At first glance, chromosomes seem like simple structures. Tucked into the cell's nucleus, they're made of long strands of DNA twisted together into a double helix. Since the early twentieth century, chromosomes have been recognized as the source of inherited traits. As such, they faithfully reproduce themselves in a complex dance every time a parent cell divides into two daughter cells.

Beyond that, there is much that is still mysterious about the chromosome's structure and functional mechanics. To learn more about chromosomes and the genes they contain, biologists began to build artificial chromosomes in the lab. The first ones were bacterial artificial chromosomes, or BACs.

BACs are simple loops of bacterial DNA that can exist and reproduce outside the cell. BACs are adept at picking up chunks of introduced DNA from human or other sources and incorporating them into their loops in a kind of gene library. This library, which is preserved and duplicated along with the BACs, has helped researchers map the genomes of humans, yeast, fruit flies, and other species.

There's a limit, however, to how much DNA a BAC can take up. To study longer DNA sequences and intact genes, researchers turned to another microscopic organism, the yeast cell. Yeast artificial chromosomes (YACS) have helped molecular biologists to copy human genes, including a gene believed to contribute to Alzheimer's disease. Using YACs, researchers can insert human disease genes into mice and study their effects in the body.

The real challenge was creating an artificial human chromosome. In 1997, after years of false starts, researchers at Case Western Reserve University in Cleveland did just that. Their feat may help scientists better understand what natural chromosomes do and how they do it. Artificial chromosomes may also prove useful in understanding how groups of genes work together. Finally, human artificial chromosomes (HACs) may even provide a better way of administering gene therapy.

The researchers created HACs by reducing normal human chromosomes down to their basic constituent parts and injecting the parts into human cell cultures. The cells reassembled the pieces into a new chromosome and started copying it during cell division as if the extra artificial chromosome were one of its own. The genes on the artificial chromosomes survived intact through 240 cell divisions in the lab.

The key to success was identifying and recreating the critical pieces of a chromosome. In addition to a gene or two, these pieces included the telomeres, which are located at the ends of a chromosome and thought to be important in protecting it from damage during cell division. Another necessary element was the centromere, a section of pinched-in DNA located in the center of two pieces of a duplicated chromosome. During cell division, the centromere splits in two along with the two sister chromosomes. With the help of specialized structures in the cell, the two duplicated chromosomes are dragged by their centromere pieces to opposite ends of the dividing cell.

After creating artificial chromosomes, the next step was testing whether they can survive in a living organism. In 1999, biologists in Canada introduced an HAC into mice. The mice successfully passed the extra chromosome, and its cargo of genes, to their offspring. In the future, artificial chromosomes could prove to be a much more precise way of introducing desired genes into livestock to create herds of genetically modified animals.

HACs could also potentially replace other forms of human gene therapy. Gene therapy attempts to introduce functional genes into people who have a genetic disease. Viruses are one way to ferry therapeutic genes into the body. This gene therapy technique takes advantage of the natural ability of a virus to enter a cell and insert genes into the host's DNA. Scientists modify the virus by inserting a therapeutic gene into the viral DNA before introducing the virus into a patient.

But the technique is haphazard, often failing to deliver the genes to their intended target in the chromosome. If put into the wrong place on the chromosome, the genes can interfere with the normal cell function of other genes. Introducing viral cells into a patient also carries risk.

In 1999, an Arizona teenager volunteered to help test the safety of a new form of gene therapy. Jessie Gelsinger had a rare inherited liver disease, but his condition was being treated with drugs and he was relatively healthy. After receiving a massive infusion of modified cold virus, the teenager died of a severe allergic reaction and multiple organ failure. It was the first death directly attributed to gene therapy, raising questions about the ethics, effectiveness, and safety of what is still an experimental and unproven treatment.

Jessie Gelsinger's tragic death also highlighted the need to find new ways to introduce therapeutic genes into patients. Artificial chromosomes have an advantage over viruses for gene therapy because they can carry much more DNA and they are theoretically safer. Because artificial chromosomes exist separately from other chromosomes, they shouldn't interfere with the cell's normal genetic machinery. Finally, HACs are less likely than viruses to be rejected by the body.

But don't look for artificial chromosomes to revolutionize gene therapy any time soon. Researchers haven't been able to mass-produce HACs or to find an efficient way to sneak them into the cells of a patient.

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