In 1969, Peter H. Duesberg and Clarence (Budd) Colby published a paper in Nature  in which they showed that the very small amount of double-stranded (ds) RNA, that is produced in cells after infection with vaccinia virus is a potent interferon inducer. "Interferon" is the first and best natural defense complex, mammalian, cell systems have evolved against viruses, and until Duesberg and Colby's demonstration, its molecular induction was an important and unsolved question.
The interferon system works in two stages. In the first, an incoming virus triggers the synthesis of a diffusible protein (the interferon) which, in the second stage, itself induces an antiviral response that can stop some viruses dead in their tracks long before an immune response can be mounted. Deciding what the inducer of the interferon looked like was not easy. In the first instance, the molecule must be a general enough one to be in the limited biochemical repertoire of viruses, and yet unusual enough so that cells do not encounter it except when a virus is present. The most obvious candidate, ds-RNA -- a molecule that is not normally synthesized from the cell's own genes, but is present at one stage or another after an RNA virus infects, had a big problem. Large DNA viruses like vaccinia are also very good interferon inducers.
Colby had the idea that such viruses also make a little double-stranded RNA because they have genes that are transcribed from opposite strands of the helix, and at their head and tail ends some overlap is expected, which after trimming away the single-stranded, messenger RNA molecules, would leave ds-RNA as a diffusible, nuclease resistant, molecular species. A nice idea, and one that he and Duesberg proved in the paper cited above.
It can legitimately be said that this paper, which was extremely well read, ushered in the era of the molecular biology of interferon and aroused the interest of pharmaceutical giants in its cash poential. And as the essay below - written in 1999 for a Liber Amicorum presented to the distinguished phage and plant molecular biologist, Marc Van Montagu on his retirement from the Univ. of Gent - remembers, it was one of the first 'molecules' to make biotech a big ticket commodity.
It is of some interest to note that Budd Colby was a senior scientist at Cetus very early, where he worked on the cloning of interferon using a cell line he had developed that over-produced the molecule and thus its message -- a precious and unstable substance that was needed for cloning before Kary Mullis' invention came along to save the whale from the financial abyss. Before joining Cetus, Budd spent a few years at Sloane-Kettering, also working on interferon, along with Mathilde Krim, the founder of AmFAR.
It was September 1971, I was 26, and am remembering with the kind of burnished, selective clarity that comes after almost 30 years. Timotha, my wife of the time and I had arrived in Europe after saying goodbye to our dear friend Paul Blackburn, the poet and first translator after Pound of the troubadors, who, on his cancer stricken deathbed in NY, told us we could be in Toulouse on the week they took the picture postcards for the next year (it was a joke, like the length of the Danish summer).
The previous year I had made the transistion from phage genetics to interferon research, after completing my Ph.D. with Richard Calendar at UC, Berkeley, and had joined my friend Budd Colby at the University of Connecticut, where he was completing the proof that interferon induction required a double nucleic acid helix with at least one strand containing its 2 prime hydroxyls. We had been invited to an interferon congress at the Catholic University of Louvain, and I had arranged to visit Marc's laboratory at the close of the meeting.
A journal entry of the time notes: "The rector of theological studies informed us at the champagne dinner tonight that 'interferon is a religious substance' -- something we could all appreciate since, like god, although we have many different ideas of its exact nature, we all agree that whatever it is, it is very big."
The meeting was sponsored by Merck, which was investing in the idea that synthetic interferon inducers would turn out to be magic bullets for the common cold as rhinoviruses are quite sensitive to its action. I was arguing, unsuccessfully, that such a course was fatally counterproductive because the interferon system, which worked with such small amounts of protein that until then nobody had purified enough to accurately determine its molecular weight (if indeed it had one, which it turned out it doesn't, being a community not an entity) had clearly evolved in order to keep us alive until the immune system could do its job. Therefore the last thing we wanted to do was give interferon resistant viruses a selective advantage. Cassandra-like warnings that also turned out (fortunately) to be quite unnecessary since interferon(s) are themselves responsible for many of the cold symptoms they were imagined to prevent.
