DIABETES, FROM STEM CELLS TO INSULIN PRODUCERS
Harvard stem cell
researchers announced that they have made a giant leap forward in the quest to
find a truly effective treatment for type 1 diabetes, a condition that affects
an estimated three million Americans at a cost of about $15 billion annually: With
human embryonic stem cells as a starting point, the scientists are for the
first time able to produce, in the kind of massive quantities needed for cell
transplantation and pharmaceutical purposes, human insulin-producing beta cells
equivalent in most every way to normally functioning beta cells.
Doug Melton, who led
the work and who twenty-three years ago, when his then infant son Sam was
diagnosed with type 1 diabetes, dedicated his career to finding a cure for the
disease, said he hopes to have human transplantation trials using the cells to
be underway within a few years.
"We are now just
one pre-clinical step away from the finish line," said Melton, whose
daughter Emma also has type 1 diabetes.
A report on the new
work has been published by the journal Cell.
Felicia W. Pagliuca,
Jeff Millman, and Mads Gurtler of Melton's lab are co-first authors on the Cell paper.
The research group and paper authors include a Harvard undergraduate.
"You never know
for sure that something like this is going to work until you've tested it
numerous ways," said Melton, Harvard's Xander University Professor and a
Howard Hughes Medical Institute Investigator. "We've given these cells
three separate challenges with glucose in mice and they've responded
appropriately; that was really exciting.
"It was
gratifying to know that we could do something that we always thought was
possible," he continued, "but many people felt it wouldn't work. If
we had shown this was not possible, then I would have had to give up on this
whole approach. Now I'm really energized."
The stem cell-derived
beta cells are presently undergoing trials in animal models, including non-human
primates, Melton said.
Elaine Fuchs, the
Rebecca C. Lancefield Professor at Rockefeller University, and a Howard Hughes
Medical Institute Investigator who is not involved in the work, hailed it as
"one of the most important advances to date in the stem cell field, and I
join the many people throughout the world in applauding my colleague for this
remarkable achievement.
"For decades,
researchers have tried to generate human pancreatic beta cells that could be
cultured and passaged long term under conditions where they produce insulin.
Melton and his colleagues have now overcome this hurdle and opened the door for
drug discovery and transplantation therapy in diabetes," Fuchs said.
And Jose Oberholtzer,
M.D., Associate Professor of Surgery, Endocrinology and Diabetes, and
Bioengineering at the University of Illinois at Chicago, and its Director of
the Islet and Pancreas Transplant Program and the Chief of the Division of
Transplantation, said work described in today's Cell "will
leave a dent in the history of diabetes. Doug Melton has put in a life-time of
hard work in finding a way of generating human islet cells in vitro. He made
it. This is a phenomenal accomplishment."
Melton, co-scientific
director of the Harvard Stem Cell Institute, and the University's Department of
Stem Cell and Regenerative Biology -- both of which were created more than a
decade after he began his quest -- said that when he told his son and daughter
they were surprisingly calm. "I think like all kids, they always assumed that
if I said I'd do this, I'd do it," he said with a self-deprecating grin.
Type 1 diabetes is an
autoimmune metabolic condition in which the body kills off all the pancreatic
beta cells that produce the insulin needed for glucose regulation in the body.
Thus the final pre-clinical step in the development of a treatment involves protecting
from immune system attack the approximately 150 million cells that would have
to be transplanted into each patient being treated. Melton is collaborating on
the development of an implantation device to protect the cells with Daniel G.
Anderson, the Samuel A. Goldblith Professor of Applied Biology, Associate
Professor in the Department of Chemical Engineering, the Institute of Medical
Engineering and Science, and the Koch Institute at MIT.
Melton said that the
device Anderson and his colleagues at MIT are currently testing has thus far
protected beta cells implanted in mice from immune attack for many months.
"They are still producing insulin," Melton said.
Cell transplantation
as a treatment for diabetes is still essentially experimental, uses cells from
cadavers, requires the use of powerful immunosuppressive drugs, and has been
available to only a very small number of patients.
MIT's Anderson said
the new work by Melton's lab is "an incredibly important advance for
diabetes. There is no question that ability to generate glucose-responsive,
human beta cells through controlled differentiation of stem cells will
accelerate the development of new therapeutics. In particular, this advance
opens to doors to an essentially limitless supply of tissue for diabetic
patients awaiting cell therapy."
Richard A. Insel,
M.D., chief scientific officer of the Juvenile Diabetes Research Foundation, a
funder of Melton's work, said the "JDRF is thrilled with this advancement
toward large scale production of mature, functional human beta cells by Dr.
Melton and his team. This significant accomplishment has the potential to serve
as a cell source for islet replacement in people with type 1 diabetes and may
provide a resource for discovery of beta cell therapies that promote survival
or regeneration of beta cells and development of screening biomarkers to
monitor beta cell health and survival to guide therapeutic strategies for all
stages of the disease."
Melton expressed
gratitude to both the Juvenile Diabetes Research Foundation and the Helmsley
Trust, saying "their support has been, and continues to be
essential."
While diabetics can
keep their glucose metabolism under general control by injecting insulin
multiple times a day, that does not provide the kind of exquisite fine tuning
necessary to properly control metabolism, and that lack of control leads to
devastating complications from blindness to loss of limbs.
About 10 percent of
the more than 26 million Americans living with type 2 diabetes are also
dependent upon insulin injections, and would presumably be candidates for beta
cell transplants, Melton said.
"There have been
previous reports of other labs deriving beta cell types from stem cells, no
other group has produced mature beta cells as suitable for use in patients,"
he said. "The biggest hurdle has been to get to glucose sensing, insulin
secreting beta cells, and that's what our group has done."
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