Semler, Bert L

Spindler, Katherine R

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UC IrvineUC Irvine Previously Published WorksTitleIn Memoriam John J. Holland (1929-2013): a Pioneer in Molecular VirologyPermalinkhttps://escholarship.org/uc/item/6t85149xJournalJournal of Virology, 88(11)ISSN0022-538XAuthorsSpindler, Katherine RSemler, Bert LPublication Date2014-06-01DOI10.1128/jvi.00653-14 Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of CaliforniaIn Memoriam John J. Holland (1929-2013): a Pioneer in MolecularVirologyKatherine R. Spindler,a Bert L. SemlerbDepartment of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USAa; Department of Microbiology and Molecular Genetics,School of Medicine, University of California, Irvine, California, USAbJohn J. Holland, ProfessorEmeritus of Biological Sci-ences at the University of Cali-fornia, San Diego (UCSD), diedon 11 October 2013 after a shortillness. John was a pioneer inRNA virology, changing theway we think about RNA virusevolution. He was a scientificleader who served the virologycommunity at the international,national, and university levels.John was an outstanding teacherand mentor who will be greatlymissed. We thank John’s manyfriends, colleagues, trainees, andfamily for contributing their re-membrances of this remarkablescientist.John died in Mesquite, Ne-vada, where he had enjoyed re-tirement with Dottie, his wife ofmore than 50 years. Prior to re-tirement, John was a Professor inthe Department of Biology atUCSD and a member of the Uni-versity’s Center for MolecularGenetics. Professionally, Johnwas an outstanding leader in virology research and teaching, estab-lishing paradigms in RNA virus molecular biology, persistence, andevolution. Personally, he had a zest for life and an intense interest inthe professional and personal success of his scientific colleagues, stu-dents, and postdoctoral fellows. John is remembered for his tremen-dous intellect, integrity, and rigorous science and the way in which heinfused enthusiasm, joy, and laughter into the pursuit of excellence.His humility and self-effacing nature would cause him, if he were stillalive, to wave this all off with a loud, irreverent comment and a cackleof laughter.John Holland was born on 16 November 1929 in Pittsburgh,Pennsylvania. He graduated from Loyola University in Los Ange-les (now Loyola Marymount University) in 1953 with a B.S. inbiology and chemistry. He had served in the U.S. Army from 1950to 1952 during the Korean War, with service as a combat infan-tryman in North Korea. Holland subsequently completed hisPh.D. in microbiology at UCLA. For his doctoral research, heworked with M. John Pickett on genetics and immunity of Brucellainfections in primary cells. From 1957 to 1959, Holland was apostdoctoral fellow at the University of Minnesota with JeromeSyverton, a virologist and chairman of the Department of Bacte-riology. Holland wanted to dopostdoctoral research with Sy-verton because of his expertisein primary and immortalizedhuman and monkey cell cul-tures and his pioneering studiesdemonstrating the replicationof different viruses in such celllines. In fact, Holland had twopostdoctoral mentors at Minne-sota; Syverton had Hollandwork in Lee McLaren’s lab.McLaren was an Assistant andthen Associate Professor whileHolland was there. Hollandpublished his first virology pa-pers while at Minnesota, pro-viding fundamental knowledgeabout poliovirus replication.His work was the first to dem-onstrate that the block to polio-virus growth in nonprimatecells was due to the absence ofspecific receptors and that po-liovirus nucleic acid alone couldbe used to infect nonsusceptiblecells (1, 2). Beyond their crucialbiological implications, thesestudies demonstrated how Holland would emerge as a central fig-ure in applying molecular biology approaches to the study of vi-ruses.Holland was an Assistant Professor in the Department of Bac-teriology and Immunology at the University of Minnesota from1959 to 1961, and then he moved to the University of Washington,where he was an Assistant and then Associate Professor of Micro-biology from 1961 to 1964. His research during this time focusedon receptor affinities as major determinants of the tissue tropismsof enteroviruses (3). Holland and his colleagues also obtainedsome of the first convincing evidence that poliovirus replicationoccurred in the cytoplasm of infected cells and