Perspectives

Anecdotal, Historical and Critical Commentaries on Genetics Edited by James F. Crow and William F. Dove

Edward Novitski: Drosophila Virtuoso

James F. Crow,*,1 Dan Lindsley† and John Lucchesi‡ *Genetics Laboratory, University of Wisconsin, Madison, Wisconsin 53706, †Section of Cell and Developmental Biology, University of California, San Diego, California 92093, and ‡Department of Biology, Emory University, Atlanta, Georgia 30322

DWARD Novitski, 1918–2006, was the acknowledged attempts to extricate himself make an amusing story. E master of that special art of manipulating chro- The second part of Ed’s book is the story of his own life. mosomes during what Lucchesi (1994) called ‘‘the age The third is his account of the rift between Alfred of Drosophila chromosome mechanics.’’ Following the Sturtevant and Theodosius Dobzhansky. Novitski had Sturtevant tradition, his guiding principle was to derive the unique vantage point of having been successively a as much information as possible from breeding experi- student of each of them, and he is clearly in Sturtevant’s ments with minimum use of direct cytological examina- corner. The fourth part is titled ‘‘The Pleasure of Find- tion. Nobody could perform this kind of chromosome ing Things Out.’’ It recounts some of his most interest- manipulation as well as Ed and he relished new chal- ing intellectual challenges. The book is as idiosyncratic lenges. (Novitski’s closest friends and relatives, especially as Ed himself, a mixture of deep science, anecdotes, in later years, called him Eddie, a name he seems to have intellectual depth, and whimsy. preferred. Those, such as ourselves, whose acquaintance extends over many years, knew him as Ed, which we shall A BRIEF BIOGRAPHY adopt here.) He continued this kind of work long after the development of microbial and molecular genetics Edward Novitski was born in Wilkes-Barre, Pennsylvania, had carried the field in new directions. on July 24, 1918. He had an early interest in science, Another side of Novitski was a love of pranks and prac- leading him to chemistry experiments and building a tical jokes, which were indeed clever, sometimes di- radio receiver. He also had an interest in collecting ani- abolically so. He reached what must be the pinnacle of mals, especially snakes, a practice he engaged in after achievement in this rarified atmosphere, for his repu- slipping out of highly unpleasant church services. Sig- tation was such that pranks that he never carried out nificantly for both their later careers, he and E. B. Lewis were attributed to him nonetheless. He admired Richard attended the same high school and were the leaders of a Feynman, a physics genius who also enjoyed such things biology club. One day, while perusing the journal Sci- as safe cracking, bongo drums, and practical jokes. Both ence, Ed Lewis noticed an ad for Drosophila cultures, so men took great pleasure in ‘‘finding things out’’ and most of the club’s small treasury was used to get some shared highly creative minds and a love of pranks. stocks. It was the beginning of two illustrious Drosophila Fortunately, Ed completed an autobiographical mem- careers. Novitski carried on a correspondence with the oir not long before his death (Novitski 2005). He was Purdue faculty member S. A. Rifenburgh, who had fur- unusual; so, naturally, the book is unusual. It has four nished the flies for the biological supply house. With main sections. The first is ‘‘Fun and Games,’’ a series of Rifenburgh’s help, he got a scholarship to Purdue, with- anecdotes and practical jokes. The first prank is his most out which college would have been unattainable for him. famous, perpetrated on Herschel Roman. Ed manipu- While in high school Ed discovered a mutation, heldout lated the seminar clock to run slowly so that Herschel, (Novitski and Rifenburgh 1938), shown to be an after finishing his talk, seemed to have an embarrass- allele of a gene that was subsequently named decapenta- ingly long period of time remaining to be filled. His plegic. This is a key regulatory gene in dorsal–ventral patterning of the embryo. He also found the mutation, later called asteroid, which he sent to Ed Lewis; this 1Corresponding author: Department of Genetics, University of Wisconsin, mutation marked the beginning of Lewis’s famed ca- Madison, WI 53706. E-mail: [email protected] reer (Crow and Bender 2004). Novitski carried on an

Genetics 174: 549–553 (October 2006) 550 J. F. Crow, D. Lindsley and J. Lucchesi

Edward Novitski. Courtesy of Charles Novitski.

