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BARBARA McCLINTOCK fune ~ 6, Z 902-September 2, ~ 992 BY NINA V. FEDOROFF BARBARA MCCLINTOCK'S remarkable life spanned the his- tory of genetics in the twentieth century. Though tech- nically rooted in Menclel's experiments carrier! out decacles earlier, the science of genetics began with the rediscovery of his work at the turn of the century. In 1902, the year of McCTintock's birth, William Bateson wrote prophetically that "an exact determination of the laws of heredity will prob- ably work more change in man's outlook on the worIcI, and in his power over nature, than any other advance in natural knowledge that can be clearly foreseen." And indeed, the science of genetics, to which McClintock made seminal con- tributions both experimental and conceptual, has come to dominate all of the biological sciences, from molecular bi- ology, through cell and clevelopmental biology, to medicine and agriculture. Bateson's immodest guess was arguably an underestimate of the impact of genetic knowledge on hu- mankind. The chromosomal basis of heredity was aIreacly well established by the time McClintock began her graduate training in the Botany Department at Cornell University. McCTintock made her first significant contribution as a gradu- ate student, cleveloping cytological techniques that allowed 211
212 BIOGRAPHICAL MEMOIRS her to identify each of the ten maize chromosomes. These early experiments laid the groundwork for a remarkable series of cytogenetic discoveries by the Cornell maize ge- netics group between ~ 929 ant! ~ 935. By all accounts, McClintock was the intellectual striving force of this tal- entecl group and either contributed substantially to or was exclusively responsible for many of the discoveries. These include identification of maize linkage groups with indi- viclual chromosomes, the well-known cytological proof of genetic crossing-over, evidence of chromatic crossing-over, cytological determination of the physical location of genes within chromosomes, identification of the genetic conse- quences of nonhomologous pairing, establishment of the causal relationship between the instability of ring-shapecl chromosomes and phenotypic variegation, discovery that the centromere is divisible, and identification of a chromo- somal site essential for the formation of the nucleolus. In the years following completion of her ctoctoral work, McClintock continues! her maize cytogenetic studies, even- tually becoming interested! in chromosome breakage, mak- ing important observations on the behavior of chromosomes lacking telomeres. Using knowledge gained from these stud- ies, McCTintock cleveloped a methoc! for using broken chro- mosomes to generate new mutations. Among the progeny of plants that hacI received a broken chromosome from each parent, she observer! unstable mutations at an unex- pecteclly high frequency, as well as a unique mutation that clefinecI a regular site of chromosome breakage. These ob- servations so intrigued her that she began an intensive in- vestigation of the chromosome-breaking locus. Within sev- eral years she hacI learned enough to reach the conclusion, published in 194S, that the chromosome-breaking locus did something hitherto unknown for any genetic locus: it moved from one chromosomal location to another, a phenomenon
BARBARA McCLINTOCK 213 she callecl transposition. The study of transposable genetic elements and transposition became the central theme of her genetic experiments from the micI-1940s until the end of her active research career. As with Menclel's experiments, it took decades for the generality anct significance of McClintock's discovery of trans- position to be appreciated. McClintock's extraordinary sci- entific talent and the importance of her early cytogenetic work were quickly recognized. She became a member of the National Academy of Sciences in 1944 at the young age of forty-two, only the third! woman ever to have been elected. But her subsequent work on transposition led to a periocl of intellectual aclumbration. While no one doubted her repu- tation for impeccable experimentation, the concept that genes count move was so at variance with the regularities of genetic transmission that permit the construction of ge- netic maps that its generality was doubted. But in the late 1960s evidence began to accumulate that bacteriophages and bacteria contain mobile DNA sequences. During the following two clecacles, it became clear that transposable elements are not only ubiquitous but are extraordinarily abundant in the genomes of many organisms. As awareness of the importance of her discovery grew, so clid public rec- ognition. Commencing with the National Mecial of Science in 1970, McCTintock received a number of prestigious awards, culminating in the award of an unshared Nobel Prize in Physiology or Medicine in 1983 for her discovery of trans- position almost forty years earlier. EARLY LIFE AND EDUCATION Barbara McClintock was born in Hartford, Connecticut, to Sara Hancly McClintock and Thomas Henry McCTintock. Her mother was an accomplished pianist as well as a poet and painter, and her father was a physician. Barbara was
