The Fevers of Reason

by Gerald Weissmann

  “Henry James,” Lewis Thomas snapped, “from The Golden Bowl, Chapter One.” He went on, “All right then, you won’t earn very much, but you’ll have a lot of fun in the lab and time to read. If you’re lucky, you may also discover something. It’s a great life.”

  The life of Lewis Thomas spanned the golden age of American medicine, an era when—in his words—our oldest art became “the youngest science.” Thomas played a major role in that transformation; he was known among scientists as an innovative immunologist, pathologist, and medical educator. He became far better known as a deft writer whose essays bridged the two cultures by turning the news of natural science into serious literature. Witty, urbane, and skeptical, he may have been the only member of the National Academy of Sciences to have won both a National Book Award and an Albert Lasker Award. He is certainly the only medical school dean whose name survives on professorships at Harvard and Cornell, a prize at Rockefeller University, a laboratory at Princeton, and a book that is eleventh on the Modern Library’s list of the best 100 nonfiction books of the twentieth century.

  Thomas made three important discoveries in immunology, the field of which he was a pioneer; each had implications for human disease. He found that the white cells of blood, the leukocytes, were important mediators of fever and shock brought about by bacterial endotoxins; this taught us how microbes kill us if we don’t first kill them. He also made the novel observation that proteolytic enzymes such as papain could injure cartilage when injected into the circulation and the same sort of damage results when our own cells release papain-like ferments; this line of investigation showed us how joints destroy themselves in arthritis. But perhaps his most prescient suggestion, made years before the HIV pandemic, was that our immune system is constantly patrolling our body to find and destroy aberrant cancer-prone cells; we now attribute Kaposi’s sarcoma and other AIDS-related tumors to defects in Thomas’s “immune surveillance.” Those discoveries were made during a very intense period of bench research (1950–1965) at the University of Minnesota and at NYU before he turned his attention to broader issues of science and to his writing.

  The lifetime of Lewis Thomas coincided with a special period in American medicine, a time when its scientific base became the strongest it had ever been and its social impact the greatest. Indeed, judging from the numbers who came from overseas to learn from it, American medicine became the envy of the world. That shift of balance from the old world to the new happened at the same time that doctors dropped the laying on of hands and took up monitoring machines. It was not by accident but by design that American medicine was turned from a nineteenth-century folk art into a twentieth-century—and now a twenty-first-century—science. After the Flexner Report of 1910, medical instruction became largely concentrated in university hospitals where the modern sciences of immunology, biochemistry, and genetics could be pursued as eagerly at the bedside as in the lab. Lewis Thomas and his generation of immunologists presided over the conquest of polio and rheumatic fever and the achievements of blood-banking, cardiac surgery, and the transplantation of organs, not to speak of the discovery that DNA was the basic unit of genetic information. In the words of C. P. Snow, they had the future in their bones. Like Snow himself, they were, in the main, committed skeptics.

  LEWIS THOMAS GREW UP AS A BRIGHT LAD in a loving family in a comfortable house in Flushing, Queens. His father, Dr. Joseph Simon Thomas (Princeton, 1899; Columbia Physicians and Surgeons, 1904), was a good-natured, hard-working doctor who had met the love of his life, Grace Emma Peck of Beacon Falls, Connecticut, at Roosevelt Hospital, where she was a nurse and he was an intern. They were married on October 30, 1906, and thereafter, in the words of her son, Emma Peck’s nursing skills were “devoted almost exclusively to the family.”

  Lewis Thomas was born on November 25, 1913. As were his three older sisters and younger brother, Lewis was sent to the local schools. But soon the family decided that Flushing High School was not quite ready to prepare another Thomas for Princeton. After three semesters in Queens, Lewis Thomas transferred to the McBurney School, a less than exclusive prep school in Manhattan. He graduated in 1929 in the top quarter of his class. Medical practice was to protect the Thomas family against the worst of the Great Depression, which began on Black Tuesday, exactly one month after fifteen-year-old Lewis left for Princeton in September 1929.

