14 May 1971, Volume 172, Number 3984

Preface to a Grammar of Biology

A hundred years of nucleic acid research.

Erwin Chargaff

I

Darwin's Origin of Species, probablyone of the most influential books in thehistory of science (1), was publishedin 1859. The loud-mouthed, pompous,and insincere admiration of naturalscience, so characteristic of our time,began much later. It was, for example,possible for wise old Peacock, who inhis youth had been Shelley's friend, tolet two of the principal figures of hislast novel, published in 1860, converseas follows.

"Lord Curryfin: .. . We ought to havemore wisdom, as we have clearly morescience.-The Rei'. Dr. Opimiatn: Scienceis one thing and wisdom is another. Sci-ence is an edged tool with which menplay like children and cut their ownfingers. If you look at the results whichscience has brought in its train, you willfind them to consist almost wholly in ele-ments of mischief. . . The day wouldfail, if I should attempt to enumerate theevils which science has inflicted on man-kind. I almost think it is the ultimate des-tiny of science to exterminate the humanrace" (2).

Now that we have come so muchnearer to this destiny, who would stilldare write thus? It is not pleasant tobe denounced by dark times as a virobscurus. Still, Jean Paul took this riskin his "War Declaration against the

The author is professor of biochemistry andchairmar of the department at the College ofPhysicians and Surgeons, Columbia University,New York. This is a translation of an article pub-lished in Experientia 26, 810 (1970), which wasadapted from the Miescher Memorial Lecturedelivered on 30 May 1969, in the aula of theUniversity of Basel on the occasion of the 25thanniversary of Experientia.

c Circle No. 11 on Readeis' Service Card

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comes from Kierkegaard, who in 1849noted in his diary: "A single man can-not help his time, he can only expressits collapse" (5).

I use the first saying in reference toMiescher, the second applies to ourtime. It is now exactly a hundred yearsago that Friedrich Miescher in 1869discovered the nucleic acids. First fromthe nuclei of lymphocytes, and laterfrom the spermatozoa of the Rhinesalmon, he was able to isolate what wenow would designate as DNA, deoxy-ribonucleic acid. Miescher himself-and this appears clearly from his cor-respondence and from the tone of hiscompact papers-was well aware ofthe importance of his observations(6). They failed, however, to makemuch impression on his time; and howlittle echo there was can perhaps bededuced from the fact that even todaythe best history of the natural sciences,in the volume devoted to the 19th cen-tury and published in 1961, mentionsthe name of Darwin 31 times, that ofHuxley 14 times, but Miescher not atall (7). There are people who seemto be born in a vanishing cap. Mendelwas one of them and Willard Gibbsand David Keilin, and so was alsoMiescher. They all were no foxes, andArchilochos would not have hesitatedto classify them as hedgehogs.

It is almost impossible to retrace thecourse of the history of science to anearlier stage, for not only should webe required to forget much of what wehave learned, but much of what a pre-vious epoch knew or believed to knowhas simply never been learned by us.We must remember that the naturalsciences are as much a struggle againstas for facts. Every 30 years, a newgrowth makes the old forest impassable.Hence, I shall not even attempt to de-pict the scientific and intellectual cli-mate in which the first faltering stepsof hiochemistry occurred. It is, in gen-eral, true of every scientific discoverythat the road means more than thegoal. But only the latter appears in theordinary scientific papers. Probably,this is mostly to be welcomed, sinceotherwise there would be no end to

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War," part of that odd and wonderfulbook whose publication cost so muchtrouble; 137 years before the explosionof the first atom bomb:

"And who can guarantee, seeing theimmense developments in chemistry andphysics, that there will not be finally in-vented an infernal engine which similarto a mine will start and terminate a battlewith one shot; so that the enemy can dono better than to deliver the second, andtowiards evening the entire campaign isfinished?" (3).

I should like to start this essay withone of the quiet in the land, with Fried-rich Miescher, who a hundred yearsago, in 1869, discovered the nucleicacids, somehow between Tiubingen andBasel. As was to be expected, nobodypaid any a,ttention to this discovery atthat time. The giant publicity machines,which today accompany even the small-est move on the chessboard of naturewith enormous fanfares, were not yetin place. Seventy-five years had to passbefore the importance of Miescher'sdiscovery began to be appreciated. Forthat it required the appearance of an-other quiet man whom I shall mentionsoon.

