xt7kkw57hp5x https://exploreuk.uky.edu/dips/xt7kkw57hp5x/data/mets.xml University of Kentucky. Office of the Vice President for Research and Graduate Studies Kentucky University of Kentucky. Office of the Vice President for Research and Graduate Studies 2005 volumes. Call Number: LD2762.9 .K38c. Accession Number: 2018ua049 journals LD2762.9 .K38c English Office of the Vice President for Research and Graduate Studies Contact the Special Collections Research Center for information regarding rights and use of this collection University of Kentucky Odyssey Magazine Research -- Kentucky -- Periodicals Education -- Research -- Periodicals Research -- Kentucky Odyssey: The Magazine of University of Kentucky Research and Graduate Studies, Spring 2005 text images Odyssey: The Magazine of University of Kentucky Research and Graduate Studies, Spring 2005 2005 2005 2026 true xt7kkw57hp5x section xt7kkw57hp5x

Lee T, Todd Jr., President

Wendy Baldwin, Executive Vice President for Research
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for Research Faculty Programs
Agriculture

M Scott Smith, Dean
Arts and Sciences

Steven Hoch, Dean
Business and Economics
De\anathan Sudharshan, Dean
Communications

and Information Studies
J, Daiid Johnson, Dean
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Sharon P Turner, Dean
Design

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Education

James Cibulka, Dean
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Thomas W. tester, Dean
Fine Arts

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Lori Gonzalez, Dean

Law

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Medicine

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Nursing

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Social Work

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Cover Story

Features

Putting the Brakes on Paint Waste

Kozo Saito in the College of Engineering
is collaborating with Toyota to help solve
manufacturing and waste problems

His design of a novel scrubber, a device
that sucks up oversprayed paint in

the automotive coating process, saves
significantly more paint and uses

much less energy than conventional

scrubbers.

Spring 2005

Primitive Powerhouses:
Tapping into Blood-forming Stem Cells

In his 10 years at UK, Gary Van Zant has probed the
bone marrow’s stem cells, and his findings have
implications ranging from the immediate (better
cancer treatment) to the seemingly sci-fi (organ
regeneration). But what makes Van Zant’s research
unique among scientists investigating stem cells is
his angle: aging. He’s asking: What is the link be—
! tween cancer and stem-cell aging? 7

Designing More Benign Bugs

Husband and wife research duo Davy and Grace Jones
have unlocked the key to insect development—juvenile
hormone—and their findings are leading to well-targeted,
nontoxic pesticides. l6

Remote-Control Surgery

The future is now for patients at UK who opt for robotic
surgery. Guided by a surgeon at a console, the medical
centers high-tech robot lends surgeons a sure hand in
prostate. thoracic and pediatric surgery. 18

From Here to Kingdom Come

Under the leadership of wildlife biologist Dave Maehr,
researchers are helping black bear and elk flourish in
Kentucky, where they had been extinct for more than a
century And according to Maehr, helping the animals
means helping ourselves. 24

Room to Move

New Senior Associate Dean for Clinical Research William
Balke is bringing a team of up to 20 top heart researchers to
UK. This is good news for Kentucky. Heart disease is the
leading cause of death for Kentuckians. 28

In Brief

Keeping good bugs in your garden . corporate strategies to
help low-wage workers balance job and family . students
benefit from UK’s Asia Center 34

BookEnd

A History of American Higher Education
by John R. Thelin 36

In his 10 years at the University of
Kentucky, Gary Van Zant has probed
the bone marrow‘s stem cells, and his
findings have implications ranging
from the immediate (better cancer
treatment) to the seemingly sci—ti (or-
gan regeneration). But what makes
Van Zant’s research unique among
scientists investigatingstem cells is his
angle: aging.

He‘s looking at four main questions:
What is the link between cancer and
stem—cell aging. and what impact does
that have on bone marrow transptan-
tation? Does age play a role in a stem
celi's ability to find itswayhometothe
bone marrow after transplant? And
what genes are involved in regulating
stem—cell population size?

