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Do Fixed Types of Tubercle Bacilli Exist?

The Bacteriology of Tuberculosis, Ergons Darzins,

Univ. of Minnesota, 1958,

Chapter XXI, 273 286.


THE identity of human bovine tuberculosis was assumed by the earlyinvestigators, even before the tubercle bacillus itself was discovered.Villemins (1865, 1868) classical experiments on the transmission of thehuman and bovine tuberculous virus to animals led him to this conclusion.His observations were confirmed by Chauveanus (1968), Klebs (1870),and Gerlachs (1870) successful attempts at infecting animals with

tuberculosis by material of human and bovine origin. Koch (1882) held thatPerlsucht (the pearly disease of cattle) is identical to human tuberculosisand, consequently, transmissible to humans. The identity of tuberculosisbacilli derived from different sources was not questioned until Th. Smith(1898), in a comparative study of the pathogenicity of seven culturesobtained from sputum and from bovine material, demonstrated thedifferences in virulence of bacilli from these different sources. Smith foundthat the bacilli from sputum were incapable of infecting cattle, whereas heheld that bovine bacilli, because of their higher virulence were capable ofinfecting humans.

Pathogenicity is the disease-producing property of microorganisms.Virulence expresses the degree of pathogenicity of bacilli. At present, onlytubercle bacilli lethal to experimental animals are regarded as pathogenic orfully virulent. Even if bacilli should cause morbid lesions in an organismwithout killing the animal, they will be labeled nonpathogenic. Byinference, only the bacilli lethal to experimental animals are actuallyregarded as dangerous to human beings.

Trends in the Studies of the Pathogenicity of Tubercle Bacilliduring the Half-Century after Th. Smith

After the publications of Th. Smith, Koch and Schutz beganextensive investigations of the virulence of tubercle bacilli of differentorigins. Koch (1912a) communicated the results of his first series ofinvestigations to the

International Tuberculosis Congress at London in 1901. His viewsmay be summarized as a break with his original unitarian concept and the

Types of Pathogenicity of Tubercle Bacillus 1


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recognition of the plurality of tubercle bacilli types. These ideas werefurther developed by Koch and presented in a more definite form at theInternational Tuberculosis Congress at Washington in 1908.

To designate differences in origin and virulence of tubercle bacilli,Koch accepted the term type proposed by Kossel but emphasized that to

him this term is no better than the word variant or any other name. Thebiologic differences implied by these words did not interest Koch.

Kochs convictions that bovine tuberculosis is different from humantuberculosis, and that it does not seem advisable to take any measuresagainst bovine tuberculosis, were most striking, because they werediametrically opposed to the opinions which he had held before the work ofTh. Smith.

Koch defended his new views with extreme tenacity. At a specialmeeting of the International Tuberculosis Congress at Washington in 1908,he rejected the evidence of the British Tuberculosis Commission on the

existence of types of intermediate and unstable pathogenicity as well as thearguments of Calmette, Fibiger, Ravenel, Dorset, and others who defendedthe possibility of the evolution of types.

The Washington International Tuberculosis Congress split thetuberculosis workers into two unequal groups: the great majority followedKoch and accepted the existence of different constant types of tuberclebacilli, responsible for tuberculosis in humans, bovines, and birds. This wasthe beginning of the reign of the dogma of types in tuberculosisbacteriology. The scientists of the opposite camp, who regarded the types,varieties, and intermediate forms as links between the evolving forms,

remained a small minority.The seemingly high practical importance of the types of tubercle

bacilli stimulated work on this problem. The presence of the bovine typeof tubercle bacilli in humans was early discovered by Ravenel (1902),Th.Smith (1904-1905), Griffith (1914), and others. It was taken for grantedthat the persons afflicted with the bovine type of tubercle bacilli haddirectly or indirectly acquired the infection from cattle. Research projectstoward the classification of tubercle bacilli according to their types werestarted all over the world. Great national tuberculosis commissions(German, British, and American) were created for the study of tuberculosisand especially for investigation of the role of bovines in spreading

tuberculosis to humans.