that poliovirusRNA could be encapsidated in coxsackievirus virions, providingthe first demonstration of “enclosure of an animal virus genomePublished ahead of print 12 March 2014Address correspondence to Katherine Spindler, krspin@umich.edu.Copyright © 2014, American Society for Microbiology. All Rights Reserved.doi:10.1128/JVI.00653-14John J. Holland 1929 –2013EDITORIALJune 2014 Volume 88 Number 11 Journal of Virology p. 5903–5905 jvi.asm.org 5903 on August 20, 2015 by UNIV OF CALIFORNIA IRVINEhttp://jvi.asm.org/Downloaded from within the capsid of a heterologous virus” by a nonenveloped virus(4, 5).In 1963, Holland was awarded the American Society for Mi-crobiology’s Eli Lilly Award. The award is given annually for out-standing research of unusual merit, and at the time it was given toa scientist under 35 years of age. The award cited Holland’s “re-search on the early stages of cell-virus interaction that culminatedin a new concept of the dynamics of cell-virus interaction, newinformation on receptor development by cells, and an extensivedocumentation of the controlling role played by these receptors ininfection.” As an award recipient, he was invited to contribute areview article, which encapsulates his findings on the species, tis-sue, and cell specificity of poliovirus (6).Holland was recruited to be the founding chairman of the Depart-ment of Molecular and Cell Biology (now called the Department ofMolecular Biology and Biochemistry) at the University of California,Irvine (UC Irvine), in 1964, a year before classes started on campus.His first temporary lab at UC Irvine overlooked a majestic freshwatermarsh adjacent to the campus (now known as the San Joaquin MarshReserve). Holland often remarked that this laboratory setting, al-though temporary and quite rustic, was one of the favorites he expe-rienced in science. At Irvine, he embarked on experiments examiningthe fundamental molecular biology of mammalian cell protein syn-thesis, using virus-infected cells as a tool. He demonstrated that thehost cell has little influence on the relative proportion of viral proteinssynthesized but a profound role in determining the rate and totalamount of viral protein and virion synthesis (7). In a seminal paperpublished in Proceedings of the National Academy of Sciences in 1968,Holland and his colleague Don Kiehn demonstrated that mRNAs ofenteroviruses and other picornaviruses are translated to produce verylarge proteins that are then specifically cleaved into smaller functionalproteins required for virus replication (8). This work, along with sim-ilar findings made independently by Don Summers and Jake Maizeland by Michael Jacobson and David Baltimore, had major implica-tions for our understanding of how positive-strand RNA viruses gen-erate their functional polypeptides, and it paved the way for the dis-covery of virus-encoded proteinases. Holland’s work on picornavirusprotein processing and replication was highly innovative and charac-terized by a “simple but elegant” experimental approach. These char-acteristics of Holland’s approach to experimental virology formed atheme that ran throughout his entire research career.In 1968, Holland was recruited to the Department of Biology atthe University of California, San Diego. He began working onenveloped viruses and the composition of mammalian cell mem-branes at about that time. Most of his research was carried outwith vesicular stomatitis virus (VSV), an enveloped, negative-strand RNA virus, but he also studied influenza and rabies viruses.At that time, a number of investigators were characterizing heter-ologous virus interference in coinfections. Holland and his labo-ratory colleague Mike Doyle demonstrated the dominance of po-liovirus in a coinfection with VSV; VSV virion production isinhibited at the level of viral mRNA translation (9). Holland andcolleagues also investigated homologous interference conferredby defective interfering particles of VSV in vitro and in vivo. Highlypurified defective interfering particles in high doses protect miceagainst challenges of otherwise-lethal low doses of standard VSVand alter the disease process (10). This work led to subsequentfindings that VSV defective interfering particles mediate persis-tent viral infections, in part by suppressing virion transcriptase(11). To further investigate persistence, Holland started long-term persistent infections of VSV