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ROBERT W. BRIGGS December I0, I9'I-March 4, 1983 BY MARIE A. DI BERARDINO PROFESSOR ROBERT BRIGGS made pioneering research con- tributions in the clevelopmental genetics of amphibia for over four clecacles. His chief embryological interest was to unclerstanc! the genetic control of clevelopment. This focus lee! him to stucly, among other areas of research, two major problems: the clevelopmental potential of nuclei clur- ing embryogenesis by means of nuclear transplantation into oocytes en c! the role of maternal gene products in the cle- velopment of the embryo. He proviclec! the basis for cur- rent research on cloning metazoan animals en c! the genetic control of pattern clevelopment. Briggs clevelopec! with Thomas l. King a technique to transplant living frog nuclei from embryonic cells into an oocyte whose own nucleus hac! been removed. They fount! that many nuclei clirectec! normal clevelopment of the oo- cytes from early embryonic stages, whereas only a few nu- clei clic! so from acivancec! embryonic stages, indicating that most nuclei acquire restrictions concomitant with cell spe- cialization. The results of these classic studies are, still to- ciay, consistent with the changing patterns of gene expres- sion occurring cluring embryogenesis that are controller! by relatively stable alterations in the chromosomal proteins en c! DNA methylation. At least two aciclitional results ema- natec! from the nuclear transplantation studies: many acI- vancecI-stage nuclei undergo significant reprogramming of 51

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52 BIOGRAPHICAL MEMOIRS molecular function by the oocyte cytoplasm, en c! the nuclear transplantation procedure became the prototype for clon- ing metazoan animals. To unclerstanc! how genes control embryonic clevelop- ment, Briggs initiates! a program on the effect of maternal gene products in the oocyte on the clevelopment of the embryo of the Mexican axolotI, a salamancler. These stucI- ies were performed by analyzing the embryological, cellu- lar, en c! molecular changes in embryos cleveloping from oocytes whose mothers carrier! mutations. Thus, the abnor- mal gene products proclucec! in the growing oocytes re- vealec! how oocyte gene products control the initial stages of embryogenesis. This research in amphibia was one of the initial studies that revealer! how maternal gene procI- ucts control early pattern formation. I shouic! point out why I was asker! to write this memoir of Bob Briggs. I knew Bob for thirty-five years, first joining his laboratory in 194S, just two years before he embarkoc! on the nuclear transplantation experiments. By ~ 950 he hac! recruitec! Tom King, then a research fellow, to colIabo- rate on the project, en c! in 1952 they hac! their first success. Later, in the 1950s en c! early 1960s, I hac! the pleasure of collaborating with Bob on some of the nuclear transfer studies en c! cluring his years at Indiana University (1956-83) I main- tainec! contact with him. When he became research profes- sor emeritus, he remarkoc! that he felt like a postcloctoral fellow he conic! now enjoy research with no other respon- sibilities. Unfortunately, he cliec! approximately a year later. Much of what I know of Bob stems from working with him, listening to his anecdotes at 4:00 p.m. tea breaks in Philaclelphia, en c! the contact I hac! with him in later years when he was in Bloomington. Quotations that follow came from an interview concluctec! by Elizabeth Knight Patterson (no ciate) that were incorporates! in her book.

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ROBERT W. BRIGGS EARLY PERSONAL HISTORY 53 Robert William ("Bob") Briggs was born in Watertown, Massachusetts, in 1911. When he was less than two years oIcI, his mother en c! brother cliec! of tuberculosis, en c! he was raised by his grandparents (1913-29) in Epping, New Hampshire, a small town of about 1,600 people locater! in the southeastern part of the state. He grew up with his uncles en c! aunts, one of whom was only ten years oicler than Bob. He hac! a happy chilc~hoocI, as "there was an enviable stability en c! security in the social structure." Al- though his family "was rather poor like most of the other families," they clic! own a piano, en c! Bob took lessons from an aunt for several years. He recallecI, "I ciriftec! away from the piano, but the influence was a permanent one, en c! music has been a part of my life in one way or another ever since. " ~O 1 ~ At fourteen, he began to work in the summer at the local shoe factory. In the winter, he earnec! money "as a banjo player in a small ciance bane! that playact two to three nights a week for ciances in southeastern New Hampshire towns." Bob credits a teacher in high school for leacling him into biology. "The teacher turner! the students loose on projects of their own." Bob collected minnows, frogs, insects, worms, plants, etc., en c! stucliec! them uncler magnifying glasses en c! a borrower! microscope. "The effect of merely looking at life at a different level was a lasting one. At the time it never occurrec! to me that I wouIc! become a biologist, I clicin't even know that one conic! earn one's living this way." After high school, Bob left home for Boston, where he "got a job working nights en c! attenclec! classes by clay at Boston University." Initially, he enrollee! in the College of Business Administration to prepare himself to make a liv- ing. His lack of interest in those courses lee! him to take

