In 2003, the Innovation Authority (then called the Office of the Chief Scientist) established a consortium of academic institutions and commercial companies aimed at developing Israeli knowledge in the evolving field of stem cells. The technology developed in the consortium is aimed at treating various diseases by means of stem cells that are cultivated and preserved in unique conditions before being implanted in patients. This may sound like a logical step today, but one only needs to remember how elementary stem cell research was at the time to understand the innovation involved.
"Human embryonic stem cells were first produced in 1998 and Israeli researchers played a significant role in this breakthrough", explains Prof. Benjamin Reubinoff, Director of the Hadassah Human Embryonic Stem Cell Research Center and Head of Obstetrics and Gynecology Department at Hadassah, Ein-Karem. "The initial report on the subject was written by the American researcher Jamie Thomson who was then working with Prof. Joseph Itskovitz from the Technion. At the time, I was cooperating with researchers from Australia and Singapore to produce human embryonic stem cells. We were the second group in the world to produce human stem cells and the first to demonstrate stem cells' ability to differentiate themselves into somatic cells in a culture. At that time, Prof. Nissim Benvenisty from Hebrew University was also one of the pioneers of human embryonic stem cell research, so there were three Israeli academic groups operating in this field simultaneously: mine and those of Professors Itskovitz and Benvenisty. All three published hugely influential and valuable initial papers and positioned Israel as one of the leading countries in the world in the field of human embryonic stem cell research.
"This was the background for the initiative to set up the "Bereshit" consortium aimed at combining the knowledge of the academic groups and commercial entities. The person who provided the impetus was Dr. Aharon Schwartz, former VP at Teva. With his vision, Dr. Schwartz, enlisted the partners in the consortium to work together with him in developing generic technologies that would advance the use of embryonic and adult stem cells." Teva led the way with a special professional unit for developing cell therapy which was opened in Rehovot.
"The consortium operated on two fronts", Prof. Reubinoff continues. "One focused on embryonic stem cells and the other on adult stem cells but both dealt with developing generic technologies that would be used by the members of the consortium and that could advance the field and the State of Israel. As an academic, I chose to take up the challenge of developing human embryonic stem cells that would be suitable for implantation in patients."
Prof. Reubinoff, who founded Cell Cure Neurosciences and serves as its chief scientist adds: "The technology and stem cells developed in the consortium were transferred, among others, to the Israeli companies Cell Cure and Kadimastem, that develop stem cells for clinical transplants. Happily, both companies succeeded in further developing the cells, reaching the stage of clinical human trials. Cell Cure is presently conducting clinical trials in Israel and the US on patients with Age-Related Macular Degeneration (AMD) while Kadimastem is conducting a trial in clinical transplants in ALS patients.
"My personal vision for the past 20 years has been to utilize the potential of human embryonic stem cells for transplanting in patients with incurable diseases and to use the cells for regeneration. I began developing the technology for clinical use of stem cells before the foundation of the consortium which was, as far as I am concerned, an exceptional opportunity to advance this project. The consortium assisted me in realizing my vision and I derive much satisfaction from the fact that the fruits of this labor are being implemented in patients as part of clinical trials. These trials have the potential to serve as the basis for the development of cells that can cure diseases. The consortium was established at just the right time: it gave tremendous impetus to the field in which I was operating and, as part of my participation in it, we succeeded in developing stem cells that are suitable for clinical use and that are used by the companies operating in this field. I regard this as an outstanding success."
"The Innovation Authority views the biopharma field as a growth engine of primary importance," says Aharon Aharon, the Authority CEO. "The development of personally tailored medications requires a combination of innovation in biology and genetics and advances in the field of artificial intelligence. This combination changes the entire development process while blurring the boundaries between the classic biopharma field and that of information technology."
A Newly Emerging Field
Dr. Tamar Raz, CEO of 'Hadasit', the technology transfer company of Hadassah Medical Center, tells of how the consortium was founded prior to her tenure at the company: "That was the early era of global research in this field. When the embryo starts growing from the fertilized egg, it is made up of pluripotent cells that can develop into any organ of the body. With the development of the technology that enables to grow stem cells and preserve them as embryonic cells, we began to think that maybe this was the key to the future of healthcare. In other words, that if we learned how to grow and direct the cells' maturation, we would be able to transform them into cells suitable for transplant and transforming into whatever organ we wanted to treat e.g., to use them to treat the heart following a heart attack or bones after a fracture etc. That was the abstract idea.
"There were several strong academic groups and a few commercial companies operating in this field in Israel back then. That's where the Innovation Authority entered the picture with "Bereshit". They proposed connecting the worlds of medicine, the medical establishment, and industry, and for all to join forces. The objective was to discover how to grow embryonic stem cells such that they could be utilized medically without losing their traits and while ensuring their safety for human use.
"In 2003, this all seemed like a distant dream. No-one knew for sure what the outcome would be and there was no business model because this was a very complicated procedure, not a regular shelf product. Questions also arose regarding the technology's feasibility and its suitability as a medical procedure. For example, the body can reject the cells after organ transplantation. This means that patients need to be treated while silencing their immune system. Another question related to the concern surrounding the development of cancerous tumors."
