Sheba Medical Centre – Jewish Independent

High-tech medicine

A 1-year-old boy being treated with a novel gene therapy drug. “Usually, this type of injury with a hemophiliac patient would involve hours in the emergency room, with repeated doses of intravenous coagulation factors,” said Prof. Gili Kenet, director of the National Hemophilia Centre at Sheba Medical Centre. (photo from IMP)

From wearables that allow cardiac specialists at a hospital in Ramat Gan to monitor a patient’s cardiac performance thousands of miles away from home, to giving gravely ill patients a new lease on life with groundbreaking new therapies, Israeli medical innovators are almost literally thumbing their noses at the Angel of Death and changing the way we live.

According to start-up “ecosystem” sources, there are at least 6,000 active start-up companies operating in Israel. Within the realm of digital health, the number of active start-up companies engaged in this field has grown from 65 companies in 2005 to more than 400 in 2018. A significant number of these start-ups are being financially supported by global corporations such as Philips, GE Healthcare, Merck and IBM. Some of these companies have opened up offices close to start-up hubs in Haifa (near the Technion) and Metro Tel Aviv, the recognized “capital” of Israeli business and high-tech.

photo - This digital watch developed by the Sheba medical team and Datos Health is equipped with an app that contains a care path specially designed for each patient — This digital watch developed by the Sheba medical team and Datos Health is equipped with an app that contains a care path specially designed for each patient. *(photo from IMP)*

“Israel serves as a global incubator of innovative ideas for a variety of reasons,” said Dr. Eyal Zimlichman, deputy director general, chief medical officer and chief innovation officer at Sheba Medical Centre, which is located in Ramat Gan and is the largest facility of its kind in the Middle East. “First of all, it’s in our genes. Secondly, there is the military aspect, where we are taught to improvise when necessary in the field. These things allow us to be naturally innovative. This has trickled down into the medical field, where we are offering the highest level of medical care. I also believe unique innovations in medicine, that will impact the world for the next 100 years, will be developed in Israel.”

Prime examples of Sheba Medical Centre’s innovative efforts revolve around combating potentially fatal diseases such as cancer with immunotherapy, oncology’s new medical “magic bullet”; targeting hemophilia with a novel gene therapy drug; and creating an app for a wearable device used by people with serious heart and diabetes issues.

Immunotherapy is a treatment that uses our body’s own immune system to invade and destroy cancer. CAR-T (chimeric antigen receptor) and TIL (tumour-infiltrating lymphocytes) are not universal cancer cures at this stage. However, there are ongoing clinical trials being conducted for major pharmaceutical companies and America’s National Institutes of Health at Sheba Medical Centre’s oncology unit, where end-stage cancer patients are being treated with CAR-T, which specifically targets leukemia and lymphoma, and TIL, which zeroes in on melanoma and ovarian cancer patients.

Seventeen people with cancer were treated at Sheba during an initial CAR-T trial, after all of these patients had displayed zero improvement in the wake of traditional chemotherapy treatments and bone marrow transplants. Of the 17, 75% had a complete response to the CAR-T. One of those patients, an 8-year-old girl from Bnei Brak, was the first child to achieve complete remission from childhood leukemia. A Sheba centre oncologist said, “When we came to give her the CAR-T cells, she was very, very sick. She couldn’t even get out of bed. When we came back to visit her three weeks later, she was going back and forth on her rollerblades.”

A few weeks ago, a 1-year-old boy became the youngest patient in the world suffering from both severe hemophilia A and an unusual allergy to be treated with a gene therapy drug that only recently was approved for use in the United States. The new drug, developed by an American biopharmaceutical company, contained a “bispecific antibody” that was injected into the child at Sheba Medical Centre. According to clinical trial results published in The New England Journal of Medicine, the drug has shown a 90% reduction in bleeding in children and a 70% reduction in adults.

photo - Prof. Gili Kenet — Prof. Gili Kenet *(photo from IMP)*

“This is a new, exciting era with many novel options for improved care and even complete cure of patients with hemophilia,” said Prof. Gili Kenet, director of the National Hemophilia Centre at Sheba. “The child’s mother is so happy with the new treatment. The child had experienced a head trauma, but required no further therapy at all. Usually, this type of injury with a hemophiliac patient would involve hours in the emergency room, with repeated doses of intravenous coagulation factors. However, there were no complications, as his hemostasis (blood factors) was completely normal.”

Within the realm of what is known as IoT (internet of things), Prof. Robert Klempfner is blazing a trail of what he has dubbed IoMT (internet of medical things), where heart patients are able to engage in cardiac care and rehabilitation using wearables (for example, a high-tech watch), without having to return to the hospital for treatment.