Differences in Virulence

The most important difference between the human and bovine typesof bacilli was found in their virulence. The British Tuberculosis



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Commission found that rabbits inoculated intravenously with 0.01 or 0.1mg. of bacilli of bovine type died from generalized tuberculosis within fiveweeks; when infected with bacilli of human type the majority of the animalsstayed alive for three months, although some died within twenty days. Tothese findings Griffith added observations that the intravenous inoculation

of 1 or 0.1 mg. of bacilli of the human type sometimes produced in rabbitsan acute and rapidly fatal tuberculosis indistinguishable from that caused bythe bacilli of bovine origin.

Cultural Differences

A promising cultural method of differentiating between the variantsof tubercle bacilli was indicated by Th. Smith (1904-1905). It was based onthe differences in the degree of utilization of glycol by the human and thebovine types of bacilli. The acidity or alkalinity changes of the medium

during the growth of the bacilli was supposed to differentiate the types.The curve of the bovine type tends at first toward the alkaline level andthen retreats again toward greater acidity (Th. Smith). Of the two strains oftubercle bacilli isolated by Th. Smith from the mesenteric lymph nodes ofchildren, one showed the bovine, the other the human curve of growth. Theaspirations of Th. Smith were early frustrated by the work of Griffith, whoshowed that the difference between the alkalinity and acidity curves ofbacilli of human and bovine types produced in glycerol broth are onlyquantitative and not qualitative in nature and cannot serve to differentiatethe various types of bacilli. (The glycerin broth test does not bring outdistinct bio-chemical differences in the action of bovine and human tubercle

bacillus on glycerin broth.) Th. Smiths (1910) defense of his views wasvigorous but did not contribute any new facts and thus could not refute thefindings of Griffith. Further work in the direction indicated by Th. Smiththat is, toward the determination of differences in the utilization of glycerolas a source of carbon by bacilli of human and bovine typewas done bythe British Tuberculosis Commission. The amount of growth and theappearance of colonies on media containing glycerol was found to bedifferent in the cases of bacilli of human and of bovine types. The growth ofbacilli of human type on glycerol media was found to be profuse oreugonic, that of bacilli of bovine type restrained or dysgonic. A lightyellowish pigmentation was recognized as characteristic of the colonies ofbacilli of human type. No morphologic differences were found between thebacilli of the two types.

The differences between the bacilli of human and bovine type weresummarized by Jensen (1949), as shown in Table 40.

The subtle differences between the human and the bovine types ofbacilli sometimes are simplified as far as in Bergeys (1948) Manual:



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Table 40

Human Infections Caused by the Tubercle Bacilli of Bovine Type

The statistics indicating the high rate of bovine tuberculosis amongthe rural population, especially in children in localities with high incidenceof tuberculosis in cattle, seemingly support the view that the bovine type ofbacilli are acquired from tuberculous cattle. Prices (1932), study of theincidence of human and bovine tuberculous infection in children and adults

living in the same region of Canada revealed 14.1 per cent of bovineinfection in 286 tuberculous children and only 3.5 per cent in 168tuberculous adults. The bacilli of bovine type were found in 22.2 per cent ofthe 877 cases of tuberculosis in children (up to 16 years) but only in 2.2 percent of the 1,330 cases of tuberculosis of adults (Rich,1951).

The facile explanation for this very curious phenomenon (Rich,1951) offered by the supporters of the theory of stable types of bacilli isgenerally to the effect that children are more frequently exposed to bovineinfection than adults, because milk is the chief food of children, and that theresistance of adults to tuberculous infection is greater than that of children.These hypotheses are insufficient to explain why the bacillus of bovine typedisappears from the human body and why the bacillus of human type takesits place when the infected child develops into a tuberculous adult. Thetheory of the superinfection with bacilli of human type cannot explain thisphenomenon; consequently, it is necessary to seek a different answer to theproblem.

Types of Tubercle Bacilli in Cases of Extrapulmonary andPulmonary Tuberculosis



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The percentage of the bovine type of bacilli in cases of extrapulmonarytuberculosis is high, as shown in Table 41.

Table 41

Contrary to the appearance of a high percentage of the bovine type ofbacilli in cases of extrapulmonary tuberculosis, the incidence of the bovinetype of bacilli in the cases of pulmonary tuberculosis is low. Griffith andMonro (1943) found 1.5 per cent of the bovine type of bacilli amongpatients with pulmonary tuberculosis n England and 5.8 per cent inScotland, although there was no evidence that these differences had aconnection with the differences in the spread of tuberculosis in cattle inEngland and Scotland. Out of 241 cases of pulmonary tuberculosis causedby the bovine type of bacilli, in only 70 cases did the autopsy suggest thepossibility of the infections having occurred through the alimentary tract,and only 2.5 per cent of the infected persons had ever worked with cattle.The percentage of the bovine type of bacilli in cases of pulmonarytuberculosis in Hanover, Germany, was 1.9 percent (Wangener, 1950-1951).

