Vital flaw

Liver cells play fast and loose with rules governing the shuffling of genetic information. The cells’ creative dealing of cards to daughter cells ought to wreak havoc, but for some reason it actually may help the liver deal with toxins more effectively, a new study suggests.

Instead of dealing out two copies of each chromosome — one inherited from mom and one from dad — to each daughter cell, liver cells often double or even quadruple the number of chromosomes in each cell. Scientists have long puzzled over why liver cells have so many extra chromosomes, and now the story has gotten even more bizarre: Not only can liver cells have multiple full sets of chromosomes, but the number of individual chromosomes in a cell is often wrong, researchers report online September 22 in Nature.

Cells that have anything other than the usual pairwise arrangement of chromosomes — such as one or three copies of a particular chromosome instead of two — are known as aneuploid cells.

Aneuploidy is, for lack of a better word, bad. At least that is what most scientists have thought, and for good reason. Cells with the wrong number of chromosomes are a hallmark of cancer, says Chantal Desdouets, a cell biologist at the Cochin Institute, part of the French national health research agency INSERM in Paris.

But the study shows that liver cells are able to live normally with an unusual number of chromosomes. This shuffling of chromosomes produces different combinations of genetic material in liver cells, which may influence the way cells break down toxins and give some cells an advantage over others.

The new study “gives us an exciting new view on the nature of the mammalian liver; that it’s a genetically dynamic organ,” says David Pellman, a Howard Hughes Medical Institute investigator at the Dana-Farber Cancer Institute in Boston.

Andrew Duncan, a cell biologist at Oregon Health & Science University in Portland, Ore., and his colleagues transplanted liver cells containing eight full sets of chromosomes into a mouse with a mutation that causes liver failure. The transplanted cells took over the liver, eventually constituting 70 percent or more of the organ.

Instead of maintaining eight copies of each chromosome, the liver cells reduced the full sets of chromosomes to four or the usual two, the team found. Looking more closely, Duncan and his colleagues discovered that many of the liver cells had unusual combinations of chromosomes, with some cells having one type of chromosome with two maternal copies and no paternal copies or vice versa, or even three or more of one chromosome and reduced numbers of another chromosome.

The team also examined livers of normal mice and found that young mice mostly have the normal two copies of each chromosome in each cell. As the animals age, the number of cells with abnormal numbers of chromosomes increases such that more than 60 percent of cells in adult mice are aneuploid, the team discovered.  

“Initially we were really skeptical of our results because they just did not fit with the canonical view,” says Duncan.

Duncan made videos of cells with four full sets of chromosomes dividing. Most of the time, the cells simply split in two. But about 3 percent of the time, cells split into three or four daughter cells. Cancer cells sometimes divide three or four ways, but the resulting cells usually end up dying. Unlike cancer cells, the liver cells produced from the multiple splits were healthy and sometimes divided again while the scientists were filming.

“I really did not think this would happen at all” in healthy liver cells, Duncan says. “It just seemed too outrageous at the time. These are not cancer cells.”

Now the team is trying to find out how the abnormal distribution of chromosomes affects liver cells. Duncan speculates that the genetic diversity introduced by extra chromosomes may help the liver withstand assaults by toxins or may change the rate at which the liver breaks down drugs and other chemicals. Desdouets wonders if aneuploid liver cells are more susceptible to becoming cancerous.

The findings in the new study may not apply only to the liver, Duncan says. Heart muscle cells and some other tissues in the body have multiple full sets of chromosomes, and some brain cells have abnormal numbers of chromosomes, he says.

“It looks like aneuploidy is in other tissues, and that’s not very well appreciated right now,” Duncan says.