On Van Zant

Stem cell researcher Michael Clarke. a
University of Michigan colleague of
Van Zant in the mid5905, sums up Van
Zant’s research: “Gary has pioneered
ourunderstanding ofthe rolethatstem
cells play in aging. He was the first to
show that aging of an organ. specifi
cally the bone marrow. was a conse-
quence of loss of stem-cell function.

Tapping into

He then designed elegant genetic stud»
iestoidentifyspecific genesthatmodu—
late stem-cell aging."

But before this “elegant" genetic
research. in which Van Zant inserted
human stem cells into genetically
modified mice, his focus was blood.
“I've always been interested in stem
cells because they generate all of the
cellsinthecirculatingblood.andthey
have to do so for our entire lifespan
because mature blood cells have very
short lives." says Van Zant. who holds
a PhD. in cell biology and hematol—
ogy from New York University.

“Red blood cells live about 120 days,
platelets [cells that cause blood to
clot] live seven to 10 days, and granu—
locytes [a type of white btood cell}
live only a few hours. Stem cells need
to constantly replenish cells that are
lost through regular wear and tear.

“So the question I began pondering
was ‘Do stem cells themselves wear
out?”

Not onEy has this question fueled
his basic research. but the answer has
immediate practicalapplicationtothe
cEinical part of his job as director of
the Stem Cell Processing Laboratory

molt/turd on i). J

Blood-forming Stem Cells

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Stem Cells 101

“Stem cells are the ultimate resource for development,
maintenance, regeneration, and repair in an organism."
says Van Zant, but, he emphasizes, there's a clear distinc—
tion between embryonic stem cells and the “adult,” fully
developed, stem cells he uses in his research.

“The press and scientists have not done a good job in
describing to the public the difference between embry-
onic stem cells and adult stem cells. Embryonic stem
cells are controversial," he says, “and they are unique
because they can grow into any kind of cell. They are
necessary for fundamental research into understanding
how stem cells are specified." But. he stresses, adult stem
cells can yield their own important answers, and they’re
readily available.

“Adult stem cells are a resource that exists in all of us."
His excitement builds as he explains that birth itself
yields an “untouched reservoir“ of stem cells. “We can
getstem cells from the blood that exists at the time of birth
in the placenta and in the umbilical cord of the fetus. And
this resource is usually just discarded in the delivery
room.” says Van Zant. Stem cell treatment using blood
from umbilical cords does not involve human embryos.
For more on the value of umbilical cord stem cells, see
page 9.

Adultstem cells have three general properties: they are
capable of dividing and renewing themselves for long
periods of time, they are unspecialized, and they give rise
to specialized cell types.

A stem cell is unspecialized—it does not have any
tissue-specific structures that allow it to perform special-
ized functions. A stem cell cannot carry oxygen through
the bloodstream (like a red blood cell), and it cannot fire
electrochemical signals to make the body speak or move
(like a nerve cell). But stem cells spawn specialized cells
like blood cells and nerve cells.

Unlike blood or nerve cells, which do not normally
duplicate themselves, stem cells replicate many times
over—a process called proliferation. They can create
exact copies of themselves or they can breed specialized
cells—a process called differentiation.

The triggers for cell differentiation are internal (signals
from the cell's genes, which carry blueprints on how to
build cell structures) and external (other cells in the
immediate environment).

lnside our bones, Van Zant explains, stem cells have
neighbors called stromal cells, which provide a sort of
“pocket" for the stem cells, “Stromal cells provide a
poorly understood series of biochemical and physical
interactions that somehow keep stem cells from differen-
tiating willy-nilly and prevent them from proliferating in
an uncontrolled manner,“ he says, noting that uncon-
trolled cell division is the calling card of cancer.

