ihde becker conflict of concepts in early vitamin studies

8/13/2019 IHDE BECKER Conflict of Concepts in Early Vitamin Studies

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onflict of oncepts in Early Vitamin StudiesAARON $. IHDE and STANLEYL. BECKERUniversity of Wisconsin Madison Wisconsin

The concept that foods must contain organic trace nutrients inaddition to adequate amounts of fats, carbohydrates, proteins,and minerals was clearly enunciated in 1912 and became firmlyestablished as part of a continuing tradition during the nextdecade. The notion that traces of specific organic materials arenecessary for sat isfactory nutri t ion had been put forth manytimes in the past, and in some cases, quite convincingly. Butthese tentative hypotheses generally failed to make a lastingimpression on public health personnel, and they failed to dis-lodge the belief, widely held in the last half of the nineteenthcentury, that the gross constituents of foods, carbohydrates,fats, proteins, and minerals would provide adequate nourish-ment for ma n and farm animals .

As a consequence of studies at the Lister Institute, where hehad been isolating fractions of rice polishings and yeast whichwere curative of polyneuritis in birds, Casimir F unk suggestedin 1912,

It is now known that all these diseases [beriberi, scurvy,rickets, pellagra] . . . can be prevented and cured by theaddition of certain preventive substances; the deficient sub-stances which are of the nature of organic bases, we will callvitamines ; and we will speak of a beri-beri or scurvyvitamine, which means a substance preventing the specificdisease. 1The same year also saw the introdu ction of the term acces-sory food facto rs by F. Gowla nd Hopkins, 2 of Cambr idge Uni-

versity. However, Hopkins had already alluded to the need for1. c. Funk, 'The Etiology of Deficiency Disease, 1. State Med. 20(1912), 341-365. Regarding Funk's life and work, see B. Harrow, CasimirFunk Pioneer in Vitamins and Hormones (New York, 1955).2. F. G. Hopkins, Feeding Experiments Illustrating the Importance ofAccessory Factors in Normal Dietaries, I. Physiol. 44 (1912), 425-460.

1ournal of the History of Biology vol. 4, no. 1 (Spring 1971), pp. 1-33.


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C o n f l i c t o f C o n c e p t s i n E a r l y V i t a m i n S t u d ie ss a l t s w h i c h s h o u l d b e p r e s e n t i n f o o d , t h e y d i e o f d e f i c ie n c yi f t h e y a r e g i v e n w a t e r a l o n e t o d r i n k . . . I f i n p l a c e o fw a t e r , t h e y a r e g i v e n m i l k t o d r i n k , t h e y r e m a i n h e a l t h y , a l -t h o u g h t h e q u a n t i t y o f p r o t e in , m i l k s u g a r a n d f a t w i t h t h em i l k i s e x t r e m e l y i n s i g n i f i c a n t . 4M o r e t h a n f o u r y e a r s a f t e r t he p r o n o u n c e m e n t s o f F u n k a n dH o p k i n s , E . V . M c C o l l u m a n d C o r n e l i a K e n n e d y , a t th e W i s -

c o n s i n A g r i c u l t u r a l E x p e r i m e n t S t a t i o n , i n t r o d u c e d t h e t e r m sf a t- s o lu b l e A a n d w a t e r - so l u b le B f o r u n k n o w n f a c t o r s w h i c h

a r e p r e s e n t in m i l k a n d c e r t a i n o t h e r f o o d s a n d a r e e s s e n t i a l f o rt h e g r o w t h a n d w e l l -b e i n g o f e x p e r i m e n t a l a n i m a l s . 5 A l t h o u g ht h e o r g a n i c t r a c e n u t r i e n t c o n c e p t d id n o t b e c o m e f i r m l y e s ta b -l is h e d u n t i l t h e s e c o n d d e c a d e o f th e t w e n t i e t h c e n t u r y , t h e r ew e r e n u m e r o u s e a r l i e r e v i d e n c e s f o r t h e e x i s t e n c e o f s u c h t r a c es u b s t a n c e s i n f o o d s.E V I D E N C E O F F O O D D E F I C I E N C Y D IS E A S E S

T h e f o o d d i s e a se s s i ng l e d o u t b y F u n k a s p r o b a b l e d e f ic i e n cyd i se a s e s h a d h a d a l o n g h i s to r y a n d h a d e a c h b e e n a s s o c i a te dw i t h f o o d a s a c a u s a t i v e f a c t o r . S c u r v y in p a r t i c u l a r h a d b e e nd e s c ri b e d b y a n c i e n t m e d i c a l w r i t e r s a n d h a d b e e n e n c o u n t e r e dd u r i n g m i l i t a r y c a m p a i g n s , d u r i n g s i e g e s , i n p r i s o n s , a n da b o a r d s h ip . 6 F o l l o w i n g t h e o n s e t o f t h e g r e a t n a v i g a t i o n s i tb e c a m e f a m o u s a s th e s c o u r g e o f t h e s e a . B e r ib e r i w a s a n o ldO r i e n t a l d i s e a se w h i c h f l a re d u p i n v a r i o u s p a r t s o f t h e E a s t ,p a r t i c u l a r l y l a t e i n t h e n i n e t e e n t h c e n t u r y w h e n E u r o p e a nc o l o n i a l i n t e r e s t s w e r e b e i n g d e v e l o p e d . 7 R i c k e t s w a s m o s t f r e -q u e n t l y a s s o c i a t e d w i t h c h i l d re n a n d r e s t r i c te d m o s t l y to n o r t h -e r n l a n d s . 8 P e l l a g r a h a d a n e n t i r e ly m o d e r n h i s t o r y a n d p r o v e d

4. C. A. Pek elha ring , About our Knowledge of the Value of Foods fro mChemical Factories, Ned. Tijdsc hr. Genevsk 41 (1905), 111-124. For anEnglish transl ation see S. L. Becker, The Emergen ce of a Trace Nutrien tConcept through A nima l Feeding Studies, Ph.D. thesis, University ofWiscon sin, Madison, 1968, pp. 301-322.5. E. V. McCollum, and Cornelia Kennedy, The Diet ary Fact orsOperating in the Production of Polyneuritis, ]. Biol. Chem. 24 (1916),491-502.6. A. J. Lorelm, The Conquest of Scurvy, ]. Am. Dietetic Assoc. 30(1954), 665-670; H. $. van Wersch, Scurvy as a Skeletal Disease (Utrecht,1954), pp. 5-28; E. V. McCollum, A History of Nutrition (Boston, 1957),pp. 252-265; A. Hess, Scurvy--Past and Present (Philadelphia, 1920).7. E. B. Vedder, Beriberi (New York, 1913), pp. 1-10; R. R. Williams,Toward the Conquest of Beriberi (Cambridge, Mass., 1961), pp. 3-35.8. A. Hess, Rickets Including Osteomalacia and Teta ny (Philadelphia,1927), pp. 22-37. McCollum, fn. 6 above, pp. 266-290.

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t o b e e n d e m i c i n th o s e p a r t s o f t h e w o r l d w h e r e c o r n ( m a i z e )w a s a n i m p o r t a n t c o m p o n e n t o f t h e d ie t. 0

A l m o s t f o u r c e n t u r i e s b e f o re t he p r o n o u n c e m e n t s o f F u n k ,H o p k i n s , a n d P e k e l h a r i n g , s c u r v y a n d i t s c u r e w e r e c l e a r ly de -s c ri b ed . W h e n J a c q u e s C a r t ie r h a d t h r e e s h i p s i m m o b f f i z e d i nt h e ic e i n t h e S t. L a w r e n c e R i v e r d u r i n g t h e w i n t e r o f 1 5 3 5 - 3 6h i s c r e w s w e r e s e v e r e l y s tr i c k e n b y t h e d i s e a se . A l m o s t t h ew h o l e c r e w w a s s u f f e r in g f r o m l a s s i tu d e , s w o l l en a n d b l a c k -e n e d l i m b s , so r e g u m s a n d lo o s e n i n g t e e th , a n d h e m o r r h a g e s .A n a u t o p s y p e r f o r m e d o n t h e f ir s t m a n w h o d i e d r e v e a l e d aw h i t e a n d s h r i v el e d h e a r t , l u n g s b l a c k a n d g a n g r e n o u s , a n de v i d e n c e o f s e v e re i n t e r n a l h e m o r r h a g e s . F r o m t h e l o c a l I n d i a n sC a r t i e r l e a r n e d to p r e p a r e a n i n f u s io n f r o m t h e b a r k a n d l e a v e so f a t r e e n a m e d Annedda i n h i s jo u r n a l . T h e s t r ic k e n m e nd r a n k t h e u n p l e a s a n t b r e w a n d p o u r e d i t o n t h e i r l e g s . R e c o v -e r ie s w e r e m i r a c u l o u s l y r a p i d , lo I t i s p r e s u m e d t h a t t h e t re ew a s t h e C a n a d i a n f ir w h o s e n e e d l e s h a v e b e e n f o u n d to c o n t a ina s u b s t a n t i a l a m o u n t o f a s c o r b i c a c i d . 11

T w o c e n t u r i e s l a t e r t h e S c o t t i s h s h i p s u r g e o n J a m e s L i n dp e r s u a s iv e l y d e m o n s t r a t e d t h a t s c u r v y c a n b e c u r e d b y a d m i n -i s t r a t io n o f th e j u i c e o f f r e s h o r a n g e s a n d l e m o n s . I n 1 7 46 ,a b o a r d t h e Salisbury h e t r e a t e d s i x p a i r s o f s c o r b u t ic s a i l o r sw i t h s t a n d a r d r e m e d i e s . T w o sa i lo r s t r e a t e d w i t h o r a n g e s a n dl e m o n s s h o w e d r a p i d r e c o v e r y . T h e t e n re c e i v i n g o t h e r r e m e -d i e s ( c i d e r , v i n e g a r , s e a w a t e r , s u l f u r i c a c i d , o r a n a n t i s c o r b u t i ce l e c t u a r y ) s h o w e d n o i m p r o v e m e n t e x c e p t p o s s i b ly t h e t w ow h o r e c e i v e d a q u a r t o f c id e r d a ff y . I n h i s b o o k , A Treatise onthe Scurvy ~2 L i n d n o t o n l y d e s c r i b e d h is e x p e r i m e n t s b u t p r e -s e n t e d a h i s t o r y o f th e d i s e a s e w h i c h r e v e a l e d t h e v a l u e o f f r e s hf r u i ts a n d v e g e t a b l e s i n i ts t r e a t m e n t a n d p r e v e n t i o n .

W h e n C a p t a i n J a m e s C o o k e m b a r k e d o n h i s s e c o n d v o y a g eo f e x p l o r a t i o n i n 1 7 7 2 h e h e e d e d L i n d s t e a c h i n g s b y s e e i n gt h a t h i s c r e w w a s p r o v i d e d w i t h f r e s h f r u i ts a n d v e g e t a b l e s .D u r i n g t he t h r e e - y e a r v o y a g e on l y o n e c r e w m a n a b o a r d t h e

9 . S . R . R o b e r t s , Pellagra ( St . L o u i s , 1 9 1 3 ), p p . 4 3 - 7 3 ; G . M . N i l e s ,Pellagra, An American Problem, ( P h i l a d e l p h i a , 1 9 1 6 ), 2 n d e d . , p p . 1 1 - 2 4 .1 0 . H . P . B i g g a r , T h e V o y a g e s o f J a c q u e s C a r t i e r , Publications of thePublic Archives of Canada, n o . 1 1 , 1 92 4 . A l s o s e e v o n W e r s c h , f n . 6 a b o v e ,p . 9 .1 1. A . S c h e u n e r t a n d J . R e s c h k e , C o n i f e r e n n a d e l n u n d d e r e n A b s u d ea l s V i t a m i n C - tr ~ ig e r, Kiln. Wochenschr. 19 ( 1 9 4 0 ) , 9 7 6 - 9 7 9 .1 2 . J. L i n d , A Treatise on the Scurvy ( E d i n b u r g h , 1 7 5 3 , w i t h e n l a r g e d

e d i t i o n s i n 1 7 5 7 a n d 1 7 72 ) . A z e p r i n t o f t h e f ir s t e d i t i o n w a s p u b l i s h e du n d e r t h e e d i t o x s h ip o f C . P . S t e w a r t a n d D . G u t h r l e , Lind s Treatise onScurvy ( E d i n b u r g h , 1 9 5 3 ) . T h i s r e p r i n t h a s s o m e v a l u a b l e s u p p l e m e n t a r ye s s a y s o n L i n d , h i s c o n t e m p o r a r i e s , a n d t h e s u b s e q u e n t h i s t o r y o f s c u r v y .


