marcella o'grady boveri (1865-1950) and the...

Journal of Medical Genetics, 1985, 22, 431-440

Marcella O'Grady Boveri (1865-1950) and thechromosome theory of cancerVICTOR A McKUSICKFrom the Department ofMedicine, Johns Hopkins University School of Medicine, Johns Hopkins Hospital,Baltimore, Maryland 21205, USA.

SUMMARY Born into a Boston Irish family, Marcella Imelda O'Grady was the first womangraduate in biology from MIT (1885) where she came under the influence of two recent PhDgraduates of Johns Hopkins University, William Townsend Sedgwick and Edmund BeecherWilson. She taught science at Bryn Mawr School for girls in Baltimore 1885 to 1887 and wasteaching assistant with E B Wilson at Bryn Mawr College for women in Bryn Mawr,Pennsylvania, 1887 to 1889. From 1889 to 1896 she headed the Department of Biology at VassarCollege for women in Poughkeepsie, New York. On the recommendation of E B Wilson (whofrom the first edition in 1896 dedicated his famous book The cell in development and inheritanceto Boveri) Marcella went to Wurzburg to spend a sabbatical with Boveri. One year later shemarried Boveri and during the next 18 years until Boveri's untimely death in 1915 she was herhusband's close scientific collaborator, especially in his work at the marine zoological stations inNaples and Villefranche, France. She also acquired (from Freiburg) the doctorate she hadunsuccessfully attempted to get at Johns Hopkins. Marcella returned to the United States in 1926and headed the Biology Department at Albertus Magnus College in New Haven. She was therein 1929 when her English translation of her husband's 1914 monograph advancing thechromosome theory of cancer was published. The translation did much to bring that theory to theattention of a wider audience which has thereby been able to rediscover Boveri, despite lack of a

reading knowledge of German. Boveri's theory was based on the views that (1) cancer is acellular problem, (2) cancers originate from a single cell, (3) this cell has an abnormality of itschromosomal constitution, and (4) the chromosomal abnormality which is passed on to all thedescendants of the cell of origin is the cause of rapid cell proliferation.

This paper is submitted out of profound respect forSir Cyril and Lady Clarke who, like Boveri and hiswife, have worked closely for many years onproblems of biology and medicine.

Recent discoveries by high resolution cytogeneticsand new information concerning oncogenes havevalidated the chromosome theory of cancer adv-anced by Theodor Boveri (1862-1915) in a mono-graph published the year before his death.' Profes-sor of Zoology at Wurzburg, Boveri was a leadingcytologist who, with Sutton,2 is also credited formarshalling evidence for the chromosomal basis ofmendelism. Here I shall review the role of Boveri'swife and widow in the work that underlay the cancertheory and her role in making the theory widelyknown through the English translation of hismonograph.3Received for publication 10 June 1985.Accepted for publication 17 June 1985.

Marcella O'Grady

Marcella Imelda O'Grady was born in Boston on 7October 1863 and attended Boston Girls' HighSchool. Although she pursued the so-called GeneralStudies IX curriculum, she can be said to have beenthe first woman to earn the bachelor's degree inbiology from Massachusetts Institute of Technology(SB degree, 1885).4

(Several women had been awarded degrees be-fore her-the earliest was Ellen Swallow Richards in1873-but none of them graduated in biology.) MITwas then quite a different institution from the onewe know today. Located in the centre of Boston, ithad fewer than 450 students.

Marcella's thesis was entitled 'The sympatheticnervous system of Columbia livia'. At MIT she cameunder the influence of William Townsend Sedgwick(1855-1921), who had come as Professor of Biology

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at the beginning of Marcella's junior year.5 There,furthermore, she first made the acquaintance ofEdmund Beecher Wilson (1856-1939) who was to beimportant in her subse uent career.Wilson6 and Sedgwick had been classmates at the

Sheffield Scientific School of Yale University. Bothapplied for coveted fellowships to do graduate workat Johns Hopkins University with Newell Martinand William Keith Brooks,7 and both were acceptedfor appointment in 1879, merely three years afterthe founding of Johns Hopkins. Daniel Coit Gil-man's axiom "Men, not buildings" extended to thesupport of graduate students as well as faculty.8 Notonly was Johns Hopkins the first graduate universityin America but it was also an elitist institution,where able though impecunious young men couldget training. For example, Woodrow Wilson, son ofa Presbyterian minister, received his PhD fromJohns Hopkins in 1886 (further mention of thisWilson later).Sedgwick and E B Wilson completed their PhDs

in 1881. Sedgwick remained at Johns Hopkins asAssociate in Biology until going to MIT in 1883. Hewelcomed E B Wilson (who had been at WilliamsCollege in 1883 to 1884) as a volunteer member ofthe MIT faculty during the year that Wilson waswaiting to take up his appointment at Bryn MawrCollege in Bryn Mawr, Pennsylvania, when itopened in 1885. Together they wrote Textbook ofgeneral biology, first published in 1886, which washighly successful through many editions. The bookof Huxley and Martin had previously dominated thefield. Sedgwick's distinguished career in bacteri-ology, sanitation, and public health within theframework of MIT and the now long defunct jointHarvard School of Public Health/MIT programme isrecounted elsewhere.But back to Marcella. In a sketchy CV in her own

