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Professor Ian Frazer was interviewed in 2008 for the Interviews with Australian scientists series. By viewing the interviews in this series, or reading the transcripts and extracts, your students can begin to appreciate Australia's contribution to the growth of scientific knowledge.
The following summary of Frazer's career sets the context for the extract chosen for these teachers’ notes. The extract covers how he and his colleague, Dr Jian Zhou, developed the basis for a human papilloma virus vaccine. Use the focus questions that accompany the extract to promote discussion among your students.
Ian Frazer was born in 1953, in Glasgow, Scotland, into an academic family. He enrolled in Edinburgh University, originally to study physics but switched to medicine, and trained as a renal physician and clinical immunologist. He received a BSc(Med) in 1974 and an MB ChB in 1977. In 1974, as part of his studies, Frazer spent three months at the Walter and Eliza Hall Institute of Medical Research in Melbourne.
In 1981 Frazer returned to the Walter and Eliza Hall Institute where he continued his clinical training and undertook studies in viral immunology and autoimmunity. He studied a number of sexually transmitted infections and became particularly interested in human papilloma viruses (HPV). In 1985 he took up a teaching position with the University of Queensland. When he moved to Brisbane he decided to continue his work with HPV, in particular HPV and cervical cancer. He was awarded a Doctor of Medicine from the University of Melbourne in 1988.
The work of Frazer with his colleague, the late molecular virologist Dr Jian Zhou, has led to the development of a vaccine for cervical cancer. The vaccine prevents infection with the HPV that leads to cervical cancer.
Frazer is currently director of the Diamantina Institute for Cancer, Immunology and Metabolic Medicine at the University of Queensland. His research interests include immunoregulation and immunotherapeutic vaccines and he teaches immunology to undergraduate and graduate students at the university. He is also president of the Cancer Council of Australia.
Over his career, Frazer has received many honours both in Australia and overseas including the Balzan Prize for preventive medicine (Italy, 2008), the International Life Award (Sezione Ricerca Scientifica) (Rome, 2007) and the William Coley Medal from the Cancer Research Institute (New York, 2006). In 2008 he was awarded the Prime Minister’s Prize for Science. He was named Australian of the Year in 2006 and was awarded the CSIRO Eureka Prize in 2005. He received the Australia Centenary Medal in 2001.
Frazer was elected a fellow of the Australian Academy of Science in 2004. His international fellowships and memberships include being a fellow of the Royal College of Physicians of Edinburgh (1988), a fellow of the Royal College of Pathologists of Australasia (1989) and a member of the American Association of Immunologists (2002).
Making the indispensable virus-like particle
The other thing – perhaps the most important thing – that happened in Cambridge was that I met the late Dr Jian Zhou there, because he was also one of the team working in Lionel Crawford's lab. He was a visitor from China who had come as a graduate physician like myself, with an interest in papilloma virus like myself. He was the technologist; he was really good at working with gene cloning and gene expression. So if there was any gene cloning problem that I couldn't do, or indeed that anybody else in Lionel's lab couldn't do, we went always to Jian. And Jian could do it.
Did you click straight away?
I think we did. Jian, like myself, was on sabbatical, and therefore we tended to be in there doing things out of hours: nights, weekends. I had a limited time and I wanted to get a certain number of things done. Whenever I was there in the evening, Jian was there in the evening – and most of the other people were down at the pub. That meant we naturally hit it off, in the sense that we were around and trying to solve similar problems. He was interested in immunology and wanted to learn immunology, which I could help him with, and I wanted to learn molecular biology, which he was very good at. The two of us got on very well, because we were exchanging ideas all the time.
Did you bring him back to Brisbane?
Yes. I really wanted him to come back to Brisbane and work in my lab, and he really wanted to come, but it wasn't that easy. He finished up his time with Lionel Crawford, but he had to get a visa to come to Australia and that wasn't easy for a Chinese national in those days – he was there with his wife, but his son was in China still, with his wife's mother, and it was not easy to get all that fixed up. He was offered a job by CSIRO during the time I was trying to get him to come to work with me in Brisbane, but he really didn't want to go to them because they wanted him to work on something which wasn't of particular interest to him. Fortunately, he stuck it out and waited till I could get him a visa so that he could come and work on what he wanted to work on, papilloma viruses, and he came out about six months after I returned from sabbatical.
When did it occur to you both that a vaccine was possible?
Well, we set out to build reagents to work on the immune response and perhaps also on a vaccine, because even before I went to Cambridge I'd already been working on trying to get a vaccine to treat papilloma virus infection. We wanted to actually build the papilloma virus itself. We knew we couldn't grow it in the lab (other people had tried and failed) and we pretty much thought we knew why – although we were actually wrong about that too. We had the wrong reason. Anyway, it was clear that it wasn't going to work.
So what Jian set out to do, with my encouragement, was to try to make an infectious papilloma virus. And in due course, after about three years, he did that. But as part of that we really wanted to make the shell of the virus. We thought that that would be quite hard, but it turned out to be even harder than we imagined. Jian, however, had the ability to express viral genes using vaccinia virus, and that turned out to be a great asset, because of all the expression systems that we might have tried to do that work, only vaccinia worked. If we'd tried any of the other common expression vectors that people were playing around with at that time, it would have failed – for a whole range of reasons which Jian subsequently went on to discover and map out over the course of the six or eight years that he worked with me, and then in collaboration with me when he went overseas.
Vaccinia virus worked, and we made progress once we'd twigged to the fact that we needed to start expressing the viral gene from a start point different from the one that was self-evident from the sequence of the virus. I can remember actually writing the sequence out on bits of paper! Nowadays you'd get a computer to do it, but in the lab in those days we had an Amstrad which we cursed at because it never worked and we couldn't get it to do anything. So we worked on the sequence manually and decided that maybe the right place to start the gene expression from was the bit downstream of the initial start codon. Then Jian had the idea that if we put in the L2 capsid protein at the same time as the L1 capsid protein, maybe that would lead to better expression of L1 and it might form a virus-like particle. All that turned out to be true and it did, and in about March 1991 we eventually got this picture of the virus-like particle, the 'skin' of the virus.
The really interesting thing was not expressing the L1 protein – I had managed to do that, others had managed to do that, Jian managed to do that, and we all got the same result: we got the protein but it didn't assemble itself. What Jian managed to do with the various tricks that we put together was to get the L1 protein to assemble itself to make the shell of the virus.
Was this shell capable of looking at the 'universal' virus? We have hundreds of them to consider, so how do you narrow it down to get a vaccine that knocks them all off?
Well, we don't get a vaccine from that which knocks them all off. What we got was a vaccine. When we saw the shell, we knew we had the potential to make a vaccine, because I was aware that vaccines, to work, had to mimic the shape – not the protein sequence but the physical shape – of the virus. So as soon as we got something that looked like the virus, we were pretty sure that could be the basis of a vaccine. We didn't know it would work, but what we did know was that if there was going to be a vaccine, that would be how it would be made. (We couldn't make a vaccine by the conventional means, because if you can't grow the virus you can't make an attenuated virus, and neither can you make a killed virus.)
An edited transcript of the full interview can be found at http://www.science.org.au/node/325881.
Focus questions
Select activities that are most appropriate for your lesson plan or add your own. You can also encourage students to identify key issues in the preceding extract and devise their own questions or topics for discussion.
Related publication: The Science of Immunisation: Questions and Answers
capsid protein
cervical cancer
gene expression
immunology
papilloma virus
vaccine
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