Fall 2007
Volume 3 No. 2
On Board
Stem Cell Politics: 101
Stem Cell Research: What’s at Stake
Two years ago U-M announced the opening of the U-M Center for Stem Cell Biology at LSI. Center
Director Sean Morrison discusses progress with his research, the Center, and the current state
of stem cell research.
Let’s start at the beginning — why is stem cell research important?
Stem cell research is an interesting and important place to
be scientifically because there are many fundamental
scientific questions to be addressed. And there
are many questions that impact on the future of
medicine.
What are the questions your research seeks
to answer?
Michael B. Staebler, member
LSI Leadership Council; Partner,
Pepper Hamilton LLP and
U-M Law ‘69
continued on page 6
My lab tries to identify the genes that are required
in this process, because if we can identify the
genes and what they do to promote self renewing
divisions, we can understand more mechanistically
what exactly is happening. That is important because if we
could better promote self renewal, we may be able to promote
regeneration after injury, for example. We may be able to address certain kinds of birth defects that
are caused by premature depletion of stem cells. Cancer is a disease of dys-regulated self renewal.
When cancer is caused by genetic defects, stem cells inappropriately activate or hijack the normal
self-renewal mechanisms to form a tumor. Each time we identify a new
continued on page 2
Photography: Omer Yilmaz
Life sciences research
capability has become one
of the key measures of the
excellence of the world’s
great universities. To
underscore its importance
and to create new synergistic ways for life sciences
research to be conducted,
the U-M created the Life
Sciences Institute and
My lab focuses on the regulation of self
renewal. One of the defining characteristics
of stem cells is their ability to divide to make
more stem cells, and this property is what
underlies their ability to make massive
numbers of cells of interest. How a stem
cell divides throughout life to make more
stem cells is a fundamental question in cell
biology. You have blood forming stem cells in
your bone marrow that make new blood cells
throughout life, in part by dividing to make
more stem cells and perpetuating themselves.
Benchmarking
continued from page 1
The Power of Stem Cell Biology at LSI
Photography: Peter Smith
Understanding how, when and why stem
cells choose their fate involves the most
fundamental questions in genetics, cell
biology, physiology, developmental biology,
engineering and many other disciplines.
It seems that almost every day there
is something in the popular media or
scientific press about stem cells. The
political, ethical, competitive, commercial
and scientific issues are constantly in the
news, stirring up controversy, disagreements and uncertainty. With all this
attention, you might conclude that our
decision in 2005 to become the home of
the U-M Center for Stem Cell Biology was
a strategic choice to stay on top of trendy
science. Nothing could be farther from
the truth.
The LSI is about harnessing the power
of cross-disciplinary interactions. Getting
to the source of that power requires more
than casual or informative interactions
among scientists from different disciplines. It requires deep engagement in
the big questions.
2
Early in LSI’s history, we created the
Centers for Chemical Genomics and
Structural Biology to catalyze collaborations across the boundaries of chemistry,
biology, physics and computation. Many
scientists across the campus are now
engaged under the auspices of these
centers, exploring the structure and
function of biological systems in ways
they could never have done on their own.
The Center for Stem Cell Biology offers
more opportunities for cross-disciplinary
engagements.
Of the four faculty members who have
already joined the center, each has a
unique approach and perspective, and
uses a different system to get at these
issues. Yukiko Yamashita and Cheng-Yu
Lee are exploiting the power of fly genetics to learn about how stem cells decide
whether to replicate or turn into neurons or
other specialized cells. Sean Morrison and
Ivan Malliard use mice as a model system
to study how blood forming stem cells
respond to signals that instruct them to
begin the complex process of blood formation. We expect that the Center for Stem
Cell Biology will bring these scientists
together with other investigators to spark
new ideas, open our investigators to different approaches and use new tools to make
important new discoveries, even in fields
only remotely connected to stem cells.
Of course, we are also keenly motivated
by the promise that stem cells hold for understanding and treating disease. As noted
elsewhere in this issue, stem cell research
is vital for our progress in helping those
with diabetes, cancer and neurodegenerative disease. And, it is important to work
in all areas of stem cell biology to achieve
that progress. Until federal and state policy
is enlightened, we and our donors will
continue to support work with both adult
and embryonic stem cells.
In the storm that lately characterizes the
field of stem cell research, we are proud
to provide a necessary, nurturing, safe
haven for this work at U-M. But, it is the
promise of stem cell biology for sparking
discovery at disciplinary crossroads that
makes it the right choice for LSI and has
me pumped for the future.
— Alan Saltiel, LSI Director
Sean Morrison
gene we understand something new
about normal development — as well as
how those mechanisms can go wrong to
cause cancer or other diseases.
These are hard questions and most of
the things researchers try don’t work, but
when you give yourself an opportunity to
cure somebody, you don’t know up front
whether it will work or not. If it works
some of the time, then people will be alive
who might not be alive otherwise.
What are the links you’ve discovered
between stems cells and cancer?
We learned that cancer cells hijack the
mechanisms that normally regulate stem
cell self renewal to proliferate out of
control. If you try to target these mechanisms, to develop drugs that interfere
with these pathways in a cancer cell,
these drugs often kill normal stem cells
too. One of the tragedies about leukemia
is that people often die from the therapy
because it is toxic to normal blood-forming stem cells. In an ideal world you’d like
to target only those things that kill the
cancer cells without harming the normal
stem cells. And so we identified an
example of this, and also in fact identified
a drug that’s already FDA-approved for
other purposes that is incredibly effective,
at least in mice, at killing leukemic stem
cells. We plan to go into clinical trials at the
University of Michigan hospital with patients
we know we cannot cure with current
treatments and testing whether adding Rapamycin to their current therapy would cure
them. That will be really amazingly cool!
Will you clarify the differences between the
stem cells types?
Stem cells have different properties at
different stages of life. Embryonic stem
cells only exist at the earliest stages of
embryonic development, when embryos
are microscopically small and they have the
ability to make every cell type in the body.
Fetal stem cells are tissue specific stem
cells, which in fact are adult stem cells in
fetal tissue. They include fetal blood forming
stem cells, fetal skin stem cells, and so on.
Amniotic stem cells characterize a population of fetal cells that is not at all well
worked out, but those cells are different
from embryonic stem cells and at this stage
there is no evidence that they have the ability to make every cell type in the body.
Umbilical cord blood cells are blood-forming
stem cells and have been used to restore
the blood-forming system in children after
treatment for leukemia. They are useful but
they don’t have the capacity to make new
brain cells or cell types in other tissues.
So is one stem cell better for research than
another?