I had not yet met Marc, who had not yet met the Ti plasmids which were to become a cornerstone of plant biotechnology, and interferon, which was to metamorphose 10 years later into a cornerstone of pharmaceutical biotechnology (this time as an equally ineffective magic bullet against cancer), was still an activity, not yet even a molecule. What were we thinking?
On the way to meet Marc, I must have been thinking about how an overcrowded train of drunken German soccer players and their fanatics had forced us to leave our bags in an inter-compartmental space from which they disappeared, leaving us with only the clothes on our back and the few things (mostly books and papers) in our handbags, so that we arrived at the opening dinner of the interferon congress, the champagne affair I alluded to earlier, looking very much like the 60's Berkeley transplants we were, and except for Budd's long hair, and his wife Diane's flowing Indian cotton dress, very much out of place amidst the fine gowns and suits of our seriously attired colleagues and their spouses.
I may also have been thinking that here I was again, about to enter a very old university campus to give a proper seminar quite improperly clothed. But although noticing that I still had not acquired a jacket or tie, I knew I was about to meet Marc MS2 Van Montagu and his gang of phage molecular biologists and it mattered not at all how I was dressed. The only things that mattered were how interesting the problem, how clever the experiments and how good the data.
Heterologous phage interference, my thesis problem, was certainly interesting enough. In the course of working out the viral and host genes involved, it became clear that in excluding bacteriophage lambda from cells in which it resides as a prophage, P2 commits suicide. This was quite puzzling from an evolutionary point of view as the notion of altruistic genes (those that apparently function to confer replicative advantage to a population, not an individual) had yet to become a popular idea in biology.
It was the beginning of a new decade, but we did not have any idea it was also the transitional period of a molecular biology that was purely of the mind to the molecular biotechnology of today -- a biotechnology which Marc was to play a major role in shaping, and myself a minor role (as a protege of Gunther Stent) in trying to keep honest. The genetic code had been fully deciphered only a scant five years earlier, and DNA, unlike interferon, was truly a religious substance. Its very letters (Daleth, Nun, Aleph) kaballistically summing to 10. (Gunther and I had even collaborated a few years earlier in a re-interpretation of the classic Chinese text, the I Ching (Book of Changes) in which we showed that the 64 codons of molecular genetics and the 64 hexagrams of the ancient Taoist doctors represented isomorphic systems.) But something of the flavor of the future must have been in the air because the previous, and final night of the interferon congress, I had written in my journal: "if the earth is a single embryonic cell / bathed in galactic fluid/ we are the viruses."
And so it was with at least some of these thoughts, accompanied by vague feelings of being out of place, that I arrived in Marc's laboratory and all such feelings, as well as the misfortunes of the journey, the sadness at Paul's passing (which happened while we were in Louvain) and the spectre of giant drug companies intruding into the pure lands of molecular biology instantly vanished in the pleasure of encountering a kindred soul. Entering Marc's lab was like coming home.
That evening after my seminar, Timotha, Marc, and I had a long dinner and talked with subdued passion about the science, poetry and world politics of the day. Later, at their house, we met Nora, (seeing her dentist's chair caused me to remark that the next time I needed dental work, I was on the first plane to Brussels), and their equally never-to-be-forgotten civet cat, who was almost as beautiful.
I was not to see Marc for more than a decade, when the brave new world of biotechnology brought us together again. Watching this world develop over the ensuing 16 years, I have been frequently reassured by the knowledge that, despite a growing prominence, there is at least one plant molecular biologist upon whose disinterested, and considerable, intellectual acumen I can always rely, and whose heart, I continually rediscover, has remained remarkably constant.
Let me close this brief contribution to Marc's Liber Amicorum with another entry from my journal of the time. It is a quotation from Martin Heidegger's The Age of the World Picture, and applies perfectly to Marc Van Montagu. Heidegger wrote:
"But in what does the essence of research consist? In the fact that knowing establishes itself as a procedure within some realm of what is, in nature or in history. Procedure does not mean here merely method or methodology. For every procedure already requires an open sphere in which it moves. And it is precisely the opening of such a sphere that is the fundamental event in research."
Harvey Bialy is the founding scientific editor of Nature Biotechnology, and the editor of "You Bet Your Life".