beautiful handwriting,9 under Teaching, she statedthat she was in "charge of Science teaching atopening of Bryn Mawr School, Baltimore, 1885-1887" (and in the section on Education she referredto a "course in Bryology" she took at HarvardUniversity in the same period). M Carey Thomas,the first Dean and the second President of BrynMawr College, Pennsylvania, was the prime moverin the simultaneous founding of the namesakeprivate secondary school for girls in Baltimore.She was assisted in the founding of the School andCollege (both of which this year celebrate theircentennial) by her friend Mary Elizabeth Garrettwho later was to provide critical funds that permit-ted the opening of the Johns Hopkins MedicalSchool in 1893 on terms stipulated by Miss Garrett,including that women would be admitted on equalterms with men.

Reportedly, Daniel Coit Gilman, first presidentof Johns Hopkins University, "had discouraged thefounding ladies [of Bryn Mawr School] from attemp-ting such high standards . . . he disapproved tryingto model the school on schools for boys. He doubtedwomen's ability to profit by the educationoffered".'0 At the beginning, there was a physicalrelationship between Bryn Mawr School and JHU;the School was housed in a rented building onEutaw Street adjoining the 'campus' of JohnsHopkins University in downtown Baltimore.

After Baltimore, Marcella spent two years, 1887to 1889, at Bryn Mawr College in Bryn Mawr,Pennsylvannia, as a teaching fellow in biology withE B Wilson. Founded in 1885 by Quakers, thecollege included in its faculty another Wilson, whoorganised the history department and headed it forthree years before leaving for professorships atWesleyan University and Princeton University and,in due course, the Presidency of the United States.E B Wilson headed biology for the first six years.6He was succeeded by Thomas Hunt Morgan (1866-1945), PhD Johns Hopkins 1890, who spent 13 yearsat Bryn Mawr before following Wilson to ColumbiaUniversity where he spent the most productive partof his career.1 (Jacques Loeb12 was brought to BrynMawr in biology, his first position in America, butwas there for a mere two months, November 1891 toJanuary 1892.)

In 1889 Marcella went to Vassar College (foundedin 1861) in Poughkeepsie, New York, as head of theDepartment of Biology which she strengthenedgreatly during her seven years' tenure. Imbued by thescientific spirit she had acquired from Sedgwick andWilson, she carried to Vassar College the NewBiology of the day. In the summers of 1889, 1890,and 1892 she worked at the Marine BiologicalLaboratory in Woods Hole, Massachusetts, underProfessor C 0 Whitman, director of the laboratory.(E B Wilson was later director of MBL.) Inconnection with the centennial of Vassar College,Edna Carter, former Professor of Physics at Vassarand a student of Marcella in the 1890s, wrote: "Wewere fascinated by Miss O'Grady herself as well asby what she had to give. She had a warm interest inpeople and an inborn desire to be of service. Manystudents were helped in the solution of theirpersonal problems. She was young and yet mature, afull professor at twenty-five, making enduringfriendships among her students as well as in thefaculty. She worked hard giving laboratory practicealong with the class work. Biology in those days wasopen to juniors and seniors, but in her six years atthe college, the department grew from one to fourmembers and advanced courses were added".'3

Marcella's mentor, E B Wilson, became Professor

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Marcella O Grady Boveri (1865-1950) and the chromosome theory of cancer

of Zoology at Columbia University in 1891. His firstyear on the Columbia faculty was spent in Europe,in Munich and at the International ZoologicalStation in Naples, working mainly with Boveri. Onlysix years his junior, Wilson was influenced by Boveri(who was then still in Munich) to focus on cytology,which consumed his scientific attention for the restof his career. Wilson's The cell in development andinheritance (first edition, 1896) was dedicated "Tomy friend Theodor Boveri".'4 Wilson stated that

Boveri was "far more than a brilliant scientificdiscoverer and teacher. He was a many-sided man,gifted in many directions, an excellent painter, andwe found many points of contact far outside therealm of science.... The best that he gave me wasat the Cafe Heck where we used to dine together,drinking wonderful Bavarian beer, playing billiards,and talking endlessly about all manner of things".6When Marcella O'Grady was looking for an

optimal place to spend a sabbatical year, Wilson

FIG 1 Portraits ofMarcella O'Grady Boveri. (Courtesy ofArchives ofAlbertus Magnus College.) Clockwisefrom top left:in Boston, about 1885; in Poughkeepsie, NY, about 1893; in Baden, Switzerland, about 1900; in New Haven, about 1930.

