Book Review

A Commotion in the Blood: Life, death, and the immune system

N Engl J Med 1997; 337:1178-1179October 16, 1997

Article

A Commotion in the Blood: Life, death, and the immune system
By Stephen S. Hall. 544 pp. New York, Henry Holt, 1997. $30. ISBN: 0-8050-3796-9

About 25 years ago, an irreverent wag used “lymphodrek” to refer to the mysterious factors released by cultured lymphocytes or macrophages that could activate, attract, or inhibit other mononuclear leukocytes. These enigmatic phenomena seemed to depend largely on ingenious experimental conditions that outsiders found incomprehensible. Moreover, no sooner did one laboratory describe an activity — invariably with an acronym — than another reported a different acronym with similar effects. Who could have predicted that this Babel would yield not only numerous potent lymphokines but also molecules with the power to incite guile, greed, and pitiless malevolence in researchers?

Stephen Hall's absorbing, often gripping account of the development of immunotherapy begins with the story of William B. Coley, the inventor of Coley's toxin (a crude mixture of supernatants from bacterial cultures). Coley stumbled on his toxin around 1890 in his search for a factor in hemolytic streptococci that he thought caused regressions, and even cures, of inoperable sarcomas. Helped by the Rockefeller family, Coley produced spectacular results. Others, however, could not reproduce them. His downfall at the hands of James Ewing — of Ewing's sarcoma — is worthy of Aeschylus, with the American Medical Association as the chorus. Yet the fumbling Coley had uncovered a germ of truth, because in the patient his mishmash likely triggered the production of cytokines with anticancer effects. Hall's sympathetic analysis of how Coley failed is the high point of the book.

Jean Lindenmann and Aleck Isaacs discovered interferon (later found to consist of a family of cytokines) in 1956 while studying viral interference, a phenomenon in which cells infected by one virus resist infection by a different virus. In clinical trials, interferon had little success as an antiviral agent, but in 1968, when Ion Gresser showed that it caused regression of cancer in mice, this first cytokine was on the front page. A breakthrough in cancer treatment seemed imminent, except for the fact that the world's supply of interferon depended on Kari Cantell, who was painstakingly extracting it from liters of human leukocytes in his laboratory in Helsinki. Hall recounts how Charles Weissmann inveigled Cantell to help his laboratory clone the interferon gene without informing him that he, Weissmann, a professor of biochemistry at the University of Zurich, was actually a front for the Biogen Company. Weissmann and Biogen get low marks for treating Cantell disingenuously and ignoring Lindenmann — an ignominious beginning for the biotech industry.

At the center of A Commotion in the Blood are Hall's portraits of Robert Gallo and Steven Rosenberg, then both at the National Cancer Institute. Doris Morgan discovered interleukin-2 in Gallo's laboratory in 1975, but, as Hall recounts the story, Gallo would have little to do with it or her because it was not the growth factor he wanted for finding the human myeloid leukemia virus (which has never materialized). Morgan's personal dignity was no match for Gallo's egomania, and worse, her results did not fit with Gallo's preconceptions. It was a cruel injustice that Morgan was summarily dismissed from the National Cancer Institute three years after her landmark discovery. Whether Gallo was involved in the decision remains unclear, but he did nothing to reverse it. Rosenberg, unlike Gallo, recognized the clinical potential of interleukin-2, but according to Hall his hubris and lack of scientific rigor actually stalled research in cancer treatment. To infuse pig lymphocytes into terminally ill patients with cancer, as Rosenberg did in 1975, was a ludicrous if not a pathetic gesture, even if judged by the ethical and scientific standards of the time. And despite resources at the National Cancer Institute that should have ensured high-quality clinical investigations, Rosenberg's work on the treatment of cancer with lymphokine-activated killer cells and interleukin-2 was inept and never confirmed. Hall's account of Rosenberg's quarrelsome foray into gene therapy shows the same thread of false hope he spun with his uncontrolled experiments on immunotherapy.

A bright light in this book is Thierry Boon, the Belgian researcher who put the immunology of melanoma on solid ground. His work makes the prospect of an anticancer vaccine plausible. Hall skillfully traces Boon's arduous path to the discovery of a family of clinically relevant melanoma antigens.

Huge financial investments have been made in lymphokines, and fortunes have been reaped. Yet the resulting clinical benefits in cancer and autoimmune diseases have been meager. It seems unlikely that treatment with one cytokine at a time will have much effect in these complex diseases. The immune system produces many cytokines with multiple and often overlapping effects, an indication of not only fail-safe redundancy but also the coordinated mechanisms required to defend against sophisticated invaders. Like microbes, cancer and autoimmune diseases have many strategies to withstand monotherapy. Hall's excellent book brings to life the personalities and ideas in the field of immunotherapy and gives us much to ponder about the human condition.

Robert S. Schwartz, M.D.