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Sci Tech
The terrorist that subverts the host it feeds on
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273 proteins in our body, which HIV exploits in order to do its damage, have been identified
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— Photo: REUTERS
Cutting Edge Research: The paper is the result of a huge deal of work, using the latest techniques and all available approaches.
A landmark paper has been published in the 11 January 2008 issue of Science by a Harvard group of researchers led by Dr. Stephen Elledge. It is titled ‘Identification of host proteins required for HIV infection through a functional genomic screen.’ The group has identified as many as 273 proteins in our body, which the AIDS-causing virus HIV exploits in order to do its damage.
Tour de force
The work is a tour de force since it not only describes what these 273 proteins in the ‘host,’ namely us, are but also offers the possibility of looking for new drugs that could stop the virus from entering the host cell, use the genetic machinery there to reproduce itself, eat up the immune system and thus make us prone to infection by other microbes, weaken us and waste away to death.
No wonder the famous AIDS researcher Robert Gallo has said: “this is destined to be one of the key HIV papers of this decade, if not longer.”
The methods used by Dr. Elledge and his coworkers are cutting edge. Most notably, they have used the power of the RNA interference (RNAi) technique to its full advantage. They screened over 21,000 genes in our body, disabling gene after gene using its specific ‘small interfering RNA’ or siRNA and seeing what happens.
In this approach, what is done is to knock down (occasionally silence completely or knock out) the genetic message, transcribed as messenger RNA.
Upon such knock down, the protein coded by the gene is not made in the cell to the necessary level and the function performed by the protein is affected, which is detected in the experiment. This method of using siRNAs is termed functional genomic screening.
Appropriate cells
The group used a set, or library, of 21,121 pools of four siRNAs per gene. Choosing appropriate human cells as hosts, they first introduced these siRNAs into the cells, followed by infection of the virus, and monitored the viral protein called p24. This way, the proteins in the host cell needed for the entry of the virus into the cell, its assembly and budding there are monitored.
Of the 273 ‘host dependency factors’ (HDFs), that is the proteins used by the virus for its job in the infected cell, two called Rab6 and vps53 help in its entry, another called TNPO3 lets it go into the cell nucleus for making more of itself, and the mediator complex proteins Med28 help in making all the 15 proteins that the virus is made of.
As can be seen, the paper is the result of a huge deal of work, done with the latest techniques and using all available approaches. What would otherwise have taken 10-12 years and dozens of students, postdoctoral fellows and collaborators has been condensed into a far shorter time and fewer people, thanks to these new tools and techniques.
Happily, several groups in India and our national agencies appreciate this ‘systems biology’ way of doing total biology and are investing in it. This is the only way to do biology of value now.
Simple, yet complex
Accompanying the Elledge paper in the same issue of Science is a very well written commentary of the work by Dr. J. Cohen, and part of it is worth quoting. “HIV is ridiculously simple yet astonishingly complex. The virus contains a mere 9,000 bases of RNA — one millionth of the amount of genetic material in a human cell — and a paltry suite of nine genes that code for a measly 15 proteins. “Yet this virus can relentlessly nibble at immune cells until the entire system collapses, opening the door for a vast array of illnesses and ultimately, death. For HIV to do its damage, however, it must repeatedly infect new cells and copy itself, a feat that requires help from its human host”.
Reading the Cohen commentary, I was reminded how remarkably similar the virus is to a terrorist organization. The latter operates using the weak points in the target territory, and our recent world-wise experience shows that there are many equivalents of HDFs in ‘host’ nations. Some aid the entry or infiltration, some in integration into the target society and others aid to replicate the message and action.
Information content
With viruses the message or the information content is their DNA or RNA. With terrorists, it is their staunch belief, or what Richard Dawkins has termed the “meme”. He coined this word to denote an idea, philosophy or ideology. Once an idea is created, it does not vanish, nor destroyed but is spread and even implemented by a large number of individuals.
A meme is thus the gene of a thought; hence the formal similarity between a virus and a meme. Of course, a meme can be a great and helpful idea, such as Ahimsa or nonviolent struggle for independence and emancipation.
This Gandhian meme has been replicated with great success by Martin Luther King and Nelson Mandela. One would like to spread this as much as possible. It is the other memes used by terrorists that we need to control and fight against.
The challenge
In such cases, as with viruses, the challenge is the same — catalogue all weak points in the target and protect them from the enemy. Prevent the entry, find a ‘vaccine’ to kill the unwelcome entrants from spreading, shoot at sight when found plotting to do harm, and so forth. The flip side in both cases is that in stopping the harm, we may inflict some on ourselves — collateral damage.
As Cohen writes: “After all, these HDFs presumably exist to help humans, not the virus. It is also a tall order to discover effective inhibitors against HDFs.”
Herein lies the challenge in drug discovery. Now that there are 273 leads, the hope for anti-AIDS drugs is somewhat brighter.
D. BALASUBRAMANIAN
dbala@lvpei.org
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