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naturally recommended that she work with Boveri,now in Wurzburg. She was the first woman to beadmitted to a science department of WurzburgUniversity. (It is likely that Marcella aspired toadvanced study in biology at Johns Hopkins, but atthe time women were not admitted. FlorenceBascom, who for 33 years was head of the Depart-ment of Geology at Bryn Mawr College, receivedthe PhD degree from Johns Hopkins in 1893 but wasnever listed in class rolls as an official matriculant. Itis said that women during that period were permit-ted to attend lectures only if they sat behind ascreen.) In her hand written resume,9 Marcellaindicated the following: "University of Wurzburg,Germany, one year. Research in Cytology underProfessor Theodor Boveri. Thesis: "Ueber Mitosenbei einseitiger Chromosomenbindung", JenaischenZeitschrift fur Naturwissenschaft. Verlag GustavFischer, Jena, 1903".

Marcella never returned to Vassar because shemarried her professor in 1897. Richard Goldschmidt'shas a charming account of the courtship ofTheodor and Marcella, told to him by E B Wilson."One day an American girl applied for admit-tance to the laboratory. Up to that time no womanhad ever worked in the laboratory, and Boveri,a very shy man, was greatly upset by the prospect.Miss O'Grady arrived and was assigned a roomto herself as Boveri thought that she might notlike to share a room with men. Every day theprofessor, according to custom, came to check up onthe students' work, and he was very careful to leavethe door wide open while he conferred with her.After some months the other students noticed thatBoveri closed the door behind him."'5 Boveri musthave been fascinated by this woman who thoughtand talked like a scientist and who, to boot, wasfrom a religious tradition compatible with his ownBavarian Catholicism.

Marcella and Theodor were married in the UnitedStates on 5 October 1897, at the Convent of theGood Shepherd in Troy, New York. (A sister ofMarcella was a member of the order called Sisters ofthe Good Shepherd.) The Tech, MIT alumni maga-zine, announced their marriage and stated that theysailed for Europe and Wurzburg on 7 October.'6Their only child, Margreta, was born in 1901.Margreta, now dead, became a well known journal-ist and writer, living in Berlin.

Boveri's closest friend in Wurzburg was theProfessor of Physics, Wilhelm Conrad Roentgen(1845-1923). Roentgen was in Wurzburg from 1888to 1900 and it was there that he discovered x-rays in1895. The Boveri-Roentgen friendshi7 was delight-fully recounted by Margreta Boveri, who repro-duced many letters from Roentgen to Boveri.

According to Margreta, Roentgen approved stronglyof women in science; at least he approved of ascientific education for women. When Marcellaarrived in Wurzburg, he too was fascinated by the'zoological Miss', as she was called, and "she wasinvited by the Rontgens for afternoon coffee everyday while she studied there. Rontgen enjoyed herinterest in natural sciences very much and also hersheer exuberance. Even during the first year of theiracquaintance she was invited to accompany theRontgens on their vacation trips to Cadenabbiaand Baden-Baden".

In 1912 when Boveri was wrestling with thedecision of whether he should become director ofthe new Kaiser Wilhelm Institute for Biology inBerlin-Dahlem, Roentgen wrote to him: "If youshould decide in favour of Berlin and have toreorganise your scientific activities, you have acompanion and helper who will make things mucheasier for you and in this respect you would have anadvantage over other applicants". 17To the end of Boveri's life, Marcella was his

gracious hostess and scientific co-worker. Marcellawas particularly involved in Boveri's research incytology and experimental embryology at theMarine Zoological Station at Villefranche, France,and the International Zoological Station at Naples,where Boveri worked almost annually, for the firsttime in 1887 and the last time in 1914, the yearbefore his death. The sea urchin egg, to whichexperimental material he was introduced by thebrothers 0 and R Hertwig, was his focus of interestin Naples; in the winters the eggs of the roundwormAscaris megalocephala, available locally, occupiedhis attention for many years in Munich andWurzburg.

In a letter to Roentgen in 1910, Boveri wrote:"We agree completely on very many things and, inthe nearly 17 years of our contact, have livedthrough much together. We both love a quietexistence, in beautiful natural surroundings if at allpossible, with a few close friends with whom we cantalk or be silent as one needs to". ' Glasser'9recorded that Roentgen "spent his 70th birthday (27March 1915) quietly with his best friend, Boveri,who was seriously ill, in Oberstdorf, Bavaria . . .".Boveri was a patient in the sanitorium there anddied about six months later (15 October 1915). On20 March Roentgen'7 wrote to Boveri as follows: "Itseems to me that my plan to spend the twenty-seventh with you will now materialize, and that iswhy I am writing a few lines to you. I ask youearnestly to tell your wife not to make any-howshall I express myself-special preparations. Thetimes are not conducive to celebrations and I am notin the mood for them, and shall derive the greatest

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pleasure from the fact that our two families aretogether". After Boveri's death, Roentgen20 editeda book of collected remembrances of the greatcytologist and had a bust made of him.17

After her husband's death in 1915, Marcellaremained in Germany until 1926. They were difficultyears because of the post-war circumstances. Roent-gen's wife died in 1919. His loneliness was partiallyrelieved by his friendship with Mrs Boveri and herdaughter. He regularly spent the Christmas holidayswith them in Wurzburg. Many of his other friendswere now dead or lived abroad. After his death on10 February 1923, Marcella was executrix forRoentgen's estate. In accordance with his last will,Roentgen's scientific and personal papers and hiscorrespondence, with but few exceptions, wereburned.2'

