Wednesday, February 9, 2011

Making armor for the brain (The story of Moussa Youdim)

[Jerusalem Post: 11/13/2010]

  


With a surname that comes from the Hebrew word yod’im (know) as his family for over 400 years in Persia were known for their intellectual pursuits, Youdim was given the name Moussa after an official in Teheran’s American Hospital who mistook her for Muslim and told his mother that she must call him Ali. When she protested that she was Jewish, he instructed her to name him Moussa. Since then, even though he is sometimes mistaken for being a Muslim (especially by airport security personnel), he has refused to change it to Moshe.

Warm, outgoing, polite and a man of the world, Youdim holds more than 100 international patents in neuropsychiatric drug development and cardiovascular drugs. He acts as a consultant for several major international pharmaceutical companies, and serves on many national and international scientific and grant-giving committees.

Not only have the contributions of the leading pharmacology researcher been included in many standard text books, but he has published a stupendous 800 scientific articles, edited 45 books, served on the editorial boards of 44 international scientific journals, lectured around the globe and received many national and international awards and several honorary doctorates – most recently the European College of Neuropsychopharmacology LifeTime Achievement Award and election to the Leopoldina Germany Academy of Sciences.

HE GOT used to traveling and managing on his own from a young age. Around his 12th birthday, he was sent to a boarding school in the English city of Brighton, and from there left for Canada to study medicine at McGill University – until his businessman father took sick – when there were no safe medications for depression, Youdim recalls in an interview with The Jerusalem Post. His father was given electroshock treatments in England and felt better, but he had recurrent attacks and was never the same.

Youdim’s mother became the family breadwinner.

In 1960, the only existing antidepressant medication, iproniazid, had been meant for treating tuberculosis, but it was found to make people who took it happier. Yet, it killed some people who took it along with cheese or wine, launching a race to find a safe antidepressant.

After taking courses in bio- and neuro-chemistry, he became enthralled with the idea of understanding how the brain works, and wondered how to fix it. Graduating with a BSc and MSc and then his doctoral degree in biochemistry at McGill’s Allan Memorial Psychiatry Institute, he returned to England for post-graduate work at the University of London and taught at Oxford and at the College de France in Paris.

YOUDIM RECALLED that nearly 40 years ago, he heard a lecture by Holocaust survivor Joseph Knoll about work on an antidepressant called deprenyl. Unfortunately, it wasn’t effective, but it also was not harmful to people who drank wine or ate cheese. A few years later, Youdim and Prof. Peter Reiderer of Austria thought and demonstrated that deprenyl was effective in treating Parkinson’s, the degenerative disorder of the central nervous system that impairs motor skills, cognitive processes and other functions, and whose symptoms include tremor, rigidity and unstable posture, along with cognitive and neurobehavioral problems, dementia and sensory and sleep difficulties.

Deprenyl, later named selegiline in the US, became the first monoamine oxidase B inhibitor for the treatment of Parkinson’s disease. But they found that deprenyl may indeed have side effects; Youdim searched for a deprenyl-like drug that would be more effective. He finally stumbled upon a candidate drug that was in his possession; he developed it into rasagiline (now patented as Azilect and sold by the Israeli company Teva Pharmaceuticals).

Margaret Thatcher’s anti-Socialist tenure as British prime minister annoyed Youdim and other scientists no end – “she was called a ‘milk snatcher’ when she took away free milk supplies for schoolchildren – and though he was happy at Oxford, he became alienated from England.

Simultaneously, Youdim visited Israel (although most of his family ended up in Los Angeles) and was invited to see the Technion’s new medical school, where the dean offered him a job to establish and head a pharmacology department; the only one in Israel then was at the Hebrew University in Jerusalem. “I liked Europe, but I thought Israel would be exciting – and indeed it has been.”

ALTHOUGH ACADEMIC pharmacology is necessary to build the pharmaceutical industry, Israel had few prominent people in the field, and the Weizmann Institute of Science in Rehovot never set up its own pharmacology department because it didn’t regard it as pure but rather applied science. It is ironical that many people at Weizmann now consider themselves drug developers, he adds.

Although he had received enticing offers from the US and Iran, Youdim agreed to come to Haifa to live in 1977. “I had to recruit people for the department and was asked to go to ulpan to learn Hebrew, but I taught in English; I didn’t have the time to learn Hebrew. I was given five years, but I still don’t really speak it,” he admits with some amusement.

He and his first wife had three children – Shai, Tal and Avigail, none of whom went into science – and they later divorced. On a blind date 15 years ago, he met Fruma, a high-school English teacher and mother of two whose Holocaust-survivor parents moved from Austria to Israel when she was two years old. Moussa and Fruma married a decade ago, and – speaking Hebrew like a native and feeling “totally Israeli” – she makes up for his lack of fluency in the language. When not flying around the world together, they live in a penthouse on a hill in Haifa that overlooks much of the city and the sea. After chairing the pharmacology department at the Technion’s Rappaport Faculty of Medicine until 1994, he went on to direct the Technion’s Eve Topf and US National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research and Teaching.

