RESPfRATORY DISZASES AND I~~~~~~H~~~IS~RY

     Dr. Avery, Dr. Horsfafl and Associates.

Biologists, especial>i the geneticists, have long attempted by


17

chemical m6ans to ind*-o,e in higher organizms predictable and specific

changes which thereafter could be transmitted in series as hereditary

characters.  Among 174 croorganksms , the most striking and perhaps the only

known example of inheritable and specific alterations in ccl1 structure and

function t1lat can be experimentally induced end that are reproducible under

~11 defined and adequately controlled conditions is the transformation of

specific ty;?es of Pneumococcus.  This phenomenon was first described by

Griffith who succeeded in transforming an attenuated and non-tncr+psuI.at,ed
(R) variant derived from one specific t:ypc into fully encapsulated and
virulent (S) cells of a hetcrologous specific type of i'neumococcus. A

typical instince will suffice to illustrate the techniques originally used

and serve to indicate the wide variety of transformations that are possible

within the bacterial species.  For cxamplc, Griffith found that mice in-

jected subcutaneously with ;i small amount of a living R culture derived

from Pneumococcus Type II together with a large inoculum of heat killed

Type III (S) cells frequently succumbed to infection and. that heart's blood

of these animals yielded Type III pneumococci in pure culture.  The fact

that the R strain was avirulent and incapable by itself of causing fatal

septicemia, and the additional fact that the heated suspension of Type III

cells contained no viable organisms, brought convincing evidence that the

R forms growing under these conditions had newly acquired the capsular

structure and biological specificity of Type III pneumococci,  Griffith

wisely refrained from offering an explanation of the phenomenon beyond sug-

gesting that the dead bacteria in the inoculum might furnish some specific

protein that enables the R forms to manufacture a capsuLar carbohydrate of

the same si>eai.fic type as that of the S cells which serve as initial

sources of the inducing substance.


      Althou$ the experiments in mic c v;ere successful, Griffith was

unable to repro&xx the phc~;.omcmm wit&xi-l xti~t' passage, and on the basis

of negative results concluded that incubation of the bacterial mixture

in vitro failed to induce transformation.  These original observations
-_I_
were later confirmed by a i%nber of people including workers in Dr. Avery's

laboratory.  Subsequently, it was shown by Dr. Damson in Dr. Avery's labo-
ratory that the transformation under certain conditions could be brought

about in vitro.  Furtiier studies by Dr. UacLeod in Dr. Averyjs laboratory
threw light on many of the conditions necessary for the in vitro transfor-
                                                              --

matlon.

      For a number of years Dr. Avery and his associates have attempted

to obtain in pure form the substance capable of bringing about this type of

transformation in pneumococci.  He believes that during the past year he

Las accomplished this.  Vlithout going into the technical details of how

the material was obtained in a pure form, it can be stated that a substance,
which according to chemical and physical criteria is relatively pure, has
been obtained from pneumococci and that it will bring about the transfor-

mation SFOkcm of above.  This substance is desoxyribonucleic acid (thymus
type 1.

     The fact that the trnnsforming substance in a purified state
exhibits little or no immunological reactivity is in striking contrast to
its biological function of inducing highly specific changes in living

pneumococcal cells.  As little as 0.02 pg. representing a final dilution

in the reacting system of 1:100,000,000 has sufficed to bring about the
transformation of the R variant (R36A) into encapsulated Type III pneumo-

cocci.  It is impossible as yet to appreciate the full importance of this

work; in spl U;: of that there is everjr reason to heliavc that it will have


13

a profound influence on the study of many problems in the biological field

and that nucleic acids will assuzze new and broader significance,

      In 1930 it was first recognized clearly that there exists a com-

mon clinical fOrI of pneumoni a which differs from the usual bacterial

pneumonias.  In the intervening years this illness, nap: termed "primary

atypical pneumonia", has been encountered with increasing frequency. In-

terest in the condition stems from the facts that at the present time it

is seen almost as frequently as is bacterial pneumonia and that the cause

or causes of it have not been definitely established.  There is reason to

believe that this clinical syndrome is not a new disease, It was probably

recognized occasionally during the second half of the last century and un-

doubtedly was observed not infrequently during each of the first three

decades of this century.  The recent marked increase in the use of the

x-ray in acute respiratory diseases,  the establishment of active full-time

health units in some schools, colleges and camps, and the ineffectiveness

of sulfonamide chemotherapy in the illness seem to have been the most im-

portant factors in bringing this syndrome into clear relief.

