Friday, 20 July 2007

Beyond DNA and RNA

One of the basic messages of current biology, one of its paradigms is the circular flow of information and selection, in which DNA (in some cases RNA) carries the information, which directs development and some aspects of operation of organisms. These organisms then compete, cooperate, coexist; and as result of selective events, pass (or fail to pass) their DNA to their descendants. The flow of information from nucleic acids to the main building blocks of organisms --- proteins, is unidirectional. Of course when we look at the processes more carefully we see that proteins themselves are not only products of the genetic code translation, but heavily influence the process. They make the process possible, may speed it, slow it down, influence what gets translated.
But in general this cycle: `DNA -> RNA -> proteins (complete organism) -> survival and reproduction' is seen as basic and universally true rule.

The discovery of prions (and the subsequent fame of this discovery related to the `mad cow' disease and its relation to Creutzfeldt–Jakob disease in humans has shown that there might be very interesting exceptions. For me it has been exactly this sort of an exception that makes it necessary to have a deeper look at the rule itself.

I have found a short, but very readable article summarizing this subject,
by A. E. Bussard, A scientific revolution?
The prion anomaly may challenge the central dogma of molecular biology
, European Molecular Biology Organization Reports, 2005, 6, 691-694
The prion anomaly may challenge the central dogma of molecular biology. The main line of reasoning is not the existence of prions, but the fact that in some cases, relevant information may be stored and transmitted between generations not via DNA or RNA, but via proteins:

Recent discovery of prions as genetic elements that store and transmit information in various organisms, mainly yeast, the fungi Podospora and the sea hare Aplysia.

How is it possible? How does it work? The first evidence came from studying yeast, where evidences of non-mendelian transmission of phenotypic traits were found in late 1960's. As Bussard describes the situation:

Much of this evidence relies on Lindquist’s work on yeast prions. Not only did she show that prion domains in some proteins act as molecular switches that activate or deactivate the protein, she also showed that prions are non-mendelian genetic elements that have an important volutionary role by producing new phenotypes, which are often beneficial. Her work on sup35 revealed that the protein switches to its prion state [PS1+] when the environmental conditions for yeast deteriorate, which decreases translation fidelity and causes the ribosome to read beyond nonsense codons. This in turn enables the expression of formerly silent genes and gene variants, and creates new phenotypes. [PS1+] is passed on to daughter cells in which it self-replicates by imposing its conformation on normal sup35 proteins, until a new phenotype eventually emerges that is better adapted to the new environment. In another elegant experiment, Li and Lindquist showed the generality of this mechanism for controlling protein activity by fusing a yeast prion domain to a rat protein.

For more detailed informations see, for example,
True, H. L. & Lindquist, S. L. A yeast prion provides a mechanism for genetic variation and phenotypic diversity. Nature, 2000, 407, 477-483
Lindquist, S.; Krobitsch, S.; Li, L. & Sondheimer, N. Investigating protein conformation-based inheritance and disease in yeast. Philos Trans R Soc Lond B Biol Sci, 2001, 356, 169-176

When we start to think how really complex the molecular biology of life is, when we take into account the myriad of interactions and influences, then we may begin to believe in wonderful nature of life --- and, at least for me, in the wonderful nature of the study of life, of discovering the links and relationships, between various elements.

There is a very significant message that Bussard emphasizes:

Biologists need to get used to the idea that there is no end in sight when it comes to new insights and scientific breakthroughs; this idea has long been abandoned by physicists who are subject to regular scientific revolutions. I wonder if knowledge is, like the Universe, basically endless and in constant expansion, just as the complexity of life itself is also expanding infinitely.

And this is exactly what I believe myself.

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