ISIS Report, March 7, 2002
Scrambled Genomes in Human Gene Therapy and Transgenic Plants
Introducing foreign DNA into human or plant genomes both lead to genome
by Prof. Joe Cummins and Dr. Mae-Wan Ho
Human gene therapy is usually considered separate and distinct from genetic
modification (GM) of crops, but this is misleading.
Adeno-associated virus vectors (AAV) are most commonly used in clinical
gene-therapy trials. The wild-type adenovirus has terminal repeats that
enable it to integrate into human chromosome 19 at a specific site. The
AAV vector, however, has no specific integration site. It often integrates
into chromosome 19, though not at the integration site of the wild-type
virus, and it may also integrate into any of the other human chromosomes.
AAV vector is preferred for most gene therapy experiments because the
chromosome insertion is more stable and the AAV vector transforms both
dividing and non-dividing cells.
Crop GM is achieved using Agrobacterium transformation or direct plasmid
transfer using biolistic transformation (gene gun) methods. The Agrobacterium
T -DNA vector is flanked by 25 base-pair direct repeats that facilitate
integration of plasmid sequences into the plant chromosome.
The common features of gene therapy in human cells and crop GM is the
presence of integrating vector sequences flanking transgene(s) each equipped
with a promoter to drive expression.
While many studies have been carried out on transgenic DNA in plants,
there have been relatively few that analyze host genome at the site of
insertion. In a recent issue of Nature Genetics, researchers in the Department
of Medicine, University of Washington Seattle, report that integrated
AAV are associated with chromosomal deletions and other rearrangements
and are frequently located on chromosome 19 (although not at the wildtype
AAV integration site).
The researchers analysed the chromosomal DNA flanking the site of vector
insertion. By searching the human genome sequence databases, the junctions
were located to 6 different chromosomes. Four integrated into genes. Four
of nine inserts went into a relatively large, 22-Mb (millions of base
pairs) region of chromosome 10, but not the wild type site, which only
Chromosomal deletions and additions were found, as well as translocations
of parts of one chromosome to another. There were also unexpected vector
sequences at integration sites.
The study is reminiscent of the recent finding of unexpected sequences
and genome scrambling associated with transgenes in GM crops such as soybean
(see "Scrambled genome of Roundup Ready Soya", ISIS News 9/10
www.i-sis.org.uk). Further analysis is likely
to show that scrambled and unexpected sequences are commonplace in GM
crops. We have questioned the legality and safety of approving crops that
contain unknown, uncharacterised DNA sequences. If scrambled and unexpected
sequences are found even in the most widely distributed and established
commercial GM crop, the problems are likely to be worse with newer transgenic
crops of corn, cotton or canola, which have yet to be analysed. Certainly,
government regulators and their academic satellites seem passive and submissive
in dealing with important findings that question the safety of GM crops.
that gene scrambling occurs in both human gene therapy and in GM crops
suggest that there is a fundamental flaw in both genetic engineering technology
and in the auditing of molecular properties of the modified humans or
The corporate audit of molecular characteristics in gene therapy vectors
and those of GM crops may be analogous to the Enron audits of the Arthur
Anderson Accounting Firm. Those outside of direct involvement in gene
therapy and crop genetic modification should be well enough informed to
require full and truthful molecular audits of gene therapy vectors and
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