PNOT TRE PRCR MIRE R ta Oswald Future historians may remember this century for three scientific events: the splitting of the atom, the first exploration of outer Space, and the discovery of the structure of DNA. This last marked the start of genetic engineering, a science with the potential for changing life as we know it. The discovery was by Watson and Crick, whose work on the double helix brought them the Nobel Prize. Without Oswald Avery, however, it might not Avery == andthe Cascad of Surprises Inalaboratory forty years ago, an obscure researcher foundthe key that unlocked the secrets ot the cell BY LEWIS THOMAS ne of the liveliest problems in cancer research | problems for the scientists who work on DNA. these days is the behavior of oncogenes, strings | The intimate details of genetically determined of nucleic acid that were originally found in sever- | diseases of childhood are coming under close : scrutiny, and the precise nature of the error in al of the viruses responsible for cancer in labora- tory animals, later discovered to exist in all normal cells. By itself, an oncogene appears to | be a harmless bit of DNA, maybe even a useful one, but when it is moved from its normal spot to a new one on another chromosome, it switches the cell into the unrestrained growth of cancer. It is not vet known how it does this, but no one doubts that an answer is within reach. Some of the protein products of oncogenes have already been isolated and identified, and the site of their action within the cell, probably just beneath the cell membrane, is now being worked on. The the DNA molecule has been observed in several, sickle-cell disease, for example, with more to ‘come. The immunologists, embryologists, cell ' biologists, and. recently, even the endocrinolo- work is moving so fast that most recent issues of | Science and Nature contain several papers on oncogenes and their products. But cancer ts only one among dozens of new si te gists have observed the wavs in which small modifications of DNA affect the behavior of the systems that they study. Observed is exactly the right word here: the DNA molecule can be in- spected visually, purified absolutely, analyzed chemically, cut into whatever lengths vou like, transferred from one cell] to another or into a test tube for the manufacture of specific proteins. The techniques and instruments now available for . studying DNA have become so sophisticated that ] recently heard a voung colleague, one of the new breed of molecular geneticists, complain rma ay. ene Re en LR are 2 r ey a LA February 19-1-4 Avery's paper on DNA opened the door to the new biology. wy ESQUIRE DECEMBER 1483 that “even a dumb researcher can do a perfectly beautiful experiment.” It is indeed a biological revolution, un- questionably the greatest upheaval in biol- ogy and medicine ever. It began just fifty vears ago in a small laboratory on the sixth Hoor of the Hospital of the Rockefeller Institute for Medical Re- search, overlooking the East River at Six- ty-sixth Street in New York. Professor Oswald T. Avery, a small, vanishingly thin man with a constantly startled expression and a very large and agile brain, had been working on the pneumococcus—the bac- tertum causing lobar pneumonia—since the early vears of World War I. Avery and his colleagues had discovered that the virulence of pneumococci was de- termined by the polysaccharides (complex sugars) contained in the capsules of the organisms and that different strains of pneumococci possessed different types of polysaccharide, which were readily dis- tinguished from one another by specific antibodies. It was not clear at that time that the type of polysaccharide was a genetic property of the bacterial cells—it was not even clear that genes existed in bacterla— but it was known that the organisms bred true; all generations of progeny from a pneumococcus of one type were always of that same type. This was a solid rule, and like a good many rules in biology there was an exception. An English bacteriologist, Fred Griffith, had discovered in 1923 that pneumococci could be induced to lose their polysac- chandes and then to switch tvpes under special circumstances. When mice were injected with a mixture of live bacteria that had lost their capsules (and were therefore avirulent), together with heat-killed pneu- mococcliofa different type, the animals died of the infection, and the bacteria recovered from their blood were now the same type as the heat-killed foreign organisms. Avery became interested in the phe- nomenon and went to work on it. By the early 1930s it had become the main preoc- cupation of his laboratory. Ten years later, with his colleagues Colin M. MacLeod and Maclyn McCarty, the work was com- pleted, and in 1944 the now-classic paper was published in the fowrieal of Experimen- tal Medicine, tormidably entitled “Studies on the Chemical Nature of the Substance Inducing ‘Transtormation of Pheumococcal Types: Induction of Transformation by a Desoxvribonucleic Acid Fraction Isolated from Pneumococcus Type HI.” The work meant that the genes of pneu- mococel are made of DNA, and this came as a stunning surprise to evervone—not just the bactertologists but all biologists. Up until the announcement, the concept of the gene was a sort of abstraction. [t