Perspectives

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

Tending Neurospora: David Perkins, 1919–2007, and Dorothy Newmeyer Perkins, 1922–2007

Rowland H. Davis1 Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697

HE death of David Perkins and his wife, Dorothy compelled to retire ‘‘officially’’ at the age of 70 in T Newmeyer Perkins, just after the new year is a 1989, David maintained an active laboratory at Stanford great loss to fungal genetics, but the work to which they as professor emeritus until his death in 2007. devoted their lives has left the field in vibrant health. Dorothy (‘‘Dot’’) Lorraine Newmeyer Perkins died The contributions that David made, with the long- of natural causes on January 6, 2007, a few days after standing collaboration and support of his wife, extend David. Born on May 28, 1922, she ultimately had four over many areas of study using the model organism, the siblings. Both of her parents were musicians. Dot main- fungus Neurospora. These include pioneering work tained an interest in music, but yearned to have a career on its formal genetics, the most extensive studies per- as a research scientist. Thinking at the time that this goal formed with any eukaryotic microorganism at the time: was unattainable for a woman, she enrolled in the its cytogenetics, its genomic organization, the biology Philadelphia College of Pharmacy and graduated with of its mating systems, and an extensive exploration of its high honors in the mid-1940s. She took a job as a natural populations. During that time, David sustained chemist in a drug factory, but escaped its routines for a the research of investigators worldwide by methodo- position as a lab technician, and later as a graduate logical innovations, running compendia of mutants student, with Edward L. Tatum at Yale University. She and genetic maps, recruitment of women and young completed her Ph.D. at Stanford in 1951, following investigators, and illumination of the path to future Tatum’s move back to the West Coast. She married research problems. He thereby furthered the role of David Perkins in 1952 and worked thereafter on Neurospora as a model for studies of filamentous fungi Neurospora genetics as a Senior Research Scientist in in general for .50 years (Davis 2000). Indeed, no David’s lab. Poor health forced her to work part time in single investigator can claim a greater role in the origin mid-career and to retire early, although she continued and development of the large field of fungal genetics to contribute to the work of the laboratory. and biology. David and Dorothy Perkins are survived by their only David Dexter Perkins died on January 2, 2007, at the child, Susan, born in 1956. In addition to science, the age of 87 in Stanford, California, after a short illness. entire family enjoyed hiking and camping trips in the Born in Watertown, New York, on May 2, 1919, he California coast range and Sierra Nevada Mountains. received his bachelor’s degree in biology in 1941 at the Sue Perkins became a geologist, and she and her hus- University of Rochester. After serving as an intelligence band, John Bergin, live in Seattle. officer in the Army Air Force in England during World War II, David received his Ph.D. degree in 1949 at Columbia University for work in genetics with Francis AMAN,AMODEL,AMISSION Ryan. He took a position in the Biology Department at David entered the field of genetics in one of its glori- Stanford University the same year. Since 1951, David’s ous decades. Beadle and Tatum had begun a revolution- work on the genetics of the fungus Neurospora con- ary program in 1941 with their discovery of mutations in tinued without interruption for 58 years. Although Neurospora that blocked biosynthetic reactions (Beadle and Tatum 1941). Francis Ryan, David’s Ph.D. mentor, 1Author e-mail: [email protected] was an early postdoctoral associate of the Beadle–Tatum

Genetics 175: 1543–1548 (April 2007) 1544 R. H. Davis

products (ascospores) of a single meiosis, together with the increasing availability of biochemical markers, pop- ularized Neurospora for genetic investigations. With the further investigations and development of standard strains by Carl Lindegren in the 1930s and the Beadle laboratory in the 1940s, tetrad analysis came into its own, and David became one of its greatest practitioners. Formal genetic work and the formation of the Neu- rospora community: David’s early work on N. crassa focused on linkage analysis using tetrads and random progeny to study mapping functions and interference and to construct dependable genetic maps. The methods were especially useful for species with unordered tetrads. He could now use many new mutants isolated in his own and other laboratories, especially Beadle’s, which had by then moved to the California Institute of Technology. At this time, he and Dot had teamed up Figure 1.