No pain, all gain

The possibility of a longer-term local anesthetic that works only on pain is being hailed as one of the most important medical discoveries of all time.

By JUDY SIEGEL-ITZKOVICH
Dr. ALEXANDER BINSTHOK (photo credit: Judy Siegel Itzkovich)
Dr. ALEXANDER BINSTHOK
(photo credit: Judy Siegel Itzkovich)
Moving from an instructor’s position in anesthesia at Harvard Medical School and Massachusetts General Hospital to a lab at the Hebrew University-Hadassah Medical School is regarded as a step up by Dr. Alexander Binshtok, whose work on pain-selective local anesthesia has been ranked by leading scientists as one of the most important medical discoveries of all time.
The 38-year-old, Odessa-born physiotherapist with a HU doctoral degree in neuroscience was not persuaded to cancel his plans for a return to Israel despite the fact that he could easily find an excellent job anywhere.
On making aliya from the Ukraine in 1990 with his parents (a construction engineer and a piano teacher) and grandparents when the gates opened to Soviet Jewry, Binshtok does not recall being a Zionist. “But I am definitely a Zionist now. By that I mean Israel is my home, and I want to be at home. Jews should live anywhere they like, but I hope and believe the Jewish future is here,” he told The Jerusalem Post  a few days after returning with his Israeli-born wife and three young daughters. “It’s a beautiful country, and should be further developed.” 
Walking through HU’s leafy Givat Ram campus after the two-hour interview, Binshtok enthuses: “The Harvard University campus is pleasant, but Jerusalem, the university and the medical school campus in Ein Kerem are stunning.”
AS A YOUNG man, he lived in Beersheba and Bat Yam. After receiving his bachelor of science degree (with highest honors) in physical therapy at Ben-Gurion University of the Negev in Beersheba five years after making aliya, he worked in the profession for a decade. But wanting to help his patients even more, he developed an academic interest in pain mechanisms.
“I had concentrated mostly on treating pain, and while treating hundreds of patients, I came face to face with all forms of it. With time I realized that, although most patients recover well after acute trauma, those that develop chronic inflammatory or neuropathic pain usually do not respond well to the  available treatments. I tried to optimize commonly used physical therapy techniques and develop new ones,” he recalled.
Although he became one of Israel’s leading experts in electro- and thermo-therapy for pain management, pilot clinical trials of these techniques did not show improvement with chronic pain, he said. He realized that to develop more effective treatments, he needed a much more detailed understanding of the mechanisms involved. So Binshtok decided to change direction and, through doctoral studies in HU Prof. Michael Gutnick’s lab, targeted the electrophysiological properties of neurons in rodent brains and an understanding of tactile sensation; his goal, through this basic research, was to help people recover from pain, which affects 20 percent of mankind.
In 2005, Binshtok left Israel with his physiotherapist wife – she is modern Orthodox, while he is secular – to Massachusetts General and Harvard to do a post-doctoral fellowship with leading pain expert Prof. Clifford Woolf in his neural plasticity research group. “It was a great opportunity to be at Harvard, where there is a huge amount of scientific collaboration. I suppose that if I had come directly from Russia rather than from Israel where I had lived for 15 years, I probably would have stayed in the US.” 
Local anesthetics are vital for blocking pain, but they also prevent muscles from working and nerves from feeling other sensations. Blood pressure can also be affected, he said. Thus, a way to suppress pain without affecting the other sensations is needed. Working for years on rodents – and always doing the maximum to prevent them from suffering – Binshtok focused on proteins called sodium channels in nerves.
Electricity flows as sodium ions moving in a well-timed manner over tiny fractions of seconds across cell membranes. Binshtok and his team focused also on an ion (pain) channel called TRPV1 (transient receptor potential, subtype 1), which expresses exclusively by the pain fibers and opens in the presence of capsaicin, the substance in chilli peppers that produces the burning feeling when rubbed on skin. He found that when a local anesthetic called QX-314 (which by itself has no effect) and capsaicin are combined, they can shut off the sodium channel only on pain fibers and selectively block pain. Injected into rats, the effect lasted for nine hours, which was equivalent to several days in humans.
“It’s like a closed hole, which is opened by capcaisin, giving the local anesthetic the ability to penetrate selectively. Nobody had done this before.” Although proven in rodents, a cocktail of TRPV1 modulators and capsaicin that will work in humans is being developed by Endo, a US company that bought the patent rights. Binshtok credits the concept to Harvard Prof. Bruce Bean. “He gave me the challenge of investigating sodium channels and the possibility of blocking pain selectively.”
Investigating mechanisms underlying the development of inflammatory pain, Binshtok contributed to advances in the development of novel and efficient techniques to reduce pain. The results of his post-doctoral work were published in leading journals (Neuron and the Journal of Neuroscience), and he received the prestigious Schlomiuk Prize.
