Viruses with integrated gene switch

August 21, 2012

Scientists of the German Cancer Research Center have developed "RNA switches" which allow them to specifically turn on and off genes in viruses. This will help to enhance regulation of gene therapy and viral therapy of cancer.

Numerous viruses are used in the service of science today. They serve as gene taxis to transfer therapeutic genes into body cells or as therapeutic viruses targeted to infect and destroy . For such applications, the viruses are often equipped with additional genes, such as for immune mediators or for proteins inducing programmed . However, these can harm the body if they are released at the wrong moment or at excessive levels. "Ideally, we want to be able to turn on and off the transferred genes at a specific time," says Dr. Dirk Nettelbeck, a from DKFZ.

To this end, Patrick Ketzer of Nettelbeck's group experimented, jointly with colleagues from Konstanz University, with what are called RNA switches. In order to construct such a switch, the researchers inserted synthetic segments of DNA into the viral genetic material in the direct vicinity of the transferred gene. In the infected cell, this construct is transcribed together with the transferred gene into a single (mRNA) molecule. The switch is operated using an agent which is added to cells infected with the virus. The substance is precisely fitted to bind to the RNA molecule and induces it to cut itself up. Thus, the potentially dangerous protein cannot be produced. The researchers copied this regulation mechanism from bacteria which use RNA switches to regulate production of numerous proteins.

The DKFZ virologists first constructed an RNA switch that is kept in permanent "off" position by the substance. The production of the foreign protein does not start as long as substance is added. "This was a first proof that RNA switches work in viruses at all. But it is just as well possible to construct switches that do not allow production of the protein until the substance is added," Dirk Nettelbeck explains.

In cells, it has been possible for many years now to specifically turn on and off genes. To do so, scientists modified specific natural regulatory regions called promoters in the cellular genetic material. As a result, addition of the antibiotic tetracycline causes mRNA production to be turned on or off.

"However, this type of switch is too big and complex to be used in viruses or doesn't work there," says Dirk Nettelbeck. "The RNA switches, in contrast, are only 100 base pairs long." Using the RNA switches, the researchers managed to increase the production of the therapeutic gene by ten times. "But there is still room for a lot more," Nettelbeck explains. "The construction of RNA switches is extremely variable. Once the technology is fully developed, we will be able to better equip and regulate for many therapeutic applications." Nettelbeck and his team are convinced that the useful RNA switches will become established for many other uses in research and medicine.

Explore further: Molecular 'Signature' Protects Cells from Viruses

More information: Patrick Ketzer, Simon F. Haas, Sarah Engelhardt, Jörg S. Hartig and Dirk M. Nettelbeck: Synthetic Riboswitches for External Regulation of Genes Transferred by Replication-Deficient and Oncolytic Adenoviruses. Nucleic Acids Research 2012; doi:10.1093/nar/gks734

Related Stories

Molecular 'Signature' Protects Cells from Viruses

October 12, 2006

Viruses are cunning little parasites: they breed by forcing the affected cells to do what they want. By fake commands they get them to produce new viruses. However, the cell often notices that there is something fishy going ...

Hairpins for switches

December 12, 2006

How does an organism know when it must produce a protein and in what amount? Clever control mechanisms are responsible for the regulation of protein biosynthesis. One such type of mechanism, discovered only a few years ago, ...

RNAi shows promise in gene therapy, researcher says

February 19, 2007

Three years ago Mark Kay, MD, PhD, published the first results showing that a biological phenomenon called RNA interference could be an effective gene therapy technique. Since then he has used RNAi gene therapy to effectively ...

A mystery solved: How genes are selectively silenced

October 18, 2010

Cells read only those genes which are needed at a given moment, while the others are chemically labeled and, thus, selectively turned off. Scientists at the German Cancer Research Center have now been the first to discover ...

Recommended for you

Sixth sense: How do we sense electric fields?

October 13, 2015

A variety of animals are able to sense and react to electric fields, and living human cells will move along an electric field, for example in wound healing. Now a team lead by Min Zhao at the UC Davis Institute for Regenerative ...

A better way to read the genome

October 9, 2015

UConn researchers have sequenced the RNA of the most complicated gene known in nature, using a hand-held sequencer no bigger than a cell phone.


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.