Zanvil A. Cohn

Zanvil Alexander Cohn (November 16, 1926 – June 28, 1993) was a cell biologist and immunologist who upon his death was described by the New York Times as being “in the forefront of current studies of the body's defenses against infection.”, professor at Rockefeller University. There Cohn had been the Henry G. Kunkel Professor for seven years. Cohn was senior physician at the university as well as vice president for medical affairs. Until two years before his death, he also served as principal investigator of the Irvington Institute for Medical Research. Although Cohn never won the Nobel Prize, Ralph M. Steinman, with whom he ran a laboratory at Rockefeller University for many years, was named in 2011, eighteen years after Cohn's death, to win the Nobel Prize in Physiology and Medicine for the work on dendritic cells done in their lab.

By way of explaining Cohn's importance, one commentator has noted that macrophages “are scavenger cells of the immune system that engulf and digest invaders, including bacteria and other pathogens, as well as toxins and dead cells. They are central to so-called innate immunity—immune defenses that can act without previous exposure to a pathogen. They are central to inflammation, the responses of the body to infection and injury, and also when inflammation becomes chronic during diseases like atherosclerosis and tuberculosis. When Zanvil Cohn (1926-1993) began studying macrophages in the early 1960s, little was known about them. Immunologists had for decades focused on the chemistry of the second major component of the immune system—the acquired immune response, in which the body produces antibodies in response to exposure to an antigen. In pioneering studies, both at the laboratory bench and with human subjects, Cohn helped launch the new field of cellular immunology.”

“Dr. Cohn's experiments,” reported the Times in his obituary, “threw light on the functions of T-cells, made in the bone marrow, and macrophages, large cells that can surround and digest foreign substances like protozoa and bacteria. He applied these insights to patient-oriented investigations of leprosy, tuberculosis and AIDS. He also established that macrophages can release a multitude of biologically active products. Since the mid-1980's he used hormone-like products of the immune system to increase patients' resistance to microbial infections. This work took him to parts of Asia and Latin America where leprosy and tuberculosis are endemic.”

In a 2009 biographical memoir, Carol L. Moberg and Steinman wrote that “Zanvil Cohn may be most remembered as the founder of modern macrophage biology and for leading the shift in mid-twentieth-century research from bacterial cells to host-parasite relationships.”

Early life and pre-war education

Cohn was born in New York City, the son of David and Esther (Schwartz) Cohn; he had one sibling, a brother, Donald, who was three years younger. Zanvil, a Hebrew version of Samuel, was a family name. His father had come to New York from Dusseldorf at age 19 in 1905 and after working for some years in his Uncle Josef’s butcher shop in Manhattan became an owner of Kansas Packing, a meat packing firm in New York. Cohn's mother, born in the United States of parents from Budapest, was raised in Huntington, Long Island, and worked as a buyer for Oppenheim, Collins & Co., a Manhattan clothing store, later becoming a partner in an apparel firm. As a child, Cohn spoke both German and English. He attended public schools in Queens, then Columbia Grammar School in Manhattan, where he played baseball and football, was president of the student government, and played piano at graduation. After graduating from Columbia Grammar at 16, Cohn attended Bates College in Maine, where he majored in biology. He was the first member of his family to attend college.

World War II

During World War II, Cohn joined the U.S. Merchant Marine, became a hospital corpsman, and served from 1944 to 1946 “as purser-pharmacist on Liberty ships in the Atlantic and Pacific,” where he was sometimes “the only medically trained person among the ship’s crew and 1,500 soldiers, with responsibility for preventing epidemics, administering vaccines and antibiotics, and treating wounds.”

Post-war education

Returning to Bates after the war, Cohn met Fern Dworkin in 1946 in an organic chemistry class. After graduating in June 1948, they married in December of the same year. Unable to gain entrance into Harvard Medical School because of his grades, he entered Harvard's graduate program in bacteriology in the Department of Microbiology, where he did so well that he was able to enter Harvard Medical School a year later. It was while he was a medical student there that he published his first scientific paper, based on work begun in the Department of Microbiology. He received his M.D. degree in 1953 and was one of an extremely small number of students in that medical school's history to be awarded an M.D. summa cum laude. His thesis concerned host-parasite relationships, which would be the focus of his career.

