life devoted to science (in commemoration of the 100th anniversary of the birth of barbara...

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1022-7954/02/3808- $27.00 © 2002 MAIK “Nauka /Interperiodica” 0984 Russian Journal of Genetics, Vol. 38, No. 8, 2002, pp. 984–987. Translated from Genetika, Vol. 38, No. 8, 2002, pp. 1163–1166. Original Russian Text Copyright © 2002 by Bogdanov. In 2002, there was the 100th anniversary of the birth of Barbara McClintock (1902–1992), a world- renowned geneticists and cytogeneticist, the discoverer of transposable elements, author of many other classi- cal cytogenetic works, and Nobel Prize winner. McClintock’s discovery of transposable elements of the genome in 1951 opened a new epoch in genetics. Some publications on this theme state that McClintock demolished the dogma of the constancy of the genome created by T.H. Morgan and his followers. More cor- rectly, McClintock complemented the postulate on the constant linear arrangement of genes on chromosomes, which was put forward by Morgan’s school, by the discov- ery of the previously unknown class of genetic elements capable of moving within the genome, incorporating into the vicinity of fixedly located genes or into the genes themselves, and causing their mutations. The main postu- lates of Morgan’s theory held but the views on the organi- zation and function of the genome have changed. The functions and modes of inheritance of transposable ele- ments proved to be fundamentally different from those of classical genes studied by Mendel and Morgan. McClintock discovered transposable elements (transposons) in maize. A decade after this discovery, transposons were found in bacteria, and, after another 17 years, in Drosophila. This succession of discoveries provided the basis for the concept of genome instabil- ity. An idea appeared on the “horizontal” transmission of genes under natural conditions. This has caused a impact on the theory of evolution. Why did McClintock and not another researcher discover transposable elements of the genome? Why were these elements first discovered in maize, and only afterwards were similar phenomena found in bacteria and Drosophila, more “convenient” genetic objects? To answer these questions, we should year by year follow the development of McClintock’s studies and take into account their historical background. Barbara McClintock was born on June 16, 1902, in Hartford, Kentucky, United States, in a doctor’s family. She graduated from the College of Agriculture of Cor- nell University in Ithaca, New York, in 1923 and received her Ph.D. degree in botany there in 1927. Hav- ing been appointed to a professorship at the same col- lege, she began intense research work. McClintock worked at Cornell University, with intermissions, until 1936. In the same period, she won scholarships to post- graduate training at the laboratories headed by L. Sta- dler and T.H. Morgan (in the United States) and R. Goldschmidt (in Germany). McClintock left Ger- many in 1934, before the scheduled end of her training, because conditions for her research became unfavor- able when the Nazis came to power. She returned to the United States and, while waiting for a vacancy, worked without salary for nine months. From October 1934 to 1936, McClintock worked at Cornell University again. In 1936–1941, she was an assistant of L. Stadler at the University of Missouri. In 1941–1967, McClintock was a personal researcher at Carnegie Institution with a fixed workplace at the Cold Springs Harbor Biological Station, where she settled when she retired. According to her biographer Evelyn F. Keller, McClintock’s development as a researcher was already completed in the first years of her work at the labora- tory headed by Professor R.A. Emerson in Ithaca. In the late 1920s, a group of talented young researchers was formed around Emerson. In this group, George W. Bea- dle (who afterwards won the Nobel Prize for his studies on Neurospora) and Marcus M. Rhoades (a future clas- sic of the genetics and cytogenetics of maize) were the Life Devoted to Science (In Commemoration of the 100th Anniversary of the Birth of Barbara McClintock) CHRONICLE

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Page 1: Life Devoted to Science (In Commemoration of the 100th Anniversary of the Birth of Barbara McClintock)

1022-7954/02/3808- $27.00 © 2002

MAIK “Nauka

/Interperiodica”0984

Russian Journal of Genetics, Vol. 38, No. 8, 2002, pp. 984–987. Translated from Genetika, Vol. 38, No. 8, 2002, pp. 1163–1166.Original Russian Text Copyright © 2002 by Bogdanov.

In 2002, there was the 100th anniversary of the birthof Barbara McClintock (1902–1992), a world-renowned geneticists and cytogeneticist, the discovererof transposable elements, author of many other classi-cal cytogenetic works, and Nobel Prize winner.

