© 1999 Macmillan Magazines Ltd

Master Control Genes inDevelopment and Evolution: The Homeobox Story by Walter J. GehringYale University Press: 1999. 296 pp. $35, £25

William McGinnis and Peter A. Lawrence

“ ‘It’s a poor sort of memory that only worksbackwards,’ the Queen remarked” —Through the Looking-Glass by Lewis Carroll.

The past 20 years have seen embryologytransformed into developmental biology: weno longer transplant bits of embryos but rungels, identify genes and try to think up catchynames for them. Walter Gehring has livedthrough this transition, and he and his co-workers have made many important discov-eries on both sides of the divide. The mostcharismatic of these is the identification ofthe homeobox, a piece of DNA that encodes aprotein motif, a signature written into someof the most illuminating genes ever defined.

In Master Control Genes Gehring writesclear and accessible prose, free of theacronyms and stilted jargon of most scientif-ic text. He takes us on a roller-coaster ride,mainly down into the demanding depths ofheavy-duty description, occasionally up tothe entertaining heights of lyrical reminis-cence, giving us a book that is part primer,part autobiography, part gossip. After a Swis-socentric introduction that reviews howinformation is transferred from genes toproteins, the book introduces its centralthemes, homeotic genes and the homeobox.

With a sense of wonder, Gehring recountsthe history of homeotic mutations that, forexample, transform antenna into leg, andthen shows how the homeobox became awindow through which one could see thathumans, bugs and worms are all sistersunder the skin, all built and designed by thesame genes. This window also showed us thatinvertebrates and vertebrates share, in part,an immemorial body plan — a grand sur-prise with evolutionary, even philosophicalimplications.

The homeobox has also proved to be anaid in picking out some of the special genesconcerned in animal design, genes thatembody instructions to single cells, directingtheir differentiation or, more significantly,acting in cell groups, telling them whichparts of the body to make. Gehring conveyssome of the excitement of the early homeo-box era as unifying results were discoveredand new models emerged. Indeed, hedelights in reliving Ah Hah! moments of dis-covery, and also reveals a few scars lingeringfrom defunct intellectual disputes. The bookthen hunkers down to basics, telling in text-book style how embryos are constructed atthe cellular level, and how stripes of gene

expression are generated. He next describeshow homeotic proteins may work, and, in aparticularly vivid section, how a “mastercontrol gene” specifying eye was discovered.

For the general reader, the book brings tolife recent discoveries in developmental biol-ogy. Historical vignettes garnish the stories:most chapters begin with personal memo-ries from Gehring’s travels that relate to thescientific problems discussed. An interestingsection describes how molecular biology wasembraced by only a few embryologists likeGehring, who took up cloning with messian-ic fervour. Today it seems obvious to studyboth cells and gels, but it cannot have been soin the mid-1970s or more would have doneit. Gehring was prescient in this and otherdecisions and one is at first impressed by hisunerringly accurate predictions. But after afew of them, as he and his eager subordinatesuncover one developmental secret afteranother, most readers will feel their amaze-ment turning to incredulity. In one passagehis predictive prowess takes wing in a timemachine, as Gehring assures the reader “Iwould have predicted [that result]”.

Readers will want to know exactly when,how and by whom the homeobox was dis-covered. First let’s consider the method:DNA probes made from a homeotic genewere hybridized to gels carrying DNA frommany genes. It was found that some probeshybridized to several places on the gel, show-ing that several genes shared at least a piece ofsequence. This piece was the homeobox andturned out to encode about 60 amino acids.Now the history: in the front of the bookthere is a chronology, starting with The Ori-gin of Species and including the homeoboxdiscovery; the former is credited to Charles

Darwin, the latter to Matthew Scott andGehring himself. Indeed, the discovery wasmade independently at about the same timein the United States and Switzerland. How-ever, when the key observations were madeby Scott and Amy Weiner in Indiana, theywere postdoc and graduate student inThomas Kaufman’s laboratory, and thoughit was, and is, common practice for lab chiefsto co-author the papers of postdocs and stu-dents, Kaufman generously did not insist onit. Kaufman had done fine work, identifyingand describing the Antennapedia complex ofhomeotic genes, upon which Scott andWeiner’s amazing discovery depended, sothere is no doubt he deserves considerablecredit for preparing the ground in Indiana,just as Gehring himself does in Basel.

