Hippo, Warts and Other Thugs of the Genetic Realm

These are not characters from a Damon Runyon story but a crew of genes that work together to switch other genes on and off. A team of biologists led by James F. Martin and Todd Heallen of the Texas A&M System Health Science Center has now found that these genes block the heart from growing new heart muscle cells, at least in mice.

Knock out Hippo, for example, and the mouse’s heart grows two and a half times bigger than usual, they report in Science.

This and other advances, including the discovery this year that infant mice can regenerate their hearts for the first seven days after birth, is evoking considerable interest among researchers trying to develop new treatments for heart attacks.

The findings “will mark a renaissance of interest in the genetics of cardiac muscle growth control because of the potential therapeutic applications,” said Michael D. Schneider, a heart biology expert at Imperial College in London.

The reason that heart attacks are so serious is that when a large number of heart muscle cells die, they are not replaced. Yet the heart does slowly generate new muscle cells during a person’s lifetime, showing that a growth program is in place. It is firmly repressed, however, presumably to avert the danger of cancer.

Surgeons have tried injecting stem cells of all kinds into stricken hearts, but despite many clinical trials, there is little evidence that the cells do much good. This setback has led to renewed interest in trying to unlock the heart cells’ inherent growth program.

Dr. Martin started with the Hippo gene because it is known to regulate the size of a fruit fly’s organs. Fruit fly biologists are often the first to recognize new genes and to work out what they do. The names they confer on genes are colorful and often grotesque because they are inspired by what happens to the fly when you knock out a specific gene from its genome.

If you delete the Hippo gene, the fruit fly grows an enormous head with folded skin around the neck. Hence Hippo.

By engineering a mouse in which Hippo was deleted just in the heart, Dr. Martin’s team showed that the chain of genes in which Hippo acts serves as at least one of the natural restraints on the proliferation of heart muscle cells.

Zebra fish can regenerate the tip of the heart when it is cut off. Researchers have recently found the fish can even replace the scar tissue that forms when muscle cells die, which is often a problem for failing human hearts. The finding that infant mice can also regenerate the heart means that mammals, perhaps including people, may also have this ability, even though it is lost in adults.

If the mouse and zebra fish have some natural way of escaping the Hippo gene’s clamp on heart cell growth, it is possible that some drug could be developed that would close down the Hippo pathway in people for a few days after a heart attack, allowing the heart muscle cells to enjoy a much-needed spurt of proliferation.

Dr. Martin said his next step would be to grow adult mice with a disabled Hippo gene and see if they recover faster after a heart attack. He also plans to see if human heart muscle cells grown in a laboratory dish proliferate better if the Hippo pathway is disrupted.

In fruit flies, an organ can produce more cells only if two gene promoters, called Yorkie and Armadillo, get to penetrate the cell’s nucleus and switch on the suites of genes required for the cells to grow and divide. But when Hippo is active neither Yorkie nor Armadillo can do its work. The signal that activates Hippo in the fly is called Dachsous, which must first trigger a receptor protein called Fat in the cell’s surface. But receptors like Fat can respond to many different signals. So it is not yet clear that the mouse or human counterparts to Dachsous and Fat are the triggers for the effect Dr. Martin’s team has seen, Dr. Schneider said.

If the human counterparts are identified, then a drug that blocked them, switching off Hippo, might let heart muscle cells regenerate themselves, leading to a novel and fundamental treatment for heart attacks.

But Hippo, Warts, Merlin and crew would not be part of the story. When mouse researchers look for the counterparts of fruit fly genes in mice, they give them new and duller names. Human geneticists are even more fearful that colorful gene names will create an aura of frivolity that discourages serious grant money. “They ruin it,” Dr. Martin said. The gene that fly biologists call Ménage-à-trois 1 is called MAT 1 by human geneticists. The poetically named Son-of-Sevenless in flies is the prosaic SOS 1 in people. As for Hippo, mouse researchers have already decolorized it to MST 1.