Copyright 0 1995 by the Genetics Society of America Perspectives Anecdotal, Historical And Critical Commentaries on Genetics Edited by Jams F. Crow and William F. Dove Two Genes, No Enzyme: A Second Look at BARBARAMCCLINTOCK and the 1951 Cold Spring Harbor Symposium Nathaniel C. Comfort Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 1I724 and Department of History, State University of New York, Stony Brook, New York 11 794 didn’t understand a word of it, but if BARBARAsaid this essay is attributed by GREEN(1992) to ALFRED STUR- “Iit, it must be true!” With these words, the great TEVANT, who, GREENsays, had attended theSymposium. Drosophila geneticist ALFRED STURTEVANTreportedly Yet the only STURTEVANT listeda participant as in 1951 gave his opinion of BARBARAMCCLINTOCK’S firstpublic is one FRANKSTURTEVANT, of Northwestern University! presentation of transposable elements, at the 1951 Cold The error is quite excusable; while his is the only pub Spring HarborSymposium (GREEN1992). A legend has lished version, this story has been repeated many times sprungup around MCCLINTOCK’Spresentation, ac- by many people, and doubtless in many versions. It is cording to which she gave her talk with great expecta- part of the legend, amythology that continues to grow, tion of acceptance and interest, only to be ridiculed even among demythologizers. and ignored by her colleagues. The subtext is that A re-examination of the 1951 Symposium can help MCCLINTOCKwas discriminated against, whether be- replace the myth with a more rational explanation of cause of her views or her sex. In her biography of the reaction to MCCLINTOCK’Spaper. It also shows how MCCLINTOCK,EVELYN FOX-KELLER writesthat MCCLIN- data and scientific theory are intertwined with the cul- TOCK’S talk “was met with stony silence. With one or ture of science. MCCLINTOCKwas not apassive recipient two exceptions, no one understood. Afterward, there of her colleagues’judgments. She defiantly and deliber- was mumbling-even some snickering-and outright ately challenged the paradigm viewof the gene-a complaints. It was impossible to understand. What was gutsy move, but one that brought upon herself some this woman up to?” (KELLER 1983, p. 139). of the confusion that so distressed her. MEL GREEN,writing in the 1992 Festschrift for It is certainly true thatMCCLINTOCK’S workwas highly MCCLINTOCK,The Dynamic Genome, seeks to redress the respected by the time she presented her data on trans- legend: “There is a widely extant viewpoint that BARBA- posable elements. Since the 1920s she had published RA’S research was much unappreciatedand appropriate paper after importantpaper on maizecytogenetics. recognition was too longdelayed. I believe this view- With HARRIET CREIGHTONat Cornell, MCCLINTOCKpro- point to be a half-truth” (GREEN1992, p. 117). Some duced the firstvisual evidence of crossing-over, just of the legend springs from MCCLINTOCK’S own lips.In barely beating out CURTSTERN’S similar work on Dro- an interview with KELLER, MCCLINTOCKsaid, “It was sophila. Subsequent work took her ever deeper into just a surprise that I couldn’t communicate; it was a genomic instability and chromosome structure. First surprise that I was being ridiculed, or being told that I she showed the existence of ring chromosomes. Then was really mad” (KELLER 1983, p. 140). Unexplained, she showed that ring chromosomes were a special case MCCLINTOCK’Scool reception supports the idea that of broken chromosomes, one in whichthe endsbecame her colleagues were obtuse in failing to see the truth “sticky” and fused to each other. In 1936 MCCLINTOCK and beauty of her discovery, or worse, that they refused moved to the Universityof Missouri, where she was to accept her results because MCCLINTOCKwas outside hired byLEWIS STADLER,who with R. A. EMERSON, the geneticists’ old boys’ network. MCCLINTOCK’Smentor atCornell, was one of the reign- Some of the legend seems to stem from scientists ing lions of maize genetics. At Missouri, MCCLINTOCK wishing to squelch it. The quote at the beginning of discovered the “breakage-fusion-bridge” cycle, a fur- ther extension of her observations of chromosomal in- Address fw correspondace: Cold Spring Harbor Laboratory, 1 Bung- stability. The breakage-fusion-bridge cycle led MCCLIN- town Road, Cold Spring Harbor, NY 11724. TOCK to two important conclusions, one a prediction Genetics 140 1161-1166 (August, 1995) more [before transposons], MCCI.INTO(:Kwould have become a major figure in the history of genetics” (FED- and the other hermost profound discovery. The obser- OROFF and BOTSTEIN1992). vation of the “stickiness” of the broken ends of chro- The 1951 Symposium took place in the years between mosomes led MCCLINTOCKto the prediction of special OSWALDAVERY’S demonstration that the transforming structures onthe ends of chromosomesneeded to principle in Pneumococcus was DNA, and the double maintainthe stability lost when thechromosomes revelations of ALFRED HERSHEYand MARTHA CHASE’S broke. She called them telomeres, the study of which “blender experiment” andWATSON AND CRICK’Smodel today is undergoing