body. Furthermore, it is possible that the Coronavirus can enter the human body via additional gateway receptors, which could also potentially be targeted for therapy. Such other players are yet to be discovered. 

It is clear that some recovered COVID-19 patients subsequently suffer from a range of illnesses, for example inflammation of the circulatory system in different organs. It is unclear whether the cells of these organs display gateway cells that permit infection by the virus.

Studying Healthy Cell Samples to Learn About Infection 

Hebrew University scientists Dr. Oren Parnas and Dr. Yotam Drier, in collaboration with Hadassah lung surgeon Dr. Ori Wald, hope to provide answers to these questions. To this end, they are collecting cells from the lungs and other organs of non-COVID-19 patients. They are characterizing the exact gene activity profile of each cell and identifying which cell types display active ACE2 receptors. To date, they have profiled thousands of cells and measured the expression of hundreds of thousands of genes. Powerful computational tools are the only possible way to analyze such a vast dataset.

At the same time, the researchers are comparing their findings to existing cell databases to identify cell types with a proclivity towards SARS-Cov-2 infection. Their working hypothesis is that by identifying the type of cell, they will glean clues about the mechanism underlying COVID-19 symptoms. For example, inflammation of the circulatory system could be caused by direct infection of blood vessel cells.

"It may become possible to understand and treat the disease’s symptoms by understanding how it spreads in the human body – on a cellular level. This type of detective work can really allow us to trace the virus’s advancement within the body."

          Dr. Oren Parnas

Looking Ahead: Uncovering a Gene Regulatory Network through Computer Analysis

Within our bodies, molecular networks regulate our genes, affecting when each gene is turned on and off. To fully understand how these networks are organized and how they work, Dr. Parnas and Dr. Drier will disrupt each of the known human genes in cells, one gene at a time, and then measure whether these perturbations change the cell’s ability to become infected with SARS-CoV-2. 

It is possible that an eventual drug will target the regulatory mechanisms that enable infection, rather than combatting the virus at the site of infection. By creating a computational network of the genes’ regulatory mechanisms, scientists will be able to better understand – and disrupt – the chain of events that makes cells susceptible to infection. 

The next step will be to translate these computational findings into lab experiments, in order to verify findings and determine the best course of treatment for patients.

"The impact of this groundbreaking work isn't limited to the current SARS-CoV-2 pandemic but will open the door to an entirely new understanding of how molecular networks affect disease and treatment - enabling us to treat numerous diseases more effectively."

          Dr. Yotam Drier

Photo credit: "Novel Coronavirus SARS-CoV-2" by NIAID. Accessed on Flickr, used under a CC BY 2.0 license. The image has been cropped.

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Identifying Drugs that Target ACE2 Genetic Networks

Genetics Image
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Understanding Human Cells – Through Animal Evolution

What can we learn by comparing our genes to those of a giant squid, a frog, or a blind mole? Turns out, a lot. Especially if you throw in 1,600 other species whose full genomes have been decoded in recent years. This is the specialty of Dr. Yuval Tabach at the Hebrew University’s Faculty of Medicine – taking apart the genes of thousands of animals, comparing them to one another, and extracting important conclusions about what human genes do, how they influence cancer and other diseases, and how they can be targeted by drugs.

Thanks to exponential developments in genomics, Dr. Tabach now has access to the genomes of 1,600+ species. This is Big Data: the ability to compare millions of genes, representing hundreds of millions of years of evolution. (For comparison, Dr. Tabach’s first paper, published in 2013, was based on 87 species, and in 2019 he had access to 600 species). 

Mining such vast amounts of data to benefit humans is far from simple. Dr. Tabach’s lab develops artificial intelligence algorithms that can search and compare these genomes for evolutionary patterns – identifying distinct networks of genes that execute a particular function. 

Co-Evolving Genes 

How is this done? A guiding principle is that if two genes co-evolve closely together across many species, they are likely to play a similar role and even work together. Co-evolution means that these genes are always found together within a given species, and both absent in other species. In other words, if two genes have evolved together and changed at a similar rate across species, they may rely on each other to execute their tasks. 

Using his powerful methods, Dr. Tabach recently discovered new functions of genes involved in human breast cancer. By tracking the co-evolution of genes associated with DNA repair (genes that maintain the integrity of our genome) he discovered new genes involved in this important function. When these “repair” genes mutate in cancer, this contributes to the disease. 

