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; e-mailbrock_reeve@harvard.edu.

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.

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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