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Exploring the unknown: the challenges of a career in biomedical research

Gordon L Ada
Med J Aust 2000; 173 (11): 612-615.
Published online: 4 December 2000

The Research Enterprise

Exploring the unknown: the challenges of a career in biomedical research

Gordon L Ada

Gordon Ada reminisces on his career as a researcher and a facilitator

MJA 2000; 173: 612-615

Getting started - Walter and Eliza Hall Institute, Melbourne - John Curtain School of Medical Research, Canberra - World Health Organization, Geneva - Retirement projects - The take-home message? - References - Authors' details

- - More articles on Immunology and allergy


  The attractions of a career in research are many, but first among these is the opportunity to be involved in important discoveries, either personally or though close association with other researchers. Experimenting first with viruses and then in immunology at the Walter and Eliza Hall Institute (1948-1968) was a great start. Later, by becoming head of a world-class microbiology department at the John Curtin School of Medical Research at the Australian National University, I was able to establish an environment that spawned important discoveries in medical science.



Getting started

I had a happy childhood. I was the fourth in a family of six children -- three boys and three girls. My father studied electrical engineering at Sydney University and later became a senior executive with the New South Wales Railways, but my mother had to leave school early when her mother died. When I entered Sydney University in 1940, my aim was to study biochemistry, having received a fascinating book the previous Christmas -- The science of life, by H G Wells, Julian S Huxley and G P Wells.

My years at university might not have been so enjoyable if Jack Still had not returned to Sydney University in 1941 from Gowland Hopkins' Biochemistry Department at Cambridge. He enthused us with stories about the exciting research being done there.

My first research position at the Commonwealth Serum Laboratories (CSL) (1944-1946), studying ways of stabilising human serum and avoiding denaturation, convinced me of the need for new techniques to isolate and study individual proteins. I applied for leave from CSL to work at the National Institute of Medical Research in London, where moving-boundary electrophoresis and ultracentrifugation were being used for this purpose. This request, although supported by the Director of CSL, Frederick G Morgan, was refused at a higher level, so I resigned, travelled to England, and worked unpaid at the Institute with Arthur S McFarlane, Head of the Biophysics Department. After a few months, McFarlane recommended my paid appointment to the research staff.



Walter and Eliza Hall Institute, Melbourne

In the early 1940s, Macfarlane Burnet, Director of the Walter and Eliza Hall Institute (WEHI), on a visit to Harvard University to give the Dunham Lectures, saw the need for his institute to gain these new techniques for studying proteins. He obtained a government grant of £20 000 to establish the technologies (including, later, electron microscopy) at the WEHI. As there was no expertise in Australia, Burnet invited me to join the staff at the WEHI and, with the senior biochemist, Henry Holden, to set up moving-boundary electrophoresis and ultracentrifugation. I arrived back in Australia in August 1948. Fortunately, Holden did much of the establishing and I was able to spend most of my time on research. I became a virologist, working mainly with influenza and later Murray Valley encephalitis viruses, studying their composition and biological properties. I crystallised the Vibrio cholerae neuraminidase.

In 1957, after publication of his clonal selection theory,1 Burnet decided to phase out virology in favour of immunology at the Institute. In 1962, I decided to make the switch and, after much reading, began studying immune responses, in particular the fate of tiny amounts of antigen (using the highly immunogenic Salmonella flagella and flagellin labelled with radioactive iodine) to establish the nature and location of cells which bind antigen.

Because of my general ignorance of this field, I asked Gus Nossal, then the Deputy Director (Immunology) at the Institute, to help me get started. He kindly agreed, but, when the first autoradiographs showing localisation of antigen over rat primary lymphoid follicles (Box 1) were so striking, Gus decided to collaborate full-time. When presented at a meeting in the United States, our findings ranked a column in the New York Times.

