Volume II Appendices I – IV Appendix I THE CASE OF BRESAGEN Parcel 1: Radionucleotides Professor Robert Symons from the Biochemistry Department at the University of Adelaide developed a technique for the efficient production of 32P-labelled radionucleotides that was published in a leading scientific journal1 in 1977. These were radioactive compounds used to label DNA and RNA, and were widely used at the time in gene technology research. At the time, production of these radionucleotides was influenced by two factors: first, being radioactive and with a short half-life of 14 days, international shipping was difficult and costly. Second, manufacture was dominated by Amersham, a UK-based company, using inefficient technology, which kept prices high. This meant that increasingly, when Professor Symons had radionucleotides that were surplus to the needs of his own Department and its Centre for Gene Technology (also established in 1982), he increasingly began providing them for free to other laboratories in Australia. By the early 1980s, Bob Symons’s head of department, Professor Bill Elliott, suggested that rather than giving the radionucleotides away, he should set up a business. However, Bob Symons did not the patent the technique; as Allan Robins, a postdoctoral researcher at the time, commented, ‘this is back in the days when we were naïve academics. Nobody patented ideas, or we didn’t anyway, Bob didn’t’ (interview, 2007). 1 Nucleic Acids Research 1 According to the Bresa Product Catalogue (1984): BRESA [Ltd] was officially set up in [31] May, 1982 to develop and prepare for sale a range of high quality materials for use in gene technology. It is wholly owned by the University of Adelaide and operates from the Department of Biochemistry, which is a major customer of BRESA products. Bresa (Biotechnology Research Enterprises South Australia) was incorporated to function as the trading arm of the Bresa Unit Trust, and at that time was located within the Department of Biochemistry at the University of Adelaide. Robins stressed that the initial intentions motivating Bresa’s establishment lay in securing research funds not private gain: The plan was to build a little reagent business … those guys were very philanthropic in those days so there were four founders of the company and none of the founders took any stock or took any money out of it. The whole idea was to bring money in to support research in the Department of Biochemistry. My understanding is that Bob [Symons], Julian [Wells], John Wallace and Bill Elliott were all down as founders of the company. Bob and Julian were really driving it. (interview, 2007) However, whilst the company Bresa Pty Ltd was freshly incorporated, the idea of making these radionucleotides was not! In fact, Symons had apparently been making them for years, as a former head of department, Professor George Rogers explained: It was in the ’70s, I think, yes. Because he [Symons] was in the [United] States in ’712 and came back and then molecular biology took off and then there was an embargo on doing cloning because of the possible hazards and there was a Asilomar conference in California in 19743 and when they were all cleared we were able to go on with it and Bob started to supply these things [radioactive nucleotides] to the department. The then head of the department was Bill Elliott and Bill said to Bob – I was around when the conversation was going on, of course – ‘You’re giving the stuff to people in Australia as well as the department, you ought to set it up as a business and commercialise it properly and make some money’ rather than being a 2 D.A. Jackson, R.H Symons, and P. Berg in Proceedings of the National Academy of Sciences (1972). 3 The Asilomar conference was actually held in 1975 in California. It is seen as a landmark in the history of genetic engineering, an event that served as an influential model for policy making at that time. Its role as a model for future policy making on DNA technologies has been broadly questioned, particularly since commercial and military interests have been seen as major influences on the field’s development. 