There are many different types of stem
cells out there and the whole conversation
about which stem cell is better, for example,
if we should work on adult or embryonic
cells, is a political artifact. There is no stem
cell biologist out there who thinks in those
terms. All of the stem cell biologists that I
know believe that work should continue on
all types of stem cells because we can’t
predict at this stage which ones are going
to be the most useful for which diseases.
We want to be able to pursue all the options
to use all the weapons at our disposal.
I’d like to emphasize that people shouldn’t
buy into this political framing of adult versus
embryonic. All the scientists and physicians
believe that we should be pursuing both
types of stem cell research because it’s not
a question of good and bad. All types of stem
cells have different properties, unique advantages and disadvantages, and there are
some things that we can do with adult stem
cells that we can’t do with embryonic and
vice versa. All scientists that I know want to
pursue research with both.
How did this research become framed as
controversial?
Journalists often come up to me and say
that embryonic stem cells is really a controversial area. In fact among people that
really understand the work, there is very
little controversy. Among the experts in the
area, including physicians, ethicists and
scientists, there is broad agreement that
first, the work should be done, and second,
they agree about the guidelines that should
be pursued to do the work ethically.
This is most clearly illustrated by the fact
that the head of the National Institutes of
Health broke from the President and testified before Congress that embryonic stem
cell research was critical to the future of
medicine in the United States. He said that
current federal restrictions put in place by
the Bush administration where slowing the
pace of that research and hampering the
ability of the NIH to fund the most important
science.
Then why is there opposition to this
research?
There are political groups who frame the
story in a different way. They try to create
fear in the minds of the general public about
science fiction scenarios like creating Frankensteins and other horrors and of course
none of that is true. In-vitro fertilization is
a mainstream fertility practice that most
people in our society have no moral problem
with. I think that stem cell research will be
much the same in 20 years after it becomes
possible to treat a disease with the products of embryonic stem cell research.
The public also hears about the adoption
option, is that viable?
There are more then enough embryos
thrown away each year to put all the
embryos up for adoption that anyone would
ever want and to make all the embryonic
stem cell lines that anyone would ever
want to make. The fact is that for every
embryo that is actually put up for adoption,
there are 100 more that are thrown away.
The reality is that almost nobody out there
wants to adopt other people’s embryos,
furthermore, most people who have leftover
embryos from in-vitro fertilization are not
comfortable with the idea of putting their
embryos up for adoption.
A recent study showed that people with
frozen embryos were more comfortable
with the idea of donating their embryos for
use in medical research then they were
with the idea of putting their embryos up for
adoption.
What is the biggest myth about stem cells?
The single biggest myth related to embryonic stem cells is the idea that opponents
of this work try to create, which is that
scientists want to divert embryos from
reproductive purposes for use in medical research. That’s not true. The existing
federal and state restrictions are defended
because “human embryos are special and
need protection under the law,” but in fact
those restrictions don’t protect a single
embryo from destruction. The embryos that
will be used for research and are currently
being used in other states, are already
being thrown away and can’t be used for
fertility purposes. The principle is not to
choose between having a baby or making
an embryonic stem cell line, the real choice
is between throwing away embryos that
can’t be used for fertility treatment versus
using them in medical research that might
one day help patients.
3
LSI
Insights
The Ethics in Favor of Stem Cell Research
My husband and I were always meant to be the
parents of our daughters, Rosemary and Rita
Mei. But in the course of becoming a family
through adoption, we — like 10% of couples in
the U.S. — underwent treatment for infertility.
For most couples
that undergo in
vitro fertilization (IVF), one
outcome is that
more embryos
are created
than are used
in the treatment. Yet, under
Michigan law,
those 8-celled
clusters cannot
be used in lifesaving medical
research. It is
lawful to freeze
them in perpetuity or to destroy them but not
to put them to good use in developing treatments for diseases like diabetes, cancer and
Alzheimer’s disease.
4
This waste is unethical and must be stopped.
Each day in the laboratories where I work,
scientists are making breathtaking advances
in our understanding of life and in how to treat
disease. Embryonic stem cells are a key tool
for understanding and treating the underlying
causes of disease. While it is true that adult
stem cells are also important, embryonic stem
cells are the only cells that can develop into any
other type of cell — and embryos are the only
source for new stem cell lines. Existing stem
cell lines are limited in number and genetic
diversity and cannot be used to study inherited human diseases. Why should we fight for
human health with one hand tied behind our
back when there are embryos available that will
otherwise be frozen forever or discarded?
We can set and enforce appropriate limits on
the use of leftover embryos in research. Scientists who are permitted to do this work have
already voluntarily adopted rigorous guidelines.
These include only using embryos slated for
disposal and making sure that couples give a
voluntary, informed consent to donating their
embryos for research. The rules prohibit the
creation of embryos solely for research purposes and paying for embryos used in research.
And, of course, the rules prohibit reproductive
cloning.
Some opponents of stem cell research argue
that frozen embryos should be preserved for
use by other couples desiring a family. If there is
a way to help others by the voluntary donation
of leftover embryos, I would be in favor of it.
But, there are so many embryos in storage —
400,000 in the U.S. alone according to a 2003
RAND report — that we do not have to choose
between these options. The best estimate of the
number of couples that would choose to implant
a leftover embryo is tiny in comparison to the
embryos available for research. In fact, in a
survey announced in July of this year, only 22%
of surveyed couples with frozen embryos would
be willing to donate those embryos to other
couples while 60% would be willing to provide
those embryos for stem cell research.
As native Michigander, I am concerned about
the economic outlook in our state and I wonder
if my daughters will be able to thrive here as
adults. Will our community continue to be the
special place I grew up in if we cannot build
a new base for our economy? When it comes
to stem cell research, our laws are the most
restrictive in the nation, tied for last place with
South Dakota. Scientists in Michigan would go
to jail for doing research that California, New
Jersey, Maryland, Illinois, and other states
are supporting with taxpayer dollars. If there
was ever a time to clear away the barriers to
economic and scientific progress, this is it. It is
time to change our laws and stop the senseless
waste of embryos that can be used today — in
our state — to make life better for many other
individuals and families.
— Liz Barry, Managing Director, Life Sciences Institute
A similar version of this essay appeared in the Detroit Free Press
in May 2007
Background image:
Metaphase spread superimposed
upon a section through the liver
of a Pten-deleted mouse with
leukemia. Hematopoietic stem
cells and leukemia initiating cells
differ in their dependence upon
Pten. This can be therapeutically
exploited to deplete leukemiainitiating cells without harming
normal stem cells. Yilmaz et al
Nature. 2006 May 25
under
the
scope
Curiouser and Curiouser
By Danielle LaVaque-Manty
Though she grew up catching bugs
and always knew she wanted to be a
biologist, there was a time when Yukiko
Yamashita considered leaving science.
