Work on unfertilized eggs gets area company noticed
By Terri Somers
UNION-TRIBUNE STAFF WRITER
September 28, 2007
CRISSY PASCUAL / Union-Tribune
Dr. Amber Buz'Zard with special cold storage facilities for human
parthenogenetic cells at International Stem Cells Corp. in Oceanside.
Alone after losing her husband and daughter in a Russian flu
epidemic, 60-year-old Elena Revazova came to California in 1997 and
began looking for distant relatives.
She had been the chief scientist at Russia's national cancer
institute. But in the United States she lived in obscurity, taking a
volunteer research job at the University of California Los Angeles
veterans hospital because she figured no one would hire a 60-year-old
woman with poor English, despite two Ph.D.s and a medical degree.
A decade later, Revazova's work is back in the scientific spotlight.
An Oceanside company she helped start, International Stem Cells,
gained worldwide attention with the publication last summer of work
done by Revazova and her team of scientists, who coaxed unfertilized
human eggs to produce embryonic stem cells.
The company showed that the embryonic stem cells could be grown into
more human embryonic stem cells, as well as differentiated into some
of the 200 different cell types in the body.
That work, scientists said, could provide a source of human embryonic
stem cells that sidestep the moral ethical debate swirling around the
cells. It could also provide a source of stem cells that would not
provoke a negative immune response when injected into humans – at
least in women who provide the eggs.
"It's a big deal, it's a very nice advance," said Kent Vrana of
Pennsylvania State University, when the article was published online
in the journal Cloning and Stem Cells. Vrana had done similar work in
monkeys.
The company is the first to intentionally create these so-called
human parthenogenetic cells – though another article published last
summer suggested that Korean stem cell researcher Woo Suk Hwang may
have created parthenogenetic cells when he falsely claimed instead to
have cloned human embryonic stem cells.
International Stem Cell is hoping to create a bank of these
parthenogenetic stem cells that can be used by researchers around the
globe, and to use cells to create new therapies for diabetes and
diseases of the eye and liver.
This month, a scientific journal article by the company showed that
they turned the embryonic stem cells into cornea tissue.
The company, which went public in January through a reverse merger
with an inactive company, has been selling shares over the counter.
Shares closed yesterday at $1.15, up 5 cents.
The founding of the company goes back to Revazova volunteering at the
VA hospital.
Dr. Gregory Keller, a plastic surgeon and scientist in Los Angeles,
had spread word that he was looking for a good scientist to work in
his lab. He was contacted by the head of the lab at the UCLA
hospital.
"He said 'we have a volunteer from Russia working in our lab, and I
don't know much about her, but she's amazing,' " Keller recalled.
Apparently the lab had many difficult problems getting cells to grow
and suddenly this Russian woman was able to make everything work,
Keller said.
Advertisement When Keller met with Revazova, she seemed surprised
that he wanted to hire her. But like the other American scientists
who worked with her, Keller was wowed by Revazova's work. In his
small lab, they worked on growing fibroblast cells to repair vocal
chords.
Over time, Keller learned more about her personal story.
Both her husband and daughter had been diabetics. The disease caused
them to be immunologically impaired. When the Russian flu epidemic
hit and medical supplies were in short supply for even an elite
scientist's family, the two could not survive.
The loss fueled her interest in therapies for diabetes.
Keller brought Revazova together with William Adams, a financial
expert he'd done some work with before who also had a personal
interest in diabetes research. And they introduced her to Kenneth
Aldrich, a venture capital specialist.
Together they decided to use Revazova's scientific skills as a basis
for a company that would target therapies for diabetes.
And they recruited Jeffrey Janus, a scientist who was a member of the
team that founded Clonetics Corporation, a San Diego company that had
been a leader in manufacturing human cells for clinical and research
use.
Janus pulled together a scientific team that could work on two fronts
for the company. One was research and development, including
Revazova's work. The second was the creation of a cell growing
business that could earn revenue to support the research.
As Revazova researched diabetes, she became frustrated with the
limitations of adult stem cells.
Adult stem cells can be derived from many different places in the
human body. Unlike embryonic stem cells, adult stem cells do not
require the destruction of a human embryo. But they are limited in
what they can become, unlike embryonic stem cells, which evolve into
the 200-plus different cell types in the body.
Revazova began looking at human embryonic stem cells but realized
that even they, as a therapy, would have an inherent therapeutic
problem – people who received a therapy made from stem cells with a
foreign DNA would have immune rejection issues and be required to
take immune suppressing drugs that have side effects.
