EDITOR’S CORNER
Alfred A. Bove, MD, PhD
Editor-in-Chief, CardioSource WorldNews
Treating Disease at
the Genetic Level
I
n 1953, we learned that all of the structures in
our bodies, and in all other living organisms, are
built from coded information contained in the cell
nucleus. Following the x-ray diffraction studies of
Rosalind Franklin, the discovery by Watson and Crick
of the double helix of deoxyribonucleic acid (DNA)
—and the means by which the sequence of nucleic
acids coded to build proteins that in turn built tissue
and organ structures—was a landmark discovery that
altered our understanding of biology. Since then, we
have learned how the DNA information is transferred
to an intermediate information system embodied in
ribonucleic acid (RNA) and how RNA codes for the
manufacture of proteins that, when fully assembled,
create the living organism.
We quickly learned that DNA was bundled into
groups called genes that held collections of specific
functions; furthermore, there were a fixed number of
genes in living species, there were differences in some
genes that defined female and male, and various characteristics of a given person or animal were related to
specific variations in the genetic structure. Genes reside
in the chromosomes, and we humans have 46 of them.
We can now trace congenital abnormalities to specific enzymes and have
developed methods to alter the outcome
via therapies designed to counter the metabolic defect. Such therapies have resulted in
normal development in many children who
had metabolic defects that otherwise would have
caused life-long disabilities. Our understanding now
encompasses the chromosomal variants that cause
congenital syndromes such as Down’s and Turner’s
syndromes, and we are identifying specific genetic
changes that relate to various forms of cardiomyopathy, channelopathies, receptor sensitivities to
medications, and metabolism of drugs. What’s
more, we have discovered that genes can be modified by environmental factors, and often are altered
by stress caused by various disease states.
These discoveries led to the new concept of
epigenetics wherein gene action could be modified
by environmental factors affecting the cell. Heart
failure is an example of epigenetic changes induced
by the heart failure condition. Attempts at modifying
genetic structure have generally been unsuccessful
The current interest is in heart failure
caused by ischemic and nonischemic
cardiomyopathies.
So many important discoveries have been made
regarding how the system functions that it is difficult
to list them all, but inevitable questions come to
mind. For example, how does the genetic structure
relate to the many inherited disorders that have
been observed over the history of clinical medicine?
Many of the syndromes that we now characterize as
defects in a specific gene structure were identified as
genetic disorders without an understanding of how
these genetic disorders evolved and where the abnormality that caused the disorder was located.
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CardioSource WorldNews
and, in a few cases, have resulted in catastrophic
results with demise of the subject. A logical advance
would be to create genetic changes that would counter cellular changes related to various disease states.
The current interest is in heart failure caused by
ischemic and nonischemic cardiomyopathies. Alterations in microvascular structure could be done
by modifying genes that result in angiogenesis and
intracellular metabolism of calcium in the failing
myocyte could be affected by enhancing calcium
transport in the myocyte. Identifying specific
proteins that would enhance cellular function has
been accomplished; the next step: induce the cell
to produce intracellular mechanisms that improve
myocyte function.
Either directly or by intracoronary infusion, we
have tried to inject stem cells into the myocardium
with marginal results. The assumption that the
progenitor cells would either proliferate in the myocardium or, through cell signaling, induce existing
myocytes to replicate has not demonstrated significant improvements in function in failing hearts. So
we come to 2016 wherein attempts to modify the
intracellular milieu by genetic manipulation unfolds
as the next frontier in heart failure therapy.
With the understanding of the intracellular
defects that accompany heart failure, we now see
the possibility unfolding to alter specific intracellular mechanisms at the protein level using welldeveloped methods for inserting specific functional
genes into the cell nucleus. These techniques and
innovations allow the cell to produce new proteins
that can improve cellular function and ameliorate
heart failure.
While our medications to improve heart
failure outcome have been successful, they don’t
get to the heart of the problem: loss of myocytes.
As you will read in this month’s cover story, this
new approach, aimed at improving contractile
function directly, is the f uture—but we still have
a long way to go. ■
Alfred A. Bove, MD, PhD, is professor emeritus of
medicine at Temple University School of Medicine in
Philadelphia, and former president of the ACC.
January 2016