In the biographical sketch quoted earlier, EdnaCarter, Professor of Physics Emeritus at Vassar,wrote: "The aftermath of the war was a very difficulttime with the changed attitudes, the depression andthe run-away inflation. In 1926 Mrs Boveri was quiteill but she resolved to pay a last visit to America. Shehad a sister and many friends here and she reco-vered in the friendly atmosphere so that before theend of the summer she was asked to start adepartment of biology at . . . Albertus MagnusCollege [founded in 1925] . . . During these years ofteaching, Mrs Boveri attended the colloquia at Yalein her field. With her knowledge of foreign scientistsand their work, she became a valuable member andmade many friends among the Yale professors. Inthis time, too, many a foreign professor had her tothank for the opportunity to lecture in thiscountry".13 Marcella may have had something to dowith the visit of Hans Spemann (more about himlater) to New Haven to give the Silliman Lectures in1933.22 Goldschmidt wrote that she "spent the restof her long life as Professor of Zoology at AlbertusMagnus College in New Haven, worshipped by thegirl students and honored by her many friends. Itwas an unforgettable pleasure to be her guest in thecozy apartment on the campus and to talk about oldtimes and about science while admiring her perfectpoise and nobility of bearing and mind". lSMarcellawas at Albertus Magnus College in 1929 when hertranslation of The origin of malignant tumors waspublished by the Williams and Wilkins Company inBaltimore.3

"Shortly after retiring, about 1942 [actually 1943],Marcella became the victim of a progressive disease,but her mind remained clear and she had lovingdevoted care to the end of her life."'3 For a time inher last years she was cared for at the Convent of theGood Shepherd, Wicatunk, New Jersey, where hersister, Mother Mary Immaculata, who died before

her, had been. Marcella died on 24 October 1950 inSt Francis Hospital in Trenton, New Jersey, and wasburied in the cemetery of the Sisters of the GoodShepherd in Wicatunk.

Theodor Boveri (18621915)18 23-26

Boveri was the second of four sons of a physician inBamberg, Bavaria. He studied anatomy in Munichunder Carl von Kupfer. His PhD thesis (1885) wason the structure of nerve fibres in vertebrates, asubject to which he did not later return. Soon afterBoveri completed his doctorate, he transferred tothe Zoological Institute in Munich. The new direc-tor of the Institute, Richard Hertwig, encouragedhim to go into cytological research. FollowingHertwig's example he combined morphological andexperimental approaches almost from the beginningof his postdoctoral career. He was privat-dozent inMunich University in 1893 when, not yet 31 yearsold, he was called to Wurzburg as Professor ofZoology. There he remained for the rest of hiscareer, declining invitations to succeed Weismann atFreiburg and to organise and direct the new KaiserWilhelm Institute in Berlin. He enjoyed manyhonours including the highest office (Rector Magni-ficus) in his university and foreign associateship inthe National Academy of Sciences of the USA. Hisuntimely death at the age of 53 was said to havebeen due to tuberculosis; the symptoms, particularly

FIG 2 Portrait of Theodor Boveri, about 1909. (CourtesyofDr Ulrich Wolf, Freiburg.26)

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fever, certainly were compatible with that diagnosis.Goldschmidt stated that "disease of the gallbladderforced him to interrupt his teaching for a year. Anoperation performed (a few days before his death)could not save his life".23

Boveri's students included Fritz Baltzer, his bio-grapher, later associated with the University ofBern, Switzerland, and, one of the first, HansSpemann (1869-1941), who remained in Boveri'sinstitute for many years after completing hisdoctorate.27 Seven years his junior, Spemann en-

joyed a close scientific relationship with Boveri anda personal friendship that continued after he was

called to Rostock. Spemann was awarded the NobelPrize in Physiology and Medicine in 1935 for hisdiscovery of the organiser effect in embryonicdevelopment.28

Boveri's theory of cancer*

Boveri came to his theory of cancer from the workby him and others of the previous 20 years indicatingthat the set of chromosomes is a constant character-istic of each species and that each chromosome has a

unique constitution. He was particularly led to hiscancer theory by his own observations of theconsequences of abnormal mitoses in sea urchineggs. In his 1902 monograph describing such studies,he "added the suggestion that malignant tumorsmight be the result of a certain abnormal conditionof the chromosomes, which may arise from multipo-lar mitosis". 31Hansemann in 1890 had advanced the hypothesis

that irregularities of the mitotic process are re-

sponsible for disordered growth,32 whereas Winge in193033 introduced the concept of selective cellularproliferation "realizing that selection must as inevit-ably operate on a genotypically mixed population ofproliferating cells as on a genotypically mixedpopulation of reproducing organisms".29 Hanse-mann focused on abnormalities of the mitoticprocess as leading to abnormal growth; Boverifocused on abnormality of the chromosomes as

fundamental. Winge's useful selection concept hasbeen elaborated greatly in recent times with studiesof the evolution of chromosomal abnormalities inleukaemia and other tumours at various stages.The essence of Boveri's theory, stated in his own

words (as translated by Marcella), was as follows(the numbers are mine).(1) "The problem of tumors is a cellular problem"t(p 33).