II

I should like to place these briefremarks under the protection of twosayings. The first comes from an an-cient Greek poet who is being creditedwith the invention of the iamb, Archi-lochos from Paros, who said: "The foxknows many things, but the hedgehogone big thing" (4). The second word

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the chatter. In the case of Miescher,however, we should have liked to knowmore. The decision to investigate thechemistry of the cell nucleus testifiesto an unusual foresight, but also to abold disregard of the consequenceswith which too fast a pioneer mustreckon.A few years ago, I attempted to

describe th;is dilemma facing the scien-tific outsider, and each pioneer is eoipso an outsider.

"The natural scientist is often facedwith a series of observations, a set ofphenomena, into which he attempts sub-sequently to introduce some sort of chron-ological or causal order. He determinesseveral points and connects them to acurve; he measures certain values in anumber of samples and estimates theaverages and deviations; he constructs areaction chain or postulates a cycle:whatever he does, there remains muchdarkness between the few points of light.Whether he emphasizes the light or dwellson the obscurities will depend upon histemperament, but even more upon thetemper of the times and upon a form ofever-changing vogue or fashion which actsas a censor forbidding him to be aheadby more than one or two steps. If he runstoo fast, he disappears from our sight; ifhe goes too slowly, he joins the 18th Cen-tury. For most people, this is not a prob-lem: they are where all the others are"(8).This is exactly what Miescher did

not do: he found himself, when he be-gan and also when he ended, not whereall the others were; and for this reason,only very few paid him the attentionthat he deserved. One might ask, how-ever, how many of the world-shakingdiscoveries, bestowed on us in the last10 or 15 years, will prove worthy ofcentenary remembrance. This brings usto a problem in the value theory ofscience-in what actually constitutesthe value of a scientific observation-and these are considerations that Ishould prefer to avoid here (9). Whatmakes the study of nature so magnifi-cent is its very givenness: it is becauseit is; it is as it is; and "tolle, lege!"remains its eternal admonition.

In the case of the nucleic acids it isnot at all difficult to describe the sig-nificance of their discovery. Quite apartfrom their important biological func-tions, recognized within the last 25years, which I shall mention later, thenucleic acids are unique among thefour principal classes of cellular con-stituents-the proteins, the nucleicacids, the lipids, and the polysac-charides-in that their discovery canbe dated precisely. Here is one man,

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one place, one date; and this man isFriedrich Miescher, 1844 to 1895. Hedied young. The frontispiece to his col-lected papers shows a fine and shy,perhaps a sad face; as if the shortnessof his life had thrown a shadow overit. I have often asked myself whatsuch a man would have done in ourghastly time.The discovery of DNA by Miescher

was followed soon after by the descrip-tion of ribonucleic acid (RNA) in thelaboratory of Hoppe-Seyler in Tubing-en. Then began the long road-inthis case nearly 80 years-which everybiologically important, complicatedchemical substance must travel: first itsstructure, then its function. Since in thenucleic acids we have to do with ex-tremely complicated structures, com-posed of a very large number of fouror five simpler substances, the gradualadvance of our knowledge progressedsomewhat differently, namely in threeprincipal stages: (i) investigation ofthe primitive structure, that is, identi-fication of all chemical substances thatparticipate in the architecture of themacromolecule; (ii) formulation oftheir biological functions as carriers ofgenetic information; (iii) recognitionof their species-specific character andof their detailed structure. This workwas carried out by many, and therewould be little sense in offering a longcatalog. A few names should, how-ever, be mentioned. In the first stagethere were, following Miescher andHoppe-Seyler, Piccard, Kossel, Alt-mann, Neumann, Jones, Steudel, Feul-gen, P. A. Levene, Thannhauser, Ham-marsten, Jorpes, Gerhard Schmidt,Dische, and Gulland. In the secondstage: in addition to Brachet andCaspersson, especially Avery; in thethird stage: my own laboratory, Wil-kins, Crick, and Watson. Many differ-ent personalities were involved, differ-ent temperaments, different characters;and the many little chips that they un-earthed gained significance and coloronly in the mosaic of the whole.The generally antlike character of

the natural sciences is made particu-larly evident in this history; only thatby now the ants have become rathermore obtrusive (10). Also, we deal lesswith a mosaic than with a jigsaw puz-zle in which it is not necessary for allpieces to fit perfectly, as long as theimage, expected or permitted by pres-ent-day opinion, is reproduced approx-imately. The so-called exact sciencesoften are not as exact as is commonly

believed. How often do they infer theexistence of a hat from the emergenceof a rabbit! Nowadays it is not seldomthat an intensive search, or only an in-tensive assertion, produces what lookslike truth: This is what could be calledveritas creata. But there is somethingmuch higher, namely, veritas creans.