was known that genes existed, but nobody had the faintest idea what they were made of or how they worked. Here. at last, was chem- ical evidence for their identity and. more ESQUIRE DECEMBER 1983 importantly, a working model tor examin- ing their functions. Several vears later anew working model was devised in other laboratories, mvaly- Ing Viruses as the source of LNA. and in 1953 the famous paper by James Watson and Francis Cries was published, delineat- ing the double-helix structure of DNA. Many biologists track the biological revo- lution back to the Watson-Crick discov- ery, but Watson himself wrote, “Given the fact that DNA was known to oceur in the chromosomes of all cells. Averv’s experl- ments strongly suggested that future ex- periments would show that all genes were composed of DNA.” Looking back. whether back to the Wat- son-Crick paper or all the way back to Avery. the progress of sclenee can be made to seem an orderly succession of logical steps, a discovery in one laboratory leading tou a new hypothesis and a new experiment elsewhere, one thing leading neatly to another. It was not really like that, not at all. Almost every important experiment that moved the field torward, trom Avery's “transforming principle” to today's “jumping genes” and cancer biology, has come as a total surprise, most of all sur- prising to the investigators doing the work. Moreover, the occasions have been exceedingly rare when the scientists working on one line of research have been able to predict. with any accuracy, what was gong to happen nest. A few vears ago certain enzymes were discovered that will cut DNA into neat sections, selectively and precisely, but it could not have been predicted then that this work would lead directly, within just a few more vears, to the capacity to insert individual genes from one creature into the genetic apparatus of another—even though this is essentially what Avery accomplished, more crudely, to be sure, a half century ago. Good basic science is impossible to pre- dict. By its very nature, it must rely on surprise, and when it is going very well, as is the case for molecular genetics today, it is a cascade of surprises. And there 1s another sort of surprise that is essential for good basic science, not so exhilarating, enough to drive many stu- dent investigators clean out of science. This is the surprise of being wrong, which is a workaday part of every scientist's life. Avery endured ten vears of it, one expert ment gone wrong alter another, variables in the system that frequently made it im- possible to move from one question to the next. Reading the accounts of those ten years in Rene Dubos’s book The Professor, The Institute. aid DNA, one wonders how Avery, MacLeod. and MeCarty had the patience and stubbornness to keep at it. Being wrong, euessing wrong, setting up an elegant experiment intended to ask one kind of question and getting back an answer to another unrelated. irrelevant, unasked Guestion, can be frustrating dispiriting, butit can, withluck, alsobe | wav the work moves ahead. Avery ». . especially good at capitahzing on mistaker ideas and miscast experiments in his labu. ratory. He is quoted by some of his associ. ates as having said, more than once “Whenever vou fall, pick something up.” This is the way good science is done: not by looking around for gleaming neg. uable bits of truth and picking them up. .¢, pocketing them lke game birds, nor \. any yift of infallible hunch of where to |: jk and what to tind. Good science is done "| being curious iv general, by asking ques- tions all around, by acknowledging the likehhood of being wrong and taking this ir good humor tor granted, by having a dee; fondness for nature. and by being made nervous and jumpy by ignorance. Aver was like this. a familiar figure, fallible bs: bevond question a good man, the kins man you would wish to have in the fair ¢ Accident-prone, error-prone, but right or the mark at the end, when it counted. One thing for a good basic scientist t have on his mind, and worry about, is how his work will be viewed by his peers. If the work is very good, very new, and looks as: it’s opening up brand-new territory, he car be quite sure that he will be criticized dow: to his socks. If he is onto something rev o- lutionary, never thought of before, con’ + dicting fixed notions within the commu: t: of science involved, he tends to keep xs head down. When he writes, he writes e Avery wrote. a cautious paper, as nor committal as possible, avoiding big extrap- olations to other fields. Not all scientists with great discoveries to their credit receive the Nobel Prize, ané Avery did not. This spectacular omissior. continues to mystify the scientific ec munity and has never been explain ¢ René Dubos thinks that the Nobel comr it- tee was not convinced that Avery knew 2c significance of his own work, perhaps be- cause of the low-key restraint with whic the manuscript was written; the paper dlic| not lay out claims for opening the gate int | a new epoch in biology, although this i¢ certainly what it did accomplish. 