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From Little Acorns ...

by Douglas R. Green

Many of us view the process of science as it is promoted by popular culture (and, alas, by many scientists themselves). We envision the scientist striving faithfully and unswervingly towards a single goal and ultimately (if he or she is any good) succeeding. We watch Paul Muni, playing the famous Dr. Louis Pasteur (The Story of Louis Pasteur, 1936), stroke his beard and mutter, "Rabies ... ," to indicate that his great intellect will now be applied to this dread disease until a cure is found, and we expect that scientists will focus on the problems of obvious concern and not waste time (and money!) on apparently trivial things. But it often turns out that these apparently trivial matters open up new windows, letting us view the world in novel and useful ways.

Towards the end of the 1970's, the field of immunology, which concerns itself with how the body naturally defends itself against disease, dramatically changed. Whole new ways of studying the immune system emerged, together with important and novel avenues of therapy-all because a few investigators, most of them tucked away in laboratories away from the mainstream, chose to study some apparently insignificant phenomena of no obvious research value.

A major player in this story is a biochemist at the University of Alberta, Dr. Vern Paetkau ('63 BSc). Looking for a research system in which to study how cells became activated to divide, he chose to study T-cells, which play an important role in the immune system. Vern's s interest in the field had been aroused by Dr. Erwin Diener, an internationally known immunologist who had recently arrived in Edmonton to accept a University appointment.

The project proceeded slowly. Then, in 1975, a technician named Vicky Monticone did an experiment with the less-than-fascinating title of "cell/volume ratio." It was an experiment that might easily have been lost in the graveyard of old notebooks, but Vern analyzed the results to determine how much DNA each individual T-cell made versus how many cells were placed into culture. That analysis led to a remarkable insight: these T-cells were feeding themselves-that is, they were making something that facilitated their own proliferation. By hindsight it was a major discovery; at the time it could not have been less exciting to most immunologists. Most of Vern's peers recommended that he not waste his time.

Certainly Vern didn't drop everything else. It was more the type of discovery that leads to "flyers," experiments which are so chancy that only a small amount of time and effort is devoted to them-the kind of project one gives to a medical student spending a summer getting a feel for the laboratory bench.

Gordon Mills ('75 BMS, '77 MD, '84 PhD) was the student who got involved while spending his summers in Vern s lab. Based on Vicky's experiments and Vern's insights, Gordon defined a crude T-cell product as a "co-stimulator," a growth factor which facilitated the proliferation of T-cells. He worked to perfect ways in which the activity of the co-stimulator could be measured.

At this point the work was starting to look a little more interesting. Interesting enough for a graduate student, Jenny Shaw ('80 PhD) to become involved. Jenny and Vern decided to treat the co-stimulator as though it were an enzyme, subjecting it to biochemical analysis (which was only possible because of the methods worked out by Vicky and Gordon). As they quietly proceeded the co-stimulator began to take shape as a molecule of real biological importance. The project, however, still failed to attract much attention.

Then, in 1979, at a historic meeting at Lake Constance in Switzerland, Vern Paetkau suggested to four other scientists (over a beer in the castle's pub) that the name "interleukin" be used as a general term to describe molecules that act between the cells of the immune system. Co-stimulator became interleukin-2, or IL-2. Vern had already exchanged some of his group's co-stimulator for a like substance from another lab which had reported a similar activity, and the collaboration had revealed that both labs were looking at the same thing. Following the Lake Constance meeting, other labs began similar exchanges and found that IL-2 had a number of different and important functions in the immune system.

Now interleukins from 1 to 5 have been identified (interleukin-6 is waiting in the wings) and are being actively studied throughout the world. IL-2 is now known to be of central importance in a wide range of immune responses, and injection of IL-2 or cells treated with IL-2 into patients with some types of tumors is likely to become an important method of cancer therapy. (It is currently in extensive clinical trials in many countries.)

Not surprisingly, IL-2 and related interleukins have become the central focus of research in Vern Paetkau's laboratory.

The IL-2 story is a classic example of a scientist following his nose, sticking with a problem that "smells right." And where did this little acorn of an idea lead? Index Medicus 1986 lists more than 500 references relating to IL-2 (by various names) for that year. A veritable forest of papers.

While very few "flyers" wind up as successfully as the co-stimulator project did, there really is no way to know from where the next major discoveries will come. We therefore support environments in which a novel project will flourish. And we encourage scientists who have the insight to follow where the science leads.

Dr. Douglas Green is an Alberta Heritage Foundation for Medical Research Scholar and an assistant professor of immunology. He is a graduate (BSc, PhD) of Yale University.

Published Spring 1988.

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