III

At this point, I should like to in-dulge in a short digression. Nature canbe explored on many levels; none ismore or less profound, none is moreor less correct, but they are different.Which one you choose depends uponinclination, talent, accident, but mostof all, unfortunately, upon fashion.Now one could say, at the risk of somesuperficiality, that there exist princi-pally two types of scientists. The ones,and they are rare, wish to understandthe world, to know nature; the others,much more frequent, wish to explainit. The first are searching for truth,often with the knowledge that they willnot attain it; the second strive forplausibility, for the achievement of anintellectually consistent, and hence suc-cessful, view of the world. To the ones,nature reveals itself in lyrical intensity,to the others in logical clarity, andthey are the masters of the world.Goethe was certainly wrong and New-ton right; but somehow I cannotescape the feeling that, as long as hu-manity lasts, the dispute will never beentirely resolved. The laughter ofSpinoza, as he watched two spidersbattling each other, can still be heard.It is almost an intrinsic part of ourconcept of science that we never knowenough. At all times one could almostsay: We can explain it all, but under-stand only Very little.Most scientists, therefore, are what

Archilochos would have called foxes,and they know many things. And thenthere still is a subdivision, much onthe ascendant in -biology, and thesewish to change the world (11). Withthem I do not wish to deal here, for Iam convinced that the attempts to im-prove or outsmart nature have almostbrought about its disappearance; justas the all too frequent performance ofintelligence tests is more likely to makethe testers more stupid than the testedmore intelligent. That the end sancti-fies the means has for more than a hun-dred years been the credo of the sci-ences; in actual fact, it is the meansthat have diabolized the end.

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IV

Physiological chemistry, still in itsinfancy, was the first science to be-come interested in the nucleic acids,and somewhat later organic chemistry,already highly developed at that time,took up the study. The constituents, thepurines and pyrimidines and theirsugar derivatives, which form the ac-tual components of the nucleic acids,that is, the nucleosides and the nucleo-tides, were isolated and characterized;better methods for the isolation of thenucleic acids from tissues were devel-oped; and finally rather complicatedstudies led to the identification of thetwo sugars, deoxyribose and ribose,which are characteristic of the twotypes of nucleic acid. At a still laterdate there began the synthetic andanalytic work which was followed bythe description of several more or lessspecific enzymes. I have mentionedbefore the principal names of thosethat participated in this work, but Ishould like to add the names of severalorganic chemists who took part in thefirst basic attempts at synthesis, namelyEmil Fischer and Traube, Wheeler andT. B. Johnson, and much later Alex-ander Todd.What was known about nucleic acids

at the end of this stage? Much andlittle. Their qualitative composition wasmore or less understood, that is, it waspossible to give a list of the types ofmolecules which were liberated by thedegradation of the nucleic acids. Thesewere in the case of DNA: (i) deoxy-ribose, a pentose sugar; (ii) two nitro-gen-containing substances belonging tothe purine group, adenine and guanine;(iii) two related nitrogenous substancesbelonging to the group of pyrimidines,cytosine and thymine; and finally (iv)phosphoric acid. RNA was found tobe very similar to DNA in its ultimateconstituents. It contains: (i) anotherpentose, ribose; (ii) the same twopurines as DNA, adenine and guanine;(iii) two pyrimidines, of which one isidentical with a DNA constituent,cytosine and uracil; and again (iv)phosphoric acid.

Further work demonstrated that inthe nucleic acids each of the purinesand pyrimidines carries a sugar moiety-these derivatives are called nucleo-sides-and that each nucleoside carriesa phosphate; these nucleoside phos-phates are designated as nucleotides.This is then the primary structure of anucleic acid: a chain of nucleotides14 MAY 1971

linked to each other via phosphatebridges, a polynucleotide. It will sim-plify the following discussion if a fewsimple abbreviations are introduced,namely, the initials of the variouspurine and pyrimidine nucleotides. Inspeaking of A, G, C, T, or U we desig-nate the corresponding nucleotides con-taining adenine, guanine, cytosine,thymine, or uracil.

