Professor Gordon Ada

Professor Gordon Ada (1922-2012)

My real research career began in mid-1948 when at Macfarlane Burnet's invitation, I joined the staff of the Walter and Eliza Hall Institute (WEHI) to help establish the biophysical techniques, moving boundary electrophoresis and ultracentrifugation.

I had learnt to use these during two years (1946-8) in London. But I was able to spend most time doing research. I became a virologist, working mainly with influenza and Murray Valley encephalitis viruses, studying their composition and biological properties, especially the nature and role of the nucleic acids. I crystallized the neraminidase of V cholerae. In 1957, after publication of his Clonal Selection Theory, Burnet decided to phase out Virology in favour of Immunology in the Institute.

I decided in 1962 to make the switch and after much reading, to study the fate of tiny amounts of antigen, using the highly immunogenic Salmonella flagella and flagellin labelled with radioactive iodide. Because of my general ignorance of this field, I asked Gus Nossal to help me get started. He kindly agreed, but soon decided to collaborate full time.

We studied the fate and role of antigen during primary and secondary immune responses, the role of antibody in antigen localisation and demonstrated the absence of antigen in antibody-forming cells. Burnet later wrote -"What I can be certain about however, is the immense importance of the work on the cellular localisation of antigen led by Ada and Nossal in the 1962-5 period". All these findings together with studies on the influence of antigen structure on immunogenicity with a new student Chris Parish were individually published and then finally woven into a broader story in a monograph.

Canberra

I was invited to succeed Frank Fenner as Head of the Department of Microbiology at the John Curtin School and took up the position in late 1968. Though much was known about the humoral response to viral infections, knowledge about cell-mediated immune responses was almost non-existent. I thought that if research projects combining both virological and immunological approaches were strongly encouraged, supported by basic research in Virology and Immunology, surely some exciting findings would be made. For example, Parish was the first to show the inverse relationship between antibody and cell-mediated immune responses which in turn led to the description of two classes of helper T cells by others.

Bruce Stillman's studies on adenovirus started him on the road to becoming Director of the renowned Cold Spring Harbor Laboratories in New York State. Robert Blanden was studying the immune response to ectromelia, a pox virus pathogenic for mice. In the next few years, he brought back from overseas meetings the technology for assaying the newly discovered cell population called cytotoxic T cells (CTLs). He became the first to show that this particular T cell response was responsible for clearing an ectromelia infection but information on how these cells recognised virus-infected cells was completely unknown though there were early indications that major histocompatibility (MHC) antigens were involved in some way. Some inbred mouse strains were imported to facilitate further studies.

Peter Doherty, a fresh Ph.D. graduate, came to the department as a postdoctoral fellow in 1972, and started work on lymphocytic choriomeningitis (LCM) virus infections of mice. Rolf Zinkernagel, a Swiss medical graduate, came out initially on a Swiss Fellowship but later was awarded an ANU PhD scholarship.

On arrival in Canberra in early 1973, Rolf worked for a while with Blanden to learn about assaying CTL activity and then I asked Peter and Rolf to share the same laboratory. In some very elegant experiments, they found that cytotoxic T cells formed during a LCM viral infection would only lyse infected target cells if effector and target cells shared at least some MHC antigen specificities, that is, the T cell lytic activity was 'MHC restricted'.They suggested that the cytotoxic T cell receptor recognised at the infected cell surface some virus-induced alteration of the MHC molecule, possibly caused by complexing with a viral antigen.

They proposed the fundamental concept - that a central function of MHC antigens was to signal changes in 'self' i.e.,to what they now called 'altered self', to the immune system. Once identified, such a cell would be lysed. This finding stimulated much research both in the Department and especially overseas, and studies investigating the details of MHC restriction of T cell responses became a leading immunological topic internationally. Both Rolf and Peter left to work overseas in the mid 1970s.

Until my retirement in 1987, my group studied in detail the activation and roles of T cells in murine influenza. For example, we showed that infected cells were recognised by CTLs within 1-2 hours after infection, many hours before infectious viral progeny was produced. This gave a window of time for the cytotoxic T cell to find an infected cell and destroy it before viral progeny were released and could infect other cells. Subsequently, analysis of crystals of MHC molecules isolated from the surface of infected cells by groups in the USA showed a viral peptide occupying a cleft in the MHC molecule so that parts of each were recognised by the CTL receptor.

The award of the 1996 Nobel Prize in Physiology or Medicine to Rolf and Peter recognised the importance of their original discovery, as it was the first description of the molecular mechanism used by vertebrates for the control and clearance of most intracellular infectious agents, especially viruses.