The first woman Ph.D. student in the lab
where she earned her Ph.D., she found
herself unable to enjoy her doctoral adviser’s approach to doing science, which
involved long hours in a tense environment, seven days per week, doing endless numbers of experiments on yeast
genetics just to see which ones would
yield results. This model, Yamashita
says, “left little room for curiosity.”
Fortunately, her postdoctoral experience
in Margaret Fuller’s lab at Stanford was
very different. “She let me have time to
think.” Fuller talked through Yamashita’s
ideas with her—“sharing the fun”—but
allowed her to learn on her own, and
soon her motivation and love of science
returned.
This is the approach Yamashita plans
to take with students in her own lab. “I
don’t think you can really teach another
person science,” she says. “But you can
provide guidance and help them figure
out what it is that they want to do.” At
the moment, she employs a technician
and two undergraduates, and she looks
forward to having graduate students and
postdocs to discuss questions with as
well. “My biggest motivation is to understand how cells control their fates, and
to share the experience with others.”
differently, dividing asymmetrically to
produce differentiated cells. A stem cell
can either differentiate—producing a
skin cell, for example—or it can selfrenew. “It’s an either/or choice for each
cell.”
In Japan, Yamashita says, there are fewer
women scientists than in the U.S.—although their numbers are growing—and
it is not unusual for women, even in her
generation, to leave their jobs when they
get married, or to retain their positions
but become less visible over time as
they try to accommodate their careers to
the demands of their personal lives and
household work. Yamashita credits her
mother, a pharmacologist, with giving her
the idea that women could keep their jobs
for life and not become financially dependent on their husbands. She thinks she
gets her curiosity about how things work
from her father, “an amateur physicist”
and admirer of Albert Einstein. He worked
in Japan’s patent office for many years
and holds patents on several inventions of
his own, including a capless, retractable
highlighting pen.
Producing too many stem cells can lead
to the growth of tumors, while producing
too few can lead an organism to run out
of other necessities, like new skin cells.
Yamashita sees no immediate medical
applications to her research (“Because
I work on fruit flies!”) but notes that
understanding how cellular mechanisms
work may eventually aid other researchers in finding ways to intervene in
processes that lead to cancer.
Trained as a cell biologist, Yamashita
has a unique approach to studying
stem cells in multi-cellular organisms,
observing the behavior of individual
cells as they divide rather than studying
them en masse. Margaret Fuller had
been studying stem cells for years by
the time Yamashita arrived at Stanford,
but nobody in her lab had used a cell
biological approach. “I see stem cells
as being cells first, before they are stem
cells,” Yamashita says, pointing out that
they share ninety-nine percent of their
characteristics with other cells. She
wants to figure out what accounts for
the one percent difference.
Using drosophila, in which stem cells
are easy to isolate, she discovered that
although stem cells have the same
components as other cells, they behave
Yamashita’s husband, Kentaro Nabeshima, is a cell biologist as well. The two
were postdocs at Stanford together,
though in different labs, and were hired
by the University of Michigan at the
same time, Nabeshima in the Department of Cell and Developmental Biology
(CDB), and Yamashita in both CDB
and the Life Sciences Institute and the
Center for Stem Cell Biology. They enjoy
living in Ann Arbor, which offers a good
environment in which to raise their twoand-a-half year-old daughter.
The LSI, Yamashita says, has been incredibly supportive in helping her make
the transition from Stanford to Michigan,
even helping her hire a technician to set
up her lab before she arrived in January,
2007, so she was able to start work on
her experiments right away. “I’ve never
heard of anyone anywhere having their
lab up and running within two weeks,”
she says, noting that making a transition
from one university to another can often
cause months of delay in one’s research.
“That was amazing.”
5
continued from page 1
housed it in a remarkable new facility. LSI
symbolizes the University’s commitment
to remaining one of the premier science
universities in the 21st Century.
While “life sciences research” is a broad,
multifaceted field, stem cell research has
been in the center of the public’s attention
and has come to be regarded popularly as
the leading edge. This perception is fueled
by the promise that stem cell
research can lead to curing some of mankind’s
greatest scourges.
So stem research
has enormous
symbolic
value
to
6
the University and to the scientific community. If U-M is to be regarded as a place
that really supports scientific inquiry, it
needs to have an outstanding stem cell
research program.
Fortunately, we have attracted Sean
Morrison, truly one of the “best and the
brightest” to lead the effort. Dr. Morrison is
internationally recognized for his individual
research and for assembling a superb team
at the Center for Stem Cell Biology. He,
and they, have made Michigan writ large on
the scientific map.
But the obstacles are great, and much
needs to be done.
While attending my
40th Harvard College
reunion recently, I
heard a prominent
Harvard stem
cell researcher’s
presentation,
during which he
spoke of how he
pitied “poor Sean
Morrison” for having
to do his work in Michigan. I am not kidding.
That is what the man said to the 300 of us
gathered for his talk.
The Harvard researcher, of course, was
alluding to the State of Michigan’s law
making it a crime to damage an embryo,
a law passed in the 1970’s when no one
had conceived of stem cell research. The
perception is that Michigan is a backwater
for serious science, a place with a medieval
mentality.
At the same time, we have an administration in Washington that has made
meaningful embryonic stem cell research
virtually impossible to conduct — unless it
is privately funded.
So the challenges for us, who love the
University of Michigan, are real.
Last fall a group of us got together and
helped raise money to support research using an imported “non-presidential” line of
stem cells. The need is ongoing, but we are
heartened by the enthusiastic support this
effort is receiving. Working with LSI Director Alan Saltiel, we will raise the necessary
money.
But we also need to change the politics in
Lansing if we are really going to be able to
retain and recruit the best and the brightest
at Michigan. The stakes are high. As
a public university in a state with
highly publicized economic troubles,
it already is difficult enough to
maintain the greatness of
our University. We need to
change the climate for stem
cell research if U-M is going
to continue to be the center
of excellence that we know
today for our children and
grandchildren.
A double helix of dividing
hematopoietic stem
cells
Photography:
Mark Kiel
Discoveries:
f r o m t h e C e n t e r f o r S t e m C e ll B i olo g y
Widely held ideas about stem cells
disputed
LSI team identifies gene that regulates
blood-forming fetal stem cells
of the paper; Morrison and U-M’s Thomas
Saunders are co-authors.
How do adult stem cells protect themselves
from accumulating genetic mutations that
can lead to cancer?