Fifth—year graduate student ting Liang
and Cary \an [ant are pursuing a
patent on a gene that she distmcred
\\hich plats a key role in expanding

stem Left numbers.

for UK‘s Markey Cancer Center Bone
Marrow Transplant Program. He ex-
plains: “We harvestand freeze human
stem cells that are going to be trans-
planted back into patients in the
course of cancer treatment. To im»
prove this process. the question I
needed to answer was. ‘Should we be
concerned about how old the stem
cells are that we‘re harvesting and
transplanting?m

Stem Cell Isolation

Blood-forming stem cells. known as
hematopoietic stem cells (HSCS). have
an identity problem.

First, they‘re rare. Scientists estimate
that only one in every 10.000 to 15.000
bone marrow cells is an HSC. They
live in the bone marrow—the soft.
sponge-like material found inside
bones—buttheyalsocirculate.atrates
of one in 100,000 cells. in the blood-
stream.

Second. you can‘t pick an HSC out
of a line—up: they have no distinguish-
ing features to separate them from
look-alike blood and bone cells. Van
Zant says. "This bedeviled hemato»
poietic researchers for a long. long
time because HSCs are so rare. so
nondescript. and have no markers of
differentiation because they’re primiv
tive. It took many years before sci-
ence could make stem cell
purification routine."

The breakthrough came withanew
technology: “Flow cytometry has been
around since the 1950s. but it really
took off with the development of
monoclonal antibodies in the Tlis."
says Van Zant. Flow cytometry takes
advantage of cell markers. special-
ized proteins on the surface of each
cell—called receptors—that have the
capability to adhere to other mol-
ecules, Cells use these receptors and
the molecules that bind to them as a
way to communicate with other cells
and to carry out their proper function
in the body, Monoclonal antibodies
were developed for all kinds of cell
markers, which allowed scientists to
identify and separate different cell
types.

The antibodies were coupled to
fluorochromes—chemicals excited

bydifferentwavelengths(,iflaserlight.
"In an extremely rapid fashion. flow
cytometry interrogates large numbers
of cells on a cell-by—cell basis using
laser beams." Van Zant explains. "Any
lab studying hematopoiesis worth
their salt has access to a very good
flow cytometry facility. And we do
here.

“Stem cells have certain markers
that no other cells have. and. in addi»
tion. they dont have markers that most
other cells do. so you can use this sort
ofyinandyangapproach called nega-
tive/positiveselectiontoisolatethem."

He pulls out a chart of results from
the last blood sample he ran through
the flow cytometer. "Here. in a two-
dimensionalchart format,we‘veana-
lyzed 30.000 cells in .10 seconds. You
can take your bone marrow or blood
sample into the flow cytometry room
and walk out with a pure population
of stem cells. Then you can study
them in isolation from all of the other
cells. and that ability has greatly ad-
vanced our work."

Age 2 Cancer

The biggest risk factor in cancer de-
velopment is age. Van Zant points out.
“and I‘m talking about all kinds of can-
cer. Between the ages of »l() and 80.
there is an exponential increase in can—
cer incidence. After age 80, it levels off.

“ln cancers of the hematopoietic
system. namely leukemias. the most
studied is acute myeloid leukemia, or
AML. AML is three times more likely to
occur in someone age 65 versus some-
one 35."

Where does leukemia come from?
Stem cells, ”Studies have indicated
that the original cell in AML was a
primitive stem cell that took a wrong
turn on the developmental pathway.

Whathappened?" he asks. “Most likely
a buildup of mutations.”

Van Zant’s lO-person team, sup-
ported by a number of National Insti-
tutes of Health grants, is studying the
age-related genetic changes that turn
a normal cell into a cancerous one.
“These genetic alterations can include
independence in growth signaling,
escape from apoptosis [cell death],
and endless ability to replicate.

“Abuildupofmutationstakesplace
overthe lifespan ofan individual. And
that buildup is due in part to repeated
rounds of cell division that provide
opportunities for editing errors in the
DNA. That genetic damage is passed
on to all of the stem cells progeny.
The inappropriate differentiation and
proliferation of that damaged stem
cell results in a tumor.“

Van Zant says the failure of current
cancer treatments just might be their
inability to attack damaged stem cells.
“Standard cancer treatments are
aimed at end-stage cells, and they
zero-in on them by exploiting the fact
that end-stage cells divide rapidly.”
This rapid division causes the tumor
to grow, but all the while the mother
stem cell is relatively quiet. “She’s not
dividing much because she doesn’t
have to. Her progeny are doing the
work.

