Book Review Detail

It is not an exaggeration to say that Professor Donald Metcalf is the premier research scientist in the field of cellular hematopoiesis and its regulators. Since the 1960s, he has been at the forefront in this fast-paced field. In fact, he has set the pace. The term "colony-stimulating factor (CSF)" originated from his culture experiments some decades ago. Were it not for his outstanding contributions, the current cytokine era might not yet have emerged, or at least it would not have developed to its present state. For this among other reasons, Metcalf deserves to be called the founder of cellular hematopoiesis and hematopoietic cytokines.

Metcalf officially retired as Head of the Cancer Research Unit and Assistant Director of the Walter and Eliza Hall Institute of Medical Research in Melbourne in 1996, and was named Professor Emeritus of the University of Melbourne. Unusual among most scientists, certainly those of his age, he continues to work at the laboratory bench nine hours a day, six days a week. This way of life, which he obviously enjoys, also tells us of his enthusiasm for the "dogged pursuit of the blood cell regulators."

The majority of the numerous new books published each year are edited books, with many authors each contributing a chapter. It is, therefore, not uncommon for authors of a given chapter to hold views entirely opposite to those of other chapter authors. Summon Up the Blood: In Dogged Pursuit of Blood Cell Regulators is refreshingly unique in that Metcalf himself wrote the entire 214 pages consisting of 16 chapters, as he says, "before too much was forgotten."

CSFs are hematopoietic cytokines widely employed in current hematological practice. A rapid and dramatic change is taking place in transplantation medicine, but it should be remembered that the first description of CSF emerged slowly from the cell culture experiments some three decades ago.

In his book, Professor Metcalf recalls the day in 1964 when Dr. Ray Bradley, working across the street at the University of Melbourne, paid a visit to his laboratory and showed him glass petri dishes containing semisolid agar cultures of mouse marrow cellscolonies of cells which continue to fascinate him even after 35 years. Metcalf suspects that "Dr. Bradley did not realize what a startling impact these colonies [would] have on me or my subsequent work." Subsequent chapters describe Metcalf's research projects and approaches, the discovery and purification of CSFs, the excitement of CSF gene cloning, the challenges and the excitement of animal and then clinical trials, followed by cloning and characterization of receptors for the CSFs and other regulators. The chapter on in vivo manipulation of CSF genes sets out the development of the transgenic and knockout models. These chapters present a chronological description of Metcalf's work, eventually leading to the birth of an exciting new field of research and clinical medicine.

Many behind-the-scenes episodes add to the appeal of this book. Metcalf coincidentally met with Dr. Leo Sachs of the Weizmann Institute, Israel, at an National Cancer Institute-sponsored meeting in 1965, and the two talked about their experiments. The Weizmann group published similar culture works in 1965 and 1966. Another episode typically illustrates Professor Metcalf's dedication. He was having the "tensest time" when he was examining the massively cellular peritoneal fluid taken from the first mouse injected with recombinant murine granulocyte-macrophage (GM)-CSF. In the middle of cell counting, the top of the glass capillary tube snapped off and stabbed into his foot. His anxiety and joy in the experiment was such that it was only after having witnessed the dramatic event that he paused and took off his shoe to remove the impacted piece of glass. He also experienced unhappy events such as the accidental discard of highly purified human urinary CSF during a routine cleanout of a refrigerator, and the use of mislabeled samples, which resulted in the waste of a year's work.

A few odd, although not surprising, events also happened in his early publications. The pioneering article on the detection of CSF in human urine was submitted to Lancet , but was returned because it was thought to be better suited for a urology journal! His first paper describing colony formation appeared in an Australian journal that did not record the submission date and, to add insult to injury, was published only after a long and inexplicable delay. "In an unkind twist of fate," as his group was sequencing murine G-CSF, he was asked to referee a submission to Nature by Dr. Nagata and his colleagues describing the successful cloning of human G-CSF. Another bombshell hit him some years later when the Nagata group published G-CSF receptor cloning. Metcalf was again asked to be the referee of this paper in which he discovered the Japanese competition. Although the Nagata group seemed to be his "private nemesis," his disappointment was short-lived, and he quickly offered help so that both papers could be published.

In the mid 1980s, many CSF genes were cloned, and this event was immediately followed by battles over patent rights and frustrations of licensing procedures. Dominant players were then "cloning companies." Those in academic laboratories were rather "naive in the relative lack of awareness of the importance of filing patent applications," devoid of a primary interest in any financial rewards. "Surely no one in those days had any firm grounds for expecting that recombinant CSFs would be billion-dollar clinical agents. Mass production of recombinant forms using a cDNA was no easy matter either." Science had become "a group exercise requiring multiple pairs of hands and multidisciplinary approach." Metcalf honestly regrets not filing provisional patent applications. However, it was not clear in those days whether a murine GM-CSF patent had dominance over subsequently cloned human GM-CSF, or whether patent application needed to be based on cloning data or on amino acid sequence data. In any case, Metcalf seems to be pleased to learn that mammalian CSFs do exist as a genuine cellular product, and that his many years of effort were not a waste of time.

This book is highly recommended for everyone working in the field. Newcomers can learn how hematopoietic regulators have been discovered. The book vividly illustrates each epoch-making discovery on the presence of CSFs, their activities both in vitro and in vivo, cloning of their cDNA and receptors, intracellular signaling mechanisms, and whole animal gene manipulation models. For senior investigators, this book provides many lessons on teamwork and the role of a team leader: "Teams work well on difficult projects if everyone, including the team leader, is carrying an equal burden." As part of his team, Professor Metcalf continues to regularly spend 6 to 8 hours each day at his microscope, even though he has had two laminectomies. Many other prominent scientists would have long ago delegated such work to an army of technicians. In spite of physical pain and global competition, Metcalf has a knack for steering his way toward productive research directions and is undaunted in the face of early obstacles.

After all is said and done, I was overwhelmed both by the excellence of Professor Metcalf's research and by the honest and frank tone of his writing.