Mutation is one of the basic processes of life. It is the ultimate
source of hereditary variability and as such an essential prerequisite for
evolution. Yet in spite of the great achievements of radiation genetics in
the last 20 years, the nature of the mutation process is still unknown. The
work presented here is an attempt to approach this problem through a study of
chemical substances affecting mutation rates. It includes one paper on spontaneous mutation which grew out of incidental observations made in the
course of an experiment with chemical treatment. Drosophila melanogaster was used throughout as test animal.
The first substances to b'e tested for mutagenic capacity were carcinogenic hydrocarbons. The use of these substances was suggested through the
theory, supported by a number of scientists, that cancer is due to mutation
in somatic cells. The results of mutation tests failed to give evidence in
favour of this theory, and work along these lines was dropped for the time
In the course of this work, a sex difference had been noted, mutation
rates being higher in the X- chromosome of males than of females, independent
of treatment. In a number of large -scale tests with untreated flies this
difference in the incidence of spontaneous mutations in the sexes could be
substantiated (2) .
In 1940, Prof.A.:.Clark and Dr J.M.Robson from the Department of
Pharmacology drew my attention to the pharmacological similarities between.
mustard gas and X -rays. We considered the possibility that mustard gas,
like X-rays, might exercise an action on the chromosomes. In collaboration
with Dr Robson, exreriments were started to test this hypothesis. The results
of these experiments, being subject to a security -ban, could not be published
during the war. They were oubritted to the ì.;inistry of Supply in two reports
(W 3979 and W 11331) which were handed in on the 14th of March and the 4th of
Tune 1942e Permission for publication has only recently been obtained. For
this reaeon most of the publications concerning this work are still in press,
_mart from a few preliminary notes (3,4,5) . The papers which are in press are
here submitted as proof or in .typescript.
Our data show that mustard as is an extremely efficient muta` :en, comparable in degree. of mutagenic activity to high -energy radiation. Like
X-rays, it causes sterility through interference with gametogenesis. It causes dominant lethality, chromosome re- arrangements, visible and recessive
lethal mutations (6) . Most experiments were carried out with doses which
- produced between 6 and 13. of sex- linked lethals, but in one experiment as many as 24;; were obtained. Visible mutations were mainly of the types which
had occurred previously after irradiation or spontaneously, and no specific
action of the gas on particular loci was observed. The frequency of translocations in several experiments fell short of what would have been expected
from a dose of X -rays producing the same frequency of recessive lethals.
A number of substances which either in their pharmacological action or their chemical structure are related to mustard as were next tested for
possible action on chromosomes and genes. Several of them, all belonging to
the class of the so- called nitrogen -or sulphur -mustards, were shown to be as
potent as mustard `as. In addition, allyl inothiocyauia.te behaved as a weak,
but definite auta-en. Two tested substances, chloaracetone and d.ichloracetore,
possibly have a slight mutagenic action. Lewisite, picric acid and o.smic acid
gave negative results. These data were submitted to the Yinistry,of ^up ^ly on Dec. 33rd 1943 (Report Y 10171). A full report is in press (7).
In addition to their Pharmacological interest, these results open
up a new ""eans of a_n lyzi'i_ the process of mutation. 7ork along these
lines MS carried out ,without the cooperation of Dr Robson, Attempts
were IA i_-dur :c, somatic mutations through treatment of Drosophila
Embryos with mustard Gigs, ri Üreat number of apparent somatic mutations
were obtained, but subsecuent analysis revealed that most or all of them. were in reality somatic crossovers (8). These tests therefore show a very
strong influence of mustard as on somatic. crossing over, At the same time
they suggest, as has indeed been urged before by Stern, that also after
X- radiation. of embryos the apparent somatic mutations may in fact be the
results of somatic crossing-over,
Partioular interest attaches to the differences between the mutagenic
action. Of radiation on the one hand, chemical substances on the other. One
of these differences consists in the strikingly high percentage of mosaic
individuals among the progeny of chemically treated males. Analysis of this phenomenon led to the assumption that mustard gas, unlike X-rays, may
exercise a delayed action on the chromosomes (9). An extension. of this work to a stud- of mosaics for sex-linked lethals lent further support to this
hypothesis (10) .