Wanted in an age of aging: A healthy brain

One can be a successful pharmacology researcher, woman and religious Jew, says Prof. Marta Weinstock-Rosin, who will on Independence Day receive the Israel Prize for Medicine for her discoveries.

By JUDY SIEGEL-ITZKOVICH
PROF. MARTA WEINSTOCK-ROSIN, who will recieve the Israel Prize for Medicine, and her husband Prof. Arnold Rosin. (photo credit: JUDY SIEGEL-ITZKOVICH)
PROF. MARTA WEINSTOCK-ROSIN, who will recieve the Israel Prize for Medicine, and her husband Prof. Arnold Rosin.
(photo credit: JUDY SIEGEL-ITZKOVICH)
At the age of 12, when most children don’t know even how to spell the word “pharmacologist,” Marta Weinstock of London saw in 1947 an article on it in the Encyclopedia Britannica and decided that devoting herself to research, chemistry and drug development would be her future career.
On Independence Day, Prof. Marta Weinstock-Rosin – who developed the blockbuster drug Exelon to slow the development of Alzheimer’s disease – will receive the Israel Prize for Medicine for her scientific work.
“My grandchildren have finished military service,” said the Jerusalem emeritus professor at the Hebrew University’s School of Pharmacy.
“But they still don’t know what they want to do,” she relates with a smile in the living room of the Katamon quarter apartment she shares with her husband, geriatrician Prof.
Arnold Rosin.
She was born in Vienna in 1935 to her father, a diamond merchant, and her mother, who was a “housewife and a good mother” to her and her brother. Just before the outbreak of World War II and the beginning of the Holocaust, her family were able to go to England “at the last minute.
It was thanks to my cousin, Guggie Graham, who celebrated her 100th birthday here just a few weeks ago.
She married an Englishman in 1937 and was able to get us to England as well.”
Yet the troubles continued. Her father, as an Austrian “enemy alien,” was arrested and interned for 18 months on the Isle of Man in the Irish Sea between the islands of Great Britain and Ireland. Her mother, unable to speak a word of English, wandered around to find work and support her two children. They survived the blitz by Nazi bombers over London, and then together went to live in Letchworth. In 1943, the family moved back to London.
“We lived in one room of an apartment, and I remember smelling the neighbors’ bacon; we remained kosher and Shabbat observant. My younger brother, a chemist, still lives in England.”
In spite of her headmistress insisting that she could only become a lab technician, Marta wanted to study science and was sent to a boy’s school to learn physics. She matriculated at 16 and went on to study physics, chemistry and biology “I always wanted to do research, not to be a doctor,” she recalled, “but the only way into science was through medical school. “There was a quota for women and Jews at the University of London, but fortunately, she managed to get in, and she switched to the school of pharmacy, which was of high standard. “It had some of the best researchers in the world. “My father worried that because of my studies, I would never get married.”
At pharmacy school, she took a special course that put her on a research track, rather than to work as a pharmacist in a hospital or pharmacy.
Colleagues considered her as something of an oddball – as a woman researcher, a Jew and an observant Jew to boot. She studied chemistry and pharmacology and completed my master’s degree at 23.
She went for a doctorate in pharmacology at St. Mary’s Hospital Medical School (where there were only three Jews) and became a lecturer in pharmacology at the University of London.
She met and married Dr. Arnold Rosin, a modern Orthodox physician born in Scotland who went into geriatrics and was a senior registrar at Wittington Hospital. The mentor who had a major impact on his career, Marjory Warren, was killed in a tragic traffic accident, and he was asked to take over. He also applied and was accepted to be head of geriatrics at London’s Guy’s Hospital at the age of 38.
By the time the Rosins realized there was no Jewish future in England, they had three children and settled in Rehovot. Five years older than Marta, Arnold was director of Gedera’s Harzfeld Geriatric Hospital. Marta went to work at Tel Aviv University’s Sackler Medical School.
