A Culture of Research
Tens of thousands bless Travelan, the over-the-counter natural health product that helps prevent traveler’s diarrhea. The ultrasound device PainShield has wrought a revolution in healing chronic wounds. And PerioChip, inserted between tooth and gum, has transformed treatment of periodontal disease.
Treating very different problems and manufactured by companies including Immuron Ltd. in Australia and Dexcel Pharma Ltd. in Israel, these three therapies nevertheless share a common bond. The idea for each as well as the early research belong to investigators at the Hebrew University–Hadassah Medical Center at Ein Kerem.
“For Hadassah, there is a golden triangle in which education and research go hand in hand with clinical excellence,” says Eyal Mishani, Ph.D., professor of nuclear medicine at Hadassah’s medical school and the medical center’s research and development director. “We believe that cutting-edge medicine is practiced when physicians are actively involved in research.”
A radiochemist who has himself published more than 130 academic papers, Mishani is proud to cite the figures: No fewer than 12 Israel Prize laureates come from the Hadassah Medical Organization. Hadassah researchers receive over 60 percent of National Science Foundation Awards for biomedical research in Israeli hospitals and have this year been awarded $17 million in grants and donations. Hadassah researchers publish 500 to 700 scientific papers annually; around 200 sponsored clinical studies and 300 investigator-initiated studies are conducted each year; and the researchers have hundreds of therapeutic, diagnostic and medical device patents, grouped in 250 active patents in multiple countries. Seven products are on the market and 30 more are in development.
This, of course, is neither random nor a matter of luck. “It is in the context of Hadassah’s culture of research,” explains Mishani. “For over 50 years, there has been constant, ongoing collaboration between the medical center’s physician-researchers and the medical faculty’s scientist-investigators—that is, between clinical medicine and basic science. This was rare elsewhere until about 15 years ago. Hadassah has practiced bench-to-bedside medicine, now called translational medicine, decades before it even had a name.”
Translational medicine, a rapidly growing discipline in biomedical research that aims to expedite discovery of new diagnostic tools and treatments by using a multidisciplinary, highly collaborative approach, has characterized Hadassah since its move to Ein Kerem 55 years ago. Its physician-researchers are practical people who take questions they encounter at a patient’s bedside into the research laboratory and bring the answers they find back to the patient.
For example, Dr. Michal Lotem, a dermatologist-oncologist, asks, “How can we stop the lethal recurrence of melanoma?” Dr. Ronen Durst is researching whether “we can prevent the fatal heart-valve disorder found in over 2 percent of the population.” “How can we know a lung cancer treatment will be effective?” asks Mishani. Endocrinologist Dr. Benjamin Glaser is exploring how to force pancreatic cells to produce more insulin. “We need to find a way to make resistant fractures heal,” says orthopedist Dr. Shaul Beyth. “How do we regenerate healthy brain cells to replace the damaged neurons of amyotrophic lateral sclerosis [ALS] and multiple sclerosis?” asks neurologist Dr. Dimitrios Karussis.
And so on and so on.
The laboratory bench where they seek answers is a quaint misnomer. Along with the hospital and medical faculty’s advanced labs, Hadassah’s laboratory bench includes a dedicated clinical trials center, Good Manufacturing Practice facilities (a United States Food and Drug Administration-compliant laboratory that produces pharmaceuticals under aseptic conditions), Israel’s National Skin Bank and two cyclotron machines. (The machines were introduced to HMO by Mishani and are used for medical research to mark and treat cancers and other diseases by teams he has trained.) Hadassah’s laboratory facilities also contain unique animal models mimicking almost every disease, Israel’s only microPET/CT scanner for small animals and a large-animal surgery room, necessary for translational medicine research, which requires full facilities for animal models as well as human patients. A recent $6.5 million Wohl Legacy grant is allowing Hadassah to upgrade and combine all this into the Translational Medicine Center.
It is at the laboratory bench that Dr. Lotem, head of Hadassah’s Center for Melanoma and Cancer Immunotherapy, is developing melanoma vaccines based on each patient’s tumor cells. The individualized vaccines she and her team have used to treat advanced disease over the past 16 years have led to a genetically engineered version that activates exhausted immune cells—and has halted progression and recurrence of melanoma in clinical trials.
“With this approach, we are seeing a revolution in melanoma treatment,” says Dr. Lotem. “We have long believed the immune system can combat cancer, and we can now show how great a role it plays.”
Cancer is a focus of Mishani’s research, too. His team is synthesizing radioactive atoms and incorporating them in biological compounds to create tracers that can be visualized by PET/CT scanners. One marker they have developed enables the diagnosis of a range of cancers, allowing oncologists to tailor anticancer medication to the patient and track its effectiveness. Another marker, a radioactive tracer, detects blockages in blood flow to the heart, reducing the need for exploratory cardiac catheterization.
