Mutation Research 546 (2004) 1–6

Obituary

The life and scientific legacy of William L. Russell(1910–2003)

Courtesy of the Oak Ridge National Laboratory,managed by UT-Battelle, for the US Department ofEnergy.

The field of mammalian mutagenesis research haslost one of its most illustrious and distinguished mem-bers. On 23 July 2003, just a few weeks before his93rd birthday, William Lawson Russell passed away.His death came after a long illness and complica-tions of pneumonia. When the management team atOak Ridge National Laboratory (ORNL) learned of

Dr. Russell’s death, this group collectively eulogizedhim as “one of the most important scientists ever tohave worked here”. This is quite a compliment sincemany distinguished scientists, including Nobel Prizewinners, have been employed at ORNL over >50 yearsof its existence. Dr. Russell, or Bill, as he was knownto friends and colleagues around the world, leaves be-hind his lifelong partner, coworker, and wife Liane(Lee) Russell, as well as a rich scientific legacy.

When Dr. Alexander Hollaender, one of the pioneersof photobiology, came to Oak Ridge in the 1940s andwas given the task of building a Biology Division in thehills of Tennessee, one of the first researchers he hiredwas Bill Russell. Bill indicated that he would acceptDr. Hollaender’s offer on condition that a similar offerbe made to his new wife Lee, who was completingher Ph.D. requirements. Dr. Hollaender made the dualoffer and both accepted, thus beginning one of themost productive research partnerships ever assembledat ORNL.

In his usual straightforward style, Dr. Hollaendertold Bill that he wanted him to develop a mammaliangenetics laboratory second to none for the purposeof studying the genetic effects of radiation and to“think big”. At Bill’s suggestion, Hollaender invitedNobel Prize-winningDrosophila geneticist HermanJ. Muller (discoverer of the mutagenic effects ofradiation) and famous population geneticist SewallWright (who had been Bill’s mentor) to brainstormapproaches. Although both had concerns about thelogistical problems of determining mutation ratesin a mammal, each had his own suggestion of amethod. Bill, however, chose yet a different approachthat he felt could address both basic and pragmaticquestions—the specific-locus method, which would

0027-5107/$ – see front matterdoi:10.1016/j.mrfmmm.2003.11.002

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recover mutations at a defined set of gene loci in themouse.

Until that time, estimates of genetic risks had beenbased solely on mutation data fromDrosophila ra-diation studies and on the principles deduced fromthem, but questions remained on the applicability ofthese results to genetic risks in humans. The relativeradiation sensitivity of mouse andDrosophila genescould be ascertained better from specific-locus studiesthan from the other methods suggested by Muller andWright. The specific-locus method detects mutationsin the first descendent generation, rather than re-quiring more complex pedigrees (e.g., back-crosses).Mutant detection is quick and objective, rather thanbeing dependent on the observer’s acuity or on com-plex technical procedures. Because of these features,Bill argued, the method was ideally suited for what heconsidered to be an essential task, namely, compara-tive studies to determine the effects of biological andphysical variables that influence radiation mutagene-sis. In the end, Wright, Muller, Hollaender, and Billall agreed that the proposed work should go forward.Thus, with Hollaender’s support and Bill’s determi-nation, one of the 20th century’s most ambitious re-search programs in mammalian radiation genetics waslaunched. The facility constructed at Oak Ridge wasto become the home of almost 250,000 mice whenthe Biology Division was at its zenith (1947–1970).From its beginning, the Mouse House has stood asthe central hub for the Biology Division’s (now theLife Sciences Division) research program.

The specific-locus test uses a cross between irradi-ated (or control) mice, wild-type for a set of markers,and tester-stock mice homozygous for recessive al-leles at these markers. A new mutation involving thewild-type allele at any of the marked loci would beseen in the F1 progeny (i.e., heterozygous for therecessive marker allele). The first order of priority inthe work was to construct a tester stock combiningmarker genes for which available recessive alleleswere readily visible and fully viable in homozygouscondition. Bill and Lee chose recessive alleles forseven autosomal genes:a (non-agouti),b (brown),p (pink-eyed dilution),cch (chinchilla, an allele atthe albino [c] locus),d (dilute), se (short ear), ands(piebald). A mutant F1 thus would be recognizable asa∗/a (the star representing an induced mutation at thea locus), orb∗/b, etc. Even lethal and semilethal muta-

tions would be recoverable opposite the viable markerallele. Presumed mutants could be saved for breedingtests to confirm allelism, determine the effect of themutation in homozygous condition, and propagate themutation for any other investigations that might be-come of interest in the future. The seven genes werelocated on five chromosomes, and one of the twosets of linkages (d–se) was extremely close, the ideabeing to provide evidence on whether the mutagenictreatment was capable of inducing deletions.