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C o n f l i c t o f C o n c e p t s i n E a r l y V i t a m i n S t u di e sesolution w a s l o s t t o s c u r v y , ia a s t r i k i n g c o n t r a s t t o t h e h e a v y

l o ss e s c u s t o m a r i l y s u f f e r e d o n l o n g s e a v o y a g e s , o r d u r i n g p r o-l o n g e d s i eg e s o n l a n d . A l t h o u g h L i n d , w h o b e c a m e P h y s i c i a n -i n -C h a r g e o f th e H a s l a r N a v a l H o s p i ta l a t P o r t s m o u t h i n 1 7 5 8,c a m p a i g n e d f o r r e f o r m o f th e B r i t i sh n a v a l d i e t , th e A d m i r a l t yr e s i s t e d h i s d o c t r in e s , a n d i t w a s o n l y i n 1 7 9 5 , t h e y e a r a f t e rL i n d 's d e a th , t h a t l e m o n j u i ce b e c a m e a r e q u ir e d c o m p o n e n to f t h e s a i l o r ' s d ie t . B e c a u s e o f p r o b l e m s a s s o c i a t e d w i t h p r e s e r -v a t i o n a n d a d u l t e r a t i o n , t h e l e m o n j u ic e f a i l e d to u n i f o r m l yp r e v e n t s c u r v y a n d m a n y m e d i c a l o f f ic e rs l a c k e d c o n f i d e n c e ini ts u s e . F u r t h e r m o r e , t h e l i m e w a s l o o k e d u p o n a s th e e q u i v a -l e n t o f t h e l e m o n , a n d l i m e j u i c e h a d o f fi ci al s a n c t i o n f o r u s e i np l a c e o f l e m o n j u i c e . L i m e ju i c e , h o w e v e r , c o n t a i n s a l o w e rl e v e l o f a s c o r b i c a c i d a n d is a le s s e f fe c t i v e a n t i s c o r b u t i c a g e n t .A c c o r d i n g t o H e s s , t h e r e is n o a r c h a e o l o g i c a l e v i d e n c e t h a tr i c k e t s o c c u r r e d i n a n c i e n t E g y p t o r G r e e c e b u t a s m a l l a m o u n to f s u c h e v i d e n c e s u g g e s t s t h a t t h e d i s e a s e w a s k n o w n i n n o r t h -e r n E u r o p e . S o r a n u s o f E p h e s u s a n d G a l e n r e f e r r e d to i t i nR o m e in th e s e c o n d c e n t u r y a f t e r C h r i s t b u t t h e r e a r e n o f u r t h e rl i te r a r y r e f e r e n c e s u n t i l t h e s i x t e e n t h c e n t u r y w h e n t h e d i s e a sew a s d e s c r i b e d b y T h e o d o s i u s o f B o l o g na . I n t h e n e x t c e n t u r yt h e r e a r e s e v e r a l m e d i c a l t r e a t i s e s d e s c r i b i n g t h e d i s e a se , t h a to f F r a n c i s G l i s s o n , 14 i n 1 6 5 0 b e i n g a c l a s s ic . T h e d i s e a s e h a db e c o m e e n d e m i c a m o n g i n f a n t s in w e s t e r n E n g l a n d t h i r t yy e a r s e a r l ie r , a n d G l i ss o n a c c u r a t e l y d e s c r i b e d t h e e n l a r g e dh e a d s o f i n f a n t s , t h e s w o l le n w r i s t s a n d a n k l e s , t h e d e f o r m i t yo f t h e c h e s t , a n d t h e d e f o r m e d a b d o m e n c h a r a c t e r i s t i c o f a d -v a n c e d c a s e s , b u t h e s o u g h t to u n d e r s t a n d t h e d is e a s e in t e r m so f G a l e n i e a l t h eo r y . R i c k e t s b e c a m e t h e s u b j e c t o f n u m e r o u sd i s s e r ta t io n s i n B r i ta i n , G e r m a n y , a n d F r a n c e , i n d i c a t i v e o f t h ew i d e s p r e a d o c c u r r e n c e o f t h e d i s e a s e , p a r t i c u l a r l y i n t h e l a r g e rc it ie s . T h i s p a t t e r n c o n t i n u e d i n t o t h e t w e n t i e t h c e n t u r y , t h ed i s e as e b e c o m i n g p a r t i c u l a r l y t r o u b l e s o m e i n t h e l a rg e c i ti esd u r i n g W o r l d W a r I . C o d li ve r o f f h a d b e e n r e c o m m e n d e d a sa n a n t i r a c h i t i c a g e n t a s e a r l y as 1 7 8 9 b y D a r b e y a n d , e v e ne a r l i e r , it h a d e x t e n s i v e u s e a m o n g f i s h e r m e n a l o n g t h e n o r th -e r n c o a s t s o f E u r o p e . H o w e v e r , w h e n t h e '~ D r e c k a p o th e k e o f

1 3. J . Co o k, T h e M e t h o d T a k e n f o r P r e s e r v i n g t h e H e a l t h o f t h e C r e wo f H e r M a j e s t y ' s R e s o l u t i o n o n H e r V o y a g e A r o u n d t h e W o r l d , a l e t te rd d r e s s e d t o J o h n P r i n g l e f r o m C a p t . J a m e s C o ok , M a r . 5 , 17 7 6, P h i l .T r a n s . R o y a l S o c . L o n d o n 6 6 ( 1 7 7 6 ) , 4 0 2 - - 4 0 6 . A l s o s e e J . C . B e a g l e h o l e ,ed . , T h e J o u r n a l s o f C a p t a i n 1 a m e s C o ol o n H i s V o y a g e s o f E x p l o r a t i o n4 v o l s . , ( C a m b r i d g e , E n g . , 1 9 6 1 ) , v o l . I I : T h e V o y a g e o f t h e R e s o l u t i o na n d A d v e n t u r e 1 7 7 2 - 1 7 7 5 p p . 1 4 , 1 5 , 1 1 1 , 1 6 5 - 6 , 1 8 7 , 1 9 1 , 9 5 4 - 6 .1 4 . F . G l i s s o n , D e R a c h i t i d e s i r e M o r b o B u e r i l i q u i v u l g o T h e R i c k e t sd i c t i t u r ( L o n d o n , 1 6 5 0 ) ; f i r s t ] E n g l is h ed . , 1 6 5 1 .


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m e d i e v a l m e d i c i n e f e l l i n to d i s c a r d d u r i n g t h e m e d i c a l e n l ig h t -e n m e n t o f th e n i n e t e e n t h c e n t u r y , t h e v il e t a s t in g c o d l iv e r o ffw e n t i n to d i s f a v o r in m e d i c a l c i r c l e s a l t h o u g h i t c o n t i n u e d t oh a v e p o p u l a r i t y a s a f o lk r e m e d y . 15

O f t h e f o u r d i s e a s e s , b e r i b e r i w a s m o s t c l e a r l y a s s o c i a t e dw i t h a f o o d i n a d e q u a c y b y 1 9 0 0 a s a c o n s e q u e n c e o f s tu d i e s int h e O r i e n t d u r i n g t h e l a s t tw o d e c a d e s o f t h e p r e c e d i n g c e n -t u ry . A l t h o u g h t h e d i s ea s e h a d b e e n k n o w n i n t h e O r i en t f r o ma n t iq u i ty , i t b e c a m e s t r ik i n g ly c o m m o n i n c e r t a i n a r e a s d u r i n gt h e n i n e t e e n t h c e n t u r y . I t b e c a m e e n d e m i c i n p r i s o n s , s a n i-t a r i a , a b o a r d s h i p , i n a r m y c a m p s , a n d i n c e r t a i n g e o g r a p h i cl o c a l i t i e s .

W h e n K a n e h i r o T a k a k i e n te r e d t he J a p a n e s e N a v y in 1879.a s a y o u n g m e d i c a l o f f i ce r h e f o u n d t h a t a t o n e t i m e t h re e -f o u r t h s o f t h e h o s p i t a l i z e d s e a m e n s u f f e re d f r o m b e r ib e r i. H eh a d l e a r n e d f r o m h i s f a t h e r , a m e m b e r o f t he I m p e r i a l P a l a c eg u a r d , t h a t a n e p i d e m i c o f t h e d i s e a s e h a d k i l l ed m a n y g u a r d s -m e n i n 1 8 6 2 . T h i s g r o u p h a d r e f e r r e d to th e p r o v i s i o n b o x a st h e k a k k e ( b e r i b e r i ) b o x , p r e s u m a b l y a s s o c i a t i n g t h e d i s e a s ew i t h f o od . 16 T a k a k i f o u n d m e d i c a l h a n d l i n g o f t h e d i se a s e i nt h e n a v y to b e t r a d i t i o n a l : p u r g a t i v e s a n d d i g i t a li s f o r e d e m aa n d p a l p i t a t i o n , e tc . ; s t r y c h n i n e , i r o n , e tc . , f o r n u m b n e s s a n dp a r a l y s i s ; t i n c t u r e o f a c o n i t e f o r h y p e r - s e n s i b f l i t y o f m u s c l e s ;a n d p u r g a t i v e s a n d v e n e s e c t i o n f o r a c u t e ca s e s . ~ I n 1 8 75T a k a k i w a s a b le t o u n d e r t a k e a f iv e - y e ar p e r i o d o f s t u d y in t h eS t. T h o m a s H o s p i t a l M e d i c a l S c h o o l i n L o n d o n . O n h i s r e t u r nto J a p a n h e w a s m a d e d i re c t o r o f th e T o k y o N a v a l H o s p i ta l .C o n d i t io n s r e g a r d i n g b e r ib e r i w e r e u n c h a n g e d e x c e p t t h a tg r o w t h o f t h e n a v y m e a n t m o r e s e a m e n , m o r e b e r ib e r i c a se s ,a n d m o r e d e a t h s . H e q u i ck ly s e t u p a s tu d y p r o g r a m a i m e dt o w a r d d e t e r m i n i n g i f e n v i r o n m e n t a l f a c t o r s p la y e d a r o le i nt h e in c i d e n c e o f t h e d is e a se . B y 1 8 83 h e h a d l e a r n e d t h a t w h i lew o r k i n g h o u r s , s a n i t a t io n , c l o t h in g , a n d h o u s i n g w e r e s i m i l a re v e r y w h e r e , t h e r e w a s a m a r k e d d i f f e r e n c e i n t h e f o o d s u p p l i e dt he s e a m e n .B y a n a l y z i n g t y p i c a l d i e t s T a k a k i o b s e r v e d t h a t t h e i n t a k e o fn i t r o g e n o u s m a t e r i a l w a s i n su f f i c ie n t to r e p l a c e t h e n i t r o g e n o u so u t p u t . H e c o n c l u d e d t h a t t h e c a r b o h y d r a t e i n t a k e w a s t ooh i g h . A r g u i n g t h a t t h e n i t r o g e n - to - c a r b o n r a t io i n t h e f o o d

15. Ru th A. Guy, Th e History of Cod-l iver Oil as a Rem edy, A m . 1 .D i s . C h i l d r e n , 2 6 (1923), 112-116.16. K. Tak aki , Three Lectures on the Preservat ion of the H eal thAm ongs t t he P er sonne l o f the J apanese N avy and Army , L a n c e t , 1 (1906),1369-1374.17. I b i d . , p. 1370.


