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Home , Oswald Avery, Rebecca Lancefield, Rene Dubos

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Irving Kushner, MD, and David Samols, PhD Dr. Kushner (AΩA, Washington University in St. Louis, time, infectious diseases were the major public health concern 1954) is professor emeritus of Medicine, and Dr. Samols and bacteriology was the most glamorous and promising field is professor of Biochemistry at Case Western Reserve in the nascent biomedical science of the day. Opportunities University School of Medicine. for research at that time were very few, but Avery did find a position at the Hoagland laboratory, a privately-endowed s the years have passed, the tremendous contributions bacteriology laboratory in Brooklyn, where he worked for six of Oswald T. Avery (1877–1955) to biomedical science years, performing largely unimaginative work. are fading from our collective memory. A modest and self-effacingA man, Avery was one of the outstanding biologi- The Rockefeller Institute for Medical Research cal scientists of the first half of the twentieth century,1 felt by At the end of the nineteenth century, John D. Rockefeller some to be the most deserving scientist not to have received was seeking guidance about how to deploy his philanthro- the Nobel Prize. His laboratory was responsible for three land- pies most effectively. He was the richest man in the world, mark contributions: perhaps the richest man in history. Rockefeller’s principal 1. The demonstration that are antigenic philanthropic adviser was a Baptist minister, Frederick Taylor 2. The discovery of C-reactive (CRP), which Gates, himself a physician’s son, who had noticed during his opened the door to study of the acute phase response2 ministry that physicians were rarely able to deal with serious 3. The demonstration that DNA conveys genetic medical problems. information. Gates read Sir ’s magisterial textbook, The Avery was born in Nova Scotia in 1877, the son of a Baptist Principles and Practice of Medicine,3 in which Osler, some- minister. The family moved to City when Oswald thing of a therapeutic nihilist, expressed his skepticism about was still a child. He graduated from ’s prevalent forms of therapy. Gates was impressed. He later College of Physicians and Surgeons in 1904, when medicine wrote: was just beginning to abandon its reliance on tradition, al- though medical practice was still largely empirical. Good I had been a sceptic before . . . This book not only confirmed outcomes largely depended on the healing power of my scepticism, but its revelation absolutely astounded and and the power of faith. American physicians generally felt that appalled me. . . . I found . . . that the best medical practice laboratory science could never contribute anything of practi- did not, and did not pretend to cure more than four or five cal value to medical practice. diseases. . . . about all that medicine up to 1897 could do was Avery practiced medicine for three years, but apparently to nurse the patients and alleviate in some degree the suffer- didn’t find it intellectually or emotionally satisfying. At that ing. Beyond this, medicine as a science had not progressed.

14 The Pharos/Spring 2011 The Rockefeller Institute for Medical Research. Left, Oswald Avery in his lab at the Rockefeller Institute, circa 1940s. Courtesy of the National Library of Medicine. In headline, pneumoniae (Diplococcus pneumoniae). Capsule stain light micrograph at 1000x. © Visuals Unlimited/Corbis.

The Pharos/Spring 2011 15 Oswald Avery and the pneumococcus

. . . It became clear to me that medicine could hardly hope anxiously for “the crisis,” the characteristic feature of lobar to become a science until medicine should be endowed and , which would not occur until a week to ten days qualified men could give themselves to uninterrupted study after the onset of illness, if the patient survived that long. At and investigation, on ample salary, entirely independent of that point the temperature, heart rate, and respiratory rate practice. To this end, it seemed to me an Institute of medical rapidly fell, and the patient recovered. research ought to be established in the . Here was an opportunity, to me the greatest, which the world Polysaccharides and type-specific serum therapy could afford, for Mr. Rockefeller to become a pioneer.1p21–22 Avery started his career at the Rockefeller working on sero- logical classification of the various pneumococcal types. This Rockefeller was receptive to this suggestion and the led to the finding that a soluble substance, specific for each Rockefeller Institute for Medical Research was dedicated in pneumococcal type, was present in the serum and urine of 1906. Its small hospital followed in 1910. The Institute, now a patients. Avery and his collaborators identified these as poly- university, still occupies its original site in on saccharides and showed that they were antigenic, which had the East River and 66th Street. When John D. Rockefeller, Jr., not been suspected previously. Most importantly, the polysac- retired as president of its board of trustees in 1950, he stated charide made up the pneumococcal capsule, which was differ- that he had always regarded the institute as “the most signifi- ent for each pneumococcal type. It is the capsule that renders cant and the most permanent (philanthropy) of any that my the organism resistant to phagocytosis. For the pneumococ- father established.” 4 cus to be virulent, it must form a substantial capsule, while unencapsulated organisms are not virulent. The “crisis” is the Pneumonia result of the appearance, after about a week, of to In 1913, three years after its opening, Oswald Avery took that capsular , which opsonized the , the job of bacteriologist at the Hospital of the Rockefeller leading to phagocytosis and clinical recovery. Institute, where a considerable effort was directed to the Type-specific serum therapy, made possible largely through treatment of pneumonia and its most common cause, the the fundamental discoveries in Avery’s lab, at that time con- pneumococcus. Avery became part of this effort. His entire sisted of administering horse serum prepared against the subsequent career was driven by a search for an understanding specific type of pneumococcus with which the patient was in- of pneumococcal pneumonia—and for its cure. fected.5 Some of the mechanics of its administration are illus- At that time, pneumonia was the leading cause of death in trated in this tribute to Max Finland, who ran the pneumonia the United States. Here is how Osler described it: service at the Boston City Hospital for many years:

Definition.—An infectious disease characterized by in- you went to the hospital laboratory to get the [pneumo- flammation of the lungs, toxaemia of varying intensity, and coccal] isolate; if the house officer was not at the City a fever that terminates abruptly by crisis. . . . Hospital, he got on the trolley and traveled to the Thorndike Incidence.—The most widespread and fatal of all acute Memorial Laboratory, where Dr. Finland was always avail- illnesses, pneumonia is now the “Captain of the Men of able; he would type the organism and hand you a bottle of Death.” 3p108 type-specific serum; then, it was back on the trolley to your hospital; finally, you administered the serum to the patient. Lobar pneumonia was not limited to the infirm or elderly; Whereas the mortality rate for untreated pneumococcal people in the prime of life were affected. Entire lobes were bacteremia was almost 90%, type-specific serum therapy consolidated, often more than one, resulting in little gas resulted in survival of more than one-half of the patients.6 exchange. Most medical care was provided in the home. X-rays and blood counts were rare. The mortality rate ran This was the only way to treat pneumonia until the introduc- between twenty and forty percent. Osler’s section on treat- tion of antimicrobial drugs in the late 1930s. ment begins “Pneumonia is a self-limited disease, which can neither be aborted or cut short by any known means at our C-reactive protein and the acute phase response command.” 3p134 Throughout his career, Avery’s approach to biological By the fourth day or so after the onset of symptoms, a hos- elucidation of the pneumococcus involved understanding its pitalized patient would typically be highly febrile, tachypneic, immunochemistry. Pursuing this line of study, William Tillett, dyspneic, tachycardic, cyanotic. He was frequently delirious. working in Avery’s laboratory, prepared a polysaccharide Bacteremia occurred in about one-third of the patients. If fraction derived not from the capsule but from the wall. infection of the meninges or of a heart valve ensued, it was He called it the “C” fraction because it appeared to be analo- invariably fatal. gous to the C polysaccharide of the hemolytic streptococcus Patients, family members, and physicians would wait studied by a few years previously. This

16 The Pharos/Spring 2011 Chart 3 adapted from Tillett and Francis, reference 7. This chart com- pares the temperature course of pneumonia in a patient (top row) with anti-capsular antibodies (second row) and C-fraction precipitation (third row).

pneumococcal C-polysaccharide, it was later learned, was response. shared by all pneumococci, regardless of their type. This phenomenon was not limited to pneumococcal pneu- To explore the serologic response to the C-polysaccharide, monia, nor to acute infections. For example, in a patient with Tillett and his colleague Thomas Francis set up precipitin bacterial endocarditis, who died on hospital day twenty-one, tests against sera from serial bleedings of pneumonia patients. the C-precipitin never went away. They also observed pre- The results were surprising—completely the opposite of what cipitin reactions with sera from patients with acute rheumatic they had expected. At the top of the figure is the temperature fever, lung abscess, and osteomyelitis, all believed to be caused curve, starting at 104°F, with the patient undergoing a crisis by Gram-positive organisms. No reaction was observed with on day six or seven. The second row shows the antibodies sera from normal individuals. These results were published to the capsule, here called “type specific agglutinins,” which in 1930.7 appear about the same time as the crisis and are responsible Avery was fascinated by these findings. He saw this for it. When Tillett and Francis looked at the reaction with C-reaction as an entrée to study of the host response to infec- the C-polysaccharide, however, they got a surprise. A pre- tion. Avery was a captivating raconteur, known for his inimita- cipitate formed when the C substance was mixed with sera ble monologues describing the various paths of research in his obtained at the time of admission and throughout the febrile laboratory. In his biography of Avery, recounts: period (the acute phase). This reaction diminished after the crisis and ultimately disappeared. This time course was the Avery never discussed the C-reactive protein without reciprocal of that seen with antibodies directed against the turning the conversation to what he was wont to call “the capsular polysaccharide, and was not how antibodies behaved. chemistry of the host.” Although he never spelled out what It took the investigators a while to digest this finding and he meant by that expression, he clearly had in mind all the for its implications to sink in. Ultimately they realized that unidentified body substances and mechanisms of a nonim- the C-precipitation phenomenon differed from an immune munological nature, both protective and destructive, that reaction, and that it was something new, different from an come into play in the course of infectious processes.1p99