The Intermediate Strains

The present situation in tubercle bacilli classification resembles thesituation that existed in biology before Darwinbefore it was found thatthe intermediate, atypical, to labile species of the plant and animal kingdomcould not be forced into the artificial classification schemes of the time.Later these rebel species were to provide the theory of evolution withimportant links between seemingly unrelated forms, and indicate the courseof their evolution.

Tubercle bacilli that could be classified as neither human nor bovinewere early discovered by the British Tuberculosis Commission. Griffith, amember of this commission, showed that tubercle bacilli cultured fromcases of lupus were seemingly of the bovine type but of low virulence for

calves, rabbits, monkeys, and guinea pigs. He further found that the bacillifrom lupus may show the characteristics of the human type but yet be oflower virulence for the monkey and the guinea pig than the ordinary bacilliof human type. These cultures are not mixtures of both types of bacilli.Griffith designated these strains as intermediate in virulence between thetrue bovine and human types. These findings of Griffith were confirmed byKirchner (1922) and Rabinowitsch-Kempner (1927).



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Griffith (1932) summarized his findings on 188 strains of acid-fastbacilli isolated from cases of lupus in the following manner:

Dysgonic Eugonic

Strain Human Human Bovine Bovine

Standardvirulence

32 2 31 0

Attenuatedvirulence

59 2 61 1

Jensen and Frimodt-Moller (1936a) found in total of 35 lupus strains30 attenuated or atypical strains. Beller (1942) investigated 203 cases oflupus. Bacilli from these cases subcutaneously inoculated in the amount of0.01 mg. into rabbits produced in only 7 animals some lesions of theinternal organs. Beller concluded that the inoculation of tubercle bacillifrom skin lesions into animals is an unsuitable method for differentiatingthese strains of tubercle bacilli. According to this author, only culturalmethods can show the type differences of these bacilli.

The problem of whether these organisms are related to the acid-fastbacilli recently isolated from skin lesions contracted in swimming pools(Mycobacterium ulcerans, MacCallum, Tolhurst, Buckle, and Sissons,1948; M.balnei, Linell and Norden, 1954) remains to be investigated.

The later investigators who attempted to differentiate types by meansof animal inoculation found a considerable number of intermediate,atypical, or labile bacilli among the human and bovine strains.



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Changes in Virulence

By repeated passage of tubercle bacilli of the human type throughcalves, Ravenel (1902) succeeded in increasing their virulence so much thatthe bacilli produced progressive tuberculosis in a calf. The BritishTuberculosis Commission recognized virulence as a transitory property oftubercle bacilli. This conclusion was based on the following findings;

1. Two strains of tubercle bacilli isolated from the horse grew like bacilli ofbovine type but were less virulent for the calf and the rabbit than theordinary bacilli of bovine type, and by passage through animals thevirulence of these bacilli was increased to the level of fully virulentbacilli of bovine type;

2. Two bovine strains of attenuated virulence isolated from cases of lupusafter two passages through calves acquired the virulence of fullypathogenic bacilli of bovine variant;

3. Two strains isolated from two cases of lupus showed the culturalcharacteristics of bacilli of human type but where of feeble virulence fora monkey. After the passage through the monkey the virulence of thestrain reached in 139 days the level of fully virulent bacilli of humantype. From these observations the British Tuberculosis Commissionconcluded that If it were to be held that virulence is a fixed quality, itwould be necessary, in order to classify the lupus bacilli, to recognize

several new types of tubercle bacilli.Borrel, Boez, and Coulon (1923a) investigated strains of tubercle

bacilli which had lost a great deal of their pathogenicity of the guinea pigafter being cultured for some time on glycerol potato. These strains (H1036,Marmorek, etc.), when inoculated subcutaneously into a guinea pig at therate of 10 mg., killed the animal after 249 days. A second animal,inoculated with material taken from the first, died within 135 days; the third



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animal, inoculated with material from the second animal, died within 82days, and the fourth, inoculated with material from the third animal, diedfrom generalized tuberculosis within 62 days. It was not possible to changethe pathogenicity by transferring the strain B.B. through the guinea pigs.

