Deck the Hall -- the Walter and Eliza Hall, that is

Australia's best-known and most venerable medical research institute, The Walter and Eliza Hall Institute of Medical Research in Parkville, Melbourne, celebrates its 90th anniversary this year. Graeme O'Neill interviewed the Hall's former director, Prof Sir Gustav Nossal, and his successor, Prof Suzanne Cory, about the institute's history and their view of science in Australia today.

O'Neill: What do you consider the most significant developments at the Institute during each of your terms as director of the Hall Institute?

Nossal: There were three. The first began when Ray Bradley [University of Melbourne] sought Don Metcalf's collaboration. This led Don to discover the so-called colony-stimulating factors (CSFs), which regulate the growth of white blood cells and which are now used as adjuncts to cancer chemotherapy and radiotherapy. Total CSF sales to date exceed US$20 billion and have benefited over 5 million patients worldwide. It's a wonderful story of integrated discovery from the lab bench to clinical and developmental research and right to the patient's bedside. Don has had over 300 scientific collaborators over a 40-year period, and has created a whole school.

The second major development was the clear-cut delineation of B-lymphocytes from T-lymphocytes, initiated by Noel Warner, but spearheaded by Graham Mitchell and Jacques Miller. B cells make antibodies and T cells help to do the job. T cells secrete lymphokines, which stimulate the B cells through a close physical association.

The third set of achievements was initiated by Ian Mackay. A large group of diseases including diabetes, multiple sclerosis, rheumatoid arthritis, chronic liver diseases, thyroid and other endocrine diseases are due to destructive autoimmune processes. Mackay was the first person who clearly articulated that there is such a thing as autoimmune disease, and he categorised them in highly intelligent ways. Ian is now an adjunct professor of medicine at Monash University but he still spends his reading time here at the Hall Institute's library and is a wonderfully young 83-year-old.

Cory: You have failed to mention your own tremendously important contributions to immunology over 40 or so years -- including the first experimental verification of Burnet's clonal selection theory! Many streams of work begun at WEHI during the Nossal era have continued to grow and flower.

The discovery of the CSFs, initiated by Don, led to the study of CSF receptors, and how CSFs signal in cells. Nick Nicola, Doug Hilton, Warren Alexander and their colleagues have done tremendously important work in this area. They are now probing, through mutagenesis experiments, the genetic regulation of blood-cell production: how CSFs regulate the positive pathways and how negative signalling through the SOCS protein family stops cells dividing. So the haematology stream continues to prosper, and has spawned or attracted excellent young scientists.

The autoimmunity theme has also flourished. When he succeeded Ian Mackay, Len Harrison began a major program on type 1 (juvenile) diabetes and identified key self-antigens involved in the autoimmune destruction of pancreatic islets. This led to reliable preclinical diagnosis of disease and now the group is engaged in clinical trials to prevent the onset of juvenile diabetes in susceptible individuals.

Another area that started during Gus's directorship was malaria research, under Graham Mitchell. Gus secured the initial funding from the Rockefeller Foundation, and then from the Macarthur Foundation, and it grew to become a major enterprise in the Institute.

When it began, we had no knowledge of the molecular biology of the malaria parasite. David Kemp worked out how many chromosomes it had, and with Robin Anders began cloning potential vaccine candidates. We still don't have a vaccine...

Nossal: but we're creeping slowly towards one!

Cory: ...and there has been a wonderful second flowering of that group under Alan Cowman They have just pulled in new funding through Howard Hughes International Fellowships, the Wellcome Trust and the Bill and Melinda Gates Foundation, and have been described as the best malaria group in the world.

[In the wake of the Hall Institute's recent quinquennial review, by an international panel headed by Australian Nobel Laureate Professor Peter Doherty, panel member Prof Fotis Kafatos, former director of the European Molecular Biology Laboratory, was asked where the Hall Institute ranked among the world's malaria research institutions. He replied, "It's simply the best in the world."]

Another major area of progress has been the molecular genetics of cancer, which started under Gus. He threw his full support behind Jerry [Cory's husband and long-time co-worker, Prof Jerry Adams] and me when we decided to switch from the molecular genetics of the immune system to cancer. We discovered that the chromosomal translocation that causes Burkitt's lymphoma activates an oncogene called myc and, together with Alan Harris, proved in a mouse model that myc activation was the critical event that precipitates this cancer. This discovery provided the paradigm for others to identify oncogenes activated by other chromosome translocations in leukemia and lymphomas, including bcl-2, the gene activated in follicular lymphoma.

