Aligning immunology and virology

Running a lab, directing a CRC and now a WHO Centre, Anne Kelso discusses her accomplished research career in microbiology, immunology and virology.

ALS: How did you first become interested in science?

Professor Anne Kelso: I always loved science as a child and I was interested in microbiology quite early - partly because my mother showed me things under the microscope. She studied botany at the University of Melbourne and introduced me to that amazing microscopic world when I was about nine years old.

I just had in my mind that I would be a microbiologist. I majored in microbiology at the University of Melbourne and during those years I just loved it more and more. Then I did honours and a PhD with immunologist Bill Boyle. Bill was terrific and I became passionate about immunology through my thesis work with him.

My PhD was on cytotoxic T lymphocytes and trying to understand what they see and how they are regulated. It seems very primitive looking back now compared with what we can do today but it was a time of tremendous growth in immunology. This was in the 1970s just after Peter Doherty and Rolf Zinkernagel had made their amazing discovery of MHC restriction.

I then went to Lausanne in Switzerland to do a postdoc with Teddy Brunner, Jean-Charles Cerottini and Rob MacDonald. Their lab had discovered cytotoxic T lymphocytes and developed the first assays for them, so it was a bit like going to Mecca for me at that stage of my career.

I spent three years there and had a fantastic time in the lab - that was when I felt most certain that I wanted to continue with research.

ALS: After three years in Switzerland, what brought you back to Australia?

AK: I heard Don Metcalf giving a talk in Europe and I was fascinated by his work on single haemopoietic stem cells in vitro, learning how to regulate their differentiation.

Don was visiting our institute in Lausanne and I nabbed him in the tea room and asked if I could come back to his lab. So I went to the Walter and Eliza Hall Institute (WEHI) as a QEII fellow in Don’s lab.

In Lausanne I had been looking at the production of cytokines by T cells, which was a pretty new field at that stage, so when I came back to Melbourne, Don suggested that I look at T cell production of the colony stimulating factors (CSFs).

I was there when the group cloned the granulocyte-macrophage colony-stimulating factor gene and some other haemopoietic growth factor genes. It was an exciting time in the world of CSFs because now the sequences could be understood, the regulation of production could be examined in a different way - which I proceeded to do in T cells - and large quantities of material could be produced. This meant that all sorts of experiments were possible - in the lab and in clinical trials in Melbourne. It was a brilliant time to be there and I learnt a lot.

After I had been in Don’s lab for four and a half years, I moved into Gus Nossal’s lab where I built up my own group as well as sharing some of the responsibility for looking after Gus’s students and postdocs. That was a great opportunity for me. Although clearly returning to the heartland of immunology, I developed a greater independence and widened my collaborative range.

I continued on the theme of trying to understand cytokine production by T cells - that core question of how T cells decide what to do in an immune response has been the main theme of all my personal research even up until now.

In the end I had 10 years at the WEHI. Don and Gus were wonderful people to work with - two men of very different personal and scientific styles - and I learnt a lot from them both.

ALS: What led you to develop a broader scientific career?

AK: In 1992, I moved to the Queensland Institute of Medical Research (QIMR). It was a time of change in my career in many ways and provided me with big opportunities in my scientific development.

At QIMR I built up a group where we continued working on functional specialisation in T cells in a variety of mouse models. However, I’d started to be more involved in activities outside the lab when I was at WEHI - for example, with the Australasian Society for Immunology (ASI) and the Australian Research Council’s Biological Sciences Panel, which I was on for four years from 1991. Then in 1995 and 1996 I was President of the ASI. These forays outside the lab gave me a different type of engagement with the scientific community, in Australia in particular.

From 1998 I was Secretary-General of the International Union of Immunological Societies for three years. That was a great broadening experience. In particular it got me involved in some teaching courses in developing countries in Asia and Africa and engaging in a different way with the international community of immunologists beyond the ones we tended to collaborate with.

Then the opportunity came up to apply for the Directorship of the Cooperative Research Centre (CRC) for Vaccine Technology. I’d been a member of that CRC since its inception in 1993 - Michael Good had been director from the beginning but in the year 2000 he resigned to become director of QIMR. So, in addition to having my research lab, my last six years at QIMR were also spent being director of the CRC for Vaccine Technology.

ALS: How did that work compare with being in a research lab?

AK: The role at the CRC gave me the opportunity to learn about research commercialisation, intellectual property, how to protect it and how to design experiments focused on the goal of making something useful.

It’s quite different from being director of an institute or the head of a lab. Running a joint venture like a CRC is about trying to make the family work - encouraging collaborative links, making decisions that everybody will be happy with, because you don’t have line management control in the way you would in a company, for example.

It was absolutely the hardest job I’ve done. There were some difficult times but I wouldn’t have missed the experience for the world. It was a huge growth experience and we also had a lot of fun working together.

It was semi-commercial. Most of the partners in our CRC were basic research labs - QIMR and WEHI, Monash, Melbourne and La Trobe Universities, the Australian Red Cross Blood Service (ARCBS), the Livestock Industries Division of CSIRO and CSL as our commercial partner.

Most of the work was firmly laboratory based in the universities and research institutes of the CRC. It was focused on developing prototype vaccines or immunotherapies to deal with real problems in humans or animals, particularly livestock animals.

CSL was at the table to give advice on the work and how to develop projects to become commercialisable, and then to have first option to commercialise that research if they wished. We had contracts with CSL and a number with other international pharmaceutical companies as time went on.

