482
C L I F F O R D G R O B S T E I N
V I I .
S U M M A R Y A N D P R O S P E C T
The best summary of what has been said seems to be a look forward.
It should be clear from the foregoing that in discussing problems of
differentiation in culture one confronts the fundamental issues of
differentiative mechanisms. It is widely recognized that insight into
these mechanisms is very high in priority on the current biological list
of "things to d o " . Increasingly, our almost complete ignorance of the
mechanisms of cytodifferentiation is becoming an obstacle to advance
on other fronts. The molecular approach to cell properties and behavior
has moved rapidly from its early emphasis on energetics to the synthesis,
replication and interaction of macromolecules—the other face of which
is growth, heredity and differentiation. Combined with the genetic
approach, molecular biology has provided powerful tools, of extremely
high resolution, to identify and manipulate some of the innermost
centers of cell activity. It has long been clear that these innermost
centers are importantly involved in differentiation, but that they must
operate under the close regulation of successively more peripheral shells
of influence—and ultimately the homeostatic control of the entire
organism. In pushing outward from the gene, now defined as a key
synthetic site, biochemical genetics has become involved in the regulatory mechanisms of cellular synthesis. In pushing inward from morphogenesis, through embryonic induction, developmentalists are increasingly recognizing their involvement with these same mechanisms. One of
the meeting grounds of the two approaches—one of the most favorable
for further progress—is differentiation as it occurs in vitro.
This is true not only because of the technical advantages of culture
procedures—accessibility, replicability, quantifiability, etc.—but because we now know that through readily introduced alterations of
culture conditions cells of complex organisms can be observed engaging
either in the discontinuous and stochastic variation familiar to the
geneticist, or in the continuous and externally regulated alteration
characteristic of ontogeny. In general, the former is observed most
readily in what usually is referred to as cell culture, the latter in what
has been called organ culture. The difference between these is primarily
the degree to which the cell remains subject to external "shells of
influence" existing in situ. In cell culture, particularly in sparse suspension cultures, the medium is the sole external shell. It must supply,
if differentiation is to occur, not only basal conditions for survival and
growth, but the wherewithal for specialized metabolism—including
initiating cues if it has not yet begun—normally provided by surrounding cells and their products. In organ culture, the outermost shell of
C L I F F O R D G R O B S T E I N
V I I .
S U M M A R Y A N D P R O S P E C T
The best summary of what has been said seems to be a look forward.
It should be clear from the foregoing that in discussing problems of
differentiation in culture one confronts the fundamental issues of
differentiative mechanisms. It is widely recognized that insight into
these mechanisms is very high in priority on the current biological list
of "things to d o " . Increasingly, our almost complete ignorance of the
mechanisms of cytodifferentiation is becoming an obstacle to advance
on other fronts. The molecular approach to cell properties and behavior
has moved rapidly from its early emphasis on energetics to the synthesis,
replication and interaction of macromolecules—the other face of which
is growth, heredity and differentiation. Combined with the genetic
approach, molecular biology has provided powerful tools, of extremely
high resolution, to identify and manipulate some of the innermost
centers of cell activity. It has long been clear that these innermost
centers are importantly involved in differentiation, but that they must
operate under the close regulation of successively more peripheral shells
of influence—and ultimately the homeostatic control of the entire
organism. In pushing outward from the gene, now defined as a key
synthetic site, biochemical genetics has become involved in the regulatory mechanisms of cellular synthesis. In pushing inward from morphogenesis, through embryonic induction, developmentalists are increasingly recognizing their involvement with these same mechanisms. One of
the meeting grounds of the two approaches—one of the most favorable
for further progress—is differentiation as it occurs in vitro.
This is true not only because of the technical advantages of culture
procedures—accessibility, replicability, quantifiability, etc.—but because we now know that through readily introduced alterations of
culture conditions cells of complex organisms can be observed engaging
either in the discontinuous and stochastic variation familiar to the
geneticist, or in the continuous and externally regulated alteration
characteristic of ontogeny. In general, the former is observed most
readily in what usually is referred to as cell culture, the latter in what
has been called organ culture. The difference between these is primarily
the degree to which the cell remains subject to external "shells of
influence" existing in situ. In cell culture, particularly in sparse suspension cultures, the medium is the sole external shell. It must supply,
if differentiation is to occur, not only basal conditions for survival and
growth, but the wherewithal for specialized metabolism—including
initiating cues if it has not yet begun—normally provided by surrounding cells and their products. In organ culture, the outermost shell of