2 benefactor, as it were. So that’s really the start of it … (interview, 2007) Bob Symons was collaborating with Paul Berg at the time. It was Paul Berg who is credited with organising the Asilomar Conference in 1975 in California and in 1980, Berg won the Nobel Prize ‘for his fundamental studies of the biochemistry of nucleic acids, with particular regard to recombinant-DNA’. On his impressive CV, only five significant papers are listed and on one of these Symons is a co-author: A Biochemical Method for Inserting New Genetic Information into SV40 DNA: Circular SV40 DNA Molecules Containing Lambda Phage Genes and the Galactose Operon of E. coli. David A. Jackson, Robert H. Symons, and Paul Berg. Proc. Nat. Sci. USA, 69, 2904 (1972). (Berg, The Nobel Institute, website accessed 2008) Moreover, an article on the significance of this paper was written by W.K. Joklik: Like the year 1940, the year 1970 occupies a unique position in the history of virology. In 1940, the conceptualization of the one-step growth cycle by Emory Ellis and Max Delbrück; the discovery of hemagglutination, which provided a rapid and simple means of quantitating virus particles; and the invention of the electron microscope and the ultracentrifuge, which provided the means for studying viruses by physical techniques, converged to initiate the era of molecular virology, molecular biology, molecular cell biology, and molecular genetics. In 1970, the discovery of restriction endonucleases by Ham Smith and K. W. Willcox (J. Mol. Biol. 51:379–391, 1970) provided the means for localizing any gene and of joining any DNA sequence to any other; the discovery of the reverse transcriptase by David Baltimore and by Howard Temin and Satoshi Mizutani extended this technology to RNA by permitting the transcription of RNA into DNA. These two discoveries initiated the age of genetic engineering. Very soon scientists realized that these discoveries would enable them to insert new or modified genetic information into the genomes of living creatures. In order to achieve this, appropriate vectors were required. The vectors of choice for introducing DNA into cells are viruses; and since the new genetic information was to be introduced into cellular genomes, the virus had to be one whose genome was inserted into the cellular genome. The first choices here were retroviruses and papovaviruses. In this paper Jackson, Symons, and Berg chose simian virus 40 (SV40) and devised techniques for inserting foreign genetic information into its genome via use of appropriate restriction endonucleases. This paper is one of the cornerstones on which all 3 subsequent ‘vectorology’ is based, which is the reason why it was selected. Paul Berg was awarded the Nobel Prize in 1980. In his autobiography, Berg talks about this important phase of his research career. The colleagues he refers to are Jackson and Symons: Soon after I returned to Stanford, I conceived of using SV40 as a means for introducing new genes into mammalian cells much in the way that bacteriophage transduce cellular DNA among infected cells. My colleagues and I succeeded in developing a general way to join two DNAs together in vitro; in this case, a set of three genes responsible for metabolizing galactose in the bacterium E. coli was inserted into the SV40 DNA genome. That work led to the emergence of the recombinant DNA technology thereby providing a major tool for analyzing mammalian gene structure and function and formed the basis for me receiving the 1980 Nobel Prize in Chemistry. (Berg, The Nobel Foundation, website accessed 2008) Rogers explained how the Centre for Gene Technology came about, ‘[it was] primarily because there was a real trend in the department for molecular biology and for gene technology and the government started to put these on paper. The whole idea of having a centre or CRC (Cooperative Research Centre) set these up to really give impetus to research in Australia’ (interview with Rogers, 2007). He also talked about the advantages and disadvantages this scheme delivered: ‘The point about that was that it produced a packet of money that was not what one usually got from normal grants. So, it gave a tremendous [boost] to research. Unfortunately, despite the fact that there were eight of us in the department, it was decided because there were limitations put on by the rules of the application we could have had five or six, I think, but we decided that we should just have four. That did give a little bit of ill feeling …’ (interview with Rogers, 2007). In terms then of the arrangement of the Centre within the department, Rogers said: … there was Bill Elliott who was head of the department, there was Bob 4 Symons, Julian Wells and myself and we all had projects which had [involvement with transgenics] - I mean, I was doing animal transgenesis then, which is putting genes into sheep and doing things. Bob was doing all that other thing and Bill had some work to do with diseases and then there was Julian who was into a lot of cloning work and fundamental work on genes regulating expression, but to do with cell differentiation so it was very basic stuff, so they fell together pretty well. That’s sort of how it came about and we applied - we had an extension for nine years, which was quite a lot. We were able to appoint post-docs and PhD students and the groups grew within magnificently. We had equipment we couldn’t otherwise afford.