For many decades the formulationof a DNA looked very simple, for in-stance: (AGCT) . One postulated theexistence of a compound composed ofall four building blocks, a so-calledtetranucleotide, which was 'repeatedseveral times in a nucleic acid. No firmassertion could be made as to the sizeof this value n, though it was consid-ered as quite small. The notion of theoccurrence of giant molecules, poly-mers, even in the living cell, prevailedonly slowly, first perhaps with regardto the proteins. How enormous the leapinto the present actually is may be seenfrom the fact that the molecular weightof a chain composed of ten tetranucleo-tides is about 12,000, whereas now the.molecular weights of various DNAspecies are computed as many millions,and even billions. Had in the early daysthe nucleic acids been considered as atext-actually, one was far from it-it could be said that in less than 30years a short aphorism has grown intoan immense epic.

Although it was known that bothnucleic acid types, DNA and RNA,occur in all living cells, no conceptionof their function, nor even of their ac-tual structure, had emerged.

V

This brings us to a period, 75 yearsafter Miescher's discovery, to the year1944. At that time there appeared apublication by Avery and collaborators(12) on the mechanism of the so-called Griffith phenomenon, the trans-formation of one pneumococcal typeinto another. The final sentence of thisremarkable paper, which was disre-garded in the widest scientific circles,reads as follows:

"The evidence presented supports thebelief that a nucleic acid of the desoxy-ribose type is the fundamental unit of thetransforming principle of PneumococcusType III."As this transformation represents a

permanently inheritable alteration of acell, the chemical nature of the sub-stance responsible for this alteration

had here been elucidated for the firsttime. Seldom has more been said in sofew words. The man who had writtenthem, Oswald Theodore Avery (1877-1955), was at that time already 67:the ever rarer instance of an old man

making a great scientific discovery. Ithad not been his first. He was a quietman; and it would have honored theworld more, had it honored him more.What counts, however, in science .is tobe not so much the first as the last.

This discovery, almost abruptly, ap-peared to foreshadow a chemistry ofheredity and, moreover, made probablethe nucleic acid character of the gene.It certainly made an impression on a

few, not on many, but probably on

nobody a more profound one than onme. For I saw before me in dark con-tours the beginning of a grammar ofbiology. Just as Cardinal Newman inthe title of a celebrated book, TheGrammar of Assent, spoke of thegrammar of belief, I use this word asa description of the main elements andprinciples of a science. Avery gave usthe first text of a new language, orrather he showed us where to look forit. I resolved to search for this text.

Consequently, I decided to relinquishall that we had been working on orto bring it to a quick conclusion, al-though the problems were not withoutinterest and dealt with many facets ofcellular chemistry. I have asked myselffrequently whether I was not wrong inturning around the rudder so abruptlyand whether it would not have beenbetter not to succumb to the fascina-tion of the moment; but these bio-graphical bagatelles cannot be of inter-est to anybody. To the scientist natureis as a mirror that breaks every 30years; and who cares about the brokenglass of past times?

I started from the conviction that, ifdifferent DNA species exhibited differ-ent biological activities, there shouldalso exist chemically demonstrable dif-ferences between deoxyribonucleic acids.From the very beginning I drew ananalogy to the proteins in assumingthat the biological activity of the nu-cleic acid probably rested on the se-quence specificity of its constituents-on the order in which the four differ-ent nucleotides were arranged in themacromolecule-rather than on the oc-currence of new, as yet unrecognizedconstituents. The prototype of this dif-ference then would be "Roma-Amor"and not "Roma-Rosa." This has provedto be correct.

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There existed, however, a difficultywhich appeared almost unsurmount-able: the lack of any method for theprecise chemical characterization of anucleic acid. The development of suit-able procedures took 2 years, 1946-48. The results were most surprising.They showed that the old and un-founded tetranucleotide hypothesis waswrong; that there existed an enormousnumber of different deoxyribonucleicacids whose composition was constantand characteristic within the speciesand within all organs of the same spe-cies; in other words, that the differentDNA species differed from each other,as is the case with the proteins, throughthe different arrangement of their con-stituents, through different nucleotidesequences. This was strictly speakingthe beginning of the notion, so com-monly accepted in the meantime, ofthe "information content" of DNA.

Retaining the previously defined ab-breviations, a DNA molecule could nolonger be formulated as (AGCT),, butas (A,,LGZCOTP), with m, n, o, and prepresenting not only very high values,but values characteristically different inDNA preparations isolated from differ-ent species. This placed the nucleicacids for the first time on the samelevel as the proteins.