In the rancorous public debate over federal
research funding, stem cells are generally
assigned to one of two categories: embryonic or adult. But that’s a false dichotomy
and an oversimplification. A new study led
by LSI’s Sean Morrison adds to mounting
evidence that stem cells in the developing
fetus are distinct from both embryonic and
adult stem cells.
“Identification of Sox17 could also facilitate
efforts to form blood-forming stem cells
from human embryonic stem cells, a goal
that could enhance bone marrow transplantation,” Kim said.
For more than three decades, many
scientists have argued that the “immortal
strand hypothesis” — which states that
adult stem cells segregate their DNA in a
non-random manner during cell division —
explains it. And several recent reports have
presented evidence backing the idea.
But in August 29 issue of the journal
Nature, lead author Mark Kiel, Sean Morrison and their colleagues dealt a mortal
blow to the immortal strand, at least as far
as blood-forming stem cells are concerned.
They labeled DNA in blood-forming mouse
stem cells and painstakingly tracked its
movement through a series of cell divisions. In the end, they found no evidence
that the cells use the immortal-strand
mechanism to minimize potentially harmful
genetic mutations.
“This immortal strand idea has been floating around for a long time without being
tested in stem cells that could be definitively identified. This paper demonstrates
that it is not a general property of all stem
cells,” said Morrison, director of the Center
for Stem Cell Biology.
It remains possible that stem cells in other
tissues use this process.
“We’ve been able to show that this is not a
mechanism by which blood-forming stem
cells reduce their risk of turning into cancer
and, presumably, we should be looking elsewhere to understand what those
mechanisms really are,” he said.
Stem cells generate all of the tissues in
the developing human body, and later in
life provide replacement cells when adult
tissues are damaged or wear out.
In the last several years, stem cell
researchers have realized that fetal stem
cells comprise a separate class. They
recognized, for example, that fetal bloodforming stem cells in umbilical cord blood
behave differently than adult blood-forming
stem cells after transplantation into
patients.
A team led by Sean Morrison has identified
the first known gene, Sox17, required for
the maintenance of blood-forming stem
cells in fetal mice, but not in adult mice.
The discovery provides a critical insight
into the mechanisms that distinguish fetal
blood-forming stem cells from their adult
counterparts.
The findings could also lead to a deeper understanding of diseases such
as childhood leukemias. Childhood
leukemias are cancers that afflict
blood-forming cells and hijack
normal stem cell self-renewal
mechanisms.
“One of the next questions
in our cross hairs is whether
Sox17 gets inappropriately
activated in certain childhood leukemias—and that’s
an idea that nobody had in
their mind before this work,”
Morrison said. “If it’s true,
it’ll give us a new target for
cancer.”
The Sox17 results appeared
online July 26, 2007 in the journal
Cell. U-M’s Injune Kim is lead author
The Sox 17 study is part of a larger, ongoing U-M effort to understand how stem
cells are regulated at different stages of
life. Last September, Morrison’s team
reported that old stem cells don’t simply
wear out; a gene called Ink4a actively
shuts them down.
“Each time we identify one of these genes,
we get a new insight into what stem cells
really are, what regulates their identity and
how their age-specific functions work,”
Morrison said. That information could
lead to new treatments for degenerative
diseases.
— Jim Erickson, U-M News and Information Services
A cluster of leukemia-forming cells from a mouse
lacking the Pten gene. Blood-forming stem
cells and leukemia-initiating cells differ in their
dependence on Pten, and this difference can be
used to selectively kill the cancerous cells without
harming normal stem cells. (Photo by Omer Yilmaz,
U-M Center for Stem Cell Biology.
7
What’s new with stem cells?
Recently, stem cell researchers have made
revolutionary discoveries that have made
headlines around the world.
While it was previously thought that differentiated cells were destined to remain
confined to one pathway or somatic cell
type, we now know that by inserting only
a few select genes into a cell taken from a
simple skin biopsy, the cell can effectively
reprogram itself to regain pluripotency,
Although attempts to replicate the experiment using human cells have not been
successful, the findings from experiments
involving the reprogramming of mouse
fibroblast cells represent exciting possibilities in the microscopic realm of stem cell
research.
Sean Morrison, director of the Center for
Stem Cell Biology, views the results of
these experiments as a promising forecast
of the developments
yet to unfold.
Photography: Injune Kim
“What’s exciting about
stem cell research is
you don’t know what’s
going to come around
the corner,” he said.
Green fluorescence protein in the inner cell mass of an embryonic day 3.5
Sox17 GFP/+ blastocyst in mouse
meaning they can revert to become any
cell in the body.
8
Three labs have been successful at
reprogramming the cellular circuitry of differentiated skin cells of mice, including the
Kyoto Univeristy lab of Shinya Yamanaka
(who is moving to California), the Harvard
Medical School lab of Konrad Hochedlinger
and Rudolf Jaenisch’s lab at the Whitehead
Institute in Cambridge, MA as reported in
Nature magazine.
This is especially
applicable in the
case of Woo Suk
Hwang, a Korean
stem cell researcher
who claimed to have
discovered the ability
to derive embryonic
stem cells through
nuclear transfer
(therapeutic cloning)
but was later found to
have falsified research
and was ultimately
discredited.
After a team of
researchers in Boston reviewed Hwang’s
work, they found that while it was not what
he originally claimed, the work did produce
the first stem cells found to be produced
from an unfertilized egg by parthenogenesis, a process by which an unfertilized egg
can be tricked into starting to divide.
Findings like those from Yamanaka’s lab,
and even Hwang’s roundabout experiment,
have revolutionary implications for the ethics of stem cell research, and some have
said that new procedures such as deriving
stem cells from a skin cell or an unfertil-
ized egg have the potential to do away
with the need to harvest pluripotent stem
cells from human embryos.
U-M’s Morrison says it is important for
stem cell researchers to be prudent about
trying to predict which applications work
best.
“We have to continue doing work on embryonic stem cells,” he said.
Morrison is optimistic about replicating the
experiment using human skin cells, and
thinks the lack of success at this point may
indicate that a different combination of
genes is responsible for resetting human
skin cells to the pluripotent state.
Recently, Morrison has been working to
identify genes required to maintain fetal
hematopoietic, or blood-forming stem
cells.
Along with LSI Research Fellow Injune Kim,
Morrison discovered that stem cells in a
developing fetus have unique properties,
and can’t be grouped into a category with
either adult or embryonic stem cells. The
team was the first to identify that Sox17
is a critical gene in the regulation of fetal
mouse stem cells, but has little or no regulatory effect on adult stem cells. The findings of his lab’s research were published in
late July in Cell, a key scientific journal.