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54 BIOGRAPHICAL MEMOIRS some science courses in the College of Liberal Arts. Still concernec! about making a living, he also took courses in the School of Education. In 1934 he gracluatec! with a B.S. and, firmly convincer! that his future was in science, went to graduate school at Harvarc! University. Uncler the spon- sorship of Leigh HoacIley, Bob "macle a cletailec! analysis of changes in metabolic rate en c! density cluring the clevelop- ment of the frog." During graduate school he was an Austin teaching fellow in biology ~ ~ 935-36), hell! an assistantship (1936-38), en c! continues! his night job. In 1938 he receiver! his Ph.D. RESEARCH CONTRIBUTIONS The contributions of Robert Briggs to clevelopmental bi- ology spanner! over four clecacles en c! comprises! four main periods of pioneering research in amphibian clevelopment, involving neoplasia, ploicly, nuclear transplantation, en c! maternal genes. After receiving his Ph.D. degree, he be- came a fellow in the Zoology Department at McGill Univer- sity (1938-42~. Here he initiates! his first periocI, the charac- terization of tumor growth in the cleveloping frog, for he recognizec! the importance of studying the behavior of tu- mors in the organization fielcis operative in cleveloping sys- tems. He was the first to incluce tumors in a cleveloping system, the larvae of Rana pipiens, en c! clic! so with a carci- nogenic agent (1940~. Also, he was the first to examine the effect of a cleveloping organism on a malignant tumor. He transplanted fragments of the frog renal adenocarcinoma (Lucke tumor) to various sites of the larva en c! fount! that they grew well, but regressed prior to metamorphosis. He also fount! that goof! growths regressed even in tacipoles in which metamorphosis was prevented by removing the pitu- itary or thyroid gland ( 1943~ . He suggested that regression of this malignant tumor might be "an expression of the

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ROBERT W. BRIGGS 55 clevelopment of tissue specificity." Extensions of this research can be fount! tociay in studies of the clevelopment of immu- nocompetence, tumor immunosurveilIance, en c! attempts to normalize cancer cells in embryonic systems. In his seconc! perioc! he focuses! on the role of the nucleus in clevelopment. This occurrec! in 1942 after he joiner! the Lankenau Hospital Research Institute (later the Institute for Cancer Research en c! now the Fox Chase Cancer Cen- ter) in Philaclelphia. First, he clevelopec! a methoc! for pro- clucing anuran triploicis with heat shock en c! analyze c! the effect of ploicly on clevelopment. He fount! that the trip- loicis clevelopec! normally (1947), except female gonads usu- ally reverser! to testes (1950~. One practical outcome of this work was the availability of a triploic! marker later to be user! wiclely in frog embryos for various types of studies. The stucly on sex reversal in anuran triploicis was clone in collaboration with Rufus R. Humphrey ant! Gerharc! Fankhauser. His association with Professor Humphrey later culminates! in a research program in amphibian clevelop- mental genetics at Indiana University. His investigation of the haploic! syndrome shower! that reduction of egg cytoplasm clecreasec! the severity of the haploic! syndrome, but it clic! not overcome the abnormali- ties (1949~. This work shower! that the nucleocytoplasmic ratio playoc! a role in the haploic! syndrome, but it sug- gestec! that cleleterious genes were mainly responsible for the haploic! abnormalities. Next, the production en c! analy- sis of embryos lacking functional chromosomes shower! that anuran embryos lacking a functional nucleus but contain- ing a normal cleavage center can clevelop into partially cleaver! blastulae (1951~. This stucly, preciating the explosion of the molecular biology of embryos, inclicatec! that gene procI- ucts former! cluring amphibian oogenesis are sufficient to support cleavage, but post-blastula clevelopment requires