Jensen and Frimodt-Moller (1936b) described seven strains of

tubercle bacilli, all of low virulence for rabbits, as bacilli of humantype. In all seven cases the authors were able to cultivate bacilli of thebovine type from rabbits inoculated with these strains. They concludedthat the appearance of bovine type of bacilli was the result of thetransformation of the original human type of bacilli into the bovinetype within the rabbit organism. Particularly interesting is the historyof strain 1832 as reported by Jensen and Frimodt-Moller (1936b). Thisstrain of human type was cultured from urine and grew dysgonic,being virulent for guinea pigs and only slightly virulent for rabbits andcalves. The passage of this strain through a rabbit produced a typicalbovine type of bacilli. This transformation of the human type into a

bovine one was performed seven times. Strain 1832 was not a mixtureof bovine and human type of bacilli.

Pinner (1935) by means of passages through guinea pigssucceeded in transforming two strains of nonpathogenic acid-fastbacilli, isolated from tuberculous patients, into bacilli producing typicaltuberculosis in guinea pigs. Smithburn (1939) restored the virulence ofattenuated bovine and human types of bacilli by serial transfer of thesestrains to rabbits and by serial brain-to-brain passages through guinea pigs.

Larmola (1947) cultured strains of acid-fast bacilli of low virulencefrom the sewage tank of a tuberculosis sanatorium. Some of these strains

recovered their virulence after passage through guinea pigs. Apparently notall attenuated strains can be restored to their former virulence by thepresently known methods. Willis (1933) did not succeed in restoring thevirulence of the R1 strain by making it traverse 900 guinea pigs, during aperiod of ten years. According to Uhlenhuth and Seiffert (1930) therecrudescence of the virulence of an attenuated strain occurs sporadicallyand cannot be forced upon the strain in any known way.

The pathogenicity differences among the various types of tuberclebacilli are restricted to a few animal species (rabbit, calf). Thedifferentiation of types can not be made in guinea pigs. In mice both types

of bacilli produce similar lesions. In dogs there are no pathogenicitydifferences between the human and bovine type of bacilli (Francis, 1956).In humans, tuberculosis caused by the bacilli of human or bovine type hasthe same course.

The experiments of Lurie and Zappasodi (1955) have indicted howeasily the resistance of rabbits to the human type of tubercle bacilli can bechanged. In the experiments with the susceptible race C of rabbits, 47



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tubercle bacilli had to be inhaled by the animals to produce a single tuberclein the lungs, whereas in the resistant race III, it took 648 bacilli to obtain thesame result. After cortisone had been administered in therapeutic does tothe rabbits, three to four times more tubercles were generated in the lungsof the hormone-treated animals than in the lungs of animals that had not

been treated.

Mixed Infections

The British Tuberculosis Commission, while studying the varioustypes of tubercle bacilli derived from cases of human pulmonarytuberculosis, discovered cultures consisting of a mixture of both the humanand bovine types of bacilli. Griffith (1919-1920) summarized these findingsand indicated that out of 1,068 cases studied, 5 were mixtures of bovine andhuman types of bacilli. According to Griffith, tow explanations for theorigins of these mixed infections are possible: (1) transformation, within the

human body, of one type of bacilli into another; and (2) the later associationof another type of bacilli with the already existing infection.

The fact that led to the correct answer to this question accumulated ata slow pace. The possibility of the transformation of the primary type ofbacilli was admitted by Rabinowitsch-Kempner (1927). Important datawere contributed to the elucidation of this transformation by Jensen (1949).In 17 cases of lung tuberculosis, caused by the bovine type, the course ofthe disease and the change of the type of bacilli were studies during aperiod of one to four years. In nine cases the initially pure bovine infectionwas transformed into a mixed infection of bacilli of bovine and humanvariants. The strains derived from mixed infections were labile and atypical.

It was shown that out of 28 colonies obtained by Jensen and his associatesfrom mixed infections, 20 had full virulence of bacilli of human type, but 8were of attenuated virulence.

