In Memoriam: Robert Hall Haynes

Bernard A. Kunz1* and Philip C. Hanawalt21School of Biological and Chemical Sciences, Deakin University, Geelong,

Victoria, Australia2Department of Biological Sciences, Stanford University, Stanford, California, USA

Robert (Bob) Hall Haynes O.C., B.Sc., Ph.D., D.Sc.,F.R.S.C. died December 22, 1998, from an apparent heartattack. Among his many colleagues in the field of environ-mental mutagenesis, Bob was best known for his pioneeringcontributions to the study of DNA repair and the develop-ment of novel mathematical approaches to analyze dose–response relations for the induction of mutation and recom-bination. Were it not for DNA repair, neither the geneticintegrity of individuals nor the evolutionary stability ofspecies could be maintained. During the past three decadesthere has been a veritable explosion of research worldwideon DNA repair, and its relation to the occurrence of spon-taneous and induced mutations, especially in human cells.This, in turn, has led to important breakthroughs in under-standing cancer, certain genetic diseases, aging, and specia-tion. Bob Haynes was an international leader whose remark-able career spanned the development of this exciting field.

Anyone who peruses Bob’s lengthy list of scientific pub-lications will be struck at once by its unusual diversity, as itnot only includes contributions to DNA repair and mutagen-esis, but also to blood rheology, radiological physics, mi-crobeam irradiation effects in mitotically dividing cells, thegenetic consequences of deoxyribonucleotide pool imbal-ances, the structure and expression of genes involved inpyrimidine nucleotide biosynthesis, and historical-philo-sophical essays on the advent of molecular biology, the roleof “chance” in evolution, biological weaponry, and theethical and technical questions that emerge from recentproposals to investigate the feasibility of implanting life onMars. Thus, his scholarly contributions have extended wellbeyond experimental research into DNA repair and mu-tagenesis, and he was one of a select group of scientists whoexplored the more far-reaching and philosophical implica-tions of the science in which they were engaged.

Bob’s breadth of interest was a consequence of both earlyparental influence and educational experiences. He was afourth-generation Canadian, born an only child in London,Ontario, Canada (August 27, 1931). His father (James Wil-son McKenzie Haynes), a salesman, was a well-informedand enthusiastic amateur scientist who introduced Bob tochemistry and astronomy in Port Colborne, Ontario, wherehe also received his primary education. His mother (Lillian

May Hall), a practical, religious woman, encouraged Bob tostudy the Bible and become a doctor. Notably, Bob de-scribed his mother as having “an insouciant sense of hu-mor.”1 During his secondary education at Brantford Colle-giate Institute (Brantford, Ontario), he read descriptions ofrecent scientific discoveries, books on Christian theology,and the Bible while also studying classical Greek and Latin.The latter studies led to a love of classical culture and thediscovery of the Greek philosophers, in particular Epicurusand aspects of the lifestyle he had advocated. Bob’s philo-sophical interests and his readings of popular accounts ofphysics and cosmology were to have a profound influenceon subsequent stages of his education.

In 1949, Bob entered the University of Western Ontario,apparently to follow his mother’s advice that he studymedicine. However, a burning desire to understand quantummechanics and the theory of relativity, and what they mightreveal about the mysteries of the universe, resulted in hisenrolling instead in physics and mathematics, much to hismother’s distress.

Upon graduation with a B.Sc. in 1953, Bob began his firstyear of graduate study in theoretical nuclear physics atMcGill University. During this period, his interest in cellbiology and genetics was sparked by readingWhat Is Lifeby Erwin Schro¨dinger,2 a book which also provided his firstencounter with genes, mutations, and chromosome behaviorduring mitosis and meiosis. Bob became fascinated by theremarkable stability of genes, and was surprised to learn thatX-rays could increase mutation rates inDrosophila. Schro-dinger’s consideration of Max Delbru¨ck’s theory that ge-netic stability and change could be explained in purelyphysical terms prompted Bob to change course once again.Prior to completing his Ph.D. at McGill, he returned to theUniversity of Western Ontario to study biophysics under thesupervision of the late Professor Alan C. Burton, F.R.S.C.,a classical physicist. Unbeknownst to Bob, Burton wasinvestigating the fluid dynamics of the circulatory system.

*Correspondence to: Dr. Bernard A. Kunz, School of Biological andChemical Sciences, Deakin University, Geelong, Victoria, 3217, Australia.E-mail: bkunz@deakin.edu.au

Environmental and Molecular Mutagenesis 33:257–265 (1999)

Published 1999 Wiley-Liss, Inc. †This article is a US Gov-ernment work and, as such, is in the public domain in theUnited States of America.

Robert Hall Haynes

258 Kunz and Hanawalt

Much to Bob’s chagrin, rather than agreeing that he couldwork on how radiation induces mutations (which Bob feltwould provide insights into “the quantum physics of life”),Burton asked him to investigate the rheology of blood. Inthis unexpected way, Bob took the initial steps in joining asmall, but historically significant, movement of physicistsinto biology that had begun, primarily in Germany andBritain, a few years prior to World War II.

Bob undertook his Ph.D. research dutifully, if not enthu-siastically, and during his candidature worked on two otherproblems. As a consequence of reading Schro¨dinger’s book,he also had become intrigued by the forces responsible forchromosome movement during mitosis. This interest, plushis work on rheology, led him to develop a theory thatchromosome movement might be explained in terms of thephysics of cytoplasmic streaming. Bob presented his ideasat the 1955 meeting of the Society of General Physiolo-gists.4 Subsequently, Burton arranged for Bob to visit theCommittee on Biophysics (later the Biophysics Depart-ment) at the University of Chicago, in particular, ChairmanRaymond E. Zirkle, who was studying the effects of mi-crobeam irradiation on chromosome movement. Discus-sions with Zirkle convinced Bob that his cytoplasmicstreaming theory was incorrect, but he was enthused by thepossibility that application of the microbeam techniquemight uncover new facts about chromosome movement.Interestingly, the introduction to Zirkle’s group was toprove important again 3 years later.

