The Why, Who, and What of Viral Studies

Why people have studied virii, who has done it, and what has it done for us.

Virology is important for many reasons. Some of these reasons have to do with the health of humans, plants, or other animals. All living organisms have viral parasites. Other reasons to study virology revolve around the consequences of this last fact, as the medical and economical results of viral infections have altered our history many times over. Finally, and in many regards most importantly, the study of virology has contributed many concepts and tools to biochemistry and molecular biology. However, it was not always realized that virus and their study was so important. It was not that long ago, either, that it wasn't even realized what a virus was. The development of the concept of the virus, as we shall see, developed slowly over a period of time until reaching it's current state.

The early period of the viral concept began in the nineteenth century, primarily thanks to three gentlemen by the names of Pasteur, Koch, and Lister. Up until these gentlemen came along, there had been no universally defined method of studying pathogens and no experimental approach for medical studies. These men changed that. Pasteur started the ball rolling when he realized the impossibility of spontaneous generation. Spon. Gen. was a theory that held that life could arise from strictly lifeless material. For instance, don't maggots appear on dead meat seemingly out of no where? Don't microbes suddenly grow on exposed petri dishes? Well yes, they do. But Pasteur demonstrated conclusively that this was do to the exposure of the medium to non-sterile conditions. The maggots were due to fly eggs, the cultures to microscopic air borne cells. Through the use of a swan necked flask, Pasteur proved Spontaneous Generation false.

From this conclusion, then, and from the ability to properly sterilize a medium such that no unwanted organisms grew on it, Pasteur was able to prove conclusively that different microbes cause different diseases. This was a major breakthrough for science in that it verified the findings of several scientists indicating microbial causes for disease and also allowed the possibility of a nearly limitless number of new microbes causing old diseases. Until this discovery, it was not possible to think about treating a disease properly, because it was not possible to think about the individual microbe causing simply because knowledge was not that advanced.

Following Pasteur's lead, Koch soon isolated the microbes that cause anthrax and tuberculosis, among others. That he did this is important, but more so is that he was able to. Koch was the first scientist to develope a solid media (agar) for microbe growth. He was the first scientist to use the petri dish (named after a laboratory assistant, Richard Petri). And he was the first scientist to develop a standardized method of isolation of a single, pure colony of bacteria and bacteria strains.

Furthermore, Koch used his experiments to develop a set of procedures known as Koch's Postulates. These postulates served (and continue to serve) as a guideline for medical studies attempting to determine the causative agent of a disease. They are as follows: 1) The organism must be regularly found in the lesions of the disease. 2) the organism must be isolated in pure culture. 3) inoculation of such a pure culture into a host should initiate the disease. 4) the organism must be recovered once again from the lesions of the host. If all of these conditions are satisfied, then so too is the researcher's question, and the microbe in question is the cause of the disease.

After Koch came Joesph Lister (of Listerine fame?). Lister was the first to recognize the importance of not just a sterile media but also a sterile field. In a sterile field the whole environment of the area in question (in Lister's case, the wound he was performing surgery on). This lead to the widespread use of antiseptics to prevent infection during surgery, and from there to household use on minor cuts and scratches.

Finally, Lister also developed a method for isolating bacterial colonies through use of liquid media. He did this by diluting the solution to the point where the individual bacteria were so spread out that the colonies arising from each were easily distinguishable. This accomplishment, along with the others mentioned in this section, were the key points in the early period of virology and indeed much of microbiology.

The discovery period of virology followed next. And, interestingly enough, it was spurred on by economic reasons not unfamiliar to modern times. From 1886 - 1903 (the dates of the period) and still today, tobacco was a very important cash crop the world over. Therefore it was no minor worry when a disease, the tobacco mosaic disease, began damaging crops everywhere. This damage lead to financial support for scientists all across the globe, including three named Adolf Mayer, Dimitri Ivanofsky, and Martinus Beijerink.