      There can be no doubt that this condition, during the past three

years, has been increasing in incidence mere rapidly than can be accounted

for on the basis merely of increased awareness and recognition of it by

physicians.  In certain Army camps in the continental United States the in-

cidence of the illness has been as high as 1.3 per cent of the total con-

mand.  It is recognized both by the Army and the Navy as responsible for

more man-days lost from duty than almost any other acute infectious disease.

The frequency with which the illness occws among civilians cannot now be

estimated due to the fact that, with the exception of New York City, the

disease is not reportable.


                                                        20

     ALnost ail investigators v;ho have studied cases of primary

atypical pneumonia think that the illness is not the result of bacterial

infection.  Sc~me workers liavc suggested the possibility that the syndrome

is caused by a virus and as a result the term "virus pneumonia" has come

into common usage.  There is evidence that the syndrome is not a single

disease entity. ?S.ach of at least three different infectiotis agents has

been shown to be etiologieslly related to certain small groups of CEEXS.

These arc the psittacosis group of viruses, Rickettsia diaporica, and a

Virus i.nfcctious for t!;e mongoose.  Additional infectious agents have been

suggested tis possessing il cuusal relationship to other cases although the

evidence upon which these suggestions have been based seems insufficient

to permit of critical assessment.

      A comprehensive study of primary atypical pneumonia was begun in

the Rockefeller Hospiixl 18 months ago.  Tho primary objectives of the

study were two-fold: firstly, a detziled study of all the clinical mani-

festations of the illness; and secondly, an investigation of the nature

of the infectious agents responsible for the syndrome.  During this period

112 patients were admitted to the hospital with acute respiratory diseases,

Of these, 80 were found to have primary atypical pneumonia. Specimens ob-

tained from them constituted the source material for laboratory studies.

In addition, specimens were also obtained from 211 patients with the

disease in other civilian and military hospitals. All specimens have

been stored %t -7O'C. and are constantly available for study. This large

library of potentially infectious material has already proven of great

value.

                                             .
        AS c? result of the detailed studies of 80 patients with primary

atypical pneumonia, it has been possiblo to formulate a fairly accurate


                                                         21


clinical pictd~e df the maisdy.  It has &isa bztn possible to show that

none oi' the usual pnc;unonia-producing bacteria and viruses was the cause

of the disease in the patients studied.  In addition,  it was found that

the ser;i of pztients with th ,e disease reacts in a peculiar manner in com-

plement-fixution tests.  This is an important observation because it in-

validates certain conclusions based on the complement-fixation test arrived

at by other workers.  Finally, Dr. Horsfall and hiis associates have shown

in a rather ingenious and indirect way that a virus is responsible for the

malady in the patients studied.  The workers accomplished t!Cs by inject-

ing material from the pa-tients into rabbits and showing that sera taken

from such rnbbits possess antibodies against a virus indigenous to white

mice and etiologically unrelated to the pneumonia in human beings.  Such


a test reminds one of the Yieil-Felix reaction in typhus fever.  In this

test, serum from convalescent typhus patients agglutinates proteus X19, a

bacillus that has nothing to do with the causation of typhus fever.

      Epidemic dysentery among members of the armed forces and civilian

population is at present 8 problem of special concern to public health

officials and to military authorities.  Since the outbreak of the world

conflict, clinical bacillary dysentery has been controlled largely through

the use of sulfonamide drugs.  The problem of procuring an efficacious

prophylactic ager.t for the prevention of the disease among closely grouped

peoples where the general sanitary conditions cannot be adequately con-

trolled, has not been adequately solved. Dr. Goebel and his associates

during the past year have attempted to isolate from ccrttain types of

Plexner dysentery bacilli, antigens which are relatively nontoxic and

which will act as prophylactic vaccine s in animals and human beings.  Most

of Dr. Coebel's work was conducted on the V strain of Flexner dysentery


                                                        22

bacilli b~ecause of the broad serological crossings which this strain ex-

hibits wi-th titi.:Lr members of the Fiexner group.  He has been able to iso-

lzti: in sevcrr;l iwys from thcsi: bacteria a carbohydrate-lipo-protein which

when injected into rabbits and human beings leads to the production of

zntibodit>s tkzt agg1utir;at.c dysentery ticilli.  Further studies of this

antigenic substc:nce arc under wy nnd it is hoped that some kind of trial

in the field nay bc curried out during the coming year.