By Sue Goetinck
Dallas Morning News
Scientists are getting to the heart of the heart.
Researchers know how the heart beats. They also know exactly how the organ
bends and twists as it grows from a few cells in the developing fetus into a
four-chambered pump. And scientists know that somehow - as for the rest of the
body - the genetic blueprint is guiding the formation of the heart.
But until recently, no one has had any idea which of the thousands of genes
that make up the blueprint of humans and other creatures are the ones that
make the heart form properly.
The heart "has been the focus of interest for centuries, but no one has really
understood how it works," said Eric Olson, a developmental biologist at the
University of Texas Southwestern Medical Center at Dallas.
Now, some clues have come in from research by Olson and his colleagues at UT
Southwestern and scientists at the University of Chicago. The researchers have
discovered that three previously known genes are crucial for heart development
in mice.
The new research eventually could help scientists predict, treat or prevent
congenital heart defects, which affect almost one percent of children born in
the United States. By understanding which genes are important for the heart to
grow in the developing embryo, scientists also might be able to trick the
heart into growing a new patch of cells after a heart attack.
While any applications are at least a few years off, scientists say that
understanding the genes that drive the growth of the heart is a critical first
step.
"I think at the moment this is the best thing going," said Paul Overbeek, a
developmental geneticist at Baylor College of Medicine in Houston. "There
aren't really any other particularly good strategies."
In humans and other animals with backbones, the heart is the first organ to
form. Between about 20 and 23 days into a human embryo's development, the
heart starts to form and takes the shape of a minuscule tube. None of the
chambers are formed, but the tube can already beat.
Next the tiny tube loops to the right - the first sign of left/right asymmetry
in the body. Only after looping do the chambers of the heart start to separate
from one another. And by seven weeks, the heart is complete - four chambers,
and all the right connections to vessels leading to and from the body and
lungs.
Four new papers published recently - three from the Dallas researchers - show
that genes known to be active in the developing heart are actually crucial for
the organ to grow properly.
A gene known as GATA4, for instance, has turned out to be important early in
heart development. Olson's research team, and a group led by Chicago biologist
Jeffrey Leiden, used genetic engineering to generate mice that were missing
the gene.
The mice without the gene had several defects and died before birth. One
prominent defect was that the heart tube didn't form properly. Instead, two
heart tubes grew - one on each side of the animal. Olson said he suspects that
the two tubes can beat, but the embryos die before the heart loops. Both
research teams published their results in a recent issue of the journal Genes
and Development.
The Dallas researchers also found that a gene called MEF2C affects some of the
later steps in heart development. The heart tube in mice missing MEF2C doesn't
loop at all. The right ventricle - the chamber of the heart that sends blood
to the lungs - doesn't form either. The results of the MEF2C study appear in
the current issue of the journal Science.
Finally, in the June issue of Nature Genetics, Olson, UT Southwestern's Dr.
Deepak Srivastava and their co-workers report studies of a gene called dHAND.
The heart tube looped in mice without a working dHAND gene, but the right
ventricle didn't form at all.
All three of the genes, along with another gene previously known to affect
looping, serve as blueprints for cells to build protein molecules called
transcription factors. The job of this variety of protein molecule is to
activate other genes. So in the case of the heart, the transcription factors
probably turn on still more genes that eventually cause the tube to form, loop
and separate into chambers.
The fact that individual genes can affect formation of individual parts of
organs comes as a surprise, said Mark Fishman, a cardiologist at Massachusetts
General Hospital in Charlestown.
Why organs take on their characteristic shapes is a new frontier for biology,
he said. And by studying animals whose organs don't develop properly,
scientists can begin to understand the process.
"Until these experiments were done, we didn't really know what could go
wrong," Fishman said. For example, he said, "You couldn't have known that
there are genes that are important for the establishment of a single (heart
tube rather) than a double heart."
Scientists don't know for sure whether the equivalent genes are also driving
the development of the heart in humans. But there are some clues to suggest
that at least similar processes occur in other animals. A gene similar to
MEF2C affects heart formation in fruit flies, for example. And Fishman said
that genetic defects can cause zebrafish, a common aquarium pet that's also
used for biological studies, to develop two heart tubes, just as the mice do.
Researchers also hope that the studies will help with children who have birth
defects of the heart. "There's no question that all congenital heart defects
we see in humans arise in this developmental pathway," Olson said.
Some heart birth defects in people resemble the defects in the genetically
altered mice. For example, some children are born without either a right or a
left ventricle. But scientists don't know yet whether the same genes are
behind the birth defects in people.
While some heart defects have a known genetic cause, most do not. Srivastava
said he will start doing genetic tests of babies with heart defects soon. If a
connection can be made between genetic makeup and a birth defect, doctors
might be able to offer parents an explanation for their child's condition, he
said. Doctors also might be able to predict the likelihood that a second child
would have the same problem.
Srivastava noted that adults also might be able to benefit from the new
research.
When a person has a heart attack, for example, heart-muscle cells are gone
forever.
"Adult heart cells are such that if you lose them, you never make more,"
Srivastava said.
Researchers suspect that a damaged heart makes an effort to repair itself,
because genes kick in that are normally active only in the developing fetus.
"It seems like it's trying to get back to that state, but it doesn't get
there," he said.
By understanding the genes that go into forming a heart from scratch,
scientists might be able to re-enact the process to form new heart muscle in
adults.
The scientists said it might take several years for any of the practical
applications to come from their research. But as with most research, they
said, it's necessary to start somewhere.
"We're so much at the beginning stages of understanding," Overbeek said. "It's
hard to predict where the breakthroughs are going to come."