Copyright � 2009 by the Genetics Society of AmericaDOI: 10.1534/genetics.109.104976

Perspectives

Anecdotal, Historical and Critical Commentaries on Genetics

In the Beginning Was the Worm . . .

Sydney Brenner1

Salk Institute for Biological Studies, San Diego, California 92186-5800

In my end is my beginning.T. S. Eliot

CAENORHABDITIS elegans genetics started formallyin the first few days of October 1967 with the first

mutant hunt, which produced a grand total of twomutants. The first, E1, was named a ‘‘dumpy,’’ becauseof its distinctive body shape; the second, E2, was termeda ‘‘variable abnormal,’’ because of the range of defectsfound in its homozygous progeny. The low yield fromthis first mutant hunt, using EMS mutagenesis, simplyshowed how bad I was initially at discerning pheno-types, but I learned the art rather quickly and, onsuccessive experiments, my yield rose to between 25and 30 per screening. I learnt by doing and manyothers have since followed the same path and foundthat the understanding of wild-type behavior comesbest after the discovery and analysis of mutations thatalter it. I cannot really describe how triumphant I feltworking with E1, backcrossing it to wild-type N2 withthe male cultures I had previously established, andproving that the resulting heterozygotes segregated itin the classic Mendelian ratio of 1:3. Getting a mutantof a complex organism and confirming Gregor Mendelin only 2 weeks was most satisfying.

The genetics of diploids was novel to most of mymolecular biologist contemporaries, who were accus-tomed only to the haploid genetics of phage andbacteria. Terms such as ‘‘dominant’’ and ‘‘recessive’’ soonbecame common currency in our lab. The self-fertilizingproperties of the hermaphrodite, with the use of malesto transport genes from one hermaphrodite to another,made genetic manipulation simple. When John Sulstondiscovered a method of freezing C. elegans, we couldembark on serious genetic research. Actually what hediscovered was a method of thawing frozen nematodesand preserving viability; everything survives freezing—it’s the thawing that typically does the damage.

Over the next few years, I found many mutants, bothdirectly and by special screens, and I developedmethods to complement and map them. In 1974, Ipublished an article entitled ‘‘The genetics of Caeno-rhabditis elegans’’ in this journal (Brenner 1974). Itreported a study of 300 EMS-induced mutants and amap of about 100 genes on six linkage groups. It hadtwo other interesting features. First, it unapologeticallygave a full account of the methods that were used inhermaphrodite genetics, which today would be con-signed to a remote database as supporting informa-tion. This has ensured that the article is cited, almostritually, in almost every article written on C. elegansgenetics, and this has given a 35-year-old article anunexpectedly long life. There used to be a similarsource in bacteriophage genetics, published by MarkAdams in Methods in Medical Research. Since thereference was often copied from the reference listof current articles, it sometimes underwent mutation,and the change generated novel citation lineages thatcould be followed in the subsequent literature. I havenot checked whether this has happened to Brenner(1974), but since nobody these days copies referencesby longhand and has them transcribed by a typist, Iwould not expect it in the era of word processingmachines. The second interesting feature of this articleis that, in the Introduction, it outlined how a re-ductionist program of research might be pursued incomplex, multicellular organisms—or, at any rate, howwe were going to pursue it for the C. elegans nervoussystem. It also proclaimed the now well-known advan-tages of C. elegans for the projected research, namelythat it is small, rapidly growing, and easily handled inthe laboratory. Today, all of this would be deleted by aneditor as obvious, and yet I feel that it is important now,as I felt it was then, to give some indication as to why Iwas going to all the trouble of developing the geneticsof a new model organism.

1Address for correspondence: Salk Institute for Biological Studies, P.O. Box85800, San Diego, CA 92186-5800.E-mail: backhill.brenner@googlemail.com

Genetics 182: 413–415 ( June 2009)

The Genetics article was accompanied in the journalby another article by John Sulston and myself titled‘‘The DNA of Caenorhabditis elegans’’ (Sulston andBrenner 1974). Although strictly speaking, such workwas not considered to be genetics at the time, the editor,Arthur Chovnick, agreed with us that the two should gotogether. The DNA article showed that the uniquesequence fraction, some 83% of the DNA, was only 20times the amount in Escherichia coli. We had no real ideathen how large eukaryotic genes were, yet in thediscussion of the Genetics article there is an argumentthat the genome of C. elegans could not be constituted ofE. coli-sized genes of 1 kb or could be, as they werereferred to at the time, NMBGs—naive molecularbiologist’s genes. I suggested that there must be a lotof noncoding DNA that was not susceptible to mutationor, at least, to mutations that would give phenotypes. Iremember that I once compared the frequency of EMS-induced mutations in a myosin gene (unc-54) in C.elegans with that in the b-galactosidase gene of theaccompanying bacteria and found that they were aboutthe same. Since the proteins are of similar sizes, thisshowed that the target for mutation was the same andthe organisms were essentially transparent to themutagen. At that time, I was very concerned with theC-value paradox, the idea that the apparent complexityof organisms could not be correlated with the size oftheir genomes and that many organisms seemed to havemore DNA than they reasonably needed. Physicists, incontrast, were concerned that organisms did not haveenough DNA to explain their complexity but the clevermolecular biologist, not to mention the thoughtfulevolutionary biologist, knew that each organism hadexactly the right amount for its needs.