214 BIOGRAPHICAL MEMOIRS the thirc! of four children born while Dr. McCTintock was struggling to establish his medical practice. By her own ac- count, McClintock was an ocic! chiTcl and her relationship with her mother was difficult from the beginning. From about the age of three until she began school, Barbara lived in Massachusetts with an aunt and uncle. She accompanied her uncle, who was a fish dealer, first in a horse-cirawn cart en c! later in his first motor truck. She reported enjoying this time and attributed her later interest in cars to watch- ing her uncle struggle with his vehicle's frequent malfunc- t~ons. McCTintock returned home to attend school, and in 1908 the family moved to Brooklyn, New York. McCTintock cle- scribec3 herself as self-containec! from a very early age, re- counting her mother's report that she couIct entertain her- self for unusually Tong periods even in infancy. Later, she preferred sports, as well as solitary occupations such as read- ing or just sitting still and thinking. Both parents were quite unconventional in their attitudes towarc! chiTc! rearing: they were interested in what the children wouIct and could be, rather than what they should be. They believer! that formal schooling was only a part of a child's education, of equal importance with other experiences. When, for example, Barbara showed an interest in ice skating, her parents bought her the best equipment available ant! let her skip school to skate when the weather was right for it. Barbara had a very special relationship with her father, who was extremely perceptive of and responsive to her as a human being. Even as a child, McCTintock had an uncanny sensitivity toward people. She recounted having a teacher who disturber] her intensely because of her perception that the teacher was spiritually repulsive. Rather than make light of her reaction to the teacher, McClintock's father took her
BARBARA McCLINTOCK 215 out of school and providecl her with a private tutor. And despite the strained relationship between them, McCTintock's mother fully supported her claughter's unconventional life style. Barbara clescribed an incident from childhood in which a neighbor chilled her for playing boys' games in the street, telling her it was time for her to learn to do the things that girls do. Upon hearing of the incident, Barbara's mother telephoned the neighbor and firmly toicl her never again to speak to her daughter in that fashion. McClintock attended Erasmus Hall High School in Brook- lyn, and during her high school years it became increas- ingly obvious that she wouIc] not outgrow her childhood! odclities and become a conventional young woman. She clis- coverect science; she lovecl to learn, and most of all, to figure things out. Barbara recalled her mother's creep con- cern that she might become a female college professor, whom her mother viewed as creatures that really didn't be- Tong to society and had a difficult life. During this period, Barbara too became increasingly aware that cloing what she wanted to do would have painful consequences. But she knew, as well, that she had to follow her own inclinations whatever the consequences. At the time McClintock graduated from high school in HIS, the family situation was difficult. Although Barbara had set her heart on attending Cornell University, there was very little money and her mother was firmly opposed to further education for her daughters, believing that it macle them unmarriageable. Barbara took a job at an employ- ment agency and spent evenings continuing her education by reacling in the library. Just clays before the semester started and with the intervention of her father, the decision was reversed. Barbara took a train to Ithaca and began her studies at Cornell, where she wouicl stay to earn her doctor of philosophy degree. . · . .. .
216 BIOGRAPHICAL MEMOIRS PROFESSIONAL HISTORY McClintock flourished at Cornell, both socially en c! intel- lectually. She lovecI learning and she was well likes! so much so that she was elected president of the women's freshmen class. But the decisions she macle cluring her university years were consistent with her adamant indivicluaTity and self-con- tainment. She enjoyoct her social life, but she knew that none of her relationships wouIc3 last. Her comfort with soli- tude ant! the tremendous joy that she experienced in know- ing, learning, and understanding were to be the defining themes of her life. In her junior year, after a particularly exciting course in genetics, her professor invited her to take a graduate course in genetics. After that, she was treated much like a graduate student, en c! by the time she hac! f~nishec! her undergracluate coursework, there was no question in her mincI: she hac! to continue her studies of genetics. But while Cornell had a group of outstanding geneticists, genetics was taught in the plant breeding department, which clicl not take female graduate students. So McClintock regis- terec! in the botany department with a major in cytology ant! a minor in genetics and zoology. She began to work as a pair! assistant to Lowell Randolph, a cytologist who had been appointee! to a position at Cornell supported by the U.S. Department of Agriculture to complement the work of the maize geneticists anti, it was hoped, strengthen the maize plant breeding efforts. McCTintock ant! Randolph ctid not get along well ant! soon dissolved their working relation- ship, but as her colleague en c! lifelong friend Marcus Rhoacles later wrote: "Their brief association was momentous because it lee! to the birth of maize cytogenetics." The initial task of reliably identifying each of the ten maize chromosomes hac! not yet been accomplished. Progress was limited by the in-
