Re: BIO/GENE: Artificial chromosome
Fri, 4 Apr 1997 16:26:05 -0500 (EST)

See search Hotz, the author.

Human Chromosome Created Artificially
Science: Technology is called a major advance in study of genes. It may
offer a way to cure inherited diseases.
By ROBERT LEE HOTZ, Times Science Writer


n 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
     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
     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
* * *
     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.
     Euchromatin with genes
     Satellite DNA
     Euchromatin with genes
* * *
     Foreign DNA with genes
     Satellite DNA
* * *
     How Cells Split
     Chromosomes and centriles duplicate
     Centrioles move towards opposite sides of the cell
     Duplicated chromosomes split; move to sides
     The cytoplasm divides and cells splits
      Source: Nature Genetics, Case Western Reserve