ALS: And you are now director of one of the WHO collaborating centres, what led you into public health?

AK: It was another one of those transition points for me and the position as director of the WHO Collaborating Centre for Reference and Research on Influenza came up at the exactly the right time.

I moved back to Melbourne in February 2007 to start the job which I currently hold. Again, it’s been a really big shift.

In the CRC for Vaccine Technology I was learning a lot about commercialisation and a somewhat different way of doing science, whereas now I’m in an arena where the goals relate directly to global public health and are not in the profit-making domain.

We have a terrific lab of people here who isolate and analyse flu viruses from around the Asia-Pacific region to monitor how flu viruses change throughout the year and from one year to the next. We do a lot of gene sequencing and antigenic analyses to understand the relationship between the flu viruses circulating in humans right now and the viruses in current vaccines.

We identify viruses that are suitable representatives of the strains we expect to be circulating in the forthcoming season. With the four other centres like ours in the Northern Hemisphere, we assist WHO in making recommendations on virus strains to go into influenza vaccines that are used worldwide, and then we make those strains available to all influenza vaccine manufacturers.

ALS: How mutable is the flu virus?

AK: This is what is so interesting about the flu virus - it has a very unstable RNA genome and mutates at quite a high rate. The main selection force for the emergence of new variants is human population immunity.

It’s a very nice alignment of immunology and virology. The human immune response drives the emergence of new variants every season or so and this means we need to update at least one of the components of the flu vaccine most years.

And in the case of antiviral drug resistance, in some cases it’s the use of the drugs themselves that drives the emergence of variance.

By monitoring the changes in influenza viruses, we can provide advice on the need to update vaccines and other important changes such as sensitivity to antiviral drugs like Tamiflu and Relenza. Then, if there is a spread of antiviral drug resistance we can alert public health authorities.

ALS: Do you maintain a hand in research?

AK: I am part of an NHMRC Program led by Peter Doherty at the University of Melbourne and I have a small lab there that continues to work on fundamental aspects of T cell immunology.

We also have quite a bit of research going on in our centre; for example, on antiviral drug resistance and in ferrets to try to understand how immunity develops in response to infection, how this can be modulated with vaccination, and how infection and vaccination can drive the emergence of new variants.

We also have a large number of collaborative links, within Australia and overseas, which allow us to spread our wings in the type of work that we do.

ALS: Can you describe what it was like to be involved in the flu pandemic in 2009?

AK: We were involved right at the beginning. The virus had apparently emerged from swine somewhere in North America and was first confirmed as a new virus in the middle of April 2009. It was Anzac Day in 2009 when we first heard that there was a significant problem and WHO started to raise the alert about the potential for a pandemic.

We heard the next day from colleagues at the National Influenza Centre in Auckland that they had a group of high school students who had returned from a trip to North America and quite a number of them had flu-like symptoms. An alert GP there realised, given where these students had been, they might have picked up this new swine flu.

The laboratory in Auckland sent us some samples to test for the new virus. At that stage there were no diagnostic tests so we went straight to gene sequencing, with some centre scientists working through the night to get the result as quickly as possible. It took about 24 hours from receiving the samples to getting the result and letting the New Zealand Ministry of Health know that they did have some H1N1 infected students, so it was really very early on in what turned out to be a pandemic.

We then prepared reference material from one of the Auckland viruses and supplied this to diagnostic labs around Australia, New Zealand and other countries in the Asia-Pacific region so that they could set up their own diagnostic tests. At that stage everybody was concerned that their flu cases might be due to this new virus and they needed to find that out quickly in case they needed to trigger pandemic plans in those areas.

It was a good test of our emergency response and the next time such an event occurs we will be better placed to be on top of it early.

I was also one of a group of people from around Australia who were on committees advising the chief medical officer and the Department of Health and Ageing on public health measures in response to the pandemic. Government, of course, makes the final decisions, but it was very interesting to be considering those issues and providing technical advice to support the policy decisions that needed to be made.

ALS: Are you concerned about the new strains of flu that are emerging?

AK: The H7N9 virus, a new one that has recently emerged in China, has been one of the most concerning events for quite a few years in the influenza world.

Our centre needs to be ready to move if this strain becomes transmissible between humans. It is apparently circulating in poultry, and when humans have been infected many have become severely ill and the death rate has been quite high.

There’s been a wave of these infections in China, particularly in Shanghai and the surrounding provinces. More than 130 cases were confirmed over about an eight-week period. So far there haven’t been large numbers of subclinical infections reported, so it seems to be a difficult virus to catch but a nasty one. In that way it is like the other bird flu, H5N1, that’s been circulating since 2003.

The reason H7N9 is such a concern is that it has a number of features that suggest it can infect mammals relatively easily, much more easily than H5N1. So it may not have to undergo many more changes to become transmissible from human to human. We are watching and waiting to see whether it acquires those changes. If it does we’ll have a serious problem on our hands.

Other WHO laboratories are working on modifying the virus so it is safe for the production of vaccine. This is well underway now so that vaccine producers will have something to work with if governments need an H7N9 vaccine at short notice.

ALS: Do you have plans for the future?

AK: I’m very happy in my role here and we have a very exciting prospect for the centre coming up. We’ll be moving into the Peter Doherty Institute for Immunity and Infection early next year with the Department of Microbiology and Immunology from the University of Melbourne and a number of other groups from Melbourne Health and the university. To be cohabiting with these other really excellent people is going to be terrific for the centre and I’m looking forward to that a lot.