Genetic Research Takes Major Leap Scientists Create Working Synthetic Chromosome

In a major milestone in the study of human heredity, researchers announced Monday that they have created the first working 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 research tool for investigating fundamental questions about the chemistry responsible for human heredity, experts said.

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

In research published in Nature Genetics today, the research team said it was 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 23 pairs of natural chromosomes - threadlike structures inherited from an individual’s parents that contain the genes that guide the body’s growth and development, including a pair that 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 coexist 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 the University of Southern California 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, such as AIDS, as well as blood disorders such as sickle cell anemia and beta-thalassemia.

Potentially, this could be done by packaging a therapeutic gene inside an artificial chromosome either to replace a defective gene or to generate a medicinal protein.

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

However, Anderson, who is working with the pharmaceutical firm Novartis on a competing gene therapy technique, cautioned 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 for helping fathom the mysteries of human genetics.

The discovery comes at a time when researchers engaged in the federal Human Genome Project rapidly are 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 physically 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. But until now, scientists have 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 who led the research team.

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