  At Princeton he “turned into a moult of dullness and laziness, average or below in the courses requiring real work.” He took little interest in physics or inorganic chemistry and dismissed athletics as a general waste of effort. By reason of youth and family standing, he ranked low in the eating club hierarchy of prewar Princeton and was grateful to find safe haven at Key and Seal, a club that was, literally, the farthest out on Prospect Avenue. But high spirits and natural wit brought him to the offices of the Princeton Tiger, where Thomas soon published satires, poems, and parodies under the nom de plume “Eltie. “After the crash of ’29, we were in thrall to Michael Arlen; we slouched around in Oxford bags and drank bootleg gin from the tub like Scott and Zelda,” Thomas recalled. “They told us we’d go out like a light from that stuff. Out like a light. I think I did a piece on bootleg gin for the Tiger about that.” He had; it’s unreadable. Then, on a winter weekend visit to Vassar in 1932, Lewis Thomas met a young freshman from Forest Hills. Her father was a diplomat, her name was Beryl Dawson, and after years of separation for one or another reason they were married a decade later. By then the moult had spread its wings.

  Years later, his editor, Elisabeth Sifton, asked me, “When was it that Thomas became so wise?” Thomas attributed his metamorphosis to his senior year at Princeton and a biology course with Professor Wilbur Swingle. Swingle’s discovery of a lifesaving adrenal cortical extract—a crude version of deoxycorticosterone—had won wide acclaim. Thomas recalled that Swingle sparked his lifelong interest in the adrenals. Swingle also introduced him to Jacques Loeb’s literary/philosophical speculations on ions and cell “irritability” in The Mechanistic Conception of Life (1912). Five years out of Princeton, young Thomas would sign up to work with Jacques Loeb’s son, Robert F. Loeb, at Columbia.

  In his senior year, the depression hit home, and Thomas knew that getting into medical school was one solution to the unemployment problem. He also confessed he had a leg up on other applicants:

  I got into Harvard . . . by luck and also, I suspect, by pull. Hans Zinsser, the professor of bacteriology, had interned with my father at Roosevelt and had admired my mother, and when I went to Boston to be interviewed in the winter of 1933 [Zinsser] informed me that my father and mother were good friends of his, and if I wanted to come to Harvard he would try to help. . . .

  Help he did, and Thomas entered Harvard at the age of 19 in the fall of 1933. Thomas’s career at Harvard Medical School turned out just fine; he received grades far better than he had at Princeton. When asked in 1983 which member of the Harvard faculty had the greatest influence on his medical education, Thomas replied, “I no longer grope for a name on that distinguished roster. What I remember now, from this distance, is the influence of my classmates.” Nevertheless, some on that roster made a lasting impression. Hans Zinsser in bacteriology showed that it was possible to function both as a laboratory scientist and a respected writer; Walter B. Cannon in physiology taught him that the details of homeostasis held the keys to The Wisdom of the Body; David Rioch in neuroanatomy had him build a wire and Plasticene model of the brain, with which Thomas trekked about for fifteen years; and in Tracy Mallory’s office Thomas came across a pickled specimen that, “like King Charles’s head,” would haunt his investigative career for decades to come.

  At one of Mallory’s weekly pathology seminars in the depths of Massachusetts General Hospital, Thomas leaned back in his chair and by accident knocked over a sealed glass jar containing the kidneys of a woman who had died of eclampsia. Replacing the jug, he noted that both organs were symmetrically scarred by the deep, black telltale marks of bilateral renal cor
tical necrosis. Thomas remembered having seen something like those pockmarked kidneys before. They had been provoked in rabbits by two appropriately spaced intravenous injections of endotoxin: the effect was called the generalized Shwartzman phenomenon, and he would tussle with it for the rest of his scientific career.

  Thomas graduated cum laude from Harvard Medical School in 1937 and began internship on the Harvard Medical Service of Boston City Hospital. A history of the Harvard Medical Unit at Boston City Hospital documents that of the 71 young physicians who trained there between 1936 and 1940, 52 became professors of medicine, and 6 went on to the deanship of medical schools.

  Thomas remained at Boston City until 1939, when the confluence of his interests in neurology, adrenal hormones, and the Loeb mystique brought him to New York. Halfway through his internship in Boston, he heard that Dr. Robert F. Loeb was becoming director of the Neurological Institute in New York, and he resolved to study with him because

  Loeb was a youngish and already famous member of the medical faculty in the Department of Medicine at P&S, recognized internationally for his work on Addison’s disease [and] the metabolic functions of the adrenal cortex and the new field of salt and water control in physiology.

