“DNA is the basis of life.” This sentence is drilled into every school child today. However, in the days when biologists could only dream of discovering the genetic material, the advent of DNA (deoxy-ribonucleic acid) as a candidate was greeted with scepticism. This was because, as a chemical, the DNA molecule seemed too simple. Proteins were then the most prominent and complex bio-molecules known. DNA was a long chain made up of 4 different subunits whereas proteins had 20. It seemed logical that proteins being the more intricate molecules would be better for encoding the complexities of heredity. Gradually, however, overwhelming evidence accumulated in favour of DNA, leaving little room for doubt.
In the 1960‟s, shortly after the structure of DNA was described, a medical doctor by name Gajdusek travelled to New Guinea to investigate a strange disease characterized by wasting away of the muscles; leading to paralysis and finally, death. It was called „Kuru‟ which meant „trembling‟ in the language of the local Fore tribe. The disease symptoms suggested that the nervous system was gradually being destroyed, suggesting an abnormality in the brain. The strange thing about the disease was this: it appeared to be spread by cannibalism. Fascinatingly, Gajdusek‟s investigations revealed that the Fore tribespeople practiced cannibalism as a ritual, where the bodies of dead people, often relatives, were routinely consumed. The most prestigious members of the tribe got to eat the brain, considered the prize portion. Kuru was found predominantly among the tribal chiefs and occasionally in very young children. It turned out that women prepared the meal with their youngest children in tow, often handing out titbits while cooking and thereby transmitting the infectious agent to them. Having traced the infectious agent to the brain, Gajdusek spent many years attempting to purify it. Finally, he came out with the startling announcement that the agent was a pure protein. It contained neither DNA nor RNA (Ribonucleic acid, also known to be the genetic material in some viruses by then). In other words, it appeared that a protein by itself could be transmitted like a virus; it appeared to be alive.
Ironically, the tide had changed. Scientific belief had turned against the possibility that proteins could be infective (that is, that they could multiply without any DNA or RNA).
Practically the entire scientific community discredited his claim. They insisted that there must be traces of DNA or at least RNA in the infective agent which he‟d evidently missed. Gajdusek went on to win the Nobel prize for his work on Kuru, but the infectious agent remained a mysterious entity. The mystery was finally solved after many years of work and many hurdles. Another medical researcher, Stanley Prusiner, was awarded the Nobel prize for the „Discovery of Prions- a new biological principle of infection‟ in 1997.
„Prions‟ stands for „Proteinaceous infectious particles‟. These unique „protein-only‟ particles do indeed make copies of themselves without the aid of any nucleic acid. Thus, they shake the belief that life must be based on DNA or RNA. Today they are best known to us as the causative agents of BSE or the Mad Cow disease. There are several more prion diseases. All are fatal, but they are so rare that they do not attract attention from the general public. So how do prions make copies of themselves? To see this, we have to look at protein „folding‟.
The accurate folding of a protein molecule is critical for its functioning. Under normal circumstances, the cell identifies and degrades misfolded proteins. Prions are accidentally misfolded forms of normal cellular proteins which escape degradation. They have the special ability to make copies of themselves using their normal cellular counterpart as a seed. In other words, they can catalyze their own formation. Therefore, once an accidental misfolding of the normal form occurs, the prion form keeps increasing in quantity. In addition, being highly resistant to degradation, they form clumps within the cell. Just as an isolated rotting apple does no damage, whereas in a fruit basket it spoils all other fruits, prions keep increasing in number in the presence of the normal copy.
The earliest known record of a prion disease is in sheep from Scotland. It was termed „Scrapie‟ because the sheep would be seized by uncontrollable itching and scrape themselves on the nearest fence, so much so that they finally bled to death. Prusiner named the human prion „PrPSc‟ with „Sc‟ standing for Scrapie. All of us carry a prion-gene whose protein is made only in the brain. It has been named „PrPC‟ with „C‟ standing for „cellular‟. We still do not know what its function is. What we do know is that a single misfolding event that produces the specifically misfolded prion form (PrPSc ) is sufficient to trigger the beginning of disease. Once formed, prions clump and in effect, strangle the neuronal cells in the brain. The hype around the Mad Cow disease and its human
counterpart focused attention on prions in mammals. What is not as well known, however, is the presence of prions in a much studied microbe, the budding yeast. At least four kinds of prions have been identified in yeast. All are misfolded forms of normal cellular proteins. They are unable to serve the normal function and therefore cause the cell harbouring them to behave abnormally. This helps in distinguishing between cells that contain prions and cells that do not. In yeast, however, it seems that prions neither help nor harm the cell. In a fungus called Podospora, a prion has been discovered which in fact helps normal cellular functioning. In other words, a misfolded protein has been selected in addition to the normal cellular form; it functions like an alternate form of the original protein. In addition, since yeasts are single celled creatures, prions are automatically transmitted from one cell to its daughter. What is special about this?
Darwin‟s theory of natural selection tells us that characters acquired during the lifetime of an individual cannot be transmitted to the progeny. Lamarck‟s theory, on the other hand, claimed exactly this. Yeast prions confer novel properties to the cell harbouring them, but they do so in the absence of any change in the yeast DNA. They can be retained in daughter cells and transmitted over many generations. In other words, they represent a case of the inheritance of characters acquired during the lifetime of an individual.
So the fact that prions exist, goes against what was believed to be a general rule in biology. Today there are two main schools of thought concerning prions. One argues that prions benefit their hosts in special conditions. If a cell has an alternate form of a normal cellular protein, and if that form can copy itself, the cell can acquire different properties without committing itself to a permanent, i.e, genetic, change. When cells have to live in changing environments, this ability could be of advantage. The other school of thought claims that prions indicate an abnormality. If the first is true, we need to understand exactly what these „special conditions‟ are that are needed for prions to be beneficial. If the second is correct, then we need to study the spread of prions and their effects in nature. Are prions „selfish‟ proteins that employ the cell for their propagation? Or are they willfully maintained by the cell for some purpose unknown? The field of prion biology remains an exciting one with much scope for investigation. With a little bit of license, the reason can be summarized in the following haiku-"DNA was prime, Till prions came, Challenging the monopoly".
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