Gehring’s account of the discovery inBasel lacks detail and a consistent timeline,and is at odds with the records and recall ofother participants. Gehring recollects that healone saw the significance of his postdoc RickGarber’s hybridization with AntennapediaDNA. But participants at the meeting (earlyautumn of 1982) where this was discussedremember that there was an anomalousband in Garber’s gel that could have led to thediscovery. However, it was attributed tooverloading of the gel, lumped into the‘uninterpretable results’ category and notfollowed up. No one besides Gehring canknow his thoughts at the time, but if the significance of this band were so obvious, it is a mystery why it was not chased upimmediately.

When Bill McGinnis arrived in January1983, he was not asked by Gehring to exploreAntennapedia cross-homology. Instead, heworked on the lethal giant larvae gene with

NATURE | VOL 398 | 25 MARCH 1999 | www.nature.com 301

Historical transformationsbook reviews

This beast is not the work of amutated “master control

gene” but rather of the Germanartist Thomas Grünfeld. Grünfeld livesand works in Cologne, where, over thepast 10 years, he has specialized intaxidermy to produce a whole bestiaryof misfits.

In “Misfit (COW)”, the 1997 workpictured here, a bull’s head isapparently seamlessly sewn onto anostrich’s body. It currently resides in theSaatchi Collection.

A homeoticnightmare

SAA

TC

HI G

ALL

ER

Y L

ON

DO

N. C

OU

RT

ESY

KA

RST

EN

SC

HU

BE

RT,

LO

ND

ON

. PH

OT

O: L

OT

HA

R S

CH

NE

PF

© 1999 Macmillan Magazines Ltd

Bernard Mechler, while looking around forother projects. Nothing homeobox-relatedwas done until March 1983, when MichaelLevine made the crucial suggestion that anAntennapedia probe be used on a blot withDNA from different species of the fruitflyDrosophila (McGinnis was intending to testfor sequence conservation in the lethal giantlarvae gene). This experiment lies at theheart of the discovery of the homeobox —they found that the Antennapedia probehybridized to multiple bands in bothDrosophila melanogaster and D. hydei,implying common sequences in other genes.As recounted in The Making of a Fly: TheGenetics of Animal Design by P. A. Lawrence(Blackwell, 1992), Ernst Hafen, AtsushiKuroiwa, Levine and McGinnis then fol-lowed this common sequence to its varioussources in the Drosophila genome, findingthat the sequence mapped to the chromoso-mal loci of two groups of homeotic genes, theAntennapedia and Bithorax complexes.Then, by hybridizing probes to tissue sec-tions, they found that genes containing thesequence were expressed locally in theantero-posterior axis of embryos. Gehringreceived DNA from Pierre Spierer thatincluded the Ultrabithorax transcriptionunit (another homeotic gene) and morecross-hybridization showed that Antenna-pedia and Ultrabithorax had the same com-mon sequence, which then acquired thehomeobox tag.

What about the discovery of homeoboxesin vertebrates? In the book Gehring creditshimself and Eddy de Robertis with the deci-sion “in a flare of boldness ... to begin lookingfor homeobox genes in vertebrates”. But healso points out that there was an earlier“zooblot”, which was done in June 1983.Now, this blot contained DNA from a Noah’sArk of animals, including vertebrates; itshowed up homeobox bands in them all (seeThe Making of a Fly). This discovery madeGehring and De Robertis’ search rather lessadventurous than portrayed. It is, of course,a difficult task to write history when nearlyall the participants are still alive. Gehringrealizes this, stating that the book “repre-sents my personal view and is therefore cer-tainly biased”. Those who have detailedknowledge of some of the events in the bookwill agree with him on this point.