BARBARA McCLINTOCK 217 acloquacy of the existing staining techniques, as well as the fact that the chromosomes in the root tip material gener- ally used for such studies could not be reliably clistinguishecI. McClintock solved both problems. As Rhoacles relater! it: It was McClintock who capitalized on the use of Belling's new acetocarmine smear technique. In the course of her triploid studies, she had discovered that the metaphase or late prophase chromosomes in the first microspore mitosis were far better for cytological discrimination than were root tip chromosomes in paraffin sections. In a few weeks' time she had prepared an idiogram of the maize chromosomes, which she published in Science. This was McClintock's first major contribution to maize genetics and laicl the groundwork for a veritable explosion of discoveries that connecter! the behavior of chromosomes with the genetic properties of the organism, cleaning the new f~elct of cytogenetics. McClintock was awardecl the cloc- tor of philosophy degree in 1927 en c! appointee! an instruc- tor. She had no thought of leaving Cornell en c! she knew exactly what needled to be clone next: the maize genetic linkage groups hacl to be assigned to chromosomes. Again in Rhoacles's words: "The years at Cornell from 1928 to 1935 were ones of intense cytogenetical activity. Progress was rapid, the air electric." The group was small, including Professor R. A. Emerson, the founder of maize genetics, McClintock, Beadle, Burnham, Rhoades, en c! Randolph, to- gether with a few graduate students. McClintock had by then cliscoverecl that the pachytene chromosomes in mi- crosporocytes were far superior to those of microspores for cytogenetic work, and the discoveries followed each other in rapid succession. Each linkage group was soon assigned to a chromosome, and the physical correlates of their ge- netic behavior became the primary focus of investigation. A new graduate student, Harriet Creighton, joined the group in 1929. McCTintock took charge of organizing her
218 BIOGRAPHICAL MEMOIRS program of graduate study, persuading her to major in cy- tology and genetics. In the spring of the following year, McClintock suggested that Creighton take on the work of establishing a correlation between genetic recombination and the chromosomal crossovers that could be observed cytologically. McClintock provided stocks that had the ap- propriate genetic and cytological markers and guided the work, which shower] for the first time that the genetic re- combination was a reflection of the physical exchange of chromosome segments. The work, authored by Creighton and McClintock, was published in the Proceedings of the Na- tional Academy of Sciences in 1931 and was perhaps McClintock's first seminal contribution to the science of genetics, many more of which were to follow. Among the most important of her discoveries during the next few years, sometimes made alone, sometimes together with others, were that sister chromatics also exhibit genetic and cytological crossing-over, that genes can be physically localized on the chromosomes, that nonhomologous chromosome pairing has genetic consequences, that the formation of ring-shaped chromosomes accounts for certain types of phenotypic var- iegation, that the centromere is divisible, that broken chro- mosomes can undergo repeated cycles of fusion and break- age, and that a particular chromosomal site, the nucleolus organizer region (NOR), is essential to the development of the nucleolus. Although McClintock's fame was growing, she had no permanent position. Cornell was hospitable to women stu- dents, but it had no women professors in fields other than home economics. Between 1931 and 1933, McClintock was supported by a fellowship from the National Research Council and worked at the California Institute of Technology and the University of Missouri, as well as Cornell. Lewis Stadler invited her to examine the chromosomes of X-irradiated
BARBARA McCLINTOCK 219 plants that showed various abnormalities. She found that the irradiation had caused a variety of structural changes in the chromosomes, including transIocation, inversions, dele- tions, and the formation of ring chromosomes. Coming to Cal Tech at T. H. Morgan's invitation, McClintock began to study the point at which the nucleolus attached to the chro- mosome. This lee! to her identification of the NOR (McCTintock rued the grammatical error she macle initially in naming this site the "nucleolar organizing bo(ly") en c! a description of its properties. She user! stocks in which a transiocation had broken the NOR into two segments, and her main conclusion was that each part of the NOR couIct organize an inclependent nucleolus and thus the NOR was genetically subdivisible. Describing the effect of McClintock's NOR publication, cell biologist Joseph Gall has written: Out of the hundreds of papers we have each read, a half dozen or so stick in our minds because of their beautiful logic, their clarification of an oth- erwise obscure set of data, or simply their technical elegance.... For me, one of Barbara McClintock's early cytogenetic papers falls in this category- her analysis of the nucleolus of maize published in 1934 in the Zeitschr~ft fur Zellforschung and Mikroskopische Anatomie under the title, "The relation of a particular chromosomal element to the development of the nucleoli in Zea ways." In 1933 McCTintock received a Guggenheim Fellowship to go to Germany. McClintock was utterly unprepared for what she encountered in prewar Germany, and she returnee! to Cornell before the year hacl elapsecI. Her prospects were clismal. She hacl completer! graduate school seven years ear- lier and had aIrea(ly attained international recognition, but as a woman she had little hope of securing a permanent academic position at a major research university. Emerson obtained a grant from the Rockefeller Foundation to sup- port her work for two years. Nominally pair! as Emerson's assistant, she continued to work inclepen~lently. McCTintock