So she began researching the possibility of coaxing an unfertilized
human egg to create embryonic stem cells. These so-called
parthenogenetic cells already exist in nature, Revazova explained
recently. For instance, unfertilized bee eggs produce the male,
worker bees. The fertilized eggs produce the female, queen bee, she
said.
And scientists had simulated that process in animals.
She thought that by stimulating the human eggs chemically, and then
controlling the temperature and oxygen in the environment in which
they are incubated, they could be coaxed to live and mature for up to
seven days and become a blastocyst, a cluster of about 200 cells.
Within the blastocyst's inner cell mass are embryonic stem cells.
But any work Revazova wanted to do on human embryonic stem cells was
made problematic because of funding restrictions that President Bush
placed on the research, Janus said.
Revazova returned to Russia in March 2002, to work on the
controversial cells with funding from the company. In her homeland,
she could work unfettered by U.S. restrictions. And she knew many top-
notch scientists who were hungry for work because they could not get
sufficient funding from the government since the dissolution of the
Soviet Union.
The researchers talked to hundreds of Russian women who had gone
through in-vitro fertilization to have children, and as a result had
leftover eggs, or oocytes, frozen in storage at IVF clinics. From the
women who sought to donate their unwanted eggs to research, the
researchers used 12 eggs, taking them only from people who had
already successfully had children, Revazova said.
From them, they successfully created six new embryonic cell lines.
"What Elena did that was so important was that she did this
repeatedly. It was not a one-time event," said Jeff Krstich,
International Stem Cell's chief executive.
The efficiency with which the lines were created is also notable,
scientists said. For an embryonic stem cell therapy to ultimately be
successful, the cell lines will have to be created with efficient use
of human eggs, which are not readily available.
Another possible advantage of the cell lines is that they may get
around federal funding restrictions in the United States because they
do not come from fertilized eggs, said Evan Snyder, who runs the
embryonic stem cell research program at the Burnham Institute in La
Jolla.
"Of course, we'd have to make sure these cells can do everything they
are supposed to do," Snyder said.
The company is now hoping to take advantage of its California
headquarters, which gives it access to a growing pool of talented
stem cell scientists and possible funding from the state's $3 billion
taxpayer-supported stem cell research fund, Krstich said.
It appears its work in eye diseases has the potential to become its
first product, since a third-party laboratory has certified that
International'
corneal tissue used for implant is taken from cadavers, and
recipients have immunological rejection issues, Revazova said.
If the company's parthenogenetic cells can be used for a therapy,
theoretically a woman's oocyte could be used to produce cornea
tissue. Or, cornea tissue can be developed from a donor oocyte and
statistically, at least, it would pose fewer rejection issues than
tissue that comes from a fertilized egg and contains the DNA of two
people, Janus said.
Hans Keirstead, a stem cell scientist at UC Irvine, has been given
some of the company's cells to evaluate and work with as an
independent adviser.
While Krstich, the CEO, is optimistic the company's work in eye
disease could be in human clinical trials within a year and a half
with Keirstead's involvement, the UC Irvine doctor is more measured.
From his work on the cells so far, they appear to be parthenogenetic
stem cells that differentiate, but Keirstead said he has no hard data
yet.
Even without those results, the company's work is still a valuable
contribution to the field because it is a new stem cell line, these
are potentially autologous cells and there are not many people
working on developing parthenogenetic cells, Keirstead said.
The advantage to having a business work on these lines is that it has
financial backing to concentrate on them, so their chances of
succeeding are higher than others, he said.
Some local scientists who have read articles about Revazova's work
but have not seen the cells are excited by it. But they cautioned
that more work must be done to investigate whether these cells can
form tumors.
Snyder, from the Burnham Institute, also said there is still not
enough known about embryonic stem cells to predict whether the
absence of one set of parental genes is important.
"It could turn out to be important to have two sets of genes. With
real fertilization you get two copies of a gene and one is silenced
and one isn't. Sometimes you want the father's genes and sometimes
you want the mother's version. It could be a problem to be stuck with
one version," Snyder said.
Krstich said the real challenge for International now is securing
another $1 million to bring the cornea project to market. Originally
that project wasn't in the business plan, but developed as the
scientists studied retinal disease.
A grant from the California Institute for Regenerative Medicine could
be a possible funding source.
"The key for us is getting the money to get to trial," Krstich
said. "Once we get to trial, getting money will be easier. Not easy,
but easier."
Terri Somers: (619) 293-2028; terri.somers@
http://www.signonsa
1b28tech.html
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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