Brief History of Virology
Viruses are still a major cause of most human diseases.
We will begin of with a few examples of common viruses. One should note
that viruses affect every " living" creature including bacterium,
||Scrapie ( prion)
||Mad Cow Disease ( prion)
|Foor and Mouth Disease
|AIDS ( HIV)
|Human T-cell leukemia
Some of these viruses such as kuru are "slow-viruses," and are models
for degenerative diseases: These are caused by prions. Alzheimer's disease
may be of a similar origin. .Diabetes,and rheumatoid arthritis may be
viral related.This is quite controversial.
The majority of viral infections occur without any symptoms, they are
subclinical. There may be virus replication without symptoms. In other
cases virus replication always leads to disease, e.g. measles.
Some viruses may cause more than one type of disease state,e.g. measles,
chicken pox. in other cases same symptoms may result from different virus
infections ( hepatitis )..
Basic characteristics of Viruses
are very heterogeneous, there is a unity of structure, basically protein
and nucleic acid.Structure
2-Replication similar.Note not binary division, but burst of virus particles.
3-Size: viruses are "filterable" agents.
4-Obligate (genetic) parasites--dependent on host cell genetic material.
5-Virus genome is either DNA or RNA not both.
have probably been around as long as life has existed.
In human history there
are references to viruses in Homer. He writes of " rabid dogs". Also rabid
dogs were known in Mesopotamia. In drawings from ancient Egypt, etc.drawings
of people with withered legs, which could have been the result of polio.
Smallpox probably played an important role in history of S. and Central
America. Yellow fever was endemic, " Flying Dutchman" may have been due
to this cause.
In looking at the economic history of the tulip trade in Hlooand, valuable
tulips were variagated, which was the result of virus infection
Experimental virology really begins with the experiments of Jenner in
1798.The idea of vaccinationwas not truly novel It had been practiced
by the Turks and possibly also in China. See paper by Langer, Immunization
against Smallpox before Jenner in Scientific American reprints. Jenner
did not know causative agent or reason for immunity, but noted that individuals
exposed to cow pox did not suffer from small pox. Probably other peoples
such as the Chinese were also aware of the technique of scarification.
Known as variolation.
It is of interest
that the virus we use today in the vaccination against small pox, is not
the same as that used by Jenner. Sequence analysis indicates that it is
not cow-pox, but a variant that arose during the last few hundred years.
It is speculated that it may be of horse origin.
Perhaps the most important paradigm for microbiology was proposed by Koch
and Henle, although known as Koch's postulates about this time. There
was great difficult in applying these Koch's postulates to viral disease.This
postulate requires a stop of in vitro growth, which is not always possible
with animal viruses. Indeed even today we have had trouble applying these
postulates to HIV and the AIDS epidemic.
Koch's postulates: Definition of a pathogen
1. The organism must
regularly be found in the lesions of the disease.
2. The organism must be isolated from diseased host and grown in pure
3. The inoculation of such a pure organism into a host should initiate
4. The organism must be recovered once again from the organism.
Two other important landmarks were the proving by Pasteur that spontaneous
generation of organisms did not occur ( see figure1.4 in Flint et al),
and the development of limiting dilution by Lister.
It was also Lister who developed the concept of sterility to obtain pure
1881-1885, Pasteur. Use of animals as model for growing and studying viruses.
Passage of rabies virus through the brain of rabbits, produced an attenuated
vaccine. When infected into dogs produced mild infection, with increased
latent period. However Pasteur did not try to identify the infectious
This method of attenuation, by producing attenuated virus in tissue culture
still used today. Importance of Pasteur's work was not only the characterization
of rabies, but also the whole concept of using animals to develop model
systems for the study of viruses.
Discovery Period. 1886-1903.
of variegation in tulips dates from 16th century. 1886 Mayer (in Wegeningen,
Holland) demonstrated infectivity of TMV. One could get disease spread
from tobacco pulp or sap. However Koch's postulates could not be satisfied.
Ivanowski observed/looked for bacteria like substance. 1898, Beijerink
demonstrated filterable characteristic of the virus and thinks virus was
obligate parasite. Chamberlain filter-candles of unglazed porcelain had
been invented for water purification. These filters retained bacterium,
and had a pore size of 0.1-0.5 micron. Filters were made of diatomaceous
earth (clay)-kieselguhr. Also substance could pass through a layer of
agar--contagium vivum fluidum "contagious living liquid." Boiling, or
treating with formaldehyde abolished infection. The term for such agents
was coined--virus, Latin from Greek, toxin. See description of different
types of filters in Flint et al. fig 1.4.
In the 1930's Elford--"collodion"
membranes, and could show that viruses are particulate and of discrete
size (10 nm for FMDV)
10-9 meter = 1 n meter. Range of size.
Loeffler and Frosch (1898) reported that the infectious agent of foot
and mouth diseases virus was a filterable agent. This could have been
a toxin, however since on dilution one still obtained material, sugget
that it was a replicating agent.
In 1900 first human disease shown to be caused by a filterable agent was
Yellow Fever by Walter Reed. He established that yellow fever virus was
present in the blood of patients during the febrile period, and that the
virus could be transmitted by mosquitoes. Yellow Fever had a very high
mortality rate. In 1853 there was an epidemic in New Orleans with mortality
Infectivity controlled by destroying mosquito population.
There were many human volunteers in the study of yellow fever, with many
deaths. Thus the basic concept arose about this time of a filterable agent
too small to be observed in light microscope but able to cause disease
by multiplying in living cell.
1908 Ellerman and Bang demonstrated that certain types of tumors (leukemia
of chicken) were infectious, and that the infectious material had characteristics
of cell free agent.