*Ford and Clarke,29 Wolf,26 and Sager,3" among others, have discussed

Boveri's theory of cancer in the light of more recent work.

tThere are some, even recently. who have challenged the validity of what theyterm 'cytologism' in cancer research.3"3"

(2) "... typically every tumor arises from a singlecell": (p 403).(3) "This primordial cell of a tumor ... contains, asa result of an abnormal process, a definite andwrongly combined chromosome-complex."§(4) "This is . the cause of thetendency to rapid cell proliferation, which is passedon to all the descendants of the primordial cell"(p 403).Boveri3 also wrote as follows. "A nuclear pathol-

ogy, which would include according to this concep-tion the theory of malignant tumors, like a nuclearphysiology, has scarcely begun to exist." Somaticcell genetic diseases, of which malignant tumoursare examples, represent one large category ofgenetic disease. In these, mutations occur in somaticcells rather than in germ cells as in the disordersgenerally viewed as proper genetic disease. 'Nuclearpathology' is a term essentially synonymous with'the morbid anatomy of the human genome'.39

Background of the Boveri theory of cancer

The chromosomes were discovered by WaltherFlemming of Kiel, Germany, in 1877. The details ofmeiosis were described in the next two decades. Amain reason that the significance of Mendel'sexperiments in the 1860s was not recognised wasthat the chromosomes were not yet known, let alonemeiosis. There was no element of plausibilityfavouring mendelism over other theories of hered-ity, such as the ancestral blending inheritancesupported by Francis Galton.The significance of reduction, as meiosis1 was

known until at least 1905, attracted attention frombiologists at the end of the last century. Theirthinking was reviewed by E B Wilson in his classicThe cell in development and inheritance, first pub-lished in 1896.14 The following quote from thissource (p 182-5) indicates that the chromosomeswere already suspected to be central to bothinheritance and development (the Weismanntheory, or Roux-deVries-Weismann theory).4This would be called the clonal theory of cancer now. Sir Macfarlane Burnetwas perhaps the first to so term it ". somatic mutation theories of cancerhave been current for many years On this view, cancer represents thedevelopment by a clone of cells (or more than one) of the capacity to

multiply freely without revtrd to the normal controls which maintain cellrelationships in the body".: Early studies of the clonality of neoplasms were

published by Charles E Ford2' and Philip J Fialkow38 and their colleagues.Clone comes from the Greek Klon meaning 'twig' or 'slip' and akin to the GreekKlan meaning 'to break'.§In a footnote on p 10.3 Marcella confessed difficulty in translating the wordChromatinbestand. Chromatin-content and chromatin-garniture were othertranslations she considered. Ford and Clarke29 translated the word as

chromosome constitution.IlThe term meiosis was introduced by Farmer and Moore in a paper in 1905.4"They spelled the word maiosis. In its etymological origin it is the same word as

miosis which as currently used refers to reduction in size of the pupil ratherthan reduction in number of chromosomes. How fortunate that we spell theterm differentially in its cytogenetic and ophthalmological uses!

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THEORETICAL SIGNIFICANCE OF

MATURATIONThe process of reduction is very obviously a provisionto hold constant the number of chromosomes charac-teristic of the species; for if it did not occur, thenumber would be doubled in each succeeding genera-tion through union of the germ-cells. But why shouldthe number be constant?

In its modern form this problem was first attackedby Weismann in 1885, and again in 1887, though manyearlier hypotheses regarding the meaning of the polarbodies had been put forward. His interpretation wasbased on a remarkable paper published by WilhelmRoux in 1883 (Ueber die Bedeutung der Kern-theilungsfiguren), in which are developed certainideas which afterwards formed the foundation ofWeismann's whole theory of inheritance and develop-ment. Roux argued that the facts of mitosis are onlyexplicable under the assumption that chromatin is nota uniform and homogeneous substance, but differsqualitatively in different regions of the nucleus; thatthe collection of the chromatin into a thread and itsaccurate division into two halves is meaningless unlessthe chromatin in different regions of the threadrepresents different qualities which are to be dividedand distributed to the daughter-cells according tosome definite law. He urged that if the chromatinwere qualitatively the same throughout the nucleus,direct division would be as efficacious as indirect, andthe complicated apparatus of mitosis would be super-fluous. Roux and Weismann, each in his own way,subsequently elaborated this conception to a completetheory of inheritance and development, but at thispoint we may confine our attention to the views ofWeismann. The starting-point of his theory is thehypothesis of De Vries that the chromatin is acongeries or colony of invisible self-propagating vitalunits of biophores somewhat like Darwin's 'gem-mules', each of which has the power of determiningthe development of a particular quality. Weismannconceives these units as aggregated to form units of ahigher order known as 'determinants', which in turnare grouped to form 'ids', the latter being identifiedwith the visible chromomeres or chromatin-granules.The ids finally are associated in linear groups to formthe 'idants' or chromosomes. Since the biophoresdiffer qualitatively, it follows that the same must betrue of the higher units formed by their aggregation.Hence each chromosome has a distinct and definitecharacter of its own, representing a particular group ofhereditary qualities. From this it follows that thenumber of specifically distinct chromosomes is dou-bled by the union of two germ-cells, a process which ifunchecked would quickly lead to an infinite complex-ity of the chromatin or germ-plasm. The end ofmaturation, or reduction, is therefore to prevent "theexcessive accumulation of different kinds of heredit-ary tendencies or germ-plasms" through the progres-sive summation of ancestral chromatins.We now come to the vital point of Weismann's

