JOURNAL OF INTERFERON AND CYTOKINE RESEARCH 20:609–611 (2000)Mary Ann Liebert, Inc.

Three Remarkable Teachers

ION GRESSER

609

PETER MED A W A R, in his Advice to a Young Scientist , said itwas most important for a scientific beginner to choose his

teachers wisely. Unconsciously, I followed his advice. Now thatI have come to the end of my scientific road, I should like totell you about three remarkable teachers I had who exemplifiedthree very different styles of doing research.

My first teacher was Francisco Duran-Reynals . When I wasa medical student at Yale in the early 1950s, the professor ofpathology, Harry Greene, introduced us one day to a speciallecture on cancer by saying, “If you want to hear a fairy taleabout cancer, come tomorrow and listen to Hans Christian An-derson Duran-Reynal s tell you about viruses causing cancer.”The next day, a white-haired Spaniard, speaking a rapid, heav-ily accented, almost incomprehensibl e English, told us in themost passionate terms that viruses were responsible for someif not all tumors. Viruses caused tumors in plants and in in-vertebrates. Viruses caused tumors in fish and frogs. Virusescaused tumors in chickens. The same virus— the Rous sarcom avirus— could cause acute inflammation and a hemorrhagicnecrosis in young chicks and sarcomas in adult chickens. Itcrossed species barriers and caused different types of tumors inducks and turkeys. The Shope virus caused benign papillomasin rabbits, which for mysterious reasons became carcinomatous.

He spoke with such passion and logic that it seemed extra-ordinary that the scientific community totally ignored or re-jected the proposition that viruses had anything to do with can-cer. It certainly seemed extraordinary to Duran-Reynals, but atthe time, you could count on the fingers of two hands the pro-ponents of the viral etiology of cancer— Oberling in France,and Duran-Reynals, Shope, Bittner, Lucké, Burmester, and Ni-grelli, in the United States. Rous himself believed that the virushe discovered in 1911 was the exception. Even the great manof virology, McFarlane-Burnet, in his classic text, Principles ofAnimal Virology , published in 1955, was skeptical and said,“These viruses have more the flavor of a laboratory curiosity.”

The Yale Departm ent of Microbiology gave Duran-Reynal sa small three-room laboratory and office at the end of the hallon the top floor, where he worked with his wife, Maria Luisa,and a dedicated Australian virologist, Joel McCrae. There weretwo technicians and two very part time and incompetent med-ical students, a classm ate of mine, Dave Nelligan, and myself.I do not think Duran-Reynals had much of a budget because hewas always buying supplies out of his own pocket, and his re-quests for grants were systematically rejected.

He could not understand the opposition to the hypothesis ofviral infection as a cause of cancer. He had helped LudwikGross publish his article on the successful transmission ofleukemia by injection of a cell-free filtrate from leukemic AKmice to newborn C3H mice, a strain of mice that rarely devel-oped leukemia. Virtually no one believed Gross’s results. I re-member he had on his desk the article by Stewart and Eddy onpolyomavirus. The authors had asked his help to get their arti-cle published after repeated rejections.

I think this photograph of Duran-Reynals taken in his labo-ratory at the end of his life is characteristic. He is leaning for-ward as if to say, “Look here at this tumor caused by a virus”(Fig. 1). Duran-Reynals was a visionary, and like many vi-sionaries, he saw the promised land only in his mind’s eye. Hedied of a rare small intestinal metastasizing cancer in 1958 atthe age of 59.

Shortly after his death, Trentin and then Huebner and theirassociates showed that the common human adenoviruses 12 and18 were oncogenic for newborn hamsters. The orthodox scien-tific community now discovered that viruses could cause can-cer. Symposia were organized on the possible role of virusesin cancer— and then there was the viral oncogene hypothesis—but I would often search in vain for references to a single oneof the many publications of Duran-Reynals .

