Outstanding Papers
in Biology

Foreword from Outstanding Papers in Biology (pp. i-vi)

by Walter Gratzer

Editor's Note: Current Biology Ltd., the publisher of Current Biology and other journals, compiled the fascinating volume Outstanding Papers in Biology in 1993. The "outstanding papers" reprinted therein were selected and introduced by luminaries such as Paul Berg, Francois Jacob, Arthur Kornberg, Joshua Lederberg, and Max Perutz, to name a few. Although the book is not available commercially, readers of HMS Beagle can obtain a free copy. The following excerpt is the book's foreword, written by Dr. Walter Gratzer. It is an erudite essay on the "golden age of biology" - pondering why some papers and discoveries made the cut, and why others did not.

The contents page of Outstanding Papers in Biology provides complete references for the selected papers, and indicates the name of each selector.

What then is an outstanding paper and how is it to be recognized? Best for a start, do you say, that it should be right? A.E. Houseman once began a book review like this: "There is much in this book that is true and much that is new. But that which is true is not new and that which is new is not true." Well you can't have everything and in science, so [Sir Karl] Popper tells us, truth is transient, and imagination may transcend mere facts. There are many examples of hugely influential papers - at least one in this collection - that make up for a shaky hold on factual accuracy by sheer intellectual elan. Crick has spoken of the need to think daringly and not submit to the tyranny of detail, and of how hard it is to inculcate this faculty in the conventionally educated young.

Importance, like beauty, is in the eye of the beholder. Max Planck believed that radically new concepts in science (paradigm shifts, in today's jargon) ultimately prevailed not by reason of the inexorable weight of evidence, but through the demise of the incumbent generation of scientists. Certainly biologists have not proved quite so obdurate as the physicists, but all the same it was a decade before Mitchell's chemiosmotic hypothesis began to impinge seriously on the tribal consciousness. The relation between citation frequency and time after publication has been shown generally to follow a first-order rate law. Mitchell used to claim (with apparent satisfaction) that the citations of his classic paper rose after a long lag to a maximum, before presumably first-order decay supervened.

Even the Watson and Crick paper of 1953, which now reverberates so majestically through the history of science, was for the most part received with an indifference, verging in some quarters on hostility. Caviar to the general perhaps: A quality product needs a discerning consumer. For the select minority - for Sydney Brenner, for example, coming fresh from his Ph.D. in a laboratory in which bacteria were held to possess no genes - the DNA structure came as an epiphany. Its impact was compounded by Sanger's demonstration not long before that proteins, as represented by insulin, had a unique amino acid sequence, and were not random copolymers, as the wisdom of the day had it. This implied to those with the keenest perception a sequence correspondence of some sort between protein and DNA.

But what of the judgments of the mandarins? In 1977, Sir Ernst Chain, Professor of Biochemistry at Imperial College, London, penned the following trenchant lines:

Predictions that human genes coding for peptide hormones, such as insulin, can be obtained from the chromosomes by specific excision or by synthesis, can be transferred to bacterial genomes, and will then direct their protein synthesis specifically toward the production of the peptide hormones so that they can be obtained in large amounts by fermentation techniques seem to me to belong at the present time more in the field of science fiction than science.

This deathless pronouncement was committed to print after Itakura et al. had written their celebrated paper in Science, describing the expression of functional somatotrophin in Escherichia coli. For good measure Chain threw in a denunciation of molecular biology in general and of what he termed the new physical techniques, notably NMR, which could never yield interpretable results, and he still had some Olympian scorn to spare for those misguided enough to pursue the study of lipids in membranes.

In this numbing display of prescience the learned professor was only following in the footsteps of his predecessor in the University of London, Dr. Dionysus Lardner, who not merely asserted that high-speed rail travel was out of the question, because all the passengers would asphyxiate, but also published calculations that proved beyond peradventure that no steamship would ever make it across the Atlantic, for the amount of coal required to power the crossing far exceeded of the maximum payload. This assertion, at least, preceded the passage of the Great Western by two years.