While working with Burton, Bob also devised (as anintellectual by-product of a part-time job in radiology atVictoria Hospital) a novel mathematical approach for cal-culating radiation doses at the centers of tumors in individ-uals undergoing “rotation” radiotherapy. This work waspresented by Bob at the 1956 International Congress ofRadiology in Mexico City,3 where he first met ProfessorJoseph Rotblat, Paul Howard-Flanders, and others active inradiobiological research. These and other encounters keptBob interested in the biological effects of radiation and thesearch for a physical explanation for genetic stability.

During the final year of his graduate program, Bob pre-sented a paper on blood rheology at the First NationalBiophysics Conference in Columbus, Ohio.5 There he firstmet one of us (P.C.H.), then a graduate student with RichardSetlow at Yale University, and we were destined to becomelifelong friends and collaborators.

As a consequence of his mathematical work on radiother-apy, Bob was awarded a postdoctoral fellowship in 1957 bythe British Empire Cancer Campaign to work with Rotblatin the Physics Department of St. Bartholomew’s HospitalMedical College, University of London, England. Whilethere, a lecture by Sir Francis Crick on the “central dogma”of molecular biology, and discussions with the medicalphysicist P.R.J. Burch, with whom Bob was collaborating,led him to despair that the physical basis of life could beunderstood without learning biochemistry. However, all

was not lost. Bob was directed to the earlier work ofRaymond Latarjet (at the Institut du Radium in Paris) on theway in which yeast ploidy influenced radiation sensitivity,6

and that seemed to support the classical target theory ofradiobiological action. Buoyed by the data, Bob visitedLatarjet in Paris and asked if he could join Latarjet’s labo-ratory, a request prompted not only by his meeting withLatarjet, but also by his discovery of the Latin Quarter!Latarjet agreed, but before he could depart for France, Bobwas advised by John Kirby-Smith, a laboratory colleague atSt. Bartholomew’s, not to go to Paris, where he wouldsquander his money and time in the restaurants and side-walk cafes, but instead to go to America and make some-thing of himself. This admonishment led Bob to write toRaymond Zirkle in Chicago to apply for a position in hislaboratory. A number of weeks later, having been offeredand having accepted a position as an Instructor (later As-sistant Professor) in the Committee on Biophysics, Bobjoined the faculty at the University of Chicago, one yearafter completing his Ph.D. He later viewed this move as “themost significant turning point in my scientific life.”

At Chicago, Bob initially worked with Zirkle and hisgraduate student Robert B. Uretz on the application ofmicrobeam irradiation (UV and alpha particles) to studymitotic chromosome dynamics in plant and animal cells.7

However, it was time-consuming to obtain sufficient quan-titative data for mathematical analysis, and both Bobs real-ized that chromosome movement at mitosis was too com-plex to be understood from this approach. Zirkle hadpreviously adopted the yeastSaccharomyces cerevisiaeas atest organism and, as part of his doctoral studies, Uretz hadcarried out experiments on the interactive lethal effects ofUV and X-rays in yeast.8 After completing his Ph.D. re-search, Uretz became interested in chemically specific waysto inactivate cells, and with his own graduate student, DavidFreifelder, developed a method for enhancing the lethalityof radiation with the aid of nucleic acid-specific dyes, thephotodynamic inactivation technique. They then discoveredin 1960 that cells treated with X-rays subsequently could be“reactivated” by the application of this technique.9 Theresult supported the possibility that the lethality of X-rayswas due, at least in part, to DNA damage (a controversialview at the time). It was this view as well as Uretz’s Ph.D.research on radiation interactions and discussions of thedata that likely stimulated Bob’s subsequent interest inDNA damage and its repair, and in using more tractableexperimental systems to study radiobiological phenomena.Thus it was that Bob began to work with radiation-sensitiveand resistant strains ofEscherichia coliand with diploidstrains of yeast.

Several important but serendipitous observations he madeover the next 2 years in collaboration with his students andco-workers at Chicago further stimulated Bob’s interest instudying DNA repair, and resulted in his later recognition asone of the first investigators to formulate what became

In Memoriam: Robert Hall Haynes 259

known as the “DNA damage-repair hypothesis.” Thesechance findings included liquid-holding recovery of diploidyeast exposed to UV, X-rays or nitrogen mustard (in col-laboration with Michael Patrick and Uretz), and synergisticinteractions with respect to killing bacteria or yeast for thethree pairwise combinations of these agents (in collabora-tion with W.R. Inch, whom Bob had first worked with atVictoria Hospital).10 Liquid-holding recovery of yeast wasfirst discovered 5 years earlier by V.I. Korogodin11 (withwhom Bob later became well acquainted) in the (former)Soviet Union, but the findings were only reported in Russianin Soviet journals. Nonetheless, Bob chanced upon one ofthese papers, tracked down the rest, and cited them in hisinitial report of liquid-holding recovery.

Significantly, in Bob’s first article on liquid-holding re-covery, three repair mechanisms were suggested: 1) directenzymatic reversal of the damage in a manner analogous tothat of photoreactivation; 2) DNA synthesis to replace dam-aged single-stranded DNA regions; and 3) genetic exchangebetween homologous DNA segments or sister chromatids.This article appeared just 1 month before the first publishedreports, by Richard Setlow and William Carrier and RichardBoyce and Paul Howard-Flanders, of nucleotide excisionrepair of UV-induced pyrimidine dimers in bacteria, andcomplemented the discovery of repair-replication by DavidPettijohn and Hanawalt.12 Collectively, the various findingsled Bob to conclude in a symposium article published in196413 that yeast andE. coli possessed enzymatic, energy-dependent mechanisms that repaired DNA structural defectscaused by radiation and chemicals. Moreover, he suggestedthat it was not necessarily alterations in the base structure ofthe DNA, but distortions in the secondary structure of thephosphodiester background that might be recognized bythese enzymes. The next year, Bob and Sheldon Wolfforganized a first international conference on “Structuraldefects in DNA and their repair in microorganisms,” held atthe University of Chicago.14 Thereafter, the field of DNArepair expanded dramatically, until it now encompassesvirtually all other aspects of DNA metabolism, includingreplication, transcription, mutagenesis and recombination,and is linked to other critical processes such as cell cycleregulation and apoptosis.

