stemcell lines - amazon s3s3.amazonaws.com/hsci_public_files/hsci_spring_summer_09.pdf · summer...
TRANSCRIPT
T his spring, the Howard Hughes Medical Institute announced the winners of the HHMI Early Career
Science Competition. Among the 50 young scientists nationwide who will have their work support-
ed for the next six years were four HSCI faculty members: Amy Wagers, PhD, Konrad Hochedlinger,
PhD, Kevin Eggan, PhD, and Bradley Bernstein, MD, PhD. A fifth Harvard researcher, Rachel Wilson, PhD,
assistant professor of neurobiology at the Harvard Medical School, was also selected for the award.
Each of the new HHMI Early Career Scientists will receive a six-year appointment to the institute,
including full salary, benefits, and research budget of $1.5 million over the six-year appointment. The insti-
tute will also cover other expenses, including a research space and the purchase of critical equipment.
These young researchers were selected for this exciting opportunity because of their demonstrated abili-
ty to approach science with creativity and innovation. In the case of the HSCI faculty, their “high risk/high
reward” work was funded in part by HSCI seed grants, of which all four were recipients.
“I am thankful for the support and mentorship I’ve received from all my colleagues at the Harvard Stem
Cell Institute; the open and interactive environment fostered by the HSCI was a tremendous help to me in
getting my lab started, and continues to enhance my research on a daily basis,” said Wagers.
An HHMI statement described the researchers as “energetic and passionate about a broad range of
scientific questions… at a career stage that many consider to be a scientist’s most productive—and
most vulnerable.”
Harvard Provost Steven E. Hyman hailed the selection of the Harvard researchers as “a great day for
these five young investigators, and a great day for Harvard. Receiving the support accorded an HHMI
Early Career Scientist relieves Kevin, Konrad, Amy, Rachel, and Brad of many of the distracting stresses
with which most young scientists struggle, and allows them each to fulfill their unique intellectual
promise,” he said.
“Similarly, having the Howard Hughes Medical Institute select five young Harvard researchers for this
honor accorded to only 50 people nationwide speaks volumes about the strength of our science, and the
Stem CellLinesFor friends and supporters of the Harvard Stem Cell Institute
Summer 2009
I N S I D E
Summer/2009 1
B l o o d S t e m C e l l
D e v e l o p m e n t
P A G E 3
S t e m C e l l s
G o i n g h o m e
P A G E 6
i P S C o r e F a c i l i t y
P A G E 7
c o n t i n u e d o n p a g e 2
Four HSCI Faculty members awarded HHMI Early Career Science awards
B.D.
Cole
n / 3
Mar
ia N
emch
uck
From left to right: Bradley Bernstein, MD, PhD, Konrad Hochedlinger, PhD, Kevin Eggan, PhD, and Amy Wagers, PhD
2 Summer/2009
Volume 4Number 1
Stem CellLinesHarvard Stem Cell InstituteExecutive Director
Brock C. Reeve, MPhil, MBA Scientific Directors
Douglas A. Melton, PhDDavid T. Scadden, MD
The Harvard Stem Cell Institute (HSCI) is a scientific collaborative established in 2004 to fulfillthe promise of stem cell biology as the basis forthe cure and treatment of a wide range of chronicdiseases and medical conditions. HSCI’s uniqueeffort unites experts across the disciplines, schools,and departments of Harvard University and all itsaffiliated research hospitals.
HSCI also sponsors public education programsconcerning scientific, legal, and ethical implicationsof stem cell research, conducts a summer researchprogram for college students, and helps educatearea high school teachers about stem cell science.HSCI depends on the vision and generosity of private individuals, and foundation and corporatedonors, to carry on its work, due to current U.S.restrictions on federal funding of embryonic stemcell research.
Stem Cell Lines is published three times each year for friends and supporters of HSCI.Inquiries from the public are encouraged; [email protected].
Stem Cell Lines and extensive information concern-ing HSCI scientific research and programs can befound at www.hsci.harvard.edu.