Very early, radiation was indeed found to inducemultilocus deletions, and Russell’s subsequent workshowed a higher proportion of these deletions undercertain biological or physical treatment conditions.Viewed from the vantage point of our current molec-ular knowledge, the choice of marker genes was veryfortunate. We now know that most radiation-inducedmutations in experimental systems are DNA deletionsoften encompassing more than one gene and that thestructural and functional attributes of genes and theirgenomic context are major determinants that permit,minimize, or exclude an induced deletion being re-covered in a viable offspring. All of the seven markergenes are non-essential for survival of heterozygotesand happen to be located in genomic regions alsonot essential for viability. Consequently, induced mu-tations (including deletions) could be identified andrecovered through marker phenotypes. Subsequentcomplementation analyses of sets of overlapping dele-tions encompassing any of the seven marked loci per-mitted Russell and colleagues to derive fine-structuremaps of genomic regions of significant length andled to the cloning of several genes within these re-gions. Knowledge of the attributes of these genes hasprovided a very useful framework for understandingdifferences in gene response to induced mutations.Additionally, these data now serve as a starting pointfor inquiries on human genes likely to cause geneticdisease when mutated.

Bill and colleagues used the specific-locus test,with its ability to explore the effects of biological andphysical variables of radiation mutagenesis, to studya variety of problems that lie at the core of radiationgenetics. Among the biological variables were sex,germ-cell stage, and age; physical variables includeddose, dose-rate, and linear energy transfer (LET) ofthe radiation. The first results published in 1951 fullyvalidated the use of the specific-locus test to gain

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insights into the radiation mutability of mouse genes[1]. Male mice exposed to 600 R of X-ray irradiationto spermatogonia yielded 53–54 mutations among48,007 progeny, while in controls 2 mutations werefound among 37,868 progeny. A series of seminal pa-pers followed, including those on radiation dose-rateand mutation frequency[2]; radiation-induced mu-tations in female mice[3]; and the effects of dosefractionation[4].

Of these and several other discoveries, the dose-rateeffect was of particular practical and basic signif-icance [5,6]. In spermatogonial stem cells of malemice (but not in spermatozoa or spermatids), muta-tion frequency following protracted low-LET radia-tion exposures was found to be only one-third thatafter acute, high dose-rate exposures with the sametotal dose. The reduction factor was even greater fordictyate oocytes of females. Until this discovery, in-vestigators involved in genetic risk estimation heldthe view (based onDrosophila data on mutations in-duced in mature spermatozoa) that mutagenic effectswere independent of radiation-delivery rate and ofspacing between exposures. As a result of Bill’s find-ings for mouse spermatogonia, the cells of primaryimportance for considerations of genetic risk to men,a dose-rate reduction factor of 3 has since been usedin genetic risk estimation. The basic significance ofthe findings was that they provided the first evidencefor the repair of premutational damage.

Another important observation was that, followingacute X-ray irradiation of stem-cell spermatogonia,mutation frequencies did not decline even up to theend of reproductive life, indicating that genetic riskswould persist once spermatogonial stem cells had sus-tained radiation exposure. In female mice, however,the situation was quite different; the interval betweenirradiation and conception had a profound influenceon mutation frequency. Mutation frequencies werehigh in litters conceived within the first 7 weeks fol-lowing irradiation (sampling of mature and maturingoocytes) but dropped to essentially zero in subsequentlitters (sampling of resting immature oocytes). Thisdiscovery was made first with fission neutrons[7] andlater extended to low-LET irradiation[8]. Althoughthese findings raised the prospect that genetic risks inirradiated human females might become lower withtime after irradiation, the comparability of mouse andhuman oocytes has been questioned, and the sensitiv-

ity of human females to radiation-induced mutationsstill remains unknown after all these years!

Over the past several decades, the specific-locustest also has been used by other mammalian radiation-and chemical-mutagenesis laboratories in the US,Germany, and UK to which Russell supplied the testerstock and the wild-type strains used in Oak Ridge.Mutations recovered at these loci (as well as dom-inant mutations with externally visible phenotypesalso frequently recovered in these experiments) havebeen used profitably at Oak Ridge and elsewhere,providing an invaluable resource for further genetic,cytogenetic, and molecular studies on the nature ofmutations induced by radiation and chemicals.