Let us gratefully return then to the annus mirabilis of 1953. It was no doubt the manner of the discovery of the DNA structure that alienated many of the established figures in the field, such as Chargaff; it had been made to seem effortless, did not depend on the rigors of experiment and brought to mind the response of the tiresome Elsa Einstein when the director of the Mount Wilson observatory explained to her that his new telescope was needed to establish the structure of the universe: "Well, well, my husband does that on the backs of old envelopes." In time they all (Chain and a few other diehards excepted) passed through the sequence of reactions that according to Charles F. Kettering has ever greeted important discoveries: First they tell you you're wrong and they can prove it, then they tell you you're right but it isn't important and then they tell you it's important but they knew it all along. Chain stood firm on the first premise. DNA, like nothing before it in the history of science, except perhaps the theories of evolution and of relativity, has entered both language and folklore; some time in the early sixties Paul Doty, one of the founders of molecular biology, who had demonstrated hybridization and annealing of DNA strands, saw displayed on a New York paper stall lapel buttons that bore the legend "DNA." Supposing that the letters must stand for some political slogan also (Democracy not Anarchy?), he asked the paper-seller what they signified. "Get with it, mac", came the reply, "dat's de gene."

Scientists (like other people) can be divided into two categories, the simplifiers and the complicators. The papers that stir the blood are seldom by complicators; they do not seek to modify or elaborate the existing picture, but rather hack away the undergrowth of complexity - which, in the nature of things, grows back later. As Poul Anderson has observed, there is no problem, however complicated, that, when looked at in the right way, does not become even more complicated. There is, however, the transcendent moment of insight, when all is suddenly and blindingly clear, time passes, and we presently become aware that we know less than we did a year ago. Albert Szent-Gyorgyi, who discovered actomyosin, declared that when actin and myosin were found to be in different filaments in the muscle he knew that it was time to leave the field. Conversely, as the peptide chemist Vincent Du Vigneaud observed, there is nothing so lethal to progress as the right discovery at the wrong time. Imagine what would have happened had the ternary complex of polyuridylic acid and polyadenylic acid (which forms in physiological media that contain magnesium) been discovered before Watson and Crick had done their stuff.

Living, as I suppose we do, in the golden age of biology, the choice of publications that would qualify for inclusion in a time capsule confronts one with an embarrassment of riches. Our contributors have been asked to nominate the papers that made the strongest impression on their thinking and on the course of their research. These are not necessarily the milestones that stand tallest on the landscape of history; otherwise we should surely have had the imperishable opus by Meselson, Stahl and Vinograd, the prediction and discovery of messenger RNA, the first phage sequence by Sanger, the establishment by Tonegawa of the basis of antigenic diversity - you may name your own candidates. Great discoveries, of course, merely define a new agenda; they clarify the questions. The famous physical chemist G.N. Lewis summed this up when he snarled at a graduate student: "Damn it, if I understood the question I'd know the answer." But there are some achievements in science that seem ends in themselves. For me, the first protein X-ray structure - that of myoglobin - was preeminently of such a kind. Here was an end to all the inference and conjecture, which had accumulated for decades like a tidal shelf; there were the ionizing groups on the surface, here the hydrophobic groups within, the histidines nestling against the haem, and lo! an alpha-helix, viewed end-on, with the hole down the middle, plain to see. It brought tears to the eyes.

Then there are the great reviews, among which are some of the most influential utterances in the literature, the precious distillates of years of experience and analysis. As R.L. Baldwin observes here, for example, the questions that now still tease the toilers in one of the busiest and most absorbing areas of biology, the basis of protein folding, can be traced back to the review in 1959 by Kauzmann and a series of remarkable papers by his student, J.A. Schellman, that followed. I have an uneasy suspicion that the ferocity of competition which the expansion of science in recent decades has generated may have all but annihilated the genre: Authors these days feel the need to keep their powder dry.

Less imposing offerings, too, can change the course of a science; most often these are papers that unveil a new technique. These are by no means always monuments of intellectual achievement (how did Maizel hit on the virtues of SDS for analyzing protein mixtures?) but the march of biology has often received a critical impetus from such deceptively modest innovations; the cesium chloride gradient, the SDS gel, Southern blots, hybridomas, the Edman degradation, the Patterson function, and more recently the polymerase chain reaction, not to mention DNA sequencing, form part of a litany of progress, surprisingly (to me at least) little represented in the selection of classics before you.

Contemplation of the finely wrought works of discovery in the pages that follow may raise in the reader's mind the question that has always vexed scientists: How can the notion of creativity be applied to their labors? It is a truism that scientists must confine themselves to exposing existing truths - and not in the sense that Michelangelo attacked his block of marble to release, as he saw it, the statue buried within. Thus, Newton could not compare with his contemporary, Henry Purcell, for had he died of the plague the calculus would have been discovered (indeed was) by someone else; but who would have left us Dido and Aeneas or the Golden Sonata?