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56 BIOGRAPHICAL MEMOIRS new gene products. In aciclition, this study lair! the founcia- tion for the interpretation of nuclear transplantation ex- periments that occupier! his thirc! perioc! of research. In 1952 in collaboration with Thomas J. King, Briggs pio- neerec! the clevelopment of the technique of amphibian nuclear transplantation in determining whether somatic nuclei remain equivalent to the zygote nucleus in clevelop- mental potential cluring embryogenesis, a question poser! previously by H. Spemann and others. Briggs and King ini- tially focuses! on cell nuclei from uncleterminec! regions of the embryo en c! shower! that, after transplantation singly into enucleated frog eggs (R. pipiens), many of these nuclei clirectec! the eggs to clevelop into normal tacipoles (1952) en c! in a later stucly into normal metamorphosec! frogs (1960~. This was the first time successful nuclear transplantation hac! been accomplishes! in metazoans. Subsequently, they testec! nuclei up to tailbuc! stages en c! fount! that simulta- neously with cell differentiation there is a progressive de- crease in the percentage of nuclei capable of supporting normal clevelopment (1977~. The importance of this tech- nique was immecliately recognized, en c! Bob generously hostel! in his laboratory numerous scientists to help them learn the procedure. Soon various laboratories arounc! the worIc! applier! this technique to different amphibian species en c! confirmed! the clecreasec! clevelopmental potential of most nuclei concurrently with advancing embryogenesis. The conservative conclusion in the classic ~ 952 paper was that "although the methoc! of nuclear transplantation shouIc! be valuable principally for the stucly of nuclear clif- ferentiation, it may also have other uses." Some of its appli- cations have been the analysis of haploidy, hybrid incom- patibility, cancer, immunobiology, and cellular aging. It provided insight into the cytoplasmic control of nuclear en c! gene function, inclucling reprogramming of nuclear

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ROBERT W. BRIGGS 57 en c! gene function. Most importantly, nuclear transfer be- came the prototype for cloning metazoan organisms en c! was extenclec! to insects, fish, en c! mammals. In 1997 the first metazoan animal (a lamb, Dolly) was clones! from an aclult cell, en c! this was follower! in 1998 by the cloning of mice en c! calves from aclult cells. During this period, the first transgenic lambs carrying the human gene (clotting factor IX) were clones! from fetal cells en c! the first transgenic calves were clones! also from fetal cells. The funciamental research begun in 1952 will now be transTatec! into impor- tant biomeclical en c! agricultural applications. In 1956 Bob Briggs resigner! from his post as heat! of the Embryology Department at the Institute for Cancer Research en c! became professor of zoology at Indiana University. He then embarkoc! on his fourth en c! final perioc! of research, the establishment of amphibian clevelopmental genetics. He hac! been convincer! for some time that the gap between embryology and genetics needed to be bridged in order to unclerstanc! how the nucleus interacts with the cytoplasm in directing embryonic development. Recognizing the impor- tance of the genetic lines of Mexican axolot! (Ambystoma me~cicanum) that Professor Rufus Humphrey hac! clevelopecI, Bob recruitec! Humphrey to Indiana University soon after Humphrey retiree! from his post at the University of Buffalo Meclical School (now the State University of New York at Buffalo). Humphrey became research scholar in the De- partment of Zoology, en c! together they built the research program in the clevelopmental genetics of axolotI. Briggs realizer! that the clevelopmental genetics of early clevelopment wouIc! be revealer! best by mutations showing a maternal effect (i.e., those that were expressed in the embryo regarcIless of the normal genes contributes! by the sperm). Previous experimental embryologists hac! shown that the pattern of early clevelopment is controller! by morpho

