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When Did Virology Start?
Despite discoveries of nearly a century ago, the unifying concept
undey?inning this discipline dates more recently to the 1950s
TONVANHELVOORT
The discovery of an infectious agent which passes
through a filter that blocks bacterial agents and causes
tobacco mosaic disease is generally recognized as the
earliest distinct piece of virus research. These initial
observations date to a report in 1892 by Ivanovski and,
independently, another report 6 years later by Beijerinck, who described tobacco mosaic virus (TMV) as a
“contagium vivum fluidum.” Beijerinck, in recognizing
this infectious agent as living but noncorpuscular,
distinguished it from bacteria, which were considered
to be more complex in their organization.
These moments in the history of virus research, and
especially Beijerinck’s work, are widely considered the
start of virology. However, a curious paradox exists
here. In 1953, the Australian microbiologist and immunologist Macfarlane Burnet claimed that virology did
not become an independent science until the 1950s.
Scholarly activities during the 1950s certainly make
it tempting to designate these years as the dawning
period of virology. For instance, several journals dedicated to virology, including ViroZogy (1955), Advances
in Virus Research (1953), Voprosy Virusologii (1956),
Acta Virologica (1957), Progress in Medical Virology
(1958), and Perspectives in Virology (1959), were started during that period. Moreover, the original edition of
Salvador Luria’s seminal textbook, GeneraZ Virology,
was published early during that decade. Critical to
these conceptual developments was the widely accepted realization that viruses replicate within host
cells during a non-infectious phase, since then known
as the “eclipse” period.
On the other hand, a quarter century earlier, there
had been a similar burst of scholarly activity, including
Ton van Helvoort, a biochemist who completed his
Ph.D. in the history of science, works as a technical
translator and a scientific writer in The Netherlands,
near Maastricht. This article is based on the author’s
History of Microbiology Lecture presented at the ASM
95th General Meeting, held May 1995 in Washington,
D. C.
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publication in 1928 of the collection of essays FiLterabLe
Viruses, edited by Thomas Rivers; introduction in 1939
of the journal Archiv fir die gesamte Virusforschung by
Springer Verlag in Vienna (continued as Archives of
Virology); and publication of more than a dozen scholarly monographs on plant and animal viruses. During
this earlier period, viruses were viewed as replicating
in the same way as bacteria and other microorganisms
by binary fission but differed from them by being
“filterable.”
Abrupt Conceptual Shift or Progressive
Unveiling?
There are two main arguments to put the birth of
virology in the 1950s. First, the latter period saw the
emergence of the concept of an “eclipse” of the virion
during the multiplication phase, a concept that sets
viruses apart from bacteria. Second, the definition of
the virus that developed during the latter period unified studies of animal, plant, and bacterial viruses.
Indeed much of the research conducted on filterable
viruses between 1920 and 1950 was held together only
loosely under the somewhat crudely developed umbrella definition that was based primarily on the filterability of the infectious agents.
If we consider the definition of viruses as filterable
agents and the modern concept of viruses as agents
with an “eclipse” phase, one can speak of two paradigms, to use Thomas Kuhn’s terminology. In this
sense, an abrupt conceptual shift or scientific revolution took place in the 1950s. However, Anthony Waterson, who was a virology professor at the ~University of
London, wrote that the history of virus research is “the
story of the progressive unveiling of the nature of the
virus particle.“.
I have come to believe that, despite its widespread
appearance in textbooks and journals of that era, the
early concept of the “filterable virus” lacked clarity and
certainty. More importantly, I also believe that during
the 1930s and 194Os, the links between the study of
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filterable viruses and bacteriology were so strong that
viruses were still considered merely another form of
bacteria-not conceptually distinct, as they now are.
Indeed, the critical and defining point came when
biologists realized that viruses multiply in host cells,
following a biological process for replication that sets
them apart from other microorganisms.
The consensus laid to rest the dichotomy between
the exogenous and endogenous interpretations of virus
multiplication. According to the first interpretation, a
virus was an exogenous and autonomous agent. This
view was pitted against the idea that a virus was an
endogenous product of the host cell. Many researchers,
particularly those who studied bacteriophage, were
adherents of the endogenous school of thought. Most
importantly, those who conceived of bacteriophage as a
product of bacterial cells did not consider bacteriophage to be viruses.