extensive correspondence with C. B. Bridges, remark- Novitski 1941). This article uncovered an error by able for the interest and professional respect that Bridges Dobzhansky, a failure to identify one chromosome arm. showed for this promising unknown scientist. No fewer During this period and later, Novitski became increas- than 36 letters were exchanged. ingly conscious of numerous Dobzhansky errors. An- In high school, Ed learned Latin over the summer other example is the ‘‘sex ratio’’ phenomenon, which and entered the second-year class in the fall. At Purdue Dobzhansky had interpreted as an extra chromosome he soon discovered that he could get credit for college replication. This was later shown to involve no unusual courses simply by learning the material on his own and processes; rather, it involved the nonfunctioning of some taking examinations. In this way, starting with calculus, meiotic products (Novitski et al. 1965). Novitski’s dis- he completed his undergraduate studies at Purdue in illusionment with Dobzhansky and his admiration of 2 years. He influenced his friend Lewis to adopt the Sturtevant argues that, although the differences were same strategy. always underplayed, he must have received considerable At Bridges’ suggestion, he applied to and was ac- satisfaction from discovering the errors, as was probably cepted by Caltech, entering graduate school in the fall true of Sturtevant as well. of 1938. Alas, Bridges was terminally ill at this time, so Novitski received his Ph.D. in 1942. While in what might have been an important scientific collabo- Dobzhansky’s group, he met Esther Rudkin whom he ration never materialized. Novitski began graduate work later married while he was in military service. His service as a student of Dobzhansky, irradiating Drosophila pseudo- in the Army Air Force lasted 3 years, from 1942 to 1945. obscura to produce inversions and using these to isolate During this time the Air Force received a new, state of lethal mutations from natural populations. These le- the art device, which was installed in bombers flying out thals were to be tested for allelism, a heroic task since of England. It failed to function as described, but char- the number of tests goes up with the square of the num- acteristically Ed was able to identify the problem and ber of mutations. Ed soon became disillusioned, think- restore its function. For this, he received a commenda- ing that the data had minimal value for distinguishing tion from his commanding officer. After his discharge among alternative ideas and that the work could, as he from the Air Force, he spent 2 years in the laboratory said, be carried out as easily by a well-trained chimpan- of Curt Stern at the University of Rochester, the first as zee. He finally gave up, destroyed the stocks, and was a Guggenheim fellow and the second on an Atomic promptly sacked as a teaching assistant. Energy project. Then came a year at the University of After some uncertainty, he was finally awarded a fel- Missouri in the laboratory of A. B. Griffen and 2 years at lowship with Sturtevant. He was now on the path that Caltech, again with Sturtevant. In 1951 he joined the he would follow the rest of his life. Together they pub- faculty at the University of Missouri where he stayed lished an article showing the chromosomal homologies until 1956. He then moved to the Biology Division of of various Drosophila species, as evidenced by the lo- the Oak Ridge National Laboratory as head of the cation of corresponding mutations (Sturtevant and Drosophila genetics group. Finally, in 1958, he became Perspectives 551