In 1964, Bob moved to the University of California,Berkeley, as Associate Professor of Biophysics in the De-partment of Medical Physics and the Lawrence RadiationLaboratory. Significantly, the move coincided with a changein his attitude regarding physical explanations of biologicalphenomena. The importance of DNA repair as a biochem-ical process led him to view the biology itself as moreimportant than the physics of the biology. At Berkeley,Bob’s graduate student, Raymond Baker, demonstrated thatUV exposure enhanced recombination of bacteriophagelin excision-repair deficient bacterial cells. In addition,Bob studied the recovery of yeast and bacteria exposedto densely ionizing radiation.15 Furthermore, Bob and

Hanawalt (then at Stanford University) collaborated to firstdemonstrate repair replication in bacteria carrying chemi-cally induced DNA damage.16 During this period, Haynesand Hanawalt also produced the firstScientific Americanreader on molecular biology (The Molecular Basis of Life).This and a succeeding volume (The Chemical Basis ofLife)17 sold widely and did much to promote interest inmolecular biology in the rising generation of biologists. Bobremained at Berkeley until 1968, when he returned to Can-ada to become Professor and Chairman (until 1973) of thenew Biology Department at York University in Toronto,Ontario.

York University had been in existence as an institutionfor 9 years, but had been established only for 2 years at thecampus (Keele/Steeles) where Bob was located, and his firsttask was to build a modern research-oriented biology de-partment. He succeeded in attracting a group of youngscientists to York to form one of the most outstandingdepartments of biology in Canada. There he continued hiswork on DNA repair, initially in collaboration with twopostdoctoral fellows, Martin Brendel from the University ofFrankfurt, and Nasim Khan from Brooklyn College, whoboth joined Bob in 1969. Together, they examined theeffects of UV, X-rays, MMS, and nitrogen mustard on therecently discovered (by Michael Resnick and Robert Mor-timer in the U.S.) radiation-sensitive mutants of yeast.18 Theresults provided evidence for epistatic and synergistic inter-actions between the mutants with respect to killing byindividual agents. The data suggested that the tested genescontrolled at least three different pathways for the repair ofDNA damage, and Bob supported this interpretation with aninsightful mathematical analysis of epistasis. One of thesepathways was known at the time to be nucleotide excisionrepair, and his group suggested that one of the other genes(UXS1 5 RAD18) they studied might be involved in apostreplication repair pathway (now known to be the case).

During the 4-year period from 1969 to 1973, Bob againcollaborated with Ray Baker on further studies of recombi-nation in phagel, and published articles on the influence ofbromouracil treatment and purine starvation ofE. colion theinteraction between UV and X-rays (with Jeremy Baptist),and the effect of bacterial growth on UV sensitivity (withRichard Morton).19 However, three major lines of research,one initiated in 1970, another in 1975, and the third in 1978,were to occupy much of his attention over the next twodecades.

In 1970, Wolfgang Laskowski’s group in Berlin reporteddiscovering a yeast strain that could import thymidylate(dTMP) and incorporate it into DNA.20 This made it pos-sible to specifically label yeast DNA (like many other fungi,yeast lacks thymidine kinase and so cannot use exogenousthymidine to make dTMP), and thereby provided a means tostudy repair replication in yeast. Shortly afterwards, MartinBrendel confirmed Laskowski’s findings at York, but alsodetermined that uptake of the nucleotide was not very

260 Kunz and Hanawalt

efficient.21 Using the dTMP permeable yeast strains, Bren-del (who had returned to Frankfurt) and Gerry Little, whohad joined Bob’s lab as a postdoctoral fellow fromHanawalt’s group, independently isolated dTMP auxo-trophs that efficiently took up the nucleotide.22 Subse-quently, with his students Orna Landman and BarryBarclay, Little detected repair replication in yeast, and dem-onstrated that starving yeast cells for dTMP induced muta-tions in mitochondrial DNA and caused fragmentation ofchromosomal DNA.23

One of us (B.A.K.) joined the Haynes lab in 1976, ini-tially to undertake doctoral studies on the kinetics of UV-induced mitotic recombination (see below). The observationthat dTMP starvation induced DNA strand breakageprompted us (Kunz and Haynes) to ask whether dTMPdepletion might cause mitoticinter-chromosomal recombi-nation, since Resnick had recently provided evidence con-sistent with the recombinational repair of DNA double-strand breaks in yeast.24 In collaboration with Barclay,Little, and John Game (at the University of California atBerkeley), Kunz and Haynes determined that dTMP deple-tion induced by chemical treatment or genetic lesion pro-voked both mitotic crossing-over and gene conversion, andalso obtained evidence for the induction of chromosomeloss.25 Much to Bob’s surprise, Kunz was unable to detectany production of nuclear gene mutations by chemically-induced thymine nucleotide deprivation.26 A subsequentstudy by Bob and Kunz in collaboration with FriederikeEckardt (then at the GSF in Munich) demonstrated thatnuclear gene mutation was induced by withholding dTMPfrom thymidylate auxotrophs, but the magnitude of theeffect was smaller than that observed for recombination.27