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58 BIOGRAPHICAL MEMOIRS genetic substances proclucec! cluring oogenesis en c! present in the egg cytoplasm at fertilization. Genes that exertec! maternal effects through mollifications of the egg cytoplasm were therefore of special interest, as they proviclec! a means to stucly how the egg cytoplasm acts to control early embry- onic clevelopment. Several such genes en c! others that act later were fount! by Humphrey. For example, four muta- tions cause early arrest. One in particular, the o+ gene, pro- clucec! a substance cluring oogenesis that is requires! for clevelopment beyonc! gastrulation. Injections of cytoplasm or nucleoplasm of germinal vesicles from normal oocytes into mutant eggs correctec! the deficiency, resulting in nor- mal clevelopment (1966~. Eight other genes exertec! spe- cific effects on embryonic organs, whereas four causer! al- terations in pigment cells en c! four clic! so in nucleoli (1973~. The action of these mutant genes on clevelopment was eluciciatec! by various methods (cytological, biochemical, embryological, molecular, and physiological) by Briggs, Humphrey, students' and others. In his 1973 review' Brings ' '7 - - -at - credits especially the pro- and postdoctoral students, who in many cases publisher! their finclings inclepenclently. This was the policy of Bob, who gladly counseled students, but encouragec! them to clevelop on their own. Various axolot! mutants en c! others to be cliscoverec! were supplier! to other investigators for their research projects, en c! this continues tociay at the axolot! colony of Indiana University. The stucI- ies on maternal genes initiates! in the ~ 950s proviclec! a backgrounc! en c! direction for the elegant molecular ge- netic experiments of others to follow in Drosophila, Xenopus, zebrafish, chorciates, en c! invertebrates, in which many genes contributing to pattern formation have been identified and, in the best cases, several genes acting in a specific bio- chemical pathway have been recognizec! en c! eluciciatecI. Bob retiree! in 1982 en c! became research professor emeri

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ROBERT W. BRIGGS 59 tus at Indiana University. He continues! his research at this time on a newly cliscoverec! temperature-sensitive mutant in the axolotI. One of the projects was completec! before his cleath from kidney cancer on March 4, 1983, en c! was pub- lishec! posthumously (1984~. He cliec! in the Krannert Pavil- ion of the Indiana University School of Medicine in Inclia- napolis, en c! was survives! by his seconc! wife Francoise en c! two sons en c! a daughter: Evan of Bloomington, Indiana, Alexancler of HilIsciale, New York, en c! Meredith Briggs Skeah of Green Village, New Jersey. His former wife, Janet Bloch Briggs of HilIsciale, en c! mother of his chilciren also sur- vivec! him. HONORS AND OTHER CONTRIBUTIONS Bob Briggs was the recipient of various honors, inclucling election to the American Academy of Arts en c! Sciences ~ ~ 960) en c! the National Academy of Sciences ~ ~ 962) . He was namer! research professor of zoology at Indiana Univer- sity (1963) en c! fellow of the International Institute of Em- bryology. He was awarclec! honorary doctorate degrees by the Meclical College of Pennsylvania (1971) en c! Indiana University (1983~. In 1973 the French Academy of Sciences awarclec! him en c! Thomas I. King the CharIes-LeopoIc! Mayer Prize for their pioneering studies in amphibian nuclear trans- plantation. During his career he participates! in many ma- jor symposia, servec! on eclitorial boards of important jour- nals, en c! proviclec! intellectual leaclership as chair of zoology (1969-72) at Indiana University. CODA Bob Briggs will be remembered both as an outstanding scientist en c! a generous en c! corclial human being. He left a legacy not only of pioneering research but also a legacy of numerous problems for other investigators to pursue. He

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60 BIOGRAPHICAL MEMOIRS enjoyoc! life en c! hac! numerous hobbies, inclucling listener en c! performer of classical music, as well as golfer, bowler, en c! sports car en c! motorcycle enthusiast. His earlier inter- est in playing classical music on the piano was followed by playing the recorder. As early as the 1950s, he owner! an Austin-Healy, later a Corvette, en c! finally a top-of-the-line BMW motorcycle. He frequently sharer! these pastimes with students and colleagues, including his weekly Sunday morning golf. REFERENCES Etkin, L. D. 1998. Personal communication. Tustus, T. 1998. Personal communication. Malacinski, G. M. 1998. Personal communication. Patterson, E. K. No date. Growth The Early History of a Cancer Re- search Institute (1927-1957J. Philadelphia: Talbot Research Library of the Fox Chase Cancer Center and American Philosophical Society.

