A History of Iron Metabolism in the Mycobacteria - Iron Acquisition by the Genus Mycobacterium - page 12

mycobacteria that could be grown in laboratory culture medium. As was subse-
quently acknowledged by Snow [ 26 ], Twort could be considered to be “… a true
pioneer in this field as the concept of vitamins and growth factors were only dimly
recognized at that time”. Yet here was a scientist proposing a radical concept of
a transferable growth factor, available from some microbial sources but not syn-
thesized by the host microorganism. This was exactly the same concept that lay
behind the discovery of many of the vitamins essential for human metabolism but
this was a novel concept for achieving growth of a microorganism.
Twort's findings, however, were not developed for another 30 years. In the mean-
while, cultivation of M. paratuberculosis , which was, and continues to be, a consid-
erable veterinary problem, in laboratory media was routinely achieved by adding a
simple extract prepared from cells of M. phlei which, of course, is a non-pathogenic
species. Cultivation of Johne's bacillus did not, therefore, require a growth factor
that was confined to pathogenic mycobacteria. A saprophytic mycobacteria could do
just as well and was obviously less hazardous to grow and extract.
We now must move to the 1940s for the development of Twort's observations
and to the laboratories of one of the major industrial chemical companies in the
UK: Imperial Chemical Industries (ICI) Ltd at their pharmaceutical research labo-
ratories at Blackley near Manchester and later at Wilmslow and finally at Alderley
Edge in Cheshire. An account of the thinking that went on in ICI for Twort's dis-
coveries to become a priority research program has been given by Snow [ 26 ]. The
person who initially took up the baton was J. Francis who pointed out in 1945,
(cited by Snow [ 26 ]) that a specific growth factor for M. paratuberculosis was
being synthesized by M. tuberculosis . As no other microorganism, other than
another species of mycobacteria, could produce such a compound, then this com-
pound must be unique to the mycobacteria. In addition, as Twort had found that
extracts of animal tissues, including those from cattle, could not support growth of
Johne's bacillus, this growth factor was not being synthesized by animals.
As there was no chemotherapeutic treatment for tuberculosis in 1945, Francis's
reasoning was clear: M. tuberculosis and other mycobacteria were synthesizing
a specific growth factor not found in humans. If this compound could be identi-
fied then it opened up the opportunity of designing an appropriate antagonist that
would then, hopefully, be specifically inhibitory to the tubercle bacillus. Such
inhibitors should not though affect the infected human as there was no suggestion
that the missing growth factor for M. paratuberculosis was synthesized in animals.
ICI Ltd obviously considered that if this aspiration could be realized then it could
be an extremely lucrative project and it is little wonder that major efforts were
expended to attain the goals.
GA Snow (see Fig. 2.3 ), always known as Alan, joined the team in the late
1940s and was to become the major driver of the entire project. He has written
that the initial work on isolating and purifying the growth factor was undertaken
by J. Madinaveitia and H.M. Macturk working with the initial project leader,
J. Francis [ 27 ]. They used massive quantities of M. phlei : in all some 50-60 kg dry
cells were used and the growth factor was eventually isolated and purified. It was
given the name mycobactin.