Nonetheless, the possibility (in 1979) that the manipulationof intracellular nucleotide levels might allow one to create ametabolic condition which induced recombination but notmutation in eukaryotic cells intrigued Bob for two reasons.First, the drugs used to provoke dTMP depletion inhibitenzymes involved in DNA precursor synthesis, and thisindicated that there are non-DNA targets for the inductionof genetic change.28 Second, the ability of the same drugs tocause transformation of mammalian cells supported thepotential role of recombination in the development of can-cer.29 Kunz and Haynes went on to investigate the role ofDNA double-strand breaks and DNA damage repair in thisphenomenon, as well as the ability of dTMP starvation tostimulate intra-chromosomal recombination.30 It was thisbody of work on the genetic consequences of DNA precur-sor imbalance that led Bob, beginning in 1980, to adopt amore broadly biochemical picture of the molecular basis ofgenetic stability and change.31 Consequently, in a reviewarticle on DNA repair and mutagenesis in yeast published in1981,32 Bob suggested that the three epistasis groups ofyeast repair mutants might represent genes that control theformation of macromolecular complexes required to medi-ate major manifestations of DNA metabolism, including

nucleotide excision repair (NER) and recombination. Overthe past half-dozen years, evidence that proteins involved inNER and recombination in yeast and humans do indeedfunction in multimeric complexes has rapidly accumulated.

The second major line of research that Bob pursued,beginning in the mid-1970s, was the mathematical analysisof dose–response relations for induced lethality, mutation,and recombination. With the initial demonstrations thatcells possess enzymatic mechanisms for the repair of DNAdamage, Bob realized that the classical target theory for theinterpretation of radiation dose–response curves would haveto be modified to be of any use. In 1966, he had outlined away in which this might be done for survival curves, andsubsequently used this approach, and data for pyrimidinedimer excision as a function of UV dose, to quantitativelypredict a survival curve for UV-irradiated yeast (in collab-oration with Roger Wheatcroft and Brian Cox at Oxford).33

By 1975, however, he had become interested in extendingthe analysis to mutation induction data. At that time, Fried-erike Eckardt arrived at Bob’s lab as a postdoctoral fellowfrom Wolfgang Laskowski’s group in Berlin. Eckardt hadcarried out extensive measurements of UV-induced muta-tion curves for wild-type and NER-deficient mutants as partof her doctoral research. The positive and negative depar-tures from linearity were intriguing, and Eckardt urged Bobto undertake a mathematical description of the curves. Bobsoon determined that the departures could be explained ifthe mutants formed clones with probabilities that differedfrom those of nonmutated cells.34 This analysis was thenextended by Eckardt and Haynes to complex dose–responsepatterns for induced mutation frequencies, and was fol-lowed subsequently by the mathematical examination ofmutant yield data.35 The latter analysis led Bob to derivemathematical expressions for comparing the mutagenicityof different mutagens and characterizing the mutability ofdifferent cell types. Furthermore, he developed equationsthat allowed the use of mutant yield data to probe mathe-matically for the existence of inducible components ofmutagenesis in yeast. In collaboration with Eckardt andKunz, the analysis was then applied to frequency and yieldcurves for UV-induced mutation and recombination in wild-type and NER-deficient diploid strains, and inducible com-ponents were detected.36 Bob also analyzed the kinetics ofphotoreactivation and liquid holding37 in collaboration withRonald Johnson (who was on sabbatical leave from TrentUniversity), and in so doing provided evidence for multipleDNA photolyases in yeast (although the data and mathe-matical analysis were not published until after two yeastphotolyase-encoding genes were discovered). Finally, Boband Darlene Ager, a Ph.D. student in his lab, carried out aseries of complex studies38 that culminated in the develop-ment of a novel mathematical technique for describing thelethal and recombinagenic interactions of a variety of phys-ical and chemical agents, including UV, X-rays, heat,and EMS.

In Memoriam: Robert Hall Haynes 261

The genetic studies of DNA precursor imbalance alsoprompted Bob, in collaboration with Evan McIntosh andGareth Taylor, who joined the lab as Ph.D. students in 1979,to initiate a new program of study on the structure andexpression of genes required for the biosynthesis of pyrim-idine nucleotides in yeast. McIntosh isolated and character-ized the deoxycytidylate deaminase and deoxyuridinetriphosphatase (dUTPase) (in collaboration with MichaelGadsden, also a Ph.D. student with Bob) genes, and Taylorrecovered and analyzed the genes encoding thymidylatesynthase (in collaboration with Barclay, Reginald Storms,and James Friesen) and dihydrofolate reductase (in collab-oration with Peter Lagosky, a postdoctoral working withBob).39 McIntosh had earlier hypothesized that the expres-sion of genes involved in DNA replication might exhibit acell cycle dependence (and subsequently went on as apostdoctoral fellow in the laboratory of Michael Smith, atthe University of British Columbia, to discover theMluI boxthat regulates this periodic expression for yeast genes). Inthe intervening years, cell cycle regulation of a number ofgenes involved in DNA replication in yeast was reported.Thus, it was surprising when Haynes’ group demonstratedthat, unlike thymidylate synthase, the other genes they hadisolated were not cell-cycle regulated inS. cerevisiae.40

Over the course of the next 10 years, McIntosh and Haynescontinued to collaborate. They demonstrated (with Gads-den) that the yeast dUTPase is an essential gene, and iso-lated (with Gadsden and Ager) the human dUTPase gene.41

In addition, they suggested that certain human retrovirusesencode dUTPase as a means of defense against the presenceof dUTP in the cytoplasm of the host cells, reverse tran-scription of the human immunodeficiency virus might relyon the expression of a dUTPase encoded by a knownendogenous retrovirus, and that dUTPase might present anew target for cancer chemotherapeutic agents and anti-viral drugs.42 As a consequence of these various studies,Bob’s personal view of his scientific image continued toevolve, and he finally came to consider himself not only abiophysicist, but also a molecular biologist.