Quite unexpectedly, David Vaux, then a PhD student in our lab, showed that Bcl-2 was unlike any of the other known oncogenes at that time. Rather than encouraging exuberant cell growth, Bcl-2 triggers cancer by preventing cells from dying. This discovery broke open the whole field of apoptosis research, which is now huge internationally. And I am proud to say that our consortium of collaborating labs -- which includes those of Adams, Strasser, Vaux and Huang -- leads the world in this arena.

Very excitingly, together with WEHI's structural biologists and medicinal chemists, headed by Peter Colman, and with funding from the Leukemia and Lymphoma Society in the US, we are now applying our knowledge of the Bcl-2 family of proteins to try to develop more effective cancer drugs.

Nossal: You get an initial breakthrough, and then there's a long pathway of exploration, where it's mined for the next 25 to 50 years. The Hall has been remarkably successful. The biggest problem for the Institute is the success of its component parts -- there have been very few 'dry wells'.

Going back to the 1960s, another immunological hero is Ken Shortman. Nature is a strange mistress, and she guards her secrets jealously. I was lucky, when I was working with Gordon Ada, to discover a new type of cell, the follicular dendritic cell, which turns out to be the cornerstone of immunological memory. We pinned this right down between 1963 and 1968.

When Gordon left the Institute, after a great five years and 25 papers, we both went on to do other kinds of work. In 1973 an American, Ralph Steinman [Rockefeller University, New York] discovered an even more important dendritic cell, which is the initiator of all immune responses - it is responsible for the initial capture of the antigen, and for the activation of T lymphocytes, which in turn activate B cells.

The follicular dendritic cell is a specialised version of the dendritic cell -- its lineage is still unclear, but it comes from the bone marrow. Enter Ken Shortman, who has spent his whole life purifying cells, discovering the relationships between cells, and exploring the fine sub-categories of cells. With Wu Li, he begins to define the different dendritic cell subsets and their relationships. Some say that, at 68, Ken is now doing the best work of his career.

Another major development was Mac Burnet's clonal selection theory -- as a PhD student, I had a role in experimentally verifying his theory. This involved terribly difficult micromanipulation to culture single cells but to our delight we found that it was one B cell, one antibody -- Burnet's theory underpinned the development of monoclonal antibodies. The 50th anniversary of his clonal selection theory is coming up in 2007.

Cory: Fast-forward to the Human Genome Project. It's had a huge impact on all of the life sciences, and we were well prepared to take advantage of that. We built a bioinformatics capability, under Terry Speed (who still spends half his time at Berkeley) that continues to grow in importance and impact, and thanks to people like Simon Foote [recently appointed as director of the Menzies Research Institute for Public Health in Hobart, but still working at the Hall Institute until January] we're in the vanguard of research into the genetics of complex human diseases such as juvenile diabetes. It's one of those stories where the science has proved to be much harder than anyone anticipated, and progress internationally has not been as fast as people anticipated, but it will break one day.

O'Neill: What makes the Hall Institute such a desirable place to work, and why has it been so successful?

Nossal: Our senior appointments have just been spectacular. They're constantly being head-hunted, because they're world class.

Cory: What makes it so successful is its star scientists. Why do they come in the first place? And what keeps them here, when they're continually being offered senior positions in the US and Europe? It's the quality of the intellectual environment, and the resources they find here.

The intellectual environment has its origins in the Burnet era. We owe a tremendous debt to Mac Burnet, because he started doing science in Australia at a time when his peers were still fleeing to the UK and staying there. He started a tradition, and a family tree of science, and Melbourne has benefited. Brilliance attracts brilliance.

The second essential requirement is to have access to state-of-the-art technologies. This is where Gus changed the nature of the Institute forever -- it became a very different place from the Institute of Burnet's era, a very modern place. And we are still continually importing, ahead of time, the latest frontier technologies, which allow our scientists to compete internationally.

There is another aspect that is not as easy to pinpoint -- it's a family spirit. This really is an organisation that becomes part of you, people have huge respect for it, and cherish it. We owe this tradition to Gus and I've tried to continue it. There's great loyalty, and our faculty, on the whole, stay for a very long time. There isn't a big turnover. We're very careful who we appoint, we choose the best, and try to keep them. Australia has a million expatriates overseas, and there are wonderful opportunities overseas. We have to be continually aware of that, and create conditions that make it so attractive that people want to live back here. Unless they find the right environment, they won't.