220 BIOGRAPHICAL MEMOIRS was cliscouraged and resentful of the disparity between her prospects and those of her mate counterparts. Her extraor- ctinary talents and accomplishments were wiclely appreci- atect, but she was also seen as "difficult" by many of her colleagues, in large part because of her quick minct and intolerance of second-rate work and thinking. And while a number of prominent colleagues sought to help secure her an appropriate academic position, the fact remained that few positions commensurate with her accomplishments were open to women. Finally, in 1936 Lewis Stadler was able to convince the University of Missouri to offer her an assistant professor- ship. She accepted the position en c! began to follow the behavior of maize chromosomes that tract been broken by X-irracliation. She learner! that the ends of newly broken chromosomes tend to fuse with each other, creating dicen- tric chromosomes that break again when a cell divicles and chromosomes are distributed to the daughter cells. She also clescribec! conditions uncler which broken chromosomes "healed" or were repaired in some way so that they could function normally. She reported briefly in a paper pub- lished in Genetics in 1944 that in a certain stock a broken chromosome end that wouic! normally "heal" during clevel- opment of the embryo failed to do so. This implied that the addition of chromosome ends, termec! telomeres, was an active genetic process ant! that the responsible gene in the stock hacI been inactivated by mutation. Elizabeth Blackburn, who discoverer! the enzyme that acicis telomeres to chromosomes, wrote that "this information was in my mincl when T macle the decision to look for an enzymatic activity that adds telomeric DNA to DNA antis." Though McClintock's reputation continued to grow (she was elected! vice-presiclent of the Genetics Society in 1939), her position at Missouri remained tenuous. She unclerstoocI
BARBARA McCLINTOCK 221 soon after her arrival that hers was a special appointment. She found herself excluclecl from regular academic activi- ties, inclu(ling faculty meetings, and eventually came to the realization that she was not only unlikely to be promoted but that her continued employment clependect on StacIler's presence. In 1941 she took a leave of absence from Mis- souri and clepartec] with no intention of returning. She wrote her friend Marcus Rhoades, who had just taken a position at Columbia University, asking where he was going to grow his corn. He was planning to go to CoIc! Spring Harbor for the summer. An invitation for McCTintock was arranged through MilisTav Demerec, who was a member of the Ge- netics Department of the Carnegie Institution of Washing- ton, then the dominant research laboratory at CoIc3 Spring Harbor. Demerec became the clepartment's director late that year and offered McClintock a year's research appoint- ment. Though hesitant to commit herself, McClintock ac- cepted. When Demerec proposed making the appointment permanent, McClintock was quite reluctant but agreed to fly to Washington to speak with Vannevar Bush, then presi- clent of the Carnegie Institution. McCTintock recalled that they took to each other immecliately ant! that both enjoyed the visit immensely. Bush supported Demerec's wish to ap- point McCTintock as a permanent member of the research staff. McClintock accepted, still unsure whether she wouIct stay. McClintock clid stay. She was a staff member of the Carnegie Institution of Washington's Genetics Department until ~ 967, whereupon she became distinguished service member of the Carnegie Institution, remaining at CoIcl Spring Harbor until her death in 1992. Carnegie gave her the freedom to do her work unfettered by teaching and other academic duties. McClintock's clisTike of making commitments was a given: she always wanted to be free free to clo exactly what
222 BIOGRAPHICAL MEMOIRS she wan tec3 to do, when she wanted to do it. Indeed, she insistec! that she would never have become a scientist in toclay's world of grants because she could not have commit- ted herself to a written research plan. It was the unexpected! that fascinated her, and she was always really to pursue an observation that clicin't fit. Settling in at Carnegie, McClintock continued her stucI- ies on the behavior of broken chromosomes, devising a methocl of using them to produce mutations on the short arm of chromosome 9. In 1944 ant! 1945, the years she was elected to the National Academy of Sciences en c! the presi- dency of the Genetics Society, respectively, McCTintock re- portecl in the Yearbook of the Carnegie Institution of Wash- ington on her analysis of progeny grown from self-pollinatecl plants obtained by crossing parents, each of which bore a broken chromosome 9. She cletectec3 many mutations among these progeny, including the expected terminal deficien- cies, some internal deficiencies of various sizes, and some "provocative" mutants that showed variegation from the re- cessive to the dominant phenotype. She further reporter! observing "an interesting type of chromosomal behavior" involving the repeated Toss of one of the broken chromo- somes from cells during development. What struck her as Otis! in the light of her previous studies on broken chromo- somes was that in this particular stock it was always chromo- some 9 that broke ant! it always broke at the same place. McClintock caller! the labile chromosome site Dissociation or Ds because "the most reacliTy recognizable consequence of its actions is this dissociation." She quickly establishecl that the Ds locus would "undergo dissociation mutations only when a particular dominant factor is present." She namer! this factor Activator (Ac) because it activated chro- mosome breakage at Ds. By the time she wrote her report for the Carnegie Yearbook publishec! in 194S, she had reached
