The Jerusalem Post, February 27, 2004

ISRAELI MEDICAL DISCOVERIES -
DISEASE BE NOT PROUD

By Jessica Steinberg

How does one define a discovery? According to Webster's Revised Unabridged Dictionary, it is "that which is discovered; a thing found out, or for the first time ascertained or recognized; as, [William] Harvey's discovery of the circulation of the blood." A discovery isn't a cure or a solution. It is a means to end. An exploration, an examination. In the action of discovering, one is exposing something to view, allowing for further insights and breakthroughs.

When determining Israel's top medical discoveries, the first stipulation was, of course, discoveries. Not cures, not even necessarily methods of treatment, nor medicines. Rather, discoveries that have led to further discoveries; findings that may lead to treatments and one day, maybe, cures for the long list of debilitating chronic diseases.

All that said, this is clearly a short list - and in no particular order - of medical discoveries. But you have to start somewhere.

Copaxone
When Eli Hurvitz, the former long-time CEO of drugmaker Teva Pharmaceuticals, first heard about a Weizmann Institute of Science mixture of polymers and amino acids that could possibly be used to treat multiple sclerosis, a disease of the nervous system, his eyes lit up, said Irit Pinhasi, Teva's vice president for innovative research and development.

"We knew this was a disease that was waiting for a medication, but molecules are problematic," said Pinhasi. "Could we take this mixture and make it into a drug?"

They could and they did. Scientists at Weizmann had been working on the research since 1971, and Teva, which had previously produced only generic drugs, took it over in 1986. It took until 1995, including scores of clinical trials, to receive the seal of approval from the US Food and Drug Administration. In 1997, Copaxone was being prescribed by doctors as a treatment for the earlier stages of MS.

"It doesn't get rid of MS because no one knows how it starts, no one knows the trigger for MS," said Pinhasi. "But Copaxone is worth taking as soon as there is an MS diagnosis because its effect grows over time. The patient sees stabilization, less shakiness, more steadiness.

"For many MS sufferers, Copaxone is the drug of choice because it makes them feel that they can deal with the illness and continue living their lives."

Beta-Interferon
Copaxone, however, wasn't the first Israeli drug to deal with multiple sclerosis. In 1968, a young molecular biologist and physician came to the Weizmann Institute from France, and two years later began working on interferon, a human gene that acts as a natural defense of the human body against viruses. Ten years later, Prof. Michel Revel discovered that interferon also modulates the immune system.

By 1979, Weizmann had persuaded Swiss pharmaceutical giant Ares-Serono Group to open Interpharm, an Israeli subsidiary in Rehovot, near the institute. The company offered the money necessary to express human genes to reproduce interferon and to isolate beta interferon. By 1981, Revel was producing the beta gene.

Twenty years later, Interpharm Laboratories' leading product is bulk recombinant human interferon-beta-1a, otherwise known by its commercial name, Rebif. With $700 million of Rebif sold worldwide, 80 percent of the estimated 700,000 MS patients worldwide are treated with interferon, although there are three companies - including Interpharm - that make the gene. It isn't a perfect solution: Interferon's side effects are flu-like symptoms, but it quiets down the immune system and reduces attacks by over 50%, and it also reduces the disease's progression rate. Unlike Copaxone, which is for relapsing-remitting MS, beta-interferon is prescribed for patients with other types of the disease.

Revel is currently working on combinational drugs that will repair the damage done to the nervous system.

Malaria
Of course, the history of Israeli medical research goes back much farther than the 1960s. Perhaps it's best to start at the very beginning, with the first medical emergency of the Zionist enterprise: malaria. When European Jews came to settle the land of Israel, they found more mosquitoes than milk and honey. With Arabs settled primarily in the mountains, Jews were settling the coastal plains, the swampy stretch from Haifa to Gedera, and hundreds of pioneers, as well as soldiers in Gen. Allenby's army, died of the disease.

By the time Dan Spira, a Czech immigrant and concentration-camp survivor, made his way to Israel and the Hebrew University in 1948, he was preceded by several scientists examining what was considered the "No. 1 enemy of the establishment," according to Spira.

"I have a feeling that the first medical research in this country was done on malaria," he said.

Following his predecessor's work in the field - Spira studied with Aviva Zuckerman, who worked on a broad malaria project in the US in the 1940s - most of their work was theoretical, since malaria had all but disappeared, particularly in the Hula Valley with the help of DDT and chlorophyll, which kill mosquitoes.

Nevertheless, to this day, there is still no vaccine against malaria, with some two million people dying each year from the disease, according to the World Health Organization.

"At a certain point, I realized I wasn't going to find the vaccine to malaria," said Spira. "Then again, I'm not sure anyone will."