  Thomas served as a neurology resident (his only specialty training) and research fellow at P&S from 1939 to 1941, with time out to marry Beryl at Grace Church in New York in January 1941. Robert Loeb abruptly moved to the chairmanship of the Department of Medicine, but Thomas found that there was a fellowship with John Dingle awaiting him back at Harvard, and he jumped at the chance.

  Almost as soon as Lew and Beryl had established themselves back in Boston, Thomas was sent by Dingle on a month-long medical mission to Halifax, Nova Scotia, where an outbreak of meningococcal meningitis had struck the wartime port. Beryl served as lab assistant. Those four weeks in the field, an important publication on the effects of sulfadiazine in meningitis, and a thorough grounding in immunology in Dingle’s lab were a prelude to a naval commission after Pearl Harbor. Thomas reported in March 1942 to the Naval Research Unit at the hospital of the Rockefeller Institute in New York and on January 12, 1945, landed with a detachment of the unit headquartered in Guam. Thomas and Horace Hodes were put to work on Japanese B encephalitis on Okinawa, and quickly identified horse blood as a reservoir for the virus.

  War ended; waiting to be sent stateside, Thomas began experiments on rheumatic fever in Guam. Putting unused lab facilities to good purpose, he knew that rheumatic fever was almost always preceded by a streptococcal throat infection and that the interval between infection and heart disease could be very long indeed. Perhaps the disease was an allergic reaction to the microbe, to the patient’s own tissues, or to a mixture of the two.

  In Guam, Thomas found that rabbits receiving a mixture of microbes (streptococci) and ground-up heart tissue became ill and died within two weeks; the microscope revealed that their hearts showed lesions that resembled those of rheumatic fever in humans. Control rabbits injected with streptococci alone or with ground-up heart tissue alone remained healthy and showed no such damage. Thomas was entirely confident that he had solved the whole problem of rheumatic fever. He hadn’t. On his return to the Rockefeller Institute, he couldn’t repeat those experiments, sacrificing “hundreds of rabbits, varying the dose of streptococci and heart tissue in every way possible.” He was vastly relieved that he hadn’t rushed into print on the basis of those rabbits in Guam.

  Thomas’s first faculty position after discharge from the navy in 1946 was as assistant professor of pediatrics at the Harriet Lane Home for Invalid Children at Johns Hopkins. Thomas tried once more to repeat those rabbit experiments. This time, he mixed streptococci and heart tissue with a devilish brew of fats (the solution called Freund’s adjuvant) that had produced tissue injury in other disease models. Bad news for assistant professor Thomas: the rheumatic fever experiments failed once again. But Thomas could not shake off those experiments that had worked so well in Guam. Perhaps the host, the rabbits in Guam, for example, but not those in New York or Baltimore, had been “prepared” by an earlier insult such as the endotoxin injection that provoked the Shwartzman phenomenon.

  He tackled the problem with Chandler (Al) Stetson, a lifelong friend who was to become his colleague in Minnesota and his successor as the professor of pathology at NYU. Thomas and Stetson “prepared” rabbits with endotoxin from meningococci. The prepared skin had an excess of acid, and they reasoned that the acid might activate the tissue’s own ferments, proteases called cathepsins. But they were neither able to measure cathepsin activity nor obtain purified cathepsins, so they next injected rabbits with enzymes obtained off the shelf, trypsin and papain. Trypsin was ineffective, but papain produced lesions in the skin that looked very much like the local Shwartzman reaction.

  When Thomas left Hopkins, he took the problem with him. He served a brief stint at Tulane, where he became a professor of medicine and director of the Division of Infectious Disease. He was diverted for a while by studies of circulating antibodies in animal models of multiple sclerosis but returned to rheumatic fever when he was appointed American Legion Professor of Pediatrics and Medicine at the University of Minnesota in 1951. In quick time, he put together a team of young investigators, most of whom were soon at work on the Shwartzman phenomenon and the streptococcus.