Nossal: There's a heavy emphasis on youth, and we have a high turnover of junior researchers -- PhDs and postdoctoral researchers. The high turnover is a good thing -- in this way, the Hall Institute has populated Australian academia in a remarkable way.

O'Neill: What about Hall Institute researchers who didn't pursue their careers in Australia?

Nossal: There was Marc Feldmann, who started his PhD on B-lymphocytes in my lab in 1968. We made the mistake of sending him to one of the best immunologists in the UK, and they made him a professor at a ridiculously young age. He was responsible for the 20th century's second-biggest discovery in rheumatology (the first was cortisone) -- the role of TNF-alpha in the inflammatory response. Now several big drug companies are marketing anti-TNF monoclonal antibodies or receptor decoys, and giving wonderful benefit to patients with advanced rheumatoid arthritis -- and incidentally making not a little money out of it!

Cory: Two other alumni who have had incredibly successful careers overseas are Prof Richard Stanley [brother of former Australian of the Year Prof Fiona Stanley], who did his PhD with Don Metcalf and has been for many years a leading scientist at the Albert Einstein College of Medicine in New York, and immunologist Prof Jonathon Sprent, recently returned from the Scripps Institute in California to the Centenary Institute as a Federation Fellow. How has science, and research, changed in recent decades?

Nossal: There have been enormous changes, in three areas. The first relates to the role of the individual in research. In the 1950s and 1960s, single-author papers were the norm -- I was sole author on all of my early papers. It was a time when one person could make a discovery, and then follow it with simple technologies. But the increasing sophistication of science, and the complexity of research challenges, means this is no longer possible. There's now a need for group-think, and collegiality, and a set of research skills. Laboratory heads these days are part researcher, part entrepreneur -- they're dragged out of the laboratory to find money for their research.

The second relates to the first: it's the march of technology. Today you can walk into a laboratory and see half-million-dollar research robots at work. You're dead in the water without them, because they're platform technologies, and they require highly skilled technical support -- the technical assistants are often PhDs themselves.

The third change is the commercialisation imperative. That's been a big change as we moved from little to medium to big science, and the demands on the public purse have grown enormously -- take the synchrotron, for example. [Victoria's new synchrotron, now under construction in Clayton, will cost nearly $200 million].

Post-genomic science is five times more expensive. Today we no longer work with single genes, we study the entire genome with microarrays, and it's expensive. It's quite understandable that society wants to get a commercial dividend from that. And scientists would wish to see their work flowering. People like Burnet and [Australian nuclear physicist Sir Marcus] Oliphant worked in theoretical fields, and they had little feel for what commercialisation is, in the broad sense. After I gave the Oliphant Lecture 20 years ago, Sir Mark told me he was against the whole business of patenting. So was Burnet -- it was just a different mindset back then.

We're still on a fast learning curve. In our deepest heart of hearts, the whole idea of patenting before we publish is counter to our instincts. On the other hand, we have to be realists, we have to understand this is a continuum, the bridge between academia and industry -- if you've gone so far, you need a commercialising partner, but I think we're still not doing it optimally.

Cory: We certainly need to recognise our responsibility for commercialisation, but our primary reason for engagement is that this is a necessary step for translating discoveries into better health. The real driving force is better health -- that is the higher-order goal.

Two years ago we held a retreat, where we challenged faculty to think about the future, and what we need to invest in to strengthen the Institute. The unanimous view was that we need to do even more to translate discoveries into clinical practice -- this will be a major theme for our next 10 years.

In Burnet's era, it was much easier to have a very strong bridge between the Institute and the hospitals, but science has become more complex, and funding in the public hospital system has become much more difficult. We recognise that WEHI needs to become more proactive, to create an environment that actively seeks to build bridges to the clinic.

We are therefore planning to create a new centre for translational research. We've also invested a lot of time helping to establish the Victorian Cancer Tissue Bank, which has recently been funded by the Victorian Government. We want all cancer researchers to have access to it, in order to greatly improve diagnosis and treatment. A quarter of a century of research into the molecular biology of cancer is now starting to bear fruit -intelligent medicines, based on the real causes of the disease, are starting to emerge. All of us sense a new era of medicine emerging, the era of targeted therapies.

Over the next decade, I want to double the size of the institute. In 1985, Gus designed the institute to house 272 staff in comfort, with 364 as the upper limit. We're now well over 500, and we support another 120 in satellite centres, including our new annexe at La Trobe University's Technology Park.