Understanding How Our Genes Enable COVID-19 Infection 

It is known that SARS-CoV-2 enters the body by binding to a receptor named ACE2, which is actually a protein displayed on our lung cells. Given that the Coronavirus appears to be a zoonotic disease (i.e. it can move between species), genetic comparisons with other species becomes especially pertinent. For example, mice have different ACE2 receptors, and are thus immune to the Coronavirus. A central strategy in fighting the Coronavirus will likely be disrupting human ACE2 receptors and thus preventing infection. 

Dr. Tabach has applied his computational tools these receptors and identified multiple genes that co-evolved with ACE2 and are functionally related to it – in other words, he has mapped a genetic network. Understanding this network may prove crucial to blocking infection or reducing the virus’s devastating effects once cells are infected. 

Next, using massive drug databases, Dr. Tabach generated a list of existing and commonly used medications that are predicted to interact with, and affect, the ACE2 genetic network. His lab is currently conducting experiments to test whether these drugs can indeed influence the activity of ACE2 receptors. In addition, 16 clinical trials are underway worldwide on drugs identified by Dr. Tabach.

"When you can identify patterns within 1,600+ species’ genomes and combine these with the known effects of existing drugs, and take into account the context of the actual disease, you can identify the perfect drug – it may already exist!"

          Dr. Yuval Tabach

The study describing this pioneering computational analysis was recently accepted for publication by iScience.

Photo credit: "Genomic Data" by Ernesto Del Aguila III, NHGRI. Accessed on Flickr, used under a CC BY-NC 2.0 license. The image has been cropped.

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Can Our Genes Influence or Predict the Severity of Illness?

Genes Image

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As Coronavirus infection rates rose worldwide, it has become clear that the disease’s symptoms and their severity greatly differ between people. As the pandemic continues to spread, it is imperative to identify which individuals, whether already affected or not, are at the greatest risk of becoming severely ill. Furthermore, accurate risk-prediction models will help public health officials determine how to best allocate medical resources. The key to such knowledge may lay in our genes, as they dictate how our bodies (organs, immune system) respond to infection. 

Hebrew University scientists are tacking this important question, taking a two-fold approach. First, COVID-19 patients are treated by Hebrew University-Hadassah clinicians, Prof. Dana Wolf and Prof. Arie Ben-Yehuda. Next, Dr. Yotam Drier, Dr. Shai Carmi, and Prof. Assaf Hellman are applying their expertise in genetic, computational, and statistical methods to patient samples, conducting large-scale genetic data analysis. By applying algorithms that cross-reference the patients’ genetic and clinical information, the researchers may be able to identify gene patterns are associated with severity of illness – explaining why some patients become severely ill, while others do not.

"As a computational biologist, I use data on genetic differences between individuals, along with statistical methods and algorithms, to find which genetic variants influence traits and diseases. I also develop genetic screens and models for disease risk prediction. I will apply these skills to tackling one of the biggest questions of the coronavirus pandemic – why are some people severely ill while others are asymptomatic? And how can we predict which individuals are at risk, in order to better protect them?"

- Dr. Shai Carmi

This study may have an immense impact on combatting COVID-19 by identifying individuals who are at high risk for disease or may respond better to a particular treatment. In the future, simple genetic tests may help predict and determine how to best treat different individuals.

Photo credit: "DNA Double Helix with Data" by Jonathan Bailey, NHGRI. Accessed on Flickr, used under a CC BY 2.0 license. The Image has been cropped.

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Revolutionizing Cancer Treatment

Benzion Amoyav

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Benzion Amoyav was always drawn to science. As a high school student, he studied both chemistry and biology, and was looking forward to continuing studying science at the university level. But at the same time, he also wanted his studies to benefit society. He decided to study pharmacy, which perfectly blended his two passions. 

During his undergraduate studies, Benzion conducted research in Prof. Ofra Benny’s laboratory, focused on developing a system that produces highly tunable micro- and nanoparticles for treating tumors. These “smart” particles primarily attack the tumor and release drugs in a controlled manner, resulting in better patient outcomes and less negative side effects.

After graduating, Benzion completed his internship at Hadassah, received his pharmacy license, and returned to Prof. Benny’s lab to continue with his research, eventually earning a master’s degree.