If one describes the history of virus research as the
progressive unveiling of the nature of viruses, one
ignores the deep controversies in virus research during
the first half of the 20th century. These conflicts are
illustrated by the history of theories of virus multiplication.
Viruses Defined as Filterable, Invisible,
Unculturable Agents
Soon after the first reports on TMV, publications
appeared establishing the filterability of other infectious agents responsible for diseases in both plants and
animals. By 1931, nearly two dozen such agents had
been associated with specific diseases, including yellow
fever, rabies, fowl pox, and foot-and-mouth disease in
cattle.
These newer filterable agents differed from bacteria
in other ways. For one thing, bacteria could be observed directly in light microscopes or made visible by
means of staining procedures. For another, bacteria
could be cultured on plates, forming colonies that are
visible to the unaided eye. The filterable viruses, however, remained unculturable on inert media and invisible by staining or upon direct examination in light
microscopes.
Because culturing of microorganisms was considered a standard technique, some early investigators
quickly concluded that viruses must be obligatory parasites that depend on other cells for growth. However,
not all investigators shared this view. Moreover, generalization was complicated because not even all kinds
of bacteria could be cultured readily. Frequently, growth
factors were needed for recalcitrant bacteria, suggesting to some early workers that the difficult-to-culture
viruses were merely fastidious forms of small bacteria
and, with patient efforts to find appropriate growth
factors, they could be cultured in much the same way
as could other once-difficult-to-grow bacteria.
Early Technical Advances Brought Additional
Insights
Eventually, microbiologists realized that none of
VOL. 62, NO. 3, 1996
the viruses could be grown on ordinary nutrient media
because they are obligate parasites that depend on host
cells to replicate. An important practical breakthrough
toward this realization came from the early studies of
Ernest Goodpasture, who grew fowl pox viruses on the
chorioallantoic membranes of chicken embryos. Later,
Macfarlane Burnet developed techniques for using
other types of tissues and membranes as host cells for
growing various viruses.
The other early defining criteria for viruses were
also subject to skepticism and misinterpretation. Filterability, for example, depended upon the techniques
and filters being used. As early as 1908, Stanislaus
Prowazek noted that “one cannot express a judgement
on the nature of the virus on the basis of filtration
experiments, as has nowadays become a dogma, because every filter is subject to individual fluctuations in
relation to its tightness.” When porcelain filters were
replaced by graded collodion membranes, the performance of such systems became a good deal more
reliable.
The seeming invisibility of viruses eventually fell
prey to better microscopes and newer techniques. In
the 1920s and 193Os, dark field illumination and UV
microscopy enabled some of the larger viruses to be
visualized. For example, Joseph Barnard in England
used UV microscopes to view several of the poxviruses
during this period.
Also during this era, several investigators began
using newly available ultracentrifuges to study the
filterable viruses. From such studies, Wendell Stanley
put together a chart comparing the sizes of selected
viruses and those of various bacteria and proteins. On
the basis of such comparisons, investigators came to
understand that viruses have discrete sizes, ranging
from that of the smallest bacteria to two- to threefold
larger than several proteins found in serum.
Is Bacteriophage a Virus?
The Phage Group was instrumental in making
bacteriophage the model for virus studies. In the 1950s
and 196Os, members of this group helped to establish
the modern field of molecular genetics. Although bacteriophage are now well accepted as the class of viruses
that infect ,bacteria, many investigators early on considered bacteriophage to be distinct from the filterable
viruses associated with diseases in plants and animals.
According to one school of thought, phage were lytic
proteins, or enzymes, rather than living parasites. But
earlier, during the 1920s and 193Os, the impact of
phage research reached far beyond the study of the
phenomenon itself.
To Ernest Goodpasture, uncertainties about bacteriophage raised serious questions about the fundamental nature of viruses and of viral diseases. “Two interpretations have been offered in explanation of the
multiplication of viruses. . .namely, that they are living
things and reproduce themselves by vital activity, or
that they are inanimate substances and are reproduced
through an interaction between themselves and the
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cells which they alter,” he wrote. Other investigators
agreed, noting that the enzyme-like behavior of phage
cast doubt on the fundamental nature of viruses, which
had once seemed more clearly to be ultramicroscopic
living organisms.