Professor of Biology at the University of Oregon where, same gamete. These could be perpetuated in subse- except for sojourns in Zurich, Canberra, and Leiden, he quent generations by selecting nondisjunction prod- remained until his retirement in 1983. He died June 29, ucts. An additional crossover could then reconstitute 2006, in his 88th year. the original long inversion sequence with the mutant allele in it. Finally, a double crossover within the larger inversion transferred the desired allele to the normal RESEARCH uninverted chromosome, and the Greens had their de- A central theme in Novitski’s work was the remaking sired allele in a manageable condition. The procedure of the Drosophila genome by attaching chromosome and Muller’s reaction to it are described in Ed’s book arms in novel ways. Attached X chromosomes were well (Novitski 2005, pp. 135ff). known, but there were five other ways in which two X Novitski’s graduate work involved species other than chromosomes could be attached to a single centromere. Drosophila melanogaster (Novitski 1946), but after that Ed succeeded in constructing all five (Novitski 1954a). time he worked exclusively with that species. He dem- These chromosomes were used to analyze various as- onstrated early that low-temperature shocks produced pects of segregation and recombination. A particularly the desemination of mated females, rendering them neat procedure was employed to join the X and Y. At- ‘‘virgins’’ (Novitski and Rush 1948). He demonstrated taching parts of the X to parts of the Y had already been that recombination between some pairs of structurally done, but Novitski and Dan Lindsley succeeded, by a heterozygous chromosomes produces heteromorphic procedure that was both logical and ingenious, in at- dyads from which the smaller element is preferentially taching the entire X and Y chromosomes (Lindsley included in the functional egg nucleus (Novitski 1951). and Novitski 1950, 1963; for a nontechnical descrip- He also studied the fate of double first anaphase bridges tion, see Novitski 2005, pp. 145–148). The experiment formed by a four-strand double exchange in an inver- was contrived so that only the desired type of male would sion heterozygote. He showed that, in the tug of war be- have all the necessary Y chromosome fertility genes, so tween centromeres at opposite ends of a bridge, the the presence of a single fertile male in a culture bottle outcome depends on the sources of the chromosomes would produce larvae—a labor-saving selective scheme involved (Novitski 1952; Lindsley and Novitski 1958). worthy of the needle-in-the-haystack experiments of Novitski later showed that the very unlikely precise re- microbial geneticists. This chromosome became essen- version of the roughest-3 inversion could be achieved tial for all subsequent studies of the Y chromosome. in heterozygous females when the two breakpoints of Novitski also produced, by judicious combination of the inversion were brought into close proximity by the recombinant types, a compound XY chromosome that looped inversion configuration (Novitski 1961). was a ring (Novitski and Childress 1976). Other Other studies included the relationship of crossing over constructions of note include assembly of the right and to nondisjunction (Novitski 1967, 1978); an explanation left autosomal arms in tandem with the centromere at of the ‘‘crowding effect’’, the tendency for chromosomes the terminus. By the equivalent of a centromere fusion in triploids to segregate in roughly equal numbers to oppo- these acrocentric chromosomes could be doubled to site poles at the expense of balanced haploid and diploid produce an attached two and attached three. Finally, products (Sandler and Novitski 1957); crossing over the tour de force: he was able to attach all four arms of within inversion heterozygotes (Novitski and Braver the major autosomes to one centromere, producing a sin- 1954); induced exchanges between the X and Y chro- gle giant chromosome (Novitski et al. 1981). The four mosomes (Lucchesi 1965); and an alternative to Rhoda arms were arranged in the order 2R 2L Á 3L 3R, where the Grell’s distributive pairing hypothesis (Novitski 1964). dot indicates the centromere. Surprisingly, these bizarre One of Novitski’s lasting contributions has been an ad- chromosomes went through meiosis in both males and dition to the genetic vocabulary. In 1957, calling attention females, although to no one’s surprise, they were trans- to frequent examples of altered segregation ratios, he mitted in reduced proportions. and Larry Sandler coined the expression ‘‘meiotic drive’’ A particularly ingenious example of Ed’s Drosophila (Sandler and Novitski 1957). (For more on Sandler,see trickery occurred early in his career (Novitski 1950). Lindsley 1999.) Soon afterward, Sandler had a golden Mel and Katie Green needed a particular lozenge allele, opportunity to study the phenomenon because of the which was locked in an inversion, too short for a recent discovery by Yuichiro Hiraizumi of Segregation double crossover. Novitski was able to recover the two Distortion in D. melanogaster. Sandler joined Hiraizumi exchanges, one in each of two successive generations. at the University of Wisconsin to work out the details. When paired with a longer inversion, however, a cross- Ironically, this best-known example of distorted segrega- over within the common inverted region produced not tion ratios in Drosophila turned out not to be true meiotic a dicentric and acentric pair, but duplication-deficiency drive, since it depends on sperm dysfunction (Hartl chromosomes. Then, by using triploids and waiting for 1969). Although many cytological and molecular details an unusual segregation, Ed was able to get the comple- are now understood, the molecular basis of the distor- mentary duplication-deficiency chromosomes into the tion process remains a mystery (Ganetzky 1999). 552 J. F. Crow, D. Lindsley and J. Lucchesi

