1110 17 MARCH 2017 • VOL 355 ISSUE 6330 sciencemag.org SCIENCE
NEWS | IN DEPTH
Anyone awed by towering redwoods hould offer thanks to stomata, the tinyporesontheleavesofalltreesand other vascular plants. These micro- scopic mouths allow plants to grow more than a few centimeters tall.
They draw in carbon dioxide (CO2) for photosynthesis while allowing moisture to escape
through transpiration, the process that
pulls water up from the roots to a plant’s
tallest tips. They can also close to slow water loss, helping plants survive drying winds
and lack of rain. Stomata, in short, helped
plants colonize the landscape and transform the planet.
But where did this evolutionary wonder
Stomata are seen in 418-million-year-
old plant fossils and are found even in
ancient plant groups like mosses. “It’s as
if they popped up fully formed, and surely
that cannot be the case,” says Alistair
Hetherington, a plant biologist at the University of Bristol in the United Kingdom.
Now, molecular studies are giving scientists glimpses of the early days of stomata and how they have changed since
then. The evidence suggests that some of
the first complex stomata evolved for reproductive purposes: to help early plants
control moisture in their spore capsules.
Other plants later exploited these pores to
breathe in CO2 and exhale water vapor. And
hundreds of millions of years later, work
reported this week in Science shows, more
sophisticated stomata evolved in grasses,
enabling them to tightly control water
loss—a feature that helped them dominate
dry landscapes around the world.
Clues to the evolutionary story come
from the molecular pathways that regulate
stomata and guide their formation. Over
the past 15 years, researchers studying
Arabidopsis thaliana, the mustard weed
that is the most popular plant model, have
retina, and is the leading cause of blindness
in the elderly.
Takahashi started investigating treatments for AMD in 2000, a time when the
only cells capable of developing into all the
tissues of the body had to be extracted from
embryos. But she was stymied by immune
reactions to these embryonic stem (ES)
cells. When Yamanaka announced that he
could induce mature, or somatic cells, to
return to an ES cell–like state, Takahashi
quickly changed course to develop a treatment based on iPS cells.
Her team finally operated on the first patient, a 77-year-old Japanese woman with
late-stage AMD, in September 2014. They
took a sample of her own skin cells, derived
iPS cells, and differentiated them into the
kind of retinal cells destroyed by the disease.
A surgeon then slipped a small sheet of the
cells into the retina of her right eye.
An operation on a second patient was
called off because a number of minor genetic mutations had crept into his iPS cells
during processing, and
cancer—has been a
worry with such cells.
“These changes do not
directly induce cancer,
but we wanted to make
safety the first priority,” Yamanaka says.
Also, Takahashi says, AMD drugs had stabilized the patient’s condition so there was
no urgency in subjecting him to the risks of
surgery, which include hemorrhaging and
Immediately after surgery the first patient reported her eyesight was brighter.
Takahashi says the surgery halted further
deterioration of her eye, even without the
drug injections still being used to treat her
other eye, and there were no signs of rejection of the graft as of last December.
The result is “a proof of principle that iPS
cell–based therapy is feasible,” says Kapil
Bharti, a molecular cell biologist at the U.S.
National Institutes of Health’s National Eye
Institute in Bethesda, Maryland, who is
also developing iPS cells for treating AMD.
Takahashi says once her team gains more
experience with the technique they will extend it to patients with earlier-stage AMD
in an effort to preserve vision.
Last month, Takahashi won approval to
try the procedure on another five patients
with late-stage AMD. But this time, instead
of using iPS cells derived from each patient,
the team will draw on banked cells from a
single donor. “It takes time to create iPS
cells, and a lot of time for the safety evalu-
ation,” Yamanaka says. It is also costly, at
nearly $900,000 to develop and test the
iPS cells for the first trial, Takahashi adds.
Using donor cells to create the iPS cells
will make it more difficult to ensure im-
mune compatibility. But Yamanaka says
that donor iPS cells can be matched to
patients based on human leukocyte anti-
gen (HLA) haplotypes—sets of cell-surface
proteins that regulate immune reactions.
HLA-matched cells should require only
small doses of immunosuppressive drugs to
prevent rejection, Takahashi says—and per-
haps none at all for transplantation into the
Kyoto University’s Center for iPS Cell Re-
search and Application, which Yamanaka
heads, has been developing an iPS cell bank.
Just 75 iPS cell lines will cover 80% of the
Japanese population through HLA matching,
he says. Trounson, a past president of the Cal-
ifornia Institute for Regenerative Medicine,
a stem cell funding agency, says banked iPS
cells have advantages. Donor iPS cells may be
safer than cells derived from older patients,
whose somatic cells may harbor mutations.
And Jordan Lancaster,
a physiologist at the
University of Arizona in
Tucson, likes the speed
of the approach. He is
devising patches for
heart failure patients
based on iPS-derived
myocardial cells that
will be “premanufactured, cryopreserved,
and ready to use at a moment’s notice.”
Patient-specific iPS cells will still have
clinical uses. For one thing, Bharti says it
will be difficult for cell banks to cover all
HLA haplotypes. And a patient’s own iPS
cells could be used to screen for adverse
drug reactions, says Min-Han Tan, an
oncologist at Singapore’s Institute of Bio-
engineering and Nanotechnology, who re-
cently published a report on the approach.
Other human trials are not far behind.
Yamanaka says his Kyoto University col-
league Jun Takahashi (Masayo Takahashi’s
husband) will launch trials of iPS-derived
cells to treat Parkinson’s disease within
2 years. Bharti hopes to start human trials
of iPS cells for a different type of macular
degeneration next year. And as techniques
for making and growing iPS cells improve,
researchers can contemplate treatments
requiring not just 100,000 cells or so—the
number in Takahashi’s retinal sheets—but
millions, as in Lancaster’s heart patches.
As clinical use approaches, Takahashi
cautions that researchers need to keep
public expectations realistic. For now, iPS
treatments may help but won’t fully re-
verse disease, she says. “Regenerative med-
icine is not going to cure patients in the
way they hope.” j
Even early plants likely
had sophisticated pores to
regulate water and swap
gases with their environment
By Elizabeth Pennisi
“Clinical work is
progressing much more
quickly than I expected.”
Shinya Yamanaka, Kyoto University