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Reprinted from Science, November 1, 1946, Viol. 104, No. 2705, page 428,

A Nutritional Concept of Cancer ,

While the etiology of cancer has been categorized under
infection by a transmissible virus on the one hand and
gene mutation on the other (not to mention a host of
other hypotheses), there has been relatively little specu-
lation on the biochemical mechanisms whereby any of
these events could lead to the process recognized as neo-
plastic growth. Recent studies by Beadle, Tatum, and
others, on the genetic control of biosynthetic reactions

in the fungus, Neurospora, have provided a foundation -

for new concepts of the biological regulation of growth.
In particular, a study by Ryan and Lederberg (Proc.
nat, Acad, Sci., Wash., 1946, 32, 163-173), on the “fadap-
tation’’ of a Neurospora mutant deficient in the syn-
thesis of leucine, has provided an experimental basis for
speculative analogy with neoplasia.

Field strains of Neurospora will grow on medium con-
taining only sugar, salts, and biotin, which is to say that
the fungus is capable of manufacturing all other essen-
tial metabolites. As the result of mutations of single
genes, the capacity for synthesis of various compounds
may be lost. A similar process presumably accounts for
the nutritional requirements of higher forms.

Following ultraviolent treatment, a mutant strain of
Neurospora, #33757, has been isolated which is incapable
of synthesizing leucine. As a consequence, this strain
reqnires leucine, and its growth is quantitatively regu-
lated by the, available supply.

Oceasionally, cultures of leucincless Neurospora ‘grown
on limiting amounts of this amino acid will ‘fadapt’?’;

. a

9-5

that is, an exceptional fragment of the mycelium will
grow autonomously, irrespective of the available leucine,
and may under certain conditions overgrow the culture
until the sugar is exhausted. By genetic analysis of
crosses between adapted and wild strains, it has been
shown that adaptation depends on the mutation, or re-
version, of the leucineless gene to an allele capable of
mediating the synthesis of leucine. .

A culture of leucineless Neurospora ‘has, then, two
growth potentialities: a regulated growth corresponding
to the leucine externally available to it, and, excep-
tionally, autonomous growth on the basis of a gene muta-
tion leading to the synthesis of that metabolite.

If one correlates normal tissue cells with a culture of °
leucineless Neurospora, both regulated by their environ-
ment, a simple analogy for cancer is evident—the newly
found capacity of a cell to synthesize an essential metabo-
lite otherwise available only in limiting and regulatory
amounts,

While the Neurospora experiments suggest a muta-

tional origin for this capacity,| virus infection, by pro- |
[viding a missing link for a blocked enzyme system, could
play a corresponding role.f A consequence of this simple

concept is that cancer cells “may be found to differ in
their growth factor requirements from cells of norma]
origin when they are grown in vitro,

 

 

JOSHUA LEDERBERG
Osborn Botanical Laboratory, Yale University, and
College of Physicians and Surgeons, Columbia University

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