Viruses, Cancer Cells, and the Genetic Concept
of Virus Infection*
S. E. LURIA
( Department
of Biology, Massachusetts Institute of Technology, Cambridge, Mass. )
CELLULABGROWTHCONTROLS
ANDTHE
CANCERCELL
The experimental evidence for the role of vi
ruses in the etiology of some cancers has recently
been reviewed by several investigators active in
this field (3, 25). A review by an outsider would
only add confusion to an already complex field.
This is one justification for not attempting any
detailed survey of tumor viruses in this paper.
Another, possibly a more valid one, is that this
conference may concern itself at least as much
with the place of virology in cancer research as
with the role of viruses in cancer. A useful intro
duction for the presentations that will follow
mine may be, therefore, a survey of recent ad
vances in basic virology, which have produced
some unifying concepts on the relation of viruses
to cellular constituents and to cellular functions.
Before discussing viruses, however, it seems
desirable to state some problems of cancer etiol
ogy in very simple terms, so that we can see what
is required of viruses when they are called upon
to act as carcinogenic agents.
A cancer cell is a cell that has become intrin
sically altered and capable of multiplying by es
caping the normal growth regulation by certain
control mechanisms. The control mechanisms can
be either internal or external to the cell. The in
ternal control mechanisms presumably include
interactions among cellular constituents, as well
as receptor systems for external factors. The ex
ternal mechanisms that regulate cellular multi
plication are partially known from studies on
compensatory hyperplasia and regeneration, on
the function of endocrine glands, and on tissue
transplantation ( 77 ). They include hormonal and
immunological mechanisms, as well as somewhat
elusive mechanisms of local regulation. The sites
of action of hormones on cell functions are main* Aided by grants from the National Science Foundation
( G-8808 ) and the National Institutes of Allergy and In
fectious Diseases, National Institutes of Health (E-3038).
ly metabolic (79). The immunological control
mechanisms act presumably through specific
"marker groups," located mainly on cellular
surfaces and acting as receptors for antibodies
(9). Alteration of immunological controls may
result either from acquired tolerance by the ani
mal or from loss of markers on the cells (41).
Local regulation among neighboring cells may be
exerted by accumulation of metabolites, by trans
port of macromolecular constituents, or even by
direct exchanges through cytoplasmic bridges;
no definite evidence seems to be available.
Evidently, the key problem in cancer research
is to clarify the mechanisms that control cellular
growth and the cellular alterations that make the
tumor cell deficient in internal controls or un
responsive to external ones. Several changes may
be needed before the full neoplastic powers of
an altered cell are expressed. This is reflected in
the so-called "progression" toward the fully ma
lignant state, in which a number of cellular prop
erties can be altered in a series of discrete steps
( 22 ). Only one or a few of these steps may con
cern the growth control mechanisms.
The most productive hypothesis is that the
basic controls, which keep the normal, differen
tiated cell of the adult animal from dividing and
which regulate the growth and division of the
stemline cells of continuously renewed tissues,
are "systems responsible for negative feedback
on specific enzyme-forming systems required for
cell division" (66). These include, probably, sys
tems needed for the synthesis of DNA and of
specific mitotic proteins. The full-fledged cancer
cell has lost these regulatory systems, so that its
ability to divide has become unrestricted. In ad
dition, it has acquired a variety of new properties
that render it destructive to the organism as a
whole.
Among the many biochemical peculiarities of
cancer cells, it is difficult to decide which are
primary and which secondary to the altered
677
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678
Cancer Research
Vol. 20, June, 1960
growth pattern. For example, the loss of a variety
of catabolic enzymes, as well as of other proteins
such as the organ-specific antigens (82), could
be secondary to a release of the synthesis of the
bulky mitotic apparatus (77). At the metabolic
level, promising candidates for key roles in the
normal repression of cell division may be path
ways that waste or destroy metabolites necessary
for the synthesis of DNA (61); a block in such
a pathway may be sufficient to unleash unre
stricted cell growth. Alternatively, activation or
induction of a normally repressed protein-form
ing system could produce a similar effect. Once
the growth-restricting mechanisms fail to func
tion, it may be expected that secondary changes
will accumulate in the expanding populations of
multiplying cells.
known tumor viruses is a direct one on the tumor
cells. These cells are carriers and producers of
the virus; they have specific properties correlated
with the specific virus strain ( 70, 80 ) ; and in vitro
transformation of normal cells into tumor cells
by virus infection can be demonstrated, for ex
ample, with the Rous sarcoma virus (55). How
ever, susceptible cells do not necessarily give a
tumoral response to a tumor virus under all cir
cumstances. Thus, with polyoma virus, the tumoral response probably requires conditions that
obtain only in certain cells and tissues at specific
stages of the development of the animal host or
at specific stages of the viral disease.
The role of a virus in the cells of the virusinduced tumor is the central problem in cancer
virology. Clearly, the relationship of the virus to
the evolution of the tumor cell may include a
SOMATICCELLMUTATIONANDVmus INFECTION variety of alternatives. At one extreme, the virus
may master-mind the whole process; at the other
Whatever the underlying biochemical mech
anisms may be, the cellular changes leading to extreme, it may trigger only a single step. Other
factors may intervene, either to promote the can
cancer can stem from two types of events.