hypothesis of reduction, about which all later resear-ches have revolved. Assuming with Roux that the

different qualities of 'ancestral germ-plasms' arearranged in a linear manner in the spireme-thread andin the chromosomes derived from it, he ventured theprediction ('87) that two kinds of mitosis would befound to occur. The first of these is characterized by alongitudinal splitting of the thread, as in ordinarycell-division, "by means of which all the ancestralgerm-plasms are equally distributed in each of thedaughter-nuclei after having been divided intohalves". This form of division, which he called 'equaldivision' (Aequationstheilung), was then a known fact.The second form, at that time a purely theoreticalpostulate, he assumed to be of such a character thateach daughter-nucleus should receive only half thenumber of ancestral germ-plasms possessed by themother-nucleus. This he termed a 'reducing division'(Reduktionstheilung), and suggested that this might beeffected either by a transverse division of the chromo-somes, or by the divergence and separation of entirechromosomes without division. By either method thenumber of 'ids' would be reduced; and Weismannargued that such reducing divisions must be involvedin the formation of the polar bodies, and in theparallel phenomena of spermatogenesis.The fulfilment of Weismann's prediction is one of

the most interesting results of recent cytologicalresearch. It has been demonstrated, in a mannerwhich I believe is incontrovertible, that the reducingdivisions postulated by Weismann actually occur,though not precisely in the manner conceived by him.

From this discussion written by Wilson in 1896, itis easily seen that the physical interpretation ofmendelism was not possible until after the discoveryof the chromosomes and that biological thinking waswell prepared for accepting mendelism when it wasrediscovered in 1900. Again, Boveri figured in thechromosome theory of mendelism, which, however,is primarily attributed to Sutton.4'As a student of McClung at Kansas University,

Walter Stanborough Sutton (1877-1916) studiedmeiosis in the Kansas grasshopper Brachystolamagna in the late 1890s for the purpose of resolvingthe contradictions referred to by Wilson.41 42 In theautumn of 1901, Sutton went to Columbia Univer-sity as a graduate student of Wilson's and was inNew York when William Bateson (1861-1926), theEnglish advocate of mendelism, lectured there inSeptember 1902. His background in studies ofmeiosis prepared Sutton for recognising the parallel-ism between the behaviour of the chromosomes inmeiosis and of Mendel's factors in segregation andassortment. In a classic paper, he presented evi-dence that the hereditary determinants* are on thechromosomes.2

Boveri's work provided a basis for the chromo-somal theory of mendelism as well as for thechromosome theory of cancer. One necessary condi-*The term gene was introduced by Johansson of Copenhagen in 1909.'Genetics' was first used in a publication by Bateson in 1906.

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tion for the chromosomal theory of inheritance wasthe continuity of each chromosome through interph-ase ('resting phase' or interkinesis) into the next celldivision. In beautiful preparations in Ascaris, heshowed that the chromosomes continue their exist-ence in specific regions of the diffuse nuclearchromatin mass of interkinesis because they reap-pear after cell division in the same positions in thetwo daughter cells.Another necessity for the chromosomal theory of

mendelism was unique genetic content of eachchromosome-the individuality of chromosomes.Until about 1902, a prevalent view was that eachchromosome was a carrier of the totality of thehereditary material. The genetic difference of sepa-rate chromosomes was demonstrated by Boveriusing his other favourite material, the sea urchinegg. As early as 1888, Boveri had found fertilisedeggs of Ascaris that formed not the normal two butfour mitotic poles. This so-called tetraster egg leads,Boveri demonstrated (see fig 318), to missegregationof the chromosomes. If chromosomes are geneti-cally non-equivalent, then defective embryos wouldbe expected to develop. The sea urchin eggsprovided the material for testing this. These eggscan be artificially fertilised and if one uses muchsperm, double fertilisation occurs with resultanttetrapolar or tripolar mitoses. Tetraster eggs cleavedto form four cells rather than the normal two.

Zur Frage der EntstehungmalignerTumoren

Von

Th. BoveriI2

Professor an der U'niersitSi Wbarzb.rg

Mit 2 Abbild-nge.