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C o n f l i c t o f C o n c e p t s i n E a r l y V i t a m i n S t u d ie ss h o u l d b e a t l e a s t 1 : 1 5 . 5 , h e f o u n d t h e a c t u a l r a t io i n n a v a ld i e t s t o r a n g e b e t w e e n 1 : 1 7 a n d 1 : 3 2 . F u r t h e r , t h e g r e a t e r th ed i f f e re n t i a l b e t w e e n n i t r o g e n a n d c a r b o n , t h e g r e a t e r t h e p r e v a -l e n c e o f b e r ib e r i . T a k a k i ' s r e c o m m e n d a t i o n o f a c h a n g e d d i et ,m a d e i n 1 8 8 2, w a s r e s i s te d , p a r t l y o n t h e g r o u n d s o2 t r o u b le sk n o w n t o h a v e o c c u r r e d in t h e I t a l i a n n a v y w h e n t h e d i e t w a sc h a n g e d d r a s t i c a l ly , b u t p r i m a r i l y o n t h e g r o u n d s o f i n c r e a s e dc o s t .S o o n t h e r e a f t e r , T a k a k i r e q u e s t e d a n i n v e s t i g a t i o n o f t h e d e-p l o r a b l e r e c o r d o f t h e t r a i n i n g s h ip R i u j i o w h i c h , o n a c r u i s eo f 2 7 2 d a y s , r e p o r t e d 1 6 9 c a s e s o f b e r i b e r i w i t h 2 5 d e a t h s i n ac r e w o f 2 7 6 m e n . T h e d ie t p r o v i d e d a n i t r o g e n - t o - c a r b o n r a t i oo f 1 : 2 8 f o r s a i lo r s , 1 : 2 0 f o r of fi ce r s. D e s p i t e o p p o s i t io n , T a k a k ir e c e i v e d a u t h o r i z a t i o n t o s e n d t h e T s u k u b a o n a s i m i l a r c r u i s e .B y ~ e p l a c in g s o m e o f th e r ic e w i t h c o n d e n s e d m i l k a n d m e a t i tw a s p o s s i b l e to m a i n t a i n a n i t r o g e n - t o - c a r b o n r a t io o f 1 : 1 6 .D u r i n g t h e c r u i s e o f 2 8 7 d a y s t h e r e w e r e 1 4 c a s e s o f b e r i b e r ia n d n o d e a t h s i n a c r e w o f 2 6 2 m e n . T h e m e n w h o c o n t r a c t e dt h e d i s e a s e h a d b e e n u n a b l e t o t a k e c o n d e n s e d m i l k o r m e a t ,a n d h e n c e h a d n o t m a i n t a i n e d a h i g h p r o t e in l e ve l. O n t heb a s i s o f T a k a k i ' s s tu d i e s t h e J a p a n e s e N a v y i n tr o d u c e d a n e wd i et in 1 8 84 . B y s u b s t i t u t i n g b a r l e y a n d m e a t f o r p a r t o f t h er i c e in t h e t r a d i t i o n a l d i et , i t w a s p o s s i b le t o b r i n g t h e d i s e a s eu n d e r c o n t r o l . T h e A r m y a d o p t e d t h e r e v i se d d i e t i n 1 8 8 5 w i t hs i m i l a r b e n e f i c ia l re s u l t s , a l t h o u g h t h e r e w a s s e r io u s b a c k s l i d -i n g d u r i n g th e S in o - J a p a n e se W a r ( 1 8 9 4 - 1 8 9 5 ) a n d t he R u s s o -J a p a n e s e W a r ( 1 9 0 4 -- 1 9 05 ) . i s

I n 1 8 86 t h e D u t c h g o v e r n m e n t s e n t a c o m m i s s i o n c o n s i s t in go f C . A . P e k e l h a r i n g , p r o f e s s o r o f p a t h o l o g y , a n d C . W i n k l e r ,r e a d e r i n n e u r o l o g y , b o t h o f t h e m e d i c a l f a c u l t y a t th e U n i -v e r s i t y o f U t r e c h t , t o th e E a s t I n d i e s t o e s ta b l i s h t h e c a u s e o fb e r i be r i. C h r i s t i a n E i j k m a n , w h o m t h e y h a d m e t i n R o b e r tK o c h ' s l a b o r a t o r y i n B e r li n, a c c o m p a n i e d t h e c o m m i s s i o n e r sa s a n a s s i s t a n t .

W i n k l e r q u i c k ly e s t a b l i s h e d t h e d i s e a s e t o b e a f o r m o f p o ly -n e u r i t i s , in a g r e e m e n t w i t h c o n c l u s i o n s r e a c h e d e a r l i e r i nJ a p a n . B a c t e r i o l o g i c a l s tu d i e s l e d to th e i s o l a t i o n o f p o l y m o r -p h i c b a c t e r i a f r o m t h e b lo o d o f p a t ie n t s . W h e n P e k e l h a r i n ga n d W i n k l e r r e t u r n e d t o E u r o p e i n 1 8 8 7 t h e i r r e p o r t 19 t e n t a -

1 8. K . T a k a k i , O n t h e C a u s e a n d P r e v e n t i o n o f K a k 'k e , S ei I K a iM e d i c a l ] . 4 (lSS5), 29-40; also see f n . 1 6 a b o v e , i n c l . p p . 1 4 5 1 - 1 4 5 5a n d 1520-1523. The lectures publ ished in T h e L a n c e t g ive much m o r edeta i l than Takald ' s or ig inal publ ica t ions in S e i - I - K a i .19. C. A. Peke].haring an d C. W inkle r, M ittheilu ng fiber die Be riberi ,D e u t s c h . ~ ne d. W o c h s c h r . 1 3 (1887), 845-848.


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A A R O N J . I H D E A N D S T A N L E Y L . B E C K E R

t iv e l y a t t r i b u t e d t h e c a u s e o f t h e d i s e a s e t o a c o c c u s i s o l a t e df r o m t h e a i r o f a b a r r a c k s c o n s i d e r e d t o b e i n f ec t e d .

E i j k m a n r e m a i n e d i n B a t a v i a a s d i re c to r o f th e n e w l a bo r a -t o r y o f b a c t e r io l o g y a n d p a t h o l o g y . H e s o o n o b s e r v e d t h a t ap o l y n e u r i t i s s i m i l a r t o b e r i b e r i i n h u m a n s w a s a p p a r e n t i n t h ec h i c ke n s h o u s e d o n t h e l a b o r a to r y p r e m i s e s . T h e h e n s w e r en o t i c e d t o h a v e a n u n s t e a d y g a i t a n d d i f f i c ul ty i n p e r c h i n g ;t h e y s o o n s h o w e d le g w e a k n e s s e s a n d a b n o r m a l b e n d i n g o f t hek n e e a n d a n k l e j o in t s ; t h e b i rd s f in a l l y c o l la p s e d a n d r e m a i n e dl y in g o n th e i r s i de s w i t h w e a k n e s s o f w i n g m u s c l e s b e c o m i n ge v i d e n t w h e n t h e b i r d s s t r u g g le d t o r i g h t t h e m s e l v e s ; s o o n t h eb i r d s c o u l d e a t o n l y w i t h a s s i s t a n c e ; p a r a l y s i s o f t h e r e s p i r a -t o r y m u s c l e s f o l lo w e d ; t h e c o m b b e c a m e c y a n o t ic ; t h e e y e sw e r e c o v e r e d b y t h e n i c i ta t i n g m e m b r a n e ; t h e t e m p e r a t u r e f e ll .A t t e m p t s t o t r a n s m i t t h e d i s e a s e , u s i n g m a t e r i a l f r o m d i s e a s e db i r d s , w e r e i n c o n c l u s i v e , i n p a r t b e c a u s e e v e n t h e b i r d s u s e da s c o n t r o l s w e r e d i s e a s e d . S u d d e n l y , t h e b i r d s w h i c h w e r e s ti lla l iv e r e c o v e r e d .

I n v e s t i g a t i o n re v e a l e d t h a t th e c h i c k e n s h a d h a d a c h a n g e o ff ee d . F r o m 1 7 J u n e t o 2 7 N o v e m b e r t h e la b o r a t o r y c a r e t a k e rh a d f e d t h e c h i c k e n s c o o k e d r ic e le f t o v e r s o b t a in e d f r o m t h en e a r b y a r m y h o s p i ta l k i tc h e n . W h e n a n e w c o o k t o o k o v e r, h er e f u s e d t o r e l e a s e m i l i t a r y r i c e f o r c i v i l ia n c h i c k e n s . T h e r e -u p o n , u n m i l l e d r i ce w a s p r o c u r e d f o r t h e b i r d s a n d t h e d i s e as ed i s a p p e a r e d . T h e d i s e a s e h a d b e e n n o t i c e d o n 1 0 J u l y ; i t d i s-a p p e a r e d i n t h e l a s t d a y s o f N o v e m b e r .

P l a n n e d e x p e r i m e n t s o n c h i c k e n s v e r if i e d t h e r e la t i o n s h i pb e t w e e n t h e d i s e a s e a n d d ie t. C h i c k e n s s h o w e d s y m p t o m s o fp o l y n e u r i t i s a f t e r 3 - 4 w e e k s o n a d i e t o f c o o k e d w h i t e r ic e . C o n -t ro l s f e d u n p o l i sh e d r ic e r e m a i n e d i n g o o d h e a l t h , a n d d i s e a se db i r d s c o u l d b e c u r e d b y s u b s t i t u t i o n o f u n p o l i s h e d r ic e . 20 P o ly -n e u r i t is w a s a l s o c a u s e d b y f e e d i n g o t h e r s t a r c h y s u b s t a n c e ss u c h a s s a g o or t a p i o c a . M e a t h a d p r e v e n t a t i v e a n d c u r a t i v ee f f e c t s b u t r i c e p o l i s h i n g s w e r e s u p e r i o r .

B e f o r e r e t u r n i n g to E u r o p e i n 1 8 96 , E i j k m a n d i r e ct e d A. G .V o r d e r m a n , m e d i c a l i n sp e c t o r o f J a v a , t o m a k e a s t u d y ofh u m a n b e r i b e r i i n t h e p r i s o n s o f t h e i s l an d . V o r d e r m a n s r e -p o r t 21 r e v e a l e d a h i g h i n c i d e n c e o f b e r i b e r i i n p r i s o n s w h e r e

2 0 . C . E i j k m a n , P o l y n e u r i t i s b i j h o e n d e r e n , Geneesk. T. Ned.-Ind. 30( 1 8 9 0 ), 2 9 5 - 3 3 4 ; 3 2 ( 1 8 9 3) , 3 5 3 - 3 6 2 ; 33 ( 1 8 9 3 ) , 1 6 3 - 2 1 7 ; 36 ( 1 8 9 6 ) , 2 1 4 -2 6 9 . A l s o s e e E i j k m a n ' s N o b e l L e c t u r e , Nobel Lectures Medicine orPhysiology 1 9 2 2 - 1 9 4 1 ( A m s t e r d a m , 1 9 6 6 ), p p . 1 9 9 - 2 0 7 .2 1 . A . G . V o r d e r m a n , Onderzoek naar bet verband tusschen den aarddir ri jstoeding in de gevange nissen op ]ava e n Madoera en her voort mmenvan beriberi onder de geinterneeden ( B a t a v i a , 1 8 9 7 ) ; ' T o e l ic h t i n g o pm i j n b e r i b e r i v e r s l a y , Geneesk. T. Ned.-Ind. 3 8 ( 1 8 9 8 ) , 4 7 - 6 2 .


