The Year in Science: Genetics 1997

A Man-Made Chromosome

By Unmesh Kher|Thursday, January 01, 1998
Although dozens of genes are identified every year, along with the flaws in them that cause disease, gene therapy is still rare. The biggest problem is how to deliver an intact gene into the body of a human who needs it. Viruses are one vehicle, but often they can’t carry long human genes, and when they can the genes don’t always produce consistent levels of protein. Last spring researchers in Ohio announced the creation of a promising new gene carrier: a human artificial chromosome (hac) that behaves just like a natural one. It is duplicated and passed along with every cell division—just the talent necessary for it to survive in the body and provide long-term relief from a genetic disease.

A chromosome is more than just dna; the dna is wrapped around ball-shaped proteins called histones. Researchers have already created artificial chromosomes in yeast, but those wouldn’t reproduce in a human cell, in part because yeast histones aren’t the same as human ones. The team led by Huntington Willard at Case Western Reserve University School of Medicine avoided this problem by giving naked dna to cultured human cells, letting them provide their own histones.

But the researchers couldn’t use just any dna. There are three key stretches of dna on a human chromosome, and without these the chromosome will not reproduce properly. The first is an origin of replication, where the two spiral strands unwind so they can be copied. The second stretch is the telomere, a protective cap that prevents the ends of chromosomes from shortening every time the cell divides. The third stretch is the centromere, the little knot that joins the two identical copies of each chromosome after replication, ensuring that each daughter cell will get one copy as the cell divides.

Telomeres and centromeres both consist of many repetitions of a single short dna segment. Willard’s team knew how many in the case of telomeres and managed to synthesize a long enough sequence. In the case of centromeres they had to guess, attaching many of the short dna segments end to end and hoping to make the chain long enough. To make the origins of replication, whose sequence is unknown, the researchers guessed again, using segments of human dna that they suspected contained the right sequence. Finally they threw a mix of all three key dna elements into human cells.

Their educated guesses proved lucky: a look at the cells under a microscope revealed a stable, if minuscule, hac, about a fifth to a tenth the size of natural human chromosomes. That is considerably longer than any viral genome, though, and long enough to carry entire human genes as well as the sequences around them that regulate how much protein is made. And since the hac carries only human dna, it is far less likely than a virus to trigger an immune response in the patient. On the other hand, whereas viruses can easily slip into a patient’s tissues, artificial chromosomes can only be put into cells that can be removed from the body and then reintroduced—blood cells, for example. I would not like to prejudge what it will or will not be useful for, says Willard, but I think the blood diseases—such as sickle-cell anemia and hemophilia—are the most obvious ones to tackle at the moment.
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