with standard virus plus defec-tive interfering particles. In the days before rapid RNA genomesequencing methods, Holland and colleagues documented VSVgenome mutations by oligonucleotide fingerprinting in virusesderived from the persistent infections over a period of more than5 years (12). This led to what are undoubtedly some of Holland’sbest known contributions among current virologists, in the area ofRNA virus evolution. In a landmark treatise entitled “Rapid evo-lution of RNA genomes,” Holland carefully reviewed the litera-ture on RNA virus mutation frequencies, accumulation of RNAgenome mutations, and RNA virus recombination and combinedit with his knowledge of rapid evolution of RNA viruses duringserial high-multiplicity passage and effects of defective interferingparticles (13). He discussed the implication of high RNA virusmutation rates for persistent virus infections and human degen-erative diseases and the implications for general evolution. Ac-cording to Google Scholar, this paper has been cited nearly 1,200times. Subsequent studies, many of which were carried out withhis long-term collaborator Esteban Domingo, led to the nowwidely accepted concept of virus quasispecies (14). Using novel,quantitative experimental approaches, Holland and his coworkersgreatly advanced our understanding of the molecular mechanismsthat have generated genetic diversity among RNA viruses and,ultimately, among living organisms in general.Holland served the virology community as a member of NIH,American Cancer Society, and U.S. Army grant review panels andjournal editorial boards and as a coorganizer of an internationalcolloquium on rhabdoviruses. He served on the Panel of VirusDiseases of the U.S.-Japan Panel for Cooperative Medical Sciencesand the U.S. Institute of Medicine/National Academy of SciencesCommittee on Microbial Threats to Health. Holland was also anexcellent classroom teacher; his undergraduate medical microbi-ology course was consistently well received.John’s scientific legacy includes not only his more than 150 orig-inal research papers and review articles in respected and prestigiousscientific journals but also his contribution to the careers of manyothers. He trained a significant number of Ph.D. students, postdoc-toral fellows, and undergraduate researchers who now have academicpositions in major universities and research institutions in the UnitedStates and Europe or positions in the biotechnology or pharmaceuti-cal industries. Many of these individuals still carry out research invirology. Moreover, he graciously hosted visiting professors on sab-batical who were enriched by and themselves enriched the Hollandlab. John’s laboratory was unique: he worked in the lab with an un-inhibited joy until retirement. This was educational, inspirational,and entertaining for those of us fortunate to work with him. He was agreat model of how to do excellent science, think critically, and persistin the pursuit of knowledge. He could laugh at his own mistakes andempathize with other lab members’ technical failures. After his train-ees left the lab, he happily corresponded regularly with them aboutpolitics, sports, science, and philosophy until a few days before hisdeath.John had a rich life outside the laboratory, both before andafter retirement. He enjoyed trout fishing and backpacking inthe Sierra Nevada Mountains, which he began at an early agewith his brother Rich. John continued the backpacking tradi-tion with his son Mark, who recalls that John was his mostrelaxed and at home in the mountains. John’s love of naturewas also fulfilled by hiking in the desert in New Mexico andNevada. He took pride in baking excellent French bread that heEditorial5904 jvi.asm.org Journal of Virology on August 20, 2015 by UNIV OF CALIFORNIA IRVINEhttp://jvi.asm.org/Downloaded from shared with the lab, and in his typical thorough style, John builtan outdoor wood-fired oven to produce the bread he had cometo love while on sabbatical in Geneva, Switzerland. John was anavid vegetable gardener, and he also painted large oil land-scapes. He had a single-engine private pilot’s license and aglider pilot license and generously treated members of the labto glider flights. In retirement, John enjoyed having more timeto satisfy his intellectual curiosity. He researched specific topicsrelated to quantum mechanics and also pursued an interest inpowering internal combustion