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C o n f l i c t o f C o n c e p t s i n E a r l y V i t a m i n S t u d ie sp o l i s h e d r i c e w a s t h e p r i n c i p a l c o m p o n e n t o f t h e d i e t, a l o wi n c i d e n c e w h e r e u n p o l i s h e d r i c e w a s u s e d .E i j k m a n ' s e x p e r i m e n t s w e r e c o n t i n u e d i n J a v a b y G e r r itG r i jn s , w h o f o u n d t h a t c e r t a i n n a t iv e b e a n s , p a r t i c u l a r l y t h ek a t j a n g i d j o , w e r e p r e v e n t a t i v e o f p o l y n e u r i t i s . H e a l so s h o w e dt h a t t h e p r o t e c t i v e c h a r a c t e r o f r i c e p o l is h i n g s , o r k a t j a n g i d jo ,w a s d e s t r o y e d b y p r o l o n g e d h e a t i n g a b o v e l l 0 C . C o n t r a r y toE i j k m a n , w h o b e l ie v e d b e r i b e r i t o b e c a u s e d b y a t o x in i n t h ee n d o s p e r m o f r i c e a n d p r e v e n t e d b y a n a n t i t o x i n in t h e p o l i sh -i n g s , G r i j n s b e l i e v e d t h e d i s e a s e w a s d u e t o d e f i c i e n c y o f a ne s s e n t i a l n u t r i e n t , s p e a k i n g o f t h e l a c k o f a p r o t e c t i v e f a c t o rin 190 1 . 22

P e l l a g r a h a s a s h o r t e r k n o w n h i s t o r y t h a n t h e o t h e r d e f ic i e n c yd i s e a s e s b u t i t s i n c i d e n c e h a s a l w a y s b e e n a s s o c i a t e d w i t h f o o d ,p a r t i c u l a r l y t h e c o n s u m p t i o n o f m a i z e , o r I n d i a n c o r n . N f l es 23t e l l s u s t h a t B a r u i n o , i n a m e d i c a l t r e a t i s e o f 1 6 0 0 , h a s r e f e r -e n c e t o a s k i n d i s e a s e o c c u r r i n g a m o n g t h e A m e r i c a n I n d i a n sw h i c h m a y h a v e b e e n p e l l a g ra . B a r u i n o a t t r ib u t e d t h e d i se a s et o t h e e x t e n s i v e u s e o f c o r n . V e r y s h o r t l y t h e r e a f t e r , F r a n c i s c oS c i p i o n e , t h e I t a l i a n p o e t , d e s c r i b e d a s i m i l a r d i s e a s e a f f e c t i n gm e n a n d h o r s e s w h i c h h e a t t r i b u t e d t o sp o i l ed g r ai n . T h e s er e f e r e n c e s , h o w e v e r , m a y e a s il y h a v e b e e n t o o t h e r d i so r d e rs ,a n d i t is n o t e a s y to a s c e r t a i n w h e t h e r p e l l a g r a w a s p r e s e n t i nE u r o p e b e f o r e t h e i n t r o d u c t i o n o f I n d i a n c o r n . M a iz e w a s i n -t r o d u c e d i n to S p a i n b e t w e e n 1 6 8 0 a n d 1 7 00 , a n d s y m p t o m s o fp e l l a g r a b e g a n t o b e d e s cr ib e d , b u t t h e d i s e a se w a s c o n f u s e dw i t h g a s t r o i n t e s t i n a l d i s o r d e r s , e c z e m a , l e p r o s y , s c u r v y , a n dn e r v o u s a n d m e n t a l d i s ea s es . T h e e a r l i e s t c l e a r a c c o u n t o f t h ed i s e a s e i s t h a t o f G a s p a r d C a s a l , 24 w h o d e s c r i b e d i t f u l ly i n1 7 3 5 , u s i n g t h e t e r m Mal d e l a R o s a . T h e d is e a se a p p e a r e di n n o r t h e r n I t a l y a b o u t t h is t i m e , a n d F r a n c e s c o F r a p o l l i 25a d o p t e d t h e n a m e pellagra ( r o u g h h a n d s ) w h i c h w a s i n u s ea m o n g t h e p e a sa n t s . T h e d is e a se a l so b e c a m e e n d e m i c i n p a r tso f F r a n c e , A u s t r i a -H u n g a r y , a n d E g y p t . E v e r y w h e r e th e d i s e as ew a s a s s o c ia t e d w i t h c o r n , p a r t i c u l a r l y t h e c o n s u m p t i o n o fs p o i l e d c o r n .

2 2 . G . G r i j n s , B e r i b e r i o n r i j s t v e e d i n g , G e n e e s k . T . N e d . - I n d . 4 1( 1 9 0 1 ) , 3 ; M e d e d e e l i n g e n v . h . L a b . P a t h . A n a t . e n B a k t . t e W e t l e v r e d e n( 1 9 0 0 ) ; R e s e a r c h e s o n V i t a m i n s 1 9 0 0 - 1 9 1 1 ( G o r i n c h e m , 1 9 3 5 ) .2 3 . N i l e s , f n . 9 a b o v e , p . 1 3 .2 4 . G . C a s a l , H i s t o r i a n a tu r a l y m e d i c a d e el P r i n c i p a d o d e A s t u r a s( M a d r i d , 1 7 6 2 ) , p . 3 2 7 . F o r a n E n g l i s h t r a n s l a t i o n s e e R . H . M a j o r , C l a s s i cD e s c r i p t i o n s o f D i s e a s e ( S p r i n g f i e l d , I l l . 3 r d e d . , 1 9 4 5 ) , p p . 6 0 7 , 6 1 0 - 6 1 2 .2 5 . F . F r a p o l l i , A n i m a d v e r s i o n e s i n M o r b u m v u l g o P e l a g r a m ( M i l a n ,1 7 7 1 ) p. 7 ; s e e M a j o r r e f . 2 4 , p p . 6 1 2 - 6 1 4 .


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The first reported instance of the disease in the United Stateswas in 1864 when cases were observed almost simultaneouslyin Utica, New York, and Somerville, Massachusetts. Descrip-tions of prison conditions toward the end of the Civil War sug-gest that the disease may have been widespread therein. Thedisease almost certainly was endemic in the South during thepostwar decades, but clean-cut descriptions are few and thedisease was usually diagnosed as unu sua l f orms of malaria,syphilis, tuberculosis, eczema, and various forms of mentaldiseases. Only after the twen tieth c en tur y beg an did the symp-toms combining dermatitis, diarrhea, and dementia come tobe diagnosed as pellagra. By then the disease was widespreadin the agricultural sections of the South and was a severe prob-lem in me nt al hospitals. 26FAILURE OF SYNTHETIC DIETS

Parallel with the dietary observations which were developingthrou gh the work of medical investigators toward the end ofthe nineteenth century were results of animal experimentswhich were consistently revealing the inadequacy of highlypurified or peculiarly unbalanced diets. When McCollum waspuzzling over the inadequacies of single-grain rations being fedto cows at the University of Wisconsin, he found 13 reports inthe literature between 1873 and 1906 revealing failure of ex-perimental animals to grow and maint ain sat isfactory healthwhen fed diets containing presumably sufficient amounts offats, carbohydrates, proteins, and mineral saltsY Additionalinstances, such as Pekelharing's paper of 1905, came to lightlater. I n all insta nces there was a failure to follow up theobvious ( ? ) c onseq uenc es of the experimen ts.

The earliest studies of this nature were oriented toward anund ers tan ding of miner al requirements. Josef Forster, 2s anassistant in physiology at Munich, fed dogs on muscle whichhad been extracted to remove all water-soluble substances (ashwas 0.8 percent), plus sugar, starch, and fat in order to observe

26. Niles, fn. 9 above, pp. 25-33.27. E. V. McCollum, A History of Nutrition (Boston, 1957), p. 201; FromKansas Farm Boy to Scientist (Lawrence, Kansas, 1964), p. 117; MyEarly Experiences in the Study of Nutrition, Ann. Rev. Biochem., 22(1953), 1-16. For McCollum's list and the citations thereto see the latterreference, pp. 6 and 15.28. J. Forster, Versuche fiber die Bedeutung der Aschenbestandtheile inder Nahrung, Zeitschr. f. Biologic, 9 (1873), 297-380.

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Conflict of Concepts in Early Vitamin Studiesany disturbance of the muscular and nervous systems undernearly mineral-free conditions. He observed that death oc-curred earlier than when dogs were completely starved. Heconcluded that certa in minerals are essential to life.Gustav yon Bunge, physiologist at the University of Dorpat,hypothesized that Forster's dogs on the low mineral diet diedearlier than starved dogs because they were being poisoned bythe sulfuric acid formed in the body by oxidation of the sulfurin the protein t hat was fed. His studen t Nicholas Lun in 29tested the hypothesis on mice, which were fed casein, canesugar, and water. On this diet they died in 11 to 21 days. Whenenough sodium carbonate was added to neutralize sulfuric acidequivalent to the sulfur present in the diet, survival was be-tween 12 to 30 days. Results were no better when potassiumcarbonate was used. When mice were fed casein, milk fat, milksugar, and a salt mixture resembling the ash of milk theyshowed no improvement in survival time, but mice given milkas their sole food remained in good health for the duration ofthe experiment (two months). Lunin said in his dissertation,M i c e can live under these conditions when receiving suitable

foods (e.g., milk) , but as the experiments show that t hey cannotsubsist on proteins, fats and carbohydrates, salts and water, itfollows that other substances indispensable for nutrition mustbe presen t in milk besides casein, fat, lactose, and salts. z0In 1885 Bunge joined the medical faculty at the Universityof Basle where he continued his interest in the importance ofinorganic substances in nutrition. His student, Carl A. Soein,alutilized simplified diets in order to study the role of several ironcompounds. Feeding a diet of blood serum, cellulose, sugar,

starch, fat, and milk ash, Socin supplied iron in the form offerric chloride, hemoglobin, hematin, or hematogen. (The latterwas a nitrogenous substance prepared from fat-free egg yolkby digestion with artificial gastric juice. It contained phosphorusand iron. Bunge believed it to be of great physiological sig-nificance.) The mice on these diets failed to survive more than39. days regardless of the source of iron; mice on a control dietof egg yolk, starch, and cellulose appeared healthy during thefull experimental period of 99 days. The egg yolk, according2 0 . N . L u n i n , ' ~ J e b e r d e B e d e u t i n g d e r a n o r g a n i s c h e n S a l ze f l i t d i eE h r n ~ h r u n g d e s T h i e r e s , Z e i t s c h r . p h y s i o l . C h e m . , 5 ( 1 8 8 1 ) , 3 1 - 3 9 .3 0 . L u n i n , i b i d . , p . 3 8; t r a n s l a t i o n f r o m M c C o l lu m , A H i s t o r y o f N u t r i -t / o n , p . 2 0 4 .3 1 . C . A . S o c i n , I n w e l c h e r F o r m w i r d d e s E i s e n r e s o r b e r t ? Z e i t s c h r .p h y s i o l . C h e m i c , 1 5 ( 1 8 9 1 ) , 9 3 - 1 3 9 .

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AARON J. IHDE AND STANLEY L. BECKER

to S oc in , a p p a r e n t l y c o n t a i n e d a n e s s e n t i a l s u b s t a n c e o f u n -k n o w n n a t u r e .

T h e c o n c l us i o ns o f L u n i n a n d S o c in w e r e n o t p u r s u e d b yt h e m , n o r d id t h e y h a v e a n i m p a c t in B u n g e s l a b o r a t o r y . N i c h o -l a s L u n i n ( 1 8 5 3 - 1 9 3 6 ) b e c a m e a s t a f f m e m b e r a t t he H o s p i t a lo f P r i n c e O l d e n b u r g i n S t . P e t e r s b u r g w h e r e h e h a d a n a c t iv ec a r e e r a s a p e d i a t r i c i a n . 32 S o c i n l i k e w i s e a b a n d o n e d t h e f ie ldo f n u t r i t io n . B u n g e h i m s e l f w a s c o n c e r n e d w i t h t h e r o le o fm i n e r a l s i n m e t a b o l i s m a n d , i n t h e s e v e r a l e d it io n s o f h is t e x t-b o o ks 2 3 s o u g h t t o d e v e lo p t h e s e re l a t io n s h i p s . I n a c c o r d a n c ew i t h t h e w i d e l y h e l d b e l i e f t h a t a n i m a l c e ll s w e r e i n c a p a b l eo f s y n t h e s i s o f c o m p l e x o r g a n i c s u b s t a n c e s h e s o u g h t t o e s ta b -l is h th e p r e s e n c e o f o r g a n i c f o r m s o f m i n e r a l e l e m e n t s inf o od s . H e w a s p a r t i c u l a r l y c o n c e r n e d a b o u t t h e p r e c u r s o r s o fi ro n i n h e m a g l o b i n , a n d h i s s tu d e n t s , H ~ i u s e r m a n n a n d A b d e r-h a l d e n , c a r r i e d o u t f e e d i n g e x p e r i m e n t s o n a n e m i c a n i m a l s .I n s tu d i e s in w h i c h d i e t s w e r e s u p p l e m e n t e d w i t h h e m o g l o b i n ,h e m a t i n , o r i r o n s a lt s , th e y c o n c l u d e d t h a t o r g a n i c a l ly b o u n di r o n w a s e s s e n t ia l .W H Y T H E T I M E L A G I N A C C E P T A N C E O F T H E T R A C EN U T R I E N T C O N C E P T ?