rapid growth. When MCCLINTOCK of the DNA double helix. The nature of the gene was left Missouri for Cold Spring Harbor in 1941, she took the central question in many biologists’ minds. Bacterio- with her strains of maize that underwent the breakage- phage and bacteria were the model systems of choice, fusion-bridge cycle. From them MCCLINTOCKdeduced with Neurospora and Drosophila close behind. Scien- the existence of transposable elements. The first set of tists working with these organisms were heavily invested experiment$ in which she observed transposition were in the classical T. H. MORGANmodel of the gene. MOR- done in 1944 (MCCI~INTOCK1984). She spent the next GAN’S group had shown the enormous intellectual pro- six years pursuing, confirmingand verifying her results. ductivity of viewing genes as unitary, particulate struc- By 1951 MCCLINTOCKwas among the best-respected tures, arranged linearly and statically alongthe cytogeneticists in the country. Even ten years earlier, chromosomes. BEXDLEAND TATUM’Sone-gene oneen- when the director of the Carnegie Department, MILI- zyme hypothesis, first developed in the early 1940s, lay SLAV DEMEREC,told staff scientist E. CARLETON MAG atop this foundation. It confirmed that geneswere uni- DOU‘EILthat he had succeeded in hiring MCCI.INTOCK, tary by showing they had unitary effects on metabolic MACDOWELI.“jumped up in theair and said, ‘We pathways. MILISLAVDEMEREC, director of the Cold should mark today’s date with red letters in the Depart- Spring Harbor Biological Laboratory and organizer of ment calendar!’ That expresses the feeling that is gen- the 1951 Symposium, acknowledged that the gene con- eral among our members” (DEMEREC1942). In 1939 cept had been unraveling in recent years. Genes, DIG- she was elected vice-president, and in 1945 president, MEREC said, “are regarded as much more loosely de- of the Genetics Society of America. By 1951 she had fined parts of an aggregate, the chromosome, which in received the Achievement Award of the Association of itself is a unit andreacts readily to certain changesin the University Women,been awarded two honoraryde- environment”(DEMEREC 1951). Whatever the gene’s grees, and been a member of theNational Academy of precise molecularnature, the working model of the Sciences for seven years. “The influence of her early gene was of a unitary entity that acted independently to work is greater than that of any of her peers, with the produce a physiologically active molecule. While many possible exception ofAL.FRED STURTEVANT,” wrote NINA at the time recognized that it was an oversimplification, FEDOROFFand DAVIDBOTSTEIN. “Had she done no the view of the genomeas a static, linear series of partic- Perspectives 1163 ulate, independently acting genes proved so successful of the original gene” (GOLDSCHMIDT 1951, p. 1). in explaining genetic observations and generating new Though he cited examples drawn from work on muta- experiments that few had cause to doubt it. ble genes in Drosophila and other organisms, promi- One who did doubt it was R~CHARDGOLDSCHMIDT. nent among GOLDSCHMIDT’Sremarks are several glow- For decades, GOLDSCHMIDT had been a gadfly to the ing mentions of MCCLINTOCK’Sdescription of the Ac/ genetics community. Brilliant and cantankerous, GOLD- Ds system in maize. For GOLDSCHMIDT, transposable ele- SCHMIDT delighted in challenging assumptions and ments provided a shining example of position effects pointing out logical inconsistencies in the evolving ge- and a dynamic genome. He referred to transposable netic theory. Since 1938, GOLDSCHMIDThad been ar- elements as “invisible” (i.e., submicroscopic) rear- guing against the theory of the gene. His observations rangements and position effects. To his fullsatisfaction, of Bar eye in Drosophila led him to conclude that the MCCLINTOCKhad proved that in Zea, “mutable loci are chromosome, not the gene,was the unitary element of actually position effects produced by genetically con- heredity (GOLDSCHMIDT1938; DUNN1965). GOLD- trolled and repeating transpositions and transloca- SCHMIDT argued from translocation data that the posi- tions” (GOLDSCHMIDT1951, p. 4). GOLDSCHMIDT waxed tion of a locus on the chromosome determined its func- poetic in his analogy for how genetic function derived tion. When a locus moved to a differentsite, its function from position: “If the A-string on a violin is stopped an changed. GOLDSCHMIDTargued in 1938 that “the whole inch from the end the tone C is produced. Something conception of the gene”was “obsolete.” GOLDSCHMIDT has been done to a locus in the string, it has been and BEADLEtook up opposing sides in a debate that changed in regard to its function. But nobody would lasted over a decade. GOLDSCHMIDT’Swas a dynamic conclude that there is a Gbody at that point” (GOLD- genome, not a static one. By playing the devil’s advo- SCHMIDT 1951, p. 7).MCCLINTOCK’S data must have cate, GOLDSCHMIDTforced geneticists to reconsider seemed a godsend to GOLDSCHMIDT,an example tailor- their assumptions. Though his style was combative and made to support his attack on the gene concept.