But there emerged also somethingmuch more surprising, which distin-guished the nucleic acids from the pro-teins, namely, a sort of equipoise be-tween the several DNA constituents, ashad not yet been observed in any othernatural polymer. This is the relation-ship between adenine and thymine onthe one hand, guanine and cytosine onthe other, to which I first referred ascomplementarity, but which severalyears later, under the name of "base-pairing," became the fundamental slo-gan of a new science. These observa-tions were reported in several lecturesin 1949 and published at the beginningof 1950 (13).

These were the observations: If thetotal formula of a DNA molecule iswritten as (AmG1tC,Tp), as has beendone above, we find in many differ-ently composed DNA species that thevalues m and p are equal, as are thevalues n and o, and that the sums(m+n) and (o+p) show equality asdo the sums (m+o) and (n+ p). Toput it in words, the DNA constituentsare paired as follows: (i) adenine withthymine; (ii) guanine with cytosine;(iii) purines with pyrimidines; (iv)the substances classified chemically as

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6-amino derivatives (adenine and cyto-sine) with the 6-oxo derivatives(guanine and thymine).

VI

The natural sciences are furiouslywriting on second volumes of whichthere exist neither the first nor the last.Nothing is ever finished in this slip-pery world. But the second volumecontaining the observations outlinedabove can be considered as concluded.In referring to this work as historicalI use a synonym for oblivion.

Before turning to the further courseof our history I should mention a sec-ond subterranean branch of the greatriver for which unfortunately nobodyhas come up with a more sensible namethan "molecular biology," namely, theearly work on bacteriophages, princi-pally Escherichia coli phages. Thenames of Delbriick and Luria, S. S.Cohen, and Hershey are connectedwith these studies.

These investigations on viruses hadthe merit of making available simpleand clearly perceivable systems. Manystudies would have come to nothing,had they been limited to plant or ani-mal cells or only to bacteria. Likeevery reformation this one too was alsoa deformation; it has served to pushthe major part of research into an areaof which it is not even clear whetherit represents a microcosmic image ofliving nature. What happens so fre-quently in the natural sciences has hap-pened again: depth engenders restric-tion. In the end, we know nearly allabout nearly nothing.What was essential in these findings

was the demonstration that the prolif-eration of bacterial viruses in the in-fected bacterial cell is mediated solelythrough the DNA of the phages. Theseresults, therefore, confirmed Avery'spreviously mentioned seminal observa-tions.What has, consequently, become evi-

dent is that DNA, at least under cer-tain conditions, can be considered asthe carrier of "biological information";that this information must be based- onsequence specificity; and that the DNAmolecules are distinguished by peculiarand unusual regularities of their com-position. The newer history is againconnected with a series of names, ofwhich a few should be mentioned:Watson and Crick, Monod and Jaccob,Holley and Nirenberg. But this newerhistory of biology is also connected

with something else, and this couldform the subject of an apocalypticintermezzo.

VII

The last 15 years have witnessed anevent that, I believe, is unique in thehistory of the natural sciences: theirsubjugation to, their incorporation into,the whirls and frenzies of disgustingpublicity and propaganda. This is nodoubt symptomatic of the precariousposition assigned by present-day societyto any form of intellectual activity.Such pursuits have at all times beenboth absurd and fragile; but they be-come ever more ludicrous when, as isnow true of science, they become massprofessions and must, as homeless pre-tentious parasites, justify their right toexistence before a period devoted tonothing but the rapid consumption ofgoods and amusements. These scienceswere always a divertissement in thesense in which Pascal used the word;but what is their function in a societyliving under the motto lunam et cir-censes (14)? Are they only a band ofcourt jesters in search of courts which,if they ever existed, have long lost theirdesire to be amused?End of the World through Black

Magic was the title Karl Kraus gaveto one of his books. (At that, his timewas, compared with ours, still bucolic;but the great prophets always live inthe future.) The black magic of ourdays, these mass media concerned withboth the production and the distribu-tion of so-called news; these forevertitillated and nauseated intimacies,splashing all over us from newspapersand magazines, from radio and tele-vision; th;is bubbling and babblingemptiness of deadened *imagination:they have all taken hold of science, asof all other intellectual products ofhumanity, they have swallowed it up.It is not difficult to understand whyour youth experiences a revulsion fromall these synthetic celebrities struttingon the television screens of the world,from the ever-increasing pollution ofour intellectual and our actual atmo-sphere; and if, at least in America,there begins to be noticeable a distinctaversion to the natural sciences on theside of the students, this is certainlydue in part to the fact that these sci-ences anppear to form part of the dis-credited trappings of a hated history.Hiroshima is more than the name of adestroyed city.