BARBARA McCLINTOCK ~3 some extraordinary conclusions about these loci. Ac was not only required for Ds-mediated chromosome breakage but could destabilize previously stable mutations, much as her friend Marcus Rhoacles hacl describecl several years ear- lier for a pair of interacting loci, one of which was an allele of the maize a locus. But more than that, and unprecedented, the chromosome-breaking Ds locus couIcl "change its posi- tion in the chromosome"; it could transpose. Moreover, she hack evidence that the Ac locus was requires! for transposi- tion of Ds en c! that, like the Ds locus, the Ac locus was also mobile. Within several years, McCTintock had establishecl beyond any doubt that both the Ac and Ds loci were not only ca- pable of changing their positions on the genetic map but also of inserting into loci to cause unstable mutations of a type initially stucTiecl by R. A. Emerson at the P locus of maize. By the time she prepared her paper for the Cold Spring Harbor Symposium of 1951, McCTintock hack iso- latect unstable alleles of at least four different genes. Some were caused by the insertion of the Ds element and so re- quirecl the presence of Ac for instability. Others were causecl by insertion of the Ac element itself and were inherently unstable. She hacT cleterminect that the instability of such mutations, which hac! long fascinated geneticists and horti- culturists, was attributable to the frequent departure of the inserted genetic element from the gene cluring develop- ment, restoring normal function and, concomitantly, the wil~type phenotype. She had also iclentified different noninteracting "systems" of mutability, later renamed trans- posable element "families." McClintock recounted that the reaction to her sympo- sium presentation ranged from perplexed to hostile. Later, she published several papers in refereed journals ant! from the paucity of reprint requests, inferred an equally cool
224 BIOGRAPHICAL MEMOIRS reaction on the part of the larger biological community to the astonishing news that genes couIct move. After that, McClintock tenclecI to write up her results as iffor publica- tion ant! file them, publishing little more than concise sum- maries of her results in the annual Yearbook of the Carnegie Institution and occasional overviews for symposia. McCTintock continued her analysis of the Ac-Ds transposable element family and began the study of a new element that she caller! Suppressor-mutator or Sum. This element, which also came in versions that could transpose autonomously ancI versions that could not, had many of the characteristics of the Ac-Ds family but exhibited an even more complex behavior. Some insertion mutations, for example, clic! not completely sup- press expression of the affected gene, except when the fully functional Spm element was present in the same genome, implying that the element conic! produce a substance that affecter! expression of the mutant gene. These descriptions of McClintock's of what proved to be the first example of an interaction between a trans-acting regulatory factor and its DNA binding site, were publishec! well before Jacob anct Monocl's seminal work on the regula- tion of the lac operon in E. colt. McClintock immecliately saw and attempted to draw attention to the parallels be- tween these regulatory phenomena by aclopting Jacob and Monocl's terminology to the regulation of maize gene ex- pression mecliatec! by transposable elements. More fascinat- ing yet, McCTintock found that the Spm element couIcI be- come heritably inactivated by a genetic mechanism that differs strikingly from conventional mutation by its reversibility. Indeect, although the element could be transmitted in an extremely inactive form through many plant generations, it remained capable of both transient and heritable reactiva- tion. In particular, McClintock came to the conclusion that an active element couIc! activate an inactive one so long as
BARBARA McCLINTOCK 225 both were present in the same genome. This suggested that an active element provides a substance that activates the element, either clirectly or by interfering with the genetic mechanism that is responsible for inactivation. By this time, McClintock's work hack taken her far out- side the scientific mainstream and in a profound sense she hacl lost her ability to communicate with her colleagues. There have been many attempts at explanations, all of which uncloubtecIly contain a measure of truth. By her own acimis- sion, McClintock hacl neither a gift for written exposition nor a talent for explaining complex phenomena in simple terms. But perhaps there are more important factors, since patient readers have founcl both her early en c! her later papers not only comprehensible but indeed intellectually elegant. First, the very notion that genes can move was in creep contradiction to the regular relationships among genes that unclerlie the construction of linkage maps en c! the physi- cal mapping of genes onto chromosomes. The evidence that genes maintain their positions relative to each other was overwhelming: the concept that genetic elements can move would undoubtecIly have met with resistance regardless of author and presentation. Tn(leecI, even twenty years after McCTintock's initial report, emerging evidence that mobile elements exist in bacteria was met with skepticism. An cl more than that, by the time McCTintock took up the study of transposition, she was not just a brilliant beginner but an accomplishe(l, experiencecl, mature cytogeneticist. Her experiments were very complex en cl cliff~cult to com- municate even to the quickest of mincis. Mel Green recounts that shortly after the 1951 CoIcl Spring Harbor Symposium, he and several other geneticists queried Sturtevant, argu- ably one of the century's leacling geneticists, about what McClintock tract said. Green quotes Sturtevant as saying: "I dicin't unclerstanc! one wore! she said, but if she says it is so,