Today, as a doctoral student, Benzion is researching liver cancer and embolization (blocking solid tumors’ blood supply), a common, yet limited-efficacy, clinical practice for treating various types of tumors. He is taking a radically different approach by countering the microenvironmental conditions that are favorable to tumors. His main effort is to develop a drug-delivery device for focused therapy in combination with embolization.

By releasing the drug in a targeted fashion in close proximity to the tumor, Benzion’s research will enable doctors to reduce side effects, increase efficiency, and improve clinical outcomes.

"I believe that research education is the key for innovation and improvement, because laboratory-based discoveries can help large numbers of people. I am grateful for having the opportunity to impact other people’s lives.

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Lifelong Partners: Our Gut Microbes and Us

Moran Yassour

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Dr. Moran Yassour joined the Hebrew University faculty in 2018, with a joint appointment at the Hebrew University’s Faculty of Medicine and the Rachel and Selim Benin School of Computer Science and Engineering. 

We are never truly alone – we have family, friends, and colleagues. But we also have billions of other close partners, which live within us. These are the bacteria in our digestive system, which are vital to breaking down food we consume, synthesizing vitamins, and teaching our immune system to differentiate between self and non-self. Together these are collectively referred to as our microbiome. 

Research has shown that people can have very different collections of types of bacteria in their intestines – thousands of different strains – directly affecting our health, such as our likelihood to suffer from diseases such as diabetes or cancer. 

The Infant Gut Microbiome and Infant Health 

Dr. Yassour’s research focuses on the microbiome. She studies one of the most basic and fascinating questions about the microbiome: how is this community established in the newborn gut? How do delivery mode and breastfeeding affect the microbiome and, in turn, how does the gut microbiome impact an infant’s health? 

To this end, she collects microbiome samples from newborns and their parents, and conducts genetic profiling and a count of the bacteria present. This reveals which genes can be uniquely assigned to specific bacteria. The result is millions of gene reads (DNA sequences). Decipher each patients’ microbiome is an immense task, impossible without computational analysis. Dr. Yassour offers the following analogy:

Suppose I enter a library, remove all the books from the shelves, and shred them into 100-letter snippets. Then I ask you to go through the shreds and tell me which books had been on the shelves. Doing this manually would be impossible. Snippets may appear in numerous books, or simply not contain enough context. This is the power of computational tools. I can sort through the snippets, see what they match, iterate, and narrow down the options – until reaching a match. Eventually, I can recreate the entire bookshelf.

Dr. Yassour applies sophisticated computational algorithms to her “snippets” of sequenced DNA, trying to characterize the microbial population and its functional potential, based on which genes are present. 

In particular, Dr. Yassour studies three key issues related to pediatric health: links between of breastfeeding and microbial composition of the microbiome; how the microbiome is related to food allergies; and how cultural differences influence microbiome composition. 

Breastfeeding & Microbial Composition 

The third most common component in breastmilk are HMOs (human milk oligosaccharides). While indigestible by babies, these sugars feed and sustain the microbes within the gut. By pairing breastmilk and stool samples, Dr. Yassour examines how sugars in the milk affect the composition of bacteria in the intestine and the bacteria’s reaction to the sugars. This would enable baby formulas to better mimic breastmilk – helping formula-fed babies develop a healthier bacterial population. 

The Microbiome and Food Allergies

Dr. Yassour is also exploring infant allergies by collecting samples from healthy infants, some of which later developed an allergy to cow milk proteins. By examining the microbial population of these infants, she can search for microbial markers and create a machine learning classifier that may predict such an allergy.

"I saw how programs meant to help repeatedly failed, causing both sides much frustration. I developed a model that was rooted in these immigrants’ resilience, not their shortcomings. This model can be adapted for any population, not just Ethiopian immigrants.'"

For her doctoral research, Shelly studied social workers and educators who work with children in distress from the Ethiopian community. She examined how these community practitioners perceive aspects of risk and protection in these children’s lives, and the context through which their perceptions are constructed. 

"I spend my days at the library, dividing my time between reading and writing. I’ve published a book based on my master’s thesis and am currently working on my dissertation and a volume of poetry. I love writing, the words just bubble up within me. Without the financial support I’ve received, I wouldn’t have been able to fully dedicate myself to my writing."