Ongoing controversy about the way stem
cells are obtained typically receives the
most media attention, and Congress continues its battle over the ethics of using the
discarded remnants of In-Vitro Fertilization
procedures to progress embryonic stem cell
research.
Although some debates are focused
entirely on where researchers obtain stem
cells, “it’s only a small piece of the equation,” according to Dr. Morrison.
For him, a large focus is figuring out
how he can use stem cells, whether in
transplantation or simply observing them
outside the body to understand their
mechanisms, or screening for new drugs.
For example, he has already begun thinking about how his discovery with fetal
blood-forming stem cells can be applied to
diseases like childhood Leukemia.
As the mysteries of stem cells begin to
unwind, many theoretical solutions have
been predicted in the lab. “The actual work
on how to treat a disease still needs to be
done,” Morrison says.
When it comes to Juvenile Diabetes, a
disease that affects about one in every 400
to 600 children according to the National
Diabetes Information Clearinghouse, stem
cell researchers have been able to successfully generate fully differentiated
normal insulin-secreting cells.
But many challenges remain before this
information can be translated into a cure.
Researchers must now figure out how to
transplant new functioning insulin-secreting cells into a patient and avoid the wrath
of an immune system that has detected a
foreign intruder.
Morrison said he hopes there will be areas
such as this that will “lurch forward unexpectedly because of a few key discoveries,” such as was the case in Yamanaka’s
most recent discovery.
“It’s one of those areas that is moving much
faster than people thought it would,” he
said.
Recently, Morrison has been finalizing consent documents to obtain stem cells with
genetic defects that cause neurodegenerative disease, but the process has been
difficult because of Michigan’s restrictive
state laws restricting embryonic stem cell
research.
In 2001, Bush’s presidential veto left only
a few viable lines of embryonic stem cells
in the National Institutes of Health stem
cell registry available for federal funding. These lines are extremely limited in
genetic diversity and none have the right
genetic background to model neurodegenerative diseases.
foundation, he can apply to obtain embryonic stem cells that were created in other
states like California that are not approved
for federal funding. Although it may be
a time-consuming process, he does not
expect resistance to his requests. Nonetheless, the need to depend on scientists
in California is one important reason why
the state restrictions on embryonic stem
cell research that are currently in place in
Michigan put Michigan researchers at a
great disadvantage relative to scientists in
other states, and slow progress in this area
within the state.
— Arikia Millikan, senior majoring in Psychology in at
U-M and Michigan Daily reporter
Learn more about stem cells:
www.lifesciences.umich.edu/research/
featured/tutorial.html
But because
Morrison’s lab
is funded
largely by
a private
9
Photography: Injune Kim
For Morrison and his associates, a deep
exploration into the cellular culprits of
neurodegenerative diseases is one area
that they plan to vigorously investigate, in
hopes that they will experience such a leap
in progress.
Morrison has been working in this area for
years and collaborates with Sue O’Shea
to figure out how to coax stem cells into
becoming components of the nervous
system, the region of the body that is devastated by diseases like Parkinson’s, Huntington’s, and Alzheimer’s. These diseases
affect millions of individuals around the
world, but most are currently untreatable.
investigations
The Function for Survival
The tight regulation of glucose levels is
necessary for the proper functioning and
survival of all tissues and organs. While
glucose deprivation can cause cellular
death, chronic elevated levels can lead to
tissue damage or dysfunction. Glycogen
metabolism represents a key step in the
storage of excess glucose. Not surprisingly,
the inability to properly store glycogen is a
characteristic found in insulin resistance/
diabetes, as well as several genetic disorders that affect hepatic, neuromuscular, or
neurological function.
I have discovered that the G1448R genetic
variant is unable to bind to glycogen, and
displays decreased stability that is rescued
by proteasomal inhibition. AGL G1448R is
more highly ubiquitinated than its wildtype
counterpart, and forms aggresomes upon
proteasome impairment. During the course
of these studies, I identified the E3 ubiquitin
ligase Malin as a novel interactor with AGL.
Interestingly, Malin is known to be mutated
in Lafora disease, an autosomal recessive
disorder clinically characterized by the accumulation of polyglucosan bodies resembling poorly branched glycogen.
My studies have led me to propose a model
regarding the regulation of AGL. When
glycogen is present, AGL localizes to it to
carry out its function to help maintain its
proper branching structure. During the
breakdown of glycogen, AGL is released
into the nucleus where Malin interacts
with it and promotes its ubiquitination, and
subsequent degradation. In Lafora disease,
the absence of Malin may lead to decreased
AGL ubiquitination and thus, an inappropriate increase in the levels of the protein.
The subcellular localization of a mutant AGL
protein that occurs in Cori’s disease. The mutant
concentrates into an aggresome (green) that is
caged by a microtuble network (red).
10
One of my research goals is to understand
the molecular mechanisms that underlie
Glycogen Storage Disorders (GSDs). Cori’s
disease (GSD Type III) is characterized by
a deficiency in the glycogen debranching
enzyme, amylo-1,6-glucosidase, 4-alphaglucanotransferase (AGL). This enzyme is
thought to be important in maintaining the
proper branching structure of glycogen,
as well as assisting in its breakdown into
glucose. Most AGL mutations identified to
date lead to premature truncation and loss
of activity. However, one missense variant,
G1448R, is located within the putative
glycogen-binding domain.
In summary, my studies indicate that
binding to glycogen crucially regulates the
stability of AGL, and further that its ubiquitination may play an important role in the
pathophysiology of both Lafora and Cori’s
disease.
—Alan Cheng, PhD, Saltiel lab, 2007
Physiological Notch signaling promotes
gliogenesis in the developing peripheral
and central nervous systems
Constitutive activation of the Notch pathway
can promote gliogenesis by peripheral
(PNS) and central (CNS) nervous system
progenitors. This raises the question of
whether physiological Notch signaling regulates gliogenesis in vivo. To test this we
conditionally deleted Rbpsuh from mouse
PNS or CNS progenitors using Wnt-1-Cre
or Nestin-Cre. Rbpsuh encodes a DNAbinding protein (RBP/J) that is required for
canonical signaling by all Notch receptors.
In most regions of the developing PNS and
spinal cord Rbpsuh deletion caused only
mild defects in neurogenesis but severe
defects in gliogenesis. This was usually
caused by defects in glial specification or
differentiation, not premature depletion of
neural progenitors, because we were able
to culture undifferentiated progenitors from
the PNS and spinal cord despite their failure
to form glia in vivo. In spinal cord progenitors, Rbpsuh was required to maintain Sox9
expression during gliogenesis, demonstrating that Notch signaling promotes the expression of a glial specification gene. These
results demonstrate that physiological
Notch signaling is required for gliogenesis
in vivo, independent of the role of Notch in
the maintenance of undifferentiated neural
progenitors.