To be added to or removed from the mail list, contact:
Harvard Stem Cell Institute42 Church StreetCambridge, MA 02138Tel: 617.496.4050
Managing EditorBrock C. Reeve
EditorMaureen Lyons
© 2009 President and Fellows of Harvard College
Summer 2009
Stem CellLines
WritingB. D. ColenNancy FlieslerMaureen HerrmannMaureen LyonsQuig LiuClaudia RizziniMichael Silver
DesignAndrade Design
Early Career Science Awards
c o n t i n u e d f r o m c o v e r
Honors andAwards
■ Amy Wagers, PhD, KonradHochedlinger, PhD, Kevin Eggan,PhD, and Bradley Bernstein, MD,PhD were winners of the HowardHughes Medical Institute EarlyCareer Science Competition. To readmore, see page one.
■ Doug Melton, PhD, was selectedas one of TIME magazine’s 100most influential people for 2009.This is the second time he hasreceived this honor; the first timewas in 2007.
■ David Scadden, MD, received anhonorary doctorate from the Facultyof Medicine at Lund University inSweden.
■ Konrad Hochedlinger, PhD, andJeffrey Karp, PhD, both appeared onTechnology Review’s TR35,which recognizes 35 outstandinginnovators under the age of 35 eachyear.
■ Popular Mechanics also listedKarp’s “Biodegradable andBiocompatible Gecko-Inspired TissueAdhesive” at number 17 in its “Top20 New Biotech Breakthroughs thatWill Change Medicine.”
■ Leonard Zon, MD, received the2009 Muhlenberg College AlumniLifetime Achievement Award, fromhis undergraduate alma mater,where he studied chemistry andnatural sciences.
■ Sean Wu, MD, PhD, received theNIH Director’s New InnovatorAward, which is designed to supportunusually creative new investigatorswith highly innovative researchideas at an early stage of theircareer.
■ Paul Huang, MD, PhD, was elect-ed to become a Fellow of theAmerican College of Cardiology, theforemost professional society repre-senting heart specialists in the U.S.and throughout the world.
■ Amy Wagers, PhD, won the Smith Family Prize, an award givenin recognition of her scientificachievements since receiving theSmith Family New InvestigatorAward in 2004.
kinds of young scientists we have been attracting and nourishing,”
Hyman added.
The HHMI statement said, “in today’s constrained research funding
environment, many early career faculty find it difficult to establish and
develop their research programs. They often launch their own labs with
start-up funds from their host institution. That support is provided with
the expectation that the scientist will establish his or her own research
program with independent funding.
“The creativity and energy that researchers bring to starting their
own labs can quickly be sapped by the time-consuming and often frus-
trating quest for funding,” the statement continues. “Within a few years
of a new faculty appointment, a researcher’s institutional start-up funds
typically come to an end. Pressure to secure federal grant money may
lead to ‘safe’ grant proposals. As a result, creative and potentially trans-
formative research projects may fall by the wayside.”
The HHMI appointments come at a particularly crucial time in the
ongoing struggle for research funding. While the NIH has received an
infusion of Economic Recovery Act funding, the agency’s support for
biomedical research has been flat for more than five years, and in real
dollars has decreased by more than 13 percent.
Because of that situation, competition for funding has become ever
stiffer, and the funding that has been available has tended to go toward
more established researchers with “safer” proposals. In fact, the average
age at which researchers now receive their first R01 grant, the major
grant that is seen as establishing their independent careers, is 43.
Hochedlinger noted that “support from the HHMI will allow me to
go into directions which I would have otherwise not been able to do in
the current funding situation. For example, I will be able to invest in
new tools and technologies to study pluripotency and reprogramming
and hire people to bring new expertise into my lab,” he said. “I am very
excited to be part of this prestigious institute [HHMI] and look forward
to working together with my new colleagues.”
“We saw a tremendous opportunity for HHMI to impact the
research community by freeing promising scientists to pursue their
best ideas during this early stage of their careers,” said HHMI President
Thomas R. Cech. “At the same time, we hope that our investment in
these 50 faculty will free the resources of other agencies to support
the work of other outstanding early career scientists,” Cech said in
explaining HHMI’s investment of about $200 million in the 50
young researchers.
Commenting on the researchers selected for the award, Jack Dixon,
HHMI’s vice president and chief scientific officer, said, “These scientists
are at the early stage of their careers, when they are full of energy and
not afraid to try something new. They have already demonstrated that
they are not apt to play it safe—and we hope they will continue to do
something really original.”
Bernstein said the HHMI appointment would provide “our laborato-
ry a wonderful opportunity to pursue hypotheses and potentially risky
new research directions aimed at understanding how genome function
is regulated in mammalian development and disease.”