“I’m not the type to push. My father once said, ‘Hens don’t crow!” Without my husband, I probably wouldn’t have gone to Israel, but he was determined. We had three children to raise, and a year after, I was pregnant with the fourth. I didn’t know Hebrew; it was hot and humid in the summer; and I didn’t like the people pushing on the buses. I had to travel to Beilinson Hospital in Petah Tikva every day from Rehovot, as the Sackler Medical School was at first there. I hired a Yemenite woman to take care of the kids, and all my salary – a good one – went for childcare. We lived very modestly.”
All four of their children live in Israel, the daughter working in pharmaceutical information and clinical trials in the Health Ministry; and the sons are a Talmud teacher in a Ma’aleh Adumum yeshiva; an electrical engineer and a businessman.
She remembers that she was not happy working at TAU medical school. “It was a young school – but at least it was better than in England.
I had some wonderful students whom I’m still in touch with, but it was then not a very stimulating place.” Then she had an opportunity to go for a year to the US National Institutes of Health, where she took a sabbatical. “It was great. I worked with lots of Jews, including someone who won the Nobel Prize. But I didn’t like living in America,” said Weinstock- Rosin, who was director of pharmacology at TAU’s medical school.
Returning to Israel, Arnold took his wife on a visit to the Hebrew University of Jerusalem. “I met Prof. Felix Bergman, the chief of pharmacology, who invited me to replace him upon his retirement. Her husband, who was at Harzfeld, always wanted to work in a teaching hospital and perform research. “I wanted to teach students,” Arnold said. He got a job in Jerusalem when Prof. David Maier, then director-general of Shaare Zedek Medical Center on Jaffa Road, invited him to head the geriatric department.
So the two of them found themselves ensconced in their dream jobs – Arnold at Shaare Zedek (which Maier moved in 1979 to a large campus opposite Mount Herzl) and Marta at the Hebrew University-Hadassah Medical Faculty in Ein Kerem.
Marta said she never had to fight for advancement as a woman. “I had no problem advancing and getting a professorship. I never felt discriminated against, even though I had young children. I didn’t even asked to be promoted,” she recalls with wonder.
“I honestly think that women should stay home and take care of the children or work if they can spend quality time with them. If you are a stay-at-home mother and have no time or patience to talk to the children, then that is no benefit. I have lovely children, and I’m not sorry I went into science. Certainly, research is not for everyone.”
Although she has devoted many years to dementia of old age, Weinstock- Rosin started with investigating prenatal stress in women and how it affects the newborn. “Stress is frustrative non-reward. It does not necessarily mean that a person works very hard and is stressed. If you’re happy with what you are doing, you can come home and enjoy your children and not suffer from stress,” continued the scientist, who has published around 200 medical journal articles and written 27 chapters in medical volumes. “I always write them myself. I’m careful what I publish.
The greatest satisfaction is when people substantiate what I’ve done.
We were the first to show that stress in rat mothers causes all kinds of abnormalities in their offspring’s behavior.”
Choosing the right animal model for research is very important. “If Alexander Fleming had worked on guinea pigs to develop penicillin, he would have failed. These mammals are oversensitive to this antibiotic,” she said.
Weinstock-Rosin had always worked on rats and rabbits, and she is pleased that she never had to kill any of them. “I did blood pressure research on rabbits. They have big ears, so it takes only a few seconds to put a catheter into ears, and I can also measure their blood pressure easily.”
She bred rabbits and developed two sub-strains – one that develops hypertension on a high-salt diet and the other that does not suffer high blood pressure despite a lot of salt.
When she found males and female with low blood pressure, she mated them to develop sub-strains. The first had low-baroreflex sensitivity that predisposed them to hypertension, and the others with high baroreflex sensitivity did not develop hypertension.
She even sent a crate of 16 rabbits to Australia for research in 1986 and had to make sure they had enough to drink along the way. “We gave them a lot of cabbage, which has high water content, and they did fine in the bottom of the plane.