“So it’s a common theme: you treat
the tumor with one of these drugs,
and thetumorshrinks. lt remainssmall
for some time, but then it grows back.
Andapossible reason,atleastinsome
cases, is thatyou haven’t touched that
‘quiescent’ stem cell. It just takes that
stem cell a little while to generate
progeny again to grow the tumor.”

The questions Van Zant is asking
about stem cells apply not only to the
link between cancer and aging.

G a

(a) Young

@ Young. active stem cell
0 Quiescent stem cell

8 Apoptotic stem cell

AL: C i Aging 8W0 Stress $98
21> (223%;

(b) Old

(1:) Old

* Old, active stem cell
0 Lymphocytes
® Granulocytes

The young stem cell population (a) starts outwith a big reserve of resting

(quiescent) cells, a fevx dying (apoptotic) cells and a healthy population of

active cells that produce more ofthemselves and enough white blood cells

(the lymphocytes and granulocytesl to protect us from infections. In (b) and

(c), aging and a stressful condition that requires extra blood cells conspire

to severely damage the ability of stem cells to do their job. Aging and stress

cause more to die from accumulated cellular damage, and the suwivors

produce fewer lymphocytes.

“My over-arching philosophy is that
the stem cells in various organs of the
body could well be the focus for the
age—related declines we see in those
organs. Each organ suffers age-related
decline in activity, but we haven’t
fully established what causes decline
in a stem cell. Is it the ability to re-
spond quickly to a signal that more
mature cells need to be produced? Is
it the inability ofstem cellsto divide in
a rapid and appropriate way? We just
don‘t know yet.”

Stem Cells, Stem Cells
Everywhere

The human body is filled with stem
cells. “it used to be thought that stem
cells were found in only a very few
organs of the body—the bone mar—
row, the gut lining and the skin. This
was the dogma for a long, long time,“
says Van Zant. “Recently—and this is

a huge area of research right now—-
numerous organs in the body are
found to contain stem cells.”

There are neural stem cells: “Of
course the big push in that field is to
find a way to repair central nervous
system damage from accident or dis-
ease—Alzheimer’s, Parkinson’s. There
are a number of childhood diseases
that affect the central nervous system,
and ifyou could go into the stem cells
and repair the damage, it would have
tremendous implications."

The pancreas has stem cells: “Dia-
betes is a huge problem in this coun-
try. lmagine if you could go in and fix
the insulin-producing cells with stem
cells.”

Heart muscle contains stem cells:
“it was thought that if you had an
infarction—a great big chunk of your
muscle was damaged—you were

continued on p. 8

Bone Marrow Transplant 101

Bone marrow is home to HSCs. "Hematopoietic tissue is
nice because it‘s almost a liquid organ." says Van Zant.
“You punch a hole in one end of the bone. stick a needle
in the other end. squirt. and the whole plug of marrow
comes out the other end. You can harvest and collect
marrow very quickly."

But the process is painful. “ln a bone marrow harvest.
a patient goes to the OR. is anesthetized. punches are
made across the back around the rim of the hipbone. and
large amounts of marrow are pulled. It involves anesthe-
sia—there's a certain risk there—and a recovery time,"
Van Zant says. but quickly points out that 10 years ago
scientists found a better way to collect HSCs.

“We can inject a patient with a drug that causes the
stem cells to leave the marrow and enter the circula-
tion—we call this mobilization. This is the most common
way of harvesting stem cells today."

The blood sample is passed through a machine (in a
process calledleukapheresis) thatseparates outthe white
blood cells, which contain the stem cells, and returns the
other blood cells to the patient.

50 what happens in a bone marrow transplant? There
are two types: autologous transplants. in which patients
receive their own stem cells: and allogeneic transplants.
in which patients receive stem cells from a brother or
sister or unrelated matched donor.