“I am thrilled and honored by this opportunity to join such a distin-
guished group of scientists,” said Wagers. “The support of the HHMI
will ensure that I can continue to pursue new and creative directions in
my research, which I hope will bring new perspectives in stem cell biol-
ogy and tissue regeneration.”
Summer/2009 3
For friends and supporters of the Harvard Stem Cell Institute
A heartbeat and blood flow are necessary for blood stem cell development
Biologists have long wondered why the embry-
onic heart begins beating so early, before the
tissues actually need to be infused with blood.
Two groups of HSCI researchers from Children’s
Hospital Boston and Brigham and Women’s Hospital
—presenting multiple lines of evidence from zebrafish,
mice, and mouse embryonic stem cells—provide an
intriguing answer: a beating heart and blood flow are
necessary for development of the blood system, which
relies on mechanical stresses to cue
its formation.
These studies, published in the journals Cell and
Nature, together offer clues that may help in treating
blood diseases such as leukemia, immune deficiency,
and sickle cell anemia, and suggest new ways that sci-
entists can make the types of blood cells a patient
needs. This would help patients who require bone
marrow or cord blood transplants but do not have a
perfect donor match.
One team, led by Leonard Zon, MD, Chair of
HSCI’s Executive Committee, and Principal Faculty
members Trista North, PhD, and Wolfram Goessling,
MD, PhD, used zebrafish, whose transparent embryos
allow direct observation of embryonic development.
Zon and colleagues discovered that compounds that
modulate blood flow had a potent impact on the
expression of a master regulator of blood formation,
known as Runx1, which is also a known marker for
the stem cells that give rise to all the cell types in the
blood system.
Confirming this observation, a strain of mutant
embryos that lacked a heartbeat and blood circula-
tion exhibited severely reduced numbers of blood
stem cells. Further work showed that nitric oxide,
of which production is increased in the presence of
blood flow, is the key biochemical regulator.
Increasing nitric oxide production restored blood
stem cell production in the mutant fish embryos,
while inhibiting nitric oxide production reduced
the number of stem cells.
Zon and colleagues went on to demonstrate that
nitric oxide production was coupled to the initiation
of blood stem cell formation across vertebrate species,
in mice as well as fish. “Nitric oxide appears to be a
critical signal to start the process of blood stem cell
production,” Zon said. “This finding connects the
change in blood flow with the production of new
blood cells.”
HSCI Executive
Committee member George
Daley, MD, PhD, led the sec-
ond team. Intrigued by the
appearance of blood progeni-
tor cells in the wall of the
developing aorta soon after
the heart starts beating, they investigated the effects of
mechanical stimulation on blood formation in cultured
mouse embryonic stem cells.
They showed that shear stress—the frictional force
of fluid flow on the surface of cells lining the embry-
onic aorta—increases the expression of master regula-
tors of blood formation, including Runx1, and of
genetic markers found in blood stem cells. Shear stress
also increased formation of progenitor cell colonies
that give rise to specific lineages of blood cells (red
cells, lymphocytes, etc.). These findings demonstrate
that biomechanical forces promote blood formation.
To further test these findings, Daley and colleagues
studied mouse embryos with a mutation that prevent-
ed initiation of a heartbeat. These embryos had a
sharp reduction in progenitor blood cell colonies,
along with reduced expression of genetic markers of
blood stem cells. When specific cells from the mutant
embryos were exposed in vitro to shear stress, markers
of blood stem cells and numbers of blood cell colonies
were restored. Finally, the team showed that when
nitric oxide production was inhibited, in both cell
cultures and live mouse embryos, the effects of
shear stress on blood progenitor colony formation
were reduced.
“In learning how the heartbeat stimulates blood
formation in embryos, we’ve taken a leap forward in
understanding how to direct blood formation from
embryonic stem cells in the Petri dish,” Daley said.
The authors of the two papers speculate that drugs
that mimic the effects of embryonic blood flow on
blood precursor cells or molecules involved in nitric
oxide signaling might be therapeutically beneficial for
patients with blood diseases. For example, nitric
oxide could be used to grow and expand blood stem
cells either in the culture dish or in patients after
transplantation.
