Source: Haaretz
Date: 29 July 2004

Food for thought

By Ruth Levi-Schuster

If Prof. Moussa Youdim is correct, in a few years you will be able to mix a spoonful of medicine into your bowl of cereal and protect your brain from the degeneration caused by aging.

In 1979, Prof. Moussa B.H. Youdim, a British-educated Tehran-born Jew, approached the Israeli company Teva Pharmaceuticals. At the time, Teva was a relatively small generic drug company with no R&D, only chemistry. Youdim suggested a collaboration to develop a drug he had invented for the treatment of Parkinson's Disease. Teva was not interested.

Ten years later, in 1987, Teva's Dr. Ruth Levy rang Youdim and asked for a meeting, explaining that Teva was now interested in getting into drug development. By that time Teva was no longer a "generic nobody." In fact, it had the third largest generic operation in the U.S. and wanted to use its profits to promote its own developments in Israel. Youdim accepted the offer and Teva set up a unit at the Technion under his direction. In the following year he and his colleague Prof. John Finberg began working on rasagiline - the revolutionary drug Teva plans to launch by the end of this year.

Rasagiline might prove to be more than just a treatment for Parkinson's. Youdim says that it might help not only to halt the process of aging but actually cure damaged brains. It may not only slow down the progression of Parkinson's; it might even help neurons recover, as indicated by cell culture and animal studies. And Youdim believes it may also be effective in treating the human heart.

For the time being, he is developing rasagiline to treat nervous system diseases, particularly Parkinson's and Alzheimer's. But it is other properties the drug seems to have that make it potentially far more important.

At present, rasagiline does nothing more than what conventional drugs do, Youdim admits, although it is more potent and has no known side effects. But Youdim hopes it will prove not only to slow Parkinson's, but to help nerve cells grow anew, something no other drug in the world can do.

Theoretically, if trials in cell cultures, rodents and monkeys present the same results in humans, you could mix a spoonful of rasagiline into a bowl of cornflakes and protect your brain from the degeneration caused by aging, or from neurodegenerative diseases such as Parkinson's, suggests the professor. In other words, the drug he's developing may serve as prophylactic.

And there are strong signs that the drug not only halts the deterioration of the cells, not only protects them from further damage, but actually promotes recovery and survival, Youdim says.

Scientists have been working all over the world to discover drugs with such properties. The potential income to drug companies would be in the billions, given the millions of people suffering from neurodegenerative diseases.

Teva and Youdim's Technion team share the patents for the neurological aspects being discovered for rasagiline. And Youdim himself has the rights to something that might be even bigger.

"Together with my colleague Prof. Ofer Binah of our Physiology Department we have discovered something bigger than rasagiline, bigger than Parkinson's and Alzheimer's," Youdim says with glee.

Rasagiline to treat the heart? That idea began to develop when Youdim heard a lecture in Cadiz about cardiac protection. He realized that what he was hearing suited what he knew about rasagiline.

"Roughly a million Americans have Parkinson's disease, but 20 million have heart trouble and 500,000 die of it each year. It is the biggest killer," he does some simple math. In fact, pharmacology-unfriendly Israel could yet find itself the place where a font of youth is developed.

Intention and fate

Youdim did not arrive at pharmacology and rasagiline by chance. He was brought there by intention and fate.

Born at the American Hospital in Tehran in 1940, he began boarding school in Brighton, England, aged 11. After high school, he left the U.K. for McGill University in Canada, where he meant to study medicine. Then his father came down with crushing depression, giving the young man a new direction in life.

There were no drug treatments for depression at the time. When the first one was discovered, by chance - a drug for tuberculosis, iproniazid, made its takers happier - it was found to have an unfortunate side effect. People who took iproniazid and then ate cheese or drank wine tended to die. The race was on to find an anti-depressant that did not have the so-called cheese effect.

Youdim abandoned a career in medicine for research in neurochemistry and neuropsychiatry, moving to the Allan Memorial Institute at McGill, where he obtained his BSc, MSc and then his PhD. His intention was to develop drugs against depression. In 1966 he returned to his first adoptive country, England, where he did post-graduate work at the Queen Charlotte's maternity school ("The Beatles all gave birth there," he laughs, with slight gender inaccuracy.) His journey to the blockbuster drug began with brains of depressed geriatrics harvested from corpses at Queen Charlotte's morgue. He also taught at the London University, at Cambridge and at the College de France in Paris.

