-MILESTONES IN BIOLOGICAL RESEARCHe:,-IS!~ From Protein Coa~ation and Reversible DenaturationIn to the Protein Folding Problem: Chris Anfimsen1- Defining the Transitions,s, Evangelos N. Moudrianakis,dIss, The name Christian B. Anfinsen is Norwegian family from Bergen that on the physical biochemistry of1f intricately interwoven with the con- settled in Pennsylvania. He received RNAase with Kai Linderstrom-Lang,r, cept of protein folding, the theme of his undergraduate degree from and again in 1962-1963 as Professorthis issue, I feel both honored and Swarthmore and his M.S. in organic of Biological Chemistry at Harvard.t humbled to have been asked to write chemistry from the University ofan appreciation of Chris's contribu- Pennsylvania. In 1939, he went on~ lions to this field of scientific en- an Ameripan-Scandinavian Founda-:1 deavor, In addition to providing the tion Fellowship to the Carlsberg i" usual vital statistics, I have decided Laboratories in Copenhagen to study ..!i, 10 paint a personal portrait of the enzyme chemistry, but World War II;, originator of the "thermodynamic hy- interrupted this visit. After returningpothesis" of protein folding. In this to .the States, he began graduate stud-way, I hope that it will become eas- ies and received his Ph,D. in biologi-ier to appreciate the elegance with cal chemistry from Harvard Medicalwhich Chris combined his sensitiv- School in 1943, In 1946 he joinedily, intuition, and sense of order and the faculty of the Department of Bio-i beauty with a persistent drive, an logical Chemistry at Harvard, whereadaptable imagination, and a quest he stayed until 1950. During that pe-for rigorous answers to fundamental riod he spent a year (1947-1948) inproblems, It was this rare combina- the laboratory of Hugo Theorell at ~ i;tion of sensitivity and rigor, self-as- the Medical Nobel Institute in Stock- ""I]'c'surance and humility, fearlessness holm developing his interests in en- ; i~;and vulnerability, that instilled feel- zyme purification and protein i ;, , "~ngs of respect, admiration, and love chemistry. I W ~In Ihose who were !ortu?ate to have In 19~0 Chris left Harvard to be- i..~" ".met and worked wIth hIm. come chIef of the Laboratory of Cel- !l~ ,Several articles have been written lular Physiology in the National ij i 1about Chris, some of which are more Heart Institute at NIH, In the years Dr. Anfinsen in his lahoratory at NIH, ,licomplete than what I can ~ope to t?at follo.we~, Chris's laborator"( ~ub- circa 1978. ;~present here. Some were wrItten by Ilshed findIngs along two dIStInct ~persons who were closer to Chris at lines of research: one more appliedI 1963 h t d t NIH (Th ~:'theP k f h 'I b h ' d d 1, 'h h b 1. f n e re urne 0 e , , ,ea 0 IS a oratory ac leve- an ea mg WIt t e meta 0 Ism 0L b t f Ch ' I B. 1 f ! ,'~m t I ' , ., a ora ory 0 emIca 10 ogy 0 ,;hen s, will not attempt to duplicate plasma lipoproteIns, and the otherth N t' 1 I t't t f Arth 't' d Iitb ,. , .e alona nSIueo nIsan '"em, ut I would like to dIrect the more basIc and addressIng funda-M t b I ., D. h h Ii,read ' ..e a 0 IC Iseases), were e re- \'Sc er to a recent artIcle by Alan mental Issues of proteID structure, .d t'l h. t' t .1981 ,;hecht(1) h I b I ' d I . h . h 1 . I b h mame un 1 IS re Iremen m. iib er t at e leve elvers w IC u tImate y ecame t e areaH th t t th :',oth aI d ' ,Ch ., ' d . b e en spen a year a e 'I'comp ete an a sensItive ac- rIS s most recognIze contn u- W ' I t't t d .1982 h .!'COunt ofCh ... d .d fi h ' h h d d eIzmann ns 1 u e, an m e 'jh ' ns as a scIentIst an as a tlons, an or w IC e was awar e ..d th £ It f th B' 1 D -:uml amtarian. Here I will summarize the Nobel Prize in Chemistry in 1972 jomte tefacjuhY oH ek ' 10 ougy. e .If;on Y th .,par men 0 0 ns op ms mver- ;~se pOints that can help one (shared wIth Stanford Moore and t~PhP:eclate the scientific world of William H, Stein of Rockefeller Uni- I'ns ').versIt .,. 'Chris (as h ..-~ , ' Address correspon.dence to Dr. Moud~lanak~sI .e was known to hIs col ChrIs s stay at NIH was Interrupted at: Department of BIology, John Hopkms Um-teagues, hIs students, and the labora- twice, once in 1954 for a second visit versity, 144 Mudd Hall, 3400 N, Charles St.,ory CUstodians) was the son of a to the Carlsberg Laboratories to work Baltimore, MD 21218-2685, USA., "':~I, 1 0 January 1996"MilESTONES IN BIOLOGICAL RESEARCHsity as Professor of Biophysical century to the early 1960s. Others tures, was, by 1939, converted tOthC.hemistry, a position he held until h.ave w~itten ?n this issue exte?- view th~t "proteins are. ...[entitiesjhIs death on May 14, 1995. slvely, III partIcular John Edsall III possessing the hallmark of Individu.Chris approached the study of the Annals of the New York Academy ality, and are in reality giant mole. Iproteins with a perspective best cap- of Sciences (3). cules ...built up according to 'tured in the following lines from his At the turn of the century, protein plan which makes every atom indi: I1959 book (2): "To construct a final solutions were considered ill-defined, pens able for the completion of thepicture of the covalent structure ofthe protein requires, in addition to--the complete sequence of each pep-tide fragment, a study of the disulfide "...there was now hope that some day one could makebridges. ...[However,] knowledge of synthetic enzymes in the laboratory; what a crazy bUtthe complete covalent structure. ..exciting idea!"-C. Anfinsenis, unfortunately, not a magic key to -the understanding of physicochemi-cal and catalytic behavior in itself. Areal appreciation of Nature's intentwith respect to protein molecules polydisperse systems. Fractionation structure" (4). Remember that be.must be sought through additional and purification methods were rudi- tween 1939 and 1948 Chris,