JenaVerlag von Gustav Fischer

1914

Boveri could show that the tetraster or triasterembryo develops with abnormalities. (Marcella was,according to Baltzer, his "most important collabor-ator, particularly in the dispermic experiments".)The linear arrangement of genes on chromosomes

was established by the works of Thomas HuntMorgan, like Wilson in the Department of Zoologyat Columbia University, and his students. Theymapped the relative position of genes on thechromosomes of Drosophila by the linkage princi-ple, starting in 1911. In the same year, E B Wilson'mapped' (assigned) the first human gene to aspecific chromosome.43 For this first gene assign-ment in any mammal, Wilson recognised that thecharacteristic pedigree pattern of colour blindness(described by Horner, a Swiss ophthalmologist, inthe 1870s) was explicable if the human has an XX/X-sex chromosome constitution, if the gene for colourblindness is recessive, and if it is situated on the Xchromosome. (We now know that there are at leasttwo colour blindness genes on the X chromosome,one for deutan and one for protan colour blindness,and that both are situated near the end of the longarm of the X chromosome. A third disorder ofcolour vision, blue-mono-cone-monochromatic col-our blindness, is also X linked (30370 in McKusick'sMendelian inheritance in man44). The genetic rela-tion of this mutation to those responsible for theother forms is unknown.)

THE ORIGINOF

MALIGNANT TUMORS

ByTHEODOR BOVERI,'\Uniwss#y of Iftdnzbug

Tr.,4.d byMARCELLA BOVEIU

T~HE

BALTIMORETHE WILLLIMS & WILKINS COMPANY

1929

FIG 3 Boveri's monograph expounding the chromosome theory ofneoplasia. Left: title page ofGerman edition;right: title page of English translation.

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The impact of Boveri's chromosome theory of cancer

Having reviewed the background of Boveri's theory,let us examine the after-effect of his 1914 publica-tion. Its early impact seems to have been minimal.In his long obituary of Boveri in 1916,Goldschmidt2- made no reference to it. Wilsonscarcely mentioned the theory and seemingly did notreference the monograph in the 1925 edition of TheCell. The fact that Marcella translated the booksuggests that she sensed a lack of general apprecia-tion for the theory. It is not clear, however, that itachieved any greater recognition after the 1929publication in translation. Was it before its time,like Mendel's work? Human cytogenetics was in aprimitive state, as seen in the uncertainty as to thecorrect chromosome number and the sex chromo-some constitution.The emphasis, in many ways not inappropriate,

on chemicals, viruses, and ionising radiation incarcinogenesis, even with an implied ultimate basisin chromosomal change, may have deflected atten-tion from the fundamental genetic aspects of cancerbiology.Under the heading, "Rediscovering Boveri",

Ruth Sager30 wrote as follows in 1983: "Boveri'scontribution to clear thinking about cancer ranksnearly with Mendel's contribution to clear thinkingabout genes".

Recapitulation

This is the story of the first woman to graduate inbiology from MIT, who had the good fortune offalling early under the influence of two leadingbiologists of the day, Sedgwick and Wilson,spawned in the new scientific atmosphere of JohnsHopkins University; who founded the departmentof biology at one American college, AlbertusMagnus, and greatly strengthened the departmentof biology at another, Vassar; who was the wife andco-worker of the leading cytologist of his day; andwho opened her husband's major theoretical workto a larger audience with an English translation.

I am endebted to Sister Thomas Aquin Kelly, OP,Assistant Librarian and Archivist, Albertus MagnusCollege, for photographs and for a copy of MrsBoveri's curriculum vitae written in her own hand;to Professor Elof Axel Carlson, Stony Brook, forhelpful comments; and to Elizabeth Craig of theMIT Archives and Lisa Browar of Vassar CollegeLibrary.

References

Boveri T. Zur Frage der Entstehung maligner Tumoren. Jena:Verlag von Gustav Fischer, 1914.

2 Sutton WS. The chromosomes in hereditv. Biol Bull 1903A4:231-5 1.

3Boveri T. The origin of mnalignzatnt tunors. (Translated byM Boveri.) Baltimore: Williams and Wilkins, 1929.

4Massachusetts Institute of Technology. 'The Teclh 1897:17(5).5Jordan EO, Whipple GC. Winslow CEA. A pionieer of publichealth, William Thompsoni Sedgwick. New Haven: Yalc Uni-versity Press, 1924.

6 Morgan TH. Biographical mcmoir of Edmund Bcecher Wilson.1856-1939. Biographical Memoirs Natl Acad Sci USA 1940:21:315-42.

7Swanson CP. A history of biology at the Johns HopkinsUniversity. Bios 1951;22:222-62.French JC. A history of the universitv fountded by JohnisHopkins. Baltimore: Johns Hopkins Prcss, 1946.

9Albertus Magnus College. Notes from the Archive Collection,New Haven, Connecticut.Beirne RR. Let's pick the daisies: the historv of the Bryn MawrSchool 1885-1967. Baltimore: Brvn Mawr School. 1970.Allen GE. Thomas Hunt Morgan. In: Dictionary of scientificbiography. Vol 9. New York: Charles Scribner's Sons,1974:515-26.

