Once more unto the breach, dear friends, once more;
Or close the wall up with our English dead!
In peace there's nothing so becomes a man
As modest stillness and humility;
But when the blast of war blows in our ears,
Then imitate the action of the tiger:
Stiffen the sinews, summon up the blood,
Disguise fair nature with hard-favour'd rage;
Then lend the eye a terrible aspect.

William Shakespeare
King Henry V
Act III, Scene 1

The first two lines of this excerpt were used by me on more than one occasion as an exhortation to my colleagues when things were going badly and spirits were sagging. Not that we were English, but we were being sorely tried.

Donald Metcalf

Introduction

The 35-year saga of the discovery, development, and medical application of the blood cell regulators, the colony-stimulating factors (CSFs), has all the elements needed for an absorbing story. There was a cast of characters who shared between them a full range of human foibles, the gradual opening of an exciting new field of medical science, distrust between opposing groups, the tedium of endless purifications, the excitement of gene cloning and expression, the tensions of animal then clinical trials, opportunities lost, battles over patent rights, the aggression or indolence of pharmaceutical companies, the frustrations of licensing procedures, and always the need to push techniques and ideas beyond existing limits.

Despite repeated requests, I had been reluctant to attempt to write a semipopular account of the CSFs, suspecting correctly that this might prove to be quite difficult. However, those of us who were involved from the early phases have been chagrined to realize that we have already begun to forget key elements of the story. There seemed no other option therefore than to set down as many of the details as could be recalled before too much else was forgotten.

As most of the participants in the saga are still alive and remain on friendly, if sometimes wary, terms, I certainly had no inclination to write a warts-and-all expose. I do have my own views on certain episodes where tensions arose but I am not well placed to describe how others felt or acted at these times.

This book was not intended to be an ordered and fully referenced scientific account of the CSFs. Such an account has already been written by Nick Nicola and me. Rather, I wished to give a chronological description of how order slowly emerged out of confusion in this field, and to attempt this without becoming so technical that a nonexpert reader would become discouraged.

My attempt to write a blow-by-blow account soon ran into difficulties. It was easy enough to write a personal account of the early days of the project when only three or four workers were involved. This became much more difficult when there were a hundred or so in various groups working in the field. It clearly became impossible to introduce any personal touches to the account when there probably were thousands involved in various aspects of the work.

By default, the account became progressively transformed to a skewed description of the activities of a single research group. This then became in danger of implying that we were the only serious contributors to the field. I have tried to avoid this distortion by inserting at various stages the important contributions of others but may not have been wholly successful in this attempt.

It became increasingly more difficult to describe, in the form of a single account, a story that became composed of quite separate issues and projects, proceeding simultaneously. In the latter part of the book, this problem forced a divergence from a single chronological account to separate descriptions of four major streams of work that were really proceeding simultaneously.

Try as I could, the account could not be restricted to the CSFs. Other hematopoietic regulators were being discovered as the work on the CSFs progressed and, because these often interact with the CSFs, they needed to be introduced from time to time.

No account of the development of the CSFs was able to be given without some reference to the target hematopoietic cells on which they act, because the characterization of these cells was making major advances throughout the period of work on the CSFs. So, from time to time, there were necessary asides in the account to fill the reader in on these simultaneous developments.

Work on the CSFs did not cease with their clinical development. Much further crucial information on these regulators needed to be discovered and indeed these studies continue today. The latter part of the account therefore is a description of what we and others felt impelled to do in the postclinical era.

While most of the salient features of the CSF story have at least been mentioned, the account has ended up neither fish nor fowl. It is heavily autobiographical but without many of the expected features of an autobiography. I have tried to portray laboratory life as it happens for a group tackling complex and prolonged projects and I hope this gives some insights into how findings slowly emerge. The description omits dramas, personal frictions, and periods of angst that of course occurred and possibly can be read between the lines.

What has resulted may well be a rather dull account of a subject that could have made a sustaining page-turner. It is interesting, in the development and expansion of a subject, how the intensely personal excitements for the few in the initial days do transform to a somewhat shapeless pattern as the field expands: advances go on, but in a manner that progressively appears to lose its personal aspects. For each individual this may never actually be the case, but as more and more investigators enter a field it becomes almost impossible to follow in detail their individual hopes and actions.

I have ended up with an account that is little more than a history of a single research unit over the past 35 years. This may interest those who know the field and perhaps not many others. If this is the case, so be it. If my account does not seem to agree with accounts of the CSFs that often appear in more recent review publications, then I suggest that the readers go back to the scientific literature and establish exactly who did what and when. They may find some surprises.

Donald Metcalf
Melbourne, 2000

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