Although Bill’s main focus was on radiationmutagenesis, he also contributed significantly tochemical mutagenesis. The most important ofthese contributions—which came 2 years after hisofficial retirement—was the demonstration thatN-ethyl-N-nitrosourea (ENU) is a highly effectivemammalian germ-cell gene mutagen[9]. The ex-tremely high mutagenic effectiveness of ENU permit-ted the accumulation of very extensive dose-responsedata for spermatogonia. In the lower portion of thecurve, below a dose of 75 mg/kg, mutation frequen-cies were significantly below a maximum likelihoodfit to a straight line. Bill interpreted this observation toindicate that, although ENU has very high mutageniceffectiveness, a significant proportion of ENU-induceddamage in stem-cell spermatogonia is reparable bycellular repair processes[10]. This interpretation wasgreatly strengthened by his finding that the mutationfrequency following 10 weekly exposures of 10 mg/kgwas only about one-eighth that following a singleexposure of 100 mg/kg, even though the total molec-ular doses measured in the testis were the same forboth exposure regimens[11]. ENU now is being usedextensively around the world in large-scale “genediscovery through mutagenesis” programs in mice.

Bill and Lee always worked as a team with com-plementary research interests and co-authored manypapers in their long and highly productive researchcareers. Both were charter members of the Environ-mental Mutagen Society (EMS) and contributed to theSociety in several capacities. Bill, for example, wasone of the founding members, served on the first EMSCouncil, and was the recipient of the distinguishedEMS Award in 1989. His presence and presentations

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at the Society’s annual meetings served as catalystsfor lively scientific discussions and debates. Whetherone agreed or disagreed with his point of view, he wasa formidable and often entertaining person with whomto debate an issue.

Scores of distinguished investigators were hired byDr. Hollaender between 1947 and 1968, and theseindividuals are proud alumni of the Biology Divi-sion. Ranking among those at the very top of thisblue-ribbon band, Bill and Lee Russell have broughtconsiderable recognition to the Division and ORNL.They have been called one of the most celebrated cou-ples in American science and have many awards totheir credit. Both are elected members of the NationalAcademy of Sciences, Senior Corporate Fellows ofORNL, and recipients of the Roentgen Medal, the En-vironmental Mutagen Society Award, and the EnricoFermi Award, the highest award given by the US De-partment of Energy. Since its beginning, the MouseHouse dominated the Biology Division’s research pro-gram and became one of the preeminent biological re-search organizations in the world, staffed with a hand-picked cadre of top-notch investigators and techni-cians. Bill remained active in the Division’s researchactivities for more than 15 years after his official re-tirement in 1977; altogether, he accumulated about 45years of service. Lee’s retirement followed in 2002 af-ter 55 years at ORNL. Even when retired, both Bill andLee maintained an active interest in the happenings atthe Laboratory and the goings-on in the Mouse House.

During his research career, Bill Russell accumu-lated many notable national and international honors,citations, and awards commemorating his scientificachievements. Here are some examples:

1955–1980 Member of NAS and NRC Committees on Biological Effects of Atomic Radiation1955, 1958, 1971 US delegate to Geneva Conference on the Peaceful Uses of Atomic Energy1962–1986 Member of US delegation to the United Nations Scientific Committee on the Effects of

Atomic Radiation (UNSCEAR)1965 Elected president of the Genetics Society of America1973 Roentgen Medal recipient1973 Elected to the National Academy of Sciences1976 Elected the first Senior Corporate Fellow of Union Carbide Corporation1976 Health Physics Society’s Distinguished Service Award recipient1976 Enrico Fermi Award recipient1989 Environmental Mutagen Society Award recipient2001 Newly constructed Mouse House at ORNL named “The William L. and Liane B. Russell

Laboratory for Comparative and Functional Genomics”

A prophetic and humorous anecdote is told aboutthe First International Conference on EnvironmentalMutagens held in 1973 at Asilomar, CA. Bill Russellwas one of the key speakers, and his talk was to takeplace in the early evening on the first full day of theconference. He arrived at the Asilomar facility just afew minutes before his talk was scheduled. When hechecked in at the registration desk, the clerk askedhim, “Are you one of those mutagens who are meetinghere?” Bill replied, “Yes, I expect I am” and went onhis way to find the auditorium and give his talk. Wesuppose we could all agree that he was a “mutagen”because both Bill and Lee changed many things inthe fields of radiation biology, genetic risk assessment,mutation research, and mammalian genetics.

