Science - May 27, 2010

Killing genes silently

Text:
Astrid Smit

Bacteria defend themselves against virus infections in the same way as plants and animals do, suspects microbiology professor John van de Oost. NWO gives him a chance to prove his theory.

RNA-interverention
John van der Oost draws a big blue circle on the board in his office. 'This is the bacteria.' In the centre, he draws a small red block. 'And this is the protein which this research project is about. I can't show more than this because we still don't know much about it. We suspect that it protects bacteria against viruses. In the next four years, we want to find out if this is what actually happens.' To this end, this professor of microbiology has received a tidy sum of money from the Netherlands Organization for Scientific Research (NWO), or a so-called TOP subsidy of 720 thousand Euros. This is enough to get a PhD student, a postdoc and a technical staff member cracking till 2014. 'It's a gamble, but I hope that we will find a new immune system in bacteria', says Van der Oost in high spirits.
Nobel prize
Fifteen years ago, the American scientists Andrew Fire and Craig Mello discovered a new immune system in moulds, plants and animals (eukaryotes), and named this RNA interference. In this proess, RNA, a relative of DNA, fends off pathogenic viruses by silencing the genetic material of the intruders in an ingenious way. (See article in box.) The Americans won the Nobel Prize in 2006 for this discovery because it enabled the work of geneticists to make a great leap forward. RNA interference can in fact also be used by the genes of plants and animals to impose silencing on themselves.
Van der Oost wants to know if bacteria too have a similar immune system. He has good reason to believe that this is the case. From analyzing genetic material, it appears that ten percent of prokaryotes (bacteria and achaea) contain a protein which resembles the argonaute, the protein which unwelcomed intruders eventually have to reckon with during RNA interference in eukaryotes. The argonaute of prokaryotes (pAgo) seems to have the same function. The genes which carry the codes of pAgo can be found near to genes involved in the breakdown of genetic material. This indicates strongly that pAgo also plays a role here, says Van der Oost. 
However, while plants and animals impose silencing on intruders using RNA, bacteria do this probably with DNA. To put it in another way, they make use of DNA interference. In fact, the protein structure of pAgo, mapped by an American colleague of Van de Oost, comprises fragments of DNA instead of RNA. 'This is logical if we consider the fact that most of the viruses which attack bacteria comprise DNA and not RNA, which is the case for eukaryotes', adds Van der Oost.
Exciting
All these indicate sufficiently that bacteria have an immune system which resembles RNA interference in plants and animals. The next step is to prove this. 'Only one article has been published so far about pAgo, and this comes from our group. We are moving into unexplored territory.' This is also what makes the project so exciting to Van der Oost. 'Everything which you can find out about this immune system is new.'
He expects, in any case, that his research team is capable of discovering how pAgo functions. If bacteria indeed have an immunity which resembles RNA interference, this will throw new light on the evolution of this immune system, adds the professor of microbiology. 'This could very well be the case in prokaryotes.'
Although his research work is of a fundamental nature, Van de Oost hopes that it will also lead to applications. 'Perhaps we can use this immune system to impose silencing on the genes of bacteria themselves, as in the case of eukaryotes. This would be a welcome addition to existing methods because there are still many types of bacteria which scientists do not have a grip on.
Virus trap
RNA is a nucleic acid, like DNA. RNA is indispensible for converting genes into proteins. Messenger RNA (mRNA) interprets the code in the gene, takes this message to a place where proteins are made and enables the protein encoded in the gene to be produced.
Fifteen years ago, it was discovered that RNA also plays a role in disarming viruses which harm moulds, plants and animals. As soon as double-stranded RNA of a virus penetrates into their cells, a dicer (a protein) gets to this viral RNA and splits it into fragments. These are then taken to an argonaute - also a protein - which cleaves double-stranded RNA into single-stranded RNA. One half of this will end up as waste, while the other half binds firmly to the argonaute. This RNA functions like a trap: as soon as complementary fragments of this RNA are present in the cell, for example the mRNA of viruses, they will adhere to these fragments of RNA. As a result, the foreign RNA does not get a chance to allow the encoded protein to be produced and replicated in the cell.
This discovery was honoured with the Nobel Prize in 2006 and has given the field of genetics a big boost. Geneticists can also use RNA interference to block the genes of plants and animals, without having to mess with their DNA. An injection of double-stranded RNA with the same code as the genes which they want to suppress, generally does the job. The mRNA which originates from these genes is retained by the argonaute by using a complementary RNA which enables the message of the gene to be carried out. 
Since its discovery, RNA interference has become a popular topic, and thousands of researchers are doing things with it. To suppress genes, or to make new medicines.  
Virus trap
RNA is a nucleic acid, like DNA. RNA is indispensible for converting genes into proteins. Messenger RNA (mRNA) interprets the code in the gene, takes this message to a place where proteins are made and enables the protein encoded in the gene to be produced.
Fifteen years ago, it was discovered that RNA also plays a role in disarming viruses which harm moulds, plants and animals. As soon as double-stranded RNA of a virus penetrates into their cells, a dicer (a protein) gets to this viral RNA and splits it into fragments. These are then taken to an argonaute - also a protein - which cleaves double-stranded RNA into single-stranded RNA. One half of this will end up as waste, while the other half binds firmly to the argonaute. This RNA functions like a trap: as soon as complementary fragments of this RNA are present in the cell, for example the mRNA of viruses, they will adhere to these fragments of RNA. As a result, the foreign RNA does not get a chance to allow the encoded protein to be produced and replicated in the cell.
This discovery was honoured with the Nobel Prize in 2006 and has given the field of genetics a big boost. Geneticists can also use RNA interference to block the genes of plants and animals, without having to mess with their DNA. An injection of double-stranded RNA with the same code as the genes which they want to suppress, generally does the job. The mRNA which originates from these genes is retained by the argonaute by using a complementary RNA which enables the message of the gene to be carried out.
Since its discovery, RNA interference has become a popular topic, and thousands of researchers are doing things with it. To suppress genes, or to make new medicines.   

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