—Merritt Taylor, PhD, Morrison Lab, 2007, now
Assistant Professor at Grand Valley State University.
Sox17: unique transcription factor for
fetal and neonatal HSCs
Fetal hematopoietic stem cells (HSCs)
have properties distinct from adult HSCs.
Fetal HSCs express specific markers which
are not expressed in adult HSCs. Fetal
HSCs proliferate rapidly while adult HSCs
are quiescent. In an attempt to find out
transcription factors important for fetal
properties of HSCs, we discovered that
Sox17 is specifically expressed in fetal
HSCs, not in adult HSCs. By generating and
analyzing Sox17 targeted mice, we revealed
that Sox17 expression within hematopoietic
system is restricted to fetal and neonatal
HSCs, not adult HSCs and that the deletion
of Sox17 induces the loss of HSCs during
development or in neonatal period, not in
mature adulthood. When the expression of
Sox17 declines gradually after birth, HSCs
expressing Sox17 hold fetal properties
phenotypically and functionally but HSCs
which don’t express Sox17 showed adult
properties. These results indicate that
Sox17 is important transcription factors for
fetal and neonatal HSCs.
—Injune Kim, PhD, Morrison lab, 2007
Structure basis of Vps4 and Vta1 function in the multi-vesicular body sorting
pathway
The Multi-Vesicular Body (MVB) pathway
functions in multiple cellular processes
including cell surface receptor downregulation and viral budding from host
cells. Proper function of the MVB pathway
requires reversible membrane association
of the ESCRTs, a process catalyzed by
AAA-protein (ATPase Associated with various cellular Activities) Vps4. Together with
its regulator Vta1 protein, Vps4 utilizes the
energy from ATP hydrolysis to promote the
dissociation of ESCRT complexes from the
endosome membrane.
To understand the function of Vps4 in a
molecular level and gain important insights
into the MVB pathway and retrovirus budding, we have performed structural and
functional studies on Vps4 and its regulator Vta1. We have determined the crystal
structure of S. cerevisiae Vps4 in both the
nucleotide-free form and the ADP-bound
form, in which Vps4 molecule displays
different conformation. The monomer
structure of Vps4 contains unique features
and the molecular organization of Vps4
in the crystal lattice reveals the potential
for Vps4 to form a hexameric ring-like
assembly. We also performed biochemical studies to examine the oligomerization
status of Vps4 in the absence of ATP, and
our data suggest that Vps4 is most likely a
monomer in contrast to the reported dimer
at its inactive state.
At the same time, we have examined the
interaction between Vps4 and its regulator
Vta1. We have mapped their interaction
regions and subsequently determined
the crystal structure of the Vps4-binding
domain of Vta1. The structure demonstrates that the Vps4-binding domain of
Vta1 forms a tight dimer with an extensive
hydrophobic dimer interface. Mutations in
this interface disrupted the dimer formation of the full-length protein. Interestingly,
the dimer is also required for the interaction with Vps4, since the dimer defective
mutant also does not bind to Vps4. Yeast
cells harboring these mutants have defect
in the MVB pathway, displaying ‘class E
Vps phenotype’.
Dimerization and DNA-Binding
Properties of the Transcription Factor
ΔFosB
The transcription factor, FosB, a splice
isoform of fosB, accumulates in rodents
in a brainregion-specific manner in
response to chronic administration of
drugs of abuse, stress, certain antipsychotic or antidepressant medications,
electroconvulsive seizures, and certain
lesions. Increasing evidence supports a
functional role of such FosB induction in
animal models of several psychiatric and
neurologic disorders.
Fos family proteins, including FosB,
are known to heterodimerize with
Jun family proteins to create active
AP-1 transcription- factor complexes,
which bind to DNA specifically at AP-1
consensus sites. We show here, using
a range of biochemical and biophysical means, that recombinant, purified
FosB forms homodimers as well, at
concentrations less than 500 nM, and
that these homodimers specifically bind
to DNA oligonucleotides containing AP-1
consensus sequences in the absence
of any Jun partner. Our results suggest
that, as FosB accumulates to abnormally elevated protein levels in highly
specific regions of the brain in response
to chronic stimulation, functional ho-
Taken together, our data suggest that Vps4
functions in an ATP-dependent monomerdodecamer transition cycle, while Vta1
acts as an assembly factor that links two
Vps4 hexameric ring together at its active
state. The results we obtained from these
studies have the potential for providing
novel insights into human disease and may
also lead to new therapeutic strategies.
—Junyu Xiao, PhD Student, Zhaohui Xu lab, 2007
modimers of FosB are formed with the
potential to uniquely regulate patterns of
gene expression and thereby contribute
to the complex processes of neural and
behavioral adaptation.
—Gabby Rudenko, PhD, 2007
The dimerization properties of DeltaFosB were
probed with analytical ultracentrifugation. The
experimental data (dots) in the top half of the
figure fit very well with a dimeric model but very
poorly with a monomeric model (model predictions
in solid lines). Our results shown that DeltaFosB
in solution can form dimers, even at low protein
concentrations, suggesting that in cells deltaFosB
upon accumulation can dimerize as well, forming
an active transcription factor.
11
currents
LSI Symposia & Events
LSI Faculty Win Exceptional Honors
Weizmann Institute/LSI Research
Partnership was held in April. LSI hosted
10 scientists from our sister institute in
Rehovot, Israel for three days of scientific exchange which included an all-day
symposium and individual meeting with
potential U-M collaborators. Over 100
faculty and students joined the Weizmann
delegation for an interactive lunch in the
LSI lobby.
In May David Ginsburg was
elected a Member of National
Academy of Sciences. Election to
the Academy is considered one
of the highest honors bestowed
upon scientists across all scientific disciplines in recognition
of distinguished and continuing
achievements in original research.
LSI Professor, Rowena Matthews
is also a member.
The Michigan Symposium on Genomic
Biology was held April 16 in the Biomedical Sciences Research Building Auditorium featuring talks by eight renowned
researchers from around the world. The
symposium was organized and hosted by
LSI faculty Anuj Kumar.
In May, LSI held its sixth annual scientific
symposium was “Frontiers in Stem Cell
Biology.” A roster of world-leaders in
stem cell biology presented their cuttingedge research with plenty of time for interaction with UM researchers and students.
Harvard’s Dr. Stuart Orkin gave the Mary
Sue and Kenneth Coleman Life Sciences
Lecture entitled “Control of stem cells.”
Xian-Zhong Shawn Xu, was named
U-M’s only Pew Scholar in June.
The Pew names only 20 awards to
America’s most promising scholars.