Capsule endoscopy
Imagine swallowing a video camera the size of a multivitamin, and allowing this video-imaging shell to glide through your digestive tract, transmitting images of your intestines to a portable data recorder worn around your waist, which are then downloaded onto a computer for examination.

To date, more than 65,000 patients worldwide have swallowed the M2A capsule, and more than 140 million Americans currently can be reimbursed by their health plans for capsule endoscopy procedures to diagnose Crohn's, an inflammatory bowel disease, celiac disease, and other small-intestine conditions. For Given Imaging, a company that has dedicated itself to imaging solutions for the gastrointestinal tract - the company name stands for GastroIntestinal, Video, and Endoscopy - the wave of approval is "incredible," according to Sandra Ziv, who heads the marketing department at the Yokne'am-based company.

The capsule endoscopy procedure was invented by Gavriel Iddan, an electro-optical engineer who spent a good chunk of his career at military manufacturer Rafael, the armaments development authority, developing guided-missile technology. During a sabbatical year in Boston, his neighbor, an Israeli gastroenterologist, challenged him to invent an endoscope that could make its way through the entire gastrointestinal tract. It took about 20 years, but in 1997, Iddan, then the company's chief technology officer, signed a patent for capsule endoscopy. The Nasdaq stock market-traded company hopes to eventually create imaging solutions for the entire gastrointestinal tract, including the large intestine and colon.

Embryonic stem cells
It was December 1985 when Joseph Itskovitz, a gynecologist involved in assisted reproductive technology at Rambam Hospital in Haifa, went to visit Madison, Wisconsin, to learn about embryonic stem cells, which have the ability to proliferate and differentiate into all the tissues of the body.

Thirteen years later, in 1998, Itskovitz and his team of researchers at the Technion-Israel Institute of Technology began studying stem cells in collaboration with the University of Wisconsin, launching Israel's stem cell research program and generating the embryonic stem cells as the "raw material" necessary to the research.

It was the infrastructure for in-vitro fertilization and micro manipulation that first offered the solution for entering into stem cell research. While stem cell research had been around since the early 1980s, having the embryonic cells at the Technion allowed Itskovitz and other teams to research and develop different theories.

The scientists developed embryonic stem cells in mice and began looking into possible applications. They first used the stem cells on rats with spinal injuries, helping them partially recover from paralysis.

They then created beta stem cells that produce insulin and injected them into diabetic lab rats to help reduce their hypoglycemia.

Another team of Technion scientists at the cardiovascular research laboratory grew heart cells from embryonic stem cells that have electric and mechanical characteristics of young heart tissue.

Stem cell research could help solve chronic diseases like juvenile diabetes and create a-beta cells for Parkinson's and spinal cord injuries and bone marrow transplants. Stem cells also allowed Itskovitz to learn about the processes tied to fetal and blood development.

"It's exponential," he said. "First there were two labs, now there are tens of labs worldwide researching human embryonic stem cells. It's almost without borders."

More stem cells
As Itskovitz and his Technion team worked on heart cells, another major stem cell breakthrough took place at Hadassah-University Hospital in Jerusalem's Ein Kerem when Prof. Shmuel Slavin, who heads the bone marrow transplantation department, used a bone marrow stem cell transplant and gene therapy to cure two toddler sisters born without immune systems, a genetic disease known as severe combined immunodeficiency, or SCID. The disease is caused by the lack of an essential enzyme, adenosine draminase, or ADA, that creates a functioning immune system.

After working with a team of Israeli and Italian researchers from the San Raffaele Institute in Milan, Slavin took one of the children's stem cells and introduced the adenosine draminase replacement gene into her stem cells. The experiment was mostly successful, but she remained immune deficient because the number of cells treated were few and ineffective compared with the overwhelming number of unhealthy cells still in her body. Slavin then took bone marrow from her healthy brother, who was a successful stem cell match for his sister. He isolated the stem cells and transplanted them in the toddler, successfully treating and curing her of the condition.

In the gene-therapy procedure, Slavin's team developed a protocol that would allow the genetically coerced cells to prevail in the patient's field of stem cells. He injected the virus-enriched, genetically altered stem cells into the toddler's body, adding medication to suppress her sick cells and to allow the new, healthy cells to develop and multiply for several days before encountering competition from the sick cells.

Two years later, Hadassah is now taking a multipronged approach to embryonic, fetal, and adult stem cell research, focusing on developing stem cells for the blood system and for the treatment of cancer, and working toward preparing nerve cells required for treating Parkinson's disease.

"It's a formidable undertaking," said Rafi Hostein, CEO of Hadasit, Hadassah's research and development company. "If we inject right neurons into the brain, we can fix the problem of Parkinson's."