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ROBERT W. BRIGGS SELECTED BIBLIOGRAPHY 1940 Tumour induction in Rana pipiens tadpoles. Nature 146:29. 1942 61 Transplantation of kidney carcinoma from adult frogs to tadpoles. Cancer Res. 2:309-23. 1943 With R. Grant. Growth and regression of frog kidney carcinoma transplanted into the tails of permanent and normal tadpoles. Cancer Res. 3:613-20. 1947 The experimental production and development of triploid frog embryos. 7. Exp. Zool. 106:237-66. 1949 The influence of egg volume on the development of haploid and diploid embryos of the frog, Rana pipiens. J. Exp. Zool. 111:255-94. 1950 With R. R. Humphrey and G. Fankhauser. Sex differentiation in triploid Rana pipiens larvae and the subsequent reversal of fe- males to males. 7. Exp. Zool. 115:399-428. 1951 With E. U. Green and T. T. King. An investigation of the capacity for cleavage and differentiation in Rana pipiens eggs lacking "func- tional" chromosomes. 7. Exp. Zool. 116:455-99. 1952 With T. T. King. Transplantation of living nuclei from blastula cells into enucleated frogs' eggs. Proc. Natl. Acad. Sci. U. S. A. 38:455- 63.

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62 BIOGRAPHICAL MEMOIRS 1954 With T. J. King. Transplantation of living nuclei of late gastrulae into enucleated eggs of Rana pipiens. f. Embryol. Exp. Morphol. 2:73-80. 1955 With T. J. King. Changes in the nuclei of differentiating gastrula cells, as demonstrated by nuclear transplantation. Proc. Natl. A cad. Sci. U.S.A.41:321-25. With T. J. King. Specificity of nuclear function in embryonic devel- opment. In Biological Specificity and Growth, ed. E. G. Butler, pp. 207-28. Princeton, N.J.: Princeton University Press. 1956 With T. J. King. Serial transplantation of embryonic nuclei. Cold Spring Harb.Symp. Quant. Biol. 21:271-90. 1957 With T. J. King. Changes in the nuclei of differentiating endoderm cells as revealed by nuclear transplantation. 7. Morphol. 100:269- 312. 1959 With T. J. King. Nucleocytoplasmic interactions in eggs and em- bryos. In The Cell, vol. 1, eds. J. Brachet and A. E. Mirsky, pp. 537- 617. New York: Academic Press. 1960 With T. J. King. Nuclear transplantation studies on the early gas- trula (Rana pipiens). I. Nuclei of presumptive endoderm. Dev. Biol. 2:252-70. 1961 With T. J. King and M. A. Di Berardino. Development of nuclear- transplant embryos of known chromosome complement follow- ing parabiosis with normal embryos. In Symposium on Germ Cells and Earliest Stages of Development, ed. S. Ranzi, pp. 441-77. Milan: Fondazione A. Baselli, Istituto Lombardo.

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ROBERT W. BRIGGS 1962 63 With J. Signoret and R. R. Humphrey. Nuclear transplantation in the axolotl. Den. Biol. 134-64. 1966 With G. Cassens. Accumulation in the oocyte nucleus of a gene product essential for embryonic development beyond gastrula- tion. Proc. Natl. Acad. Sci. U. S. A. 55:1103-09. 1968 With J. T. Justus. Partial characterization of the component from normal eggs which corrects the maternal effect of gene o in the Mexican axolotl (Ambystoma mexicanum). I. Exp. Zool. 167:105-15. 1969 Genetic control of early embryonic development in the Mexican axolotl, Ambystoma mexicanum. Ann. Embryol. Morphog. 1 (suppl. ~ :105- 13. 1972 Further studies on the maternal effect of the o gene in the Mexican axolotl. 7. Exp. Zool. 181:271-80. 1973 Developmental genetics of the axolotl. In Genetic Mechanisms of De- velopment, ed. F. H. Ruddle, pp. 169-99. New York: Academic Press. 1975 With H.-M. Chung. Experimental studies on a lethal gene (1) in the Mexican axolotl, Ambystoma mexicanum. I. Exp. Zool. 191:33-47. 1977 Genetics of cell type determination. In Cell Interactions in Differentia- tion, eds. M. Saxen and L. Weiss, pp. 23-43. New York: Academic Press. 1984 With F. Briggs. Discovery and initial characterization of a new con- ditional (temperature-sensitive) maternal effect mutation in the axolotl. Differentiation 26:176-81.