On the one hand, they may occur either in an cer career of some cells in a virus-infected indi
as with mammary cancer in mice carrying
apparently spontaneous way, or after exposure vidual,
Bittner's virus ( 13 ), or to transform a less malig
to some relatively unspecific agent (chemical
nant into a more malignant cell, as with Shope
carcinogens, radiation, or hormones, acting di
rectly or indirectly [39] ), or following changes in papilloma (72). Thus, the virus may be respon
sible for one or several of the recognized steps of
neighborhood relations among cells, such as cul
tivation in vitro or insertion of plastic films or carcinogenesis: initiation, promotion, and pro
other inert barriers between layers of tissue ( 1 ). gression to full malignancy.
In the evolution of virus-induced cancers, in
Only rarely are the cells involved in cancerization
fective virus may be recoverable at one stage and
exceptional cells to begin with, such as embry
onal residues. More often, the cells that embark not at another. When present, the virus is often
on a neoplastic career appear to be a more or difficult to transmit to uninfected animals; the
question arises, therefore, whether exogenous in
less random sample from a population of normal fection,
or "vertical" transmission through the
cells. The randomness of the process is distinct
germ cells or the genital tract, or even de novo
from the orderly processes of differentiation ob
served in normal development; rather, it recalls origin from noninfective proviruses or other cel
the randomness of mutations affecting the genetic lular constituents, may be implicated for the
material. Hence, the hypothesis that somatic cell presence of these viruses in the animals in which
are found. Especially with agents such as
mutations are responsible for the initiation and they
Gross's mouse leukemia factor (27), the narrow
progression of cellular changes toward cancer
host-range specificity and the difficulty of trans
has been very popular among biologists ( 9 ).
On the other hand, essentially similar cellular mission by extracts suggest a remarkably ineffi
changes toward neoplastic behavior are observed cient adaptation to natural spread.
It has been customary to contrast the hypoth
in a number of instances following infection with
viruses (25, 70). The virus-induced tumors in esis of somatic cell mutation as the cause of can
cer with the hypothesis of a viral causation (9,
clude all varieties, from benign to the most ma
lignant; and virus-induced tumors may exhibit 71). Nevertheless, according to current ideas
progressive changes toward malignancy similar about viruses and cellular genetics, the opposi
tion between the two hypotheses is probably
to those observed in other tumors.
more semantic than substantial.
Although in some instances a virus could pos
A somatic cell mutation may be defined opera
sibly act as an indirect carcinogen, by altering
control mechanisms normally exerted by the tionally as a cellular change which affects more
virus-infected cells on other organs or tissues, in or less stably the whole clone that stems from the
most instances the carcinogenic action of the changed cell. It is important to emphasize that,
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LuRiA—GeneticConcept of Virus Infection
679
mutually exclusive. Rather, virus infection may
be considered as a class of cellular mutations: a
class of mutations, in fact, in which we know
that the primary change, the entry of the viral
genome, is a genetic change. Undoubtedly, the
tural or genetic mechanism.
The permanent cellular change might be of any primary alterations of virus-infected cells, except
one of several types: gene mutations; chromosal for a few changes that may reflect trivial conse
rearrangements;
mutations in some nonchro- quences of viral attachment and penetration, re
mosomal genetic determinants ( plasmids or para- sult from the genetic functions of the viral gen
genes [33, 43] ); or alterations in self-maintaining
ome. These include genetic replication, gene
function (that is, control over specific biosynsteady-state mechanisms regulated by metabolic
theses ), and functional interaction with host-cell
feedback. This is the same range of mechanisms
that must be considered in connection with the genes.
The genetic concept of virus infection appears
cellular changes underlying the normal tissue
differentiation (78), which involves nuclear as to be a fertile one, especially because it provides
us with a workable prototype of the cellular
well as cytoplasmic alterations (6 ).
changes that can cause cancer. Knowing the ge
The most important distinction is between ge
netic and epigenetic mechanisms of cellular netic nature of the primary change, we can ana
change (20, 61). A change is defined as genetic lyze the exogenous genetic component in relative
(or nucleic [44] ) if it alters the genetic materials isolation and measure the amount of genetic in
of the cell, that is, the structure, size, or number formation it carries; we can alter this genetic
of the coded macromolecules—nucleic acids—that material in controlled ways; we can observe its
compatibility with other genetic elements and its
carry large amounts of detailed information
function in different host cells. We can study the
usable for coding other molecular species. Epi
genetic (or epinucleic) changes are changes in peculiar properties that make the viral genetic
the expression of genetic potentialities, such as material adapted for transfer from cell to cell
and, in so doing, discover transitions between
activations, inhibitions, or competitive interac
tions, whether exerted at the level of primary viral and nonviral constituents of the cellular
action of genetic elements or at other levels of genome.
