Stem Cell Research: The
Melton, his family, & the Harvard Stem
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January 30, 2009
Stem Cell Research: The Quest Resumes
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Excerpts [with inserts, not part of original
article, included in brackets]:
Scientific inspiration can come from any-
where - a person, an event, even an experi-
ment gone awry. But perhaps nothing can
drive innovation more powerfully than the
passion born of tragedy. Or, in Douglas
Melton's case, near tragedy.
The co-director of the Harvard Stem Cell
Institute (HSCI) is one of the leading figures
in the search for cures for presently incur-
able diseases, and his breakthrough work
is challenging many long-held beliefs about
the ways biology and human development
But it was a very personal experience that
brought Melton to stem cells, one that 17
years later he still finds difficult to discuss.
When his son Sam was 6 months old, he
became ill with what his parents thought
was a cold. He woke up with projectile
vomiting and before long began taking
short, shallow breaths.
After several hours, he started to turn gray,
and Melton and his wife Gail brought the
baby to the emergency room. For the rest
of that afternoon, doctors performed test
after test, trying to figure out what was
wrong. "It was a horrific day," says Melton.
It was not until that evening that a nurse
thought to dip a testing strip into Sam's
urine and they finally got a diagnosis. The
boy's body was flooded with sugar; he had
Type 1 diabetes.
Then, as now, the disease had no cure, and
patients like Sam need to perform for them-
selves the duties their pancreas cannot -
keeping track of how much glucose they
consume and relying on an insulin pump
to break down the sugars when their levels
climb too high.
The diagnosis changed not only Sam's life
but the lives of his parents and older sister
Emma as well. Throughout Sam's childhood,
Gail would wake every few hours during the
night to check his blood sugar and feed him
sugar if his concentration fell too low or
give him insulin if it was too high.
"I thought, This is no way to live," says Mel-
ton. "I decided I was not just going to sit
around. I decided I was going to do some-
Trained as a molecular biologist in amphibian
development, Melton began the work he pur-
sues today: trying to find a way to make insulin-
producing cells by using stem cells.
"It was a courageous thing to do because he
was at the pinnacle of his career," says Gail.
"He brought home textbooks on the pancreas
to figure it all out." Nearly two decades later,
Melton is convinced that stem cells will be a
critical part of new therapies that will treat
and maybe cure not only diabetes but also
other diseases for which there are no answers
Melton's confidence is testament to the extra-
ordinary advances in stem-cell science, some
of which have brought the promise of break-
through therapies for conditions like diabetes,
Parkinson's and heart disease closer than ever
The cells filling petri dishes in freezers and
incubators in Melton's lab and others around
the world are so vastly different - in proven-
ance, programming and potential - from the
stem cells of just two years ago that even the
scientists leading this biological revolution
marvel at the pace at which they are learning,
and in some cases relearning, rules of devel-
Until recently, the field has revolved around
either embryonic stem cells - a remarkably
plastic class of cells extracted from an embryo
that could turn into any of the body's 200 tis-
sue types - or their more restricted adult cou-
sins, cells taken from mature organs or skin
that were limited to becoming only specific
types of tissue.
On Jan. 23, after nearly a decade of prepara-
tion, the Food and Drug Administration ap-
proved the first trial of an embryonic-stem-
cell therapy for a handful of patients paralyzed
by spinal-cord injuries.
But today the field encompasses far more than
just embryonic and adult stem cells; it has
expanded into the broader field of regenerative
medicine, and Melton's lab at Harvard is at the
vanguard, bringing the newest type of stem
cells, which do not rely on embryos at all,
closer to the clinic, where patients will actu-
Last summer, Melton stunned the scientific
community with yet another twist, finding a
way to generate new populations of cells by
reprogramming one type of fully mature cell
so it simply became another, bypassing stem
"If I were in high school, I can't imagine any-
thing more interesting than stem cells," says
Melton. "This is so cool. It's so amazing that
cells in the body have this potential that we
can now unlock by asking question after ques-
A Battle Joined
That hidden power in each of us did not become
obvious until 1963, when Canadian researchers
Ernest McCulloch and James Till first proved
the existence of stem cells, in the blood. These
cells possess the ability to divide and create
progeny - some of which will eventually expire,
others that are self-renewing.
That discovery led, 35 years later, to James
Thomson's isolation of the first human embry-
onic stem cells, at the University of Wisconsin
in 1998. And that milestone in turn inspired
researchers to think about directing these cellu-
lar blank slates to eventually replace cells that
had been damaged or were depleted by disease.
The key lay in finding just the right recipe of
growth factors and nutrients to induce a stem
cell to become a heart cell, a neuron, an insulin-
making cell or something else.
... new therapies were sure to come.
Then, in 2001, everything changed. ... Presi-
dent Bush restricted federal funding for the
study of human embryonic stem cells.
The decision sent some leading scientists abroad,
to Britain, Singapore and China, where the gov-
ernments were more receptive to their work.
Federally backed scientists, like Melton, who
continued embryonic work were forced to adopt
a byzantine system of labeling and cataloging
their cell cultures and equipment so that gov-
ernment money was not used to grow forbidden
cells - and government microscopes were not
even used to look at them.
Those days may soon be over. Barack Obama
campaigned on a promise to lift the research
ban and support "responsible oversight" of the
stem-cell field. For scientists, that means "we
can stop the silliness," says Melton.
Clearly, Melton does not shrink from a fight.