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Since the end of the second worldwar-but especially since the Russiansuccesses in space flight-the financialresources, especially in the UnitedStates, being pumped into the naturalsciences have augmented in a mannerthat would have been unimaginable be-fore. This has given rise to a populari-zation, but also to an enormous vul-garization, of science. Its achievementshave begun to take on the form of a

spectator sport, and young scientistsstart like race horses. Science has beenperverted by public opinion to a sortof Hollywood and has begun to adaptitself to this brutal standard. The noise,enormous even before, has increasedwith the restriction of available funds(15). The old joke about the conver-sation between two Pavlovian dogscould be modified slightly: "Everytime, when I ring the bell, there comesa guy and gives me a prize."

Still, it is always surprising that insuch bad times-somehow betweenAuschwitz and Vietnam-so muchgood science has been produced. I donot know, though, what to conclude.(Times not so bad, sciences not so

good?) That in our days such pygmiesthrow such giant shadows only showshow late in the day it has become.

VIII

On the basis of the x-ray work onDNA by Wilkins in London and ofthe chemical observations of my lab-oratory, Crick and Watson in 1953made a very fruitful proposal with re-

spect to the macromolecular architec-ture, the secondary structure, of DNA(16). This model-a double helix con-

sisting of two intertwined DNA strandsheld together by specific hydrogenbonds, namely those predicted by theabove-mentioned principles of base-pairing-forms an important part ofthe grammar that the title of this paper

has alluded to. It is, in any event, themost intelligent explanation of the reg-

ularities discovered by us: of base-pairing, the equivalence of purines andpyrimidines, and so forth.The model of a double-stranded

DNA suggested immediately a possiblepathway for nature to bring about thereplication of a DNA molecule withthe conservation of its innate biologicalinformation, based on its nucleotidesequence. The old strand A makes the

new strand B, the old strand B makesthe new strand A; positive makes nega-

tive, negative makes positive, and so

14 MAY 1971

on ad infinitum. This process has beenrealized in vitro enzymically; but theliving cell, with its confounded multi-dimensionality, still presents us withmany question marks. Nevertheless,one may say that the problem of theconservation of hereditary biologicalinformation is relatively well under-stood, though this is less true of themechanisms through which such infor-mation can be changed. The insightinto the transmission of the text codedinto DNA, that is, its transcription intocomplementary RNA and the transla-tion of this RNA into different pro-teins, encounters greater difficulties,and these processes are understoodonly in vague outlines. The first stepconsisted in the demonstration of en-

zyme sys-tems (RNA polymerases)which, with the use of a DNA as anobligatory template, are able to syn-thesize RNA molecules of comple-mentary composition and nucleotidesequence.

These RNA molecules belong to sev-

eral different classes. We encounterhere, among others, the comparativelyhigh-molecular species of ribosomalRNA, then the small molecules oftransfer RNA, at least one type foreach of the amino acids occurring inproteins, and finally a very large num-ber of different so-called "messengerRNA" molecules-substances thattransmit the instructions of the DNAconcerning the structure of enzymesand other proteins to the ribosomeswhere the synthesis of proteins takesplace. Each of these messengers car-ries the cipher for at least one protein,read from a section of the DNA of thegenome. The RNA of plant viruses andcertain RNA-containing bacteriophagespresumably contain the code for sev-eral proteins whose synthesis is inducedby the infection.From all this, and from many other

things for which I have no room here,we have learned that the range of whatis considered as biological specificityis always in danger of being underesti-mated. If DNA is really our thread ofAriadne, the labyrinths out of which itis expected to lead us are truly in-scrutable. When in biochemistry we

employ such an innocuously soundingexpression as, for instance, that a cer-tain protein, an enzyme, "recognizes"a specific nucleotide sequence, do we

as much as suspect how much ofan anthropomorphic hypostatization we

have undertaken?All the schemes, which in several

versions represent the "central dogma"that "DNA makes RNA and RNAmakes protein," would not have car-ried us far, had it not been possibleto demonstrate, more or less conclu-sively, that RNA really contains nu-cleotide triplets, each of which formsthe code word for a given amino acid,as, for example, UUU for the aminoacid phenylalanine. I do not wish todiscuss here how valid these assign-ments really are, but prefer to limitmyself to admiring the magnitude ofthe cryptographic achievement, rejoic-ing in the fact that nature seems somuch better than Shakespeare whomDr. Johnson reproved for not havingbeen able to write "six lines togetherwithout a fault."