226 BIOGRAPHICAL MEMOIRS it must be so! " Such was the intellectual respect that McClintock commandedanti such was the strangeness of concept and complexity of her experimentation. McCTintock was deeply frustrated by her failure to com- municate, but her fascination with the unfoicting story of transposition was sufficient to keep her working at the highest level of physical ant! mental intensity she couIc! sustain. Her work on transposition was interrupted only twice. The first interruption was a visit to Stanford in 1944 in response to an invitation from George BeacIle, who thought she was precisely the person to work out the problem of identifying the chromosomes of the moist Neurospora, which hacl be- come.a popular organism for molecular geneticists. The second occurred in the late 1950s when the National Acac3- emy of Sciences established a committee to identify and collect indigenous races of maize in Central and South America out of concern that the introduction of high-yielc3- ing agricultural hybrids wouicl result in their disappearance. McClintock was asked to help train local cytologists to carry out the work of classifying the maize races by chromosome morphology. McClintock spent the winters of 1958 and 1960 in Central and South America, fascinated by the emerging realization that the spread of maize through the region couIcI be tracker! by the chromosome constitution of the indigenous populations. The work was summarized briefly in the Yearbooks of the Carnegie Institution, appearing as a full monograph in 1978. But transposition remained McCTintock's central passion. By the time of her formal retirement, she tract accumulated a rich store of knowlecige about the genetic behavior of two markedly different transposable element families. She was sufficiently confident of the importance of her work to care- fully preserve all of the stocks with mutant elements that she accumulatecl along the way, perhaps in unconscious prepa-
BARBARA McCLINTOCK 227 ration for the new generation of molecular geneticists. And incleecI, beginning at about the time her active fieldwork enclect, transposable genetic elements began to surface in one experimental organism after another. These cliscover- ies began in an altogether different age. In the two clecacles between McCTintock's original genetic discovery of transpo- sition and its rediscovery, genetics hacl undergone as pro- found a change as the cytogenetic revolution that hacI oc- currec3 in the second and thirc! decacles of the century. The genetic material had been identifies] as DNA, the manner in which information was encocled in the genes hacI been deciphered, and methods hac3 been clevisect to isolate ant! study indiviclual genes. Genes were no longer abstract enti- ties known only by the consequences of their alteration or loss: they were real bits of nucleic acid] that could be iso- lated, visualized, subtly altered, en c! reintrocluced into liv- · . ng organisms. Thus, soon after the initial realization that mutations of a certain type that occurred in bacterial viruses might be attributable to the insertion of a foreign DNA sequence, visual evidence was obtained by electron microscopic analy- sis of heteroduplexes between homologous DNA sequences having and lacking the insertion. The newly inserted mo- bile elements appeared as unpaired loops of DNA extencl- ing from the DNA cluplex. Mobile genetic elements were no longer abstract concepts. Although the study of maize transposable elements had been an active and productive fielcl of research since Emerson's original studies on varie- gation at the P locus long before McClintock explicates! the underlying genetic mechanisms, the recognition that mo- bile elements are ubiquitous and in fact extraorclinarily abun- dant components of the genomes of many, if not all, organ- isms grew slowly cluring the 1970s and 1980s. My first encounter with McClintock, which was to lead
228 BIOGRAPHICAL MEMOIRS eventually to the molecular cloning and characterization of the maize elements, took place during a visit to the CoIcI Spring Harbor Laboratory in 1978. The laboratory itself was no longer the same institution that McClintock had joined almost four decades earlier. The Genetics Depart- ment had been closed by the Carnegie Institution of Wash- ington, although a Genetics Unit consisting of McCTintock and A. Hershey, both retired, hac] been maintained. i. D. Watson was by then the director of a vastly larger complex of laboratories at Coicl Spring Harbor, all engages] in mo- lecular biological investigations. T had been asked to give a seminar at the CoIct Spring Harbor Laboratory on my postdoctoral work in Don Brown's laboratory at the Carnegie Institution of Washington's Department of Embryology in Baltimore. Although McClintock was unable to attend the lecture, T encounterer! her by chance in a hallway of the Demerec Laboratory, en c! she invites! me to her spacious laboratory for a chat. We talked for several hours, ant! ~ was drawn to the clarity en c! depth of her discourse, no matter the subject. It was so at variance with her reputation for obscurity that ~ was prompted to react her papers from be- ginning to end upon my return to Baltimore. T was intrigued with what ]: fount! to be a marvelous genetic detective story, and when ~ received an unexpected offer of a permanent staff position at Carnegie's Embryology Department, T im- mecliately decided to tackle the molecular analysis of the maize elements. The task ~ had taken on proved daunting, as much be- cause of the distance between McClintock's classical genetic approach en cl that of the molecular biologist as because plant molecular biology simply clidn't exist yet. Our rela- tionship began in earnest when ~ grew my first corn crop consisting of McCTintock's transposable element stocks dur- ing the summer of 1979 at the Brookhaven National Labo-