Shelly recently submitted her doctoral thesis and was planning on a post-doctoral position in Germany. But the Coronavirus changed her plans, and she will continue her research at the Hebrew University. She hopes to eventually join the Hebrew University faculty. Her husband, also of Ethiopian descent, is also a full-time doctoral student nearing the end of his studies. Besides raising three young children, the couple also provides financial assistance to their parents and siblings. 

In addition, Shelly has been volunteering for as long as she can remember. She’s tutored and mentored children and students, young adults in crisis, and is active in a number of organizations, including the Israel’s social work newsletter, the Coalition for Education from Birth, and Beersheba Mothers Against Police Violence.

Over the course of her doctoral studies, Shelly received four prestigious awards: The Nira Shenhar Prize for Excellence (2017); the Dean’s Award for Ongoing Volunteer Work with Individuals and the Community; The ISEF Award of Excellence (2020); and the Rector’s Award for Community Volunteering.

"The microbiome plays an important role in educating the immune system to differentiate ‘self’ from ‘non-self.’ This is, in fact, a philosophical question, since gut bacteria are clearly not ‘self,’ yet we don’t want our immune system to attack these healthy and helpful microbes"

Cultural Differences between Microbiomes 

Lastly, Dr. Yassour’s lab has begun a study of Bedouins living in the Negev, asking whether Bedouin infants are born with diverse microbiomes, or whether these develop in response to their lifestyle.

"The Bedouin’s lifestyle is far from western, and we hypothesize that their microbiome is much more diverse. Previous studies have shown great differences between the microbiomes of tribal people in South America and Africa and those living in North America. Hygiene has caused the loss of microbial diversity."

Dr. Yassour's 2019 HUJI Talk is available here.

Dr. Yassour’s lab site can be found here.

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HU Researchers Searching for a Cure

Corona Research

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Diagnostics: HU researchers are designing and testing rapid diagnostic kits, as well as ways to identify individuals who have been exposed – by detecting antibodies in their blood. This may enable us to map resistance, improve isolation modes, and minimize the spread of the epidemic. These efforts involve a number of scientists, including Prof. Yuval DorProf. Eylon YavinDr. Maayan Salton.

Vaccine development: This effort is being led by scientists with previous experience with similar viruses: SARS and MERS. Our scientists are designing new vaccines and have begun producing the necessary proteins. Many researchers are involved, including Dr. Alex RouvinskiProf. Ora Schueler-FurmanProf. Sigal Ben-YehudaProf. Ilan Rosenshine, and Dr. Reuven Wiener.

Improving the capacity of the immune system to combat the virus: The immune system can be a double-edged sword: When fighting the Coronavirus, it produces antibodies to defeat the virus, while also producing factors that aggravate the disease, particularly the virus-induced pneumonia. Our scientists are designing novel ways to reinforce the constructive components while weakening the destructive ones. These researchers include Prof. Ofer MandelboimDr. Michael BergerDr. Oren Parnas, and Prof. Yinon Ben-Neriah.

Model systems to study the virus and develop new drugs: Animal models are essential for testing new treatments and drugs. Our scientists are developing ways to infect mice (who are naturally immune), which will serve as models upon which to test vaccines and newly developed anti-viral drugs. These researchers include Dr. Lior Nissim and Dr. Yossi Buganim, among others.

Molecular epidemiology studies to identify susceptible and resistant populations: Genetic variations among people may explain why some people are infected and others not, and why some develop more severe disease than others. Genetic studies may reveal ways to stop this – and subsequent – epidemics. We are constructing a new biobank to study and screen genetic factors contributing to disease susceptibility. These include Dr. Shai CarmiDr. Yotam DrierProf. Asaf HellmanProf. Hanah Margalit, and Dr. Yuval Tabach.

Drug development to block infection and reduce tissue damage: Our cellular biologists and pharmacology scientists are experimenting with repurposing clinically approved drugs and food additives to reduce infectivity and reduce tissue damage caused by the virus. These include Prof. Shmuel Ben-SassonProf. Moshe Kotler, and Prof. Albert Taraboulos.

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Pooled Coronavirus Testing – Screening Thousands of People While Saving Time and Costs

Testing for Corona

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A team of Hebrew University scientists and physicians has come up with a way to reduce wait-time for results and conserve precious laboratory supplies – without compromising test sensitivity or result validity. 

As the Coronavirus began spreading, public health and medical professionals recognized the importance of quickly identifying, and isolating, people infected with SARS-CoV-2. This holds especially true for retirement homes, hospital staff, or workers at essential factories. There is a great need to quickly screen large groups of people, especially to rule out even the low probability of infection in individuals, thereby ensuring the safety of the work environment, essential to its functioning.  