The Pharos/Spring 2011 17 Oswald Avery and the pneumococcus

The discovery of C-reactive protein and the acute phase of the pneumococcus could be better understood. The three response in the Avery lab opened the door to contemporary major discoveries of the Avery laboratory have all led to major scientific pursuit of this phenomenon—the metabolic, physi- advances in diagnosis, disease prevention, and treatment, and ologic, nutritional and plasma protein changes that occur dur- the circumstances should remind us that accretion of sound ing inflammatory states8—as well as to the clinical use of acute basic biologic knowledge can be expected to ultimately lead phase protein determination for diagnosis and management of to practical results. Without such knowledge, practical results patients. New insights into the biological and clinical signifi- will never ensue. cance of the acute phase response continue to emerge.9 References The “transforming principle” 1. Dubos RJ. The Professor, the Institute, and DNA. New York: In 1928, Fred Griffith in London observed that heat-killed Press; 1976. encapsulated Type I pneumococci (the donor) could transform 2. McCarty M. Historical perspective on C-reactive protein. living unencapsulated (hence non-virulent) Type II pneumo- Ann NY Acad Sci 1982; 389: 1–10. cocci (the recipient) into encapsulated virulent type I organ- 3. Osler W. The Principles and Practice of Medicine: Designed isms.10 The capsule of the organism that grew out consisted for the Use of Practitioners and Students of Medicine. New York: D. of the carbohydrate that had been expressed by the killed, Appleton; 1904. donor organism. This characteristic persisted in all succeeding 4. The Rockefeller Archive Center—JDR Jr. Biographical Sketch. generations of daughter cells—that is, it was heritable. At that rockarch.org/bio/jdrjr.php. time, the chemical basis for was still unknown, and 5. Podolsky SH. Pneumonia Before : Therapeutic the vast majority of informed opinion considered it virtually Evolution and Evaluation in Twentieth-Century America. Baltimore certain that were composed of protein of some kind. (MD): Johns Hopkins University Press; 2006. Over the years Avery’s interests increasingly shifted toward 6. Klein JO. Maxwell Finland: A Remembrance. Clin Infect Dis understanding basic biological questions relating to the pneu- 2002; 34: 725–29 . mococcus, since they might bear on treatment. Over the next 7. Tillett WS, Francis T Jr. Serological reactions in pneumonia fifteen years, the Avery lab focused its attention on the nature with a non-protein somatic fraction of pneumococcus. J Exp Med of the “transforming principle.” 11 Since only encapsulated 1930; 52: 561–71. organisms could cause disease, Avery felt that an understand- 8. Kushner I. The phenomenon of the acute phase response. ing of how capsule production is controlled might lead to Ann NY Acad Sci 1982; 389: 39–48. treatment. 9. Kushner I, Samols D, Magrey M. A unifying biologic explana- This avenue of investigation ultimately led to one of the tion for “high-sensitivity” C-reactive protein and “low-grade” inflam- most important biomedical papers ever published. Avery, Colin mation. Arthritis Care Res 2010; 62: 442–46. MacLeod, and Maclyn McCarty reported in 1944 that heredi- 10. Griffith F. The significance of pneumococcal types. J Hyg tary information could be transmitted from one bacterium to (Lond.) 1928; 27: 113–75. another by purified DNA.12 The report was greeted with con- 11. McCarty M. The Transforming Principle: Discovering that siderable skepticism, and it took a few years before its validity Genes Are Made of DNA. New York: W. W. Norton; 1985. was accepted. A feverish race to solve the structure of DNA 12. Avery OT, MacLeod CM, McCarty M. Studies on the chemi- then ensued, a race won by and cal nature of the substance inducing transformation of pneumococ- nine years later, and described by Watson in his famous mem- cal types: Induction of transformation by a desoxyribonucleic acid oir The Double Helix. As we all know, the finding that genes are fraction isolated from pneumococcus type III. J Exp Med 1944; 79: made of DNA revolutionized biology. Of note, in their paper in 137–58. Nature describing the structure of DNA, Watson and Crick did 13. Carmichael M, Begley S. Desperately seeking cures. News- not credit the Avery lab for their contribution. week 2010 May 24 & 31: 38–42. 14. Wade N. A decade later, genetic map yields few new cures. A long and winding road NY Times 2010 Jun 13: A1. Several publications have recently indicated the public’s 15. Krauss LM. The Gulf spill and the limits of science. Wall impatience with the failure of recent basic science discoveries Street J 2010 Jun 11. to lead to practical results—something that helps patients.13,14 However, as has recently been pointed out, “The road from Address correspondence to: basic knowledge to successful technology is a long and wind- Irving Kushner, MD ing one, usually taking decades, not weeks or months.” 15 It is MetroHealth Medical Center worthwhile to point out that the extremely consequential work 2500 MetroHealth Drive of Avery’s lab was not carried out under the aegis of transla- Cleveland, Ohio 44109 tional research. Rather, it was carried out so that the biology E-mail: [email protected]

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