On the basis of the foregoing, one might conclude thatBob’s scientific interests during the period from 1970 to1998 focused exclusively on the genetic consequences ofDNA precursor pool imbalance, the isolation of genes in-volved in synthesizing those precursors, and the mathemat-ical exploration and analysis of dose–response data. Itshould be noted, however, that he also published articles onDNA endonucleases active on UV-irradiated DNA (withDouglas Bryant), the modulation of induced mutation andrecombination by tumor promoters (with Kunz and Moham-med Hannan), the genetic activity of actinomycin D (withEarle Nestmann), the mutagenic potential of caffeine (withJohn Collins), risk assessment (with David DeMarini, JimMacGregor, John Ashby, Paul Lohman, and Mort Mendel-sohn), the isolation of yeast mutants hyperresistant to DNAdamaging agents (with Brendel and Axel Ruhland) and the

problem of the human mutagen burden in genetic toxicol-ogy (with Helena Groot de Restrepo).43 In recent years, healso wrote essays on various topics on the history, philos-ophy, and sociopolitical aspects of science and technology,including biological warfare, and (with Chris McKay ofNASA) devoted much creative energy to the feasibility ofimplanting life on Mars.44 Indeed, the invitation to speakwhich both surprised and pleased him most was to deliverthe 1991 Sigma Lecture of the NASA Langley ResearchCenter on the occasion of the 15th anniversary of the VikingLanding on Mars. His topic was “ecopoiesis,” a word he hadcoined a few years earlier to describe the establishment,through planetary engineering, of microbial ecosystems onpresumably lifeless planets.

In addition to research and teaching, Bob was stronglycommitted to the promotion of science education and re-search as critical factors in economic and social develop-ment, and in this connection was invited to travel andlecture extensively, particularly in Asia, Latin America, andEurope. From 1972 through 1981 he was invited as anExchange Visitor or Visiting Fellow, Lecturer, or Professorto the USSR Academy of Sciences (Moscow), Oxford Uni-versity (England), Kyoto University (Japan), Yale Univer-sity (USA), the Chinese Academy of Sciences (Beijing),Fudan University (Shanghai), and the King Faisal Hospitaland Cancer Therapy Institute (Saudi Arabia). Furthermore,he played a major role in establishing a Ph.D. program at theUniversity of Los Andes in Bogota, Colombia (with Grootde Restrepo). In recognition of his international efforts, hewas elected a Foreign Fellow of the Third World Academyof Sciences in 1990 and a Foreign Member of the PakistanAcademy of Sciences in 1994.

Bob also devoted himself unselfishly to public service inthe cause of science. For example, he served as a member ofthe governing board of the National Research Council ofCanada (1975–1981), as Vice-President of the BiologicalCouncil of Canada (1975–1980), as a founding executivemember of the Canadian Institute for Advanced Research(1982–1987), and as the Chair of the Natural Sciences andEngineering Research Council of Canada Advisory Com-mittee on Life Sciences (1985–1987). He was, for the first 5years of its existence, a member of the technical advisorycommittee on Canada’s nuclear fuel-waste managementprogram (1979–1983). He also served as Chair of the De-partment of Health and Welfare Committee that drafted theCanadian guidelines on the use of mutagenicity tests in thetoxicological evaluation of chemicals. Internationally, hewas a member of the U.S. National Academy of Sciences—National Research Council Committee on Radiobiology(1963–1973), the editorial board ofEnvironmental and Mo-lecular Mutagenesis(1979–1985), as well as 15 other jour-nals, and the International Commission for Protectionagainst Environmental Mutagens and Carcinogens (1987–1992). In addition, he was a Councilor of the EnvironmentalMutagen Society (1978–1981, 1985–1988), and President

262 Kunz and Hanawalt

of the International Association of Environmental MutagenSocieties (1989–1993). Furthermore, he was instrumental inbringing the 16th International Congress of Genetics toToronto in 1988, and served as its President. The meetingattracted some 4,000 scientists from 74 countries, the largestcongress ever held in the history of genetics research. Sub-sequently, he was editor of the Monograph Publishing Pro-gram of the recently established NRC Research Press ofCanada.

Bob’s many achievements were recognized with a num-ber of honors and prestigious awards. The latter include theQueen Elizabeth II Silver Jubilee Medal (1977), the AnnualResearch Award (1984) of the Environmental Mutagen So-ciety, the Gold Medal of the Biological Council of Canada(1984), the Flavelle Medal of the Royal Society of Canada(1988), the Canada Confederation Commemorative Medal(1992), and a Presidential Citation (1989) and the Award ofExcellence (1993) from the Genetics Society of Canada. In1986, York University accorded him the honorific title ofDistinguished Research Professor. In 1984, he became aFellow of the American Association for the Advancementof Science, and in 1988 of the Berlin Institute for AdvancedStudies, where he was in residence for most of 1989. Bobalso was a Fellow of the Royal Society of Canada (1982),and was its President from 1995–1997. In 1990, he receivedthe Order of Canada, the highest civilian honor bestowed bythe Government of Canada. He also received honorarydegrees from the University of Manitoba (1995), the Uni-versity of Western Ontario (1997), and the University ofAlberta (1998).

In the summer of 1992, at age 60, Bob took early retire-ment from York University to serve as President and Editor-in-Chief of Annual Reviewsin Palo Alto, California. How-ever, he missed teaching and after one year he returned toYork University. He remained associated with the univer-sity as Distinguished Research Professor Emeritus until hisdeath.

Far beyond his numerous scientific and intellectual ac-complishments, it was Bob’s buoyant, outgoing personality,as pronounced by his hearty laugh and Epicurean philoso-phy and lifestyle, that immediately comes to mind when onethinks of Bob Haynes. He had a finely honed sense of humorand a ready willingness to target himself in his humor. Indiscussions with him, his remarkable creativity also becameevident, as did his truly impressive range of scientificknowledge (he was an avid collector of antiquarian bookson science and philosophy, and at one time held one of theforemost collections of Darwinia in North America). Therewas yet another aspect of Bob’s character that contributed tohis stature in science and as a person, and that was hisgenerosity. He selflessly gave his support to his colleagues,including graduate and postdoctoral students, and notably todedicated scientists in countries where such support hadbeen very limited. In a period when dwindling resources,and the developing view of information as currency, made

scientific research increasingly competitive (with all thenegative connotations), Bob’s professional generosity was awonderful example to all.