The reflex involves the kidney and tells it to turn off the sympathetic nerves leading to that organ. When I cut the nerve on all the rabbits with low baroreflex sensitivity, they all recovered, and even with a high-salt diet, none developed hypertension.”
This experiment was designed to show how high blood pressure develps on high salt but the way to treat it is to give anti-hypertensive drugs, diuretics and ACE inhibitors.”
Yet rabbits are not suitable for behavioral research, because while their cardiovascular systems are similar to that of humans, rats are more suitable for Alzheimer research.
HER RESEARCH into dementia “just happened.” She never really intended to do it. Her doctoral work was on opiates. In the early 80s, she was looking into how the painkiller morphine suppresses respiration. She founded that morphine slows the release of the neurotransmitter acetylcholine, making the brain less sensitive to carbon dioxide. This led to her development of a substance that prevents acetylcholine from breaking down by inhibiting the enzyme that does so, acetylcholinesterase in the brain stem. Although she produced a substance that was realtively long-acting and safer than other acetylcholinesterase inhibitors it did act very well in the brain stem but did inhibit the enzyme in the cortex and hippocampus Weinstock-Rosin nearly abandoned the molecule, but serendipitously, she went to the library and opened an issue of Science that had an article on Alzheimer’s disease.
There she found that the disease involves the lack of acetylcholine in the cerebral cortex and hippocampus, which play a vital role in attention the consolidation of information from short-term memory to long-term memory. Too little of the neurotransmitter is connected to cognitive impairment. It was a Eureka moment.
Thus she devoted herself to the development of a reversible cholinesterase inhibitor, commercially known as the oral drug Exelon for mild-to-moderate symptoms of Alzheimer’s and dementia due to Parkinson’s disease. It has been available in capsule and liquid formulations since 1997. Exelon does not cure the diseases, but it can improve symptoms or temporarily slow down their progression – benefiting some 40 percent to 70% of patients. More recently, in 2007, Exelon has become available in the form of a skin (transdermal) patch that reduces side effects such as nausea and vomiting; this was the first patch treatment in the world for dementia.
The Science Ministry gave her some funding on the condition that Weinstock- Rosin offer it first to an Israeli pharmaceutical company. As Teva Pharmaceutical was then the only significant local drug company, “we offered it to them, applied for a patent and had a year to sign a deal. But finally, Teva said it was not interested,” she recalls. “They said there was no future in Exelon. So I was delighted because Teva had no interest in or experience with Alzheimer’s.”
Through Yissum, the Hebrew University’s technology transfer arm, it was offered to the Swiss company Sandoz, which in 1996 merged with Ciba-Geigy to create the Novartis pharmaceutical company. HU benefits greatly from the royalties; Weinstock- Rosen has received enough money for her efforts to make sure that her 20 grandchildren are taken care of, and she also spends a lot on research.
Weinstock-Rosin is also the co-developer, with Prof. Moussa Youdim of the Technion-Israel Institute of Technology, of another drug named ladostigil, which she found prevents brain degeneration and mild cognitive impairment in aged rats. The drug is now undergoing Phase II clinical trials in Israel and Europe for the prevention of Alzheimer’s disease.
With her royalties, she could afford to support a company conducting clinical trials and could buy aging rats. “It costs a fortune to keep the rodents alive in good conditions until the age of 22 months, when they are considered old. One group of rats was given the drug, and the other went without. “It was amazing; the treatment group had intact memories and looked very well groomed, while the untreated aged rats did not.”
Marta and Arnold, who are officially emeritus professors, remain active.
He runs a geriatric clinic and is writing a book on communication with the elderly, while she continues to be involved in her drug research and tutoring post-doctoral students. She is optimistic that there will eventually be a cure to Alzheimer’s, which affects many tens of millions of people around the world.
“People who exercise their brains are less likely to develop dementia,” she said. “This leads to increased blood flow. Exelon helps increase blood flow to parts of the brain involved in memory. If you don’t get oxygen to these areas of the brain, they won’t function properly. You have to exercise them like muscles.”