  He reverted to the notion that proteases, either secreted by the streptococcal microbe or released from the victim’s own cells, caused damage in a “prepared” heart or joint. With a young Minnesota pediatrician, Robert A. Good (“the smartest investigator I ever met,” he once told me), he found out that if one removed white cells from the Shwartzman equation, kidney injury was prevented. The kidneys were also spared if one gave heparin, which prevented blood vessels from becoming plugged by fibrin, platelets, and white cells. Good and Thomas suggested that “a combination of humoral and cellular factors made by the host caused the tissue injury.” Nowadays we invoke complicated systems with complicated names such as anaphylatoxins, Toll receptors, apoptosis, caspases, and cytokines to explain the Shwartzman phenomenon. But in the 1950s Good and Thomas had provided a satisfactory explanation, and the flow of satisfying, explanatory papers followed Thomas from Minnesota as he moved to NYU in 1954.

  Thomas was recruited to NYU by Colin McLeod to become professor and chairman of the Department of Pathology. He was delighted to return to the metropolis with Beryl and his three daughters, Abigail (born 1941), Judith (born 1944), and Elizabeth (born 1948), and to set up his household at Sneden’s Landing, a small town up the Hudson from the city. He remained at NYU for fifteen years and proceeded to turn it into a world center of immunology, first in the Department of Pathology (1954–1958), then as professor and chairman of the Department of Medicine, and finally as dean of the New York University School of Medicine and deputy director of NYU Medical Center (1966–1969).

  Over those years he attracted and/or trained a legion of scientific stars and superstars at NYU: Frederick Becker, Baruj Benacerraf, John David, Edward Franklin, Emil Gottschlich, Howard Green, H. Sherwood Lawrence, Robert T. McCluskey, Peter Miescher, Victor and Ruth Nussenzweig, Zoltan Ovary, Jeanette Thorbecke, Stuart Schlossman, Chandler Stetson, Jonathan Uhr, and Dorothea Zucker-Franklin. Thomas’s international colleagues were frequent visitors: Sir Macfarlane Burnett, Dame Honor Fell, Philip Gell, James Gowans, Sir Peter Medawar, Thomas Sterzl, and Guy Voisin.

  Early in his NYU days Thomas hit a rough patch. Whereas cortisone, the miracle drug, clearly stopped inflammation in the clinic, Thomas was astonished to find that cortisone not only proved ineffective against the Shwartzman phenomenon but actually provoked it. This puzzle took the wind out of his sails. He was indeed “in irons on his other experiments” and “not being brilliant.” Then came the “floppy-eared bunnies”: injections of a protease, papain, into New Zealand white rabbits caused their ears to droop as their cartilage melted away.

  After papain, new discoveries proceeded apace. If an exogenous protea
se caused connective tissue damage, where might endogenous proteases reside? Thomas spent a summer with Dame Honor Fell, director of the Strangeways Research Laboratory in Cambridge. Fell had been studying vitamin A and had found that it produced depletion of cartilage matrix in mouse bone rudiments growing in a dish. Fell and Thomas decided to trade experimental systems. They first added papain to the little bone cultures in the dish and were able to produce vitamin A–like lesions in mouse cartilage. Thomas then returned to NYU to do the reciprocal experiment. Together with Jack Potter and R. T. McCluskey, Thomas and I stoked rabbits full of the vitamin A, and sure enough: twenty-four to forty-eight hours later, their ears drooped as if they had been given papain. We were convinced then that vitamin A in some fashion released an endogenous papain-like enzyme from cartilage cells and that this enzyme proceeded to break down cartilage matrix. At the time we supposed that the enzyme was present in lysosomes, subcellular “suicide sacs” that had just been described by Christian de Duve at Louvain. We suggested that vitamin A had ruptured the walls around these organelles, and that cortisone and its analogues must therefore stabilize the lysosomes.

  These days the answer is more complicated. We now believe that metalloproteinases are released from cells and that synthesis of these proteases is under opposing transcriptional control by vitamin A and cortisone acting via well-defined cytoplasmic and nuclear receptors. It all seemed simpler a generation ago. But these experiments, the last in which Thomas played a hands-on role, pointed the way for Thomas’s students and, in turn, their students, to explore other areas of human biology: how infection and immunity make our white cells clump and stick to blood vessels; how stimulated white cells release molecules (cytokines) that cause fever, fatigue, and inflammation; how tissues are recognized as foreign and transplants are rejected; how cortisone and aspirin-like drugs work in arthritis—and, as a follow-up of the cortisone/lysosome experiments, how to design, manufacture, and bring to the clinic tiny drug-bearing lipid structures called liposomes, which have saved thousands of lives.