12 Fleming D. Jacques Loeb. In: Dictionary of scientific biography.Vol 8. New York: Charles Scribner's Sons, 1973:445-7.

13 Carter E. Marcella I O'Grady, Mrs Theodor Boveri. VassarCollege Archives, Poughkeepsie. New York.

14 Wilson EB. The cell in development and intheritance.New York:Macmillan, 1896.Goldschmidt R. Portraits from memory: recollections of azoologist. Berkeley: University of California Press, 1956:111.

16 The Tech. MIT alumni magazine, 1897, vol XVII, No 5.17 Boveri M. Personal reminiscences of W C Rontgen. In:

Glasser 0, ed. Wilhelm Conrad Rontgen and the earls' history ofthe Roentgen rays. Springfield, Illinois: Charles C Thomas,1934:118-98.

'8 Baltzer F. Theodor Boveri. (Translated by C Stern andE Stern.) Science 1964;144:809-15.

'9 Glasser 0. Dr W C Rontgen. Springfield, Illinois: Charles CThomas, 1945.

21) Rontgen WC, ed. Erinnerungen an Theodor Boveri. Tubingcn:JCB Mohr, 1918.

21 Glasser 0. Wilhelm Conrad Rontgen and the early history of theRoentgen rays. Springfield, Illinois: Charles C Thomas, 1934.

22 Eakin RM. Great scientists speak again. Berkeley: University ofCalifornia Press, 1975.

23 Goldschmidt R. Theodor Boveri. Science 1916:43:263-70.24 Baltzer F. Theodor Boveri. Life and work of a great biologist

1862-1915. (Translated by D Rudnick.) Berkeley: University ofCalifornia Press. 1967.

25 Oppenheimer J. Boveri, Theodor. In: Gillispic CC, ed.Dictionary of scientific biography. Vol 2. New York: CharlesScribner's Sons, 1970:361-5.

26 Wolf U. Theodor Boveri and his book 'On the problem of theorigin of malignant tumors". In: German J, ed. Chromosomesand cancer. New York: John Wiley, 1974:3-20.

27 Mangold 0. Hans Spemann. Stuttgart: WissenschaftiicheVerlagsgesellschaft, 1953.

28 Spemann H. Emnbryonic development and induction. NcwHaven: Yale Universitv Press, 1938.

29 Ford CE, Clarke CM. Cytogenetic cvidence of clonal prolifera-tion in primary reticular neoplasms. Can Cancer Conf 1963;5:129-46.

30 Sager R. Genomic rearrangements and the origin of cancer.Rediscovering Boveri: the problem of causality. In: German J,ed. Chromosome mutation and neoplasia. New York: Alan RLiss, 1983:333-46.

3 Boveri T. Uber mehrpolige Mitosen als Mittel zur Analyse desZellkerns. Verh Phys-med Ges Wiurzburg 1902;35:67-90.

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32 Hansemann D. Uber asymmetrische Zeilteilung in Epithel-kerbsen und der biologische Bedeutung. Virch Arch [PatholAnat] 1890;119:299-326.

33 Winge 0. Zytologische Untersuchungen fiber die Natur malig-ner Tumoren. Il. Teerkarzinome bei Mauzen. Z Zellforsch1930;10:683-735.

34 Smithers DW. Cancer: an attack on cytologism. Lancet 1962;i:493-9.

35 Rubin H. Is somatic mutation the major mechanism of malig-nant transformation? J Natl Cancer Inst 1980;64:995-1000.

36 Rubin H. Some remarks of cancer as a state of disorganization at

the cellular and supracellular levels. In: Le Cam L, Neyman J.eds. Probability models and cancer. New York: North-Holland,1982.

37 Burnet M. The clonal selection theory of acquired immunity.Nashville: Vanderbilt University Press, 1959.

38 Fialkow PJ, Gartler SM, Yoshida A. Clonal origin of chronicmyelocytic leukemia in man. Proc Natl Acad Sci USA 1967;58:1468-71.

39 McKusick VA. The morbid anatomy of the human genome. ClinGenet 1985;27:238-9.

4" Farmer JB, Moore JES. New investigations in the reductionphenomena of animals and plants. Philos Trans R Soc Lond[Bioll 1905;72:336-53.

41 McKusick VA. Walter S Sutton and the physical basis ofMendelism. Bull Hist Med 1960;34:487-97.

42 McKusick VA. Sutton, Walter Stanborough. In: Gillispie CC,ed. Dictionary of scientific biography. Vol 13. New York:Charles Scribner's Sons, 1976:156-8.

43 Wilson EB. The sex chromosomes. Arch Mikrosk Anat Entwick-lungsmech 191 1;72:249-71.

"4 McKusick VA. Mendelian inheritance in man. 6th ed. Balti-more: Johns Hopkins University Press, 1984.

Correspondence and requests for reprints to Pro-fessor V A McKusick, Department of Medicine,The Johns Hopkins Hospital, Baltimore, Maryland21205, USA.

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marcella o'grady boveri (1865-1950) and the...

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