In this fluorescent image of azebrafish embryo, endothelialcells (blood vessels) arelabeled green and erythrocytes(red blood cells) are labeledred and imaged by confocalmicroscopy. In the picture, thered “lines” are red blood cellsflowing through the large ves-sels (like the aorta where thestem cells are formed) andheart in a live embryo.
Image courtesy of Wolfram Goessling, MD, PhD, and Trista North, PhD
4 Summer/2009
Stem CellLines
It is the generosity of our donors that enables HSCI’sresearch to go forward. Below are three stories that areas equally inspiring as they are important to HSCI’ssuccess.
Making music that funds muscular dystrophy research Neil Brewer is a poet, musician, educator, and experi-enced ping-pong table rafter. He is also an HSCI donor.
After teaching fifth and sixth graders for the firsttwenty years of his education career, Neil wrote TheEight O’Clock Bell, a collection of stories and songs about “all thingsschool.” Over the past six years, he has performed works from his bookat over 200 schools, on stage, and at special events for educators, stu-dents, and the general public. Now teaching upcoming educators atIndiana University Southeast, Neil continues to write poetry and musicassociated with school experiences so many of us have in common.
But Neil’s performances do more than encourage audiences to reflecton bullying, school dances, and homework, because 100% of theshows’ proceeds are donated to HSCI to help find a cure for musculardystrophy. He will be soon releasing a CD of the music from The EightO’Clock Bell and proceeds from this album will also be donated to HSCI.
When asked why he continues to make these generous gifts, Neilexplains, “Oh, I’d say we humans can be pretty much like animals onoccasion. A lion probably won’t bite you, unless it—or something itloves—is a bit threatened, and since I am very much aware of the feel-ing, I’m ready to lay teeth into muscular dystrophy for as long as I possibly can.”
Giving to HSCI is his way of fighting back against muscular dystro-phy, and being a man who once wrestled a black bear, Neil is quite afighter. To find out more about his upcoming album and shows, and tolearn about how to schedule a performance, visit www.neilbrewer.com.
Coordinating events that help fund diabetes researchEver since her son Ryan was first diagnosed with diabetes 12 years ago,Jane Harvey has actively participated in fundraising efforts to help find acure for the disease. And over the years the Harvey family has walked
and ridden their bikes countless miles to help raise money for research.
But after Ryan left for college, the Harveys became lessinvolved in the fundraisers. That is, until this past November,when Jane was in the library while visiting her son at collegeand read the TIME magazine article about HSCI’s co-Director,Douglas Melton, PhD. It was then that she decided it was timeto get involved again.
Using the skills from her career as an events coordinator, Jane is organ-izing a fundraiser to take place on Cape Cod. The proceeds will be donatedto HSCI.
“I knew that I could help,” said Jane. “It’s easy to do something whenyou are working toward a cure. Better to be putting positive energy into the problem.”
In the wake of tragedy, a “Rally for Ali”After nearly 25 years of fighting, 48-year-old Alison Urzan died from com-plications of type one, insulin-dependent diabetes. And yet even after herdeath, there was a need for hope, and her family requested that contribu-tions in Alison’s memory be made to HSCI.
Three weeks after her death, family and many friends organized anevent in her honor called “Rally for Ali.” Ali and her husband enjoyed rid-ing motorcycles through the beautiful landscapes of upstate New York andthe day included a 50-mile motorcycle trek to some of her favorite places.At the end of the ride a benefit was held, which included food, live music, asilent auction, and a 50/50 raffle. While the majority of the proceeds raisedwent toward funeral and medical expenses, the balance was donated toHSCI.
When Ali’s mother, Alice, was asked why they chose HSCI, she said,“That’s where Ali would want the contributions to go. To go to researchtoward a cure.”
Continuing to make a difference in Ali’s honor, her friends and familyare currently organizing another rally for this fall.
Supporting HSCI
2009 HSCI Seed Grant Recipients Announced
For the fifth consecutive year, HSCI awarded seed grants to scientists throughout the Harvard
community to provide critical early funding for stem cell research. In May, eight seed grants total-
ing nearly $1.5 million were awarded to investigators selected from a large pool of applicants
across the HSCI-affiliated institutions.
HSCI’s Seed Grant Program provides two years of funding for projects in areas of stem cell
research that will advance HSCI’s mission. A multi-institutional panel conducts a rigorous review
process with the difficult task of selecting a set of the most promising projects from many
superbly qualified applications. Highest priority is given to projects that are difficult to fund from
other sources because they are early stage, high risk, or lack sufficient preliminary data.