Thomas Rivers summarized
the confused state of affairs concerning viruses in an article
published in PhysiologicaL Reviews in 1932. In addition to
proposing a mechanism for the
etiology of malignancy, he presented three possible mechanisms for the production of viruses by a host cell. In the first
and second mechanisms, a stimulus induces a normal cell to
make a substance X. This x may
Rivers
remain free or become closely
bound to a part of the cell. In the
third mechanism Rivers mentioned, x is a minute
living organism. It enters cells, multiplies, and produces disease. Rivers concluded that x in the first and
second mechanisms was distinct from the third case. In
the former instances, x is an inanimate agent and the
product of cellular perversion. In the latter case, x is
viewed as an autonomous organism.
Thus, in outlining these alternative processes for
virus infection of a host cell, Rivers distinguished
between the notions of exogenous and endogenous
formation of viruses.
Virus Multiplication as an Endogenous Process
It is important to realize that the exogenous and
endogenous interpretations of virus multiplication
sharply divided virus researchers into two camps. To a
large extent, this division resulted from studies of
bacteriophage. The possibility that viruses are products of host cells was not an idea limited to those
studying phage. Robert Doerr, one of the outstanding
scientists of that period, became an influential defender of this notion. Perhaps all filterable viruses are
products of host cells, he pointed out.
Doerr, whose own research focused on herpesviruses, cited in a 1938 publication several observations
as consistent with the intracellular formation of viruses, including (i) generation of viral diseases from
latent virus infections but without external contact
with the infectious $gent, (ii) generation of viral diseases through nonspecific causes (e.g., chemical irritation), (iii) serologic relationships between host and
viral proteins, (iv) association of virus multiplication
with enhanced host cell metabolism, and (v) “lifeless”
viral properties that contradict those of living organisms and point to endogenous formation of viruses in
host cells.
Within the field of plant virus research, Frederick
Bawden and Bill Pirie defended the position that a
virus infection could be understood best as a disturbance of host metabolism. They criticized Wendell M.
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Stanley, who claimed that viruses were nucleoproteinaceous particles of specific, characteristic lengths.
Bawden and Pirie had observed that the mean length
of particles in a virus preparation is influenced by the
“past history and present environment in the preparation.” In the late 1940s they stated that, in effect, no
one physicochemical method could produce the virus
particle.
Although in general members of these two distinct
camps dominated the study of viruses, other researchers tried to reconcile the two groups. For instance,
Constantin Levaditi of the Pasteur Institute in Paris
tried to steer a middle course between the view that
viruses are exogenous agents or that they are an
endogenous product of host cells. He viewed all cells as
existing amid two competing processes, called assimilation and dissimilation.
According to Levaditi’s model, a virus infection
could hijack the control center of the cell and instruct it
to multiply unrestrictedly or to produce viral offspring,
which would lead to death (lysis) of the cell. The notion
for virus reproduction developed during the 1950s by
Salvador Luria, known as “genetic parasitism,” is very
much related to Levaditi’s concept. However, Levaditi’s
contributions have been largely neglected in the literature describing th.e history of virology.
The Modern Concept of the Virus
Andre Lwoff at the Pasteur Institute brought new
insights to these questions when he reexamined the
issue of lysogeny. Lysogeny was the apparently spontaneous formation of bacteriophage from seemingly
phage-free bacteria. This phenomenon was crucial to
those investigators who held to the view that phage
was not a virus but a product of bacterial metabolism.
In 1950, Lwoff asserted that the lysogenic function is
transmitted from one generation of bacteria to the next
by an endomicrobial route.
Lwoff’s most remarkable proposal was that the
phage was not infectious when transmitted from one
generation of bacteria to the next. He called this phase
of the phage life cycle the probacteriophage, or prophage. Only when the phage is in the prophage stage
could it live in harmony with its bacterial host, he
noted. And, by some process of induction (stimulus),
the prophage again became an infectious particle.
Other important observations were incorporated
into this model of the phage life cycle. For instance,
August Doermann had reported that the phage particle
went into an “eclipse” during the multiplication cycle.
Moreover, nucleic acid was recognized as the carrier of
genetic information, in large part because of the Hershey-chase experiment.
Less well known is the work from the late 1940s of
Leslie Hoyle on the eclipse phase of the influenza virus.