Was Bill Russell’s life all about research with themouse? Hardly. He and Lee had a full agenda ofextracurricular activities, many stemming from theirfondness for nature and environmental conservation.They were active in community affairs, especially theTennessee Citizens for Wilderness Planning (TCWP),an organization they were instrumental in founding.This group seeks to protect natural lands and waters,especially those of the Cumberland and Appalachianregions that surround Oak Ridge. Just as they did withtheir research pursuits in the Mouse House, Bill andLee devoted themselves whole-heartedly to the workof TCWP and, among other things, helped to cre-ate two National Park System areas centered on rivergorges that they had saved from dam projects.

These accomplishments give only a glimpse of theextraordinary life of Bill Russell, who was born inNewhaven, UK, on 19 August 1910. It was proba-bly at Newhaven, located on the south coast, that Bill

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acquired a love for nature, the sea, and sailing. Heearned a scholarship to Oxford, from which he grad-uated in 1932 with a degree in zoology. While at Ox-ford, he participated in several sports such as rowing,sailing, and judo. Yes, judo, and he had several inter-esting stories to tell about his exploits in this martialart. He later said that his judo training helped him sur-vive unhurt after several falls in his later years.

Following his graduation from Oxford, he receiveda year’s fellowship at Amherst College in Mas-sachusetts. During his time at Amherst, he workedwith Drosophila and became interested in genetics tothe point of applying for graduate school at the Uni-versity of Chicago to study under the noted populationgeneticist Sewall Wright. Before starting his gradu-ate studies, he decided to see the country that wasto become his adopted home. He hitchhiked acrossAmerica on his way to the West Coast, living on 25cents a day. This excursion set a trend for travelingthat would continue throughout his life. He completedhis graduate studies in 1937 and accepted a positionat Jackson Laboratory in Bar Harbor, Maine, wherehe stayed until 1947, the year he came to work inOak Ridge.

Bill Russell was an exceptional person who had agreat sense of humor. He wrote poems, some in thestyle of the American poet and humorist Ogden Nash,just for fun. Wherever he was or whatever he wasdoing, Bill Russell the scientist always came through.The last time the authors saw him was in 2002, whenSankar (K.S.) was on one of his visits to ORNL andwe had been invited to Bill’s home for an evening. Heshowed us the record he was keeping of informationgleaned from obituaries in the local newspapers onthe sex and age of persons dying in the Oak Ridgearea. He proudly pointed out the graph he had madefrom these data and noted, “I am now 92, and, as youcan see, I am ahead of the plot.” The oldest man onhis graph at that time was 81. Yes, Bill, you wereahead of the plot then, and your many friends andcolleagues will always have you ahead.

One of the authors of this article (K.S.), althoughnot a direct student, had the unique privilege of learn-ing about mouse radiation genetics from Bill in the1970s and the pleasure of interacting with him sci-entifically and socially over many years, both in OakRidge and at meetings of the United Nations Scien-tific Committee on the Effects of Atomic Radiation.

Bill was a member of the US delegation to UN-SCEAR while K.S. was a consultant. The best wayto sum up Bill’s contribution to science is to quote apassage by Frits Sobels and Sankar from their prefaceto a special issue ofMutation Research honoring himand published in March 1991. They said, “It seems afair assessment that no single person has contributedmore to the field of mammalian mutagenesis, andthus to genetic risk assessment in man, than Dr. W.L.Russell.” His passing has left some mighty big shoesto fill.

Somewhat ironically, just a few weeks after Bill’sdeath in July 2003, the last remaining mouse ofthe Mouse House stocks was euthanized (2 October2003). From a colony that numbered in the thousandsover the years, now there were none alive. Just a yearearlier, 60,000 had been on hand. The euthanizedstocks of mice—or we should say frozen embryos,sperm, and ova from these stocks—were processedfor later rederivation into a new facility being built atthe main ORNL campus. Work on this new “MouseHouse” was completed in August 2003, and the build-ing was appropriately named in honor of Bill andLee. By naming the newly constructed Mouse House“The William L. and Liane B. Russell Laboratory forComparative and Functional Genomics”, ORNL notonly honored these two outstanding researchers butalso ensured that their names will be remembered inscience far into the future. Barry Berven, Director ofOperations for ORNL’s Life Sciences Division, andDabney Johnson, Leader for the Mammalian GeneticsGroup, have high expectations for the new Labora-tory. The frozen embryos are to be kept in storage andat the appropriate time transplanted into clean femalemice obtained from certified suppliers. The frozensperm and ova will remain in storage until needed.These resources will be ready for use in determiningand assigning organismal functions to specific DNAsequences and correlating DNA-sequence informationwith functional information obtained from analyzinginduced mutations in the mouse. The house Bill andLee built still will be contributing to science on into the21st century.