W e h a v e o b s e r v e d t h a t b y 1 90 0 t h e r e w a s a n a c c u m u l a t i o no f e v i d e n c e f o r t h e n e e d f o r d i e t a ry c o m p o n e n t s o t h e r t h a np r o t e in s , f a t s , c a r b o h y d r a t e s , a n d m i n e r a l s . Y e t i t w a s a n o t h e rt w e lv e y e a r s b e f o r e s e r i o u s s t a t e m e n t s s u g g e s t i n g t h a t t r a c eo r g a n i c n u t r i e n t s w e r e e s s e n t i a l b e g a n t o a p p e a r i n t h e m e d i c a ll i t e r a tu r e . W h y w a s t h e r e a t i m e la g o f o v e r a d e c a d e b e f o r et h e r e b e g a n to b e a s l o w r e c o g n i t i o n i n n u t r i t i o n c i rc l es t h a tt h e g r o ss n u t r i e n t m a t e r i a l s a l o n e w e r e n o t a d e q u a t e f o r g r o w t ha n d m a i n t e n a n c e o f a n i m a l s o r h u m a n b e i n g s ?

A n e x a m i n a t i o n o f th e t h i n k i n g o f th e t i m e r e v e a l s th a t a tl e a s t f iv e c o m m o n l y h e l d c o n c e p t s d e l ay e d t h e d e v e l o p m e n t o ft h e t r a c e n u t r i e n t c o n c e p t .T h e s e w e r e :

1. T h e g e r m t h e o r y o f d i se a s e2 . T o x i n s a s t h e c a u s e o f d i s e a s e32. S. A. Goldblith and M. A. Joslyn, eds., Milestones in Nutrition(West port , Conn., 1964), p. 97.33. G. yon Bunge, Lehrbuch der physiologischen und pathologischenChernie (Leipzig, 1887; 4th ed., 1898) was translated into five languages,including English. For biographical information on Bunge, see C. M.McKay, Gustav von Bunge, J. Nutrition 49 (1953), 3-19, and H.Schriefers, Dictionary of Scienti~c Biography (New York, 1970) II, 585-586.

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Conflict of Concepts in Ear ly Vitamin Studies3. The Liebig-Voit views on nut rit ion

a Adequate plastic foodsb Adequate albuminous foods4. The Schmidt-Bunge views on minerals in nutriti on5. Prox imate Principles in Food AnalysisIf these five factors are carefully analyzed we find that theywere quite capable of leading medical scientists in directionswhich caused them to ignore the possible role of organic tracenutrients as factors in the avoidance of certain diseases. Infact, appreciation of such trace nutrients would ultimatelycome primarily from the activities of agricultural chemists

rather than from human physiologists. Nevertheless, chemistswere also delayed in their recognition of the role of food inpreventing deficiency diseases by adhering too long to simplis-tic nineteent h-century views of nutrition and placing excessivefaith in proximate chemical analysis.Germ Theory of isease

Following the improvement of the microscope, which oc-curred in the first third of the nineteenth century, the cell be-came firmly established as the fundamental unit in animal andplant life and the science of microbiology was born. Althoughbacteria had been described by Anton van Leeuwenhoek3~ inletters dating from 1674, the pre-nineteenth-century micro-scope was inadequate to advance knowledge of such organismspersuasively. Only with the improved instrument could micro-biology advance. In scarcely more than a generation fermenta-tion became clearly associated with unicellular forms of life,spontaneous generation suffered still another setback, and dis-eases became associated with specific causative organisms.Although Agostino Bassi had associated the museardine dis-ease in silkworms with a minute fungus by 1836 and JohannSchSnlein had associated a certain skin disease with a fungusin 1839, it was actually the work of Louis Pasteur between1860 and 1870 that focused attention on the role of micro-organisms in causing disease. Paste ur had already demonstratedthat different kinds of fermentation were associated with spe-cific microorganisms. Through his studies of fermentationsproduc ing ethyl alcohol, amyl alcohol, butyl alcohol, lactic acid,

34. C. Dobell, ed., Antony van Leeuwenhoek and his Little Animals(New York, 1958), pp. 109ft. Many of Le euwe nhoe k s letters we reoriginally published in the Philosophical Transactions of the Royal Societyin condensed form.

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A A R O N ff I H D E A N D S T A N L E Y L B E C K E R

a n d a c e t i c a c id h e b e c a m e c o n v i n c e d o f t h e s p e c i f i c it y o f a c t i o no f p a r t i c u l a r m i c r o o r g a n i s m s . W h e n h e s t u d ie d th e d i se a se so f w i n e , h e a s s o c i a t e d t h e s p o il a g e w i t h e l o n g a t e d o r g a n i s m sm i x e d w i t h t h e n o r m a l l y p r e s e n t g l o b u l a r y e a s t s . H i s w o r k o nt h e pd rine d i s e a s e o f s i l k w o r m s i n 1 8 6 5 c l e a r l y a s s o c ia t e d t h ed i se a s e w i t h m i n u t e b a c t e r i a i n f e c t i n g t h e w o r m s a n d t h e i rf o o d . H i s s u b s e q u e n t i n t e r e s t in c o m m u n i c a b l e d i s e as e s f o r -t if ie d h i s b e l i e f t h a t s u c h d i s ea s e s w e r e c a u s e d b y t h e p r e s e n c eo f sp e c if ic o r g a n i sm s i n t h e e n v i r o n m e n t .

T h e B r i t is h s u r g e o n J o s e p h L i s t e r v e r y q u i c k l y m a d e u s e o ft h e n e w k n o w l e d g e b y i n t ro d u c i n g t h e u s e o f a p p ro p r i a t e c h e m -i c a l s s u c h a s p h e n o l t o c r e a t e a n t i s e p t i c c o n d i t i o n s , w i t h as u b s t a n t i a l d e c r e a s e i n d e a t h s f r o m p o s t o p e r a t i v e i n f e ct io n s .D e s p i t e o p p o s i t i o n , s u r g e r y s o o n t o o k n o t i c e o f t h e r o l e o f m i -c r o o r g a n i s m s a s a c a u s e o f i n f e c t i o n , a n d a s e p t i c t e c h n i q u e sw e r e c o m i n g in t o u s e w i th i n a n o t h e r d e c a d e .F e r d i n a n d C o h n p i o n e e r e d in t h e d e v e l o p m e n t o f t h e n e ws c i e n c e o f b a c t e r i o l o g y , p a r t i c u l a r l y i n t h e f i e l d o f c la s s if i ca -t io n . H e e n c o u r a g e d R o b e r t K o c h i n h is e a r l y w o r k w h e n K o c hb r o u g h t t o h i m t h e r e s u l ts o f h i s s tu d i e s o n a n t h r a x i n 1 8 7 6.K o c h h a d t r a n s f e r r e d t h e d i s ea s e f r o m c a t t l e to m i c e , c a r r y i n gt h e d is e a se t h r o u g h a se q u e n c e o f m o u s e g e n e r a t io n s , a n dr e c o v e r i n g t h e b a c i ll u s a t t h e e n d w i t h i ts v i ru l e n c e u n a b a t e d .H e l e a r n e d t o c u l t i v a t e th e b a c i l l u s o u t s id e t h e a n i m a l b o d y ,u s i n g b l o o d s e r u m a t b o d y t e m p e r a t u r e a s a m e d i u m . H e a l sop i o n e e r e d i n t h e d e v e l o p m e n t o f s t a i n in g t e c h n i q u e s a n d i n t r o -d u c e d t h e u s e o f s o li d m e d i a , g e l a t in , a n d a g a r - a g a r f o r t h ec u l t i v a t i o n o f b a c t e r i a . I n t r o d u c i n g t h e p o s t u l a t e s t h a t a c a u s a -t iv e o r g a n i s m m u s t b e i so l a te d f r o m a n a n i m a l s u f f e r in g f r o mt h e d i s e a s e , m u s t b e c a r r i e d a s a p u r e c u l t u r e t h r o u g h r e p e a t e dt r a n s f e r s o n s y n t h e t i c m e d i a , a n d m u s t b e a b le t o c a u s e t h ed i s e a s e w h e n i n o c u l a t e d i n t o a h e a l t h y a n i m a l , h e i d e n t i f i e dt h e b a c t e r i a r e s p o n s i b l e f o r t u b e r c u l o s i s i n 1889., a n d f o r c h o l e r ai n 1 8 83 . A w h o l e g e n e r a t i o n o f m i c r o b e h u n t e r s r e c e iv e d t h e i rt r a i n i n g i n h i s l a b o r a t o r y ( G a f f k y , K i t a sa t o , B e h r i n g , E h r l i c h ) .P a r a l l e l w i t h C o h n ' s w o r k o n b a c t e r i a , K a r l L e u c k a r t w a sc a r r y i n g o n s tu d i e s o f a n i m a l p a r a s i t e s s u c h a s t a p e w o r m s a n df l u k e s , a n d s h o w e d t h a t d i s e a s e s s u c h a s t r i c h i n o s i s a r e c a u s e db y t i n y m u l t i c e l lu l a r a n i m a l s .F o l l o w i n g K o c h ' s w o r k o n t h e a n t h r a x b a c i l l u s , P a s t e u r c o n -f i r m e d t h e s p o r e - f o r m i n g c h a r a c t e r i s t i c s o f th e o r g a n i s m . H ea ls o r e c o g n i z e d t h a t t h e f e w a n i m a l s w h o r e c o v e r e d f r o m t h ed i se a s e h a d a c q u i r e d a n i m m u n i t y t o f u r t h e r a t t a c k s a n d h e

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Conflict of Concepts in Early Vitamin Studieswas successful in producing attenuated anthrax bacilli by ex-posing them to heat. Sheep inoculated with the attenuatedbacilli in 1881 developed an immunity which enabled them tosurvive inoculation with virulent anthrax organisms. Pasteurwent on to develop immunization techniques for chicken chol-era and rabies. In the case of the latter disease, he was neverable to isolate a causative organism, but he nevertheless hadfaith that one must be there.In 1883 Koch traveled in Asia to study human cholera andbubonic plague and to Africa to study sleeping sickness. Heshowed, at the turn of the century, that bubonic plague wastransferred by a louse carried by rats and that sleeping sick-ness was transmitted by the tsetse tty. At about that time therole of the nopheles mosquito as a transmitter of malaria wasclearly established as a result of the studies by investigatorsfrom France (Laveran), Italy (Marchiafava, Golgi, Bignami,Bastianelli, Grassi), and Britain (Manson, Ross), and the lifecycle of the malarial parasite was established. As early as 1877Manson had established that the parasite causing elephantiasisis transmitted by a Culex mosquito. All of those countries hav-ing colonial interests in the tropics supported vigorous inves-tigation toward the control of such diseases. Significantly, vir-tually all of the research was directed toward the isolation andunderst anding of a causative organism.The development of vaccines for the creation of immunitytoward specific diseases became a popular and fruitful area ofresearch toward the end of the century. Emil yon Behring,working in Koch s laboratory in 1890, discovered that it waspossible to immunize an animal against tetanus by inoculatingit with graded doses of blood serum taken from another animalafflicted with the disease. A portion of the serum from theimmunized animal (the antitoxin) then conferred temporaryimmunity in another animal. Behring believed that a cure fordiphtheria might be prepared by using antibodies produced inanimals inoculated with the germ which had been identifiedby Edwin Klebs and Friedrich L5ffler. Together with Paul Ehr-lich, Behring developed the technique of preparing and usingdiphtheria antitoxin in 1899.. It proved remarkably effective notonly in preventing the dread childhood disease, but even incuring the disease after it had begun. Ehrlich went on to de-velop chemical agents which were active in the control of cer-tain disease-producing microorganisms, specifically the dyeTrypan red for the treatment of trypanosomal diseases such as

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A A R O N J I H D E A N D S T A N L E Y L B E C KE : R

s l e e p i n g s i c k n e s s , a n d a r s e n i c - c o n t a i n i n g o r g a n i c c o m p o u n d sf o r t h e t r e a t m e n t o f sy p h i li s .T h e g e r m t h e o ry o f d i se a s e p ro v e d a d r a m a t i c b r e a k t h r o u g h

i n m e d i c i n e . B y 1 9 06 t h e c a u s a t i v e o r g a n i s m s o f m o r e t h a nt w e n t y d i s e a se s h a d b e e n i s o la t e d a n d e s t a b l i sh e d a c c o r d i n gt o K o c h s po s tu la te s .3 5 T h e n o t i o n t h a t a d i s e a s e w a s c a u s e db y a s p e c if ic m i c r o o r g a n i s m p r o v e d e x c e e d i n g l y a t t r a c t iv e , p a r -t i c u l a r l y w h e n t h e r e w e r e s u c c e s s e s i n c o n t r o l a s s o c i a t e d w i t ha n t i s e p s i s a n d a s e p s i s , s e r u m t h e r a p y , c h e m o t h e r a p y , a n d m a n -a g e m e n t o f i n s e c t v e c to r s .