In 1971 Youdim attended a lecture in Sardinia by Joseph Knoll, an Auschwitz survivor living in Hungary, who was developing a drug called deprenyl as an anti-depressant. Downside: it didn't work. Upside: it didn't cause the dread "cheese effect". In October 1973, Youdim met Prof. Peter Riederer and the two scientists ultimately realized that deprenyl could be used to treat not depression, but Parkinson's. They even wrote up the subject for the prestigious publication Scientific American.

But deprenyl did prove to have serious side effects. Sales of the drug evaporated, and Youdim set out to find a better drug.

Youdim's own eureka moment was when he realized something about a barely-noticed drug by an Australian company. "I woke up one night and said Holy Moses, that looks like deprenyl," he says. "Maybe it can treat Parkinson's like deprenyl, without the side effects."

The company gave him the rights to the drug for free, and that was the drug that eventually was developed into rasagiline, a relatively safe treatment for Parkinson's with no cheese effect and possibly some significantly powerful upsides as well.

Meanwhile, in 1976, despite his contentment at Oxford, life in England, with the brewing Thatcherite revolution, was not to Youdim's liking. So, although he had been offered several positions in the United States as well, he decided to accept an offer to build a pharmacology department at the Technion. "I saw Israel as an adventure for two years or so," he recalls. In January 1977 he packed up his bags and, with his newly wedded wife, moved to Haifa, a wasteland in pharmacology that he thought he could help.

Very quickly, Youdim found himself aghast at the Israeli establishment. It was an "extremely difficult" struggle, and the dapper, courteous England-educated Iranian was prepared neither for the climate nor for the organizational culture. Maybe things had come too easily in England's halls of academia to the brilliant young scientist and he had failed to appreciate them properly, he admits today.

His non-Jewish wife, in the meantime, was encountering her own difficulties in her attempts to convert to Judaism through Israel's Chief Rabbinate. Ultimately she was converted with the help of Israel's "tribal culture": A high-placed official at the Technion put the Youdims in touch with the head IDF chaplain Rabbi Gad Navon, who converted her - "she knew the Shabbat prayers" - and became a close family friend.

Youdim became so bogged down fighting for budgets and the terms he had been promised that he had no time to study Hebrew during his aliya period. Now, after almost three decades in the country, he still speaks hardly a word of the language.

Weizmann's biggest mistake

At the time of his immigration, Israel had almost no prominent pharmacologists, nor did it have any drug development industry. To develop pharmacology as a discipline, you need a pharmaceutical industry, Youdim explains. Israel's pharmacological industry consists of copying drugs made by other innovators - in other words, making generic drugs.

But nobody wanted to help him change that. On the contrary. "Israel is a tribal country," Youdim explains, promoting insiders and scorning views from people perceived to be outside the establishment. And the science establishment has scant respect for pharmacology, mistakenly viewing it as an applied science. That is why the Weizmann Institute never developed a pharmacological department of its own; they felt it was below their standard, failing to see that it is the culmination of the pure sciences, biology, chemistry and medicine.

"Pharmacology is the science of how drugs interact within the body and produce their effect," Youdim clarifies, with passion in his eyes. "There was talent in Israel but it had not mustered into a cohesive band. The biggest mistake the Weizmann Institute ever made was not to set up a pharmacology department."

Iron age, the sequel

Youdim is not content with attacking Parkinson's with rasagiline. He also wants to conquer Alzheimer's disease. Working with Prof. Marta Weinstock and Teva, he has developed a new type of bifunctional drug called TV3326, or ladostigil, that combines rasagiline against Parkinson's with the anti-Alzheimer component of Weinstock's anti-Alzheimer drug, rivastigmine.

This drug, now undergoing clinical trials, uniquely offers both anti-Parkinson and anti-Alzheimer activity. Some 40% of dementia patients suffer from both diseases, Youdim explains.

Research in Alzheimer's is 10-20 years behind studies on Parkinson's, because cognition, which is impaired by Alzheimer's, is far more complex than movement, the victim of Parkinson's. Youdim is studying the effect of iron on the brain. "We have several animal models and different types of drugs," he explains, but he's pretty sure that ridding the brain of excess iron could be another way to fight neurodegeneration.

Excessive iron results in oxygen free radicals, which cause brain damage. This is one reason why so many people are obsessed with antioxidants and vitamin E, because they can remove these damaging radicals.

"Rasagiline is not a classic iron chelator radical scavenger," Youdim explains, "but I considered developing a version with an iron chelator to absorb the excess iron, to treat Parkinson's." And he did, in collaboration with colleagues. The drug is another unique development, treating Parkinson's with its rasagiline component while cleaning the surplus iron out of the brain.

At least the drug, named VK-28 for now, works in the animal model, Youdim avers. What it will do to rusting humans brains remains to be seen.

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