The Innovation Authority looked forward though. The logic was simple: the state would finance the research conducted by the groups participating in the consortium and the accrued knowledge would serve all its members. Among the members were: Procore, Teva, MGVS, Hapto and Harlan. On the academic side, participants included researchers from the Hebrew University, Hadassah Medical Center, the Technion and Ben-Gurion University. The vision was that the new knowledge would assist the Israeli companies in becoming world leaders in this field, thereby benefitting the entire Israeli economy – a true national mission.
"Bereshit" amalgamated the leading Israeli professionals and researchers in their fields and enabled them to cooperate with each other. The financial investment in the consortium was critical – no single commercial company could invest such sums on its own in a field of knowledge that is still in its infancy. The consortium's activity focused on developing technologies for producing stem cells from various sources, and on growing, directing, transporting and preserving them.
Despite the difficulties encountered over the years, Dr. Raz says that: "A serious group of people who didn't give up worked on this project and they succeeded in developing the technology for growing and preserving embryonic stem cells."
"The technology born at "Bereshit" enabled 'Hadasit' to transform the stem cells into a product that we still supply today to companies interested in using them as the basis for the development of new medicines. There are several Israeli and global companies today that received cells from us and that are using their own technologies to develop them as part of innovative treatments for different diseases.
"In my opinion", says Dr. Raz, "the Consortium's Program is important and significant because it succeeds in connecting academic and industrial entities in such an innovative field. In turn, this collaboration leads to the creation of innovative knowledge that will enable the members of the consortium and Israeli industry to develop unique and economically valuable products. In short, 1 + 1 +1 equals 10, i.e., the consortium's whole is greater that the sum of all its parts. Therefore, the program succeeds in the areas where joint efforts can effect a change and have a true impact."
Among the consortium's prominent achievements in the field of embryonic stem cells are the development of technologies that enable the creation of embryonic stem cell lines and supportive lines suitable for clinical use, and the evaluation of different reactors for growing cells and safety checks. The field of adult stem cells has witnessed the development of different methods for producing cells from peripheral blood, bone marrow and fat, for identifying mesenchymal cells and separating them from other cells, for directing osteogenic differentiation and bone healing. Different growing factors were also checked, and a variant of alternative splicing involved in the differentiation processes was identified.
A Sequential Chain
Biologist and researcher Dr. Rami Skaliter is the CEO of Cell Cure which was founded in 2005 as a subsidiary of Hadasit Bio-Holdings (HBL). The company's activity is based on the line of stem cells and technologies developed by Prof. Benjamin Reubinoff who was later joined by Prof. Eyal Banin.
In 2017, Cell Cure was acquired by an American company that is focused on developing stem cell-based medicines and today operates as a subsidiary that constitutes the development and manufacturing base. Cell Cure operates from within the Hadassah complex and in close cooperation with the two researchers who established it based on their acquired knowhow.
"Cell Cure's main focus is the development and manufacture of cell stem-based medications", says Dr. Skaliter. "To do so, it uses a cell line of high clinical quality stem cells developed by the "Bereshit" consortium.
"The company initially worked in developing medications for neurological diseases of the nervous system and later moved to focus on degenerative eye diseases. The method was first developed at Hadassah and all the technologies were subsequently transferred to Cell Cure.
"We set up a manufacturing facility to develop medications based on stem cells' diseases. Our central product includes cells intended to replace defective cells in the eye (RPE) that were damaged as a result of degenerative retinal diseases. We are presently working on manufacturing a medication according to GMP conditions and on developing methods for its release at a clinical level.
"Simultaneously, we are also working on other things such as upscaling the existing process i.e., to facilitate the manufacture of larger quantities via more efficient methods. Furthermore, we are involved in additional innovative projects of research and development aimed at expanding the uses of our technologies to contend with other eye diseases and other cell types – and even on applying them to fields unrelated to eye disease."
As mentioned, Cell Cure's basic infrastructure is a direct result of the cell line developed at Hadassah within the framework of the "Bereshit" consortium. "It's a continuous chain dated back to the late 1990s until today", Dr. Skaliter describes. "The key is to preserve it in such a way that it continues to be available for subsequent developments. People in the field know that the original preparation method is what determines today's product quality. Two decades later, we see that the choices made by "Bereshit" are still valid as we are still capable of creating clinical batches based on that same original stem cell line.
"The ability to preserve things over time is especially critical in this case", Dr. Skaliter continues. "In my opinion, one of the consortium's biggest achievements – beyond the ability to use these cells – is the capability to suitably preserve them. Our advantage is that we know how to continue the preservation in such a manner that the authenticity of the original line is maintained, allowing us to implement processes that aid the optimal development of the medications. This is a dual achievement.
"In this field of stem cells, there aren't many companies such as ours that have both a manufacturing facility and development capability. It's almost unique. One of the results is that we are the world's leading clinical development company in the field of eye disease."