Continuing federal funding restrictions for the creation of new human embryonic stem cell lines
also make projects with such a component of interest to HSCI. The grants are also intended to
support primarily junior faculty in the early stages of their independent careers, but also some-
times more senior faculty entering the field of stem cell research from another concentration.
This year’s grants will support stem cell research in a variety of targeted disease areas, such as
cancer, liver disease, nervous system disorders, and obesity, as well as research in broadly applica-
ble areas of stem cell biology, such as DNA repair, embryonic stem cell differentiation, and bone
formation. As HSCI continues its work to support and grow the clinician scientist community
in stem cell research, we are pleased to announce that three of this year’s recipients are MD/PhD
scientists.
2009 HSCI Seed Grant RecipientsWolfram Goessling, MD, PhD*, Brigham andWomen’s Hospital
Mark Damone Johnson, MD, PhD, Brigham andWomen’s Hospital
David Langenau, PhD, Massachusetts GeneralHospital
Trista E. North, PhD*, Beth Israel Deaconess MedicalCenter
Sharad Ramanathan, PhD, Harvard Faculty of Arts & Sciences
Derrick Rossi, PhD, Immune Disease Institute
Yu Hua Tseng, PhD, Joslin Diabetes Center
David Weinstock, MD, Dana-Farber Cancer Institute
Paul Yu, MD, PhD, Massachusetts General Hospital
*Collaborators on a joint seed grant
Proceeds from Neil Brewer’s performances of The 8O’Clock Bell are donated to HSCI to help find a curefor muscular dystrophy.
Summer/2009 5
For friends and supporters of the Harvard Stem Cell Institute
For those of us who’ve been around for a while, we know that
our ability to heal or recover from our injuries or illnesses can
take longer than it used to when we were young. That’s one
real life example of what may be the result of changes that occur in
stem cells as we age. The latest Junior Faculty Program to be sup-
ported by HSCI takes a close look at this phenomenon and the
molecular pathways of aging in stem cells. Keeping with the tradi-
tion of earlier Junior Faculty Programs, the convening members are
approaching the study from multiple angles, including the effects of
aging on blood production (Derrick Rossi, PhD, and Benjamin
Ebert, MD), muscle (Andrew Brack, PhD), the cardiovascular system
(Caroline Burns, PhD), and the viability of pluripotent stem cells
(Alex Meissner, PhD).
The HSCI Junior Faculty Programs are unique in their support for
highly collaborative, “high risk/high return” projects. The research
proposed by the faculty members typically explores new approaches
in which their individual labs can accelerate their own work by col-
laborating with others to tackle a large question. By pooling their
efforts, junior faculty members can secure funding from HSCI to pur-
sue their ideas, which can then be further supported with outside
grants as the results roll in. The programs not only offer a chance to
make bold new discoveries, but they also serve as an important
bridge to stability at the early stage of a scientist’s career.
In 2006, a cadre of six HSCI junior faculty members considered
the merits of mining the fundamental biology that underlies the
behavior of stem cells. It was the beginning of a remarkably success-
ful and dynamic program that supported a collaborative group of
young investigators across five HSCI-affiliated institutions. Several
breakthroughs have emerged from the Cell Development Program,
including the discovery by Konrad Hochedlinger, PhD, of the
sequence of molecular events that occurs during the conversion of
adult stem cells into embryonic-like stem cells, the demonstration
by Amy Wagers, PhD, of muscle regeneration using stem cells in a
model of muscular dystrophy, and a landmark study by Kevin
Eggan, PhD, showing that human pluripotent stem cells can be
derived from the cells of patients suffering from a genetically-based
disease, in this case amyotrphic lateral sclerosis (ALS, or Lou
Gehrig’s disease).
Inspired by the success of this first Junior Faculty Program, a
second crop of young investigators gathered around an effort called
the Stem Cell Regulation Program, which looks at the molecular
pathways that regulate stem cell differentiation and maintenance in
both normal development and disease. HSCI investigators Paola
Arlotta, PhD, Chad Cowan, PhD, Richard Gregory, PhD, Hanno
Hock, PhD, and Carla Kim, PhD, recognized that one of the greatest
obstacles to generating tissue specific cells in the laboratory at will is
that the methods used to derive and maintain specialized cells from
embryonic or induced pluripotent stem cells are still very inefficient,
and knowledge of the molecular pathways that lead to differentiation
is poorly defined.
