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which are fraught with both technical and ethical issues. The cells
are usually derived from four- or five-day-old embryos that would
otherwise be discarded from in vitro fertilization clinics (although
sometimes embryos have been created expressly for research pur-
poses). Using this technique to create a robust cell line is tricky
and highly ine cient. Not only are the embryos themselves hard
to obtain, but the cells are delicate and di cult to grow.
Another technique, human therapeutic cloning, is even more
controversial, and both technically and practically challenging.
Scientists transfer the nucleus of an adult cell into the hollowed-
out shell of an unfertilized egg cell---which can then develop into an
embryo, yielding stem cells that are genetic clones of the adult cells.
But the lack of human eggs for research has proved a huge hurdle,
and scientists have yet to generate cloned human cell lines.
But three years ago Shinya Yamanaka, of Kyoto University in
Japan, figured out how to return adult mouse cells to an embryonic-
like state in a process that never involved an actual embryo. He
found that using a virus to deliver genes for just four specific pro-
teins to the nucleus of an adult cell could give it the ability to dif-
ferentiate into a wide variety of cell types, just like the stem cells
derived from embryos. Those proteins, typically found in devel-
oping embryos, appear to turn other genes on and o in a pattern
characteristic of embryonic rather than adult cells. A year after
Yamanaka's discovery, his group and two others reported that they
could induce human cells to do the same thing.
As a physician and venture capitalist closely following stem-
cell research, Beth Seidenberg saw the potential almost immedi-
ately. Seidenberg, a partner at Kleiner Perkins Caufield and Byers,
teamed up with another venture capital firm, Highland Capital
Partners, to found iZumi in 2007, funding the company with $20
million. After 20 years in pharmaceutical research, Seidenberg has
had a lot of time to think about what the industry is doing right
and where it's going wrong. She says, "I became really intrigued by
the idea of starting with a patient who had a disease and working
backwards, which is exactly the opposite of how we pursue new
therapies for treatment of disease today."
To illustrate the role iPS cells could play in drug discovery, John
Dimos points to amyotrophic lateral sclerosis (ALS), a neuro-
degenerative disease he has studied for years. About 2 percent of
all cases have a known genetic cause---a mutation in a gene called
SOD . Nearly all the work in animal models has focused on this
rare form of the disease, because researchers know how to use
the gene to trigger it in mice. With the new technology, however,
scientists can use a skin biopsy to generate pluripotent stem cells
from any patient with ALS. The genetics and other possible fac-
tors underlying the disease are captured in the cells, even if no one
knows explicitly what those factors are. The same holds true for
Alzheimer's, diabetes, autism, heart disease, and myriad other con-
ditions whose complex origins have proved di cult to identify.
As a postdoc at Harvard, Dimos built a cellular model of ALS,
making it possible to study a neurodegenerative disease outside an
animal for the first time. He and his colleagues collected skin cells
from an 82-year-old woman with ALS, reprogrammed them into
iPS cells, and directed the cells to di erentiate into motor neurons
that were genetically identical to the donor's defective cells. "It was
the first paper to show that you can use a stem cell to see disease
pathology in a petri dish," says Douglas Melton, codirector of the
Harvard Stem Cell Institute. "That means you can now study dis-
eases in petri dishes and not in people. That's huge."
Because they are derived from human patients with documented
medical histories, iPS cells are accompanied by reams of previ-
ously inaccessible information. "You can see from their medical
history the progression of the disease, how they responded to dif-
ferent drugs, exactly what symptoms they experienced, and when,"
says Dimos. Certain drugs may be more or less e ective depending
on a patient's genetic makeup; some people, for instance, respond
well to the breast-cancer medication taxol, while others may have
no response at all. If scientists knew that specific medications
worked for certain people or, conversely, caused them to su er
severe side e ects, they could use their cells to try to figure out
why---and use that information to develop better therapies.
So far, Harvard Stem Cell Institute scientists and their col-
leagues have used iPS-cell technology to create more than 20
disease-specific stem-cell lines designed to help them study condi-
tions including Parkinson's and type 1 diabetes. While the field is
still in its early stages, researchers have begun to see evidence that
they can replicate certain aspects of human disease in a dish.
The first goal for iZumi is to establish its own bank of repro-
grammed cells. To start, the bank will be stocked with cells derived
from patients with various neurodegenerative diseases---ALS, spi-
nal muscular atrophy, and Parkinson's---as well as a cardiovascular
disorder known as calcific aortic valve disease, which they're study-
ing in conjunction with collaborators at the Gladstone Institute at
the University of California, San Francisco. By creating complex
systems of cells that incorporate the di erent cell types a ected in
each disease, such as motor neurons and skeletal muscle cells, they
can watch precisely how ALS and the other conditions develop.
The company wants to develop drugs, focusing on therapies
for neurodegenerative diseases. It will also work with other phar-
maceutical companies to find treatments for other diseases. "We
believe that we'll have our own proprietary therapeutics in devel-
opment in the fifth year---by 2012," says CEO John Walker.
A BUMPY ROAD
If iPS-cell scientists have learned anything from the saga of
embryonic-stem-cell research, it's that potential doesn't always
translate into profit or success: despite the vast promise of embry-
onic stem cells, building a business model around their thera-
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