“Today, the challenge for both heart doctors and cardiac care patients is what happens after a coronary event (heart attack), intervention or heart surgery,” said Klempfner. “What kind of regimen can be created for someone who might have had surgery at Sheba but lives and works in faraway places such as the United States or other countries? Within the new world of telemedicine and digital health, we have the technology to create rehab programs that are a win-win experience for both the hospital and the patient.

“We give cardiac care patients a watch,” he explained, “that is equipped with an app developed by the Sheba medical team and Datos Health [an Israeli start-up company]. The app contains a care path specially designed for each patient, containing rehab regimens, education material and secure communication with our patients. The medical centre receives data from wherever he/she is located when they are walking, exercising, doing other physical activities. Our technicians then analyze the info and provide ongoing feedback, assisted by smart algorithms provided by the innovative system.

“The program is also primed,” he said, “for patients who suffer from hypertension and diabetes that are now able to transmit all their measurements automatically to our system. This not only saves the patient time, by not having him/her return to the hospital, it saves the hospital time and bed space, so we are able to treat more patients. This ushers in a new era in digital healthcare.”

Jumping gene research

Dr. Gideon Rechavi, who founded Sheba Cancer Research Centre, was in Vancouver in January for an international conference at which he presented new findings on “jumping genes.” (photo from Sheba Cancer Research Centre)

Dr. Gideon Rechavi, who founded Sheba Cancer Research Centre, in Ramat Gan, Israel, was in Vancouver in January for an international conference on DNA and RNA methylation.*

“I described a new work we just published, regarding ‘jumping genes,’” he told the Independent about his presentation at the conference. “Forty-five percent of our genome, part of what people used to call ‘junk DNA,’ is composed of genes that can jump from one place to another.”

As far as what this means for the functioning of a body, he explained, “When they jump, they can activate genes and they can also inactivate genes, and it’s a random process. Actually, when I was PhD student in ’82 at the Weizmann Institute, I found the first example of such an event in mammals.” And, he added, “We were also the first to show the role of such events in cancer.”

Rechavi explained, “In cancer, there is a set of genes called oncogenes, genes that usually are normal genes in our genome but, when they are over-activated or activated in the wrong cell or at the wrong time, they can push the cell to proliferate and can cause cancer.”

Now, he said, many years later, using advanced technologies based on whole genome sequencing, they have found that, “in a variety of neurodevelopmental disorders, such as autism and Rett syndrome and similar diseases, there is a basic gene defect in the family or in the affected child. However, the clinical presentation can differ even between identical twins. Nobody understands why the same genome and the same genetic background will result in such a difference, one patient will be affected by epilepsy, the other one by autism or mental retardation.

“The mechanism that we show is that, in the brain, there is, normally, a constant level of jumping of such genes and, probably, it’s essential for diversity of neurons and brain plasticity and activity.”

This is happening all the time in neuronal stem cells, he said. “During the differentiation of neuronal stem cells … there is a very precise time window of 48 hours when such transposition events can take place. And, probably, it’s essential, because you find it in mice, in monkeys and in humans. However, in all the diseases that we are studying, there is over-activation of the mechanism, so you have many more jumping events.”

We have neuronal stem cells dividing in the brain our whole life, said Rechavi. “In the past, we used to think that all of the neurons are created during pregnancy or soon after, but now, in the last 20 years or so, we know there are also adult neuronal stem cells. When you do gymnastics or when you take Prozac, there are more neuronal stem cells. And, in these neuronal stem cells, these transposable elements – jumping genes – are jumping and probably contribute to brain function.”

The process seems to be quite regulated, he said. “The mechanism we suggest, we call it the ‘lightning rod’ mechanism or hypothesis.”

He explained, “The majority of jumping events occur in sequences in the genome where integration will not cause harm. So, in a normal level of jumping, we expect it will be beneficial, and the chance for damage is low. Although, if, in a variety of diseases, there is uncontrolled activation of this mechanism, so there are many more jumps, then it can saturate the lightning rod safeguard mechanism and then affect genes that are relevant to neuronal diseases, and we have a lot of examples where such things happened.”

To study this, said Rechavi, they sequenced the genomes of 100 samples, which included normal, diseased and control brain samples. “We were able to show that there is a particular normal level of transposition … and, then, over-activation, with many more transposition events, in the brains of disease-affected children.”

From these results, he said, we know that “the genes affected by such insertions from these transpositions, you see that many of them are relevant to neuronal functioning, neural development and a variety of neuronal disorders, such as autism and schizophrenia.”