T h e r e h a s b e e n a t e n d e n c y t h r o u g h o u t m e d i c a l h is t o r y t o b ea t t r a c t e d b y a u n i t a r y v i e w o f d i s e a s e - - t h a t i s , t o b e l ie v e t h a td i s e a se c a n b e e x p l a i n e d a n d t r e a t e d o n t h e b a s is o f a s i m p l ea n d s in g l e p o i n t o f v ie w . T h e g e r m t h e o r y o f d i s ea s e p r o v e dto b e v a s t ly m o r e s u c c e s s f u l t h a n a n y p r e v i o u s m e d i c a l c o n -c e p t. W i t h t h e e m p h a s i s w h i c h b e g a n t o b e p la c e d o n s a n i t a t io ni n th e p e r i o d f r o m 1 8 7 0 o n w a r d , t h e r e w a s a n e w s u c c e s s i nm e d i c a l p r a c t i c e a n d s u r g e r y w h i c h c r e a t e d a t e m p t a t i o n t ob e l ie v e t h a t m i c r o o r g a n i s m s m i g h t b e r e sp o n s i b l e f o r a ll d is -e a s e s a n d t h a t t r e a t m e n t s i m p l y c o n si s te d o f c o n tr o l o f t h ec a u s a t i v e m i c r o o r g a n i s m s . T h u s , i t i s h a r d l y s u r p r i s i n g t h a tt h e g e r m c o n c e p t p r o v e d a m a j o r b a r r i e r t o t h e r e c o g n i t i o na n d s t u d y o f d e f i c i e n c y d i s e a s e s . 36

I n t h e c a s e o f e v e r y d i s e a se m e n t i o n e d b y F u n k , c l a i m s w e r ep u b l i s h e d f o r t h e d i s c o v e r y o f a c a u s a t i v e o r g a n i s m . V e d d e r ~Tc i te s a l e n g t h y l i s t o f a u t h o r s c l a i m i n g t h e d i s c o v e r y o f a c a u s a -t i v e o r g a n i s m i n h is b o o k o n b e r i b e r i i n 1 9 1 3 . F i v e i n v e s t i g a t o r sa t t r ib u t e d t h e d i se a s e t o p r o t o z o a , th r e e t o n e m a t h e l m i n t h a e ,1 5 t o s o m e f o r m o f b a c t e r i a , a n d o n e b e l ie v e d t h e d i s e a s e a t-t r ib u t a b l e t o a f u n g u s o n m o l d y r ic e . W e h a v e a l r e a d y n o t e dt h a t t h e P e k e l h a r i n g t a s k f o r c e w a s s e n t t o J a v a t o l o c a te t h ec a u s a t i v e o r g a n i s m . P e k e l h a r i n g a n d T W inkler a c t u a l l y r e p o r t e ds u c h a n o r g a n i s m u p o n t h e i r r e t u r n , 3s w h i l e E i j k m a n s o u g h t

35. See C. Singer and E. A. Underwood, A Short History of Medicine,2nd ed., (Oxford, 1962), p. 391, for a c hronolog ical list ing of discoverie sof disease-producing bacteria.36. For a good study of this pr obl em see R. H. Follis, St., Cellul arPathology and the Development of the Deficiency Disease Concept, Bull.Hist. Med., 34 (1960), 291-317.37. Vedder, fn. 7 above, pp. 89 and bibliog raphy.38. Pek elha ring and Winkler (see fn. 19 above); also Mitth eilun g ueberdie Beriberi, Centralblatt fi2r Bacteriologie, 3 (1888), 77-86; and Re-serches sur la nature e la cause du beriberi e~ sur le mo ye ns de lacombattre (Utrecht, 1888), trans. J. Cantlie (Edinburgh, 1893).

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Conflict of Concepts in Early Vitamin Studiesto transmit the disease to healthy chickens until he was for-tuna te in mak ing the association with unpolished rice.Scurvy was likewise associated with bacterial infections.Stewart has said,

One factor which undoubtedly held up the development ofthe concept of deficiency diseases was the discovery of bac-teria in the nineteenth century and the consequent preoccu-pation of scientists and doctors with positive infective agentsin disease. So strong was the impetus provided by bacteri-ology that many diseases which we now know to be due tonutritional or endocrine deficiencies were, as late as 1910,thou ght to be toxaemias ; in defaul t of any evidence of anactive infecting micro-organism they were ascribed to theremote effects of imaginary toxins elaborated by bacteria. 39As late as 1916 Jackson and Moore40 claimed to have isolateda diplococcus from the tissues of scorbutic guinea pigs. Aftercultivating the organism in the laboratory, they injected it intohealthy guinea pigs and reported hemorrhages. They were ableto isolate the diplococcus from the lesions.The Italian physiologist Morpurgo41 argued strongly for thecausative role of a diplococcus in rickets after he isolated theorganism from rats in which an outbreak of rickets occurredspontaneously. In 1911 J. Koch~2 injected a streptococcus lon-gus into dogs and observed swellings and deformities at variousjoints.The infection theory was also popular in the case of pellagra.In his treat ise on the disease, Roberts 43 discusses at length thepathological and ecological evidence of infection. Dr. LouisSambon of the Liverpool School of Tropical Medicine set up aseries of postulates to prove that pellagra is a parasitic dis-

39. C. P. St ewart in Stewaxt and Gut hrie, fn. 12 above, pp. 408-409.40. Leila Jack son and J. J. Moore, Studies on Exp eri men tal Scurvy inGuin ea Pigs, J. Infe ctious Diseases 19 (1916), 478-510.41. B. Morpu rgo, Ueber ein e infecti/Sse For m der Osteoma lacle beiWeisssen Ratten , l~eitv~ge path Anat . u. Path . 28 (1900)~ 620-626; alsosee 'Dutch Infekti on hervorger ufene malaci sche un d rachitischeSkeletvertinderungen an jungen weissen Ratten, Centralblatt allg. Path.u. 1garb. Anat . 13 (1902), 113--119.42. ft. Koch, Un te rs uc hu ng en fiber die Lokalization der Bakterien, dasVerha l ten des Knoch enmarkes und die Veraenderung en der Knochen,inbesondere der Epiphysen bei Infektionskrankheiten. Mit Bemerkungenzur Theorie der Rachitis , Zeitschr. fiir Hyg. 69 (1911), 436-459.43. S. R. Roberts, fn. 9 above, pp. 247-26 5.

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AARON J. IHDE AND STANLEY L. BECKERe a se . 44 W h e n J o s e p h G o l d b e r g e r b e g a n h i s s t u d ie s o n p e l l a g r ai n t h e U n i t e d S t a t e s i n 1 9 1 4 h i s d e f ic i e n c y i d e a s w e r e v i g o r-o u s l y r e s is t ed , e v e n a f t e r h e h a d f a i l e d t o t r a n s m i t t h e d i s e a set o h i m s e l f a n d h u m a n v o l u n t e e r s b y i n je c t io n , i n h a l a t i o n , o rs w a l l o w i n g o f b l oo d , n a s a l s e c r e t io n s , u r i n e , f e c e s , o r s c a le s o fs k i n t a k e n f r o m p e l l a g r o u s p a t i e n t s . 4~

T h u s , e a c h o f t h e i m p o r t a n t d e f ic i e n cy d is e a s e s w a s a ss o ci -a t e d w i t h p o s i t iv e i n f e c t i o u s a g e n t s , i n 1Lne w i t h t h e p r e v a i l i n gm e d i c a l d o g m a s o f th e t i m e s . F o ll is h a s s a i d ,

A s a r e s u l t o f t h e t r e m e n d o u s i n f l u e n c e o f th e s e p o s i t iv ea g e n t s , t h e b a c t e r i a a n d t h e i r p r o d u c t s , i t w a s d i ff ic u lt tot h i n k i n t e r m s o f n e g a t i v e c a u s e s o f d is e a s e. M e d i c a l s c i e n c e ,j u s t a s h a s t h e la w , h a d d if f i cu l t y e v e n c o n s i d e r in g , m u c hl e s s p r o v i n g , a n e g a t i v e , p a r t i c u l a r l y i n t h e f a c e o f a l l t h ep o s i t i v e f a c t o r s . E v e n a s l a t e a s 1 9 0 7 , M a r i n e h a s s a i d t h a th e f r e q u e n t l y h e a r d t h e c r i t i c i s m t h a t i t w a s d if f i c ul t t o c o n -c e iv e o f a d e f ic i e nc y o r a b s e n c e o f s o m e t h i n g c a u s i n g s o m e -t h i n g . 4 6I n d e f e n s e o f t h e m e d i c a l m e n i t m u s t b e sa i d t h a t t h e r e w e r e

n u m e r o u s f a c t o r s w o r k i n g a g a i n s t th e u n a m b i g u o u s r e c o g n i-t i o n o f t h e s e d i s e a s e s a s a t t r i b u t a b l e t o a d i e t a r y d e f i c i en c y . I ne x p e r i m e n t a l a n i m a l s a n d i n h u m a n b e i n g s t h es e d i s e as e s a rer a r e l y u n c o m p l i c a t e d . W h e n a f o o d i s l a c k i n g in q u a l i ty t h e r ei s f r e q u e n t l y a m u l t i p l ic i t y o f s h o r t c o m i n g s , n o t t h e l a c k o f as i n g le e s s e n t i a l s u b s t a n c e . T h e l a t e r d i f fi c ul ti es o f th e n u t r i -t i o n is t s i n d e s i g n i n g r a t i o n s l a c k i n g o n l y a s i n g le f a c t o r a t t e s tt o th e m a g n i t u d e o f t h i s p r o b l e m . F u r t h e r m o r e , a n a n i m a l s u f-f e r i n g f r o m a d e fi c ie n c y d i s e a se i s i n a w e a k e n e d a n d f r e q u e n t l yi n f l a m e d c o n d i t io n . I t is t h e r e f o r e r e a d i l y s u s c e p t i b le t o t h ei n v a s i o n o f m i c r o o r g a n i s m s . S e a r c h e r s f o r b a c t e r i a i n e v i t a b lyf o u n d t h e m , a n d w h e n u s i n g f a u l t y e x p e r i m e n t a l t ec h n iq u e s ,p e r s u a d e d t h e m s e l v e s th a t t h e m i c r o o r g a n i s m s c a u s e d t h e d is -e a s e in s t e a d o f r e a l iz i n g t h a t t h e u n h e a l t h y s t a te o f th e a n i m a lp r e v e n t e d r e s i s t a n c e t o t h e i n v a s i o n o f p a r a s i t e s i n t h e e n v i r o n -m e n t .Tox ins as the ause of Disease

I t h a d b e e n r e c o g n i z e d f r o m a n t i q u i ty t h a t c e r t a i n s p e ci fi cs u b s t a n c e s h a v e t h e c a p a c i t y to c a u s e i l ln e s s a n d d e a t h . U s e o f

44. Acco rdi ng to Niles, fn. 9 above, pp. 52--54.45. $. Goldberger, The Tran smis sib ili ty of Pellagra. Exp eri ment alAttemp ts a t Trans miss ion to the Hu ma n Subject~ U.S. Public HealthReports 31, no. 46 (1916), 3159-73. Reprinted in M. Terris, ed., Gold-berger on Pellagra (Baton Rouge, La., 1964), pp. 95-110.46. Follis, fn. 36 above, p. 307.