ALTHOUGH HE says he has has never regretted becoming an Israeli, Youdim encountered roadblocks in the bureaucracy and the academic establishment.

“It’s a small country, with one pie, and everybody wants a piece of it. If you didn’t grow up here, you may have difficulty. Politics is important and intertwined with other things.” But, he says, all this can be overcome, and his own success story proves it.

Two years after his arrival, he suggested to Teva – then a small generic medicine producer – that they offer a deal for rasagiline, but officials turned him down. But in 1987, as Teva was beginning to develop original drugs such as Copaxone for multiple sclerosis, Youdim got a call, this time to invite him to establish a unit to work on his Parkinson’s drug along with Technion colleague Prof. John Finberg.

Today, approved by the US Food and Drug Administration, it offers hope to millions of Parkinson’s patients (1.5 million Americans and four million Chinese alone). With annual sales worth $400 million and royalties earned by the Technion and the scientists, Azilect is now being marketed worldwide; it is considered the first neuroprotectivedisease modifying drug for Parkinson’s.

Azilect does not cure the disease, says Youdim, but it has been shown to slow the degenerative process in the brain and has been found in lab studies to actually improve damaged neurons. “The jury is still out. I have nothing to do with clinical studies, but all reports show it helps and has no more side effects than a placebo. There are patients who have been taking it for six or seven years and still benefit from it.”

There are also signs, he says, that a derivative of rasagiline named Cardiamit would help patients suffering from cardiovascular disease, and this is about 20 times more common than Parkinson’s; he has conducted research in this with Technion physiologist Prof. Ofer Binah. This drug is being developed at the Technion’s Alfred Mann Institute.

Asked about implants of electrodes in the brain to alleviate tremors, Youdim says those are not the solution for the large numbers of Parkinson’s patients. A drug is their only hope, as you can’t perform such operations on everyone, he adds.

Youdim has an even bigger target – Alzheimer’s disease. Working with Hebrew University pharmacology Prof. Marta Weinstock-Rosin and Teva, he has developed a new type of drug called Ladostigil (TV 3326), which is now entering Phase II clinical trials in Europe. It integrates rasagiline’s anti-Parkinson benefits with the anti-Alzheimer effects of Weinstock- Rosin’s drug rivastigmine. This is natural, he says, as many Parkinson’s patients also suffer from this dementia disease. The exclusive commercial rights for Ladostigil, which is already the first multi-functional anti-Alzheimer’s drug to reach clinical trials, have been granted to Avraham Pharmaceuticals by the technology transfer arms of the Technion and HU. If everything works out, he believes that Ladostigil will be his second original drug to be put on the market.

Youdim has established the importance of monoamine oxidase and brain iron metabolism for brain function that can lead to cognitive impairments and neurodegenerative diseases. Excessive iron produces oxygen free radicals, which cause degeneration and aging, including brain damage.

Alzheimer’s, he notes, is a very complex, multifactorial disease. “It is not purely neurological; there are probably also some psychiatric aspects, as many patients also have a predisposition to depression.”

More recently he has developed with Prof. Mati Fridkin of Weizmann Institute novel multifunctional iron chelators with monoamine oxidase and cholinesterase inhibitory activity for treatment of amyotrophic lateral sclerosis (ALS or Lou Gehrig disease, a form of which afflicts British theoretical physicist Prof. Stephen Hawking and many others around the world) as well as Lewy Body disease and Type 2 diabetes. “We’ve already published a paper on it, and are working on Huntington’s as well – the familial [genetic] degenerative neurological disease that is even more terrible. I work harder than ever before, even though officially I am retired.” He has been invited twice to Beit Hanassi to see President Shimon Peres, who has asked a group of Israeli neuroscientists to advise him on the establishment of a virtual neuroscience institute linking via Internet a number of research institutions that would collaborate on developing novel approaches to treat neuropsychiatric disorders and benefit the Israeli economy.

As for his native country of Persia, Youdim recalls that in 1978, when he was in Israel, the Shah of Iran invited him to Teheran, decorated Youdim on the monarch’s birthday and gave him a royal medal. “The Soviet Union fell, so fundamentalist Iran could as well. If I were one day invited back, I would visit. It’s a beautiful country.”

Youdim says he hasn’t even asked how much money his share of the EMET Prize will be, but “I don’t care about money; we have enough. I have received so many honors in Israel and abroad that a Nobel Prize is not my goal. There are so many brilliant scientists who have not become Nobel laureates. What is important to me are the many e-mails and phone calls I receive from grateful patients who have been helped by rasagiline. One example was a woman who called at 4 a.m. from Dallas to thank me because her husband had responded to the drug.”

But he will be excited and moved at the EMET Prize ceremony, he concludes. “I will surely think of my father and mother, who meant so much to me. They would certainly be proud.”

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