McClintock’s discovery of transposable elements ofthe genome in 1951 opened a new epoch in genetics.Some publications on this theme state that McClintockdemolished the dogma of the constancy of the genomecreated by T.H. Morgan and his followers. More cor-rectly, McClintock complemented the postulate on theconstant linear arrangement of genes on chromosomes,which was put forward by Morgan’s school, by the discov-ery of the previously unknown class of genetic elementscapable of moving within the genome, incorporating intothe vicinity of fixedly located genes or into the genesthemselves, and causing their mutations. The main postu-lates of Morgan’s theory held but the views on the organi-zation and function of the genome have changed. Thefunctions and modes of inheritance of transposable ele-ments proved to be fundamentally different from those ofclassical genes studied by Mendel and Morgan.

McClintock discovered transposable elements(transposons) in maize. A decade after this discovery,

transposons were found in bacteria, and, after another17 years, in

Drosophila

. This succession of discoveriesprovided the basis for the concept of genome instabil-ity. An idea appeared on the “horizontal” transmissionof genes under natural conditions. This has caused aimpact on the theory of evolution.

Why did McClintock and not another researcherdiscover transposable elements of the genome? Whywere these elements first discovered in maize, and onlyafterwards were similar phenomena found in bacteriaand

Drosophila

, more “convenient” genetic objects? Toanswer these questions, we should year by year followthe development of McClintock’s studies and take intoaccount their historical background.

Barbara McClintock was born on June 16, 1902, inHartford, Kentucky, United States, in a doctor’s family.She graduated from the College of Agriculture of Cor-nell University in Ithaca, New York, in 1923 andreceived her Ph.D. degree in botany there in 1927. Hav-ing been appointed to a professorship at the same col-lege, she began intense research work. McClintockworked at Cornell University, with intermissions, until1936. In the same period, she won scholarships to post-graduate training at the laboratories headed by L. Sta-dler and T.H. Morgan (in the United States) andR. Goldschmidt (in Germany). McClintock left Ger-many in 1934, before the scheduled end of her training,because conditions for her research became unfavor-able when the Nazis came to power. She returned to theUnited States and, while waiting for a vacancy, workedwithout salary for nine months.

From October 1934 to 1936, McClintock worked atCornell University again. In 1936–1941, she was anassistant of L. Stadler at the University of Missouri. In1941–1967, McClintock was a personal researcher atCarnegie Institution with a fixed workplace at the ColdSprings Harbor Biological Station, where she settledwhen she retired.

According to her biographer Evelyn F. Keller,McClintock’s development as a researcher was alreadycompleted in the first years of her work at the labora-tory headed by Professor R.A. Emerson in Ithaca. In thelate 1920s, a group of talented young researchers wasformed around Emerson. In this group, George W. Bea-dle (who afterwards won the Nobel Prize for his studieson

Neurospora

) and Marcus M. Rhoades (a future clas-sic of the genetics and cytogenetics of maize) were the

Life Devoted to Science(In Commemoration of the 100th Anniversary

of the Birth of Barbara McClintock)

CHRONICLE

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LIFE DEVOTED TO SCIENCE 985

closest to McClintock, in both business and sociallife.Charles Burnham (who later became, along withRhoades, one of the best experts in maize genetics),H. Perry, and H. Lee also belonged to this circle. LewisStadler, a future leader of American genetics, often spe-cially came from Missouri to visit their seminars.McClintock was highly respected and trusted in thisotherwise purely male circle due to her professionalexpertise, analytical mind, efficiency, and enthusiasmin research. She never married and devoted her entirelife to science.

In the 1920s, plant genetics was noticeably behindthe genetics of

Drosophila

in its development. In plantgenetics, there were no examples of identifying genelinkage groups with specific chromosomes identifiedunder a microscope. Emerson set the researchers thetask of cytological identification of linkage groups ofmaize genes and their chromosome mapping. Theyoung research team worked enthusiastically and fruit-fully. Between 1929 and 1931, McClintock publishednine works in this field. In the same period, she devel-oped a method of pachytene chromosome analysis,which she successfully applied to construction of chro-mosome maps of maize. McClintock found cytologicalmarkers of chromosomes (heterochromatic nodules)and determined that the differences in the pattern ofthese nodules on chromosomes are inherited in maizestrains. She used radiation mutagenesis to study anddescribe radiation-induced translocations in maize andbegan systemic studies on deletion chromosome map-ping, detecting the phenotypic expression of recessivemutations in a hemizygous state resulting from het-erozygous deletions.

McClintock and her student H. Creighton usedpachytene analysis to demonstrate that crossing over inmaize was accompanied by exchange of cytologicalmarkers (chromomeres) between homologous chromo-somes. These results, together with the results of a sim-ilar study on

Drosophila

performed by Kurt Stern inGermany about the same time, became generallyknown as the cytological proof of crossing over.T.H. Morgan, who visited the laboratory headed byR. Emerson in 1931, highly appraised this work andsent their paper to the

Proceedings of the NationalAcademy of Sciences of the USA

, requesting to publishit as soon as possible. The paper was published twomonths later. The reports by Stern and by Creightonand McClintock attracted general attention at theVI International Genetic Congress in the United Statesin 1932 and entered the treasury of cytogenetics.

