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Unicellular Organisms

Prion and Viruses

We may not know exactly the kind of organisms existing at the beginning of life. However, there are some organisms living today on the border line between non-life and life. Infective agents smaller than viruses were found in the 1960s. The things can survive and somehow multiply after, for example, spending over two years in formalin (which kills viruses) and being irradiated for three quarters of an hour with ultraviolet light (which destroys the nucleic acid for reproduction). It was not until 1982 that it was shown to be a protein named prion with about 250 units of amino acid sequences. Its normal form is harmless. However, when the prion protein is converted into the "wrong" conformation it acts as a template and induces the same conformational change in other 'healthy" prion proteins. Thus the prion can reproduce without the genes. They become
Prion "infectious" agents and cause many kinds of diseases including the "mad-cow" disease. The normal and misfolded configurations are shown in Figure 11-05. In a healthy individual, the normal prion molecule (left) typically resides on the surfaces of cells, including neurons in the brain. In an infected person or animal, the normal protein is converted into the misfolded prion, which accumulates in plaques that clutter the diseased brain. The structure of the normal protein has been confirmed by nuclear magnetic resonance, whereas the structure of the misfolded protein is predicted from moleculear modeling techniques. Validity of this "protein only" (no transmissible nucleic acids) hypotheses has been demonstrated by research in 2004 (Nature, 265,

Figure 11-05 Prion

319, 323; 18 March 2004). The existence of different prion strains has also been confirmed.

A study published in 2011 suggested that many diseases such as the prion, Alzheimer's and Parkinson's are caused by protein misfolding, which in turn is the result of "genetic drift" - changes in the gene pool due to the reproductive success of certain individuals by chance rather than by superior fitness. In order to cover the negative effect of drift, the cell has invoked complicated interactions between proteins such as sticking loosely to one another so as to shelter the water-sensitive regions from misfolding. It is recognized that such short-term fix will ultimately fail rendering a species vulnerable for diseases such as the prion, ...

Virus RNA Retrovirus The structure of viruses consists of a protein capsule containing DNA or RNA with 1000 - 200000 base pairs. Figure 11-06a shows the virus known as T4 bacteriophage that preys exclusively on bacteria. The lower 69000X image reveals a swarm of viruses attacking an E. coli bacterium with the contractile sheath, which acts like a syringe to squirt the genetic material (DNA) into the host cell. In the spring of 2003 a new strain of coronavirus (see Figure 11-06b) causes the "Severe Acute Respiratory Syndrome" (SARS), which is much harder to control than influenza (Orthomyxovirus infection of the upper respiratory tract and lungs) or common cold (Rhinovirus infection of the upper respiratory tract). Viroids are even simpler organism consisting only of a short chain of naked RNA containing 240 - 375 bp, there is no capsid to house the genetic material. Viruses survive and reproduce by infecting a cell

Figure 11-06a Virus [view large image]

Figure 11-06b RNA Retro- virus [view large image]

and commandeering the cellular synthetic machinery to make more viruses. Then the viruses lyse (destroy) the cell and start the cycle over again. Figure 11-06c shows the
DNA Virus replication process for the DNA virus. After entering by endocytosis, the virus becomes uncoated. The DNA then replicates more of its kind and simultaneously making new coating proteins. These parts assemble to form more viruses, which exit from the host to infect more cells. The RNA retrovirus (such as the coronavirus) does it somewhat differently because the genetic material is in the form of RNA. It has to undergo a reverse transcription to form cDNA (DNA copied off from the RNA), which is then integrated into the host DNA. It commandeers the host's replication mechanism to make more RNAs, which in turn make more coating proteins for the final assembly of new viruses (see Figure 11-06b).

Figure 11-06c DNA Virus [view large image]

Virus Evolution
    There are three theories of virus evolution including relatively recent origin from "running away" host RNA, and the very ancient existence related to the RNA world in the origin of life (Figure 11-06d):
  1. Regressive Theory - It proposes that viruses arise from free-living organisms like bacteria that have progressively lost genetic information to the point where they become intracellular parasites dependent upon a host to supply the functions they have lost.
  2. Run-away RNA - It proposes that viruses arise from the host-cell RNA or DNA, which gain a self-replicative but parasitic existence. One or a few genes (or the mRNA) acquires the ability to replicate and evolve independently of its host gene.
  3. Coevolution - This theory proposes that viruses originated and evolved along with the most primitive molecules that first contained self-replicating abilities. While some of

Figure 11-06d Virus Evo- lution [view large image]

these molecules were eventually collected into units of organization and duplication termed cells, other molecules were packaged into virus particles that coevolved with cells and parasitized them.

Recently in 2004, another theory proposes that the cell nucleus itself is of viral origin. The advent of the nucleus, which differentiates eukaryotes from prokaryotes, cannot be satisfactorily explained solely by the gradual adaptation of prokaryotic cells until they became eukaryotic. Rather the nucleus may have evolved from a persisting large DNA virus that made a permanent home within prokaryotes. Some support for this idea comes from sequence data showing that the DNA polymerases (a DNA copying enzyme) of eukaryotes and bacteria are more closely related to similar enzymes found in viruses than they are to each other. This implies that the ability to copy DNA molecules did not originate with cells, but with their parasites. This theory implies that virus has been in existence before the emergence of eukaryotic and bacterial cells. Indeed, huge numbers of viruses are constantly replicating and mutating. This is evident from the diversity of genetic systems in contemporary viruses. They have genomes made from double- and single-starnded DNA, double- and single-stranded RNA, and even DNA in which the chemical base uracil replaces the usual thymine. The genome can be carried on a single string, on a closed loop, or as a set of fragments. They would be very much adoptive to the ancient as well as the modern environment.

Viral DNA A report in 2006 indicates that viruses are continually and randomly recombining with whatever DNA (Figure 11-06e) they might encounter while infecting a cell. Success relies on the huge number of new viruses being created in the world - estimated to be some 1024 per second. Almost all of this would be junk, but it's happening often enough that the few that survive are still a significant number. It's Darwinian evolution on a grand scale. The new gene finds its way into host genome as prophage gene (a stable form of virus infection, with genetic material that is integrated into and replicated with that of its host without harming the host), which then produces a useful protein for the host. Some researchers now believe that viruses have been instrumental in assembling the various molecular components that define the cell types associated with life's three

Figure 11-06e Viral DNA [view large image]

domains - bacteria, archaea, and eukaryotes. They may lie behind many early leaps in complexity, such as the transition from the RNA world to DNA and the invention of the cell nucleus.

Antibody News in February 2009 reports the discovery of a group of antibodies that neutralize a wide range of influenza viruses, including the H5N1 avian influenza, the 1918 Spanish flu and some seasonal strains. Influenza is notoriously adept at mutating, meaning that flu vaccines must be reformulated almost every year. Most antibodies target the hemagglutinin, the viral protein responsible for getting the virus into cells. The new antibodies interacted not with the hemagglutinin's head, as antibodies often do, but rather with its stem (Figure 11-06f, the H5 hemagglutinin (yellow and blue) bound to an antibody (red)). They poke deep into a pocket of the stem, apparently paralyzing the hemagglutinin so it cannot change its shape (mutate) in the way needed for the virus to fuse with the cell membrane. Based on these results, a vaccine that directed the immune system to the hemagglutinin's stem could provide broad, long-lasting protection. Making such a vaccine would involve engineering a hemagglutinin in which the head is

Figure 11-06f Antibody [view large image]

deleted or somehow covered up, but which maintains the stem structure. According to influenza experts, it is a challenge but doable.

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