The Pew program invests in early
to mid-career scientists, seeks to
expand foundation of biomedical
knowledge & advance scientific frontiers. As a Pew Scholar, each scientist
will receive a $240,000 award over
four years to help support his or her
research, as well as gain inclusion
into a unique community of scientists
that encourages collaboration and
exchange of ideas.
12
Awards
Andrea Baines in the Ginsburg Lab will be
awarded the Rackham Predoctoral Fellowship for the upcoming year.
Christopher G. Evans who is a 2nd year
graduate student in the Gestwicki group
and the Chemical Biology PhD Program
was awarded a Cellular Biotechnology
Training Program (CBTP) Fellowship.
Huan Tang (Mike) Li in the GarneauTsodikova lab won a spot in the Cellular
Biotechnology Training Program.
David Ginsburg received the Distinguished
Career Award as part of the “13th Biennial
Awards for Contributions to Hemostasis”
at the XXI Congress of the International
Society on Thrombosis and Hemostasis in
Geneva Switzerland, July, 2007.
Structural Enzymology: A Symposium
Honoring Rowena E. Matthews, was
held in May and is traditional for a faculty
member who will be retiring. The two day
celebration recognized Rowena’s contributions to science, particularly in the field of
Biological Chemistry, and brought together
scientists from all over the country. It was
cosponsored with University of Michigan Department of Biological Chemistry,
Biophysics Research Division, and the Life
Sciences Institute.
The LS-CAT Sector 21 Dedication
Ceremony in May opened the beamline at
the Argonne National laboratory outside
Chicago. Spearheaded by the late Martha
Ludwig, the new beamline is a collaboration between LSI and researchers from the
University of Michigan, and many other
institutions including Michigan State Uni-
versity, Wayne State University, Van Andel
Institute, Northwestern University, the University of Illinois, University of Wisconsin
and Vanderbilt University. LS-CAT or the
Life Sciences Collaborative Access Team
is a consortium of academic and research
institutions engaged in cutting-edge structural research with X-radiation to solve
3-D structures. Gabby Rudenko, Janet
Smith, Jeanne Stuckey, John Tesmer,
and Zhaohui Xu of LSI and the Center for
Structural Biology are the primary users of
the facility in the LSI.
a transfer student to Baylor College of
Medicine in Houston, Texas and will be
starting clinical rotations in July toward
completion of her MD.
Chung-Han Lee from the Kun-Liang Guan
lab defended June 4, 2007. “Glucose Starvation Induces Apoptosis of TSC-/- cells in
a p53-dependent Manner.”
Brian A. Moore from Zhaohui Xu’s lab.
“Structures of Exocyst subunit Exo70 from
Yeast and Mouse.” Dr. Moore will be a
postdoc at Harvard with Allen Steere.
Angela Fleischhaker from Rowena Matthews’ Lab defended in May. “Governing
conformation in cobalamin-dependent
methionine synthase: Probing the roles of
the axial cobalt ligands.”
Of Note:
Janet Smith displays a diffraction pattern at Argonne
National Laboratory, home of LS-CAT
PhD Defenses
Ju Huang from Dan Klionsky’s lab defended June 4. “Studies of the molecular
components of autophagy and the sorting
mechanism of the multivesicular body
pathway in Saccharomyces cerevisiae.”
Ju will be doing a postdoc with Dr. John
Brumell at the Hospital for Sick Children in
Toronto, Canada.
Abigail (Abby) Fahim from the David
Ginsburg lab defended her thesis on May
15, 2007. “Directed Evolution and In
Vivo Function of Plasminogen Activator
Inhibitor-1”. Abby has been accepted as
The ISI Web of Knowledge has calculated
an impact factor of 6.71 for Autophagy
—Daniel Klionsky is Editor-in-Chief. This
is a higher factor than some of the journals
considered to be competitors including
Molecular Microbiology (5.63), Journal
of Biological Chemistry (5.81), Journal of
Cell Science (6.43), Molecular Biology of
theCell (6.56) and Traffic (6.61).
Zhouhui Xu and Brian Moore at his defense
suggested that the function of TBX15 will
have to be carefully explored. “Studies
in mice indicate that TBX15 may have
widespread functions and may impact
multiple tissues such as bone and skeletal
development,” he told Medscape. “It will
also be interesting to determine whether
TBX15 also correlates with markers of
insulin resistance.”
Jordan Shavit, of the Ginsburg lab M.D.,
Ph.D., will give a presentation at the XXIst
Congress of the ISTH 2007 Meeting in Geneva, Switzerland, July, 2007. “Regulation
of Plasma von Willebrand Factor (VWF) by
Modifier Genes”.
LSI was featured in an article published
by the American Diabetes Association
regarding “Potential Weight-Regulating
Gene Identified” by Emma Hitt excerpted
here: A gene called T-box 15 (TBX15) may
be involved in regulating body fat amount.
Carey Lumeng, MD, PhD, with the University of Michigan Life Sciences Institute,
who moderated the session on obesity
during which the presentation was made,
13
currents
Genome-wide mapping of DNase hypersensitive sites using massively parallel
signature sequencing (MPSS). Crawford
GE, Holt IE, Whittle J, Webb BD, Tai D,
Davis S, Margulies EH, Chen Y, Bernat JA,
Ginsburg D, Zhou D, Luo S, Vasicek TJ,
Daly MJ, Wolfsberg TG, Collins FS. Genome
Res 16:123-31, 2006.
Dauer. Hu PJ, WormBook, ed. The C.
elegans Research Community, WormBook,
doi/10.1895/wormbook.1.144.1, http://
www.wormbook.org, 2007.
Lunch with scientists from the Weizmann Institute in LSI lobby
Top discoveries include
Selected Publications
Yukiko Yamashita’s laboratory published
research discussing asymmetrical division
of adult stem cells showing that adult stem
cells often divide to produce one selfrenewed stem cell and one differentiating
cell, thus maintaining both populations.
(Science, January 2007)
Drug Targets in Mycobacterial Sulfur
Metabolism. Bhave D, Muse WB, Carroll
KS. Infectious Disorders - Drug Targets
7:140-158, 2007.
A team led by Jiandie Lin discovered how
metabolic pathways work in concert with
the circadian clock to create the predictable
daily patterns of energy storage or usage.
By creating genetically altered “knockout”
mice, they uncovered a new job for an old
protein called PGC-1α (alpha), a master
regulator of genes that control energy production in the cell. (Nature, May 2007)
14
Jason E. Gestwicki and Daniel J.