The standard polymerase chain reaction (PCR) test is conducted on genetic material extracted from patient swabs. Each patient’s sample has to be processed and tested individually: from inactivating the virus, extracting the genetic material, and conducting the positive/negative test. This requires substantial effort and cost of the materials for each sample. Furthermore, very early in the pandemic, world shortages of necessary materials became apparent, limiting the numbers of tests that could be conducted at once.

A team including Dr. Yotam Drier, Dr. Maayan Salton, and Prof. Yuval Dor of the Hebrew University’s Faculty of Medicine, together with Prof. Dana Wolf of the Hadassah Medical Center, rose to the challenge, by initiating effective pooled patient testing. The Hebrew University was among the first in the world to safely implement this approach, which is currently being adopted globally.

What is pooling? Say only three of 80 people to be tested actually carry the virus. This means that most tests will turn out negative. The researchers surmised that the 80 samples could be pooled into ten groups samples, each containing samples from 8 individuals. This “pool” can then be tested as if it were only one individual, thereby conducting 10 instead of 80 tests. If a particular pool comes back negative, it means that all eight people are uninfected and there is no need to test them individually. If, on the other hand, a pool comes back positive, that particular batch will be “unpacked” and retested, to identify the infected person. This results in substantial reduction in cost and time, particularly when the positive results are a low percentage of the tests, and allows much more cost-effective screening of large groups of people.

While the principle behind this approach sounds simple, it is in fact much more complex, both theoretically and practically. The researchers conducted robust mathematical and statistical modelling, providing the theoretical basis of why and how pooling would work, and determining the optimal pool sizes. Practically, pooling requires robots to be programmed to pool eight samples, and assurances must be in place to guarantee sample quality. 

This method’s success has expanded the testing capacity of the joint Hebrew University-Hadassah virology lab, reaching several thousand tests a day, and consequently in Israel as a whole. The lab operates 24/7 under the leadership of Prof. Wolf, with Hebrew University students and volunteers running the tests and conducting the lab work.

"We are happy to be able to contribute to the national effort fighting COVID-19. The unique strengths of the Hebrew University, including expertise in molecular biology and computer sciences, the close cooperation with the Hadassah Medical Center, the availability of cutting-edge equipment, and the positive spirit of the university’s staff, students, and researchers – who volunteered by the hundreds – have made it possible for the Faculty of Medicine and Hadassah to turn our campus into a national leader of Coronavirus testing. We continue our R&D to further improve diagnoses and identify potential interventions."

          Prof. Yuval Dor, Faculty of Medicine

Rising Infection Rates

Yet the efficiency of pooling goes down as the percentage of positive swabs goes up. As infection rates began rising in late June, it became increasingly likely that pools would test positively – requiring all eight swabs be tested individually. Dr. Moran Yassour, whose research bridges medicine and computer science, sees this first and foremost as a mathematical question.

"The optimal assignment of samples into pools will make or break this. We must mathematically predict a way to triage samples as they arrive at the lab, assigning each test its ideal testing scheme to minimize the number of tests while maximizing their sensitivity and specificity."

          Dr. Moran Yassour

Dr. Yassour is evaluating the entire testing process, by working backwards. The joint Hebrew University-Hadassah virology lab currently has a collection of over 120,000 swabs; by analyzing data from multiple test features (e.g. the protocol used, machine type, specific extraction kit and other parameters) and correlating these with clinical variables (such as patient age, gender, and symptoms), Dr Yassour can develop algorithms to determine the exact combinations in which specific samples should be pooled with each other to ensure the highest efficiency. "This will allow us to simulate the effectiveness of different pooling techniques, and continuously recommend optimal pooling techniques for any given time,” Dr. Yassour says.

"The optimal assignment of samples into pools will make or break this. We must mathematically predict a way to triage samples as they arrive at the lab, assigning each test its ideal testing scheme to minimize the number of tests while maximizing their sensitivity and specificity."

          Dr. Moran Yassour

Together with with Prof. Yuval Dor and Prof. Dana Wolf, Dr. Yassour would like to use this data to train a machine learning based model to predict the probability of a false negative.  

For more details and a complete list of researchers involved in this project, see the publication in Clinical Microbiology and Infection.

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