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Conflict of Concepts in Early Vitamin Studiesarsenicals figures prominently in the history of political andsocial murder. Knowledge of the toxic properties of plants con-taining certain alkaloids, glucosides, and resins was of longstanding, as was knowledge of the dangers from the bites andstings of certain reptiles and insects. No medical theories wereable to ignore the effec ts of toxic substances.The development of knowledge of microbiology fortified thefield of toxicology since it quickly became evident that in somecases illness was attributable, not to any direct action of amicroorganism, but to the effect of toxins produced by it. Insome cases the toxin was produced by the organism after in-vasion of the body; in others by its action in food outside thebody. August Gaertner, a military surgeon, became deeply in-terested in hygiene and food bacteriology after studying underKoch. In 1888 he discovered Salmonella enteritidis an or-ganism whose toxin in foods causes severe digestive upsets. In1896 Emile van Ermengen, professor of bacteriology at theUniversity of Ghent, isolated Clostridium botulismum the or-ganism responsible for the production of one of the most toxicsubstances known. At the end of the nineteenth century therewas also a great deal of interest in the alleged production of

ptomaines by intestinal bacteria, and autointoxication of thebody throu gh absorption of such intes tinal toxins.It is not surprising tha t the deficiency diseases were fre-quently caught up in the toxin concept. We recall that Eijk-man attributed beriberi to a toxin in the endosperm of rice,arguing that the polishings must contain an antitoxin. In histreatise on beriberi, Vedder~ makes reference to authoritiesattributing the disease to inorganic toxins (arsenic, oxalate,carbon dioxide) as well as to organic toxins produced by bac-teria or even by higher plants.In his book on diseases of the bones, Mar fan 48 attributedrickets to a variety of poisons, including some produced bybacteria. Cheadle and Poynton49 believed the disease was dueto toxic substances e laborated in farinaceous foods.Pellagra was widely believed to be due to the consumption ofspoiled maize. Casal held this view as early as 1762, and theidea remained popular up to the very time that pellagra wasestablished to be a deficiency disease. 5o Various molds wereparticularly suspect.

47. Vedder , fn . 7 above, pp. 88---89.48. A. B. Marfan, M a l a d i e s d e s o s (Paris, 1912).49. W. B. Cheadl e and F. J. Poya ton, Rickets in A U b u t t s S y s t e m o fM e d i c i n e , (London , 1901).50. For a su mma ry o f this view see Niles, fn. 9 above, pp. 34-44.

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A A R O N J H I D E A N D S T A N L E Y L B E C K E R

T h e L i e b i g - V o i t V i e w s o n N u t r i t i o nP a r a l l e l i n g t h e g e r m a n d t o x i n c o n c e p t s o f d i s e a s e w a s t h e

p e r s i s t e n c e o f n u t r i t i o n c o n c e p t s d e v e l o p e d b y J u s t u s v o n L i e -b i g i n h i s b o o k , A n i m a l C h e m i s t r y , 51 p u b l i s h e d in 1 8 4 2 . T h e s ev i e w s w e r e e x t e n d e d a n d s y s t e m a t i z e d , a n d s o m e t i m e s c o r -r e c t e d , b y K a r l y o n V o i t , a f o r m e r L i e b i g s t u d e n t a n d a l e a d i n gi n v e s t i g a t o r o f n u t r i t i o n a l p r o b l e m s d u r i n g t h e l a s t h a l f o f t h en i n e t e e n t h c e n t u r y . T h e s e v i e w s h a d a p r o f o u n d i n f l u e n c e , b o t hi n a g r i c u l t u r a l c i r c le s a n d a m o n g h u m a n p h y s i o l o g i s t s .

L i e b i g e m p h a s i z e d t h e i d e a t h a t g r o w t h a n d h e a l t h o f a na n ~ n a l w o u l d b e s a t i s f a c t o r y i f t h e f o o d s u p p l i e d 1 ) a n a d e -q u a t e q u a n t i t y o f h e a t - p r o d u c i n g f o o d s , a n d 2 ) a s u f f i c i e n tq u a n t i t y o f a l b u m i n o u s m a t e r i a l f o r r e p l a c e m e n t o f n i t r o g e n o u sm a t e r i a l d e s t r o y e d d u r i n g m u s c u l a r a c t i v i t y . ~2

S o o n a f t e r p u b l i c a t i o n o f L i e b i g ' s b o o k , t h e r e w a s i n t e n s ei n t e r e s t i n r e s p i r a t i o n c a l o r i m e t r y , r e f l e c t in g a s y m p a t h e t i cr e a c t i o n t o t h e i n t e r e s t o f p h y s i c i s t s i n e n e r g y r e l a t i o n s h i p s ,p a r t i c u l a r l y t h e c o n c e p t o f c o n s e r v a t i o n o f e n e r g y . T h e p i o n e e r -i n g w o r k o n a n i m a l r e s p i r a t i o n b y V i c t o r R e g n a u l t a n d J u l e sR e i s e t w a s f o l l o w e d i n t h e n e x t d e c a d e b y t h a t o f V o l t a n d h i ss c h o o l . V o l t a n d P e t t e n k o f e r w e r e u s i n g a c a l o r i m e t e r a d e q u a t ef o r t h e s t u d y o f a n a d u l t h u m a n b y 1 8 6 6 . 53 D u r i n g t h e c o u r s eo f t h e s e s t u d i e s i t b e c a m e a p p a r e n t t o V o i t i n 1 8 6 1 t h a t , c o n -t r a r y t o L i e b i g , m u s c u l a r a c t i v i t y d i d n o t i n c r e a s e t h e r a t e a tw h i c h p r o t e i n s w e r e m e t a b o l i z e d .

S i n c e p r o t e i n s a r e u n i q u e a m o n g m a j o r f o o d c o n s t i t u e n t s i nc o n t a i n i n g n i t r o g e n , t h e r e w a s a s p e c i a l i n t e r e s t i n t h e s e s u b -

5 1 . L i e b i g , J u s t u s , A n i m a l C h e m i s t r y o r O r g a n ic C h e m i s t r y i n it sA p p l i c a t i o n t o P h y s i o l o g y a n d P a t h o l o g y , e d i t e d f r o m t h e a u t h o r ' s m a n u -s c r i p t b y W i n . G r e g o r y ( L o n d o n , 18 42 ). A G e r m a n e d i t i o n w a s p u b l i s h e ds i m u l t a n e o u s l y i n B r a u n s c h w e i g a n d a n A m e r i c a n e d i ti o n s h o r tl y th e re -a f t e r i n C a m b r i d g e , M a s s . A r e a d i l y a v a i l a b l e a n d u s e f u l e d i t i o n i s th ef a c s i m i l e r e p r i n t o f t h e C a m b r i d g e e d i t i o n o f 1 8 42 ( N e w Y o r k , 1 9 64 ).T h i s e d i t i o n h a s a lo n g a n d e x c e l l e n t i n t r o d u c t o r y e s s a y b y F r e d e r i c k L .H o l m e s . F o r a c r i t iq u e o f t h e i n f l u e n c e o f L i e b i g 's b o o k s e e H o l m e s ,a b o v e ; F . R . M o u l t o n , e d . , L i e b i g a n d A f t e r L i e b i g ( W a s h i n g t o n , 1 9 4 2 ) ;A . J . I h d e , A n I n q u i r y i n t o t h e O r i g i n s o f H y b r i d S c i e n c e s : A s t r o -p h y s i c s a n d B i o c h e m i s t r y , I . C h e m . E d u . , 4 6 (1969) , 193-196; S . L .B e c k e t , f n . 4 a b o v e. T h e l a t t e r w o r k h a s a c o n c i s e s u m m a r y o f L ie b i g 'sn u t r i t i o n a l v i e w s ( p p . 4 - - 7 ) a n d o f t h e i n f l u e n c e o f t h e s e v i e w s o n l a t e rp h y s i o l o g i s t s (p p . 8 - 1 1 ) .5 2 . L i e b i g , A n i m a l C h e m i s tr y , p p . 6 0 - 9 2 .5 3 . O n t h e h i s t o r y o f a n i m a l c a l o r i m e t r y s e e G . L u s k , 'A H i s t o r y o fM e t a b o l i s m , E n d o c r i n o l o g y a n d M e t a b o l i s m , L . F . B a r k e r , R . G . Ha s k i n sa n d H . O . M o s e n t h a l , e d s . ( Ne w Yo r k , 19 22 ), I I I , 3 - 7 8 . E . M e n d e l s o h n ,H e a t a n d L i f e ( C a m b r i d g e , 1 96 4) h a s a g o o d t r e a t m e n t o f t h e p r o b l e m o fa n i m a l h e a t i n t h e p e r i o d b ef o re t h e r i s e o f t h e r m o d y n a m i c s .

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C o n f l i c t o f C o n c e p t s i n E a r l y V i t a m i n S t u d ie ss t a n c e s . T h e D u t c h c h e m i s t G e r a r d u s M u l d e r i n t r o d u c e d t h ew o r d p r o t e i n , f o r o f f ir s t i m p o r t a n c e i n 1 8 3 8 , f o l l o w i n g as u g g e s t i o n o f B e r z e l iu s . ~4 H e d e v e l o p e d t h e i d e a o f a p r o t e i nr a d i c a l w i t h t h e f o r m u l a C 4 0 H ~ 2 N 1 0 0 1 2 . D i f f e r e n c e s i n i n d i v i d u a lp l a n t a n d a n i m a l p r o te i n s w e r e l o ok e d u p o n a s c o m b i n a t i o n so f t h e p r o t e i n r a d i c a l w i t h a t o m s o f s u l f u r a n d p h o s p h o r u s .C a s e i n w a s l O P r - [ - S ; f i b r in a n d e g g a l b u m i n w e r e 1 0 P r -~- S P ;g l u t e n w a s 1 0 P r -[ - $ 2; b l o o d a l b u m i n , 1 0 P r ~ S ~P . P r o t e i np r e c i p i t a t e s w i t h t a n n i c a c i d , h y d r o c h l o r i c a c i d , o r l e a d o x i d ew e r e f o r m u l a t e d i n th e s a m e m a n n e r , t h e s u p p o s it io n b e i n gm a d e t h a t a d o u b l e d e c o m p o s i t i o n o c c u r r e d i n w h i c h t h e s u l fu ra n d p h o s p h o r o u s w e r e d i sp l a c ed , s5

W o r k i n L i e b i g 's l a b o r a t o r y t h r e w d o u b t o n t h e r a d i c a l c o n -c e p t s i n c e s u l f u r - f re e p r o t e i n p r e p a r a t i o n s c o u l d n o t b e p re -p a r e d , a n d M u l d e r ' s c o n c e p t f e ll i n t o d is c a r d . L i e b i g , h o w e v e r ,h e l d t h a t f ib r in , c a s e i n , a n d a l b u m i n , t h e c h i e f p r o t e i n s o fn a t u r e , h a d t h e s a m e c o m p o s i t i o n 56 a n d t h is i d e a w a s h e l di m p l i c i t ly o r e x p l i c it ly d u r i n g t h e r e m a i n d e r o f th e c e n t u r y i nm o s t p h y s i o l o g i c a l a n d a g r i c u l t u r a l c i r c le s . L i e b i g w a s r e s p o n -s ib le f o r th e i d e a t h a t t h e a l b u m i n o u s m a t e r i a l s o f p la n t s w e r ei n g e s t e d d i r e c t l y i n th e a n i m a l b o d y to b e c o m e t h e a l b u m i n o u sm a t e r i a l s o f b l o o d a n d m u s c l e s . A l t h o u g h s u b s e q u e n t p h y s io -l o g i c a l w o r k i n v a r i o u s q u a r t e r s l e d to g r a d u a l r e c o g n i t i o n o ft h e ro l e o f d i g e st iv e e n z y m e s i n b r i n g i n g a b o u t t h e d e g r a d a t i o no f f o o d c o m p o n e n t s to s i m p l e r u n i t s , t h e a c t i o n w a s l o ok e du p o n a s a s o l u b f li z in g e f f e c t w i t h o u t b r e a k d o w n t o s m a l l u n i ts .T h i s w a s p a r t i c u l a r l y t r u e w i t h r e s p e c t t o th e d i g e s t i o n o f p r o -t e in s . A l t h o u g h t e n n a t u r a l l y o c c u r r i n g a m i n o a c id s w e r ek n o w n b y 1 8 80 , o n l y s i x o f th e s e w e r e a s s o c i a te d w i t h p r o t e i nh y d r o ly s i s . B y 1 9 00 f iv e m o r e a m i n o a c id s w e r e k n o w n a n dn o w 1 3 w e r e f o u n d a s s o c i a te d w i t h p r o t e i n h y d r o ly s i s . 57 W h e nE m i l F i s c h e r i n t r o d u c e d t h e e s te r f r a c t i o n a t i o n t e c h n i q u e f o rt h e s e p a r a t i o n o f a m i n o a c i d s a n d d e v e l o p e d t h e p e p t id e h y -p o t h e s i s o f p r o t e i n s t r u c t u r e t h e r e w a s s ti ll l i t tl e a p p r e c i a t i o n

54. H . B. Vickery, Th e Origin of the W ord Protein, Y a l e 1 . B i o l . M e d .2 2 (1950), 387-393.55. G. J. Mulder, T h e C h e m i s t r y o f V e g e t a b le a n d A n i m a l P h y s i o l o g yt rans la ted f rom the D utch by P . F. H. F rom berg (Edinburgh , 1845) , p . 73 .Also see Berzelius J a h r e s - B e r i c h t 1 8 (1839), 534; 1 9 (1840), 639; and 27(1848), 569.56. 1. Liebig, Ue ber die stickstot~naltingen N ah ru ng sm ittel de sPf lanzenre ichs , A n n a l e n d e r C h e m i e 3 9 (18 41 ), 129-160. Also see N.Laskow ski , 'Ueber die Protein Theo rie, i b i d . 5 8 (1846), 129-166.57. H. B. Vickery and C. L. A. Schmidt , 'The History of the Discove ry ofthe Amino Acids, C h e m . R e v i e w s 9 (1931), 169-318.