BARBARA McCLINTOCK 229 ratory, where we were kindly offered space and help by Ben and Frances Burr. Although McClintock was highly critical of mY first efforts at maize genetics, enough of the right crosses got done despite my ignorance, so that ~ had the material ~ needed to begin the molecular cloning of first the Ac and Ds elements and, later, the sum element. Our first interactions were difficult, and it took several years before we were comfortable with each other's way of think- ing. But in time we both came to value deeply the intellec- tual as well as the personal side of our relationship. By the time the maize elements were cloned and their molecular analysis began, the importance of McClintock's discovery of transposition was widely recognized. She re- ceived the Kimber Genetics Award in 1967, the National Medal of Science in 1970, and the Lewis S. Rosensteil Award and the Louis and Bert Freedman Foundation Award in 1978. In 1981 she was named prize fellow laureate of the MacArthur Foundation and received the Wolf Prize and the Lasker Basic Medical Research Award. In 1982 she shared the Horwitz Prize. Finally, in 1983, thirty-five years after publication of the first evidence for transposition, McClintock was awarded the Nobel Prize for Physiology or Medicine. Yet while the money attached to these prizes increased her financial security, something to which she'd given little thought in earlier years, she found the ceremonies arduous and the attendant publicity and adulation utterly repug- nant. She longed for her privacy, and she was exhausted and disturbed by the endless stream of requests that only seemed to grow in volume with each award. Suddenly ev- eryone wanted her: there were honorary degrees, keynote speeches, lectures, interviews even autograph hunters. And still, through it all, McClintock never lost her con- nection with science- she never retired. She continued to live at Cold Spring Harbor, spending her last years in a
230 BIOGRAPHICAL MEMOIRS spartan apartment on the ground floor of Hooper House, a women's (lormitory heavily used during the summer meet- ings season at the laboratory. She attencled every session of the annual Cold Spring Harbor Symposium, as well as semi- nars, the year around. She react voraciously, lamenting her failing vision. Her laboratory was fillet! with books on all subjects, and the tables were coverer} with stacks of articles copied from current journals, many with sentences care- fully underlinecl here and there, giving evidence of careful attention. She was keenly aware of every clevelopment in the molecular and genetic analysis of the maize transpos- able elements as it unfoIclec3 in my laboratory and else- where. She took special interest in the analysis of the com- plex ant! elegant Spm family of elements, my own particular favorite. Not until the last few years of her life diet the molecular en c! genetic studies on this family of elements become so complex that she began to Once it cliff~cult to follow and remember the details. Even when ~ visited CoIcI Spring Harbor in 1991 to give a course lecture on the mo- lecular genetics of the maize transposable elements, McClintock sat through the entire session, which lasted late into the evening. Her questions were penetrating en c! her observations invariably wicienecI the discussion: the students were amazed. It was during this visit that I was approached by Jim Inglis of the CoIcl Spring Harbor Press to assemble a volume in honor of McClintock's ninetieth birthday the following year. T took on the project, despite qualms that Barbara wouIc3 find this not a gift but another burden. David Botstein, who joined me in this effort, anct ~ approached a number of individuals whose lives hac! intersected with McClintock's to write for this volume. What emerges! was The Dynamic Genome, a collection of varied essays each reflecting the pur- suits and passions ignited by the sparks ant! embers scat-
BARBARA McCLINTOCK 23 terecl from the fierce blaze of McClintock's intellect through the clecacles of this century of genetics. Many of the au- thors joiner! in the celebration of her ninetieth birthday at the home of Jim Watson, not far from her moclest apart- ment on the laboratory grour~cis. She knew nothing of the book but recognized her friends even Harriet Creighton, her first "unofficial" graduate student, had macle the trek to Coicl Spring Harbor. We settlecl Barbara on Jim's front porch and T began to react aloud the introduction and the list of authors and their essays. At first she joker! a bit, ctiscomf~tec! by the attention. But soon her face began to glow as she perceives! the depth of unclerstanding and re- spect gathered arounc! her, lovingly collectecl between the covers of the book. She said later it was the best party ever for her, though she acimitted that it had taken a week to recover at her age. She was sure that she would die at ninety and a few months later she was gone, drifting away from life gently, as a leaf separates from an autumn tree. What Barbara McClintock was and what she left behind are elo- quently expressed in a few short lines written many years earlier by her friend and champion Marcus Rhoades, whose cleath precedes! hers by a few short months: One of the remarkable things about Barbara McClintock's surpassingly beautiful investigations is that they came solely from her own labors. Without techni- cal help of any kind she has by virtue of her boundless energy, her com- plete devotion to science, her originality and ingenuity, and her.quick and high intelligence made a series of significant discoveries unparalleled in the history of cytogenetics. A skilled experimentalist, a master at interpret- ing cytological detail, a brilliant theoretician, she has had an illuminating and pervasive role in the development of cytology and genetics.