Ix

These then, sketched with repre-hensible superficiality, are the elementswhich made possible the first step to a"grammar of biology." If the Frenchsaying "I1 n'y a que le premier pas quicoute" were correct, the rest ought tobe easy. In other words, today thesmallest of the small bacteriophages,tomorrow the brain that conceived DieZauberflote. But in my laboratory thereexists an old house proverb saying"The first success in an experimentcomes from the devil; but then theway drags on." And truly, it will stilltake a long time from the relativelyprimitive structures, such as phages andviruses, with which molecular biologyis principally concerned, to the higherunicellular organisms, let alone themulticellular ones.

Total knowledge requires a limiteduniverse, but the realm of life has noboundaries recognizable to us exceptdeath itself. This has had the conse-quence that, as we cannot define it,life as a category has practically dis-appeared from modern biology. Wereally still are very far from an actualgrammar of the living cell, not to speakof that of an organ, an organism, or,even more, a thinking organism. It isnot by accident that the grammar ofthe tower of Babel was not written.The processes of cell differentiation,morphogenesis, and cellular organiza-tion still are entirely obscure. Onecould almost say that we have re-mained as far from the goal as ever.For it still remains our goal to under-stand nature, not to talk it to death.Do we really understand the world?

We designate what we understand as

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the world. Humanity has an enormouscapacity to disregard the incompre-hensible. There are many peculiar ex-pressions to be read in our journals.A phage is said to "commit suicide,"an infected bacterial cell to "abort."I myself may have been heard to saythat a nucleic acid chain is being read,copied, or even translated: that it isthe carrier of biological information,of a message acquired through tran-scription and transmitted as a transla-tion. Are these all not expressionswhich, if we try to think them to theirend, make the epistemological twilightof our sciences appear even more livid?We posit intelligence where we denyit. We humanize things, but we reifyman. I am afraid our sciences havenot escaped the process of alienation,of dehumanization, so characteristic ofour time. The attempt to describe lifein its generalized contours leads to anautomatization before which every-thing-the leap of the cat or the Gold-berg variations-appear equally in-comprehensible.

In the study of biology, the severaldisciplines exist next to each other, butthey do not come together. We haveno real idea of the inside of a livingcell, for we lack what could be calleda science of compressed spaces, welack a scientific knowledge of a whole;and while a sum can be subdivided,this is not true of a whole. I know fullwell, science progresses from the sim-ple to the complex. I, too, have beentaught that one must begin at the bot-tom; but shall we ever emerge at thetop?

I look out of the window. There isa dog; he barks; he wags his tail. Whatis his molecular biology? The new doc-trinaire biology has won great triumphsand caused great damage. By its readi-ness to explain all, it has blinded us tothe fact that we understand only little.It has furnished us the key to a verysmall lock; but the door it has openedfor us, is it perhaps merely a door toa castle in the air? Somehow I cannotrid myself of the feeling that we stilllack an entire dimension that is neces-sary for the understanding of a livingcell; and I am not thinking of the visvitalis.

Our biology no less than our tech-nology is a product of capitalism, gov-erned by unwritten rules of supply anddemand. Just as the ones poke aroundthe moon, the others ransack life. Theslogan always is: Eritis sicut diaboli,scientes bonum, facientes malum. I be-lieve, we have not reflected sufficientlyon the real goals of these new naturalsciences. When I began my studies thebattle cry was "knowledge"; now it is"power." It was much later that I dis-covered that already in 1597 FrancisBacon had announced the identity ofthese goals. But what is "power" inbiology? The type of answer I getpromises, for instance, the productionof heaps of thoroughly healthy Ein-steins. But is this desirable? Who willsew the pants for these Einsteins and,still more important, who will write thenewspaper articles about them? But,really, these are only jokes. Since noteven the most primitive of the smallestbacteriophages has been uniraveled, thistype of debased creation will still re-quire much time; and warners and of-fenders will long before be buried inone and the same Nirvana of oblivion.Perhaps-but I have little hope-hu-manity will in the meantime have be-come more intelligent.