No one in Cohn's family had a medical or academic background. Moberg and Steinman say that he was motivated by Paul de Kruif’s book Microbe Hunters and by Sinclair Lewis’s novel Arrowsmith, as well as by his experiences with penicillin on the Liberty ships, to become a doctor and medical researcher. They also suggest that his interest in medicine, and particularly in the study of infectious diseases, might be traced back to a childhood “brush with death from scarlet fever that quarantined the whole family” and/or to his experiences with “the caring family physician who looked after his father, bedridden nearly a year following a severe bout of pneumonia.” (Cohn's father died at 57 while Cohn was in high school.)A 1983 profile of Cohn indicated that “While he was still in medical school, his interest in research had been spurred by a series of technological advances that were dramatically expanding the scope of cell biology. His interest in Rockefeller stemmed from the fact that many of the advances, in electron microscopy, cell fractionation, and immunology, were happening there.”

Career

Cohn performed his internship and residency at Massachusetts General Hospital, then entered the Army Medical Corps as a captain, working in the laboratory of virologist Joseph Smadel at the Walter Reed Army Institute of Research. For two years Cohn “explored respiratory enzymes and the cell wall of the intracellular parasite Rickettsia tsutsugamushi.”

Rockefeller Institute for Medical Research

In October 1957 Cohn was appointed assistant physician and research associate at the Rockefeller Hospital and what was then called the Rockefeller Institute for Medical Research (later Rockefeller University) in New York, where he worked in the laboratory of René Dubos, whose 1954 monograph Biochemical Determinants of Microbial Diseases he considered “visionary and provocative” and “always kept within reach.”Dubos's studies in microbiology had played a key role in the development of antibiotics. Yet there was little understanding of how these “wonder drugs” worked. Cohn's first project in Dubos' lab, which he conducted with Steven Morse, was to confirm that it is polymorph leukocytes that kill the bacteria that cause staph infections.

Moberg and Steinman describe the situation in the Dubos Laboratory of Bacteriology and Pathology,as follows: “Dubos fostered investigators, not mere problem solvers, thus allowing newcomers independence to plan experiments and progress at their own pace. As [Cohn] said in a 1983 interview, Dubos had a habit of talking to newcomers 'for the first two days, and if he thought they could get along on their own he would not talk to them again for another year. I was terribly upset, I must say.'” Cohn worked at Rockefeller for the next 35 years, “most of them on the fourth floor of Bronk Laboratory.”

When Cohn began working under Dubos, as Moberg and Steinman explain, “the study of leukocytes was still in its infancy....It was also the time when the new science of cell biology was emerging at Rockefeller....This was making it possible to explore the world inside cells: electron microscopy for showing cell structures never before observed and centrifugation methods for separating and analyzing cellular constituents.” Cohn and his colleague James Hirsch “used these new tools to address the question of whether phagocytes contained preformed bactericidal substances or whether these substances developed after foreign particles were engulfed. They isolated granules from the rest of the cell contents, used phase and electron microscopy to visualize them, and determined chemically that they were lysosomes, the cell organelles recently identified by Belgian biochemist Christian de Duve. These discoveries, which traced the phagocytic digestive system to the fusion of phagocytic vacuoles and lysosomes, became widely available to the community after Jim and Zan made a remarkable series of films showing living phagocytes discharging their abundant lysosomes to kill bacteria.”

In 1966 Cohn was made full professor at Rockefeller, which had just changed its name from the Rockefeller Institute for Medical Research to the Rockefeller University, and, with Hirsch, formed a Laboratory of Cellular Physiology and Immunology. There they explored macrophages, about which little was known. Cohn's “adroit tissue culturing of macrophages made it possible to observe, challenge, and manipulate them to figure out how they worked.” He showed how “the cell’s outer membrane folds around the captured material, forms a sac or vacuole that is pinched off from the cell surface and enclosed within the cell, and fuses with the lysosome where the contents are then digested.” The result, as Moberg and Steinman put it, was the transformation of endocytosis into “a central field of cell biology, because it is pertinent to all cells for extracting from their surrounding environment the nutrients needed for survival as well as for capturing and destroying toxins and pathogens.” A Rockefeller University source puts it this way: “Cohn's discoveries on endocytosis in macrophages have proved fundamental to cell biology, since endocytosis is a process universal to all cells, and is the mechanism by which cells digest materials from their surroundings, ranging from microbes to proteins carrying nutrients.”