Is science then a Tolstoyan activity? Perhaps not altogether, if style and aesthetic are given their due. One can scarcely imagine that if the structure of DNA had emerged piecemeal - the helical diffraction, Chargaff's rules, reciprocity between purines and pyrimidines from acid-base titrations perhaps, the halving of the molecular weight in alkaline solution, all adding up to a structure based on two complementary strands - it would have caused such a spectacular ebullition of ideas and launched a thousand careers on a tide of E. coli genetics. What caught the imagination was the drama of the discovery and the shock of the implications.

The allosteric hypothesis, celebrated here by Max Perutz, made an instant impression, for all that it contained little that had not been prefigured in earlier studies. The ideas bordered on the obvious, a little like the insight of the farmer in the story by Josh Billings, who, troubled by the evidence that his white horses always consumed more fodder than his black horses, made careful quantitative investigations, which revealed that there were more white horses than black. Indeed, a review on subunit enzymes by a distinguished enzymologist compared the work of Monod and his colleagues to the rediscovery of the Mediterranean by successive waves of barbarians, each of which bestowed on it a new name. Allosterism became an industry, and irritated many by seemingly claiming the laws of thermodynamics as a sort of corollary. Nevertheless, the paper by Monod and his friends, spattered as it proved to be with half-truths and truisms, engendered an upheaval in the way in which biochemists and others approached complex systems, and became, as Perutz testifies, a landmark in biological thought. There is also here another underlying principle: Linus Pauling, when taxed after a lecture with annexing an old idea of his interlocutor's, is supposed to have replied: "Ah, but you see, I believe it." Ideas, that is to say, have their time.

It is in the character of modern science that new matter is rapidly assimilated into the common store of wisdom. Like the revolution, science devours its children and the precursors of today's discoveries are quickly forgotten. The dust accumulates undisturbed on the back issues in the library. Chargaff's apothegm is that in today's science it is more important, if you wish to attract notice, to be last than to be first. And yet the classic papers disinterred here retain their effulgence to a remarkable degree. They afford us the opportunity to return, as every so often everyone in science should take time to do, to the wellsprings of creativity. Those of us not endowed with the mysterious and elusive knack, that divine afflatus, which includes the capacity to be illuminatingly wrong, can perhaps find comfort in the lines of Emily Dickinson:

Faith is a fine invention
For gentlemen who see;
But microscopes are prudent
In an emergency.

Walter Gratzer is Professor of Biophysical Chemistry at King's College, London, Ontario. He is editor of A Literary Companion to Science (Norton, 1990) and A Bedside Nature: Genius and Eccentricity in Science, 1869-1953 (Nature, 1993).

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The Grand Profession and the Petty Professionals: Reflections on the Golden Era of Microbiology - HMS Beagle's opinion piece in Issue 9, describing two classic books' coverage of the drama of the emerging field of microbiology - Arrowsmith by Sinclair Lewis and Microbe Hunters by Paul de Kruif. Register your vote/see readers' responses on the merit of reading classic science books and papers in our poll.

Nature Past - a wonderful collection of full-text classic science papers originally published in Nature, including A structure for deoxyriibose nucleic acid by Watson and Crick, Charles Darwin: A great mind remembered and obituary by T.H. Huxley, and a nesting dinosaur fossil photograph. The Web material is excerpted from A Bedside Nature: Genius and Eccentricity in Science, 1869-1953, edited by Walter Gratzer, and can be purchased at the site. (Nature subscribers - #14.95/$24.50; nonsubscribers - #19.95/$29.95.)

Classic Papers in Genetics - links to PDF-format versions of classic papers by Mendel, Bateson, Wright, etc., with helpful annotations about the papers' subjects and import. Link to MendelWeb provides further useful genetic resources including original papers by Mendel.

World Scientific Series in 20th Century Chemistry - this series aims to provide a historical perspective on the development and progress of the varied fields now to be found in chemistry. The Web site lists volumes available for purchasing in collections of the major papers published by great chemists of this century. Topics include molecular structure and thermodynamics, modern alchemy, NMR in structural biology, and organic chemistry.

Evolution CD-ROM by Mark Ridley - published in December 1996 by Blackwell Science, this CD-ROM (based on Ridley's textbook) includes 20 classic papers and text extracts by Darwin, Fisher, Dobzhansky, Gould, and others. The Web site has an ordering button, plus further details of the CD including videos of theorists, animations, virtual experiments, and color images. (#29.50; $59.95 for book and CD.)

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