FIRST ARTIFICIAL HUMAN CHROMOSOMES
By Sean Henahan, Access Excellence
CLEVELAND (4/02/97) Artificial human chromosomes have been created
for the first time. This feat will help scientists better understand what
natural chromosomes do and how they do it, and could prove useful in gene
"This opens the door to a whole new avenue of research in chromosome
biology and gene therapy," said Huntington F. Willard, Ph.D., the
senior author of the study, and chairman of genetics at Case Western Reserve
University School of Medicine and University Hospitals of Cleveland.
"While it's been known since the early years of this century that
chromosomes carry genes, until now the complexity and size of normal chromosomes
has limited our ability to analyze their structure and function.
The synthetic microchromosome system now allows us to perform detailed
studies on the nature of chromosomes -- essentially the next phase of the
Human Genome Project which is to move from just mapping genes to actually
understanding how they work and influence human disease."
Natural chromosomes are consist of hundreds or thousands of genes, along
with specialized elements that are believed to be important for chromosomal
stability and function. Telomeres, which consist of DNA and protein,
are located at the ends of chromosomes, protecting them from damage.
Centromeres are specialized regions of DNA that are essential for the proper
control of chromosome distribution during cell division. Human
centromeres are believed to consist of large segments of highly repetitive
DNA, called alpha satellite DNA, which is thought to play a significant
role in centromeric function.
"Our successful creation of functional centromeres and incorporation
of them into artificial chromosomes were the
critical achievements enabling the stability and normal behavior of the
chromosomes throughout the cell cycle," noted Dr. Willard. He
added that past attempts at producing synthetic chromosomes have failed
because they lacked proper centromeres, and thus could not persist through
multiple cell divisions.
The research team created artificial chromosomes from normal human material
using combinatorial genetic techniques. The researchers first synthesized
arrays of alpha satellite DNA, then introduced the resulting centromeric
material into human cells in conjunction with telomeres and genomic DNA.
cells, the independent elements assembled to form miniature chromosomes,
or synthetic microchromosomes, that were structurally similar to human
chromosomes, but contained less genetic material.
Analysis of the newly introduced artificial chromosomes demonstrated normal
centromeric activity, genetic stability, and continued gene expression
through repeated rounds of the cell cycle.
"Synthetic chromosomes have the potential to overcome a major stumbling
block in gene therapy," said John J. Harrington, Ph.D., a postdoctoral
fellow at Case Western Reserve University. "The characteristic stability
of our synthetic chromosomes enables, for the first time, the potential
long-term expression of therapeutic proteins in target tissues of patients
treated using gene therapy."
The synthetic microchromosome remains independent within the host
cell and functions essentially as an accessory chromosome. In contrast,
most gene therapy systems currently under development utilize viral vectors,
which often require the integration of the therapeutic gene into an existing
chromosome and thus can result in chromosomal damage or interference with
normal gene expression. Viral vectors can also induce immune
responses that limit therapeutic efficacy. In addition, unlike other
vectors, which lack many of the elements that control normal gene expression
due to size constraints, the synthetic chromosomes could be engineered
to contain all of the machinery necessary to promote and regulate the stable
The next step will be to refine the system and begin building an efficient
vehicle for the introduction and stable maintenance of therapeutic genes
in human cells. This might ultimately provide treatments for a wide variety
of genetic disorders."
The research was published in the April 1997 issue of Nature Genetics.
Related information on the Internet
AE: Cloning from Adult Vertebrate Cells
AE: Cloning into a Yeast Artificial Chromosome (YAC)
NHGRI: Bacterial Artificial Chromosome
NHGRI: Human Artificial Chromosome
AE: Genetics Websites
AE: Telomerase, the End of Cancer?
Links updated: April 21, 2008