With a third program underway, the Junior Faculty programs
have become a major component of HSCI’s impact on the field of
stem cell biology and the Harvard scientific community, and an
indispensable resource for supporting early scientific careers.
Junior Faculty Programs examine fundamental stem cell biology
The new HSCI Junior Faculty Program, which will explore the epigenetic
regulation of stem cell function and aging, will take a close look at how
stem cells change during the aging process.
6 Summer/2009
Stem CellLines
In the field of ecology, the term “homing” refers to a species’ ability to
return to a given place, often over great distances. The primary navi-
gational clues used during homing seem to be the same as those used
in migration, but homing may occur in any compass direction and dur-
ing any season. How pigeons do this has fascinated people for centuries.
In stem cell science, the word “homing” describes stem cells’ ability
to find their destination, or “niche.” Identification of specific cues that
steer stem cells to their niche and increase the efficiency of the homing
process is an area of intense investigation. The effort has several parts:
making the destination more attractive; making the navigation cues more
obvious to the cells; and making the stem cells more responsive to the
cues.
Finding their niche Understanding how blood stem cells home has
many implications for bone marrow transplants, a life saving treatment
that was first performed more than 30 years ago. In this procedure,
donated marrow, which carries blood stem cells that will provide a new
blood-producing system, is transplanted into the patient. The more
blood stem cells that find their way to their niche in the patient’s bone
marrow, the more likely the transplant will be successful. Thus, by
increasing the efficiency of stem cell homing, it’s possible to increase the
efficiency of bone marrow transplants.
Recent studies by HSCI co-Director David Scadden, MD, and col-
leagues have identified a cellular mechanism that directs blood stem cells
to their destination. This finding holds the promise of greatly increasing
the efficiency of the bone marrow transplants and also has implications
for future therapies utilizing other types of stem cells.
“Figuring out the mechanism that tells stem cells how to get to where
they need to go is a major problem when we’re thinking about stem cell
therapies,” said Scadden.
In their study, the team treated blood stem cells with pharmacologi-
cal agents that were known to stimulate a pathway believed to be
involved in stem cell homing. When injected, the cells that were treated
with the drugs homed to the bone marrow much more efficiently than
untreated stem cells.
In another seminal study in understanding the mechanism of blood
stem cell homing to the bone marrow, Scadden’s group, in collaboration
with Charles Lin, PhD, a colleague at MGH’s Wellman Center for
Photomedicine, developed a technique that provides a real-time view of
a single stem cell making its way to its niche inside a bone marrow cavi-
ty of a living mouse.
“Now,” said Scadden, “we can actually watch the cells divide and can
see the process by which cells engraft and regenerate the bone
marrow.”
Arriving at the scene of the crime Mesenchymal stem cells
(MSCs) are another population of cells with therapeutic poten-
tial. MSCs are generally defined as multipotent cells that are
capable of self-renewal and can also give rise to a number of
unique, differentiated cell types that result in connective tissue,
bone, and cartilage. Scientists have shown that these cells exist
in many parts of the body and are capable of contributing to
the repair of a variety of damaged tissues and organs. Although local
transplantation or injection may prove therapeutically useful, the ability
to target these cells to specific tissues with high efficiency will be crucial
in developing new treatments.
Damaged or inflamed tissues call for repair by sending out signals,
some of which act as cues for MSCs and attract them to the injured tis-
sue, and many of these signals have been identified, including stromal
derived factor 1 (SDF-1). Though SDF-1 can be effective in attracting
MSCs, under normal conditions it is kept in an inactive state by enzymes
in the body.
In order to increase the number of stem cells that home to a damaged
tissue, HSCI faculty member Richard Lee, MD, created a version of SDF-
1 that could not be inactivated. He found that by directly injecting this
version of the SDF-1 into the injured heart of a rat, more stem cells were
recruited to the damaged heart and were observed to improve heart
function.
“This is a very promising field for stem cell therapy and there is a lot
to do, but also a lot of unknowns,” said Lee.
A recent study in Germany has produced a similar finding, in which
drugs were used to keep SDF-1 active in combination with factors that
help mobilize stem cells, resulting in improved heart function in labora-
tory mice.