—David and Dot Perkins in the 1970s. Photo- with Raymond Barratt, another Tatum student, to pub- graph kindly provided by Susan Perkins. lish the first ‘‘compendium’’ of Neurospora mutants in 1954 (Barratt et al. 1954). This was less a curatorial job than the first bible of Neurospora genetic theory and laboratory at Stanford in 1941 and returned to his home techniques. The long work included not only theoret- base at Columbia University, dedicated to the study of ical analysis of recombination, but also phenotypic de- microbial and biochemical genetics. After World War II, scriptions of all known mutants and their alleles and David joined Ryan as one of the first generation of maps of Neurospora’s seven chromosomes. Barratt had students in the new era. David, inspired by Neurospora already proposed the main nomenclatural and certain tetrad analysis, chose the corn pathogen, Ustilago maydis, other conventions of the field. Their joint work led for his thesis work, but switched to Neurospora there- Barratt, at Dartmouth after 1954, to establish the Fungal after, doubtless recognizing its methodological advan- Genetics Stock Center, to organize the first Neurospora tages and the increasing visibility of Neurospora research. Information Conference (now the Fungal Genetics Con- David eschewed direct involvement in biochemical work ference), and to publish the Neurospora Newsletter (now and instead embarked upon detailed studies on the the Fungal Genetics Newsletter). These achievements estab- genetics of Neurospora, which he continued for the rest lished and bound together a Neurospora research com- of his career. This put him in a unique position as a munity that has endured to this day. David, while still pioneer in the genetics of haploid eukaryotes and as the collaborating with Barratt in the curatorial work, con- facilitator of research by all later investigators who used tinued his steady output of original work. He would Neurospora as an experimental organism. As Charley soon become the central player in keeping the Neuros- Yanofsky said in a recent memorial, ‘‘Beadle and Tatum pora community together and in defining Neurospora initiated research using this organism, but it was David as a model organism for many areas of research. Part of who made certain that this interest would continue.’’ the success of this effort reflects David’s instilling a lack The sexual phase of Neurospora was discovered by of competitiveness into the field as a whole; he shared B. O. Dodge (Shear and Dodge 1927). An arresting and trusted, expecting the same from others. (A para- feature of the eight-spored species, N. crassa and N. gon of fairness, he never put his name on articles from sitophila, was the alignment of meiotic products (each his lab unless he had done some of the experimental duplicated in a postmeiotic division) in the linear tet- work.) rad, or ascus. The products of the first-division segrega- Chromosomal aberrations and cytogenetics: In the tion remain in the upper and lower halves, and the early 1960s, David focused on chromosomal aberra- second-division segregation products remain adjacent. tions. X-ray and ultraviolet mutagenesis, the latter Dodge discovered not only that alleles of a single gene commonly used by Neurospora workers, yield chromo- (the mating type A/a, in his case) segregated 4A:4a, but somal rearrangements, some associated with mutations also that some asci displayed a 2A:2a:2A:2a pattern. The at the breakpoints. David’s linkage studies uncovered latter was interpreted by Beadle, among others, as a these aberrations, which he interpreted straightfor- result of second-division segregation, showing clearly wardly as chiefly reciprocal or insertional translocations. that crossing over occurred at the four-strand stage of Such rearrangements led to characteristic patterns meiosis. Analysis of tetrads displayed the highly de- of ascospore abortion in tetrads. David developed his terministic nature of meiosis more clearly than earlier observations into a methodology of detecting and char- analyses. Nevertheless, the technical ease of dissecting acterizing genetic aberrations in ways the rest of the Perspectives 1545 community could use routinely for creating duplica- gone from what many might have considered an exotic tions, deficiencies, and fine-scale mapping of closely hobby to a major tool in the study of genome dynamics linked mutants by duplication coverage. in this simple organism. One of the most useful tools emerging from this work In 1974, Namboori Raju (‘‘Raju’’) joined the Perkins was a multiply translocated strain called alcoy, in which laboratory and extended its work in important ways. interchanges had occurred among six of Neurospora’s For .32 years, Raju worked closely with David, taking