Geneva and Stockholm

For 20 years beginning in 1971, I successively became associated with eight different Programmes of the World Health Organization, most being concerned with the development and use of vaccines. These experiences caused my own research to concentrate on defining the roles of different components of the immune response to viral infections. As I approached retirement (December, 1987), I was invited to do a six month consultancy at WHO, to spend my retirement at Johns Hopkins School of Hygiene and Public Health (JHSHPH), Baltimore, by Dr. Noel Rose, and finally, to give the plenary lecture on 'The prospects for HIV Vaccines' at the Fourth International AIDS Congress in Stockholm in May, 1988. By 1986, HIV RNA had been largely sequenced, and there was great optimism that a vaccine could quickly be developed. In the next two years, however, several disturbing findings were made, especially the very great sequence variation of the envelope antigen in different HIV isolates. At the Stockholm talk, I listed 7 reasons why it would be very difficult to develop an HIV vaccine based primarily on strong infectivity-neutralising antibody formation. Two of my Canberra departmental colleagues, David Boyle and Ian Ramshaw, had shown that DNA coding for antigens of other infectious agents and of cytokines could be inserted into the DNA of a pox virus, such as vaccinia virus. Vaccination with this 'chimeric' virus could protect against persistent infection by the agent which was the source of the inserted DNA. Drawing on this recent research, I suggested that because the internal antigens of HIV, which are the source of many T cell epitopes, showed considerably less variation, a vaccine might be developed based on vaccinia virus containing the genes coding for the internal HIV antigens, gag and pol, as well as for the cytokine, interferon gamma. In mice, such a construct generated a strong cytotoxic T cell response; in man, this might be sufficient to better control, if not clear, an HIV infection. The 8,000-strong audience was largely stunned by my assessment of the situation, though none subsequently disputed it. However, major vaccine manufacturers ignored it, determined to make an antibody-inducing subunit vaccine based on the HIV envelope antigen. Baltimore, Washington. On arrival in Baltimore in July, 1988, I was warmly welcomed, made Associate Director of a new Center for AIDS Research and later became Director. In Washington, I was asked to participate in meetings and activities of the Division of AIDS (D.AIDS), of the National Institute of Allergy and Infectious Disease (NIAID). Though my wife and I decided to return to Australia in 1991 after three years in the USA, I was invited to continue the relationship with D.AIDS and to join a new HIV vaccine working group. The crunch came in 1995 when the Director of the NIAID refused to support a phase III clinical trial of the then leading HIV candidate vaccine, based on the envelope antigen. Many reasons were given but two critical ones were: Antibody from volunteers immunised with this candidate vaccine did not prevent infection by newly isolated HIV field strains; and The vaccine did not induce cytotoxic T cell formation in the volunteers. This was a major turning point in international research aimed at developing an HIV vaccine. NIAID decided to completely revamp their HIV vaccine development programme, and my hectic travel schedule to and from the USA came to an end. My last task for the Working Group was to review the evidence supporting a role for cytotoxic T cells in controlling HIV infections.

Back to Canberra

On my return, I was appointed Visiting Fellow in the (now) Department of Immunology at the John Curtin School, and appointed chairman of the Australian HIV Vaccine Working Group in Sydney. Ian Ramshaw had recently shown that a vaccination schedule involving priming with plasmids containing DNA coding for selected antigens, followed by boosting with chimeric fowlpox virus coding for the same antigens gave a greatly enhanced immune response in mice. Stephen Kent (now University of Melbourne) and Ramshaw, with colleagues, showed that M. nemistrina monkeys immunised in this way developed a strong cytotoxic T cell response and rapidly cleared a subsequent HIV infection. Any antibody induced was irrelevant. Supporting findings for this approach were later reported from the USA. It now seemed that Australia could develop an HIV vaccine initiative based on this vaccination technology. At a meeting of the HIV Vaccine Working Group, Prof. David Cooper was elected to Head an Australian HIV Vaccine Consortium. Earlier this year, out of 20 international applications received, the NIAID awarded four contracts, three to USA groups and the fourth to the Australian consortium ($AUS27 million over 5 years) to carry out clinical trials of their vaccine formulation. It is anticipated that a strong immune capability based on cytotoxic T lymphocyte activity will greatly reduce viral titres so that those infected by HIV will live longer and be much less infective for others. If this vaccination technology can be shown to generate strong CTL responses in humans, it heralds a new approach to control other difficult infectious diseases, caused by plasmodia (malaria), chlamydia (trachoma and pelvic inflammatory disease) and even pandemic influenza.

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