Ubiquitin
As the story goes, Prof. Avraham Hershko doesn't hold any patents for one of his greatest discoveries, the ubiquitin system of regulated protein degradation - a fundamental process that influences vital cellular events, including the cell cycle, the appearance of cancerous cells, and responses to inflammation and immunity.

"Nobody else seemed interested in this then, but I thought it was important. Proteins have a set lifespan, after which they break down in a process called proteolysis. Many people knew how the body produces proteins, but not how they were destroyed," said Hershko.

"Proteins provide ways to moderate the body's machinery."

It was more than 20 years ago that Hershko and his then-student - now Technion biochemistry professor Aharon Ciechanover - were intrigued by how cells go about discarding proteins and what impact the process has on disease. Working with proteins from bacteria and other organisms, they finally succeeded in purifying the agent that caused this degradation. They named it APF-1 (for ATP-dependent proteolysis factor 1) or ubiquitin.

While at the Massachusetts Institute of Technology for a post-doctoral degree, Ciechanover worked with another research team, uncovering the ubiquitin system and its role in DNA repair, the cell cycle, and the understanding that cellular protein turnover is vital to understanding how cells malfunction and cause disease.

Ubiquitin also seems to have a role in inflammation of tissue, so that applications of the team's basic scientific discoveries could eventually be developed for chronic inflammatory diseases such as asthma and autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. The biochemical mechanism of ubiquitin could also help improve the efficacy of chemotherapy drugs.

B-Stent
First things first. B-Stent does not stand for Beyar Stent, although its inventor, Prof. Rafael Beyar, an invasive cardiologist and biomedical engineer at the Technion and former dean of its medical school, did come up with the original design for a metal stent, used to keep clogged arteries open.

"The B is for balloon expandable, not Beyar or best," said Beyar, who developed the idea with his brother, Motti, a mechanical engineer.

It was 1989, and the Beyar brothers were considering a heart stent based on the stent used by urologists.

"People didn't believe you could have a stent for the heart," said Beyar.

"But our concept was, if you could do it for urology, why not for cardiology?"

The advantage of a stent, which is a wire mesh tube used to prop open an artery that's recently been cleared, is its ability to hold arteries open while offering enough flexibility for "the tortuous path of arteries," added Beyar.

The stent stays in the artery permanently, holds it open, improves blood flow to the heart muscle, and relieves symptoms such as chest pain.

"The results in patients were remarkable," said Beyar. "You could see where the [diseased] artery starts and ends. You could get around curves and get good results. No one else had that."

By then, Instent, the brothers' startup, had been formed, and clinical trials in the early 1990s led to the final product in 1995. By that time, Instent merged with the American company Medtronics, which took the product to market worldwide.

"We were racing against the clock to get it out there," said Beyar. "Some investors said we were wasting our time, that it was too risky. But we stuck with it because we saw the results and believed it would change the world."

Cancer cells
When it comes to medical discoveries and research, everyone is looking to cure cancer, or at least, to conquer it.

Cancer research was introduced to Israel in the 1950s by the Weizmann Institute, with the first studies engaged in understanding malignancy and finding weapons to fight it.

One of Israel's first cancer-research discoveries was made by Prof. Isaac Birnbaum and Prof. Leo Sachs, who laid the foundation for differentiating between cancer cells and normal cells, and understanding the transformation of a normal cell into a cancerous cell. While working on blood cells, Sachs discovered that cells have to "make decisions" as to whether they will grow or differentiate further, explained Prof. Benny Geiger, dean of the faculty of biology at Weizmann.

"He understood that the balance between the decision to stay on line in normal growth patterns or to continue proliferating is a critical event, and that a malfunction could throw a cell into a cancerous state," Geiger said.

That early discovery led to other cancer-cell discoveries, including the properties, activities, and biology of the P53, a protein that is central to cancer biology, and was characterized, cloned, and studied extensively by several research groups at Weizmann. P53 can be mutated in a large percentage of human cancers because it acts as a guardian, instructing cells to stop proliferating and die, rather than mutate into cancerous cells. But when P53 mutates, there is nothing to prevent cells from developing cancer.

The P53 research brought about more recent discoveries, including a DNA repair mechanism that could enable cells to repair damage and reconstruct a normal gene from a damaged one, as well as the existence of programmed cell death, an apparently common process that is activated when something goes wrong with a cell.

"Discovery is understanding something you didn't understand before," said Geiger.

"It's understanding a process in both specific and intuitive terms. If you want to know the difference between a cancer cell and a normal cell, it is very clear. If you can fix a gene, you can think of a therapy."