McClintock was the first to describe, in 1930, thecytological pattern of cross-shaped synapsis of homol-ogous chromosomes at the pachytene stage of meioticin heterozygotes for reciprocal translocation. In 1933,she demonstrated that inversion does not entail homol-ogous synapsis unless the inverted chromosome seg-ment forms a reverse loop. The drawing of the inversionloop of the pachytene bivalent made by McClintock

was included in all textbooks on genetics. McClintockand Rhoades discovered that chromosome pairingoccurs in the meiotic prophase I even at the cost of non-homologous synapsis and described all types on nonho-mologous synapsis of maize chromosomes.

In 1932, McClintock discovered that the centromereis a complex structure. She found a radiation-inducedbreak of maize chromosome 5 at the centromere, withboth fragments of the centromere being functionallyactive. This study served as a basis for a series ofgenetic and experimental cytological studies on theorganization and function of the centromere. Based onthe results of this study, C.D. Darlington explained themechanism of formation of isochromosomes.

In 1934, McClintock published a work that madeher expertise in cytogenetics a center of general atten-tion once more. This was the study on the structural andfunctional characteristics of the chromosome regionthat forms the nucleolus. She found that the nucleolusis formed anew at the end of each mitosis on a second-ary constriction of maize chromosome 6. When thischromosome region is broken by radiation, it neverthe-less retains its activity: although its two unequal frag-ments go to the nuclei of different haploid microsporesduring the cell division, they can form normal nucleoliof the same size. McClintock concluded that this regionplayed an active role in the formation of the nucleolusand termed it the nucleolar organized region (NOR).This term, coined by McClintock, became generallyaccepted in cytogenetics.

In her study published in 1938, McClintockexplained the cytological mechanism of formation ofdicentrics and acentric fragments during single andmultiple crossing over within the inversion loop. Sincethen, the cytological patterns of these chromosomerearrangements in meiotic anaphase I have been used asa quick test for heterozygosity for inversions.

In the same year, McClintock resumed her earlierstudies on the behavior of ring chromosomes, whichresult from junction of the broken chromosome endsduring mitosis and meiosis in maize. McClintockobserved terminal deletions that were caused by addi-tional accidental breakage of the rings, recorded thephenotypic expression of recessive genes that becamehemizygous because of the deletion, and mapped thesegenes on chromosomes. She was the first to relate thechromosome rearrangements that are repeated whenring chromosomes are broken with the mosaic colora-tion of grains. These works formed the basis for study-ing the causes of instability of the mosaic coloration ofgrains, which, in the 1950s, led McClintock to the dis-covery of transposable elements.

McClintock won a reputation of one of the world’sbest cytogeneticists, and her discoveries laid the basisfor the principles of cytogenetics. In all her studies,McClintock combined genetic and cytological analy-ses. She never blindly followed an authority, alwaysanalyzed all deviations from the generally accepted

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BOGDANOV

concept, and never ignored “details.” She always didthe important work herself. Outstanding powers ofobservation and researcher’s intuition were her charac-teristic features. The power of insight and creativeimagination extended beyond rational knowledgehelped McClintock to overstep the boundary betweenthe known and the unknown and formulate new, “here-tic” concepts.

In 1941–1942, McClintock described the phenome-non of chromosome breakage and rejoining recurringin successive mitoses in the endosperm of some strainsof maize. The ends of broken chromatids were rejoinedafter the chromosome replication. In the anaphase ofmitosis, such chromosomes formed a chromatid bridge,which was broken when the chromatids moved towardsthe cell poles. The broken ends were rejoined in theinterphase of the next mitosis, and the cycle wasrepeated. This phenomenon was called the breakage–rejoining–bridge cycle and was included in all funda-mental textbooks on cytogenetics. Several years later,McClintock discovered genetic instability and the well-known transposable genes.

During the World War II (in 1944), McClintock pub-lished one of her most brilliant articles on the relationshipof homozygous deficiencies, mutations, and allelic seriesin maize, which summarized her long-term experience infine cytogenetic studies on maize chromosomes.

On the suggestion of G.W. Beadle, who, togetherwith E.L. Tatum, had already published the famouswork on the genetics of

Neurospora

where they put for-ward the one gene–one enzyme theory, McClintockperformed the first cytological study of the chromo-somes of

Neurospora crassa.