Once we consider viruses as genetic elements,
cellular metabolism.
specialized for transfer because they possess cer
The distinction between genetic and epigenetic
types of somatic mutations is relevant to the tain specific genetic functions, but otherwise akin
question of viral infection, because it is now to the genetic materials of all cells in basic struc
widely held that the essential constituents of ture and in primary action, we can formulate
meaningful questions about latency, persistence,
viruses are genetic elements. In fact, virus infec
tion has been interpreted as a kind of infective hereditary transmission, and even de novo ap
pearance of viruses, as well as about the transferheredity ( 43, 51 ). Three groups of findings un
derlie this viewpoint in virology: the central and ability of genetic elements not endowed with
specialized devices for transfer.
often exclusive role of viral nucleic acid in ini
It seems especially important, whenever a
tiating virus infection; the interactions between
viruses and genetic constituents of the cell; and transmissible subcellular agent is found to be
responsible for a pathological condition such as
the viral control of cellular functions through
cancer, to ask whether the agent is a virus, that
determination of the structure of specific pro
is, a genetic element with a specialized infective
teins. The concept of viruses as agents of infec
tive heredity underlies some recent definitions of form, or a cellular constituent that can acciden
viruses (51,54). According to this concept, a tally withstand the artificial manipulations in
volved in the transmission test.
virus is considered as a genetic element, consist
ing of RNA or DNA and adapted for cell-to-cell
Such questions have been raised by every stu
dent of viruses and cancer. Our point is that the
transfer because it can determine the biosynthesis
questions can be put into operationally answer
of specific proteins for the shell that surrounds
the mature, infective virus particle. Some of the able form only in terms of cellular genetics,
based, on the one hand, on the structural bio
pertinent evidence will be discussed in the fol
chemistry of genetic materials and, on the other
lowing sections.
It seems, therefore, unnecessary to consider hand, on the biochemistry of gene action and
the somatic mutation hypothesis and the virus cellular regulation.
The genetic approach to virology has been reihypothesis of cancer origin as alternative and
at present, in dealing with mammalian cells, we
can hardly be more specific and that we must
refrain from attributing to the term "somatic mu
tation" any connotation implying a specific struc
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Cancer Research
atively successful in the study of bacterial virus
es: bacterial genetics, phage research, and the
study of biosynthetic regulation in bacteria, de
veloping hand in hand, have provided us with a
satisfactory, if still incomplete, picture of the
functional organization of the bacterial cell. The
stage is now set for a similar approach to the
genetics and virology of animal cells. Animal
cells, normal or abnormal, chosen almost at will
for genetic or pathological reasons, can be culti
vated in carefully controlled chemical environ
ments (17,67). Genetic changes, such as muta
tion, chromosomal alterations, and even genetic
recombination ( if it occurs ) can be detected and
analyzed. Virus infection, especially the various
steps of cellular reactions to a virus, can be
studied with precise quantitative methods (16).
In this "microbiological" approach to the func
tional organization of the mammalian cell, the
bacterial picture is widely used as a model. It is,
therefore, useful to discuss in some detail those
aspects of bacterial genetics that relate to the
controls over cell functions and to the role of in
fective heredity, including viral infection, in these
controls. Needless to say, the situation in bacteria
should not be taken as an analogical model by
which to interpret phenomena observed in other
organisms, but as a methodological model illus
trating the approaches and concepts that have
proved useful in a more advanced field.
After discussing the present status of bacterial
viruses in the framework of the genetics of the
bacterial cell, we shall discuss some recent find
ings in animal virology that provide additional
leads for the study of infective heredity at the
cellular level.
BACTERIAL
GENETICSANDINFECTIVEHEREDITY
A bacterial cell, typified by Escherichia coli,
contains one or more nuclear equivalents, each
consisting of a single chromosome-like structure
with a linear genetic map and a continuous ma
terial backbone consisting mainly or exclusively
of DNA (36). This DNA presumably carries the
basic genetic information. In some bacterial spe
cies ( although not yet in E. coli ) most and pos
sibly all hereditary traits can be transferred from
one cell to another by fragments of purified
DNA, each fragment carrying one or more ge
netic factors in linear sequence; the transferred
factors become integrated in the genome of the
recipient cell. This transformation (32) is the
most striking example of infective heredity.
When a male (Hfr) and a female (F~) cell
of E. coli mate, there is an oriented, generally
incomplete, transfer of a male chromosome to
Vol. 20, June, 1960
the female cell; the transfer can be interrupted
mechanically or by DNA-breaking events (36).
Even short fragments, once transferred, can act
as donors of genetic factors, which become inte
grated by genetic recombination with the chro
mosome of the female recipient. Thus, the ge
netic results of mating and of transformation are
operationally similar.
Two groups of findings need stressing. First,
the DNA of each group of bacteria has a charac
teristic base composition ( 14 ). Successful genetic
recombination has been observed only between
organisms of the same base-ratio group; a simi
larity of base ratios may be required to permit
the DNA to participate in closely homologous
pairing. ( Such "code similarity" is probably also
required for successful integration of a phage
with the bacterial chromosome, but not for vege
tative phage multiplication; see below.) Within
a given group of bacteria with the same base
composition, successful integration of factors
from the donor chromosome, as measured by the
frequency of integration, depends critically on
the degree of genetic homology between donor
and recipient; the closer the philogenetic rela
tionship, the higher the frequency (53, 73).