For decades animal viruses had been believed to be
ultramicrobes that, like larger bacteria, multiplied by
means of binary fission. The work of Hoyle was crucial
for the acceptance of an eclipse phase for the animal
viruses. “Before 1948 it was almost universally beASM News
lieved by animal virus workers that viruses had
evolved from bacteria by increasing parasitism. . .only
retaining the ability to multiply by some process of
growth and fission,” he wrote in 1968. As other investigators came to accept his views of the eclipse phase
during animal virus multiplication and, also, Doermann’s similar observations for bacteriophage, earlier
assumptions about viral replication had to be discarded.
Even though much was yet to be learned about how
viruses multiply, there was no longer any doubt that it
was not by binary fission. “When the controversy [over
the eclipse of influenza virus] was finally over, the
study of viruses was no longer regarded as a branch of
bacteriology, the similarity of plant, animal, and bacterial viruses was established, and virology had become a science in its own right,” wrote Hoyle.
In the late 1950s Lwoff reformulated his model for
phage and prophage again, widening it to include
viruses in general. He also incorporated a refined
understanding of the role played by nucleic acids in
carrying genetic information. His definition from 1957,
stating that viruses are infectious agents made up of
nucleic acids and proteins but unable to grow autonomously or reproduce by binary fission, has stood up
well for nearly four decades.
This definition anchors the autonomous and exogenous character of a virus in the continuity of its genetic
material, while the dependence of virus multiplication
on host cell metabolism is grounded in the takeover of
the cell’s metabolic machinery by the genetic material
of the virus. This takeover corresponds to what Luria
described in 1950 as “parasitism at the genetic level.”
Around the middle of the 20th century, important
theoretical and social changes took place in virus
research. These changes were reflected in the publication of books and the launching of several new periodicals that centered on viral research.
In 1952 Wendell M. Stanley set up the Virus Laboratory at the University of California, Berkeley, that
bears his name. Two years later, the Max-PlanckInstitut fur Virusforschung was established in Tubingen, Germany. Such events established virology as an
VOL. 62, NO. 3, 1996
independent discipline, a development that was based
on a new definition of viruses formulated at this time.
Is the Centenary of Virology at Hand?
If we take the modern concept of the virus as the
beginning of the discipline of virology, the centenary of
virology is surely not at hand. If the earlier concept of
filterable virus is called the starting point, then 1998
will mark the centenary of Beijerinck’s publication.
Undoubtedly, many virologists will choose 1998 to
commemorate the birth of this discipline. However,
this paper indicates that researchers were engaged for
half a century in diverging interpretations and deep
controversies before their conflicting views about bacteriophage, plant viruses, and animal viruses were
brought together coherently as the modern concept of
the virus. Because dynamic processes such as controversy and consensus formation lie at the heart of all
scientific research, it may be useful to keep this history
in mind when virology’s anniversary celebrations are
cl
under way.
Suggested Reading
Cairns, J., G. S. Stent, and J. D. Watson (ed.). 1966. Phage and the
origins of molecular biology. Cold Spring Harbor Laboratory, Cold
Spring Harbor, N.Y.
Doerr, R., and C. Hallauer (ed.). 1938. Handbuch der Virusforschung- erste Halfte. Springer, Vienna.
Fenner, F., and A. Gibbs (ed.). 1988. Portraits of virology: a history of
virology. Karger, Basel.
Grafe, A. 1991. A history of experimental virology. American Chemical Society, Washington, D.C.
Levaditi, C., P. Lepine, et al. 1938. Les ultravirus des maladies
humaines. Maloine, Paris.
Luria, S. E. 1953. General virology. Wiley, New York.
Rivers, T. M. (ed.). 1928. Filterable viruses. Williams & Wilkins,
\
Baltimore.
van Helvoort, T. 1991. What is a virus? The case of tobacco mosaic
disease. Stud. Hist. Philos. Sci. 22557-588.
van Helvoort, T. 1994. History of virus research in the twentieth
century: the problem of conceptual continuity. Hist. Sci. 32:185235.
van Helvoort, T. 1994. The construction of bacteriophage as bacterial
virus: linking endogenous and exogenous thought styles. J. Hist.
Biol. 27:91-139.
Waterson, A. P., and L. Wilkinson. 1978. An introduction to the
history of virology. Cambridge University Press, Cambridge.
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