ISRAEL: Disease Be Not Proud

[Murray Charters <mcharters@xxxxxxxxxxxxxx>]

Disease Be Not Proud
By JESSICA STEINBERG
Feb. 26, 2004

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 f             
irstmedicalemergencyoftheZionistenterprisemalaria.WhenEuropeanJewscameto
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."

SOURCE: Jerusalem Post, Israel


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