engines with carbohydrates, forwhich he received a patent in 2007 (15).John is survived by his wife, Dottie (Mesquite, NV), his chil-dren, Mark (Albuquerque, NM) and Lynn, and grandchildren,Molly and Megan (San Clemente, CA), and three siblings, MaryFrieze (Los Angeles, CA), George Holland (Mammoth Lakes,CA), and Bob Holland (Mesquite, NV). John’s beloved dogs, Miloand Millie, also survive him. Dogs were a very large part of John’slife from childhood on, and one anecdote vividly illustrates that.When John returned from his army service in Korea, his dog hada moment of hesitation; then, when she remembered who he was,both the dog and John had the most joyous reunion, happy thatthey hadn’t forgotten each other.John once wrote that all three of his mentors, Drs. Pickett,Syverton, and McLaren, loved bench science, worked at the benchwhenever they could all their lives, and were smarter and workedharder than John, and that he tried to emulate them as humanbeings. Not surprisingly, those of us who worked with John wouldsay the same about him. He was also a model of scientific altruism,ethical behavior, and the highest standards of excellence. He had aprofound impact on virology and scientists, and his intellect, wit,and imagination will be long remembered. An annual lectureshiphonoring John Holland at the American Society for Virologymeeting has recently been announced.REFERENCES1. Holland JJ, McLaren LC, Syverton JT. 1959. Mammalian cell-virusrelationship. III. Poliovirus production by non-primate cells exposedto poliovirus ribonucleic acid. Proc. Soc. Exp. Biol. Med. 100:843– 845.2. Holland JJ, McLaren LC, Syverton JT. 1959. The mammalian cell-virusrelationship. IV. Infection of naturally insusceptible cells with enterovirusribonucleic acid. J. Exp. Med. 110:65– 80.3. Holland JJ. 1961. Receptor affinities as major determinants of enterovirustissue tropisms in humans. Virology 15:312–326. http://dx.doi.org/10.1016/0042-6822(61)90363-4.4. Holland JJ, Bassett DW. 1964. Evidence for cytoplasmic replication ofpoliovirus ribonucleic acid. Virology 23:164 –172. http://dx.doi.org/10.1016/0042-6822(64)90279-X.5. Holland JJ, Cords CE. 1964. Maturation of poliovirus RNA with capsidprotein coded by heterologous enteroviruses. Proc. Natl. Acad. Sci.U. S. A. 51:1082–1085. http://dx.doi.org/10.1073/pnas.51.6.1082.6. Holland JJ. 1964. Enterovirus entrance into specific host cells, and sub-sequent alterations of cell protein and nucleic acid synthesis. Bacteriol.Rev. 28:2–13.7. Holland JJ. 1968. Virus-directed protein synthesis in different animal andhuman cells. Science 160:1346 –1348. http://dx.doi.org/10.1126/science.160.3834.1346.8. Holland JJ, Kiehn ED. 1968. Specific cleavage of viral proteins as steps inthe synthesis and maturation of enteroviruses. Proc. Natl. Acad. Sci.U. S. A. 60:1015–1022. http://dx.doi.org/10.1073/pnas.60.3.1015.9. Doyle M, Holland JJ. 1972. Virus-induced interference in heterologouslyinfected HeLa cells. J. Virol. 9:22–28.10. Doyle M, Holland JJ. 1973. Prophylaxis and immunization in mice by useof virus-free defective T particles to protect against intracerebral infectionby vesicular stomatitis virus. Proc. Natl. Acad. Sci. U. S. A. 70:2105–2108.http://dx.doi.org/10.1073/pnas.70.7.2105.11. Holland JJ, Villarreal LP. 1974. Persistent noncytocidal vesicular stoma-titis virus infections mediated by defective T particles that suppress viriontranscriptase. Proc. Natl. Acad. Sci. U. S. A. 71:2956 –2960. http://dx.doi.org/10.1073/pnas.71.8.2956.12. Holland JJ, Grabau EA, Jones CL, Semler BL. 1979. Evolution of mul-tiple genome mutations during long-term persistent infection by vesicularstomatitisvirus.Cell16:495–504.http://dx.doi.org/10.1016/0092-8674(79)90024-2.13. Holland J, Spindler K, Horodyski F, Grabau E, Nichol S, VandePol S.1982. Rapid evolution of RNA genomes. Science 215:1577–1585. http://dx.doi.org/10.1126/science.7041255.14. Domingo E, Holland JJ. 1997. RNA virus mutations and fitness forsurvival. Annu. Rev. Microbiol. 51:151–178. http://dx.doi.org/10.1146/annurev.micro.51.1.151.15. Holland JJ. August 2007. Apparatus and method for using pure dry bio-mass carbohydrates as fuels, fuel extenders and fuel oxygenates. US patent7,261,063.EditorialJune 2014 Volume 88 Number 11 jvi.asm.org 5905 on August 20, 2015 by UNIV OF CALIFORNIA IRVINEhttp://jvi.asm.org/Downloaded from 

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