seven chromosomes (Perkins et al. 1969). The strain advantage of a variety of mutants affecting meiotic also carried the ‘‘visible’’ mutations al-1, cot, and ylo development in Neurospora. The cytological insight (albino, colonial temperature sensitive, and yellow, emerging from this work is without parallel in the fungi respectively). Because translocations restrict recombi- (Raju 1992). This side of the laboratory’s effort has nant survival, the chromosome assignment of a new contributed to the remarkable molecular biological mutation could be inferred by visual inspection of knowledge of meiosis, covering nuclear interactions, progeny in as little as a single cross. Follow-up crosses spore delimitation, gene expression in the meiotic could quickly lead to the assignment of the map posi- stages (through the use of green fluorescent protein), tion of the alteration in the new mutant. This enabled and meiotic silencing. The work has illuminated in even biochemists unfamiliar with genetics (or, more retrospect much of the previous work in the laboratory commonly, their students unfamiliar with genetics) to about the formal genetics of aberrant chromosomes, map new mutations and to submit the information to the behavior of duplications and deficiencies in meiosis, the Fungal Genetics Stock Center. Through contribu- and the many mutant loci affecting ascus development tions like alcoy and a variety of efficient genetic and (many initially isolated by Dot). microbiological techniques, David’s laboratory took Genetics of natural populations: Eighty-four years its place as an international intellectual resource. His separated the description of the asexual and the sexual laboratory underlay the growing fusion of genetics phases of Neurospora. As indicated above, mating is with biochemistry and, eventually, with molecular bio- governed by the mating-type locus, with two alleles. Both logy, in Neurospora research. strains can mate as males (in the lab, via asexual spores, The major outcome of the work on chromosomal or macroconidia) or females (via protoperithecia, the aberrations in David’s own laboratory was the develop- unfertilized sexual structure). Yet, only strains of oppo- ment of Neurospora cytogenetics, at first in collabora- site mating type can cross, rendering Neurospora an tion with his student, Edward Barry (Perkins and Barry outbred species. Perithecia, the fertilized female struc- 1977; Perkins 1997). McClintock and Singleton had tures in which the meiotic cells develop, rarely become shown that the cytology of meiosis in Neurospora was visible in nature. However, Neurospora colonies appear orthodox (McClintock 1945; Singleton 1953), and rapidly after fires in forested areas or areas with burned David showed that chromosomal aberrations behaved as vegetation, revealing themselves with their abundant they did in corn. But the cytogenetic work soon became tufts of orange macroconidia. This is consistent with the a window on novel phenomena of considerable interest, knowledge that, in the laboratory, ascospore germina- some of which continue to surprise current researchers. tion requires heat activation, a technique used in the Most duplications, arising in crosses of translocations laboratory since the time of Dodge. David began to with normal-sequence strains, are viable (although pursue the biology of natural Neurospora populations mostly infertile with the standard strain). These pro- with simple questions: Was Neurospora a clonal species, vided material for the study of gene dosage and the propagating locally by means of macroconidia? What relation of alleles in a single nucleus vs. their relation in are the means of dispersal of Neurospora propagules? Is heterokaryotic mycelia (where alleles are located in the mating pool global, regional, or highly parochial? different nuclei). It also provided, through duplications What is the genetic heterogeneity in local and global arising in standard X translocation crosses, the means populations? These matters had rarely been investi- for detecting and analyzing the variety of vegetative gated in haploid eukaryotes, and David recognized incompatibility genes in nature: heterozygotes for such Neurospora as extremely favorable material for such genes (arising as duplications in meiosis) are likely to be studies. seriously debilitated as the result of incompatibility After some difficulty with collections of airborne reactions (Mylyk 1975). More recently, David showed spores, David decided to sample Neurospora spp. all over that nonhomologous (ectopic) integration of trans- the world, both by travel and by asking trusted collab- forming DNA is often associated with chromosomal orators to make collections in their areas. He rarely went aberrations. The sterility of many duplication strains can abroad without a large supply of collection envelopes. now be attributed in many cases to extensive repeat- He visited exotic locations spanning the globe from induced point mutation (RIP) in the premeiotic stage of Indonesia, Africa, South America, and much of the rest the ascus (Selker 1999) or to meiotic silencing of of the habitable world (and, as Ambrose Bierce would unpaired DNA during meiosis itself (Shiu et al. 2001). say, Canada). His letters home about his adventures rival The extraordinary collection of aberrant strains has his scientific findings in interest. 1546 R. H. Davis