1911 Peyton Rous discovered that non-cellular agent could transmit solid
tumors: virus now known as the Rous Sarcoma virus (RSV).
Twort (1915) working with vaccinia virus, attempting to grow the
virus in medium, got bacterial contamination, micrococcus noted the existence
of a substance that cleared bacterial cultures, termed this substance
bacteriophage. Twort abandoned this work after World War I and reported
it in a short paper
1917 D'Herelle, a Canadian working at the Pasteur made same discovery
with the Dysentery bacillus. Developed limiting dilutions, plaque assays,
and proposed that virus was particulate in nature.
Note: Novel by Sinclair Lewis: Arrowsmith; idea was to use bacteriophage
to destroy bacterial infections. This idea constantly re-occurs.
Chemists had shown that virus could be purified using all the techniques
of protein chemistry.
1935: Wendell Stanley, an organic chemist, reported the crystallization
of T.M.V. This material was infectious.
Analysis of the crystals showed them to be predominantly proteins in nature
of very high molecular weight (- 90% protein). The observation that viruses
could be crystallized gave rise to controversy of whether TMV was a living
organism, or a "pure" inert chemical substance. 0.5% phosphorus and 5%
Stanley defined TMV as an "autocatalytic" protein, which may be assumed
to require the presence of living cells for multiplication cf. with trypsinogen-trypsin.
1938-1970. Development of the phage group and Molecular Biology
The 1940's and
1950's was the era of the Bacteriophage and the animal virus. The great
surge in virology occurred as a result of the work with bacteriophage
in the 1940's by Delbruck and co-workers. Delbruck considered father of
modern molecular biology although really was a physicist interested in
About the same time identification or correlation was found between tumor
viruses and tumors in mice.
Delbruck and Ellis (1940) worked out the replication cycle of the bacteriophage
using the one step growth curve experiment, and in 1952 Hershey and Chase
showed that it was the nucleic acid portion that was responsible for the
infectivity and carried the genetic material.
Delbruck worked with Luria to form the phage group. The first phage CSH
meeting took place in 1947 with 8 participants. From this meeting and
group developed the whole field of molecular biology.
In 1954 Watson and Crick elucidated the structure of DNA.
Discovery of lysogeny by Lwoff in 1949, and later zygotic induction was
an important milestone in tumor biology.
1.It showed that virus could behave like a bacterial gene on the chromosome.
2. Showed quiescent negative regulation
3. Led to Jacob/Monod model of gene induction and repression, the foundation
of the operon model.
The development of lambda genetics is one of the great intellectual adventures
of our time. Work on lysogeny led to the idea that genetic material (foreign
and host) could be transferred by viruses.
See table 1.1 from
Flint et al.
Animal Virology and tissue -Culture
Simultaneously with this work there was the development of tissue culture
techniques. Alex Carel in 1910 had already shown that it is possible to
grow chick embryo fibroblasts in culture, and in the 1930's chick embryos
were using for growing viruses such as pox virus. By 1940 Earle and associates
had developed media for the growth of cell lines.
1949 Enders et al. worked out human tissue culture--used for growth
of poliovirus. In 1954 received Nobel Prize. Era of polio research extremely
important in virology led to quantitative methods of measuring animal
viruses--development of defined media for tissue culture, and eventually
animal virus plaque assays.
1953 Salk vaccine (killed poliovirus) introduced and by 1955 poliovirus
had been crystallized. Later Sabin introduced attenuated polio vaccine.
Dulbecco in 1950's described animal virus plaque assays similar to phage
plaque assays, and viral transformation analogous to tumor formation in
1965 Spiegleman and coworkers obtained complete replication of
nucleic acid of QB phage in a cell free system; thus showing the RNA was
also genetic material.
1970 Temin and Baltimore independently demonstrated the presence
of reverse transcriptase in RNA tumor viruses (RNA --> DNA --> RNA).
1980's ....Cloning of viral genes.
..................Sequencing of complete
..................Production of hybridomas.
..................Isolation of AIDS virus.
and relationship of virus to cancer.
................. Monoclonal antibodies.
................ .Discovery of cytokines
and growth factors.
................ .Knowledge of immunology.
................ .Development of PCR techniques.
Gene therapy a product of virus, with the development of vector systems.
By 1977 we have the complete eradication of smallpox. Last natural case.
What should we do with smallpox in labs? we wil discuss the threat of
bioterrosim at a later time.
Definition of a Virus
Lwoff in 1957 proposed to define a virus as potentially pathogenic entities
with an infectious phase and: (1) possessing only one type of nucleic
acid, (2) multiplying in the form of their genetic material (3) unable
to undergo binary fission and (4) devoid of a Lipmann system. This is
basically a negative definition, and stresses the non-cellular nature
Viruses are infectious entities whose genomes are either RNA or DNA, and
that replicate inside living cells using the cellular synthetic machinery
and causing the synthesis of specialized components that can transfer
the viral genome to other cells.
Thus viruses are intracellular parasites at the genetic level. They are
obligatory parasites--cannot be grown outside of the cell. Absolutely
dependent on host cell energy yielding and protein synthetic apparatus.
Viruses persist in two stages:
1) dormant phase--extracellular; this phase is neither "alive nor dead"
rather should be described as functionally active or inactive.
2) Vegetative phase--intracellular.
One should note that the nucleic acid of the virus, in some cases, is
All viruses consist of RNA or DNA and a protein coat. Some viruses are
enclosed within envelopes that contain both proteins and lipid.
An interesting question: Is a virus an organism? Is it more of an organism
than a chromosome? Could viruses have evolved from chromosomes or some
other organelle? What about transposons?