I often wondered whether Duran-Reynals was disappointedor bitter. I don’t know, but I don’t think so. I remember him asconvinced of the correctness of his insight that viruses were insome manner implicated in the causation of some if not all can-cers. His life’s goal was to try to verify this hypothesis.

My second teacher was Lewis Thomas. He gave a lecture atYale on the generalized Shwartzman reaction. If you thoughtthe Shwartzman reaction was a minor scientific oddity beforehis lecture, you came away convinced that the secret of all im-munologic processes was contained in this phenomenon. LewisThomas was a magician. He convinced you—not by logic butby the lightness of his touch, his sense of poetry, his humor.His interests were encyclopedic. He could never be confined toone scientific problem. Everything was mystery, and all sub-jects were to be explored— from the aggregation of slime moldsto the relationship among smell, histocompatibili ty antigens,and sexual attractiveness— from why papain causes the collapseof rabbit ears to the virulence of Japanese B encephalitis virusfor mice and the discovery of antibodies to the StreptococcusMG antigen in patients with atypical viral pneumonia.

Institut Curie, INSERM U 255, 75248 Paris Cedex 05, France.Presented on election as an Honorary Member of the International Society for Interferon and Cytokine Research at the annual meeting, Oc-

tober 1997, San Diego, CA.

HISTORICAL PERSPECTIVE

He loved life and enjoyed the responsibilities of high office.He could not be confined to one department, to one university,to one city. He enjoyed working at the Rockefeller Institute andbeing a neurologist at Presbyterian Hospital, a professor of in-fectious diseases at Tulane, a professor of pediatrics at JohnsHopkins and the University of Minnesota, a professor of pathol-ogy and then medicine in New York, dean of NYU and YaleMedical Schools, and finally president and chancellor of theMemorial-Sloan Kettering Cancer Center.

He called himself a biology watcher, but he was really a bi-ology lover. His ideas overflowed. When I was a sleep-starvedintern at Bellevue Hospital, he had me transferring lymphocytesin rabbits, looking for megakaryocytes in the femoral blood ofpregnant women, and trying to determine whether hypothermiacould reduce the effects of liver toxins. The word that mostcharacterized him was enthusiasm, which derives from theGreek and means “God within.”

I think this photograph of Thomas, too, is characteristic (Fig.2). Unencumbered by the tools of the laboratory— no whitecoat, but a well-cut suit— he looks out with good humor, withcuriosity, and with elegance.

If passion characterized Duran-Reynal s, and enthusiasm, po-etry, and elegance characterized Lewis Thomas, the solid Yan-kee values of common sense, patience, hard work, and thriftcharacterized my third teacher, John Franklin Enders. Manyconsidered him the foremost virologist of his day. He won theNobel Prize in Medicine in 1954, which he shared with his two

young postdoctoral students, Tom Weller and Fred Robbins.Together, in 1949, they showed that the poliomyelitis viruscould be cultivated and proven cytopathic in extraneural cells—cultures of human embryonic intestine and skin and muscle—opening the way to easy quantitation of virus and antibody andthe development of killed or attenuated vaccines.

The history of tissue or cell culture is long, dating back tothe early 1900s, and its use for experimental propagation ofviruses dates back to the work of Steinhardt with vaccinia virusin 1913. Usually, however, despite attempts at aseptic tech-niques, the cultures had to be discarded because of bacterialcontamination. After World War II, Enders established a labo-

GRESSER610

FIG. 1. Francisco Duran-Reynals

FIG. 3. John Franklin Enders in the laboratory of HansZinsser.

FIG. 2. Lewis Thomas

ratory for research on infectious diseases at Children’s Hospi-tal in Boston and decided to try to grow mumps virus in sus-pended cell cultures. It was not a novel idea, but Enders thoughtthat it was a good time to take a new look at the possibility ofgrowing viruses in cell culture.