The field of environmental mutagenesis is fortunate tohave attracted a considerable share of able scientists. Weshould not forget that the scientific enterprise is, above all,a human endeavor. Bob Haynes “lived” his science. Helucidly conveyed his own excitement about it in his writ-ings, his many public lectures, and in his direct interactionswith other scientists. Those of us who knew him personallyare fortunate to have been enriched by his insights andthrough his sincere friendship. His loss is deeply felt by themany people, worldwide, whose careers he influenced andwhose lives he touched.

He is survived by his wife, Jane Banfield, his sons MarkDouglas, Geoffrey Alexander, and Paul Robert Haynes, andhis grandchildren Jennifer, Matthew, and Liam Haynes.

NOTES

1. All quotations are taken from: Haynes RH. 1993. My road to repair inyeast: the importance of being ignorant. In: Hall MN, Linfer P,editors. The early days of yeast genetics. Cold Spring Harbor: ColdSpring Harbor Laboratory Press. p 145–171.

2. Schrodinger E. 1944. What is life? Cambridge: Cambridge UniversityPress.

3. Haynes RH, Froese G. 1957. Idealized body contours in rotationdosimetry. Acta Radiol 48:209–226. (We have not cited all ofBob’s articles on each topic referred to in the text. Instead, wechose the listed publications to indicate the variety of Bob Haynes’scientific and scholarly interests during the course of his career.)

4. Burton AC, Haynes RH. 1955. A new “vortex” theory in the mecha-nism of mitosis. J Cell Comp Physiol 46:360 (Abstr). (Bob with-drew the full paper (Haynes RH, Burton AC. 1957. A theory ofchromosome movements based on protoplasmic streaming) fromthe same journal at the publication stage. Although Bob had con-cluded that the theory was wrong, Burton felt that the data andcalculations presented might have been of use to other investiga-tors, an opinion with which Bob later agreed.)

5. Haynes RH, Burton AC. 1958. Axial accumulation of cells and therheology of blood. In: Quastler H, Morowitz HL, editors. Proceed-ings of the First National Biophysics Conference (1957). NewHaven: Yale University Press. p 452–459. (Bob published oneother article with Burton, and six other single-authored articles onrheology, the last of which appeared in 1962.)

6. Latarjet R, Ephrussi B. 1949. Courbes de survie de levures haploids etdiploides soumises aux rayons. C R Acad Sci 229:306–308.

7. Zirkle RE, Uretz RB, Haynes RH. 1960. Disappearance of spindlesand phragmoplasts after microbeam irradiation of cytoplasm. AnnNY Acad Sci 90:435–439.

8. Uretz RB. 1955. Additivity of X-rays and ultraviolet light in theinactivation of haploid and diploid yeast. Radiat Res 2:240–252.

9. Freifelder D, Uretz RB. 1960. Dye-sensitized photo-reactivation ofX-ray damage in diploid yeast. Nature 187:953–954.

10. Haynes RH, Inch WR. 1963. Synergistic action of nitrogen mustardand radiation in microorganisms. Proc Natl Acad Sci USA 50:839–846.

Patrick MH, Haynes RH, Uretz RB. 1964. Dark recovery phenomenain yeast. I. Comparative effects with various inactivating agents.Radiat Res 21:144–163.

Patrick MH, Haynes RH. 1964. Dark recovery phenomena in yeast. II.

In Memoriam: Robert Hall Haynes 263

Conditions that modify the recovery process. Radiat Res 23:564–579.

11. Korogodin VI, Malumina TS. 1959. Recovery of viability of irradiatedyeast cells (in Russian). Priroda 48:82–85.

12. Boyce RP, Howard-Flanders P. 1964. Release of ultraviolet lightinduced thymine dimers from DNA inE. coli K12. Proc Natl AcadSci USA 51:293–300.

Pettijohn D, Hanawalt PC. 1964. Evidence for repair replication ofultraviolet light damaged DNA in bacteria. J Mol Biol 9:395–410.

Setlow RB, Carrier WL. 1964. The disappearance of thymine dimersfrom DNA: An error-correcting mechanism. Proc Natl Acad SciUSA 51:226–231.

13. Haynes RH. 1964. Role of DNA repair mechanisms in microbialinactivation and recovery phenomena. Photochem Photobiol3:429–450. (Printer’s omission of four summary paragraphs cor-rected in Photochem Photobiol 4:839–840, 1965.)

14. Haynes RH, Wolff S, Till J, editors. 1966. Structural defects in DNAand their repair in microorganisms. Radiat Res Suppl 6. 243 p. (Themeeting was sponsored by the U.S. National Academy of Sciencesand National Research Council and was held October 18–20,1965.)

15. Baker RM, Haynes RH. 1967. UV-induced enhancement of recombi-nation among lambda bacteriophages in UV-sensitive host bacteria.Mol Gen Genet 100:166–177.

Dewey DL, Haynes RH. 1967. Sensitivity ofMicrococcus radio-durans to densely ionizing radiations. University of CaliforniaLawrence Radiation Laboratory Report UCRL-17481. p 138–144.

Lyman JT, Haynes RH. 1967. Recovery of yeast after exposure todensely ionizing radiation. Radiat Res Suppl 7:222–230.

16. Hanawalt PC, Haynes RH. 1965. Repair replication in bacteria: irrel-evance of chemical nature of base defect. Biochem Biophys ResCommun 19:462–467.