The next six years studying the fate and role of antigen during primary and secondary immune responses were like a taste of researcher's heaven, and Gus was a great colleague. We studied 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.2

All these findings, together with studies on the influence of antigen structure on immunogenicity with a new PhD student, Chris Parish, were published individually and then finally woven into a monograph.3



John Curtain School of Medical Research, Canberra

Despite the attractions of working at WEHI, an invitation to head a department with an international reputation in virology was too exciting to refuse, and in 1968 I succeeded Frank Fenner as Head of the Department of Microbiology at the John Curtin School of Medical Research.

Although much was known about the humoral response to viral infections, knowledge about cell-mediated immune responses was almost non-existent. I reasoned that research projects combining both virological and immunological approaches, supported by basic research in both these fields, would surely lead to some exciting findings. This turned out to be the case. For example:

  • In 1972 Chris Parish was the first to show the inverse relationship between antibody and cell-mediated immune responses, which led others to describe two classes of helper T cells.

  • Bruce Stillman's studies on adenovirus in 1978 started him on the road to becoming Director of the renowned Cold Spring Harbor Laboratories in New York State.

  • Robert Blanden was to lay the foundations for a major finding. Our department was acknowledged as a world leader in poxvirus research,4 and Blanden was studying the immune response to ectromelia, a poxvirus pathogenic for mice. In the next few years, using technology for assaying the newly discovered cytotoxic T cells gleaned from overseas meetings, Blanden, in late 1972, became the first to show that cytotoxic T cells would kill cells infected with ectromelia virus. But how did these cells recognise virus-infected cells? Early indications were that major histocompatibility (MHC) antigens were involved in some way, so some inbred mouse strains (members of the same strain having identical MHC antigen specificities) were imported to facilitate further studies.

  • Peter Doherty came to the department as a postdoctoral fellow in 1972, and started work on lymphocytic choriomeningitis (LCM) virus infections of mice. In early 1973, Rolf Zinkernagel, a Swiss medical graduate, worked for a while with Blanden to learn about assaying cytotoxic T cell activity. I then asked Doherty and Zinkernagel to share the same laboratory, as they clearly had similar research interests. In some very elegant experiments, they found that cytotoxic T cells formed during an LCM viral infection would only lyse infected target cells if effector and target cells shared at least some MHC antigen specificities (ie, 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.5 They proposed the fundamental concept -- that a central function of MHC antigens on cells was to signal changes in "self", to what they now called "altered self", to the immune system.6 Once identified, such a cell would be lysed.

This finding stimulated much research both in the department and elsewhere, and studies investigating the details of MHC restriction of T cell responses became a leading immunological topic internationally. Needless to say, Zinkernagel was awarded a PhD scholarship and graduated in record time. Both he and Doherty left to work overseas in the mid-1970s. Subsequently, analysis of crystals of MHC molecules, isolated from the surface of infected cells by US researchers, showed a viral peptide occupying a cleft in the MHC molecule so that parts of each were recognised by the cytotoxic lymphocyte receptor (Box 2).

The award of the 1996 Nobel Prize in Physiology or Medicine to Rolf Zinkernagel and Peter Doherty (Box 3) 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.



World Health Organization, Geneva

For 20 years, from 1971, I became associated with different World Health Organization programs, concerned mostly with the development and use of vaccines (Box 4). I was the first Chairman of the Programme for Vaccine Development (1984-1989), which is now a much larger WHO program with Gus Nossal as Chairman. These experiences focused my own research towards defining the roles of different components of the immune response to viral infections.



Retirement projects

As I approached retirement (December 1987), I was invited to do a six-month consultancy at WHO (to plan for a major review of studies on developing a vaccine to control pregnancy in women), to spend my retirement at Johns Hopkins School of Hygiene and Public Health in Baltimore, and to give the plenary lecture on The prospects for HIV vaccines at the Fourth International AIDS Congress in Stockholm in May 1988. I had never worked with HIV, but the Swedes apparently wanted an "independent" opinion.