Van Zant sets up a hypothetical scenario for an autolo-
gous transplant. “You have cancer. You're early in your
disease, so you‘re going to be responsive to drugs. We
give you drugs. and you go into remission. We collect
stem cells from your peripheral blood. We freeze those in
liquid nitrogen down in the stem cell lab and put them
away for later.

“We turn around and give you. essentially. a lethal
dose of radiation or chemotherapy. and. we hope. this
huge dose will kill all of your tumor cells, and maybe
even some of the mutated. cancer-causing stem cells.“
He notes that this is the rationale for high-dose chemo»
therapy.

“You would die if we didn‘t have those bone marrow
stem cells frozen. A day or two after your chemo. we
injectintoyourbloodasmall numberofstem cells.Those
stem cells are going to have to replenish your entire
hematopoietic system. and that’s going to take some
time. Meanwhile you‘re extremely vulnerable to infec-
tion, and the longer it takes for you to recover your white
blood cell count. the more at risk you are from complica»
tions post-transplant.“

” \s ti print ipal in\ t‘Slleltii, | hm t‘ a tremendous rcsponsibilih to maintain funding lor these projct ls bcr ausc
Ili(‘\ support all Hi the Dt‘i)Dlt‘ in nix lab. |’\c got to look after rm rcscart h family,” saxs (1am \an Zant. Ba< l\
mu llt‘ll to iithl, \lHQ I tang, \dricnnv l llis, Jcll Yates, Barn Grimes, Carol Snidtrrski, and \manda \\atcrstrat.

lront ro\\: \lindi llalm, Dclihic Boll, trin Oakley \an /ant, and \Iison \\i|lcr.

.« an?" r; m i

Grad student Alison \tiller (left) and postdoc Debbie Bell (center, background) haw \\orkcd in \an /ant’s researr h lab for

two years. Grad student -\manda \\atcrstrat (right) has spent one war as part of a lab team that’s been lttt using on stem

cell "homing” and population size.

pretty much out of luck. Now it‘s be-
coming apparent that quite a bit of
regeneration occurs in the heart. and
cardiac muscle stem cells apparently
play a role in some degree of turn—
over.”

Another exciting, albeit controver-
sial. area of stem cell organ research
istransdifferentiation.which Van Zant
defines as “the abilityofan adultstem
cell to switch specificities to suit the
environment in which it finds itself."

He sets up a transplant scenario:
“Let's say you get a bone marrow trans-
plant from a sibling. ln half the cases
that graft is going to be sex mis-
matched—because it‘s just as likely
that your brother would be matched
to you as your sister. 50 you, as a
female, get a bone marrow transplant
from your brother.

“In a real case. a woman got a bone
marrow transplant from a man. Years
after the transplant and after that

woman died, the doctor performing
the autopsy wondered if the trans—
plant had replenished any tissues
other than the bone marrow. And low
and behold. he looked in her heart
andthere were cardiac cellsthatwere
male. They could have only gotten
there fromthe bone marrow cellsthat
were transplanted into that woman.
This is one of the strongest arguments
for transdifferentiation."

Van Zantaddsthere‘s also evidence
that scientists can take an adult stem
cell from bone marrow, transplant it
into a damaged liver. and replenish
the liver cells. "There‘s also evidence
that bone marrow stem cells can re-
generate. or at least generate prog—
eny. in the brain.

“But why doesn‘t this happen nor-
mally? Why don't the stem cells float—
ing around in your blood ‘get off the
train‘ and migrate into damaged tis-
sues? Well. there are obviously things

we don‘t understand. but the data‘s
pretty tantalizing that. in fact, under
some conditions. stem cells from the
bone marrow can fix damage in other
organs."

Mice as a Model

“If we measured the number of HSCs
in the bone marrow of two ‘normal‘
humans. like you and me, we may
find that the difference is about 100-
fold between us. And yet. we're both
apparently normal. How can that be?"
Van Zant asks more animated with
each word. “And what are the ramifi-
cations for the chances of one or the
other of us getting leukemia or aging
faster? These are the kinds of ques-
tions we hope to answer with mice.
“Mice mimic the vast majority of
biological features that we find in
humans, including aging. Only it‘s on
a much accelerated chronological
scale—in two years a mouse goes

through a series of processes that
are mimicked in humans over eight
or nine decades,” he explains.

