Oswald Avery and the Irving Kushner, MD, and David Samols, PhD Dr. Kushner (AΩA, Washington University in St. Louis, time,infectiousdiseaseswerethemajorpublichealthconcern 1954) is professor emeritus of Medicine, and Dr. Samols andbacteriologywasthemostglamorousandpromisingfield 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 stheyearshavepassed,thetremendouscontributions bacteriologylaboratoryinBrooklyn,whereheworkedforsix ofOswaldT.Avery(1877–1955)tobiomedicalscience years,performinglargelyunimaginativework. arefadingfromourcollectivememory.Amodestand self-effacingA man,Averywasoneoftheoutstandingbiologi- The Rockefeller Institute for Medical Research calscientistsofthefirsthalfofthetwentiethcentury,1feltby Attheendofthenineteenthcentury,JohnD.Rockefeller sometobethemostdeservingscientistnottohavereceived was seeking guidance about how to deploy his philanthro- theNobelPrize.Hislaboratorywasresponsibleforthreeland- pies most effectively. He was the richest man in the world, markcontributions: perhaps the richest man in history. Rockefeller’s principal 1. Thedemonstrationthatpolysaccharidesareantigenic philanthropicadviserwasaBaptistminister,FrederickTaylor 2. The discovery of C-reactive protein (CRP), which Gates,himselfaphysician’sson,whohadnoticedduringhis openedthedoortostudyoftheacutephaseresponse2 ministrythatphysicianswererarelyabletodealwithserious 3. The demonstration that DNA conveys genetic medicalproblems. information. Gates read Sir William Osler’s magisterial textbook, The AverywasborninNovaScotiain1877,thesonofaBaptist Principles and Practice of Medicine,3inwhichOsler,some- minister.ThefamilymovedtoNewYorkCitywhenOswald thingofatherapeuticnihilist,expressedhisskepticismabout was still a child. He graduated from Columbia University’s prevalent forms of therapy. Gates was impressed. He later CollegeofPhysicians 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 nature my scepticism, but its revelation absolutely astounded and andthepoweroffaith.Americanphysiciansgenerallyfeltthat appalled me. I found . that the best medical practice laboratorysciencecouldnevercontributeanythingofpracti- did not, and did not pretend to cure more than four or five calvaluetomedicalpractice. 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/Spring2011 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, Streptococcus pneumoniae (Diplococcus pneumoniae). Capsule stain light micrograph at 1000x. © Visuals Unlimited/Corbis. The Pharos/Spring2011 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 pneumonia,whichwouldnotoccuruntilaweektotendays qualified men could give themselves to uninterrupted study aftertheonsetofillness,ifthepatientsurvivedthatlong.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 rapidlyfell,andthepatientrecovered. research ought to be established in the United States. 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 AverystartedhiscareerattheRockefellerworkingonsero- logicalclassificationofthevariouspneumococcaltypes.This Rockefeller was receptive to this suggestion and the ledtothefindingthatasolublesubstance,specificforeach Rockefeller Institute for Medical Research was dedicated in pneumococcal type, was present in the serum and urine of 1906.Itssmallhospitalfollowedin1910.TheInstitute,nowa patients.Averyandhiscollaboratorsidentifiedtheseaspoly- university,stilloccupiesitsoriginalsiteinNewYorkCityon saccharidesandshowedthattheywereantigenic,whichhad theEastRiverand66thStreet.WhenJohnD.Rockefeller,Jr., notbeensuspectedpreviously.Mostimportantly,thepolysac- retiredaspresidentofitsboardoftrusteesin1950,hestated charidemadeupthepneumococcalcapsule,whichwasdiffer- thathehadalwaysregardedtheinstituteas“themostsignifi- entforeachpneumococcaltype.Itisthecapsulethatrenders cantandthemostpermanent(philanthropy)ofanythatmy theorganismresistanttophagocytosis.Forthepneumococ- fatherestablished.”4 cus to be virulent, it must form a substantial capsule, while unencapsulatedorganismsarenotvirulent.The“crisis”isthe Pneumonia resultoftheappearance,afteraboutaweek,ofantibodiesto In1913,threeyearsafteritsopening,OswaldAverytook that capsular polysaccharide, which opsonized the bacteria, the job of bacteriologist at the Hospital of the Rockefeller leadingtophagocytosisandclinicalrecovery. Institute, where a considerable effort was directed to the Type-specificserumtherapy,madepossiblelargelythrough treatment of pneumonia and its most common cause, the thefundamentaldiscoveriesinAvery’slab,atthattimecon- pneumococcus. Avery became part of this effort. His entire sisted of administering horse serum prepared against the subsequentcareerwasdrivenbyasearchforanunderstanding specifictypeofpneumococcuswithwhichthepatientwasin- ofpneumococcalpneumonia—andforitscure. fected.5Someofthemechanicsofitsadministrationareillus- Atthattime,pneumoniawastheleadingcauseofdeathin tratedinthistributetoMaxFinland,whoranthepneumonia theUnitedStates.HereishowOslerdescribedit: serviceattheBostonCityHospitalformanyyears: 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 Thiswastheonlywaytotreatpneumoniauntiltheintroduc- between twenty and forty percent. Osler’s section on treat- tionofantimicrobialdrugsinthelate1930s. mentbegins“Pneumoniaisaself-limiteddisease,whichcan neitherbeabortedorcutshortbyanyknownmeansatour C-reactive protein and the acute phase response command.”3p134 Throughout his career, Avery’s approach to biological Bythefourthdayorsoaftertheonsetofsymptoms,ahos- elucidationofthepneumococcusinvolvedunderstandingits pitalizedpatientwouldtypicallybehighlyfebrile,tachypneic, immunochemistry.Pursuingthislineofstudy,WilliamTillett, dyspneic,tachycardic,cyanotic.Hewasfrequentlydelirious. working in Avery’s laboratory, prepared a polysaccharide Bacteremia occurred in about one-third of the patients. If fractionderivednotfromthecapsulebutfromthecellwall. infectionofthemeninges or of a heart valve ensued, it was Hecalleditthe“C”fractionbecauseitappearedtobeanalo- invariablyfatal. goustotheCpolysaccharideofthehemolyticstreptococcus Patients, family members, and physicians would wait studied by Rebecca Lancefield a few years previously. This 16 The Pharos/Spring2011 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 antibodyresponse. sharedbyallpneumococci,regardlessoftheirtype. Thisphenomenonwasnotlimitedtopneumococcalpneu- ToexploretheserologicresponsetotheC-polysaccharide, monia,nortoacuteinfections.Forexample,inapatientwith Tillett and his colleague Thomas Francis set up precipitin bacterialendocarditis,whodiedonhospitaldaytwenty-one, testsagainstserafromserialbleedingsofpneumoniapatients. the C-precipitin never went away. They also observed pre- Theresultsweresurprising—completelytheoppositeofwhat cipitinreactionswithserafrompatientswithacuterheumatic theyhadexpected.Atthetopofthefigureisthetemperature fever,lungabscess,andosteomyelitis,allbelievedtobecaused curve,startingat104°F,withthepatientundergoingacrisis byGram-positiveorganisms.Noreactionwasobservedwith on day six or seven. The second row shows the