Using hamster cells to fight multiple sclerosis

Rebif® remains one of the leading drugs used to treat multiple sclerosis (MS), a chronic disease in which the nerves are attacked and destroyed by the immune system. Rebif® was discovered and developed by Michel Revel, who has dedicated his entire career as a researcher to the search for MS treatments. In the process, he founded Israel’s flourishing biotech industry.

Michel Revel was supposed to become a doctor. As a medical student at the University of Strasbourg in the early 1960s, he earned excellent grades. Nevertheless, "the work that was involved with patient care — it really wasn’t my kind of job," he says. In the laboratory, on the other hand, he thrived, so he shifted to biochemical research. It was a decision that led to the discovery of the first and most important drug to treat multiple sclerosis, turning Revel into the founder of Israeli’s biotechnology industry. 

It was the time when molecular biology was being born. At the Pasteur Institute in Paris, Revel studied the translation of genes into proteins, the working molecules of the cell. He was looking for a way to switch the protein production process on and off: "It had just been discovered back then that a messenger molecule called interferon beta was able to block the synthesis of virus proteins." At the time, no one suspected that this messenger substance could help MS patients. 

In order to study interferon beta, Revel needed larger quantities of it: "Back then, you couldn’t just order proteins; you had to make them yourself." Interferon beta is primarily found in the cells of connective tissue and in Israel, there is enough of that available because of the many circumcisions of male infants in keeping with Jewish custom.

Revel, who comes from a French-Jewish family, had wanted to help build up an Israeli state ever since childhood, and so he moved to the Weizmann Institute in Rehovot, not far from Tel Aviv, in 1968. He delivered the first lecture on molecular biology to be heard in Israel, and during the same period, he continued his research into interferon beta. With the consent of a rabbi, Revel was able to collect enough connective tissue to obtain interferon beta from it. 

After Revel had shown in the laboratory that interferon beta can be produced in this way, he began looking for a partner capable of producing the molecule on a larger scale. "Our condition was that the plant would have to be located in Israel," says Revel. Initially, no one seemed interested, but then Revel met Fabio Bertarelli, who at that time headed the Italian-Swiss pharmaceutical company Serono, which became part of Merck KGaA, Darmstadt, Germany in 2007. Serono had experience with the production of therapeutically relevant proteins. At the time, the company was extracting the hormone gonadotropin from the urine of women — even women in convents, with the consent of the Vatican. Bertarelli understood what Revel and other researchers suspected but couldn’t yet say with certainty: interferon beta could help patients with multiple sclerosis. 

The latter is a disease in which the immune system attacks the body’s own myelin, a material that is wound around the nerve tracts, like insulation around an electrical cable. If the myelin is destroyed, stimuli are no longer conducted and the nerve cells gradually die. At the beginning, patients might only stumble. Later, they’re no longer able to hold a coffee cup, or control their leg muscles, or even their respiration muscles. Interferon beta prevents the white blood cells that attack myelin from getting into the brain. This can at least delay the progression of the disease.    

In 1978, Serono established the company InterPharm in Ness Ziona together with the Weizmann Institute. Revel became research director, but he also continued to pursue research in his laboratory at the Weizmann Institute. When his team eventually discovered the gene for interferon beta, it opened up the possibility of biotechnological production — in other words, introducing the gene into cells that then produce the interferon beta. 

The production of interferon beta in mammal cells was decisive for the success of this approach. This provides them with the finishing touch needed to work properly in human beings — in contrast to the interferon beta that is produced in bacteria and yeast fungus cells. In the technique using mammal cells, for example, sugar residues are attached at the correct positions in the protein.

During a period of research at Yale University, Revel learned of mammal cells that could easily be made to multiply. Excited about the possibilities this raised, he packed some Chinese hamster ovary cells (CHO) into his luggage on his return flight to Israel. To this day, Rebif®, the variant of interferon beta produced biotechnologically, is still made by CHO cells in bioreactors. "This technique is now used worldwide for the biotechnological production of drugs," says Revel. 

Following his retirement in 2010, Michel Revel became a company founder himself: his company Kadimastem in Ness Ziona develops new treatments for multiple sclerosis with support from Merck KGaA, Darmstadt, Germany — this time using stem cells. "Research is my life," says Revel. Now 76 years old, his back sometimes gets tired, but his spirit remains youthful when he talks about molecules and cells and ideas for new therapies. "A researcher’s work is never done," he says. "What you’ve found is always only one step and there are many to follow." Michel Revel has no feelings of smug satisfaction. "There is always the dream of doing an even better job."