Second, if we assume the (unproved) hypoth
esis that the nucleotide sequence in DNA acts
as a code for the amino acid sequence in proteins
(11) we can evaluate from data on infective
heredity the "coding ratio" between DNA and
protein. The best current estimate is 4 or 5 nucleotides per amino acid ( 46 ), in fair agreement
with theoretical expectations of a 3:1 minimum
ratio (11).
Another application of infective heredity in
bacteria is the analysis of control mechanisms
over gene action by the study of the function of
newly entered genes. The essential conclusion is
that the function of genes that determine specific
enzymes is regulated by specific repressors pro
duced under the control of other genes (regu
lating genes [64]). This mechanism is related to
the well known situation, observed in bacteria
and also in mammalian cells ( 12 ), in which exog
enous or endogenous metabolites control by re
pression the function of specific enzyme-forming
systems ( 26, 59 ). These metabolites may actually
be transformed into specific represser substances
by the action of the regulating genes ( 10 ). Exog
enous inducers presumably act by relieving the
repressions that normally prevent the function of
inducible genes (64).
The systems of repressive functions in bacteria
provide the most promising model for the anal
ysis of the controls that maintain alternative
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LuRiA—GeneticConcept of Virus Infection
functional states of a cell (63). Similar controls
presumably function in the regulation of growth
versus nongrowth states. Any genetic change,
whether endogenous or viral, that would produce
inability to repress a reaction needed for cell
division might unleash uncontrolled growth ( 66 ).
The bacteria do not provide clear models for
the mutual antagonism between reproduction
and differentiation, which is observed in many
animal tissues. There is, however, in bacteria one
instance of reversible differentiation, namely,
spore formation, in which growth is arrested
when new functions and structures appear in the
bacterial cell. Recent genetic analysis by means
of transformation indicates that spore formation
results from a release of controls over the syn
thesis of certain specific proteins and is physio
logically comparable to an induced biosynthetic
process (74).
PHAGEINFECTIONASINFECTIVEHEREDITY
The phenomena observed in phage infection
fit and complete the above picture of the func
tional genetic organization of the bacterial cell.
The phage particle consists of a core of DNA in
a protein shell equipped with devices for inject
ing the DNA into the bacterium ( 28 ). The entry
of phage DNA into a susceptible bacterium ini
tiates a variety of reactions, which may be com
patible or incompatible with one another and
with other cellular functions. One series of reac
tions leads to lysogeny, with spatial and repro
ductive integration of the phage genome, as prophage, with the bacterial chromosome. Another
series of reactions that can be initiated, either by
entry of a phage or by "induction" of a prophage,
leads to the vegetative multiplication of the
phage genome, the production of phage-coat
proteins, the maturation of phage particles, and
the formation of lytic enzymes that permit the
new phage particles to be set free.
In addition, phage infection may produce a
variety of alterations in bacterial functions. Some
of these alterations, such as changes in the anti
gens of the bacterial surface (81), are mutations
perfectly compatible with cell life; others, such
as the release of destructive enzymes, lead inev
itably to the death of the bacterium. We call
temperate a phage that can achieve the prophage
state and establish lysogeny; virulent a phage
that is genetically incapable to do so; and intem
perate a phage that initiates destructive processes
as a prerequisite to its own replication.1
Two sets of considerations are most relevant
here: first, the nature of the primary action of
phage in controlling cellular functions; and, sec
681
ond, the nature of the regulatory interplay be
tween mutually exclusive functions.
Genetic nature of phage functions.—The geiletic nature of the primary action of phage is
elucidated by the effect of phage mutations.
Thus, for example, the series of reactions leading
to lysogeny require at least three steps controlled
by three adjacent phage loci; mutations within
these loci prevent or hinder lysogeny and in
crease the virulence of the phage ( 38, 45 ). The
initiation of vegetative phage multiplication, on
the other hand, requires certain key functions
that are controlled by specific phage genes, since
they can be suppressed by prophage mutations
which render the prophage defective (34). The
defective prophage can continue to multiply in
association with the host chromosome and to
control a number of cell properties; but it can
neither initiate vegetative multiplication nor pro
duce mature virus particles (unless the blocked
genetic reactions are supplied by an unmutated
phage of the same species). The mutation that
makes a prophage defective transforms a viral
element into what we may consider as a nonviral
one, since it has become unable to control the
production of mature virus particles.
The structure of phage-coat proteins can be
altered by phage mutations and is under the
coding control of specific phage genes (5, 76).
Interestingly enough, with the temperate phages
it is the initiation of the synthesis of coat proteins
that coincides with irreversible events incompat
ible with persistent bacterial integrity. The con
tinued life of the cell appears to depend on sup
press ive control over a set of specific syntheses.