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AAI:tON 3. IHDE AND STANLEY L. BECKER

o f t h e c o m p l e x i t y o f p r o te i n s , o r o f t h e d i f f e r e n c e s b e t w e e nt h e m . T h e e x t e n s i v e s tu d i e s o n t h e d e c o m p o s i t i o n o f p r o t e i n sw h i c h w e r e m a d e i n t h e l a b o r a t o r i e s o f W i ll y K / i h n e a t H e i d e l-b e r g a n d R u s s e l l C h i t t e n d e n a t Y a le w e r e a i m e d , f o r tw o d e c-a d es , t o w a r d t h e u n d e r s t a n d i n g o f m a j o r p r o te i n f r a g m e n t s( a l b u m o s e s , a n t ip e p t o n e s , h e m i p e p t o n e s ) . I t w a s r ec o g n i ze dt h a t f o o d c o m p o n e n t s w e r e a b s o r b e d f r o m t h e i n te s t in e s o n l yw h e n i n a s o l u b le f o r m . S i n c e t h e p e p t o n e s w e r e d i f f u si b le , i tw a s f e l t t h a t t h i s d e g r e e o f d e g r a d a t i o n w a s s u f f ic i e n t f o r a b -s o r p t i o n i n t o t h e b l o o d s t r e a m . F u r t h e r d i g e s t i o n t o a m i n oa c i d s w o u l d b e a w a s t e o f p h y s i o l o g i c a l e n e r g y . T h i s p o i n t o fv i e w w a s a n a t u r a l o n e b e f o r e t h e d i s c o v e ry o f e r e p s i n b yO t to C o h n h e i m i n 1 9 01 . 58 T h i s e n z y m e , w h i c h w a s u l t i m a t e l ys h o w n t o b e a m i x t u r e b y t h e w o r k o f E . W a l d s c h m i d t - L e i t z , M a xB e r g m a n n , a n d o t h e r s f r o m 1 9 30 o n w a r d , p r o v e d to b e r e-s p o n s i b l e f o r t h e f i n a l s t e p s in t h e h y d r o l y s i s o f p r o t e i n s t oa m i n o a c id s . F u r t h e r , i t w a s o n l y i n 1 9 13 t h a t a n a l y t i c a l m e t h -o d o l o gy w a s a d e q u a t e to p e r m i t E m i l A b d e r h a l d e n 59 t o e s ta b -l i s h t h e p r e s e n c e o f a m i n o a c i d s i n t h e b l o o d . 60The Schmidt Bunge Views on Minerals in Nutrit ion

T h e m i n e r a l p r o b l e m w a s a s o m e w h a t s p e c ia l o ne . I t h a db e e n r e c o g n i z e d i n t h e e i g h t e e n t h c e n t u r y t h a t c e r t a i n i n o r g a n i ce l e m e n t s a r e p r e s e n t i n p l a n t s a n d a n i m a l s . S t ud i es o f g ro w t hi n s y n t h e t i c s o i ls r e v e a l e d t h a t p l a n t s c a n u t i l i z e s u c h e l e m e n t si n th e f o r m o f i n o r g a n i c c o m p o u n d s . T h e r e w a s , h o w e v e r , ar e l u c t a n c e t o a c c e p t t h e i d e a t h a t a n i m a l s w e r e a b l e t o u t i l i z es u c h e l e m e n t s i n i n o r g a n i c f o r m . L i e b ig g a v e a t t e n t i o n t o th ep r o b l e m b u t t h e id e a s w e r e m o r e f u l l y d e v e l o p e d b y a f o r m e rL i e h ig s t u d e n t , C a r l S c h m i d t , a t D o r p a t a n d b y h is s t u d e n t ,G u s t a v v o n B u n g e , a t D o r p a t a n d B a se l. A s e a r l y a s 1 8 5 0,S c h m i d t s a n a l y s i s o f b l o o d s h o w e d t h a t m o s t o f th e s o d i u mw a s i n t h e p l a s m a w h i l e m o s t o f t h e p o t a s s i u m w a s i n t h e c el l s .D u r i n g t h e n e x t t h i r ty y e a r s t h e r e w a s a s te a d y f lo w o f p u b l ic a -t io n s f r o m D o r p a t o n t h e s u b j e c t o f m i n e r a l s i n l i v i n g ti ss u e s.

58. O. Cohnhelm, Die Um wa nd lu ng des ~.iweiss dut ch Da rmwan d,Z. physiol. Chem. 33 (1901), 451 -46 5; 'Weitere Mit the il ung fiber dasErepsin, ibid. 35 (1902), 134-140.59. E. Abderhal den, Der Nach wei s yon freien Aminos~iuren im Bluteunte r normalen Verha lmissen, ibid. 88 (1913), 478--483.60. For a good study of the whole problem of protein composition seeH. B. Vickery and T. B. Osborne, A Review of Hyp oth eses of the Stru ctur eof Proteins, Physiological Reviews 8 (1928), 393-446, esp. pp. 395--400.

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C o n f l i c t o f C o n c e p t s i n E a r l y V i t a m i n S t u di e sB u n g e , w h o b e c a m e i n t e r e s te d i n s o d i u m c h lo r id e m e t a b o l i s md u r i n g h i s s t u d e n t d a y s , c a m e t o b e l i e v e i t t o b e t h e o n l y i n -o r g a n i c n u t r i e n t w h i c h w a s u t i l i z e d d i r e c t l y a s t h e s a l t . S u c he l e m e n t s a s i ro n , c a l c i u m , a n d p h o s p h o r u s , h e b e l ie v e d , m u s tb e s u p p l i e d t o t h e a n i m a l i n t h e f o r m o f o r g a n i c c o m p o u n d s .T h e f e e d i n g e x p e r i m e n t s c a r r i e d o u t in h i s l a b o r a t o r y b y S o c inw e r e in i t i a t e d t o s h e d l i g h t o n t h e s o u r c e o f i r o n i n h e m o g l o b i n .

T h e e x p e r i m e n t s o f b o t h L u n i n a n d S o cin , a l th o u g h d e s ig n e dt o s h e d l i g h t o n t h e i r o n p r o b l e m , p o i n t e d c l e a r l y t o t h e i n a d e -q u a c y o f s y n t h e t i c d i e t s . T h e c l u e w a s n o t p u r s u e d i n B u n g e ' sl a b o r a t o r y . I n h is N o b e l A w a r d A d d r e s s H o p k i n s d e c l a r e d :

. . B u n g e , t h o u g h i n h is w e l l - k n o w n b o o k h e r e m a r k st h a t i t w o u l d b e w o r t h - w h i l e t o c o n t i n u e t h e e x p e r i m e n t sw h i c h h a d s u g g e s t e d t h e e x i s t e n ce o f u n k n o w n n u t r i t i o n a lf a c t o r s , w a s , a s I h a p p e n to k n o w , h i m s e l f i n c l in e d t o d is -b e l ie v e i n t h e m . H e t h o u g h t t h a t t h e r e a l e r r o r i n th e s y n -t h e t i c d ie t s u s e d b y h i s p u p i l s ( w h i c h w a s , s o to s p e a k ,

d i ss e c te d m i l k ) w a s t h a t t h e m e t h o d o f i t s p r e p a r a t i o n h a di n v o l v e d th e s e p a r a t i o n o f i n o r g a n i c c o n s t i tu e n t s f r o m c e r-t a i n o r g a n i c c o m b i n a t i o n s i n w h i c h l a t t e r f o r m a l o n e c o u l dt h e y a d e q u a t e l y s u b s e r v e t h e p u r p o s e s o f m e t a b o l i s m . 61I n t h e c a s e o f p h o s p h o r u s , s i g n if i c a n c e w a s p l a c e d b y in v e s-

t ig a t o rs o n th e i n s t a n c e s w h e r e o r g a n i c a l l y b o u n d p h o s p h o r u sw a s p r e s e n t i n a n i m a l s : l e c i th i n , c e p h a l i n , n u c l e o p r o t e in s , a n dp h o s p h o p r o t e i n s s u c h a s c a s e i n a n d v i t e l li n . F e e d i n g e x p e ri -m e n t s o n d o g s, m i c e , p ig e o n s , a n d c h i c k e n s w e r e r e p o r t e d b yf o u r i n v e s t i g a t o r s 62 i n 1 8 9 9 a n d 1 9 00 . A l l o f t h e m s o u g h t t oc o m p a r e t h e v a l u e o f p h o s p h o r u s - f r e e p r o te i n s ( e g g a l b u m i n ,m y o s i n , b lo o d a l b u m i n , e d e s t i n ) w i t h p h o s p h o r u s - c o n t a i n i n gp r o t e i n s ( c a s e i n , v i t e l l i n ) a s s u p p l e m e n t s to h i g h l y p u r if ie dd i et s . I n a l l c a s e s t h e a n i m a l s r a p i d l y lo s t w e i g h t a n d d ie d . Y e tt h e r e w a s a f a i l u r e to r e c o g n i z e t h a t t h e p r o b l e m w a s o n e o fa d e q u a c y o f t h e b a s a l r a t i o n r a t h e r t h a n o n e o f s o u rc e o f p h o s -p h o r u s . T h i s w a s s t i l l t r u e i n 1 9 0 6 w h e n F a l t a a n d N o g g e r a t h

61. Fro m ~-n. 3 a bove, N ee dh am and Baldw in, p. 194; or see NobelFoundat ion , N o b e l L e c t u r e s , C h e m i s t r y , 1 9 2 2 - 1 9 4 1 (Amsterdam, 1964),p. 214.62. F. Steinitz, ~Oeber das Ve rhal ten pho sph orha l t igen Eiweissk~rpe~im Stoffwcchsel, P~/~ger's A r c h l y Physiol. , 72 (1898), 75-104; H. Zadik,S toffwechselversuche m i t pho sphorhal t igen u nd phosph orfre ien Eiweiss -kSrpern , i b i d . , 7 7 (1899), 1-2 1; R. Leipziger, U eb er Stoffwechselversuchemi t Edes t in , i b i d . , 7 8 (1900), 402-422; P. Ehrl ich, S t o f f w e c h s e l v e r s u c h ernit P-h altige n un d P-fr eien EiweisskSrpern, In au g. Dissert ., Breslau , 1900.

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Conflict of Concepts in Early Vitamin Studiesfat, carbohydrates, and protein than to know the amounts ofspecific compounds present. Besides, the analytical chemistryof the day was ha rdly adequate to more specific tasks.The development of analysis for proximate principles aroseout of the Liebig school of chemistry, particularly among thoseformer pupils who became associated with the rapidly develop-ing agricultural experiment stations. Johann Wilhelm Henne-berg, the director of the German station at Weende, nearGSttingen, was particularly active in promoting this type ofanalytical approach and in applying the results to agriculturalproblems. With his associate, Friedrich Stohmarm, he developeda system of analyzing feeds and excrements of farm animalsas a basis for studying digestibility and animal response tofeeds.

Proximate analysis lent itself very well to the study of bio-logical materials since closely related substances responded toanalytical techniques

ihde becker conflict of concepts in early vitamin studies

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