17. Hanawalt PC, Haynes RH, editors. 1973. The chemical basis of life.San Francisco: WH Freeman. 405 p.

Haynes RH, Hanawalt PC, editors. 1968. The molecular basis of life.San Francisco: WH Freeman. 368 p. (An important article on DNArepair co-authored by Hanawalt and Haynes (Hanwalt PC, HaynesRH. 1967. The repair of DNA. Sci Am 216:36–43) was reprintedin each book and was translated into several languages, as was TheMolecular Basis of Life.)

18. Brendel M, Khan NA, Haynes RH. 1970. Common steps in the repairof alkylation and radiation damage in yeast. Mol Gen Genet 106:289–295.

Khan NA, Brendel M, Haynes RH, 1970. Supersensitive double mu-tants in yeast. Mol Gen Genet 107:376–378.

Brendel M, Haynes RH. 1973. Interactions among genes controllingsensitivity to radiation and alkylation in yeast. Mol Gen Genet126:197–216.

19. Baker RM, Haynes RH. 1972. UV-induced recombination and repairof parental lambda bacteriophages labelled by means of host-controlled modification. Virol 50:11–26.

Baptist JE, Haynes RH. 1972. The UV-X-ray synergism inEsche-richia coli B/r. I. Inhibition by the incorporation of 5-bromouraciland by purine starvation. Photochem Photobiol 16:459–464.

Morton RA, Haynes RH. 1969. Changes in the UV sensitivity ofEscherichia coliduring batch culture. J Bacteriol 97:1379–1385.

20. Jannsen S, Lochman E-R, Megnet R. 1970. Specific incorporation ofexogenous thymidine monophosphate into DNA ofSaccharomycescerevisiae. FEBS Lett 8:113–115.

21. Brendel M, Haynes RH. 1972. Kinetics and genetic control of incor-poration of thymidine monophosphate in yeast DNA. Mol GenGenet 117:39–44.

Brendel M, Haynes RH. 1973. Exogenous thymidine 5’-monophos-phate as a precursor for DNA synthesis in yeast. Mol Gen Genet126: 337–348.

22. Brendel M, Fa¨th WW. 1974. Isolation and characterization of mutantsof Saccharomyces cereviasiaeauxotrophic and conditionally auxo-trophic for 5’-dTMP. Z Naturforsch 29c:773–738.

Little JG, Haynes RH. 1979. Isolation and chracterization of yeastmutants auxotrophic for thymidine monophosphate. Mol GenGenet 168:141–151.

23. Little JG. 1985. Genetic and biochemical effects of thymidylate stressin yeast. In: de Serres FJ, editor. Genetic consequences of nucleo-tide pool imbalance. New York: Plenum Press. p 211–231.

24. Resnick MA, Martin P. 1976. The repair of double-strand breaks in thenuclear DNA ofSaccharomyces cerevisiaeand its genetic control.Mol Gen Genet 143:119–129.

25. Kunz BA, Barclay BJ, Game JC, Little JG, Haynes RH. 1980. Induc-tion of mitotic recombination in yeast by starvation for thyminenucleotides. Proc Natl Acad Sci USA 77:6057–6061.

26. Barclay BJ, Kunz BA, Little JG, Haynes RH. 1982. Genetic andbiochemical consequences of thymidylate stress. Can J Biochem60:172–194.

27. Eckardt F, Kunz BA, Haynes RH. 1983. Variation of mutation andrecombination frequencies on a range of thymidylate concentra-tions in a diploid thymidylate auxotroph. Curr Genet 7:399–402.

28. Haynes RH, Little JG, Kunz BA, Barclay BJ. 1982. Non-DNA primarytargets for the induction of genetic change. In: Sugimura T, KondoS, Takebe H, editors. Environmental mutagens and carcinogens.New York: Alan R. Liss. p 137–146.

29. Haynes RH, Kunz BA. 1985. A possible role for deoxyribonucleotidepool imbalances in carcinogenesis. In: Muhammed A, von BorstelRC, editors. New York: Plenum. p 147–156.

30. Kunz BA, Haynes RH. 1982. DNA repair and the genetic effects ofthymidylate stress in yeast. Mutat Res 93:353–375.

Kunz BA, Taylor GR, Haynes RH. 1986. Intrachromosomal recombi-nation is induced in yeast by inhibition of thymidylate biosynthesis.Genetics 114:375–392.

31. Haynes RH. 1985. Molecular mechanisms in genetic stability andchange: the role of deoxyribonucleoside pool balance. In: de SerresFJ, editor. Genetic consequences of nucleotide pool imbalance.New York: Plenum. p 1–23.

32. Haynes RH, Kunz BA. 1981. DNA repair and mutagenesis in yeast. In:Strathern JN, Jones EW, Broach JR, editors. The molecular biologyof the yeastSaccharomyces: life cycle and inheritance. Cold SpringHarbor: Cold Spring Harbor Laboratory Press. p 371–414.

33. Haynes RH. 1966. The interpretation of microbial inactivation andrecovery phenomena. Radiat Res Suppl 6:1–29.

Wheatcroft R, Cox BS, Haynes RH. 1975. Repair of UV-induced DNAdamage and survival in yeast. I. Dimer excision. Mutat Res 30:209–218.

34. Eckardt F, Haynes RH. 1977. Kinetics of mutation induction byultra-violet light in excision deficient yeast. Genetics 85:225–247.

35. Haynes RH, Eckardt RH. 1979. Analysis of dose–response patterns inmutation research. Can J Genet Cytol 21:277–302.

Eckardt F, Haynes RH. 1980. Quantitative measures of mutagenicityand mutability based on mutant yield data. Mutat Res 74:439–458.

36. Haynes RH, Eckardt F, Kunz BA. 1985. Analysis of non-linearities inmutation frequency curves. Mutat Res 150:51–59.

Kunz BA, Eckardt F, Haynes F. 1985. Analysis of non-linearities infrequency curves for UV-induced mitotic recombination in wild-type and excision repair deficient strains of yeast. Mutat Res 151:235–242.