Another set of new functions in phage-infected
cells is the appearance of unusual enzyme ac
tivities, by which intemperate phages prevent
the synthesis of normal bacterial constituents and
retool the synthetic machinery in order to make
phage. The most remarkable ones are the en
zymes that shift the synthesis of DNA from host
type to phage type in bacteria infected with the
T-even phages. The DNA of these phages, in
stead of cytosine, contains 5-hydroxymethyl cytosine, which may be variously glucosylated (83).
Within a few minutes after infection of a bac
terium with one of these phages, a whole set of
new enzyme activities appears. Some provide
building blocks for the new DNA; others carry
out its glucosylation; still others destroy specific
1 These terms can be defined for phage in more specific
manner than the terms moderate, submoderate, and cytocidal, which have been proposed to describe various types
of relations between animal viruses and their host cells
(15).
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682
Cancer Research
intermediates for host-type DNA or degrade the
préexistentcellular DNA to fragments usable for
phage synthesis ( 21, 40, 42, 65 ). In this instance,
the virus appears to take over completely the
control of the biosynthetic function of the cell;
but even this radical shift can be traced to rel
atively few changes in key reactions. The most
interesting reaction, as a possible model of regu
lation of cellular growth, is one that specifically
degrades deoxycytidinetriphosphate to the monophosphate, thereby preventing the synthesis of
host type DNA (40,42). In a normal cell, such
an enzyme could prevent DNA synthesis and,
therefore, suppress cell division. In turn, a block
in the synthesis of such an enzyme could unleash
cell proliferation and lead to unrestricted cellular
growth.
There is as yet no proof that the new enzymes
appearing after infection with T-even phages
are directly coded by phage genes. It is interest
ing, however, to estimate the amount of genetic
information contained in a phage. The DNA of
a phage like T2 contains about 2 X IO5 nucleotide pairs, enough, according to current views
(11), to code 7 X 10* amino acids, that is, about
70 protein molecules of average molecular weight
100,000. (The DNA in an E. coli nucleus con
tains about IO7 nucleotide pairs.) Even if only
one-third of the T2 DNA is genetically relevant
(47), it can still code over twenty such proteins;
this can account for many biochemical functions.
Other phages, however, are smaller; the small
est ones, such as those of the S13 group, have a
single strand of DNA with about 5000 nucleotides (75), which could code 1600 amino acids.
The coat of these small phages consists of twelve
protein units, each containing about 4000 amino
acids. Assuming, by analogy with the small
plant and animal viruses, that all protein units
are identical and that they are not built up from
smaller identical subunits, there would hardly be
enough genetic information available in this
phage to determine the protein coat, let alone
other proteins. Most effects of the phage on the
cell would have to be indirect, secondary to the
extremely few genetic actions that initiate phage
synthesis.
With the intemperate phages, even in the ab
sence of specific host-destructive biosyntheses,
the switch between host-controlled and phagecontrolled patterns of synthesis might be due to
different DNA base ratios; competition between
two incompatible templates for the DNA-synthesizing enzymes might cause a complete shift from
using one set of directions to using the other.
It will be worth while comparing DNA-contain-
Vol. 20, June, 1960
ing animal viruses and their host cells in this
respect.
It is interesting to speculate also on the possi
bility that the mechanisms that regulate or sup
press cell division in differentiated animal cells
may include inhibitions on DNA synthesis acting
specifically on DNA of a characteristic base com
position. Entry of DNA elements of different
composition, such as DNA viruses, might con
ceivably upset the repression system and unleash
uncontrolled cellular growth and multiplication.
Regulation of alternative sets of phage-controlled functions.—The role of specific repression
mechanisms in the regulation of phage functions
is best illustrated by the phenomenon of immu
nity, clarified largely by the work of Jacob and
his colleagues (34). Once a temperate phage be
comes prophage, vegetative multiplication of the
phage genome ceases, its maturation is pre
vented, and the multiplication of similar phages
introduced by superinfection in the lysogenic
cells is also inhibited. The lysogenic bacteria are
immune to superinfection with phage similar to
the prophage. The mechanism of this immunity
is the production of specific represser substances
which, acting through the cytoplasm, prevent the
vegetative multiplication of the phage and the
synthesis of the phage-coat proteins. Destruction
of the repressor substance is probably the initial
step in the induction of vegetative phage multi
plication from the prophage state. By mutation,
a phage can acquire the ability to produce the
immunity substance even when not yet estab
lished as prophage (35). The analogy with the
repressive regulation of enzyme biosynthesis is
quite close (34).
We may ask if specific repressers of the im
munity type play some role in maintaining the
genetic constancy of the bacterial cell by pre
venting the anarchistic replication of chromo
somal bits. There are in bacteria, besides the
phages, other dispensable genetic elements or
episomes (37), which can be either present or
absent from a cell and which can either multiply
vegetatively or attach themselves to certain chro
mosomal sites. When attached, they multiply
with the chromosome and suppress further vege
tative multiplication. Some episomes, such as the
fertility factors of E. coli, can be transferred by
contact from cell to cell. The genetic functions
controlled by episomes are clearly unessential
for cellular life since an episome can be lost with
out death or damage to the bacterial cell.