By understanding the biochemical mechanism in these patients, what activates the jumping, “then you can intervene,” said Rechavi. For example, perhaps a drug could be developed that would decrease the level of transposition.

“This is the next step,” he said. “Now, we have several patients where we know the gene defect involved in the syndrome and, therefore, is involved in the enhanced transposition, so now we have to find a way to shut it off, to lower the activity.”

Rechavi said his lab is researching these jumping genes and their effects in both cancer and neuronal disorders, and that they are currently looking for funding to study the involvement of such genes in Alzheimer’s and in aging.

The purpose of the jumping genes is not certain. “What people suggest,” said Rechavi, “is that it has to do with diversity.” Recalling that it is a random process, he explained, “So, instead of having all the neurons in a particular part of the brain being identical, now you have diversity and probably the diversity increases the efficiency of the brain circuits, etc. It can also be relevant to plasticity. We know that specific brain regions can take over following damage or following a kind of environmental influence and change the activity and perform new activities. So, maybe the ability to create diversity in the brain is an advantage.

“A similar model has to do with the immune system,” he added. “With the immune system, we know that there are genetic mechanisms that increase diversity and, then, the cells of the immune system of an individual can respond to any virus and any bacteria.”

The main focus of his lab at Sheba Medical Centre, he said, is to find new genetic and epigenetic mechanisms, “and then to ask, what is their relevance to normal physiology and what’s their relevance to diseases. That’s how this story that started with cancer research turned out to be very relevant to neuronal disorders and psychiatric disorders.”

Rechavi said the phenomenon of jumping genes, or transposable elements, was first identified by American scientist Barbara McClintock (1902-1992) in experiments with maize. (She won the Nobel Prize in 1983 for this and other contributions to the study of genetics.) “She found it in maize,” he said. “We found it in mammals.”

Conferences like the one Rechavi was attending in Vancouver when he spoke to the Independent by phone Jan. 23 from his room at the Fairmont Hotel Vancouver, where the conference was being held, are useful for several reasons.

“Some people, after my talk, came and they wanted to collaborate, they want to learn the methodologies. Some people suggested samples we could analyze…. This is the basis for scientific collaboration, the main reason to do scientific meetings. You can read everything on the internet,” he said, “but when you discuss with people the findings and you drink coffee together and discuss the details, you can get new information, new non-published information, and also collaborations and friendships.”

Sheba Medical Centre doesn’t have many partnerships with Canadian institutions, said Rechavi. The centre’s main collaboration in Canada, he said, is with Toronto’s Hospital for Sick Children, especially in the field of brain tumours, because one of Rechavi’s former trainees, Dr. Uri Tabori, went to SickKids to study such tumours and stayed there.

Before obtaining his PhD at the Weizmann Institute of Science, in Rehovot, Rechavi earned his doctor of medicine at Tel Aviv University’s Sackler School of Medicine. He is a professor of hematology at Sackler School and heads the Cancer Research Centre at Sheba Medical Centre, the largest hospital in Israel, which serves as a university teaching hospital (affiliated with Sackler) and as a tertiary referral centre. He has published more than 450 scientific papers.

In addition to treating some 1.5 million patients annually, Sheba Medical Centre has 75 laboratories and more than 2,000 ongoing clinical trials; 30% of Israeli medical research is performed at Sheba, which files, on average, 15 biomedical patent applications per year.

In October 2017, Sheba Medical Centre inaugurated the Wohl Institute for Translational Medicine. The idea, said Rechavi, is to take the “findings emerging from basic research and try to translate it into taking care of patients; to better diagnose, to [develop] better treatments.”

* Methylation, explained Dr. Gideon Rechavi, “is the addition of a chemical group known as methyl on the four basic letters of the genetic material (DNA and RNA) to generate a new expanded ‘alphabet.’”

NCSY at Sheba centre

Dr. Amit Segev gets his heart checked out by one of the participants in NCSY Canada’s Jewish Journeys summer program. Segev gave all the teens a stethoscope to commemorate their visit to Sheba Medical Centre. (photo from SMC)

More than 30 teenage participants from NCSY Canada’s Jewish Journeys summer program were recently treated to a VIP tour of Sheba Medical Centre’s Olga and Lev Leviev Heart Centre.

Dr. Amit Segev, director of Sheba Medical Centre’s cardiac division, showed the group a short presentation of how the heart can malfunction and what doctors can do to save patient’s lives in such instances. As there is nothing like a dose of reality to enhance the experience, Segev showed the teens a live view of a medical procedure being performed on a patient suffering from a heart malfunction.

As a token of appreciation for their visit – and perhaps spur their interest in a future medical career – Segev gave each participant a Sheba Medical Centre stethoscope.