I believe that, to be competitive on the national and international stage, we need to be larger. We compare ourselves with the Salk Institute, the Whitehead Institute and Cold Spring Harbour, which have around 1000 scientists each, and budgets around three to four times the size of ours. We need more space to provide lebensraum for the upcoming generation of star scientists!

O'Neill: What are the qualities of a star scientist?

Cory: A passion for science. Originality. Ability to think laterally. And huge commitment -- forget the 35-hour week. There's also a bit of luck in it, as Gus mentions. Ability to work in multidisciplinary teams, and to inspire others to work with you. None of our stars are alike, yet everyone knows who they are. There are many ways of excelling -- look at the huge differences between Fred Sanger and Francis Crick, one a brilliant bench scientist, the other a brilliant theorist. Some are obviously brilliant, others have a slower trajectory of growth and maturation.

O'Neill: Brilliance tends to come with ego. As director, how do you manage that?

Nossal: The tremendous thing that Burnet taught me was to give credit where credit is due. You have to be generous -- Don Metcalf, for example, is a unique researcher but he always gives credit to all the people who have worked with him over the years.

Cory: In big collaborative endeavours, it is important that everyone has a part of the project that 'belongs' to them, their own niche. I would never countenance putting two people on the same project and asking them to compete.

O'Neill: The Hall Institute has won an extraordinary number of major research grants for malaria in recent times. How did it become pre-eminent in malaria research?

Nossal: It goes back to 1964, when I was first asked to join a committee of the World Health Organisation. In 1971 I was invited to join their central research group -- the WHO Advisory Committee on Health Research. It was heady stuff -- three or four Nobel Laureates, and distinguished people from the third world. It was a tremendous privilege to serve on it, and it made me think about global health problems.

Burnet had also done so, to a certain extent. He was influential in establishing the Papua New Guinea Institute of Medical Research. Then there was the happenstance of Graham Mitchell needing to find a goal beyond cellular immunology -- that was a definite impulsion point.

For me, the acme was my desire to get more involved with health problems in the third world. In 1976, I spent a whole year in WHO's Tropical Disease Research Program, and we were highly successful raising funds from international donors -- $30 million a year for the following decade.

There are many tropical parasitic diseases, but by far the worst is malaria, followed by schistosomiasis and filariasis. It seemed very logical that if Graham Mitchell wasn't going to devote his career to cellular immunology, he should run a human parasite program.

We tried to purify parasite antigens, but weren't getting very far until Rob Saint, who had been working at Stanford University, brought back a technique for expression cloning antigen genes in E. coli bacteria.

Robin Anders and David Kemp made the breakthrough with malaria parasites and human sera from Papua New Guinea, and all of a sudden the bottleneck that had blocked us for two years broke, and we had a surfeit of antigenic riches -- loads of 'cloned' pure antigens. We owe a tremendous debt to Robin and David -- but it's just a part of the incredibly proud history of malaria and parasitology research in Australia.

This really goes back to 1928, when the Hall Institute's assistant director, Sir Harold Dew, discovered the key facts of hydatid disease [a parasite that infects pigs, dogs and humans]. Then Sir Neil Hamilton Fairley helped the war effort by discovering that if you pop an atabrin pill -- it prevents malaria. It was much more toxic than chloroquine, and it turned your skin bright yellow. Malaria killed 10 times more Aussies in New Guinea than did Japanese bullets.

Modern malaria research began at the Hall Institute in about 1980, and it grew into a mighty stream. We started with good people, and we've trained many others, some of whom have gone on to other institutions, but we continue to be very strong.

The motivation is the same ideation that drove Bono and Bob Geldof at Gleneagles: it's just not right that a third of humanity is deprived of proper health. It's been absolutely remarkable since Bill and Melinda Gates came in and started empowering researchers through the world's largest foundation.

Cory: We must give credit to our politicians who have been very pleased to support malaria research. It's an important international contribution, because we're sitting in a part of the world where our northern neighbours suffer from malaria.

O'Neill: Where do you both see research taking us over the next few decades?

Cory: We're going to see wonderful new anti-cancer drugs emerging, and many types of cancer will become a manageable. I think we're entering the era of molecular medicine, and intelligent medicine.

Nossal: As a non-genomics, non-molecular biology person we haven't even begun to scratch the surface of what the Human Genome Project means. There's a lot of hue and cry, but with each passing year, we realise more profoundly what this dictionary and encyclopaedia really mean. The first advances from genomics will be more powerful and intelligent drugs, and vaccine developments are also very imminent through genome mining.