Attachment of a genetic element, such as an
episome or a temperate phage ( itself an episome
with potential viral functions ), to a chromosomal
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LuRiA—Genetic Concept of Virus Infection
683
sufficient phage development; but this may well
site can probably activate specific genetic func
be
accidental. A piece of bacterial chromosome
tions not only in the episome itself but also at
neighboring chromosomal sites. An episome such might, however, become part of a phage element
viral functions remain fully effective. This
as the fertility factor, which can attach itself at whose
could be the mode of origin of "converting"
any one of many chromosomal sites (37), may
produce a variety of different genetic results. phages, which contain in their genome some
This situation is not without counterpart in genes that control cellular properties, such as sur
face antigens, which have no apparent relation
higher organisms. Genetic elements that can as
to the viral functions of the phage (81).
sume different chromosomal locations and acti
vate neighboring genes are known to occur in
PHAGEANDOTHERVIRUSES
maize (7, 57). One wonders as to the possible
The findings outlined above illustrate the basis
role of changes in state and position of such
genetic elements in determining the response of for the integration of phage research and bac
terial genetics into a unified subject. Will such
cells to external stimuli such as carcinogenic
an integration be possible and valid for other
agents.
The episomes provide examples of the two virus-cell systems?
On the one hand, the intimate relationship of
ways by which an added, unessential genetic ele
phages to the bacterial chromosome need not
ment can persist in a clone of cells: (a) persist
disqualify them as model viruses. Phages are
ence in a form materially and reproductively in
tegrated with the chromosomal apparatus of the simply a group of viruses whose relation to hostcell; (£>)persistence by autonomous vegetative
cell organization is already fairly well under
multiplication. These are the two kinds of state stood. On the other hand, the bacterial model
which the genome of a persistent virus may has important limitations. For example, RNA
assume in its host cell. It is interesting to point transfers have not yet been observed in bacteria,
out that at least one episome, the fertility factor and the phage model may prove misleading if
followed too literally in the exploration of RNA
in E, coli, can be eliminated by chemical treat
ments of the bacteria that carry it in the non- viruses. Also, the bacterial model does not pro
integrated condition (29). This may provide an vide any direct analogy for those regulatory
interesting lead to the chemotherapy of some processes that depend on interactions among dif
ferentiated cells in a complex organism, nor for
persistent virus infections.
the role of viruses in altering these regulatory
It is also worth recalling that for temperate
phages, as well as for other bacterial episomes, processes.
The phage model has a close counterpart in at
the chromosomal location and the number of
least one instance of genetic control of host prop
copies of the integrated form can be determined
only by tests of genetic linkage and of genetic erties by a group of animal viruses, the agents
that produce sensitivity to CO2 in Drosophila
competition between related elements ( 4 ). Simi
lar tests will be needed to analyze the genetic
(48). The responsible agent, virus a, can assume
condition of persistent viruses in animal cells.
in the flies two alternative conditions resembling
Transfer of bacterial genes to phage.—Tem the vegetative and prophage states. The "properate phages illustrate not only how viral genes viral," stabilized form exerts a repressive influ
become integrated with the bacterial chromo
ence on vegetative multiplication, recalling that
of prophage. Stabilized a can mutate to defecsome, but also how chromosomal genes can be
come part of a phage element. This is observed
tiveness, that is, to inability to produce the ma
in special transduction ( 2, 52, 60 ). In the known ture infective forms. The reverse mutation is
cases, the gal (galactose utilization) genes can also observed. The stabilized form of virus <ris
become part of phage A, and the lac (lactose)
regularly transmitted through the gametes.
Thus, o- is a genetic element that, in animal
genes can become part of phage PI. The cor
responding chromosomal segments are apparent
cells, can shift from the state of a cellular constit
ly incorporated into the phage genome in place uent transmitted in noninfectious form from one
of specific phage segments. The combined ge
cell generation to another to the state of an infec
netic elements thereby produced behave in most tious agent transmissible by cell-free extracts.
respects like phages and can enter mature phage Natural transmission from one fly to another has
particles.
not been demonstrated; if it occurs, it may in
In the two instances mentioned above, the volve some specific vector.
phages that have acquired bacterial genes are
The case of a provides a model study of a
defective, lacking some functions needed for self- process that may play a role in cancer: the reg-
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684
Cancer Research
ular transmission of a virus through gametogenesis and fertilization. Such transmission is not
exceptional in insects; many plant-pathogenic
viruses are regularly transmitted in their insect
vectors from one generation to the next through
the egg (56). The case of a is the only one in
which the genetic analysis has implicated a ge
netically stabilized proviral state.
Incidentally, it seems worth mentioning here
the possibility that insect vectors may play some
role in the natural spread and perpetuation of
some tumor viruses that are notoriously difficult
to transfer mechanically by means of cell ex
tracts.