“Of the millions of diagnostic heart catheterizations performed globally each year, close to half prove merely diagnostic,” notes Mishani. Clinical trials of the tracer (exclusively licensed to Polish medical imagers Synektik S.A.) begin this year at Hadassah Hospital, with the support of a $4 million European Union Horizon 2020 grant—awarded to only three of 110 applicants.
Senior cardiologist Dr. Durst is also investigating the heart. With an international team, he has found the first gene whose mutation causes mitral valve prolapse, a disorder that affects 2.4 percent of the population, can lead to sudden death and costs over $2 billion in surgery each year. Reporting on a study in September 2015’s Nature, Dr. Durst is first author among over two dozen experts.
If cancer and heart disease have long dominated the West’s healthscape, diabetes is close on their heels. Recent World Health Organization statistics show that the high blood-sugar levels of this incurable illness are linked to an annual 3.7 million deaths worldwide. Some 422 million people are now affected by diabetes, a fourfold increase over the last 25 years, with commensurate medical care costs.
“Diabetes is a malfunction of the pancreatic beta cells, which produce insufficient insulin to control blood-glucose levels,” says Dr. Glaser, head of Hadassah’s Endocrinology and Metabolism Service. “Replenishing depleted supplies of normally functioning beta cells is the holy grail of diabetes research.”
Dr. Glaser’s team, one of a dozen at Hadassah seeking to prevent, control or cure diabetes, is working to persuade pancreatic beta cells to replicate quickly and efficiently produce more insulin. Expecting younger cells to be most competent, they were surprised—as was the scientific community with whom they shared their findings in March 2015’s Developmental Cell—to learn that beta cells of young children respond poorly to glucose, in terms of secreting insulin and compensatory replication. Insulin production increases after weaning, when carbohydrate-rich food replaces the fat-rich milk diet.
Funded by the National Institutes of Health, Pfizer, the Juvenile Diabetes Research Foundation and the Israel Science Foundation, the team is now tracking the molecular signal that triggers the replication of adult beta cells. Meanwhile, their finding that mature beta cells can be coaxed to proliferate more rapidly is important for researchers at Hadassah and elsewhere seeking to increase beta cell mass and function to prevent or treat diabetes.
Another area in which Hadassah’s research expertise is globally recognized is stem cells. In its orthopedics department, researchers Dr. Beyth and Dr. Meir Liebergall have demonstrated that the application of these cells reduces the normal six- to 12-month healing time of severe fractures to two or three months. In a clinical trial that followed 15 years of research, stem cells were drawn from 24 pelvic-fracture patients, treated and then reinjected into the fracture site, where they differentiated into osteoblasts, the cells responsible for bone formation.
Stem cell therapy is also poised to transform treatment of neurodegenerative diseases, from multiple sclerosis and ALS to Parkinson’s disease and dementia. HMO researchers have shown that stem cells not only regenerate diseased brain tissue but also facilitate its natural repair processes. Earlier this year, senior Hadassah neurologist Dr. Karussis reported in JAMA Neurology that progression of fatal ALS had been halted for the first time in 23 of 26 patients, with several also experiencing improved physical and cognitive functioning.
“We harvested stem cells from the bone marrow of each patient, passed them to [Petah Tikvah-based] BrainStorm Cell Therapeutics to enrich, enhance and nudge into powerful neuron-supporting cells, and then reinjected them into patients,” says Dr. Karussis.
He is conducting a similar breakthrough trial, reinjecting treated stem cells in 48 multiple sclerosis patients. The transplanted neural cells are migrating into the brain, inhibiting inflammation and improving the disease’s clinical course. The researchers hope that this approach, which is showing such promise in ALS and multiple sclerosis, may be effective in other neurodegenerative diseases as well.
This therapy, however, together with the others described, is at best five years away from clinical practice. Safety is of course paramount and testing is exhaustive. Added to that are the vast costs of biomedical R&D. “Scaling up to early production and beyond is both very expensive and extremely high risk,” explains Mishani. “From the clinical stage, only one in about 250 compounds makes it to the market, and it can take seven to 10 years and more than $800 million to get it there.”
Which is why the Travelan, PainShield and PerioChip technologies are not generally known as Hadassah products. They, along with most startups birthed by Hadassah’s technology transfer arm, Hadasit, and, most likely, the research now underway, are eventually sold off and brought to market by wealthy multinationals. While they are not generally known as Hadassah discoveries, the medical center’s researchers are confident they will contribute to global therapies and well-being.