Stockholm

By 1986, HIV RNA had been largely sequenced, and there was great optimism that a vaccine could be developed quickly. However, in the next two years, several disturbing findings were made, especially the very great sequence variation of the envelope antigen in different HIV isolates. There are three desirable properties of an infectious agent which can facilitate vaccine development (Box 5). At the Stockholm lecture,7 I listed seven reasons why it would be very difficult to develop an HIV vaccine based primarily on strong infectivity-neutralising antibody formation (Box 5).

I then drew on recent research by two of my colleagues, David Boyle and Ian Ramshaw, at the John Curtin School of Medical Research. They had shown that DNA, coding for antigens of other infectious agents and of cytokines, could be inserted into the DNA of a poxvirus, such as vaccinia virus. Vaccination with this "chimeric" virus could protect against infection by the agent which was the source of the inserted DNA. I therefore 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.7 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 8000-strong audience was largely stunned by my assessment of the situation, although none subsequently disputed it. However, major vaccine manufacturers ignored it, determined to make an antibody-inducing subunit vaccine based on the HIV envelope antigen, a strategy driven by the success of the hepatitis B viral vaccine which contains the surface antigen of that virus.

Baltimore and 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 (DAIDS) of the National Institute of Allergy and Infectious Disease. In 1991, after three years in the United States, my wife and I decided to return to Australia, but I was invited to continue the relationship with DAIDS and to join a new HIV Vaccine Working Group. The crunch came in 1995, when the Director of the US National Institute of Allergy and Infectious Disease 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 HIV vaccine research. The National Institute of Allergy and Infectious Disease completely revamped its HIV vaccine development program, and my hectic travel schedule to and from the United States 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.8

Return to Canberra

In 1991, I was appointed Visiting Fellow in the (now) Division of Immunology and Cell Biology at the John Curtin School and Chairman of the HIV Vaccine Working Group, one of the committees of the National Centre in HIV Epidemiology and Clinical Research 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 at the University of Melbourne) and Ramshaw and their colleagues showed that Macaca nemestrina monkeys immunised in this way developed a strong cytotoxic T cell response and rapidly cleared a subsequent HIV infection.9 Any antibody induced was irrelevant. Supporting findings for this approach were later reported from the United States.

Now Australia was set to develop an HIV vaccine initiative based on this vaccination technology. At a meeting of the HIV Vaccine Working Group, David Cooper, Head of the National Centre in HIV Epidemiology and Clinical Research, was elected to head an Australian HIV Vaccine Consortium.

In June this year, out of 20 international applications received, the National Institute of Allergy and Infectious Disease awarded four contracts, three to US groups and the fourth to the Australian consortium ($27 million over five 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. Thus, those infected by HIV will live longer and be much less likely to infect others.

If this vaccination technology can be shown to generate strong cytotoxic lymphocyte responses in humans, it heralds a new approach to controlling other difficult infectious diseases, such as malaria, trachoma and pelvic inflammatory disease, and even pandemic influenza.



The take-home message?

From a career path in biochemistry, I switched to virology, then to immunology and became an enthusiastic supporter for the application of immunisation technology, not only for the more difficult infectious diseases but also for non-communicable diseases. Young researchers should jump at the chance to switch fields when exciting opportunities arise.

Acknowledgement: I wish to acknowledge with gratitude the great support of my wife, Jean Ada, during my career.