Enders, Robbins, and Weller introduced several importantinnovations. They added the newly available antibiotics, peni-cillin and then streptomycin. They used trypsin to dissociatecells from tissues, a technique described 30 years earlier byRous at the Rockefeller Institute. Most importantly, instead oftransferring the cell culture fluid from the inoculated culturesto fresh cultures after an interval of 3 or 4 days, as had beenstandard procedure to avoid bacterial contamination, the cul-tures were maintained, and the nutritive medium was removedand then replenished. In this way, the cells were preserved, al-lowing time for viral multiplication. A simple idea but crucial.Then they waited. That was always a trademark of Enders. Heknew how and when to wait. Their techniques changed virol-ogy, permitting easy cultivation of known viruses and openingthe Pandora’s box of heretofore unknown viruses.

I should like to add a historical footnote. In medical research,very few discoveries are totally original. In 1942, the Chinesemicrobiologist Huang, working in the department of medicineand bacteriology at Columbia University, had clearly shownand published in a series of four articles in the Proceedings ofthe Society for Experimental Biology and Medicine and in theJournal of Experimental Medicine that Western equine en-cephalitis virus multiplied and destroyed chick embryonicskeletal muscle cells in culture. These important observations—showing that a neurotropic virus could multiply in extraneuralcells, that there was an easily discernible criterion for viral mul-tiplication in vitro , and that in vitro techniques might be evenmore sensitive in detecting viral multiplication than the usualin vivo techniques— were curiously enough ignored, possiblybecause they were published during the war. Perhaps the moralof the story is, “If you are going to make a discovery, makesure it’s at the right time and that the right people are listen-ing.”

I include a picture of Enders as a young man in HansZinsser’s laboratory at Harvard (Fig. 3), where he worked onpneumococcus and bacterial immunity. The next photo (Fig. 4)shows Enders 30 years later, sitting at his beloved microscope,having moved a distance of a couple of blocks to the JimmyFund building. He never wanted to leave Harvard or Boston.“After all,” he said, “why should anyone want to live anywhereelse, if he didn’t have to?” His door was always open and hewas always eager to discuss a problem, to look at some cellcultures, always ready to say with great caution and modesty,“Doc, why don’t you try such and such,” or to reflect on thewonders of biology, for example, how salmon went out to mid-ocean only to find their way back to the streams where theyhad been hatched.

Enders was a diehard Republican. He was careful aboutspending money— his and the government’ s. He insisted on re-turning unspent funds to the granting agencies, even thoughthey did not know how to deal with the returned monies. Noone had ever done that before.

Once we talked about patents and scientists deriving profitfrom their discoveries. He believed that the rewards belongedto the public not to the scientists. “Geez, Doc, if I had wantedto make money, I could have patented the feline panleukope-nia virus vaccine, the mumps skin test, the cell culture tech-niques for polio and the means of making the vaccine, and theEdmonston strain of the measles vaccine, which we developedright here.”

By his own admission, Enders had a happy and, for the mostpart, fortunate life. He thought, too, that he had had consider-able luck. He was fond of quoting Ehrlich’s formula for suc-cess in research— in German—the four Gs that translate intoEnglish as money, patience, fate, and luck. Herodotus is cred-ited with saying, “Call no man happy till you know the natureof his death.” By this standard, too, Enders was fortunate be-cause he died suddenly, quietly, and peacefully at the age of 88sitting in his lovely garden on a glorious early September day,reading the poems of T.S. Eliot to his devoted wife, Carol.

These three men had different styles, but they all shared theessential qualities of wonder, of curiosity and joy in their work,and of honesty. They were all highly moral men with a pro-found sense of honesty, which I too believe is essential to allwe do.

In wishing you all Ehrlich’s four Gs and a fifth G that I add,that of health, I am thankful for the opportunity to express mygratitude to my three remarkable teachers.

Address reprint requests to:Dr. Ion Gresser

Institut CurieINSERM 025526, rue d’Ulm

75248 Paris Cedex 05France

Accepted 12 March 2000

HISTORICAL PERSPECTIVE 611

FIG. 4. John Franklin Enders 30 years later.