CONTROLMECHANISMS
IN VIRALINFECTIONS
OF ANIMALCELLS
We turn now to some aspects of animal virol
ogy that concern the role of viruses in the genetic
control of cellular properties.
Viral control over cellular functions.—First, let
us consider once more the coding ratio. Animal
viruses include both DNA and RNA viruses
(whereas all the plant viruses that have been
analyzed contain RNA). Since viral RNA can
initiate infection and can control the production
of complete virus (30), including the exact rep
lication of mutational changes, the RNA must act
genetically. It seems reasonable to assume that
the coding ratio for RNA is similar to that postu
lated for (single-stranded) DNA. We find that
the amount of genetic information in certain ani
mal viruses must be quite limited. Thus, rabbit
papilloma virus, with about 4 X IO6 MW DNA,2
or polio virus, with 2 X 10°MW RNA, can each
code about 2200 amino acids at most. Since some
of this code is needed for the characteristic viral
proteins, not much information is available to
code other proteins and enzymes. Thus, the virusinfected cell is genetically not very different from
the uninfected cell; and any switch in growth
pattern due to a virus must depend on one or
few virus-controlled reactions. Most of the bio
chemical changes in virus-infected cells, especial
ly in virus-induced tumor cells, are probably
caused indirectly by an altered balance among
biosynthetic pathways or by secondary genetic
alterations. It is not surprising, therefore, that the
same key changes may result from exogenous
viral infection, or from endogenous genetic
changes, or from epigenetic changes due to en
vironmental stimuli.
In view of the limited amount of genetic in
formation available in a virus, whenever a spe2 This value may be too low by a factor 2 ( J. D. Watson,
personal communication).
Vol. 20, June, 1960
cific biochemical activity appears in the cells of
a virus-induced tumor, it becomes important to
decide whether this activity is directly controlled
by viral genes, because any such new function
has a significant chance of being the key function
in the tumoral transformation. The most intrigu
ing case ( 69 ) is that of arginase, which is found
at high levels in the cells of viral papillomas of
rabbits as well as in the cancers that originate
from the papillomas ( and which presumably still
carry the viral genome, possibly in a defective
form). The tumor-carrying animals contain in
their blood serums a precipitin, absent in the
control animals, which reacts with the tumor
arginase. This finding is suggestive of a viral
control over the protein specificity of the en
zyme (69a). Genetic analysis of this situation,
however difficult it may appear at the present
time, should be very rewarding.
Cellular controls over viral maturation.—With
bacteriophage, as well as with some animal vi
ruses, there have been observed "host-induced
modifications" (31, 50), in which the host-range
of a virus is altered in a reversible way. The al
teration may be a restriction of the range of host
cells in which the virus can multiply. The mech
anism of these modifications is unknown, but it
probably operates on viral maturation. The pos
sible role of host-induced modifications in tumorproducing viruses can only be guessed at.
More interesting, from the viewpoint of mech
anisms that control viral maturation, are examples
of incomplete virus growth cycles.
There are at least two ways in which the mat
uration of a virus into infective virus particles
can fail: failure to synthesize an essential com
ponent of the viral shell, and failure of the var
ious components to assemble together. Incom
plete growth cycles in myxoviruses ( the influenza
virus group) illustrate both possibilities.
In the normal growth cycle of these viruses,
the S element, containing RNA and protein, is
produced first and probably only in the nucleus,
the hemagglutinin component is formed in the
cytoplasm, and the outer virus coat, partly con
tributed by the host cell, is assembled at the
cellular surface (8). In the chorionic cells of the
chorioallantoic membrane of the chick embryo,
however, the growth cycle is incomplete; only S
nucleoprotein is formed, but no hemagglutinin
(24). The host-cell has become, through differ
entiation, incapable of fulfilling some of the virusdictated orders, and no complete virus can be
made.
A different situation is observed with fowl
plague virus in the L cell line of mouse fibro-
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LuHiA—Genetic Concept of Virus Infection
blasts in tissue culture (23). Infection here is
abortive, and no new virus is produced, although
all the known constituents of the virus are pro
duced in the cell. Maturation fails because the
S nucleoprotein, although formed in normal
amounts in the nucleus, is not released into the
cytoplasm and cannot, therefore, participate in
the assembly of mature infectious particles, even
though the other viral components, including the
hemagglutinin, have also been synthesized.
These situations illustrate the fact that viral
maturation, and the production of complete in
fective virus particles, may fail not only because
of genetic changes in the virus ( defectiveness ),
but also because of genetic or developmental
changes in the virus-carrying cells.
In this respect, a remarkable situation is one
observed in rabbit papilloma, which reveals a
subtle interplay between viral controls over cel
lular growth and cellular controls over viral mat
uration. The virus-induced papillomas consist
of a core of proliferating epidermal cells derived
from the cells of the basal layer of the epidermis.