Faced with this enormous throng ofsorcerer's apprentices, I should like toadd only one remark. It would seem tome that man cannot live without mys-teries. One could say, the great biolo-gists worked in the very light of dark-ness. We have been deprived of thisfertile night. The moon, to which as achild I used to look up on a clearnight, really is no more; never againwill it fill grove and glen with its softand misty gleam (17). What will haveto go next? I am afraid I shall be mis-understood when I say that througheach of these great scientific-techno-logical exploits the points of contactbetween humanity and reality are di-minished irreversibly.

References and Notes

1. Biological hypotheses are in general acceptedby the public much more readily and rapidlythan chemical or physical discoveries. Thus,the index to the Schlechta edition of Nietz-sche's works records 33 references to Darwin,one mention each of Robert Mayer andVirchow, and none of Helmholtz, Clausius, or

Liebig. In his enormous receptiveness Novalisis a great exception among German thinkers.

2. Thomas Love Peacock, Gryll Grange, chapter19.

3. Jean Paul, "Dammerungen fUr Deutschland,"in Samtliche Werke (Reimer, Berlin, 1862),vol. 25, p. 91. A not dissimilar passage alreadymay be found even in Montesquieu, in the105th letter of his Lettres persanes.

4. E. Diehl, Anthologia lyrica Graeca (Teubner,Leipzig, 1949-52), No. 103.

5. Taken from the German translation: SorenKierkegaard, Die Tagebucher (Brenner-Verlag,Innsbruck, 1923), vol. 2, p. 33.

6. Friedrich Miescher, Die histochemischen undphysiologischen Arbeiten, 2 volumes (Vogel,Leipzig, 1897). The letters contained in thefirst volume and also the introduction byWilhelm His are particularly worth reading.

7. R. Taton, Ed., Histoire Gen&rale des Sciences(Presses Universitaires de France, Paris,1961), vol. 3, pt. 1.

8. E. Chargaff, "On some of the biological con-sequences of base-pairing in the nucleic acids,"in Developmental and Metabolic ControlMechanisms and Neoplasia (Williams & Wil-kins, Baltimore, 1965), p. 7.

9. I should like to venture one remark. Onegains the impression that nowadays the valueof a piece of research is being measured interms of its potential for productive unem-ployment relief: He who gives something todo to the greatest number of idling scientistsis a great man. For this purpose we have now,for instance, a citation index from which onecan ascertain how often he has been cited byothers. This is a worthless standard. Meis-sonier and Bouguereau certainly were men-tioned, and bought, more often by their con-temporaries than Cezanne and Sisley. If, onthe other hand, the value of a scientific ob-servation is to be appraised on the basis ofits unexpectedness, its originality, this requiresa distance in time, a sort of bird's-eye view.This is true of the sciences no less than ofthe arts. We only have to think of the lackof appreciation with which Jean Paul orHolderlin were treated by Goethe and Schil-ler; except that a scientific Holderlin wouldnot even have achieved a publication. Unap-preciated geniuses in the natural sciences re-main unrecognized; for them there is no pos-terity.

10. J. D. Watson's The Double Helix (Atheneum,New York, 1968) depicts the hectic climateof present-day research quite adequately.

11. This is surely not the kind of change con-

templated by the young Marx in his 11thFeuerbach thesis.

12. 0. T. Avery, C. M. MacLeod, M. McCarty,"Studies on the chemical nature of the sub-stance inducing transformation of pneumococ-cal types," J. Exp. Med. 79, 137 (1944).

13. E. Chargaff, "Chemical specificity of nucleicacids and mechanism of their enzymatic deg-radation," Experientia 6, 201 (1950).

14. I have resisted the temptation to translatethis phrase, more expressively, as moondoggle.

15. Not infrequently, quite banal discoveries,especially in the field of virus and phagegenetics, are being celebrated with a news-

paper and television ballyhoo that would havedeserved a better soap. Although these are

mostly pseudo discoveries, not even applicableto unicellular organisms, one uses press con-

ferences, interviews, and the like, to alludeto the imminent "synthesis of life" or to im-pending cures by "genetic engineering." Thepublic, which forgets rapidly, retains thepleasant taste of the greatness and vigor ofthe sciences.

16. J. D. Watson and F. H. C. Crick, "Molec-ular structure of nucleic acids," Nature 171,737 (1953).

17. This passage alludes, of course, to the firstlines of Goethe's celebrated song An denMond: "Fullest wieder Busch und Tal / Stillmit Nebelglanz.

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