At the beginning of the most famousautobiographical essay in modern biology,James Watson wrote that he had “never seenFrancis Crick in a modest mood”, and Wat-son goes on to describe events and peoplewith unbridled candour. Gehring’s autobio-graphical stories provide candour too, butunlike the The Double Helix, this book omitsthe fits and starts, the blind alleys pursued,the struggles with techniques and the endlessdoubts. It does not illustrate the part thattimeliness and luck play in nearly every dis-covery. In sum, Master Control Genes con-

tains a deeply personal view, told in a heroicstyle, of how a fruitful collision betweenembryology and molecular genetics of fliesand other animals changed how we thinkabout development and evolution. But someof the pictures painted in the book should beviewed through the looking-glass.William McGinnis is in the Department of Biology0349, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0349, USA. e-mail: wmcginnis@ucsd.eduPeter A. Lawrence is at the MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK.e-mail: pal@mrc-lmb.cam.ac.uk

Painting a picture ofdevelopmentThe Art of Genes: How OrganismsMake Themselves by Enrico CoenOxford University Press: 1999. 392 pp. £20

John Maynard Smith

“Over the past twenty years there has been arevolution in biology: for the first time wehave begun to understand how organismsmake themselves.” These are the openingwords of the preface to Enrico Coen’s book,and I think they are true. In The Art of Genes,Coen tries to explain to readers with no spe-cial knowledge of biology or developmentwhat is happening in the world of genetics.

He does so by means of a protracted anal-ogy with artistic creation; but this is not anattempt to obfuscate or mystify. Coen hashimself contributed to the revolution that isunder way and he is a mechanist at heart,with a passion for communicating. He uses

the artistic analogy to emphasize the differ-ence between the process of development

and the fabrication of a machine by follow-ing a plan or blueprint. Before a painterstarts painting a picture, he does not have animage in his mind of the completed picture.

Instead, he reacts continuously to the pat-tern of paint already on the canvas.

Coen introduces the analogy by describ-ing Curt Stern’s 1956 study of the effects of

the scute gene on bristle patterns in the fruit-fly Drosophila. (One of the book’s great mer-its is Coen’s sense of the history of his subject,from debates between preformation and

epigenesis to the premolecular era of devel-opmental genetics.) Stern studied flies thatwere mosaics of genetically scute and normaltissue. He explained the resulting bristle pat-terns as arising from an interaction betweenwhat he called a ‘prepattern’ (correspondingroughly to what Lewis Wolpert later calledpositional information) and the compe-tence of cells locally to respond to it. Hefound that the prepattern in scute flies wasunchanged from the normal but cell compe-tence to respond was impaired.

I remember being both excited and dis-appointed by Stern’s paper — excitedbecause it showed how genetics could beused to analyse development, but disap-pointed because the prepattern wasunchanged. After all, it is the pattern, not theresponse, that is the exciting thing we wantto understand. There is no longer any needto feel disappointed. Genetic analysis is alsorevealing how prepatterns are laid down, asCoen illustrates by describing, in somedetail, the development of segmentation inDrosophila and of flower morphology .

Following the artistic analogy, prepatternis described in terms of regions of differingcolour, eliciting different responses. Coengives a detailed account of early Drosophiladevelopment along these lines, including adiscussion of how colours spread, how someresponses depend on the presence of twocontrasting colours, and so on. At least theanalogy helps him to avoid the clumsy termi-nology of Drosophila development, with itsbicoid and hedgehog, Notch and fushi-tarazu,and to intersperse the geometric diagramswith pictures by Magritte, Escher, Picassoand Heath-Robinson.

I am delighted that one of the leadingpractitioners in the field should have takentime off from the lab to tell the rest of us whatis going on. How far has the attempt suc-ceeded? It does avoid any assumption of pre-vious knowledge: there is nothing here youcannot understand if you want to. But it isnot an easy read. If you want a book entitled“A Brief History of Development”, to browsethrough for an hour, learning enough of thevocabulary to keep your end up in cocktailconversation, this is not for you.

But there is an alternative reader forwhom the book is ideal. When I have

302 NATURE | VOL 398 | 25 MARCH 1999 | www.nature.com

Different perspectives: as Lewis Carroll pointedout, your view depends on where you’re standing.

book reviews