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Science: A triple helix to cripple viruses
https://www.newscientist.com/article/mg13017644-100-science-a-triple-helix-to-cripple-viruses/
A technique to insert a third strand of DNA into the double helix of
specific genes could be used to throw a spanner into the works of the cell’s
machinery. The American scientists who developed this triple helix, or triplex,
technique hope to eventually cripple viruses in this way. The same approach
could also inhibit the hormone progesterone, and so terminate pregnancies.
Ever since the discovery of the double helix, it has been known that
there is room for a third strand of DNA, filling in a groove in the helix,
says Michael Hogan of Baylor College of Medicine in Houston, Texas. But
until recently, there was no way to predict which sequence of nucleotides
– the letters of the genetic alphabet – would form this third strand.
In 1986, Hogan began to investigate ways to design such a third strand.
He founded a company in Houston called Triplex to develop commercial products
based on this technology. Hogan worked from the exact sequence of a target
gene, and deduced rules for designing a single strand of nucleic acids that
would bind to that gene. He then synthesised a strand, generally only 25
to 35 nucleotides long. Such short pieces of DNA are readily assimilated
into the cell’s nucleus, where they attach to the gene.
At places where this third strand attaches, forming a triple helix,
genes are prevented from functioning normally. Proteins known as ‘transcription
factors’, which normally bind to the double helix and switch on specific
genes, cannot gain a foothold on the triple helix.
Adding a third strand of DNA to genes that respond to progesterone,
for example, would block the effects of the hormone. Progesterone, when
it combines with its receptor, normally activates these genes and causes
the lining of the uterus to grow, providing a home for the fertilised egg.
Blocking progesterone in this way would be different from the mechanism
of RU486, the abortion pill. RU486 is a steroid hormone that blocks the
progesterone receptor in the uterus, preventing progesterone from taking
effect.
Bert O’Malley, also at Baylor College, has shown that this actually
works, at least in cells in a test tube. O’Malley has just begun experiments
to see whether his single strands of DNA will block the effects of progesterone
in mice.
The triplex technique may prove effective in shutting down viruses whose
genetic structure is well understood. Much of the research of triplex is
aimed at designing single strands of DNA that will bind to key parts of
the genetic material of HIV and the herpes simplex virus type-1. The company
hopes that shutting down activity at these sites will render the virus impotent.
As scientists accumulate more knowledge of the sequence and function
of human genes, the triplex approach should allow scientists to turn genes
on or off at will, says Hogan. It might be possible to stop the growth of
tumour cells by turning off genes which cause cancer. He admits, however,
that such applications are at present ‘wishful thinking’.
The Triplex company owns a European patent that covers the design principles
for creating the third strand of DNA. It has applied for similar patents
in the US. The question of whether a patent can cover a concept for designing
molecules may eventually be tested in court. Other companies using the same
approach include Gilead Sciences in Foster City, California, and Sterling
Drug in New York.
These products confront government regulators with difficult questions.
The long-term effects of the artificial strands of the DNA that they attach
to is largely unknown. ‘If there is any effect, it will be sophisticated,’
says Hogan. Any harmful effects on human genetic material probably would
not show up for many years.