In addition to the chromosome mechanics of Dro- of originality. One example is a picture of several sets of sophila, Novitski contributed a number of insights into identical twins and, without any instruction, the mem- other areas of genetics. He reported a relationship be- bers of a pair held their hands in similar positions. tween the human sex ratio and paternal age (Novitski Among Novitski’s diverse interests was the interpre- 1954b). He found a simple, nonmathematical way of tation of Mendel’s results. Were they too good to be showing that the A and B blood group determinants true? He remained convinced that some of Fisher’s cri- were alleles (Novitski 1982, pp. 403–407). With Everett ticisms were unfounded, or at least that the question was Dempster, he showed that selection against one of two still open. He provided several reasons. Some hinge on homozygous classes can lead to apparent heterosis uncertainty as to the number of plants Mendel scored (Novitski and Dempster 1958), which had caused in determining from progeny which dominant plants some confusion in Drosophila population experiments. were heterozygous. His method of correcting led to a de- One of Ed’s ventures outside Drosophila happened parture from the 2:1 expectation that was opposite and while he was still a student at Caltech. Working with almost equal to Fisher’s correction. Ed’s approxima- C. A. G. Wiersma, he found that the nerves of the cray- tions were mathematically generalized by his son Charles fish heart could be stimulated by chemicals. Seeing (C. E. Novitski 2004). Contrary to several who have that acetylcholine had a stimulating effect, they guessed engaged in this polemic, Ed took the trouble to learn a that this substance was actually produced by the nerve great deal about garden peas. This led him to infer that (Wiersma and Novitski 1942), which has turned out to Mendel very likely used seed-coat color rather than the be correct. While in Curt Stern’s laboratory, he partic- usually assumed flower color in the trihybrid crosses. ipated in a heroic experiment, producing the impor- This made it possible to do all the scoring from seeds, tant result that ‘‘recessive’’ lethals regularly have slight, removing the necessity for progeny testing and making but detectable, viability effects in the heterozygous con- Fisher’s corrections unnecessary (E. Novitski 2004). dition (Stern et al. 1952). This is of great significance Was Fisher’s hypothesis correct? The debate goes on. because this means that the most effective selection Ed’s final paper was published the week of his death against recessive lethals is directed against the much (Novitski 2006). It is a critical appraisal of T. H. more common heterozygotes. The result also supported Morgan, his wonderfully gifted students, and their suc- an earlier observation of Sturtevant that lethals in nat- cessors. In typical Novitski style, it is thoughtful, per- ural populations are less frequent than would be ex- sonal, candid, and sometimes acerbic. From first-hand pected from their mutation rate if they were completely knowledge he makes clear his views of the people and recessive. their research. Ed was a natural and self-taught mathematician; he Ed Novitski also contributed to the advancement of always thought in algebraic terms when considering genetic knowledge of Drosophila through his students problems in chromosome behavior. Therefore it was and postdocs. Among these were Larry and Iris Sandler, natural that he would gravitate toward computers. When Stan Zimmering, John Lucchesi, and Jim Peacock. Dan he arrived at Oak Ridge, he encountered a computer Lindsley and Claude Hinton were his de facto students, called the ORACLE (Oak Ridge Analog Computer and although they were formally students of Sturtevant. He Logical Engine). It was in an air-cooled room full of also influenced a number of undergraduates, including vacuum tubes. Ed set about to learn how to program Nick Cozzarelli, Mark Ptashne, and Charles Laird. using hexadecimal code and later the first version of Despite his powerful intellect and striking originality, FORTRAN. He convened a meeting of a few geneticists Novitski never received a proportionate amount of to introduce them to the new tool and his mathematical recognition. Why? The main reason surely is his insis- proclivities led to fruitful associations with population tence on continuing to work on chromosome mechan- geneticists such as Everett Dempster and Richard ics in Drosophila for its own sake, long after the winds of Lewontin. popularity had moved the center of genetic interest Michael Ashburner has compiled a comprehensive, elsewhere. In a more popular field his ability would three-volume compendium on the biology and genet- surely have brought him to the fore. Nevertheless, ics of Drosophila, which has become an invaluable ref- among Drosophila geneticists, he will always be known erence. Ed coauthored the first volume (Ashburner as the master manipulator of chromosomes. And stories and Novitski 1976). The second was coauthored by about his eccentricities and practical jokes will be told Ted Wright and the third by H. L. Carson and J. N. whenever Drosophilists get together—and will undoubt- Thompson, Jr. edly improve with age. Novitski wrote a textbook on human genetics Edward Novitski is survived by his wife, Esther, whom (Novitski 1982). It was intended for undergraduate he cared for lovingly through her long and difficult dec- students and gave considerable attention to social is- line; two sons, Charles and Paul; two daughters, Barbara- sues, such as radiation effects (an important issue at the Jo and Ellen; and five grandchildren. time), racial differences, and genetic counseling. As Plans are underway in the Genetics Society of America one would expect from Novitski, there were also touches for a Novitski Prize. The details will be announced later. Perspectives 553

