The Research Enterprise
Exploring the unknown: the challenges of a career in biomedical
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? -
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.
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
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
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:
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
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
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
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:
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
- 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
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.
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.
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
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
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
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
Acknowledgement: I wish to acknowledge with gratitude the
great support of my wife, Jean Ada, during my career.
- Burnet FH. A modification of Jerne's theory of antibody production
using the concept of clonal selection. Aust J Sci 1957: 20;
Macfarlane Burnet I. Walter and Eliza Hall Institute, 1915-65.
Melbourne: Melbourne University Press, 1971.
Nossal GJV, Ada GL. Antigens, lymphoid cells and the immune
response. New York: Academic Press, 1971.
Fenner F. Nature, nuture and my experience with smallpox
eradication. Med J Aust 1999; 171: 638-641.
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.
Doherty PC, Zinkernagel RM. A biological role for the major
histocompatibility antigens. Lancet 1975; 1: 1406-1409.
Ada GL. Prospects for HIV vaccines. J Acquir Immune Defic Syndr
1988; 1: 295-303.
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.
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.
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.
|1: Antigen in the immune response
|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
|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
|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
||Member, Fellowship Selection Committee
||Member, then Chairman (1975-1976), Scientific
Council, International Agency for Research on Cancer, Lyons, France
|| Member, Scientific and Technical Advisory
Committee, Tropical Diseases Research
||Member, Global Advisory Committee on Medical
||Chairman, Scientific Advisory Group of Experts,
Programme for Vaccine Development. Member and later Consultant (1988), Vaccination
Committee, Human Reproduction Programme
||Member, Regional (Western Pacific) Advisory
Committee on Health Research
||Member, Research and Development Group, Expanded
Programme on Immunization
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|5: Factors for and against the development of an effective
|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
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