Like normal epidermal cells, the papilloma cells
ultimately undergo keratinization and stop pro
liferating. The papillomas contain large amounts
of virus particles, which consist of DNA in a pro
tein shell. Microscopic examination with fluores
cent antibodies reveals that the viral protein and,
hence, the mature virus are found only in the
cell nuclei (58). The significant finding is that
the viral protein is present only in the nuclei of
those cells that have started keratinization and
have lost their ability to divide. The proliferating
cells of the tumor do not contain any detectable
viral proteins. These cells must contain the viral
genome in some naked, replicating, but presum
ably noninfectious form.
It appears, therefore, that the virus induces in
the basal type cells an increase in cellular pro
liferation; proliferation, in turn, represses the
synthesis of viral protein. Keratinization, a typi
cal cellular differentiation, occurs when cell pro
liferation stops, and at this point the synthesis of
viral protein is also released. Thus, cell prolifera
tion is mutually exclusive with two expressions
of differentiation: formation of keratin in the cell
cytoplasm and formation of viral protein in the
cell nucleus.
Nucleic acid transfers.—Fromsome of the RNA
viruses, or from tissues infected with these vi
ruses, one can extract RNA fractions more or less
free of proteins and capable of infecting host
cells and of initiating virus production. Interest
ingly enough, the free RNA has a wider range of
host cells than the intact virus particles, even
685
though its absolute infectivity (infectious units
per unit of nucleic acid) may be much lower
(30). This suggests that the process of matura
tion, on the one hand, enhances the transferability of a virus by increasing its infectivity but, on
the other hand, restricts the range of host cells
that the virus can parasitize. Like all adaptations,
the adaptation of the viral genome for transfer
also limits its potential spread.
This observation raises several interesting pos
sibilities. First, we may suspect that in an in
fected animal the occasional transfer of naked
viral nucleic acid may bring virus to certain cells
which may respond anomalously to it or which
would be virus-resistant if exposed to mature vi
rus particles. Infection of such cells, even if it
led to production of mature virus particles, could
not spread by cell-to-cell transfer of the particles.
Different cells would be needed as indicators in
testing for virus production.
Second, the extended host range of viral RNA
suggests that the restrictions on RNA replication
may not be very stringent. This, in turn, raises
the question whether some classes of cellular
RNA, even though they have not evolved a viral
maturation process, may not be able to establish
themselves in a variety of cells if they can gain
access to them.
A possible role of cellular nucleic acid trans
fers in the control of normal differentiation has
been postulated repeatedly but has never been
substantiated. We may recall, however, the sug
gestive similarity in RNA content between the
small RNA viruses and the ribosomes, which con
tain about 2 X 10" MW RNA (68). The struc
tural proteins of ribosomes may bear to their
RNA a relation somewhat analogous to that of
the protein coat of virus particles to the viral nu
cleic acid. Ribosomes might exceptionally be
transferred from cell to cell in functional form.
In fact, we may even speculate whether some of
the more highly specialized •
tumor-inducing
agents, like Gross's virus, may not be transmissi
ble ribosomes.
A recent report (18) suggests a remarkable
role of a virus in facilitating the transfer of other
determinants of cellular functions. In these ex
periments, chick heart muscle was mixed with
Rous sarcoma tissue, and the mixture was ex
tracted to isolate the sarcoma virus. The joint ex
tract ( but not a combination of two separate ex
tracts ), when placed on the chorioallantoic mem
brane of the chick embryo, gave rise to tumors
that contained striated muscle fibrils in many of
their cells. This observation, if confirmed, would
suggest that a rather firm association was estab-
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686
Cancer Research
lished during the extraction process between vi
rus particles and specific cellular constituents of
the muscle fibers—apeculiar type of man-made
transduction.
CONCLUDING
REMARKS
This discussion has been concerned primarily
with controls over cellular functions, in an at
tempt to relate control reactions to specific ge
netic functions and genetic functions to viral
functions. We have also encountered
some
mechanisms whereby genetic elements can gain
or lose the specialized transferability that is the
essential feature of viruses.
As we prod into the functional organization of
cells, we are bound to find other examples of
transitions between endogenous and exogenous
constituents of cells. From the standpoint of the
oretical biology, the most significant questions
concern the origin and relationships of the vari
ous types of cellular constituents and the respec
tive roles of infective heredity and of intraclonal
changes in the evolution of cells as genetic sys
tems (19,43,49).
From the standpoint of cancer biology, the dis
tinction between viral and endogenous causation
is of immediate practical importance, because it
concerns the role of natural infection. The ques
tion of the type of genetic elements that control
the growth properties of tumor cells is also rele
vant to the problem of therapy, since treatments
may selectively suppress or eliminate the less
stably integrated genetic elements.
Personally, I am inclined to believe that the
majority of cancers stem from genetic changes
affecting long established cellular elements rath
er than from the entry or activation of relative
newcomers such as full-fledged viruses. Yet, I
also believe that the most rapid progress in can
cer research, considered as a branch of cellular
fenetics, will come from the study of virus-inuced tumors, because they provide us with the
opportunity to analyze the role of individual ge
netic elements in the transformation of normal
cells into tumor cells.
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Viruses, Cancer Cells, and the Genetic Concept of Virus
Infection
S. E. Luria
Cancer Res 1960;20:677-688.
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