Cohn's team discovered other key functions of macrophages, moving beyond endocytosis to study macrophages' secretions and identifying more than 50 products of macrophages that play “active roles in inflammation and immunity.” The team found that “activated macrophages release active oxygen intermediates, such as superoxide and hydrogen peroxide, to destroy bacteria and tumor cells. A further demonstration that macrophages could be activated by lymphokines in vivo was important in the laboratory’s subsequent clinical efforts to treat diseases in which macrophages achieve both intracellular and extracellular killing.” Cohn called macrophages the “versatile element of inflammation,” with some of their secretions resulting in the healing of wounds, the repair of tissues, or the destruction of microbes and tumors, while excessive amounts of secretions from overstimulated microphages can intensify various diseases, including rheumatoid arthritis and atherosclerosis.

An interview with Cohn described the discovery of the secretory role of macrophages as follows: “A major immunological finding, which has come primarily from work in Dr. Cohn's laboratory, is that macrophages are not just eaters. In addition to the chemicals they make to kill and degrade the cells they ingest, they also secrete many molecules into their surrounding environment, affecting the activity of other cells. 'This is an important part of the inflammatory process, which may lead either to wound healing and tissue repair or to destruction of tissues,' says Dr. Cohn. 'Among the secreted chemicals are those that stimulate the formation of blood cells and blood vessels; pyrogens, the fever-producing substances; and enzymes involved in lipoprotein metabolism. A delicate balance exists in the amount and nature of the secretory products. When present in excessive amounts disease states suchas rheumatoid arthritis, glomerulonephritis, and even atherosclerosis may be potentiated.'”

Looking into the genesis of macrophages, Cohn and his colleague Ralph van Furth “used a radiolabeled isotope to label blood monocytes and trace their production and development. They identified the blood monocyte as the precursor for tissue macrophages and the bone marrow as the source of monocytes.” At the same time, electron microscope studies he performed with Hirsch and Martha Fedorko provided further insight into macrophage formation and differentiation. This work, according to Moberg and Steinman, “illuminated a pivotal pathway to host defense and captivated the minds and spirits of innumerable scientists,” resulting in five international conferences on mononuclear phagocytes held at Leiden between 1969 and 1991.

Ralph Steinman joined the Cohn-Hirsch laboratory in 1970, and eventually it became the Cohn-Steinman laboratory. In 1973, in the course of studying macrophages, Steinman and Cohn discovered “an entirely distinct class of immune cells” which differed “in structure, appearance, and function from macrophages” and which would come to be recognized as “powerful initiators of the immune response and major controllers of both innate and adaptive immunity.”As one source puts it, this cell, which Steinman named the dendritic cell, would later be found “to be the sentinel cells of the immune system.”

In the early 1980s, wanting to discover “why in certain diseases the macrophages, after ingesting pathogens, not only fail to kill them but instead provide a hospitable environment for them to thrive, multiply, and reactivate disease,” and thus develop therapies, Cohn and other members of his team began visiting hospitals in Brazil, and later in Colombia, Ethiopia, India, Nepal, and the Philippines, to study patients with leprosy and various other diseases, including tuberculosis and AIDS. “For some reason,” Cohn said in a 1983 interview, “no one had ever really looked very hard at the local skin lesions of leprosy patients. Diagnosis has usually been based on analysis of cells in the blood stream. So when we first went to Brazil, we decided that we would examine the cells in the skin. In the virulent lepromatous lesions we found bacteria-filled macrophages together with a large number of suppressor T cells. As we studied patients in the intermediate stages of the disease and on to the tuberculoid form, we found that the number of so-called helper cells began to increase relative to the number of suppressor T cells.”

This, Cohn said, suggested “that the suppressor cells produce a factor which, in effect, turns off the macrophage. Or else, the macrophages don't work because of the absence of helper cells. The question is, Can you suppress the suppressors or help the helpers? Some experiments we've been doing in the lab with cells of other diseases indicate that either or both may be possible, but we need to know a lot more about the bacteria and the immune cells before we can manipulate them clinically....What we can learn about these suppressor cells...is also of great interest because there's a fair amount of evidence in many animal models that suppressor cells modify the ability of a host to fight off tumors, and that if you can destroy the suppressor cells, you'll allow normal body defenses to come back and destroy the tumor.”

The examination of T cells in leprosy patients led Cohn and his team to develop treatments that “restored some of the patients’ immune function at both the local and systemic level, although they did not cure the disease.” Cohn developed “high expectations that lymphokines and other agents interacting with macrophages would someday enter the physician’s armamentarium to fight disease.” At the time of his death, Cohn was arranging “an expanded program to enhance the immune system of immune-compromised individuals with [[AIDS and tuberculosis.”

See also

• Dendritic cell
• Ralph M. Steinman

External links

• National Academy of Sciences Biographical Memoir