37. Johnson RG, Haynes RH. 1986. Kinetics of photoreactivation andliquid-holding recovery in yeast cells. Photochem Photobiol 43:413–421.

Johnson RG, Haynes RH. 1986. Evidence from photoreactivationkinetics for multiple DNA photolyases in yeast. Photochem Pho-tobiol 43:423–428.

38. Ager DD, Haynes RH. 1988 Analysis and quantification of the inter-

264 Kunz and Hanawalt

active effects between ultraviolet light and X-rays for cell killing invarious microorganisms. Radiat Res 115:127–140.

Ager DD, Haynes RH. 1990. Analysis of interactions between muta-gens. II. Ethylmethane sulfonate and ultraviolet light inSaccharo-myces cerevisiae. Mutat Res 232:327–336.

39. Taylor GR, Barclay BJ, Storms RK, Friesen JD, Haynes RH. 1982.Isolation of the thymidylate synthetase gene (TMP1) by comple-mentation inSaccharomyces cerevisiae. Mol Cell Biol 2:437–442.

McIntosh EM, Haynes RH. 1986. Sequence and expression of thedCMP deaminase gene inSaccharomyces cerevisiae. Mol Cell Biol6:1711–1721.

Lagosky PA, Taylor GR, Haynes RH. 1987. Molecular characteriza-tion of theSaccharomyces cerevisiaedihydrofolate reductase gene(DFR1). Nucleic Acids Res 15:10355–10371.

Gadsden MH, McIntosh EM, Game JC, Wilson PJ, Haynes RH. 1993.dUTP pyrophosphatase is an essential enzyme inSaccharomycescerevisiae. EMBO J 12:4425–4431.

40. McIntosh EM, Gadsden MH, Haynes RH. 1986. Transcription ofgenes encoding enzymes involved in DNA synthesis during the cellcycle of Saccharomyces cerevisiae. Mol Gen Genet 204:363–366.

41. McIntosh EM, Ager DD, Gadsden MH, Haynes RH. 1992. HumandUTP pyrophosphatase: cDNA sequence and potential biologicalimportance of the enzyme. Proc. Natl. Acad. Sci USA 89:8020–8024. (See also Ref. 39.)

42. McIntosh EM, Haynes RH. 1996. HIV and human endogenous retro-viruses: a hypothesis with therapeutic implications. Acta Biochimi-cal Polonica 43:583–592.

Harris JM, Haynes RH, McIntosh EM. 1997. A consensus sequencefor a functional human endogenous retrovirus K (HERV-K) dUT-Pase. Biochem Cell Biol 75:143–151.

McIntosh EM, Haynes RH. 1997. dUTP pyrophosphatase as a poten-tial target for chemotherapeutic drug development. Acta Biochimi-cal Polonica 44: 159–172.

43. Bryant DW, Haynes RH. 1978. Endonuclease alpha fromSaccharo-myces cerevisiaeshows increased activity on ultraviolet irradiatednative DNA. Mol Gen Genet 167:139–145.

Kunz BA, Hannan MA, Haynes RH. 1980. The effect of tumorpromoters on UV-induced mutation and mitotic recombination inSaccharomyces cerevisiae. Cancer Res 40:2323–2329.

Nestmann ER, Nasim A, Haynes RH, Kowbell DJ. 1981. Genetic

activity of actinomycin D inSaccharomyces cerevisiaebut not inEscherichia coli. Mutat Res 89:229–236.

Haynes RH, Collins JDB. 1984. Mutagenic potential of caffeine. In:Dews P, editor. Caffeine. Berlin: Springer-Verlag. p 221–238.

Haynes RH. 1985. Where the future? In: Woodhead AD, ShellabargerCJ, Pond V, Hollaender A, editors. Assessment of risk from low-level exposure to radiation and chemicals. New York: PlenumPress. p 455–468.

Ruhland A, Brendel M, Haynes RH. 1986. Hyperresistance to DNAdamaging agents in yeast. Curr Genet 11:211–215.

Groot de Restrepo H, Haynes RH. 1990. The human mutagen burdenand other problematic aspects of genetic toxicology. In: von BorstelRD, Plewa M, editors. Latin American symposium on geneticmonitoring for protection of human health and the environment.Revista Latinoamericana de Genetica, Volumen Extraordinario,Number 1:41–57.

Lewtas J, De Marini DM, Favor J, Layton DW, MacGregor JT, AshbyJ, Lohman PHM, Haynes RH, Mendelsohn ML. 1994. Risk char-acterization strategies for genotoxic environmental agents. In:Brusik DJ, editor. Methods for genetic risk assessment. Boca Ra-ton, FL: CRC Press. p 125–169.

44. Haynes RH. 1987. The ’purpose’ of chance in light of the physicalbasis of evolution. In: Robson J, editor. Origin and evolution of theuniverse: evidence for design? Montreal: McGill-Queens Univer-sity Press. p 1–31.

Haynes RH. 1989. Genetics and the unity of biology. Genome 31:1–7.Haynes RH. 1991. Biological weapons and ecology: public imagery.

In: Geissler E, Haynes RH, editors. Prevention of a biologicaland toxin arms race and the responsibility of scientists. Berlin:Akademie-Verlag. p 29–48.

Haynes RH, McKay CP. 1992. The implantation of life on Mars:feasibility and motivation. Adv Space Res 12:133–140.

Haynes RH. 1999. Evoking transmutational dread: military and civil-ian uses of nuclear and genetic alchemies. In: Singh RS, Krimbas C,Paul D, Beatty J, editors. Thinking about evolution: historical,philosophical and political perspectives. Cambridge: CambridgeUniversity Press (in press).

Accepted by—T.A. Cebula

In Memoriam: Robert Hall Haynes 265