Barbara Turner joined the laboratory in the 1960s. elements kill sibling ascospores that do not carry them, She was mainly responsible for processing the collected leading to segregation distortion similar to meiotic drive material, beginning with David’s first collecting trip in elements in Drosophila, but more accessible to exper- 1968. She developed testers for species assignments, imental work. Studies on the geographic distribution, purified strains, maintained the expanding records, heterogeneity, cytology, and suppression of meiotic and worked independently on novel findings (Perkins gene silencing by Sk elements have preoccupied the et al. 1976; Perkins and Turner 1988). By the time of the laboratory for .30 years (Turner 2001; Raju 2002). last publication on wild-collected strains (Turner et al. David, with his enormous body of work on genetics, 2001), a massive amount of work had been done with cytogenetics, and population biology, remained in close the strains by the Perkins laboratory and many others contact with Neurospora workers around the world, around the world. As David concluded early on, ‘‘The both at meetings and in reciprocal visits between labo- collections are a source of variants in structural and reg- ratories. He was a superb listener. Participants at the ulatory genes, of genes governing vegetative incompat- official meetings of Neurospora workers and fungal ibility, and of information on genetic variability within geneticists at the Asilomar Conference Center near and between populations’’ (Perkins et al. 1976, p. 310). Stanford would extend their stays by visiting his labora- The findings arising from the wild collections sur- tory. His interests were broad, his memory phenomenal. prised most of us. First, using multiple samples from Years after a visit, he would send a short note or card to single areas, the laboratory established that .75% of the visitor, bringing to his or her attention an item or new colonies were homokaryotic and that the mating idea that might be helpful. Such attention from David types of colonies were approximately equal in frequency. was more than flattering to investigators; it inspired new Later it was found that heterokaryon compatibility experiments and bound them more closely to the alleles (which restrict mycelial fusion) were quite di- community. verse among samples (Mylyk 1976) and that allozyme The genomic era: David’s continuing attention to variation in one site was comparable to the variation his resources for the Neurospora community led him among all the sites sampled in a broader area (Spieth to take part in the advent of molecular work on the 1975). Second, crosses of samples from widely separated organism, beginning in the 1980s. His laboratory was a areas were usually fertile, rendering fertility with au- source of particular strains and other genetic tools for thentic testers the most practical indicator of species molecular biologists. At this time, Charley Yanofsky, (Perkins 1994). In fact, a new species, N. discreta, was after many years of work on bacteria, returned to Neuro- identified during the course of such tests (Perkins and spora research at the instigation of his student, Erik Raju 1986). Selker. Charley’s laboratory was across the hall from the The conclusions from this work were that ascospores Perkins laboratory. Together, David and Charley fos- initiate most Neurospora growth following fires and tered a new generation of research on Neurospora by a that, although conidia are produced in abundance, they sophisticated group of graduate students and post- are not viable for long and may not account for long- doctoral associates. The informal collaboration and range dispersal. They could, however, account for local social interactions of the two laboratories speeded the dispersal in unburned substrates such as bakeries, sugar pace of discovery and placed Neurospora in the cane processing plants, and the like. An interesting, forefront of molecular research on fungi. detailed study of this matter has been published by By the mid-1980s, molecular approaches to all fungi Pandit and Maheshwari (1996). David Jacobson, were the norm, and, now sharing a common language, a more recent senior associate in the laboratory, has the