Mayer was able to show that something from infected plants could kill healthy plants. He ground up infected tobacco plants to a pulp, and then exposed uninfected plants to the serum produced. The uninfected healthy plants soon showed signs of the disease, something that was one of the first demonstrations of the infectiousness of disease.

Ivanofsky then decided to work off of Mayer's experiments. He produced the same sap as Mayer, but instead of exposing the healthy plants to it directly, he first filtered it through a special type of porcelain filter called a Chamberlain filter. It was known at the time that the Chamberlain filter would filter out all known bacteria and fungi, but it was not known that the sap Ivanofsky filtered would still be infectious to the tobacco plants. It was. The plants still became sick when exposed.

Beijerink then took Ivanofsky's work another step forward. He not only filtered but also diluted the sap, and showed that diluting the filtrate did not significantly weaken the infectious nature of the sap. Initially the infection progressed more slowly than the non dilute version, however the sap regained strength as the virus replicated in living growing hosts. Finally now then the world was ready for virii. The first definition was penned shortly after this point: "A virus (latin for slimy liquid or poison) is a filterable agent too small to observe in the light microscope but able to cause disease by multiplying in living cells."

Shortly after this time it was noticed there were not only different types of microscopic organisms (virii, bacti, fungi), but also different types of virus. For instance, those that infect humans don't do so well in plants, and those that infect most deer don't live in mice. In fact, it was found that virii were very host-specific; in other words they can often only live in one very specific type of organism. The study of viruses then therefore took another turn; studying one virus just wouldn't do to study all of them, although many analogies can be made. And studying a bacteria is very cost efficient. Therefore, the study of viruses that infect bacteria, or bacteriophages, became very chic among microbiologists, and the science world has been thankful ever since.

Max Delbruke was one of the first to ask an interesting question: what happens before the virus is produced? Dr. Delbruke was interested in the growth curve of virii, and to study this he developed what is called the One Step Growth Curve. For this he made sure he infected EVERY cell in culture with the virus at one time by exposing the culture to more viral particles than there were cells. This allowed simpler assays of the times and stages of viral development.

Following up on this work was Seymour Cohen, who wondered curiously what the effect of phage infection was on the DNA and RNA levels of infected cells. Using the One Step Growth Curve, he was able to determine (by checking the experiment at certain intervals and seeing what was present) that a series of events proceeds after infection. First, all RNA synthesis stops. Then DNA synthesis ceases, but only momentarily before resuming at five to ten times the previous rate. Further investigation showed that the synthesis of cellular proteins then stopped. From this then eventually A LOT was learned.

Immediately it was seen that viral infections changed the physiology of the cell. Follow up investigations of the questions raised by this knowledge led to the development of such tools as gel electrophoresis and ultimately to a large amount of information on bacteriophages in general and eukaryotic viruses in analogy. Furthermore, research into what happens after infection led to large chunks of knowledge regarding cell replication, development, transcription, translation, and so on. If not for the study of virii, the study of life sciences would be greatly hindered.

The next people to make a dent in the viral shroud of mystery were named Hershey and Chase. They settled (after several equally competent attempts by others) that DNA is sufficient for life. Other experimenters, including Avery et al, had shown that DNA was the method of inheritance. By irradiating viruses (producing radioactive phosphorus on DNA and radioactive sulfur on the viral protein capsid) and then infecting cells, Hershey and Chase were able to demonstrate that generally only the DNA of viruses infected cells while the protein coat remained outside. Therefore, they reasoned, DNA is sufficient for life.

The moral of this story of the origins of viral research blends down to one final fact: The central dogma of Biochemistry and Molecular Biology comes from and is supported by viral studies. This trend continues today as virii have an invaluable role in the recombinant DNA revolution. Primary in this are reverse transcription (and reverse transcriptase of retroviruses), restriction mapping, and minimal size cloning (a logical extension of restriction mapping, and pioneered by PSU alum Paul Berg, the nobel Laureate).

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