1 doubt very much that Oswald Aver was ever troubled by the absence of a *o- bel Prize or even thought much about He was not in any sense a disappoir man. He understood clearly, while © work was going on, what its implication: were, and when it was fimshed he we: deeply pleased and satished by what © meant for the future. He had set the stage tor the new biology, and he knew that. Contrary to the general view, not & scientists do their best work in their thir ties, peak in their forties, and then > * side. Avery was sixty-seven years | when his DNA paper was published. {c reured four vears later and died of can ¢: at the age of seventy-seven, at peace wil the world. Dossier Oswald Theodore Avery was born in Halifax,Nova Scotia, on October 21, 1877, four years after his parents emigrated from England. His father started out as a paper- maker; but discontented with that trade and possessed of a mystical nature. he became a Baptist minister. When his father established his ministry in New York, the Baptist community helped the family live on a meager salary. After a fire destroved the Avery home in December 1890, Mrs. John D. Rocke- feller sent a check for one hun- dred dollars. In 1892 both his father and his older brother, Ernest, died, and Oswald became the man of the family. His mother went to work for the Bapust City Mission Society. Her work allowed her to nungle with the Rockefellers. Vander- bilts. and Sloans, who took an interest in her sons and invited them to their estates: and Avery acquired sophisticated tastes unusual for his background. As an undergraduate at Col- gate, he earned excellent grades. His vearbook said that only the acoident of his being born in Canada prevented him from fulfilling “his aspirations for the presidency.” He ma- jored in the humanities and took only those seclence EsQUERE DECEMBER Tus) BORN OCTOBER 21,1877 courses that were required. Nevertheless he went on to Columbia University’s medical school. At Columbia he was called Babe, because of his small size and youthful demeanor. One classmate said he had an ‘aristocratic daintiness. ” After receiving his medical degree in 1904, he practiced general surgery in New York for about three vears. But he found it upsetting to deal with patients suffering from chronic pulmonary diseases and intrac- table asthma, for whom he could do nothing useful. Al- though he was successful in his relations with patients, chnical practice did not satisfy him in- tellectually or emotionally. His favorite haunt was Deer Isle, Maine. He never misseda chance to go sailing. He also walked through the Maine woods collecting wild flowers. He left clinical medicine when, in 1907, the Hoagland Laboratory in Brooklyn ap- pointed him associate director at a salary of 81,200 4 vear. His next important move— to the Rocketeller Institute in 1913—almost didn’t occur be- cause, in keeping with his neglectful attitude toward cor- respondence, he failed to an- swer two letters offering him the job. -He walked to work every day and, from 1915 to 1448, o¢- cupied the same small, immac- ulate office. He ate very litthke—he prob- ably never weighed more than one hundred pounds—but was fastidious about the tood he did eat. He was immensely popu- jar and received many dinner invitations, but seldom did he accept. After joming the Institute, he shunned large gatherings and gave up public speaking. ' diagnosed as cancer of thé ‘ liver. His terminal illness w But his office door was always | open to people needing advice, and he was an effective lec- turer. In college his best grades had been in public speaking, and decades later. he still enjoved declainung the graceful phrases of a speech on Chinese civilization. one of his early oratorical trramphs. His shirts, shoes, suits, and ties were always impeccable and always subdued. His voice was soft and his manner retir- ing, but his handwriting dis- plaved a daring, enthusiastic flourish. He traveled little, outside of his trips to Maine. When he won the Paul Ehriich Gold Medal in 1933, he did not go to Germany to receive it; nor did he go to Sweden to receive the Pasteur Gold Medal awarded him in 1950. He wouldn't hurry; he used to quote an old black patient who, upon watching the doc- tors rush by, said. “What's vour hurry, Doe? By rushing that way you passes by much more than vou catches up with.” On rare moments when he DIED FEBRUARY 20, 1955 An accomphshed musician, Oswald | Avery plaved the cornet in church during his childhood. At Colgate Unwersin, he joined the college band Un photo Avery isin the firse row, third from lete) and eventually beeame its leader. was alone in the lab, he wag prone to move slowly, wi histing the lonely shepherd's son from Tristan wid [solde. In 1948 he moved to a ston house in Nashville. near the home of his brother, Rov. Sig years later, while at Deer Isle he felt pain that was eve ntuall painful: he bore it with chara teristic patience. He died the age of seventy-seven o February 20, 1955, at Vande bilt Hospital. *lAvery isla doctor’s dector wholly devoted to the progress of the profession; redoubtable pioneer in the chemistry of immunology, whose laboratory conquests have quelled the ravages of dread . pneumonia; he is a professor without portfolio to a host of the country’s leading medical teachers and researchers, and himself one of the truly great scientists of modern times....”’ -HAROLD 0. VOORHIS VICE-CHANCELLOR OF NEW YORK UNIVERSITY, UPON AWARDING AVERY AN HONORARY DOCTORATE IN 1947