With a $5 million five-year federal grant, the Johns
Hopkins
School
of Medicine is establishing what is believed to be the
first university-based research center devoted to studying
epigenetics, an effort that will set the stage for learning
as much about our epigenetics as the Human Genome Project
taught about the sequence of building blocks that make up
our genes.
Much as our genetic sequence is passed from parent to
child, epigenetic "marks" that sit on our genes are also
inherited. These "marks," usually small methyl groups, are
attached to genes' backbones and convey information, such
as identifying which parent the gene came from. The marks
also normally turn genes on or off. But just as changes in
genes' sequences can cause diseases such as cancer, gain or
loss of epigenetic marks can, too, by improperly turning
genes on or off.
"Epigenetics may be as important in certain
conditions, or in contributing to the risk of developing
certain conditions, as the genetic sequence is in other
cases," says Andrew Feinberg, King Fahd Professor of
Medicine and principal investigator of the epigenetics
grant. "Epigenetics doesn't underlie all human disease, but
we definitely need to develop the technology to figure out
when and where epigenetic changes do influence health and
disease."
Feinberg, who pioneered the study of epigenetics in
cancer, will lead the new Center for the Epigenetics of
Common Human Disease at Johns Hopkins, which is funded by
the National Human Genome Research Institute and the
National Institute of Mental Health. Through the center's
grant, Feinberg and his colleagues will first develop tools
to create comprehensive information about epigenetics and
then apply that information to the study of autism and
bipolar disorder. The epigenetic information and
technologies will also be available to researchers
investigating other conditions.
According to Francis S. Collins, director of the
National Human Genome Research Institute, "Having the human
DNA sequence is just the first step in our quest to
understand the complexities of the biological systems in
the human body. Epigenetic effects undoubtedly play an
important biological role, and learning more about these
effects is essential to deciphering the mysteries of human
health and disease. So we are thrilled that Johns Hopkins
has pulled together this world-class team of researchers to
move this important field forward."
The ambitious Hopkins center is the ninth grant funded
through the NHGRI's and NIMH's Center for Excellence in
Genome Science program, and the first to focus on
epigenetics.
Chi Dang, vice dean for research at the School of
Medicine, says "this center reflects a trend at Hopkins to
shift toward interdisciplinary research, really pulling
together those working on related problems, regardless of
their department affiliations, to tackle important basic
questions whose answers will advance human health." He adds
that Hopkins'
Institute for Cell Engineering and the Institute for
Basic Biomedical Sciences are both advancing such
multidisciplinary research models.
Given its own "multidisciplinary" status, the center
will be bigger than Feinberg's laboratory alone. Among the
key players are 15 other researchers from Hopkins and
elsewhere whose work and collaborations will be critical to
the center's success.
"As we studied epigenetics in cancer, it became clear
that we needed to 'genomicize' epigenetics, to really
investigate the issue more broadly than simply its role in
cancer," Feinberg says. "This center is a first, critically
important step toward creating a comprehensive picture of
epigenetics and its role in human health."
First on the researchers' to-do list is development of
technology to speed identification of epigenetic marks and
their locations in the genome and then adapt these methods
to examine multiple sections of the genome and many samples
at once.
Next, with Johns Hopkins colleagues and collaborators
from a German company called Epigenomics, the Icelandic
Heart Foundation and Pennsylvania State University, these
new technologies will be used to examine the entire
epigenomes of specific groups of people to hunt for clues
to human disease. The first groups to be analyzed will be
families — at least a "trio" of parents and child
— from two Johns Hopkins groups studying the genetic
bases of autism and bipolar disorder, and from the 30-year
effort of the Icelandic Heart Foundation.
"Iceland isn't much different from Northern Europe in
terms of its genetic diversity, but organizations like the
Icelandic Heart Foundation boast great documentation of
familial relationships, medical histories and thorough and
quantitative medical examination to go along with blood and
tissue samples," Feinberg says. "There is great scientific
value in what they have and what they do."
In particular, Feinberg points out that researchers at
the IHF invented high-throughput, quantitative phenotyping
— the ability to rapidly assess the biologic traits
and characteristics that stem from genetic, epigenetic and
environmental influences. With the IHF information and
samples, Feinberg and his colleagues will determine whether
and how epigenetic marks shift over time and how a child's
epigenetic marks differ from his or her parents'.
"The genetic sequence is essentially fixed for life,
but we believe epigenetic marks are more subject to
change," Feinberg says. "The IHF collaboration will let us
really test the stability of epigenetics and the passage of
those marks from parents to child, perhaps even over
successive generations."
At the heart of the center's work is epigenetics'
importance in proper cell function and in development. One
example of epigenetics is "imprinted" genes--genes whose
activity is determined not by the regular dominant and
recessive rules of Mendel's genetics but solely by which
parent provided the gene copy. For example, for some
imprinted genes, only the copy from the mother is used,
while for other imprinted genes, only the copy inherited
from the father is turned on. (Our cells contain two copies
of every gene, one from the mother and one from the
father.)
At some point before, during or after egg meets sperm,
epigenetic marks such as those used for imprinting must be
reset and re-established, so that a gene passed from father
to daughter to son is appropriately marked, for example.
Knowing how and when this happens, and whether the process
can be controlled, has important implications for
understanding human development and the viability of
animals and stem cells created through somatic cell nuclear
transfer, a process colloquially known as cloning.
As part of the center, Feinberg and his colleagues
will implement a "minority action plan" to encourage racial
and ethnic minorities to pursue education and careers in
genetics and genomics. The plan offers select local
students the chance to conduct genetics and genomics
research during their summer breaks, and Feinberg will work
with staff at the Center for Talented Youth, a Johns
Hopkins endeavor with sites across the country, to add a
genomics component to the program's summer classes.
Starting in 2005, the Epigenetics Center will fund four
minority students each year to attend these classes.
"The idea is to groom an interest in science and in
genomics from a young age, hopefully increasing the number
of minorities who pursue education and careers in genome
sciences," Feinberg says.
Others closely involved with the center's work are
Karl Broman and Margaret Fallin, Johns Hopkins
Bloomberg School of Public
Health; James Potash, Hengmi Cui, Patrick Onyango, J.
Raymond DePaulo, Hans Bjornsson, David Nichols and Jef
Boeke, Johns Hopkins School of Medicine; Kurt Berlin,
Epigenomics AG; Vilmundur Gudnason, Icelandic Heart
Foundation; Webb Miller, Pennsylvania State University;
Eric Green, NHGRI; Tamara Harris, National Institute on
Aging; and Lea Ybarra, JHU's Center for
Talented Youth. Nichols and Ybarra will be principally
involved with the center's minority action plan. Feinberg
is also a member of the
McKusick-Nathans Institute of Genetic
Medicine at Johns Hopkins.