102
BRIAN POOLE
Recently the development of the autoradiographic technique with
tritiated thymidine (MacDonald and Mallory, 1959) has made possible
the accurate determination in a tissue of the relative number of cells which
are synthesizing DNA in an experimental interval. This method is certainly
superior to mitotic index determinations, but it is still measuring a variable
which is related only indirectly to the tissue growth rate. Determinations
of the rate of uptake of P
32 and C
14
-orotic acid into RNA are valuable
(Fujioka et al., 1963; Nygaard and Rush, 1955), but are complicated by
the large turnover of these metabolites even in cells which are growing
very slowly or not at all. In addition there is a diurnal rhythm in the uptake of P
32 into phosphatides and RNA (Barnum et al., 1958) which is
probably related to the rate of inorganic phosphate exchange between the
cells and the extracellular fluids (Nelson, 1964).
B. Injection of Tissue Extracts
Many experiments have been carried out in which cell-free extracts,
homogenates, minces, or even whole pieces of tissue have been injected
into experimental animals. We shall discuss the results of some of these
experiments below, but we must first consider what predictions about the
results of such experiments can be made on the basis of the theories of
growth control described above. According to Weiss's (1952) theory of
feedback inhibition, tissue extracts should contain both inhibitors and sites
which bind inhibitors. In adult tissue the concentration of inhibitors should
be just about enough to saturate all the binding sites. However, we would
not expect these substances to persist unchanged in a solution as rich in
enzymes as broken cells. Both the inhibitors and the binding sites could
be destroyed, in which case the extract would have no effect; the binding
sites could be destroyed, in which case the liberated inhibitors would have
an inhibitory effect on the growth of homologous tissue; or the inhibitors
could be destroyed, and leave binding sites capable of binding inhibitors
from the host and thus stimulate growth. In fact, any result could be
interpreted on the basis of Weiss's theory, and we could predict that small
differences in the preparation and handling of the extract could reverse
the observed effect on growth.
Teir's (1951) theory predicts that tissue extracts should have a stimulatory effect or no effect, depending on the extent of autolysis which occurred.
According to the other two theories, functional overload and blood flow,
tissue extracts should have no direct effect on growth rate.
C. The Interpretation of Results
With these considerations in mind we shall now move on to consider
the results of the many attempts at an experimental analysis of the mecha-
BRIAN POOLE
Recently the development of the autoradiographic technique with
tritiated thymidine (MacDonald and Mallory, 1959) has made possible
the accurate determination in a tissue of the relative number of cells which
are synthesizing DNA in an experimental interval. This method is certainly
superior to mitotic index determinations, but it is still measuring a variable
which is related only indirectly to the tissue growth rate. Determinations
of the rate of uptake of P
32 and C
14
-orotic acid into RNA are valuable
(Fujioka et al., 1963; Nygaard and Rush, 1955), but are complicated by
the large turnover of these metabolites even in cells which are growing
very slowly or not at all. In addition there is a diurnal rhythm in the uptake of P
32 into phosphatides and RNA (Barnum et al., 1958) which is
probably related to the rate of inorganic phosphate exchange between the
cells and the extracellular fluids (Nelson, 1964).
B. Injection of Tissue Extracts
Many experiments have been carried out in which cell-free extracts,
homogenates, minces, or even whole pieces of tissue have been injected
into experimental animals. We shall discuss the results of some of these
experiments below, but we must first consider what predictions about the
results of such experiments can be made on the basis of the theories of
growth control described above. According to Weiss's (1952) theory of
feedback inhibition, tissue extracts should contain both inhibitors and sites
which bind inhibitors. In adult tissue the concentration of inhibitors should
be just about enough to saturate all the binding sites. However, we would
not expect these substances to persist unchanged in a solution as rich in
enzymes as broken cells. Both the inhibitors and the binding sites could
be destroyed, in which case the extract would have no effect; the binding
sites could be destroyed, in which case the liberated inhibitors would have
an inhibitory effect on the growth of homologous tissue; or the inhibitors
could be destroyed, and leave binding sites capable of binding inhibitors
from the host and thus stimulate growth. In fact, any result could be
interpreted on the basis of Weiss's theory, and we could predict that small
differences in the preparation and handling of the extract could reverse
the observed effect on growth.
Teir's (1951) theory predicts that tissue extracts should have a stimulatory effect or no effect, depending on the extent of autolysis which occurred.
According to the other two theories, functional overload and blood flow,
tissue extracts should have no direct effect on growth rate.
C. The Interpretation of Results
With these considerations in mind we shall now move on to consider
the results of the many attempts at an experimental analysis of the mecha-