Tubercle Bacilli of Human Type in Domestic Animals

Important information about the pathogenicity of tubercle bacilli ofthe human type was provided by the studies of tuberculosis in domesticanimals, often living in close contact with tuberculous human beings.

Nocard (1898) investigated a case of horse tuberculosis. The bacillicultured could not be classified as mammalian although they also deviated

from the standard avian type of bacilli. F. Griffith (1928) investigatedmaterial from eight cases of tuberculosis in horses. Three of the strainscultured from this material exhibited the virulence of the bovine type ofbacilli but the other five strains were of low virulence for the rabbit. Notwithstanding these results, Griffith concluded that the horse undoubtedlyderives its infection from the ox, and that the bovine type of bacillibecomes modified in the organism of the horse. Influenced by the doctrine



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of types, Griffith did not question the possibility of a human source ofinfection.

Stableforth (1929) investigated material from 16I tuberculous dogsand in 10 of these cases found the human type of tubercle bacilli as acausing agent. In four of these cases definite association of the dogs with

tuberculous persons was established. From a tuberculous parrot bacilli ofhuman variant were cultured. The bacilli of human type are also known tobe the cause of tuberculosis in pigs.

Cases of infection of bovines with tubercle bacilli of human type areknown, although rarely observed. The early experiments of Ravenel (1902)showed that a typical tuberculosis infection can be produced in young cattleby the repeated inoculation with large doses of tubercle bacilli of humanorigin. Feldman and Moses (1941) isolated from the lung lesions andbronchial lymph nodes of an adult cow tubercle bacilli with the cultural andpathogenic properties of the human type. In the same publication, Feldman

and Moses also summarized the earlier discoveries about the infection ofbovines with tubercle bacilli of human type.

Cattle can become sensitized to tuberculin as a consequence ofcontact with open tuberculous persons. McKinstry and Blampied (1955)described six instances of the appearance of reactors in an otherwisetuberculin-negative herd. This led to the discovery of open pulmonarytuberculosis in five persons who were in contact with the cattle.

The discovery of the bovine type of tubercle bacilli in human and theinfectiousness of the human type of bacilli to animals established beyondany doubt the intercommunicability of the disease.

The Ultimate Attempts at Typing Tubercle BacilliA great amount of work and large sums of money have been spent on

the typing of tubercle bacilli during the half-century that has elapsed sincethe investigation of Th. Smith. It could be expected at least that definitemethods for the differentiation of types and the standard characteristics ofthe types would be established. The steady flow of new publications dealingwith the problem of the differentiation of types indicates that this goal hasnot yet been achieved. Gervois (1937) composed a list of no fewer than 221works dealing with differentiation of types all over the world before 1937,when the projects of the great national tuberculosis commissions were

concluded. Since 1937, a considerable number of additional works haveappeared. The impossibility of classifying the mammalian tubercle bacilliinto two types, either by culture methods or by means of animalinoculations, was clearly recognized by the latest investigators of theproblem.

Grumbach (1949a), in a total of 157 human strains studied, found 33strains (21 per cent) impossible to classify into the two types. Wangener



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(1950-1951) in his investigation of 160 strains of tubercle bacilli, found 33that could not be classified on the basis of their cultural characteristics.Wangener and Mitscherlich (1951) in order to differentiate the types tried toreceive the method of Th. Smithdistinguishing the human and bovinetypes of bacilli by their different rates of utilization of glycerol. The

titration method was not applied to determine the pH changes in themedium, but, instead, an indicator (bromocresol purple) was added to themedium, and changes in color observed. Ninety-nine mammalian strainsinvestigated revealed that the bovine strains BCG and Vallee had becomeintermediate between human and bovine types. Animal inoculationconfirmed these findings. The strains K221 and Kalo, originally classifiedas bovine, could neither by culture nor by animal inoculation bedifferentiated from the bacilli of human type. Mitschelich 91952)emphasized the difficulty of typing freshly isolated tubercle bacilli bymeans of animal inoculations (Koch had put all the emphasis on the use offreshly isolated bacilli for the determination of their types). The lungs of

rabbits subcutaneously infected with bacilli of bovine type were regularlyaffected, but similar lesions were also found in 24 per cent of ht rabbitsinoculated with bacilli of human variant. According to Mitscherlich, theextension and number of lung lesions in infected rabbits has only arestricted value for the differentiation of types of tubercle bacilli.