“In the bone marrow itself, the
age-related changes in HSCs are very
similar. In humans the bone marrow
becomes hypocellular, that is, the
numberofcellsinagiven volume of
bone marrow decreases with age.
The same is true in the mouse. The
nice thing about mice is you can get
a group of mice that are genetically
identical.”

One such group, or “strain," of
mice is immunodeficient (labeled
by scientists as NOD/SCID—
nonobese diabetic/severe com—
bined immunodeficient). “This is a
strain in which the immune system
is completely wiped out. They have
no immune response to anything.
Scientists have used that mouse as a
transplant model into which they‘ve
put human cells, and that’s what
we’ve done.

“You can give a mouse virtually
the same treatments that are admin-
isteredtoahumanin cancertherapy,
andyou can doabone marrowtrans—
plantinamousethat’svirtuallyiden-
tical to one in a human. And the
recovery patterns are very similar."

These similarities have allowed
Van Zant’s team to make two impor-
tant discoveries.

“We’ve taken bone marrow stem
cells from different age groups:
people age 80 and older, middle
age, adolescent, and newborns—
from umbilical blood. We can study
the differences in these stem cells
very precisely by putting these cells
into NOD/SCID mice. We can get
actual numbers of stem cells, and
see how quicklythey repopulatethe
bone marrow.

Umbilical Cord Blood & UK’s Cord Blood Bank

“Umbilical cord blood is a tremen-
dous source of stem cells that’s vir-
tually untapped, because it’s usually
just thrown away in the delivery
room,“ says Van Zant, who empha-
sizes that these are “adult,” fully
developed, stem cells.

“Go to any OBGYN waiting room,
andyou’llsee brochures fornational
commercial companies that will
make sure your child’s cord blood
is harvested and stored indefinitely.
Many parents are now getting sawy
and paying to freeze their child’s
cord blood just in case the child
develops leukemia or otherdiseases
that can be treated with stem cells.

“At UK we’re not in the business
of storing blood for families," says
Van Zant, who directs the year-and-
a—half—old UK Cord Blood Bank. He
adds that there are certain regula—
tory and liability issues to do so that
the institution hasn’t delved into.
“We’re interested in experimental
and investigational use.

“So how do we obtain our blood?
It’s a partnership between the Cord
Blood Bank and the people in OB—
GYN, who get consent, as part of the
regular paperwork mothers fill out,
to donate their child’s cord blood
to research. A very large number of
mothers agree to this.

“It takes a lot of cooperation from
the OB—GYN residents who are actu—
ally in the delivery room, because,
obviously, this is an afterthought to
the big event," Van Zant says with a
smile.

“At best you can get 50 to 100
milliliters of blood from the pla-
centa and umbilical cord of a new-
born. Although this blood is rich in
stem cells, until recently it was sim—
ply not thought to contain enough

stem cells to transplant and repopu-
late the entire hematopoietic sys-
tem of an adult. So it was used only
in children who weighed 50 pounds
or less."

But in December 2004, at the an-
nual American Society for Hema-
tology conference, two findings
came out that may have a huge
impact on umbilical cord blood
transplantation.

“The first big finding, from a group
at the University of Minnesota, was
that it is feasible to pool cord blood
from different~even completely
unrelated—births to get enough
stem cells for transplantation.” Van
Zant points out that scientists had
been wary of combining sources
because this could trigger undesir-
able immune responses. “The cord
blood stem cells are very young,
and they have diminished immune
sensitivities, and it looks like you
can, under some controlled condi-
tions,combinethemto getthe num-
bers you need."

