50 years after its discovery, interferon is at the center of an industry that generates billions of dollars a year, and saves thousands of lives. And the research is still ongoing
He who disturbs your enemy, is your friend. Thus, for example, infection with one virus can help the body defend against another virus. Prof. Michel Rebel was a teenager when Alec Isaacs and Jean Lindenman discovered how this process takes place. Until that discovery, many believed that the first virus interfered, in some way, with the action of the second virus. But Isaacs and Lindenman showed that in response to the invasion of the viruses, the living cells themselves (the study was carried out in chicken embryos) produce a substance that interferes with the viral activity. They called the substance "interferon".
Today, 50 years after the discovery, drugs based on various interferons are sold worldwide for billions of dollars every year. They are used to treat viral diseases such as hepatitis, certain types of cancer and multiple sclerosis. Weizmann Institute of Science scientists played a central role in the study of interferons, deciphering their modes of action, isolating their genes and developing the medical applications based on them.
Polio viruses
Prof. Michel Rebel immigrated to Israel in 1968 with his wife Claire and their four young children, and joined the Weizmann Institute of Science. In his previous studies, at the Pasteur Institute in Paris, Rebel discovered control factors that regulate the initiation phase of the translation (initialization) of the genetic information, from RNA molecules to protein, and he was looking for a biologically and medically significant system in which he could apply this research. At that time, knowledge about the properties of the substance that interferes with viruses and their modes of action was very little, and the young scientist decided to get into the thick of it and investigate how interferon affects the expression of genes in the virus. In 1970, Prof. Rebel met with two scientists from Argentina who were working in Paris on the preparation of crude interferon, Ernesto and Rebecca Falkov, and began to collaborate with them. This collaboration produced, in a relatively short time, an article in which the scientists showed how interferon interferes with the activity of viruses that carry their genetic information in RNA molecules, instead of DNA (November 29, 1972 Nature). These viruses include, among others, the polio virus.
The scientists discovered that the interferon interferes with the translation of the genetic information of these viruses, which is an essential step in the production process of viral proteins. Later, Prof. Adi Kimchi, who was then a postdoctoral researcher in Prof. Rebel's research group, isolated factors that allow interferon to control the translation phase of the viral genetic information, and in this way prevent the construction of viral proteins. Later in the study, Dr. Judit Shabat, from Prof. Rebel's research group in the Department of Molecular Genetics at the Weizmann Institute of Science, identified a group of genes whose expression is increased when cells are exposed to interferon, and it was proven that these genes encode the information for building enzymes that are involved in the activity of interferon against the creation of the virus proteins. As early as 1975, when he worked as a visiting scientist at Yale University, Prof. Rebel discovered that the interferon transmits a message, or command, to the cells when it binds to a certain receptor, displayed on the cell membrane. He also showed that the gene that codes for this receptor is on human chromosome 21. Thanks to these studies, the Weizmann Institute of Science was recognized in the international scientific community as one of the three leading research centers in the study of the mechanisms of interferon activity.
Towards the end of the 70s, the members of Prof. Rebel's research group decided to produce interferon from humans for medical purposes, and chose a type called beta interferon. This choice was due to the fact that this type of interferon is created in all the body's cells found in the various organs (as opposed to alpha interferon, which is created only in the white blood cells). A well-known scientist stated at that time, that the interferon beta injected into the muscle or the skin does not appear in the blood circulation, and from this many concluded that it would not be possible to produce medicines based on this substance. But Dr. Amichai Shatner, a physician who currently heads the internal department at the Kaplan Medical Center in Rehovot, who then joined Prof. Rebel's research group for a period of six months as part of a medical internship process, attacked the problem from a new angle. He remained in the group for two years, and published, together with Prof. Rebel, an article explaining that interferon beta that is injected into the body leaves traces of its activities in the genes it activates. This work put interferon beta back on the map for the development of medical applications, and widened the horizon for the scientists of the Weizmann Institute.
Made you a rabbi
To obtain a sufficient amount of beta interferon, the team decided to use a young and available human tissue - foreskin. At first the Mohals refused to give the scientists the foreskins, which according to tradition should be put in the ground. But by chance, one researcher in the group, Dr. Dalia Gur-Ari Rothman, was the niece of the Lubavitcher Rebbe, and she managed to get a permit for a regular supply of foreskins, which made it possible to develop the production of interferon in quantities. Later, the cell cultures from the foreskin proved to be extremely useful in the search for the gene responsible for the production of beta interferon in the human body.
In those years, the race to develop ways to produce quantities of pure interferon was in full swing. Interferons are produced in the body in tiny amounts, so it is difficult to isolate them. The almost impossible task of finding a way to isolate the interferon was assigned to a young postdoctoral researcher who came from the Weizmann Institute of Science to the Roche Institute of Molecular Biology in New Jersey. It was Prof. Menachem Rubinstein, currently a member of the Department of Molecular Genetics, and Chairman of the Scientific Council of the Weizmann Institute of Science.