What, the reader may ask, did we do in the 6 yearsbetween starting C. elegans genetics and publishing thefirst article on it? Since the animal has a short life cycleof 3.5 days, it should not have taken all that much timejust to complement and map the mutations. Manyvisitors who came to the MRC Lab in Cambridge thoughtthat we spent far too much time eating, drinking, andtalking. Observing us only during normal workinghours, you could see their point. If one arrived at thelab at the reasonable hour of 10 am, there was just time toopen one’s mail before adjourning to the canteen formorning coffee, usually prolonged by a very interestingdiscussion on some aspect of science. This did not leavemuch time before lunch, which naturally was alsoaccompanied by discussion that was terminated only byrushing off to attend an afternoon seminar on the Bohreffect in hemoglobin or the like. That brought one toafternoon tea and after that there was hardly enoughtime to start anything in the lab before adjourning to thepub for liquid and intellectual refreshment. It was onlyafter dinner that the real work started and the lab thenfilled up with the owls. Even these bouts of work had tobe interrupted, of course, for midnight coffee and more

discussions. Often, the few larks like myself, who came tolab very early in the morning, met the owls going home,and there were many nights when I became an owl as well.

The right answer is that we were very busy with manyother aspects of the project at the same time. I could easilydo my genetics in the morning, with my assistant MurielWigby, and I then spent a lot of my time getting theelectron microscopy going with Nichol Thomson. Whenwe looked at the mutants using polarized light micros-copy, we quickly discovered that some of the paralyzedmutants had muscle defects and that this reflected effectsof the mutations on the thick filaments, as was soonconfirmed by electron microscopy. We began a long seriesof experiments on developing molecular biology in thenematode through the protein chemistry of myosin andother muscle components. Sandy McCleod was an earlycolleague, and Bob Waterston and Henry Epstein en-tered C. elegans research this way. This work culminatedlater in the cloning of the myosin gene by Jon Karn.

I also spent an inordinate amount of time withcomputers. We thought we would try to automate thereconstruction of serial section electron micrographs,for comparing mutant and wild-type nervous systems,and John White joined me for this purpose. He startedby writing programs in binary for a Ferranti computerthat Ulli Arndt was using to automate crystallographyand that had originally seen service in Royal Navysubmarines. I learnt computing and managed to per-suade the MRC to buy a Modular I computer for us,which we were later able to expand very cheaply bytalking to the ‘‘liquidator’’ (who had nothing to do withthe present Governor of the State of California, but wasa gentleman disposing of the assets of our now bankruptcomputer company). I recklessly took on projects,writing in assembly language, such as altering Fortrancompilers to interface with a graphics system that JohnWhite had implemented. David Marr joined the lab andGraeme Mitchison became a user, and we all spent manydays and nights crawling on the floor, gluing pieces ofpaper tape together. Although I learned a lot, all ofthis turned out to be ridiculously premature and thereconstruction was finally done by hand, by EileenSouthgate and Rita Fishpool. Only now, with cheapcomputing power, is automatic reconstruction becom-ing feasible, and I am told that a ‘‘wiring diagram’’ of theC. elegans nervous system can be assembled in a week.

During this period, most people viewed C. elegansalmost as a joke organism and, adding insult to insult,

Figure 1.—Wild type hermaphrodite Caenorhabditis elegans.Courtesy of Maria Gallegos.

414 S. Brenner

often confused it with the flatworm. Jim Watson, inparticular, said he would not give me a penny for thiswork, complaining that I was 20 years ahead of my time.What changed everything was the advent of cloningand sequencing. It opened up all of genetics and gaveus direct access to genes. We were no longer subject tothe tyranny of the reproductive cycles of organisms, butcould study the genomes of everything. In addition, anincreasing number of talented and enthusiastic post-doctoral fellows came to join the lab and the nextdecade saw an explosive growth in the number ofpeople in the field. Some years ago I was shown alineage of C. elegans workers by Philip Anderson: Apartfrom the Cambridge group of Tony Stretton, JohnWhite, and John Sulston, and later Jonathan Hodgkin,the F1’s included David Hirsh, Richard Russell, DavidBaillie, Don Riddle, Sam Ward, Donna Albertson, andBob Waterston and later Bob Horvitz, Jon Karn,Barbara Meyer, Cynthia Kenyon, and many others.Some of these lineages extended to F4’s, and they mustbe deeper now. (Perhaps if the compilers of thisAlmanac de Gotha of C. elegans workers are still pursuingthis research, they could send me a copy.) I was toldthat there are now 400 C. elegans labs and that new onesare being established at a rate of one a week, more thanMcDonald’s is achieving with new restaurants. I do not

believe the last statement but would like to believethe first.

People often ask me why I left C. elegans research justwhen it was getting really interesting. The answer issimple: The people doing it were much better thanI was, and attendance at one meeting showed me thattheir students were even better than they were. I haveoften quoted J. D. Bernal, who compared science to agame of chess: The middle game is extremely boringand it is given to very few of us to play the end game.There remains only the opening game, which, for me, isthe most exciting part of scientific research. I think I amquite good at it, but, of course, it is interesting andsatisfying only when it has a successful outcome. Youhave only to look at the articles in this and other journalsto gauge what C. elegans researchers have achieved inchanging biology, and it pleases me to know that theyhave succeeded in this not only through their ownindividual endeavors but also by creating a uniquecommunity of sharing scientists.

LITERATURE CITED

Brenner, S., 1974 The genetics of Caenorhabditis elegans. Genetics77: 1–94.

Sulston, J. E., and S. Brenner, 1974 The DNA of Caenorhabditiselegans. Genetics 77: 95–104.

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