Then, in 2007, a paper Binshtok and his team published in Nature was ranked by the F1000 (an international body of the world’s leading scientists who judge the impact of current research) as the #1 research publication of all time in neurology and #2 in a variety of medical and science fields. The F1000 called it “exceptional – A landmark paper representing the top 1% of publications” and the second - highest ranked research article of all time in all categories of medicine. It even reached Time magazine and was joked about (due to the chilli pepper connection) on late-night American talk shows. Binshtok was promoted to the status of “instructor” at Harvard (equivalent to an Israeli lecturer), and his research continued to focus on the molecular mechanisms underlying pain. 
IN THE meantime, the growing Binshtok family was ensconced in a home in the upper-class suburb of Brookline, with many Jews nearby. Alex, though secular, gets along perfectly with his modern-Orthodox wife (who was born at Kibbutz Alumim in the Negev), willingly keeps a kosher home, and does not violate Shabbat. “It is all based on respect for the other,” he said, noting that there is a small number of such mixed families, such as Natan and Avital Sharansky. “It was hard to imagine my kids being Orthodox, but knowing my wife, it will be easier to contemplate. We expose them to the options so they will be able to choose their lifestyles and beliefs when they grow up.”
He “was raised under communism, and my family suffered from anti-Semitism on a governmental and private level,” he recalled. “If you were not Jewish and wanted to go to university, you had to pay bribes. If you were Jewish, you had to pay twice as much. If you didn’t attend university, you had to join the Soviet Army and fight in Afghanistan. I didn’t want to do that.” So, with Alex as an only child, his parents looked for a better place to live and decided to move to Israel. It was communism – “a perfect idea” that went wrong due to Soviet dictatorship – that made him feel as if he “couldn’t believe in anything anymore.” Since 1990, he has not returned even for a visit to the former Soviet Union, although he does not rule it out. “I don’t really miss it, but Odessa is a beautiful city.” He doesn’t like politics. “Maybe it has to do with what communism did to me. In Israel, I voted, but I didn’t discuss politics.”
At Harvard, Binshtok was not discriminated against as a Jew, even though he felt the atmosphere was left wing and sometimes anti-Israel. “I didn’t hide what I was. There are many, many Israelis there. My wife and I created a group of Israeli scientists in the area who met in our house every other Saturday night. We called it the ‘Motzash Club’ [short for night following Shabbat]. There were 150 on the mailing list, and between 20 and 40 present at gatherings. The meetings were an amazing academic discussion of high-end research by beautiful Israeli minds. Most of these people want to return home, but it is tough to find scientific jobs in Israel. It’s a real pity, as Israelis in the US are very smart, but there are not enough potential positions here. This is the only thing that keeps them away.”
He found that there are few Jews, and even fewer native-born Americans, going into scientific research. “They want to make money, so they go to business or law or medical school. The bulk of young researchers come from China, Korea and Japan.”
Binshtok wishes he knew what Israel needs to create more jobs in science. “A new medical school is being planned in Safed, and that will create more jobs. State allocations are all about priorities; if the government makes science a top priority, the quality of Israelis who return will be better.”
It is ironic, he says, that while the average educational level of its pupils has fallen according to international tests, “Israel continues to produce a huge number of excellent professionals. If the government were to invest in education at all levels, it would pay off. In Russia, the teaching profession was one of the most highly prestigious, but certainly not in Israel.”
Living in materialistic America, he noted, “is much more comfortable. American salespeople may not mean it when they say ‘Have a good day!’ but they know how to give service. Many of their Israeli counterparts are not like that. But Israel is home.”
Binshtok speaks fluent Hebrew (with a slight accent) and excellent English, as well as Russian. His two older children, both under five, speak perfect Hebrew even though they were born in the US. Their two-month-old was born in Boston too.
WHEN HIS boss at Harvard heard of his plans to return to Israel, “he hinted I would have a promising scientific future in the US if I stayed. But we didn’t want to, even though life was very comfortable.” To return was the couple’s “mutual decision.” Over the course of a year, he applied to Israeli medical schools and other potential workplaces. “Most of them responded,” and he was offered a job at the Jerusalem medical school, which was his first choice. He hopes to work with HU pain expert Prof. Marshall Devor and other outstanding specialists. He said he doesn’t want to lose his connection with physiotherapy, and hopes to teach physiotherapists a few times a year. The family, assisted by his in-laws, have a car and hope eventually to live near the capital.
He looks forward to a fruitful research career in Israel. “Pain management is a very unmet field. People can die from heart attacks, but they don’t die from pain. They live with pain, but it has a tremendous economic impact and causes great suffering. Only about 30% of them get relief today.”
Binshtok regards complementary medicine, including acupuncture, asunproven. “I personally see it as rubbish. A lot of the claims that itrelieves pain is due to the placebo effect. I’ll be happy to be provenwrong, but one has to understand the mechanism. Studies have to bescientifically conducted.”
He plans to work on things beyond what he did at Harvard; it could berelevant to arthritis and other chronic inflammatory pain, as well asitch, which can be very troublesome. As his new approach is selective,it could target other types of cells, maybe even cancerous ones. Itcannot work for general anesthesia, as that involves a differentmechanism, he said. The Endo technology “could eventually be applied toa skin patch, a tablet or even a nasal spray.”
Binshtok concluded that he hopes his work in Jerusalem will be aschallenging as it was in Harvard. “It is a privilege to be in thisplace.”