232 BIOGRAPHICAL MEMOIRS THE QUOTATIONS ATTRIBUTED to McClintock are from her publica- tions on transposition, primarily the annual reports appearing in the Yearbooks of the Carnegie Institution of Washington; all of these are reproduced in The Discovery and Characterization of Transposable Elements: The Collected Papers of Barbara McClintock (New York: Gar- land Publishing, 1987~. All other quotations, with the exception of the first and last (Bateson and Rhoades), appear in the chapters by the individuals to whom they are attributed in The Dynamic Genome: Barbara McClintock's Ideas in the Century of Genetics (ea. N. Fedoroff and D. Botstein; Cold Spring Harbor: Cold Spring Harbor Press, 1992~. The Bateson quotation appears in E. A. Carlson's, The Gene: A Critical History (Philadelphia: W. B. Saunders). The final quota- tion of M. M. Rhoades was taken from an undated document in the files of the Carnegie Institution of Washington titled "Barbara McClintock: Statement of Achievements," possibly prepared in sup- port of her nomination for an award. Other than my own recollec- tions of conversations with McClintock, my principal source of in- formation about her early life and the chronology of later events was E. F. Keller's, A Feeling for the Organism: The Life and Work of Barbara McClintock (San Francisco: Freeman, 1983), as well as a copy of McClintock's curriculum vitae, given by her to me in about 1980 together with one of her two complete collections of her reprints.
BARBARA McCLINTOCK SELECTED BIBLIOGRAPHY 1929 Chromosome morphology in Zea mays. Science 69:629. 1930 233 A cytological demonstration of the location of an interchange be- tween two nonhomologous chromosomes of Zea mays. Proc. Natl. Acad. Sci. U.S.A. 16:791-96. 1931 With H. E. Hill. The cytological identification of the chromosome associated with the R-G linkage group in Zea mays. Genetics 16:175- 90. The order of the genes C, Sh, and Wx in Zea mays with reference to a cytologically known point in the chromosome. Proc. Natl. Acad. Sci. U.S.A. 17:485-91. With H. B. Creighton. A correlation of cytological and genetical crossing-over in Zea mays. Proc. Natl. Acad. Sci. U.S.A. 17:492-97. 1932 A correlation of ring-shaped chromosomes with variegation in Zea mays. Proc. Natl. Acad. Sci. U.S.A. 18:677-81. 1933 The association of non-homologous parts of chromosomes in the mid-prophase of meiosis in Zea mays. Z. Zellforsch. Mibrosk. Anal. 19:191-237. 1934 The relation of a particular chromosomal element to the develop- ment of the nucleoli in Zea mays. Z. Zellforsch. Mibrosk. Anat. 21:294- 328. 1939 The behavior in successive nuclear divisions of a chromosome bro- ken at meiosis. Proc. Natl. Acad. Sci. U.S.A. 25:405-16.
234 BIOGRAPHICAL MEMOIRS 1941 The stability of broken ends of chromosomes in Zea mays. Genetics 26:234-82. 1942 The relation of homozygous deficiencies to mutations and allelic series in maize. Genetics 29: 478-502. The fusion of broken ends of chromosomes following nuclear fu- sion. Proc. Natl. Acad. Sci. U.S.A. 11:458-63. 1945 Neurospora: I. Preliminary observations of the chromosomes of Neu- rospora crassa. Am. f. Bot. 32:671-78. 1948 Mutable loci in maize. Carnegie Inst. Washington Yearb. 47: 155-69. 1950 The origin and behavior of mutable loci in maize. Proc. Natl. Acad. Sci. U.S.A. 36:344-55. 1951 Chromosome organization and genie expression. Cold Spring Harbor Symp. Quant. Biol. 16:13-47. 1953 Induction of instability at selected loci in maize. Genetics 38:579-99. 1956 Intranuclear systems controlling gene action and mutation. Brookhaven Symp. Biol. 8:58-74. Controlling elements and the gene. Cold Spring Harbor Symp. Quant. Biol. 21:197-216. 1961 Some parallels between gene control systems in maize and in bacte- ria. Am. Nat. 95:265-77.
BARBARA McCLINTOCK 1965 235 The control of gene action in maize. BrooLhaven Symp. Biol. 18:162- 84. 1968 Genetic systems regulating gene expression during development. Dev. Biol. Suppl. 1:84-112. 1971 The contribution of one component of a control system to versatil- ity of gene expression. Carnegie Inst. Washington Yearb. 70:5-17. 1978 Development of the maize endosperm as revealed by clones. In The Clonal Basis of Heredity, ed. S. Subtelny and I. M. Sussex, pp. 217- 37. New York: Academic Press. Mechanisms that rapidly reorganize the genome. Stadler Symp. 10:25- 47. Significance of chromosome constitutions in tracing the origin and migration of races of maize in the Americas. In International Maize Symposium, ed. W. D. Walden, pp. 159-84. New York: Wiley. 1984 The significance of responses of the genome to challenge. Nobel lecture. Science 226:792-801.