References

  1. Burnet FH. A modification of Jerne's theory of antibody production using the concept of clonal selection. Aust J Sci 1957: 20; 67-69.
  2. Macfarlane Burnet I. Walter and Eliza Hall Institute, 1915-65. Melbourne: Melbourne University Press, 1971.
  3. Nossal GJV, Ada GL. Antigens, lymphoid cells and the immune response. New York: Academic Press, 1971.
  4. Fenner F. Nature, nuture and my experience with smallpox eradication. Med J Aust 1999; 171: 638-641.
  5. Zinkernagel RM, Doherty PC. Restriction of in vitro cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semi-allogeneic system. Nature 1974; 248: 701-702.
  6. Doherty PC, Zinkernagel RM. A biological role for the major histocompatibility antigens. Lancet 1975; 1: 1406-1409.
  7. Ada GL. Prospects for HIV vaccines. J Acquir Immune Defic Syndr 1988; 1: 295-303.
  8. Ada GL, McElrath MJ. Perspectives. HIV type-1 vaccine-induced cytotoxic T cell responses: potential role in vaccine efficacy. AIDS Res Hum Retoviruses 1997; 13: 243-248.
  9. Kent SJ, Zhao A, Best SJ, et al. Enhanced T-cell immunogenicity and protective efficacy of a human immunodeficiency virus type 1 vaccine regimen consisting of consecutive priming with DNA and boosting with recombinant fowlpox virus. J Virol 1998; 72: 10180-10188.



Authors' details

John Curtin School of Medical Research, Australian National University, Canberra, ACT.
Gordon L Ada, AO, DSc, FAA, Emeritus Professor, and Visiting Fellow in the Division of Immunology and Cell Biology.

Correspondence: Professor G L Ada, John Curtin School of Medical Research, P O Box 334, Canberra, ACT 2601.


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1: Antigen in the immune response
Image of antigen
Autoradiograph showing localisation of antigen over primary lymphoid follicles of rat popliteal lymph nodes, after footpad injection of Salmonella flagellin labelled with radioactive iodine.
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2: The function of major histocompatibility antigens
Diagram of the cytotoxic T lymphocyte
Schematic diagram of the cytotoxic T lymphocyte receptor recognition of the complex between the major histocompatibility antigen molecule and a nonapeptide derived from an infectious agent protein expressed on the surface of the infected cell.
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3: At the 1996 Nobel Prize awards
Photo of Gordon Ada
Evening banquet after the awarding of Nobel Prizes, Stockholm, December 1996. From left to right: Gordon Ada, Peter Doherty and Frank Fenner at the display of Nobel Prize medals and citations (photograph courtesy of Peter Pockley).
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4: Involvement with World Health Organization programs
1971-1973 Member, Fellowship Selection Committee
1973-1976 Member, then Chairman (1975-1976), Scientific Council, International Agency for Research on Cancer, Lyons, France
1978-1984 Member, Scientific and Technical Advisory Committee, Tropical Diseases Research
1981-1984 Member, Global Advisory Committee on Medical (Health) Research
1984-1989 Chairman, Scientific Advisory Group of Experts, Programme for Vaccine Development. Member and later Consultant (1988), Vaccination Committee, Human Reproduction Programme
1985-1988 Member, Regional (Western Pacific) Advisory Committee on Health Research
1987-1989 Member, Research and Development Group, Expanded Programme on Immunization
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5: Factors for and against the development of an effective vaccine
Factors favouring the development of an effective vaccine
  • Only one or a few strains of the infective agent exist; little or preferably no antigenic variation within a strain.
  • Infective agent causes an acute infection; host completely recovers from a sublethal dose of the agent; agent does not persist.
  • Agent is moderately (rather than highly) infectious
  • .
Factors militating against development of an effective vaccine (all these factors apply to HIV)
  • Great antigenic variation; antigenic drift.
  • Integration of viral DNA/cDNA into the host cell genome.
  • Infection may be transmitted by cells which are latently infected.
  • Immune enhancement: antibody can enhance infection of macrophages/monocytes if these cells are susceptible to infection.
  • Agent infects cells in immunoprivileged sites in the host.
  • Crucial cells of the immune system are infected, and either destroyed or their function is impaired.
  • Failure to produce protective antibody and/or persisting cell-mediated immunity responses.
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Received 20 September 2018, accepted 20 September 2018

  • Gordon L Ada


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