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If salamanders, worms, and fish can regrow lost limbs or damaged
organs, why can't humans? That's a question that has long intrigued
Mark Keating. By studying the molecular mechanisms of organ
regeneration, he eventually hopes to regenerate healthy human hearts
from damaged heart tissues. His research also focuses on cardiac
arrhythmias, with the goal of improving their prediction, prevention,
and treatment.
Keating, who was trained as a cardiologist, fully intended to pursue
a career treating patients. But he quickly recognized that it was the
basic science behind diseases that intrigued him most. He became
interested in the field of regeneration after observing that inadequate
regeneration is a fundamental mechanism of many diseases, including
atherosclerosis, heart failure, and arrhythmia. "I wanted to know: What
triggers regeneration? Why don't human limbs and organs regenerate? And
what can we do to change that?"
In experiments conducted over the past decade, Keating has
challenged the theory that fully differentiated mammalian cells can't
reverse their development and revert to stem cells. While doing
research on human heart disease at the University of Utah, Keating and
his colleagues identified a gene called
msx-1
, which is turned
on in newts whenever these animals need to grow a new limb. Mice have a
similar
msx-1
gene, and Keating demonstrated that mouse skeletal
muscle cells can be coaxed in vitro to revert to stem cells (a process
called "dedifferentiation"), and then respecialized into cells
resembling bone, fat, and cartilage. The finding suggests that mammals
have retained the intracellular signaling pathways required for
dedifferentiation and that the major obstacle to regeneration in
mammals may be the lack of signals to jump-start the process.
More recently, Keating and his colleagues found that zebrafish can
regenerate their hearts after injury, giving hope that understanding
cardiac regeneration in this fish may lead to ways to repair injured
human hearts. Human hearts do not regenerate. On the contrary, damaged
cardiac tissue in humans is replaced by scarring. If significant, this
scarring can lead to an "epidemic of heart failure, arrhythmia, and
death," Keating said.
Keating's focus on regeneration research is a deviation from his
earlier successful studies of long QT syndrome and Williams syndrome.
In the 1990s, Keating identified mutations in five genes that cause
long QT syndrome, an inherited disorder that causes sudden death in
young, otherwise healthy people. These mutations disrupt the rhythmic
functioning of five distinct ion channels in the heart, which increases
the excitability of heart tissue and the risk of life-threatening
arrhythmias. He also defined the role of elastin in vascular disease
and Williams syndrome, a disease that often causes mental retardation
and other disabilities.
In other research, Keating and his colleagues have discovered
several genes associated with cardiac arrhythmias, a condition that
causes 450,000 sudden deaths each year in the United States. Recently,
they found that a variant form of a gene found in the hearts of some
African Americans may increase their risk of developing a potentially
deadly cardiac arrhythmia. This genetic defect creates sodium channels
in heart muscle cells that stay open longer than normal, which prolongs
contraction of the heart and contributes to the arrhythmia. They have
also pinpointed the genetic cause of a devastating but rare childhood
disorder, called Timothy syndrome, which underlies a form of severe
cardiac arrhythmia.
Dr. Keating is Professor of Cell Biology at Harvard Medical School and Professor of Cardiology at Children's Hospital Boston.
RESEARCH ABSTRACT SUMMARY:
Mark Keating's laboratory focuses on the molecular mechanisms of organ regeneration and the human molecular genetics of cardiovascular disease.
View Research Abstract
Photo: FAYFOTO, Inc.
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