Saturday, May 9, 2015

The Muscle That Allowed Us to Evolve

The muscles connected to the ears of a human d...
The muscles connected to the ears of a human do not develop enough to have the same mobility allowed to many animals. (Photo credit: Wikipedia)


BY CARL ZIMMER


Some muscles get all the glory. But deep inside of us, a sheet of muscle does heroic work in obscurity. The diaphragm delivers oxygen to us a dozen times or more each minute, a half-billion times during an 80-year life.

“We are completely dependent on the diaphragm,” said Gabrielle Kardon of the University of Utah.

All mammals have a diaphragm. But no other animal has one. Before the evolution of a diaphragm, our reptile-like ancestors probably breathed the way many reptiles do today. They used a jacket of muscles to squeeze the rib cage.

Once the diaphragm evolved, breathing changed drastically. Mammals gained a more efficient means to draw in a steady supply of oxygen. The evolution of a diaphragm may have made it possible for mammals to then evolve a warm-blooded metabolism. Without a diaphragm, humans might not have been able to evolve giant – but oxygen-hungry – brains.  

Scientist suspect that the diaphragm evolved through a change in the way mammal embryos develop: Mutations caused certain embryonic cells to grow into a new muscle. Dr. Kardon and other researchers are trying to understand that shift and why the muscle sometimes fails to develop, with catastrophic consequences.

One in every 2,500 babies is born with a hole in its diaphragm. The baby’s liver, intestines and other abdominal organs can push up through this opening against the lungs, stunting their growth and restricting breathing. About a third of babies born with congenital diaphragmatic hernias die.

Scientists have found that mutations in certain genes can increase the risk of developing hernias. But they have struggled to figure out exactly how these genes build the diaphragm. Dr. Kardon and her colleagues developed new tools to get a closer look. They published the research in Nature Genetics.

The scientists engineered mice so that certain types of cells would glow inside mouse embryos. Then they tracked the cells as they multiplied and migrated.

The diaphragm begins as a pair of folds flanking the esophagus, they found. These folds then expand in two waves. “It’s beautiful, aesthetically,” said Dr. Kardon. In the first, the cells become connective tissue across the top of the liver.

In the second wave, cells form a second sheet sandwiched inside the membrane. “The muscle cells are kind of dumb, and they’re just following the connective tissue,” said Dr. Kardon.

The researchers then examined GATA4, a gene linked to diaphragmatic hernias. They engineered mouse embryos so they could shut down GATA4 in certain types of cells at certain points in development. In one trial, the scientists turned off GATA4 in the muscle cells in the diaphragm. In these cases, the mice formed diaphragms. When they shut down GATA4 in the connective tissue, the mice developed hernias. Connective tissue cells must be using GATA4 to lay down a chemical trail for muscle cells, Dr. Kardon concluded. They can still lay down the trail if they have one defective copy of the GATA4 gene.

Each time the connective tissue cells divide, there is a chance that a working copy of GATA4 may mutate, too. If that happens, the mutant cell and its descendants can’t lay down a trail, resulting in a gap in the sheet of muscle. As the liver pushes against the diaphragm, the pressure creates intense stress in the gap, causing the diaphragm to rupture.

John J. Greer, a biologist at the University of Alberta, said he was skeptical that this scenario could account for most hernias.

He noted that most medical cases of congenital diaphragmatic hernias occurred in the back left or right corners of the diaphragm. Dr.Kardon and her colleagues produced many hernias in the middle or front of the diaphragm of their mouse subjects.

Dr. Kardon countered that a lot of hernias occur in other parts of the diaphragm, but doctors fail to notice many of them, because the lungs sit at the back of the diaphragm, hernias there can be dangerous. Hernias elsewhere can be harmless.

“Because they don’t have serious medical consequences, they go un-noticed,” she said.

Clifford J. Tabin, a geneticist at Harvard Medical School, said that the new study offers a molecular explanation for how congenital diaphragmatic hernias occur. “I think it is a beautiful study and terribly important,” he said.


Taken from TODAY Saturday Edition, The New York Times International Weekly, 25 April 2015