Signal sensitivity In addition to making the desired destination more
attractive, scientists are also working on ways to make the stem cell sur-
face more responsive to homing factors by using genetic engineering or
chemical modification.
Robert Sackstein, MD, PhD, an associate professor of medicine at
Harvard Medical School, has shown that attaching a sugar molecule,
which acts as a binding site for bone marrow homing cues, to MSCs
helps the cells home to the bone marrow more efficiently. Similar studies
led by HSCI faculty member Jeffrey Karp, PhD, have shown other chemi-
cal modifications of MSCs help them find their way to the bone marrow
more easily.
For stem cell therapy and tissue regeneration to be suc-
cessful, it is important to increase the efficiency of stem cell
homing, and that is not a simple task. For stem cells to navi-
gate back to their niche or be recruited by injured tissues, a
sequence of coordinated interactions between the cells and
their environment provide the signals and sign posts that
guide the cells along their journey. Meeting the challenge of
unraveling these complex mechanisms will be rewarded with
therapeutic potential across the field of stem cell biology.
Stem Cells Going Home
An image of a singlebrightly labeled stem cell(white) captured withinthe bone marrow cavity ofa recipient mouse onehour after transplant.
In stem cell
science,
the word
“homing”
describes
stem cells’
ability to find
their destina-
tion or
“niche.”
Image courtesy David Scadden, MD,Cristina Lo Celso, PhD, and Charles Lin, PhD
Summer/2009 7
For friends and supporters of the Harvard Stem Cell Institute
The pace of discovery in stem cell
research went into overdrive recently as
scientists unveiled new methods for
returning mature adult cells (such as skin cells)
to an immature, embryonic-like state. The
implications for both scientists and patients are
vast, suggesting that these “induced pluripotent
stem cells” (iPS cells) can one day be used to
generate and replace any cell in the human
body, or to create laboratory cell lines that
model a specific disease from a specific patient,
without resorting to the use of embryos.
HSCI investigators, recognizing the broad
applications for the technology and the need
for further improvement, established an iPS
Core facility. Located at Massachusetts General
Hospital, the shared facility serves as a central
lab to derive and store the iPS cells produced
by HSCI scientists and makes them available to
the scientific community.
Just one month after establishing the facili-
ty, HSCI researchers were creating new disease-
specific iPS stem cell lines at a prodigious rate.
Harvard scientists George Daley, MD, PhD,
Chad Cowan, PhD, and Konrad Hochedlinger,
PhD, announced they had produced over 20
cell lines made from skin cells of patients with
Parkinson’s Disease, Type I diabetes,
Huntington’s Disease, Down Syndrome, a form
of combined immunodeficiency (“Bubble Boy’s
Disease”), Lesch-Nyhan syndrome, Gaucher’s
Disease, and two forms of Muscular Dystrophy.
These cell lines were added to those produced
by HSCI investigator Kevin Eggan, PhD, which
were derived from patients suffering from amy-
otropic lateral sclerosis (Lou Gehrig’s disease).
Moving forward, priority will be given to
the development of cellular models for nervous
system diseases, blood diseases, kidney disease,
cardiovascular disease, and diabetes.
These “diseases in a dish” will permit scien-
tists to watch their development in the labora-
tory, separate from the patient. In addition to
helping us understand the mechanism of a dis-
ease, these cells will help us find new drugs.
By screening chemical compounds on the cells,
it may be possible to find drugs that affect that
cell type and can slow or stop the progression
of a disease. Screening on disease specific
human cells will enable us also to learn much
more about a drug, its effect, and its safety
before it is given to a single patient. Daley,
chairman of the faculty steering committee that
oversees the iPS Core, holds out much hope
for its potential to contribute greatly to
our knowledge.
“Our work is just the beginning for study-
ing thousands of diseases in a Petri dish,”
said Daley.
Having a centralized resource allows HSCI’s
individual laboratories to focus on the biology
of human disease, without having to develop
the specialized skills or maintain their own
resources for the creation, storage and dissemi-
nation of iPS-derived cell lines. The iPS Core is
also better equipped to adapt rapidly to the
changes caused by a technology that is new and
evolving (for example, including the discovery
of “safer,” i.e., non-carcinogenic, factors for
converting cells to an embryonic state).