Beadle specially invitedMcClintock to Stanford University for this study; hedeclared that only McClintock could manage to per-form the sophisticated microscopic analysis of

N. crassa

meiotic cells and small chromosomes.McClintock not only studied the karyotype and meio-sis of

N. crassa

in detail (1945), but also described theentire life cycle of this ascomycete, which became aclassical genetic model.

In 1944, McClintock began systematic studies onthe mechanisms of the mosaic color of maize grains andunstable inheritance of this mosaicism. Finally, she dis-covered a system of interacting dominant genes thatwere responsible for these phenomena and could moveover chromosomes. McClintock called these gene thedissociator (

Ds

) and the activator (

Ac

). The

Ac

con-trolled the transposition of the

Ds

from chromosome 9,which was accompanied by breakage of the chromo-some. A “dissociation” of the

Ds

and the neighboringgene of aleurone color occurred. The aleurone-colorgene was released from the suppressing effect of the

Ds

and transformed into the active form, which initi-ated the pigment synthesis in cells. The

Ds

transposi-tion in different cells was random, which caused thecolor mosaicism, with the size of the colored spot onthe seed being determined by stage of the seed develop-

ment at which the “dissociation” occurred. McClintockfound that the instability determined on the number of

Ac

copies in the cell. McClintock called the

Ac

and

Ds

transposable elements controlling elements; later, theywere termed transposons.

Many geneticists did not adequately estimated or evenunderstood McClintock’s first publications and reports onthis subject, although the main results were considered“worth noticing” and included into some textbooks. Thesediscoveries were underestimated mainly because theunusual facts were described and interpreted in terms oforthodox genetics, which merely had no “language” forthat. Moreover, McClintock’s idea that gene mutationsand transpositions are parts of the normal switching overgene functions in the course of plant ontogeny was funda-mentally new and difficult to comprehend. An importantcircumstance that prevented the scientific communityfrom appreciating the discovery was the appearance ofmolecular biology in the 1950s, which shifted the generalinterest towards molecular mechanisms of genetic pro-cesses. Therefore, new phenomena did not seem interest-ing unless their molecular bases were known. Only whentransposable elements were found in bacteria (1960) and

Drosophila

(1977), and their molecular structure andtransposition mechanism were established, did geneticistsand molecular biologists realize the meaning and priorityof McClintock’s discovery. The

Ac

and

Ds

were isolatedand analyzed by genetic engineering methods only in the1980s. The

Ds

proved to be a deleted and, hence, inactivevariant of the

Ac.

The structure of the

Ac

was found to besimilar to the structure of the transposable elements ofbacteria and

Drosophila.

In the late 1970s, it was generally recognized thatMcClintock had been the first to discover transposableelements. This recognition played the same role in thedevelopment of knowledge as the rediscovery of Men-del’s laws in 1900: the facts forced geneticists to under-stand and accept what was originally considered eithera “heresy” or specific features of some maize strains.A new period began in genetics, which was the periodof studying the genome instability. As noted above, thisproperty of the genome does not disprove the principleof constant location of the genes responsible for metab-olism and morphogenesis. However, it ensures a genet-ically regulated variability of the genome, explainsspontaneous mutation, illegitimate recombination, andthe molecular mechanisms of chromosome rearrange-ments. McClintock’s discovery was one of the discov-eries of the fundamental laws of heredity.

McClintock was elected the Vice President (1939)and then President (1945) of the Genetic Society ofAmerica. In 1944, she was elected a member of theNational Academy of Sciences of the United States. Inaddition, McClintock was a member of the Academy ofArts and Sciences at Boston, was bestowed honorarydoctoral degrees at Harvard, Rockefeller, Yale, andother universities, won the National Academy of Sci-ences of the United States Kimber Prize in Genetics

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(1967), was awarded the National Medal of Sciences ofthe United States (1970) and other prestigious awardsand prizes, and, finally, won the Nobel Prize in physiol-ogy and Medicine (1983).

The 100th anniversary of the birth of McClintock isa good occasion to remember the great discoveries thatwere made in genetics in the 20th century, which wasthe golden age of this science.

REFERENCES

Bogdanov, Yu.F., Barbara McClintock (on the 90thAnniversary of Her Birth),

Genetika

(Moscow), 1992,

vol. 28, no. 6, pp. 185–191 (with bibliography of mainworks by McClintock).

Golubovsky, M.D.,

Vek genetiki: Evolyutsiya idei i po-nyatii

(The Century of Genetics: Evolution of Ideas andConcepts), St. Petersburg: Borei-Art, 2000.

Nobel Prize Winners

, Wilson, H.W., Ed., New York:H.W. Wilson, 1987.

Keller, A.A.,

A Feeling for the Organism. The Life andWork of Barbara McClintock

, New York: W.H. Freeman,1983.

Yu. F. Bogdanov