Thiel (1956) found that tubercle bacilli of bovine type often causegeneralized tuberculosis in wild mice but that bacilli of human typesometimes also produce similar lesions in these mice. The size of thetuberculous lesions in wild mice could not be used as a criterion indifferentiating tubercle bacilli of bovine and human types.

Altevogt and Kuckhern (1955) made one or more attempt todifferentiate the types of strains of tubercle bacilli grown for 3 to 4 years inthe laboratory. Neither by animal inoculation nor by the use of bromocresolpurpleglycerol or other medial, was it possible to determine the type ofthese bacilli. The authors agreed with Wagener and Mitscherlich thatthrough cultivation on artificial media the bovine type of bacilli doesacquire the properties of the human type.

The investigations of Heidelberger and co-workers revealed thatthere are no serological differences between polysaccharides of differenttypes of tubercle bacilli. Polysaccharides extracted from human type H37were built up mostly of D-arabinose and D-mannose. None of thesepolysaccharides appeared to be type-specific (Heidelberger and Menzel,1937). The horse serum prepared with the polysaccharides from human typegave definite precipitin reaction with the polysaccharides extracted from thebovine type of bacilli (Menzel and Heidelberger, 1939).

Agglutination test (Furth, 1926) and the reaction to tuberculin protein(Seibert and Morely, 1933) did not reveal any differences between thetypes. The studies of Schaefer (1940) on the serologic differentiation of



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bovine and human types of bacilli, confirmed the findings of earlier authorsthat lipid and polysaccharide antigens are present in pathogenic and non-pathogenic acid-fast bacilli and that these antigens cannot be used as acriterion for the differentiation of bacilli of bovine, human and avian types.In the filtrates of the bovine type of bacilli, Schaefer discovered an antigen

of protein nature. The protein antigen was identified in complement fixationreaction, by the use of filtrates from the cultures and serum of rabbitsprepared by the injection of bacilli killed by heat and enrobed in paraffinoil. Only the smooth colonies of the bovine type of bacilli contained proteinantigen. This antigen was not discovered in the BCG and TB-18 Uhlenhuthstrains of bacilli, both of attenuated virulence and of bovine origin.

In his further work, Schaefer (1947) simplified the technique for thedemonstration of the presence of protein antigen in tubercle bacilli. Insteadof complement fixation reaction of precipitation was applied to demonstratethe presence of the antigen. This technique was identical to the ringprecipitation technique of Ascoli as it is used to demonstrate the heat-stable

antigen of Anthrax bacilli. Schaefer prepared his antigen from the tuberclebacilli of smooth colonies by boiling the bacilli in N/5 hydrochloric acid.This antigen, in the reaction with specific rabbit serum, showed that in thecase of human, avian or saprophytic acid-fast, bacilli the ring precipitationappeared considerably later and was considerably weaker than in the case ofbovine bacilli. On the basis of these findings, it must be concluded that theprotein antigen, just like the lipid and polysaccharide antigens, is alsopresent in acid-fast bacilli of different origin and pathogenicity and that theserologic differences between the types of acid-fast bacilli are quantitativeand not qualitative.

Tubercle bacilli of high virulence are found in bovines. These bacilliare pathogenic to humans, but the assumption that all bacilli of highvirulence found in humans have been acquired from bovine sources has notbeen substantiated in spite of a half-century of efforts. Hedvall (1941) in asystematic study of bovine tuberculosis in man in southern Sweden, couldfind some connection between the infected persons and tuberculous cows orinfected milk is only 12 cases out of 67. Francis (1947) indicated that thespread of bovine tuberculosis in humans is not simply related to theincidence of tuberculosis in cattle. Bovine tuberculosis in man does notdiffer in any of its forms from human tuberculosis, being on the contraryindistinguishable from the latter in its appearance and development. Nor is

any aid obtained in this respect from tuberculin tests (Hedvall, 1941).We do not know the cause for the high percentage of tubercle bacilli

of high virulence (bovine type) in the cases of nonpulmonary tuberculosisand in infantile tuberculosis, just as we do not know why these bacilli arerarely the cause of pulmonary tuberculosis in humans, and moreover whythe tubercle bacilli from cases of lupus are of low virulence.



