Human Chromosome Created Artificially

By ROBERT LEE HOTZ

April 1, 1997 12 AM PT

TIMES SCIENCE WRITER

In a major milestone in the study of human heredity, researchers announced Monday that they have created the first artificial human chromosome, which experts said represents a quantum leap in the ability to probe the complex molecules that make up humankind.

The new technology offers scientists a powerful new research tool for investigating fundamental questions about the chemistry responsible for human heredity, experts said.

Its inventors at Case Western Reserve University in Cleveland and Athersys Inc. hope the techniques may also offer a way to cure inherited diseases by altering a cell’s genetic structure, bypassing biochemical stumbling blocks that have so far stymied efforts to accomplish that task.

As a medical tool, a custom-tailored chromosome could potentially be used as a package for introducing a therapeutic gene into a cell. The new gene could either replace a defective gene or generate a medicinal protein.

In research published today in Nature Genetics, the researchers said they were able to use the human cell itself to perform the trickiest portion of creating a synthetic chromosome. The scientists basically gave the cell a molecular construction kit developed after a decade of experiments and let the cell do the actual work of assembling it.

On at least two occasions, the result was a new artificial human chromosome, the researchers reported.

A normal cell has 22 pairs of natural chromosomes--threadlike structures inherited from an individual’s parents that contain the genes that guide the body’s growth and development. An additional pair determine gender. Natural chromosomes are built in pieces, made up of hundreds or even thousands of genes, bracketed by special protein structures that enhance the structure’s stability and guide its functions--turning genes on and off, for example. Taken altogether, the natural chromosomes contain roughly 100,000 separate genes--the molecular blueprint for human development.

The artificial chromosome appears to co-exist with the natural ones. It appears to divide and multiply normally, surviving as a kind of accessory chromosome for at least six months, the researchers said.

French Anderson, a molecular biologist at USC who helped pioneer the concept of human gene therapy, called the new research “a very important advance.” The invention of synthetic human chromosomes is, he said, “the next big step.”

Melissa A. Rosenfeld, a senior researcher at the National Genome Research Institute, called it “an important landmark.”

Officials at Athersys said they hope eventually to use artificial chromosomes as a way to package treatments for diseases affecting the human immune system, like AIDS, as well as blood disorders like sickle cell anemia and beta-thalassemia.

If the technology proves itself clinically, it could be applied to an even wider range of inherited or infectious diseases, they said.

Anderson, who is working with the pharmaceutical firm Novartis on a competing gene therapy technique, cautioned, however, that the danger of chromosomal abnormalities may be too high to make artificial chromosomes work as a medical product. In addition, the manufacturing problems in producing complex chromosomes in industrial quantities may be too formidable, he said.

Even so, he said, artificial human chromosomes would be a powerful tool to help fathom the mysteries of human genetics.

The discovery comes at a time when researchers engaged in the federal Human Genome Project are rapidly charting the unexplored regions of the human genetic structure, determining where each human gene is located.

But mapping a gene is only the first step in determining what it does in the larger universe of the human body, researchers said. Despite their high-speed gene machines and DNA microprocessor chips, scientists know more about where genes are located--having mapped more than 16,000 human genes so far--than they do about how they function.

Even with their rudimentary knowledge of individual genes, researchers have been able to create a bestiary of novel life forms, from genetically engineered crops to bacteria that produce drugs for humans. But until now, scientists had no way to assemble human genes together with all the chemical elements necessary to their proper function, the way nature does in the large daisy-chains of protein and DNA that make up a human chromosome.

“This opens the door to be able to study human genes in their normal context--as part of a chromosome,” said Huntington F. Willard, chairman of the Case Western Reserve genetics department and leader of the research team.

The Case Western Reserve team and Athersys, the team’s privately held business partner, have patented the new technology and are seeking patents on the artificial chromosomes.

For more than a decade, gene experts have been able to assemble the chromosomes that guide the simplest living organisms--yeast, for example.

Last year, researchers at Chromos Molecular Systems created the first mammalian chromosomes, stitching together the gene packages that shape a mouse. By February, the company had completed a manufacturing plant capable of churning out 3 million to 5 million of them a day.

But the chemical essence of a human chromosome had eluded researchers until now.

To make a human chromosome, the Case Western Reserve researchers added to a normal human cell separate portions of ordinary DNA, protein structures called telomeres, which help protect the chromosome from damage, and other structures called centromeres, which help control the way a chromosome divides and reproduces.

The cell did the rest.

“We were letting nature takes its course,” Willard said. “For all intents and purposes, they are ‘real’ chromosomes . . . to our delight.”

(BEGIN TEXT OF INFOBOX / INFOGRAPHIC)

Hacking the Human Chromosome

Researchers created the first working artificial human chromosome by inserting the raw material into a normal human cell--ordinary DNA, telomeres and centromeres--which then assembled a working package of genes.

HUMAN CHROMOSOME

Telomere

Euchromatin with genes

Satellite DNA

Centromere

Euchromatin with genes

Telomere

ARTIFICIAL CHROMOSOME

Centromere

Foreign DNA with genes

Satellite DNA

Telomere