As Washington's squeeze on stem-cell research
tightened in the early part of this decade, he
decided to take action, providing life support
for what remained of the U.S. stem-cell com-
Not convinced that an entire field could make
much progress relying on a few dozen cell lines
of questionable quality, in 2004 he used funds
HSCI receives from the Juvenile Diabetes
Research Foundation and the Howard Hughes
Medical Institute, as well as from Harvard
alumni, and developed a more streamlined
method for generating stem-cell lines from
He created more than 70 new ones and has
since distributed 3,000 copies to scientists
around the country for free.
"Doug drew a line in the sand," says Alan
Trounson, president of the California Insti-
tute of Regenerative Medicine, the organi-
zation charged with dispensing state money
for embryonic-stem-cell research.
"He turned the tables on an Administration
that was incredibly negative toward stem
cells and showed [it] we are not going to
tolerate being put out of this field by ideo-
logical views that we don't think are correct."
Melton's motivation was, again, both pro-
fessional and intensely personal. Two months
after Bush announced his ban, Melton's daugh-
ter Emma, then 14, also received a diagnosis
of Type 1 diabetes.
In 2004, voters in California approved a mea-
sure providing $3 billion in state funding to
embryonic-stem-cell research. That threatened
to draw scientists in the stem-cell community
west, and Melton took pains to foster a "band
of brothers" mentality.
"I tried to create a cocoon here," he says, "and
tell people that your job is to focus on the sci-
ence. Don't worry what the politicians say."
By then, Melton's team was one of only a hand-
ful in the country working on embryonic stem
cells and was making headway in teasing apart
the myriad critical steps needed to guide these
impressionable cells into becoming insulin-
Both as a scientist and as a father, Melton re-
mained convinced that the federal restrictions
simply could not survive. He continued to
insist that "the science is so significant that it
will change the policy."
The true power of reprogramming ... does not
stop with the stem cell. This summer, Melton
flirted with the rules of biology once again when
he generated another batch of history-making
cells, switching one type of adult pancreatic
cell, which does not produce insulin, to a type
that does - without using stem cells at all.
Why, he thought, do we need to erase a mature
cell's entire genetic memory? If it's possible to
reprogram cells back to the embryo, wouldn't
it be more efficient in some cases to go back
only part of the way and simply give them an
Using mouse cells, Melton did just that, creating
the insulin-producing pancreatic cells known as
islets. "The idea now is that you can view all
cells, not just stem cells, as a potential thera-
peutic opportunity," says Scadden. "Every cell
can be your source."
Realizing that potential - and with it, the pros-
pect of successful treatments for conditions
like Parkinson's or diabetes - may still be a
few years away.
Even if iPS cells do not prove as stable and as
versatile as embryonic stem cells when they're
transplanted into patients, they remain a power-
ful research tool. And if nothing else, they will
have opened our eyes to the remarkable plasti-
city of biology and made possible new ways
of thinking about repairing and replacing dam-
aged tissues so we may consider not only treat-
ing but also curing disease.
"It's a wonderful time," says Scadden. "Keep
your seat belt on, because this ride is going to
For patients like Sam and Emma Melton, that
ride carries with it the possibility of being free
[of a chronic disease and the risk of premature
death and the fact they have to manually replace
a body function that's critical for life, with 24by
7by365, 366 every leap year, walking on a tight
rope] ... they endure to keep their blood sugar
under control [manually, as if that's even possi-
ble without becoming a human pin cushion ob-
sessed with trying to manually be like 'normal'
(an oxymoron -and- an impossibility, currently)
and at the same time acting as if everything is
fine aside from that manually taking over a cri-
tical body function thing].
"I definitely think about how my life would be
different if there is a cure," says Sam. His father
is keenly aware that the ability of stem cells and
reprogramming science to provide that cure is
far from guaranteed. But his initial confidence
in the power of the technology hasn't waned.
"Everything we learned about stem cells tells
us this was a really powerful approach," he
says. "It would be a great shame if we let it
wither and just go away." Melton, for one, is
determined not to let that happen.
Science in Steps
A decade of conflicts and breakthroughs
James Thomson, U of Wisconsin, isolates
human embryonic stem cells
President Bush restricts federal funding for
research on human embryonic stem cells
Douglas Melton of Harvard creates more
than 70 embryonic-stem-cell lines using
private funding and distributes free copies
of the cells to researchers around the world
Shinya Yamanaka, Kyoto University, turns
back the clock on mouse skin cells to create
the first induced pluripotent stem (iPS) cells,
or stem cells made without the use of embryos.
He uses only four genes, which are inserted
into a skin cell's genome using retrovirus
Yamanaka and Thomson separately create
the first human iPS cells
Kevin Eggan at Harvard generates the first
patient-specific cells from iPS cells - motor
neurons from two elderly women with ALS
Melton bypasses stem cells altogether and
transforms a type of mouse pancreatic cell
that does not produce insulin into one that
Konrad Hochedlinger at Harvard creates
iPS cells in mice using the common-cold
virus rather than retrovirus vectors - an
important step in making the technology
safer for human use
Melton's team makes human iPS cells by
replacing two of the four genes, known to
cause cancer, with chemicals. All four must
be swapped out before iPS-generated cells
can be transplanted into people
Yamanaka creates mouse iPS cells using
safer plasmids of DNA instead of retrovirus
Read Stem Cells: The Hope and The Hype.
Scientists who are having surprising success
with adult stem cells find their progress being
used by activists to argue that embryo research
is not just immoral but also unnecessary. But
to those in the field, the only answer is to press
ahead on all fronts.
"There are camps for adult stem cells and embry-
onic stem cells," says Douglas Melton, a co-dir-
ector of the Harvard Stem Cell Institute. "But
these camps only exist in the political arena.
There is no disagreement among scientists over
the need to aggressively pursue both in order to
solve important medical problems."
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