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We do not know an outside source for the bacilli of intermediate orattenuated virulence. If these strains were found in some animal, we wouldnot hesitate to incriminate the animal as the source of tubercle bacilli ofhuman skin afflictions. This is precisely what is being done when bacilli ofhigh virulence are found in the cases of tuberculosis of human joints or

lymphatic nodes.Pneumococci were classified in serologically well-defined types,

more distinct than those of tubercle bacilli. Some of these types arepathogenic, others apathogenic to animals. These types were regarded asstable and unchangeable until F. Griffith (1953) and Dawson and Sia (1931)showed that the types of pneumococci can be transformed by means of invitro and in vivo methods (see p. 52). Braun (1947) observed that a tumor-inducing principle is required to transform normal cells into crown-galltumor cells. Klein and Klein (1953) showed that avirulent crown-gallbacteria (Agrobacterium tumefaciens and other species) were transformedpermanently into virulent, tumor-inducing bacteria when grown in the

presence of deoxyribonucleic acid from virulent crown-gall bacteria.

The opinion of the British Tuberculosis Commission, expressed in itsfinal report in 1911, that mans liability to infection from animals remains,of necessity, purely a matter of inference, still stands unshaken.

Conclusions. Fifty years work toward the typing of tuberclebacilli has shown the inconstancy of the types, and in a great manycases impossibility of differentiating them. The unity of the variousclinical manifestations of tuberculosis indicated by Laennec in 1804,the transmissibility of human and bovine tuberculosis to animalsdiscovered by Villemin (1865, 1868), the identity cause of human and

bovine tuberculosis discovered by Koch (1882), and theintercommunicability of the diseaseall these facts are not compatiblewith the opinion of Th. Smith and the final views of Koch on theconstancy of the types of tubercle bacilli. The assumption of Park andKrumwiede (1910) that the culture and rabbit give us all theinformation needed for the differentiation of type, cannot be upheld.A return to the early unitary concept is necessary.

We used the expressions type or variant in the above discussion,not because constant types or variants of tubercle bacilli to exist in nature,but to indicate their relative virulence and frequency of distribution in

animals and humans. The bacilli of bovine type are those with highvirulence to experimental animals and more frequent in bovines than inhumans; the bacilli of the human type are bacilli less virulent toexperimental animals than the bovine ones and more common in humansthan in bovines.

Mode of Origin of the Strains of Different Virulence



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Ravenel said as early as 1902, that it is certain that the various typesof tubercle bacilli known to us sprung from a stock common to them all,and that they have acquired their racial peculiarities by residence indifferent animals. In opposition to this theory of adaptation as the cause forthe development of new types of tubercle bacilli is the theory of mutation of

bacilli, which was greatly in favor when children vaccinated with BCGvaccine developed tuberculosis.*

Petroff and Steenken (1930) published the observation that acid-fastbacilli can be dissociated in apathogenic R and pathogenic S forms.These authors claimed that four strains of BCG produced colonies thatcaused progressive tuberculosis in animals.

Dysgonic tubercle bacilli cultured from human cases of tuberculosisproduced in subcultures eugonic and dysgonic colonies. Typical bovinecultures after six to eight months of cultivation on Lowensteins mediumyielded a few eugonic secondary colonies emanating from primarily

dysgonic primary strains, whereas six eugonic cultures were of more or lessattenuated virulence to guinea pigs and rabbits. Two of the eugonic similarto the BCG strain in every respect. The change in virulence resulting fromdissociation proved to be unstable. The possible reversion of the BCG stainfrom nonpathogenic must be admitted, although such reversion may happenrarely (Frimodt-Moller, 1939).

The observation of Petroff, Steenken, Frimodt-Moller, and othersprovoked a controversy that has not yet been settled. The new data on thepathogenicity of BCG indicate the necessity for further work on thepathogenicity of seemingly nonlethal strains of mycobacteria (see p. 303).

The knowledge of the origin and development of new races oforganisms was advanced by the studies of the action of X-rays onNeurospora, by the investigation of the development of streptomycin-resistant strains of bacteria, and by the discoveries of sexuality in bacteria(see p. 70). In any case, there is no doubt that, at present, experimentalscience is in possession of tools capable of influencing directly thehereditary substance of the organisms.

*Concerning the catastrophe of Lubeck, 1929-1930, see the report of the state

investigation commission, Arbeiten aus dem Reichgesundheitsamte, 1935, vol. 69.


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