field of fungal genetics and biology was born (Davis promoted more extensive studies of Neurospora in and Perkins 2002). Workers on all species of filamen- nature. Studies emerging from this work have given tous fungi recognized the importance and the uses of more texture to the picture of variation and dispersal of the model organism that Neurospora had become for Neurospora spp. It may be that these plants may have to this group of organisms. David’s genetic work greatly die (by fire or other means) before they become sub- facilitated the sequencing of the N. crassa genome, com- strates for profligate growth of Neurospora; ascospores plete by 2000 (see Galagan et al. 2003). It was a great may be activated more often in nature by chemicals (e.g., satisfaction to him and the field that the last major furfural) released by decaying plants than by heat; and compendium of Neurospora mutants and maps, pub- the identity of propagules that initiate infections re- lished in 2001 (Perkins et al. 2001), could incorporate mains unclear (Powell et al. 2003), especially in view the molecular findings of many genes. The molecular of the very few reports of finding perithecia in nature. research on Neurospora to which the Perkins laboratory A remarkable novel factor turned up early in the study contributed include studies of mating type, the RIP of the wild-collected strains. Turner and Perkins process, biological clocks, vegetative and meiotic gene (1979) detected strains of N. sitophila and N. intermedia silencing, evolutionary studies of individual systems (the carrying chromosomal meiotic drive elements named mating-type chromosome especially), the genome se- Spore killer (Sk-1, -2, and -3). In individual asci, these quence of N. crassa, and the origin and differences Perspectives 1547 among Neurospora spp., especially by molecular phylo- she absorbed a great deal and could point to missing genetic means (e.g.,Skupski et al. 1997; Dettman et al. elements in almost any scientific argument that her 2003). Thus the Perkins laboratory became a virtual friends might make. She did so with a relentless logic continent on which Neurospora studies have evolved, and an equally relentless decency that inspired those and on which the rest of fungal genetics received its with whom she spoke. bearings and began to diversify in its own new ways. Her intellectual strength, combined with equal de- David took pride that he was funded by the National votion to David and to good science, made her a fit Institutes of Health (NIH) continuously for a record 42 collaborator and companion for the 54 years of their years and by the National Science Foundation for all his marriage. Unhappily, her health began to fail in the years of research thereafter. He received an NIH Re- 1970s and she therefore had less to give to the laboratory search Career Award (1964–1989) and an NIH MERIT as time went on. Nevertheless, she remained engaged Award (1987–1996). with scientific interests, political activity, music, and lit- David was a citizen of science. In the world of genetics, erature until late in life. Through her life, we can ap- he contributed his scientific findings in a modest, but preciate how far we have come in bringing women to very public way. He assumed the job of editor-in-chief biology (if not to the other sciences). She was a woman of Genetics (1963–1967), reviving the journal from a in the science of her time, working with enthusiasm and period of decline in quality and timely publication. He responsibility in an environment illuminated by an became president of the Genetics Society of America equally gracious and generous husband. in 1977. He was elected to the National Academy of Sciences in 1981, was named a Guggenheim Fellow from A MARRIAGE OF TWO MINDS 1983 to 1985, and was awarded the Genetics Society of America Morgan Medal in 1994. The British Mycolog- Dot and David shared personality traits and interests. ical Society made him an Honorary Member in 2005. They will be remembered by friends well after their laboratory’s contributions become ‘‘nameless’’—that is, so embedded in the field that the discoverers are no A WOMAN IN SCIENCE longer cited. Both of them grew up in strong families As I indicated at the beginning of this article, Dot was that became impoverished during the Great Depres- understandably unsure of a future in science. She took sion. They learned the values of hard work, frugality, a tortuous path from pharmacy, to the biomedical education, cooperation, and generosity. These traits industry, to a role as a lab technician, and finally to were strengthened as they worked their ways through her Ph.D. work with Tatum. Unlike David, her original college and graduate school. They were generous to interests lay in biochemical genetics, developing rapidly visitors, carried