The second finding, the result of
collaborative studies between Duke
University, the University of Minne-
sota and the New York Blood Cen-
ter, showed that perhaps the number
of stem cells needed for an adult
transplant is lower than scientists
originally thought. Van Zant says,
“They foundthat the numberofstem
cells actually needed, for most
people, iswithin reach with the stan-
dard cord blood harvest. Now, that’s
only one study, and it needs to be
followed up and duplicated, but it’s
very encouraging.

“Together these findings have re-
ally enhanced the possibility of ex—
panding cord blood use for a wider
number of transplants.”

“We’ve learned two interesting
things. First, old bone marrow doesn't
repopulate the NOD/SClD mousevery
well—not nearly as well as umbilical
cord blood. And second, we have
very convincing evidence that old
stem cells have a greatly diminished
capacity to find theirway home to the
bone marrow."

Scientists don‘t know a lot about
stem cell “homing," and these are the
questions Van Zant is tackling. “ls
homing a random process? ls it just a
scatter-gun approach—they go in,
some of them hit the target, but 99.9
percent don’t? Or can it be directed?
Why do old stem cells find home less
effectively than young stem cells?"

Van Zant says his findings so far are
clinicallyimportantbecausetheysug—
gest that you may not want to bother
harvesting stem cells from older do-
nors. “Even if the stem cells them-
selves are ‘good,’ their age seems to
automatically lower their chances of
making it into the bone marrow.“

Looking Forward

The very method of Van Zant’s re—
search means he can’t predict where
it’s going to lead. He explains: “We
know these mice are different in a
very reproducible way, but what pos-
sible genes can cause that difference?"

The first step to identify genes is
zeroing-in on the appropriate chro—
mosomes. (Humans have approxi-
mately 30,000 genes on 23 pair of
chromosomes—one of each pair you
got from your mother, the other from
your father. Mice have roughly the
same number of genes on 20 pair of
chromosomes.) “When you're look-
ing at all possible genes, you never

know where you’re going to end up.
And that’s exciting.“

The most recent source of excite-
ment is a genetic discovery by fifth—
yeargraduatestudentYing Liang,who
works in Van Zant’s lab. Van Zant
cautions that he can’t divulge too
many details about this discovery be-
cause he and Liang are pursuing a
patent on it, but he comments, “Her
work makes us almost completely
certain that this gene, that had never
before been shown to have an effect
on hematopoietic stem cells, appears
to be very important.“

Liang. a native of mainland China,
says her work focuses on the regula-
tion ofstem cell numbers. “HSCs are
veryimportantin bone marrowtrans-
plantation. However, a big obstacle
for this procedure [see sidebar on
umbilical cord blood, previous
page] is that inadequate numbers of
stem cells are available for trans-
plantation. Right now, we are look-
ing for genes that might be
responsible for expanding stem cell
numbers, and we’ve already found a
gene that may play such a role. l’m

testing the functions of this gene by
overexpressing it [purposely produc-
ing excess] in HSCs to see whether
or not the stem cell population in—
creases.“

Van Zant’s team has located an—
other target gene on Chromosome ll.
“We have a very strong candidate,
RadSO, a gene vital to DNA damage
repair. This is important because the
long-standing damage-response
theory arguesthatagingisthe resultof
accumulated damage to the macro-
molecules of cells—protein, lipids,
nucleic acids—andthat accumulated
damage accounts for the physical
manifestations we associate with age,“
he says.

Because stem cells are capable of
spawningso many progeny, they must
have “robust mechanisms of DNA re—
pair. Defects in a critical DNA repair
component such as Rad50 could seri—
ously affect the ability of stem cells to
function—particularly in old age,“
Van Zant says.

“If stem cells can’t supply the ap—
propriate numbers of progeny, aging
is accelerated. And if DNA damage is
not properly repaired by RadSO, mu-
tations may result in tumor forma—
tion.”

It all comes down to this: “The
natural course of aging and its unde-
niable association with cancer is not
lost in a stem cell, despite its amaz-
ing ability to self—renew and restore
tissue in times of need. Stem cells
have tremendous potential. And
we’re here to help answer the basic
questions that will lead to a new
generation of cellular therapies." r‘?

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