v=) me - 
January 20, 1923] 
NATURE 
85 

Natural Resistance and the Study of Normal Defence Mechanisms.' 
By Prof. J. C. G. Lepincuam, C.M.G., F.R.S. 
ERTAIN aspects of immunity have long baffled 
the experimental pathologist and are certain to 
receive in the future more adequate consideration when 
the fundamentals of the science of immunity, like those 
of all experimental sciences, come to be relaid. 
The phenomena to which I would direct attention 
come in the category of what is known as natural 
immunity or natural resistance—a subject vast and 
many sided—and I would propose to consider simply 
what amount of light has been thrown on the elucidation 
of certain well-known instances of natural immunity 
to bacterial infection, by the study of the bactericidal 
functions of body cells and fluids. The infection | 
would choose for illustrative purposes is that of anthrax, 
largely because it has been in connexion with the 
peculiar and fascinating divergencies of susceptibility 
_ exhibited by animal species towards this infection, 
that defence mechanisms have been tested with a view 
of their elucidation. 
When one considers the enormous output of literature 
on immunity which, since the beginning of the century, 
has followed regularly the discovery of some new defence 
mechanism, one has reason to feel that some sufficient 
explanation might have been vouchsafed us for the 
existence of these peculiar resistances, but as I hope 
to show you now, there is no subject in immunity 
which has been so persistently and yet so inadequately 
explored. The discovery of anew immunity mechanism 
has led in the first instance, as a rule, to its intensive 
exploitation for diagnostic or therapeutic purposes, 
and rightly so in the main. Some mechanisms have 
lent themselves more readily than others to such ex- 
joitation. Many again have failed to attract anything 
t a passing fancy and they have been promptly 
forgotten or ignored, while the great flood of freshly 
gathered facts and fictions has continued to roll on 
uninterrupted. And yet if it be true, as I believe, that 
knowledge is best grasped in its historical setting, then 
surely these half-forgotten theses must claim the atten- 
tion of the serious investigator. With the colossal mass 
of literature on pathology, bacteriology, and immunity 
on our shelves, it is no easy task to comply with the 
historical method, but I maintain that the ambition 
should ever be to build truly on the historical past so 
that when the time comes for synthesis the old bricks 
may simply require relaying. The real expert must 
aim at being a man of vision with a working knowledge 
of and a pride in a glorious historical accomplishment. 
A mastery of technique is often, in my opinion, of much 
less relative value. 
Natural immunity remains a dark corner in our 
edifice. Immunology as an essentially experimental 
science has undoubtedly gained its chief triumphs in 
the domain of acquired immunity. It has sought with 
marked success not only to imitate the immunity that 
is seen to follow successful combat with the actual 
disease naturally contracted, but also to transfer the 
chief bearer of that immunity from the immune subject, 
be it recovered human or immunised horse, to the acute 
case. In some notable instances we seem to know 
From the presidential address delivered before the Section of Patho 
of the Royal Society of Medicine on October 17. “ey 
NO. 2777, VOL. 111] 
with certainty what we are doing in so acting, that, 
for example, the passive fluid injected represents simply 
so many units of an accurately titrated substance sus- 
pended, we shall say, in a vehicle of serum. So far 
as we are able to judge experimentally, the vehicle 
itself. might be indifferent. In other cases in which 
the passive transference of immune serum is followed 
by undoubted success, as, for example, in anthrax, it 
has so far been impossible to determine precisely what 
particular principle in the serum so injected is responsible 
for the success. In other infections again, such as the 
coccal septicaemias, the success achieved has been but 
partial and fortuitous. Either the systems of titration 
on an in vitro basis have been unsatisfactory or, when 
biological titration has been partially possible, the 
existing great variety of coccal types both in man and 
animals and their contrary affinities for various animal 
species will doubtless for long militate against the 
elaboration of any rational and stereotyped scheme of 
serotherapy in these infections. We may learn, how- 
ever, from our difficulties. We can see that Nature 
specifically unaided can successfully circumscribe the 
sphere of operation of a coccal or even an anthrax in- 
fection while she may fail to control a general invasion. 
We note also that Nature not infrequently appears to 
derive much assistance in the control of infection from 
the inoculation, for example, of a normal serum or from 
the inoculation of some type ofcolloid fluid circumspectly 
administered. Possibly the not infrequently observed 
phenomenon of the incompatibility of double infections 
may be placed in the same category of facts. In any 
case there would appear to be abundant justification 
at the present stage of immunological research for the 
closest study of the normal defence mechanisms. 
THE MECHANISMS OF DEFENCE. 
It is a strange circumstance that those curious 
instances of normal resistance which are referred to in 
all the text-books should rest on such an insecure basis 
of fact from what one might call the quantitative point 
of view. They, and the alleged explanatory mechan- 
isms, appeared to fascinate the earlier workers intensely, 
but it does not appear that the experimental work 
devoted to their solution can now be regarded as 
authoritative in the light of present knowledge. It 
would seem that as each new mechanism of defence 
was discovered it was immediately tested and generally 
found to explain the observed resistance to the satis- 
faction of the discoverer. In what follows I shall 
illustrate what has happened in the case of anthrax 
and draw certain inferences as to future lines of progress. 
Put succinctly, the problem is simply this: Is the 
mechanism of a certain case of natural resistance 
capable of full and satisfactory expression in terms of 
test-tube analysis? Or must other mechanisms than 
those with which we are familiar be called in to explain 
the phenomenon ? 
The mechanisms are not many, and it would appear 
advisable to summarise them briefly before discussing 
their application to the problem in question. What 
contributions to the mechanism of defence were made 
by the great masters of general pathology and cytology 