Dreams in the lab
Prof. Rubinstein used the techniques he developed at the Roche Institute, together with his advisor and friend Sidney Judenfriend. He spent days and nights in the laboratory, with his wife, Sara, assisting him as a laboratory technician, and they both shared the care of their two small children. But one of the clues on the way to the solution is not found in the laboratory, but in a dream. When he arrived the next day at the laboratory, and examined the dream clue, it became clear to him that it had indeed led him to the long-awaited breakthrough. In the end, Prof. Robistein accomplished the impossible task, and developed a way to produce pure interferon, within only 10 months. Under his contract with Roche, he and his co-worker, Sid Pestka, were paid $XNUMX per patent registered on the process. Since then, this patent has made the company billions of dollars.
Prof. Rubinstein returned to the Weizmann Institute of Science, and joined the Department of Virology, which at the time was headed by Prof. Rebel (this department was later merged with the Department of Genetics, now called the Department of Molecular Genetics). Prof. Rebel was then immersed in an effort to obtain funding for the development of medical applications based on interferon beta.
He managed to excite Aharon Mittal, who was then CEO of the "Yade" company, the industrial applications arm of the Weizmann Institute. "Yade" managed to recruit the Swiss pharmaceutical company "Serono" for the task, which agreed to Prof. Rebel's condition that the development and production plant be built in Israel. This is how the cooperation of the scientists of the Weizmann Institute of Science with the "Interfarm" company began, which began to produce interferon from foreskins, under the name "Peron".
During this period, Prof. Rebel, and Prof. David Valach (then in the Department of Virology, and now in the Department of Biological Chemistry) were able to show that a third type of interferon, called Interferon Gamma, acts on the immune system in a different way, compared to the modes of action of the interferons of the alpha and beta types. In fact, interferon beta opposes the effect of interferon gamma, which, as it turned out later, suppresses the autoimmune process that causes multiple sclerosis.
In 1980, after they succeeded in isolating the gene that encodes interferon beta in humans, the members of Prof. Rebel's research group looked for an efficient way to produce the substance in quantities. This search resulted in a new breakthrough. At that time, the only method for producing complex proteins was genetic engineering in bacteria or yeast, but the proteins obtained in this way lacked certain sugar residues, which play an important role in the immune system's ability to reject the proteins as "foreign". Prof. Rebel and his group members, who wanted to achieve greater efficiency, succeeded in creating beta interferon in cultures of Chinese stored ovarian cells. Using genetic engineering methods, they developed cells that contained up to 100 copies of the interferon beta gene, and in this way turned the cells into efficient "factories" for the production of interferon with the same chemical structure as humans. This advanced method is leading to this day in the biotechnology industry.
applications on the horizon
receptors receptors
In the transition from the laboratory to the pharmaceutical industry, a method of cleaning the interferon from any contaminant was needed. In the 70s, Dr. Daniela Novick, who completed her PhD studies at the Weizmann Institute of Science, joined Prof. Rebel's research group. Dr. Novick, Prof. Rebel and Prof. Rubinstein, together with Prof. Zelig Ashchar from the Department of Immunology, developed a relatively new and simple method for producing pure interferon beta, which was based on monoclonal antibodies that selectively bind to interferon.
In the 90s, Prof. Rubinstein and Dr. Novick succeeded in isolating the natural receptor for interferon, the same receptor displayed on the surface of various cells in the body. Together with Dr. Batia Cohen, currently in the biological control department, they cloned the receptors for alpha and beta interferons, and showed how these interferons activate the antiviral response of the cells. This discovery completed a key component of the assembly describing how the interferon activates the cellular defense system against various viruses.
After large-scale experiments carried out by the "Serono" company, in 1998 the drug "Rabif" was registered and entered the market for the treatment of multiple sclerosis. For 20 years, this interferon beta drug was produced at the "Interpharm" factory in Israel (several years as an experimental drug, and another period as a registered drug). In 2005 "Serono" decided to transfer the production to a more modern factory, in Switzerland. The establishment of "Interfarm" made a decisive contribution to the development of the Israeli biotechnology industry. Several graduates of the Weizmann Institute of Science worked in the company. Many other employees moved at the same time (2005) from "Interpharm" to the biotechnology branch of the largest pharmaceutical company in Israel, "Teva". Today, the sales of all drugs based on beta interferon, for the treatment of multiple sclerosis, amount to 4.6 billion dollars a year. "Rebif" alone was sold by the "Mark-Serono" company for $1.45 billion in 2006. In 2005, Prof. Rubinstein and Dr. Novick won the Milstein Award on behalf of the International Association for Interferon and Cytokine Research, and Prof. Rebel was appointed an honorary member of the association . His contributions to interferon research earned Prof. Rebel the Israel Prize in 1999 and the Emet Prize in 2004.
The research journey continues
Today, Prof. Rebel and his group are investigating the possibility of repairing the myelin sheath of nerves, which is damaged in many neurological diseases, including multiple sclerosis, by means of transplanting myelin-building cells, which they were able to prepare from human embryonic stem cells (in collaboration with Prof. Yosef Itzkowitz-Eldor from the center the Rambam Medical Center). In addition, research on interferon continues. In 1995, dermatologists who worked with Prof. Rebel discovered that topical application of beta interferon prevents the recurrence of genital herpes symptoms in many cases. It also turns out that interferon beta may be used to treat hepatitis C in Asian populations. This possible use was recently tested by "Serono" in clinical trials in the Far East. 50 years after the discovery of interferon, Weizmann Institute scientists continue to reveal its secrets. One discovery by Prof. Rubinstein and Dr. Novick is described in the article "Medication for a Purpose" in this issue of "The Institute".