on continuous correspondence with in Tatum’s laboratory with her thesis and first publica- friends and colleagues, and collaborated with no sense tion on tryptophan mutants of Neurospora (Newmeyer of ownership of a research program. They were both and Tatum 1953). Once she became part of David’s life knowledgeable and interested in research far from their and lab, she contributed greatly to the formal genetics own activities, allowing David to speak and write about of Neurospora, making many independent contribu- them lucidly. They nurtured the careers of those new to tions. However, she continued with biochemical genet- the field, especially the young, and set an example of ics with her definitive genetic studies of the last steps personal and scientific integrity for the field. of arginine metabolism (Newmeyer 1962), work that Charley Yanofsky always found David at work on crucially complemented my own later studies. weekends, and he endured interruptions with grace Her involvement with David’s genetic studies deepened and attention. He bicycled to work to arrive 6 o’clock with time, yet her publications reflect the independence in the morning, used the stairs instead of the elevator, with which she worked. She sought increasingly to tie up and even in his 80s, lay on the floor under his desk in the loose ends. She pursued issues meticulously, extending lab to get regular rest around noon. Dot was an ardent the formal genetics of unassigned mutants, describing peace activist, and despite her shyness and poor health, the effect of duplications, and refining the phenotypic she did as much as she could to petition the government description of problematic strains. It is a tribute to both to refrain from war. She drew David into this effort David and Dot that David did not co-author publications despite his own preoccupation with the laboratory. Both that were truly her work, nor did either one hesitate to of them lived their sense of social responsibility, with a co-author articles on which they clearly collaborated. modest house and simple personal habits. Both insisted Others recall in a memorial tribute (http://www. on integrity in political argument and reacted strongly stanford.edu/group/neurospora/index.html) that it and clearly to mendacities of the governing elite. was she who did the final editing of David’s articles, According to Susan Perkins, David spent increasing making sure that his or their arguments were clearly tied amounts of time and energy in his last years taking care to the data. Indeed, as I and many others attest, her of household affairs and of Dot as her health worsened. interests remained extremely broad. In conversation, He hired day-time help for Dot and mostly managed to 1548 R. H. Davis get to the lab 5 or 6 days a week. Generous to the end, he Pandit, A., and R. Maheshwari, 1996 Life-history of Neurospora in- spent much of his time facilitating the work of other termedia in a sugar cane field. J. Biosci. 21: 57–79. Perkins, D. D., 1994 How should the infertility of interspecies researchers and assuring the continuation of Neuro- crosses be designated? Mycologia 86: 758–761. spora’s role as a model experimental organism by con- Perkins, D. D., 1997 Chromosome rearrangements in Neurospora tributing to the online Neurospora Methods Protocols and other filamentous fungi. Adv. Genet. 36: 239–398. Perkins, D. D., and E. G. Barry, 1977 The cytogenetics of Neuros- (http://www.fgsc.net/neurospora/neurospora.html). pora. Adv. Genet. 19: 133–285. He could devote little time to his own experiments, but Perkins, D. D., and N. B. Raju, 1986 Neurospora discreta, a new het- some months before his death he celebrated submitting erothallic species defined by its crossing behavior. Exp. Mycol. 10: 323–338. the final version of an article to Genetics, work that Dot Perkins, D. D., and B. C. Turner, 1988 Neurospora from natural pronounced ‘‘a masterpiece’’ (Perkins et al. 2007). populations: toward the population biology of a haploid eukary- As shining examples of openness, diligence, breadth ote. Exp. Mycol. 12: 91–131. Perkins, D. D., D. Newmeyer,C.W.Taylor and D. C. Bennett, of interest, and robust conscience, they leave us grateful 1969 New markers and map sequences in Neurospora crassa, with for the riches they bestowed on the world of science and a description of mapping by duplication coverage and of multi- their global community of friends. ple translocation stocks for testing linkage. Genetica 40: 247–278. Perkins, D. D., B. C. Turner and E. G. Barry, 1976 Strains of Neu- I deeply thank David Jacobson, Barbara Turner, Charles Yanofsky, rospora collected from nature. Evolution 30: 281–313. erkins adford achs Robert Metzenberg, Namboori Raju, and Susan Perkins for their P , D. D., A. R and M. S. 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