An era ends, and a new one now begins.In addition to Lee and the two children from this

marriage, Bill also is survived by three children (oneson died in 1994) from his first marriage (1937–1947)to Elizabeth Shull, who died in 2001.

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Acknowledgements

The authors express appreciation to all their friendsand colleagues who assisted in the preparation of thisarticle. Specifically, we wish to thankMutation Re-search editors David DeMarini, Michael Shelby, andMike Waters for asking us to write this tribute to BillRussell. We also thank Liane Russell for her assis-tance in reviewing the article and providing insightsand background information about Bill’s research andenvironmental-conservation work. Comments and in-put from Heinrich Malling (long-time friend and men-tor of J.S.W.) are always a definite plus. Addition-ally, the help of many persons at Oak Ridge NationalLaboratory and elsewhere is gratefully acknowledged,especially Barry Berven, Po-Yung Lu, Jack Bishop,Bob Ross, Carolyn Krause, Jane Parrot, Gail Swee-den, Judy Wyrick, Mark Dickey and Judy Wassom.The capable editorial help and suggestions of AnneAdamson have been invaluable to us. She is one of thevery best at her craft.

References

[1] W.L. Russell, X-ray induced mutations in mice, Cold SpringHarb. Symp. Quant. Biol. 16 (1951) 327–336.

[2] W.L. Russell, L.B. Russell, E.M. Kelly, Radiation dose rateand mutation frequency, Science 128 (1958) 1546–1550.

[3] W.L. Russell, L.B. Russell, J.S. Gower, S.C. Maddux,Radiation-induced mutation rates in female mice, Proc. Natl.Acad. Sci. U.S.A. 44 (1958) 901–905.

[4] W.L. Russell, An augmenting effect of dose fractionation onradiation-induced mutation rate in mice, Proc. Natl. Acad.Sci. U.S.A. 48 (1962) 1724–1727.

[5] W.L. Russell, E.M. Kelly, Specific-locus mutation frequenciesin mouse stem-cell spermatogonia at very low radiation

dose rates, Proc. Natl. Acad. Sci. U.S.A. 79 (1982) 539–541.

[6] W.L. Russell, E.M. Kelly, Mutation frequencies in male miceand the estimation of genetic hazards of radiation in men,Proc. Natl. Acad. Sci. U.S.A. 79 (1982) 542–544.

[7] W.L. Russell, Effect of the interval between irradiation andconception on mutation frequency in female mice, Proc. Natl.Acad. Sci. U.S.A. 54 (1965) 1552–1557.

[8] W.L. Russell, Repair mechanisms in radiation mutationinduction in the mouse. Recovery and repair mechanisms inradiobiology, Brookhaven Symp. Biol. 20 (1967) 179–189.

[9] W.L. Russell, E.M. Kelly, P.R. Hunsicker, J.W. Bangham,S.C. Maddux, E.L. Phipps, Specific-locus test showsethylnitrosourea to be the most potent mutagen in the mouse,Proc. Natl. Acad. Sci. U.S.A. 76 (1979) 5818–5819.

[10] W.L. Russell, P.R. Hunsicker, G.D. Raymer, M.H. Steele,K.F. Stelzer, H.M. Thompson, Dose-response curve forethylnitrosourea-induced specific-locus mutations in mousespermatogonia, Proc. Natl. Acad. Sci. U.S.A. 79 (1982) 3589–3591.

[11] W.L. Russell, P.R. Hunsicker, D.A. Carpenter, C.V.Cornett, G.M. Guinn, Effect of dose fractionation on theethylnitrosourea induction of specific-locus mutations inmouse spermatogonia, Proc. Natl. Acad. Sci. U.S.A. 79 (1982)3592–3593.

John S. WassomOak Ridge National Laboratory 1

1060 Commerce Park, Oak Ridge, TN 37830, USA

Corresponding author. Tel.:+1-865-574-7774fax: +1-865-574-9888

E-mail address: wassomjs@ornl.gov(J.S. Wassom)

K. SankaranarayananSylvius Laboratories, Department of Toxicogenetics

Leiden University Medical CenterWassenaarseweg 72, 2333 AL Leiden

The Netherlands

1 Oak Ridge National Laboratory managed and operated byUT-Battelle, LLC, for the US Department of Energy under con-tract No. DE-AC05-00OR22725