The core also provides a critical link
between the research laboratory and the clinic
by drawing on the patients seen in the Harvard
hospital network. Patients with ALS,
Parkinson’s disease, cardiovascular disease, dia-
betes, obesity/metabolic syndrome, and many
other diseases who are undergoing treatment at
HSCI-affiliated institutions are recruited for
enrollment. At the time of enrollment, histori-
cal and demographic data are obtained, along
with the patient’s medical history and laborato-
ry results, and stored in a secure database.
Coding of the donated skin samples completes
the connection between scientific discovery of
disease mechanisms and patient history, open-
ing the door to new insights.
One day, iPS cell lines will become much
more than just a tool for studying disease in a
laboratory. By regenerating healthy cells from
patients, it may be possible to use them to
replace damaged or malfunctioning tissue
responsible for many incurable, chronic dis-
eases. The current iPS technology, which relies
on retroviruses with the potential to trigger
tumor growth, falls short of that promise. One
of the key objectives of the iPS Core Facility is
to improve the technology and identify factors
that induce pluripotency, but do not put the
patient at risk. Recent studies by Hochedlinger
and HSCI co-Director Doug Melton, PhD,
using alternative viral or chemical factors sug-
gest that objective might be within reach in the
near future.
iPS Technology: The Cutting Edge Resides at the Core
Laurence Daheron, PhD, is head of the HSCIiPS Core Facility, which will derive new iPSlines and make these and other lines pro-duced by HSCI scientists available to thebroader scientific community.
Mau
reen
Lyo
ns
42 Church Street
Cambridge, MA 02138
Stem CellLines
HSCIdisease programs are working
on some of the most difficult
problems in modern medicine. Cancer, dia-
betes, and diseases of the blood, cardiovascular,
kidney, and nervous systems continue to debili-
tate and kill, despite decades of research and
billions of dollars. Innumerable research
avenues are possible for investigating these
complex conditions, and, much like navigating
a labyrinth, some paths will lead to answers
faster than others. Knowing that not all experi-
ments are created equal, HSCI disease pro-
grams aim to chart the most direct route for
unlocking the mechanisms of the diseases in
order to bring new therapies to patients.
This year, building upon the approach
piloted by the Nervous System program, each
HSCI disease program organized a think tank
session as a vehicle for charting its research
strategy. The events, which are organized by
HSCI program leaders, provide a forum for the
many scientists in that program to share their
results, challenge each other’s ideas, debate the
key questions in the field, and make decisions
about the program’s focus. It’s also important
for the disease programs to engage the global
scientific community. Leading stem cell scien-
tists from around the world are often invited to
these events, allowing members of the program
to gain a more complete perspective of the state
of the field and foster collaborations across
state, national, and international lines that can
accelerate the research.
Part of charting the best course for a pro-
gram is securing the necessary funding for its
research projects. For example, at the recent
Cancer Program Think Tank, the team dis-
cussed an NIH proposal that, among other
lines of investigation, will allow further analysis
of gene expression data generated by Principal
Faculty members, and bring the program one
step closer to identifying the unique character-
istics of tumor initiating cells.
At a similar event, a group of Harvard jun-
ior faculty members working in cardiovascular
research held a day-long meeting to share their
areas of focus and discuss the challenges they
face in their current research efforts. During the
meeting, which brought together 13 cardiovas-
cular investigators from five different hospitals
and research institutions, the group identified
three new prospective collaborative projects
and will reconvene to finalize their proposals
in the upcoming weeks.
Based on the success of these sessions,
HSCI and Harvard’s new Wyss Institute for
Biologically Inspired Engineering will co-host a
one-day think tank this June to explore the
intersection of stem cell biology and bioengi-
neering. Leading experts from both institutes
will gather to learn about each other’s work,
discuss novel technology platforms, identify
resources and research challenges, and formu-
late potential avenues for collaborative efforts
that can bring about transformative solutions to
challenging medical problems that can best
leverage each group’s strengths.
An experiment is only as good as the ques-
tion it aims to answer, and in a field that can
seem to pose infinite research avenues, these
structured think tanks help HSCI programs
hone in on the critical questions. The ability to
leverage the expertise of its faculty to collective-
ly focus on the most important questions
enables HSCI to pursue its mission with the
direction and velocity needed to produce the
therapies of tomorrow.
Think Tanks—focusing on the right questions