Klionsky discussed potential therapeutic
applications of autophagy recognized to be
involved in various developmental processes and various diseases including cancer
and neurodegeneration.(Nature Reviews,
Drug Discovery, April 2007)
Covalent CouN7 enzyme intermediate for
acyl group shuttling in aminocoumarin biosynthesis. Balibar CJ, Garneau-Tsodikova
S, Walsh CT. Chem Biol. 14: 679-90, 2007.
Rescue of Degradation-prone mutants of
the FK506-rapamycin binding (FRB) protein
with chemical ligands. Stankunas K, Bayle
JH, Havranek JJ, Wandless TJ, Baker D,
Crabtree GR, Gestwicki JE. Chembiochem
9:1162-9, 2007.
Potential therapeutic applications of
autophagy. Rubinsztein DC, Gestwicki
JE, Murphy LO, Klionsky DJ. Nat Rev Drug
Discov 6:304-12, 2007.
Fatal hemorrhage in mice lacking gammaglutamyl carboxylase. Zhu A, Sun H, Raymond RM Jr, Furie BC, Furie B, Bronstein
M, Kaufman RJ, Westrick R, Ginsburg D.
Blood 109:5270-5, 2007.
Genetic regulation of plasma von Willebrand
factor levels: quantitative trait loci analysis
in a mouse model. Lemmerhirt HL, Broman
KW, Shavit JA, Ginsburg D. J Thromb
Haemost 5:329-35, 2007.
Distant conserved sequences flanking
endothelial-specific promoters contain
tissue-specific DNase-hypersensitive sites
and over-represented motifs. Bernat JA,
Crawford GE, Ogurtsov AY, Collins FS, Ginsburg D, Kondrashov AS. Hum Mol Genet
15:2098-105, 2006.
Metabolic derangement of methionine
and folate metabolism in mice deficient in
methionine synthase reductase. Elmore CL,
Wu X, Leclerc D, Watson ED, Bottiglieri T,
Krupenko NI, Krupenko SA, Cross JC, Rozen
R, Gravel RA, Matthews RG. Mol Genet
Metab 91:85-97, 2007.
Global aggregation of newly translated proteins in an Escherichia coli strain deficient
of the chaperonin GroEL. Chapman E, Farr
GW, Usaite R, Furtak K, Fenton WA, Chaudhuri TK, Hondorp ER, Matthews RG, Wolf
SG, Yates JR, Pypaert M, Horwich AL. Proc
Natl Acad Sci U S A 103:15800-5, 2006.
Genetic diversity and population structure
inferred from the partially duplicated genome of domesticated carp, Cyprinus carpio
L. David L, Rosenberg NA, Lavi U, Feldman
MW, Hillel J. Genet Sel Evol 39:319-40,
2007.
Activation of RalA Is Required for InsulinStimulated Glut4 Trafficking to the Plasma
Membrane via the Exocyst and the Motor
Protein Myo1c. Chen, X.C., Leto,D.,
Chiang, S.H., Wang, Q. and Saltiel. A. R.
(Developmental Cell, September 2007)
Background image:
Marrow cell nuclei in a section
through bone.
A hematopoietic stem cell caught
in the act of dividing (nuclei in blue,
alpha-tubulin in green, beta-actin
in red
Matthews and Elmore hold their May cover of “Molecular
Genetics and Metabolism”
The probability distribution under a population divergence model of the number of
genetic founding lineages of a population
or species. Jakobsson M, Rosenberg NA.
Theor Popul Biol 71:502-23, 2007.
Dimerization and DNA-Binding Properties of
the Transcription Factor DeltaFosB.Helena
J. M. M. Jorissen, Paula G. Ulery, Lisa Henry,
Sreekrishna Gourneni, Eric J. Nestler, and G.
Rudenko. (Biochemistry, April 2007)
Gapex-5, a Guanine Nucleotide Exchange
Factor for Rab5 that Regulates Glut4 Trafficking in Adipocytes. Lodhi, I.J., Chiang,
S-H, Chang, L. Inoue, M., Vollenweider, D.,
Watson, R.T., Pessin, J.E. and. Saltiel, A.R.
(Cell Metabolism 2007)
Bone marrow-specific Cap gene deletion
protects against high-fat diet-induced insulin
resistance. Lesniewski, L.A., S.E. Hosch,
J.G. Neels,C. de Luca, M. Pashmforoush,
C.N. Lumeng, S.H. Chiang, M. Scadeng, A.R.
Saltiel and J.M. Olefsky. (Nature Medicine,
April 2007)
Photography: Mark Kiel
15
Stem Cell Researcher joins LSI
Dr. Ivan Maillard joined the Life
Sciences Institute as a Research
Assistant Professor July 1. He is
also an Assistant Professor Dept.
of Internal Medicine, Division of
Hematology/Oncology and the
fourth faculty member of the U-M
Center for Stem Cell Biology.
“Ivan was the top young stem cell
biologist in the country on the job
market last year. We had intense
competition from other research
universities that were also trying
to recruit him,” said Sean Morrison, Director of the U-M Center for Stem Cell Biology.
“He has done important work characterizing the mechanisms that regulate the maintenance of blood-forming stem cells in the bone marrow.
Beyond this fundamental research, Ivan is also a physician, a hematologist/oncologist. We look forward to tapping his expertise as a physicianscientist to further our goals of translating stem cell discoveries to help
patients.”
Dr. Maillard earned his MD-PhD program at the Swiss Academy of Medical Sciences, University of Lausanne, Switzerland and worked on the
interaction of Mouse Mammary Tumor Virus with the immune system of
its host with Heidi Diggelmann, MD. He completed a post-doctoral fellowship with Warren S. Pear at the University of Pennsylvania, where he
subsequently was a fellow and physician in Hematology-Oncology.
Dr. Maillard joined Morrison, Yukiko Yamashita and Cheng-Yu Lee in the
Center.
Julia Donovan Darlow, Laurence B. Deitch, Olivia P. Maynard, Rebecca McGowan, Andrea Fischer
Newman, Andrew C. Richner, S. Martin Taylor, Katherine E. White, Mary Sue Coleman, ex officio
The University of Michigan is an equal opportunity/affirmative action employer. The University of
Michigan Health System is committed to Total Quality.
Copyright © 2007 The Regents of the University of Michigan, Ann Arbor, Michigan, 48109
MMD 070375
Editor: Robin Stephenson
[email protected]
Photography: Peter Smith
Image on front cover:
Hematopoietic progenitor colony from a mouse — Hematopoietic stem cells and
leukemia cells differ in dependence upon Pten, and this can be therapeutically exploited
to deplete leukemia-initiating cells without harming normal stem cells.
Nature. 2006 May 25 (cover image)
Life Sciences Institute
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The Regents of the University of Michigan