We are much indebted to Charles Novitski for help with biograph- Novitski, E., 1964 An alternative to the distributive pairing hypoth- ical information and for many thoughtful and critical comments. esis in Drosophila. Genetics 50: 1449–1451. Novitski, E., 1967 Nonrandom disjunction in Drosophila. Annu. Rev. Genet. 1: 71–86. ovitski LITERATURE CITED N , E., 1978 The relation of exchange to nondisjunction in heterologous chromosome pairs in the Drosophila female. Ashburner, M., and E. Novitski, 1976 The Genetics and Biology of Genetics 88: 488–503. Drosophila. Academic Press, New York. Novitski, E., 1982 Human Genetics, Ed. 2. Macmillan, New York. Crow, J. F., and W. Bender, 2004 Edward B. Lewis, 1918–2004. Novitski, E., 2004 On Fisher’s criticism of Mendel’s results with the Genetics 168: 1773–1783. garden pea. Genetics 166: 1133–1136. Ganetzky, 1999 Yuichiro Hiraizumi and forty years of segregation Novitski, E., 2005 Sturtevant and Dobzhansky, Two Scientists at Odds. distortion. Genetics 152: 1–4. With a Student’s Recollections. Xlibris, Philadelphia. Hartl, D. L., 1969 Dysfunctional sperm production in Drosophila Novitski, E., 2006 Genetics in the early twentieth century—a per- melanogaster males homozygous for the segregation distorter ele- sonal journey. Chromosome Res. 14: 339–347. ments. Proc. Natl. Acad. Sci. USA 68: 782–789. Novitski, E., and G. Braver, 1954 An analysis of crossing over Lindsley, D., 1999 Larry Sandler: personal recollections. Genetics within a heterozygous inversion in Drosophila melanogaster. Genetics 151: 1233–1237. 39: 197–209. Lindsley, D. L., and E. Novitski, 1950 The synthesis of an attached Novitski, E., and D. Childress, 1976 Compound chromosomes X-Y chromosome. Dros. Inf. Serv. 24: 84–85. involving the X and Y chomosomes, pp. 487–503 in The Genetics Lindsley, D. L., and E. Novitski, 1958 Localization of the genetic and Biology of Drosophila, Vol. 1b, edited by M. Ashburner and factors responsible for the kinetic activity of X chromosomes of E. Novitski. Academic Press, London. Drosophila melanogaster. Genetics 43: 790–798. Novitski, E., and E. R. Dempster, 1958 An analysis of data from Lindsley, D. L., and E. Novitski, 1963 Compound chromosomes laboratory populations of Drosophila melanogaster. Genetics 43: involving the X and Y chromosomes of Drosophila melanogaster. 470–479. Genetics 44: 187–196. Novitski, E., and S. A. Rifenburgh, 1938 Heldout, a recessive wing Lucchesi, J. C., 1965 The nature of induced exchanges between mutation in Drosophila melanogaster. Proc. Natl. Acad. Sci. USA 47: the attached X and Y chromosomes in Drosophila melanogaster 256–260. females. Genetics 51: 209–216. Novitski, E., and G. Rush, 1948 Desemination by low temperature Lucchesi, J., 1994 Sturtevant’s mantle and the (lost?) art of chro- shocks. Dros. Inf. Serv. 22: 75. mosome mechanics. Genetics 136: 707–708. Novitski, E., W. J. Peacock and J. Engel, 1965 Cytological ba- Novitski, C. E., 2004 Revision of Fisher’s analysis of Mendel’s sis of ‘‘sex ratio’’ in Drosophila pseudoobscua. Science 148: 516– results. Genetics 166: 1139–1140. 517. Novitski, E., 1946 Chromosome variation in Drosophila athabasca. Novitski, E., D. Grace and C. Strommen, 1981 The entire com- Genetics 31: 508–524. pound autosomes of Drosophila melanogaster. Genetics 98: 257– Novitski, E., 1950 The transfer of mutant genes from small inver- 273. sions. Genetics 35: 249–252. Sandler, L., and E. Novitski, 1957 Meiotic drive as an evolutionary Novitski, E., 1951 Nonrandom disjunction in Drosophila. Genetics force. Am. Nat. 41: 105–110. 36: 267–280. Stern, C., G. Carson,M.Kinst,E.Novitski and D. Uphoff, Novitski, E., 1952 The genetic consequences of anaphase bridge 1952 The viability of heterozygotes for lethals. Genetics 37: formation in Drosophila. Genetics 37: 270–287. 413–449. Novitski, E., 1954a The compound X chromosomes in Drosophila. Sturtevant, A. H., and E. Novitski, 1941 The homologies of the Genetics 39: 127–140. chromosome elements in the genus Drosophila. Genetics 26: Novitski, E., 1954b Sex ratio and paternal age. Science 119: 473– 517–541. 474. Wiersma, C. A. G., and E. Novitski, 1942 The mechanism of the Novitski, E., 1961 The regular reinversion of the roughest inver- nervous regulation of the crayﬁsh heart. J. Exp. Biol. 19: 255– sion. Genetics 46: 711–717. 265.