Vision, determination and a hint of luck

Professor Bekah Salomon from Tel Aviv University, a world pioneer in the development of treatment for Alzheimer's disease, uses bacteriophages to fight the protein deposits in the brain that cause the terrible disease

By Deborah Jacobi

"The hour of the wolves, the hour before dawn, is my hour," says Professor Beka Solomon from Tel Aviv University who was included in Scientific American's list of 50 selected for 2007 [See Scientific American Israel, February-March 2008]. Professor Solomon, Mishchima Kom, says that this was the time when she remembered the article by Max Perutz (nobel prize winner in chemistry), which showed that the structure of a certain virus that attacks bacteria (bacteriophage) is similar to carbon nanotubes. The structure of the protein deposits that settle in the nerve cells of patients with Alzheimer's disease are also similar to nanotubes, and this sparked an idea in Professor Solomon. She decided to check if the bacteriophage, whose structure is similar to the protein deposits (also known as amyloid layers or "plaque"), can dissolve these proteins, which are the source of the evil in Alzheimer's disease. The fact that the idea turned out to be correct was the stroke of luck, but in order to reach the discovery that holds great promise - the possibility of a cure for Alzheimer's - a long and determined research was needed.

Professor Solomon is not new to Alzheimer's research. For years she has been searching for a cure for the disease, which she witnessed personally and closely when her mother-in-law contracted it. Her research led her to the discovery of a possible drug, from the vaccine field, which is currently in the third and final phase of clinical trials (Phase III), before being approved by the American Food and Drug Administration (FDA). The drug is registered as a patent that brought in a lot of money to Tel Aviv University which is used for research purposes. The immune drug is actually an antibody directed against the main amyloid protein of Alzheimer's deposits, deposits that kill the nerve cells in the patients' brains. But the drug has several disadvantages: first, like many other drugs, it does not help every patient. This became clear in the clinical studies that are, as mentioned, in their final stage. Secondly, there are patients for whom the drug causes quite severe side effects. Another limitation of the immunosuppressant is that it needs to be injected into the bloodstream. In order to reach the brain, where it is supposed to attack the amyloid deposits, the drug must penetrate through the barrier that separates the blood from the brain (blood-brain barrier or BBB for short). This is a very selective barrier and few substances can pass it. Moreover, the injection of a foreign protein substance, such as the antibodies of the immune drug, into the bloodstream stimulates the body's immune system, which attacks the foreign substance and removes it from the body, therefore only a tiny part of the injected amount reaches the brain.

But it was not because of this drug that Professor Solomon was included in the prestigious list, but because of the new discovery of the use of bacteriophages that will allow crossing the BBB. The method has so far only been tested in transgenic mice that have inserted into their DNA a human gene that causes the mice to suffer from Alzheimer's disease and to produce in their brains the plaques characteristic of the disease. The new method uses a suspension of viruses from the bacteriophage family that is injected into the body by spraying into the nose, and it seems to overcome the limitations of the injection. There are several reasons for choosing this insertion method. The nerve cells that connect the olfactory cells in the nose go straight to the brain, and the BBB in the olfactory nerve is much less selective than in other areas of the brain. The introduction by spraying is not as invasive as the introduction by injection and spraying inside the nostrils once a month is enough to stop the deposition of plaques in the brains of the transgenic mice on which the study was conducted. The amount required for spraying is also much lower than the amount required for the injection of the original immunosuppressant, since the virus penetrates the brain very quickly, even before the immune system has enough time to attack it.

When the interior of the nose of the experimental mice was sprayed with the appropriate bacteriophages, it turned out that they reach the brain within 15 minutes. After the viruses penetrated the brain, not only did they stop the accumulation of plaques, but they also managed to dissolve old plaques that were already in the brain before. Transgenic mice treated with bacteriophage for six months through a monthly spray were tested in a series of tests indicating cognitive abilities, including testing the ability to distinguish between objects of different shapes. Transgenic mice treated with bacteriophage functioned as if there were no plaques in their brains at all, while mice with Alzheimer's disease in the control group, treated by spraying with a dummy drug (placebo), did not succeed in the tests. Another feature tested is the sense of smell, impairment of which is one of the first signs of Alzheimer's disease in both humans and experimental mice. Bacteriophage treatment restored the mice not only their cognitive abilities but also their sense of smell.

"Isn't this spraying, which is actually an infection with a virus, dangerous for the experimental mice? And down the road, could it be dangerous for human patients who will be treated with it?" A smile spreads across Becca Solomon's face. These bacteriophages are viruses that attack bacteria, not mice or humans, she explains. It is true that they may also attack the population of beneficial bacteria present in our bodies, but in addition to bacteria, the "flora" of the human intestines also has a large variety of bacteriophages, including the particular bacteriophage of our spray, she says. In a test conducted on experimental mice that were "infected" with bacteriophage through the nose, it became clear that the viruses are quickly excreted from the brain into the urinary and fecal systems and do not harm other organs such as the liver, spleen, kidneys, lungs and other internal organs. Another advantage of the bacteriophage treatment, compared to the treatment with the antibody drug, is that the production of the viruses in large quantities is much easier and cheaper than the production of the antibodies. However, the road to drug development is still long. The concentration of the most effective bacteriophage for the spray, its rate of action and the optimal dose needed for treatment should be checked. Once all these questions are answered, you should move from mice to larger animals, such as monkeys for example. Only then will the drug be ready to be submitted for approval as an experimental drug in humans, after which the three meticulous stages of clinical trials will begin. There is great promise in the development of the drug, since if it is given at an early stage of the disease, it will be possible to stop the growth of the plaques and the death of the nerve cells in the brain and also to save cells in which the plaques that have sunk in are not too large.

It seems that the much work expected of Professor Solomon is not an obstacle in her eyes. "It is true that I had a vision, but a vision alone is not enough, you need both luck and a lot of hard work. My luck was that the idea that came to my mind in that morning hour between darkness and light turned out to be true, and hard work never scared me." Indeed, when Professor Solomon, born in Romania, immigrated to Israel, she had to go through a difficult process as a young researcher. She did not know Hebrew, and even though she was fluent in Romanian, French and Latin, the accepted language of science in Israel was of course English. She started working as a technician in the laboratory of Professor Ephraim Katzir, then Kachelsky and later the country's president. Under the influence of her mother, who was a source of support and inspiration for Becca all her life, she completed her doctoral thesis at the Weizmann Institute of Science under the guidance of Professor Kachelsky and Professor Meir Shinitzky. After receiving her degree in 1976, she went to a postdoctoral position at Harvard University Medical School and at various research institutions in the United States and England. Professor Solomon joined Tel Aviv University in 1979, where she currently holds the Chair of Biotechnology and Neurodegenerative Diseases.

Professor Salomon is a member of the editorial board of several scientific journals in the field of neuroscience and drug development. She was the first winner in Israel of the Alzheimer's Association's prestigious Zenit Award. She was recently awarded the American Dana Foundation Award for Neuro-Immunology.

Viruses for humanity: Professor Bekah Salomon from Tel Aviv University was included in Scientific American's list of fifty leading scientists in 2007 for developing a pioneering method for treating Alzheimer's disease using a nasal spray containing viruses that dissolve the protein plaques that cause the disease in the brain.

Credit: Yoram Rashef, Tel Aviv University

* The author, Dr. Deborah Jacobi, is a member of the Scientific American Israel team and the chemistry coordinator at Hamda - the center for scientific education in Tel Aviv

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