CHANGING PATTERNS

an atypical autobiography

Sir Macfarlane Burnet Heinemann

 
72 Changing Patterns

being unjustly treated and began collecting material for a mono-
graph on antibody production which the Institute could publish
without risk of veto by editors! A thoroughly immoral attitude,
but in one way and another it opened the road that led eventually
to Stockholm.

CHAPTER 7
War-time Visit to America

Looking back on the experiences which influenced my develop-
ment as a professional investigator in infectious disease of man
and the field relevant thereto, I must place a lot of importance
on the American visit of 1943-44. I have already told of the invi-
tation to Harvard for the Dunham lectures and how I went to
America as Director-elect of the Walter and Eliza Hall Institute.
It was a critical moment of my career. It was almost inevitable
either that I should remain in America or that if I came back to
Australia my approach to directing the Institute would be very
strongly influenced by experience of the American pattern of
research. I did return to Australia deeply impressed and for at
least the next ten or twelve years I worked hard to bring medical
research in Australia into a form patterned on the American
model.

The impression that America made on me was almost over-
whelming. By the end of 1943, the early war-time confusion had
passed and the whole industrial and intellectual resources of
America had swung into action. My friends, interested as they all
were in the control of infectious disease, had more work to do
and better facilities to do it than ever before. No one doubted
that control of infectious disease in the Armed Services was as
important medically as the treatment of casualties. 1 had come
with some first-hand knowledge of the scrub typhus and dengue
which with malaria were vital factors in the war in New Guinea
and onwards. In the laboratories, viral and rickettsial diseases
were just becoming susceptible to practical approaches and
DDT, the first of the fabulous insecticides, was just off the secret
list. Penicillin was at the first stages of commercial production
74 Ghanging Patterns

and the first effective exploitation of human plasma derivatives,
gamma globulin, for example, had begun.

I found it easy to identify myself with all these activities. My
own influenza work was well known and everyone was eager to
hear anything I had to tell and more eager to tell me what they
were doing. Everywhere fundamental work was throwing up
practical applications and new fundamental work being called
for by experience in the field. It is a pattern of activity that has
now almost disappeared but it was very real then and it supplied
the conscious ideal for the subsequent activities of the Institute
in Melbourne. When I came back I put my ideas in order and
published them as a call for a combination and revitalization of
education and research in Australia on the American model. I
shall quote fairly extensively from that lecture but first I should
describe at a more personal and specific level some of the
incidents and impressions of that war-time visit.

The three weeks’ voyage across the Pacific was wholly unevent-
ful until we arrived in San Francisco on 4 December. It was a
Saturday morning and the first news we had was thoroughly
depressing. There were no hotel beds available in San Francisco,
no banks open till Monday and a waiting-list of three weeks
before one could get a train berth across the continent. I can
quote from a diary letter how I made a friend and solved all
those problems together. I had known Dr K. F. Meyer of the
Hooper Foundation in San Francisco well by scientific repute
and by correspondence when we were both working on psitta-
cosis but I had never met him. He knew I was coming to the
States and J had arranged to call on him when I arrived. I
reached the Hooper Foundation, and now I quote:

‘Then Meyer came in and has taken complete charge of me.
He is a tremendous personality—I think it highly probable
that de Kruif used him as part of the model of Sondelius in
Martin Arrowsmith. He is a Swiss by birth and a mountain-
climber by nature, still has a fairly strong German accent,
speaks loudly and forthrightly. He knows everybody, includ-
ing all the politicians and plutocrats of California, and
seems to get on very well with them despite his very liberal
views and his burning passion to smoke out plague squirrels
and rats and psittacotic birds, completely regardless of vested
interests. So, characteristically, he rang the State Health

War-time Visit to America 175

Officer to see that I got a room in the Fairmont and, of
course, there was a room just being vacated. Then he
booked me a Pullman berth to Chicago and generally
mapped out my itinerary for the next month.’

On most occasions when I have visited San Francisco since
then, I have seen ‘K.F.’ and many of our Californian experiences
have in some way been associated with him. None of them,
however, had quite the impact of my first visit. K.F., as I have
indicated, had influence in many quarters and found transport
and accommodation for me in a way which made my war-time
travels almost easy. Along the way and when I was back in San
Francisco waiting for a return passage, I heard many of his stories
and was infected by his enthusiasms. I was specially interested
in his friendship with Paul de Kruif and his association with
Sinclair Lewis’ novel, Arrowsmith.

Circumstances combined to give me a special interest in that
novel. It was published in 1924 and created a stir amongst labora-
tory people in America. Ripples reached Australia and I was
given a copy for shipboard reading when I left for England in
July 1925. I enjoyed the story and, being young and fresh from
my first dabblings with bacteriophage, which Martin Arrowsmith
in the novel had discovered independently of d’Herelle in 1917, I
more or less identified myself with the hero. With the inevitable
result that when I took the plunge and acquired a fiancée in
October 1926, Linda in her turn was given the book for ship-
board reading on the way back to Australia.

That sentimental attachment to the novel was re-awakened
when Meyer told me how he and de Kruif had first discussed the
possibilities of a novel dealing with medical research one day
when they had climbed to the top of Mount Tamal Pais, a few
miles north of San Francisco. It was after that seminal discussion
that de Kruif interested Sinclair Lewis in the possibilities and
Arrowsmith was written.

Arrowsmith deals with the period that saw my first induction
into medical research and almost the first contemporary bac-
teriological paper that I studied in relation to my own research
was one by Northropp and de Kruif in the Journal of Experi-
mental Medicine of 1923. I saw nothing of de Kruif on this first
visit and though my only contact with him came nearly ten years
later it had a spice of its own and must be told here. We were in
76 Changing Patterns

San Francisco and once again Dr Meyer was looking after us.
K.F. told us he had been bidden to dinner by the de Kruifs and
had suggested, successfully, that Linda and I should be included
in the party. We were to meet for drinks at the Fairmont and in
due course found ourselves in a room full of noise and hard
liquor. We at home were more accustomed to sherry and Linda
murmured that she would like a dry sherry. There was no sherry,
of course, and de Kruif reached for the phone. I still remember
part of the conversation: ‘Yes, sherry .. . sherry! . . . Yes, imported
sherry, of course ... Well, send bothl’ And two bottles of
Spanish sherry arrived to our embarrassment. We had dinner at
Trader Vic’s—a very pleasant meal in the course of which I
learnt that the woman sitting next me (Mrs de Kruif) was the
prototype of that most attractive of fictional heroines, Leora of
Arrowsmith.

In due course I started my three-day journey to Chicago by
taking the ferry to Oakland and learning for the first time what
a Pullman car was like. In Chicago I spent an hour or two
between trains at the municipal VD clinic where there was
a crash programme to render all patients with syphilis non-
infective in three days. Though we did not know it then, penicil-
lin was just about to take over as the primary means of treating
syphilis. In Chicago the treatment was a combination of arseni-
cals and artificial fever. It was soundly enough based, with the
knowledge then available, and had a curious side-effect which at
that time was of special interest to me. If any of the patients were
carriers of herpes virus, their artificial fever would infallibly
induce the appearance of herpes blisters on the lips. One of the
main topics I had prepared for the Dunham lectures was the
natural history of herpes infection and here was a nice corrobora-
tion of the point of view I had adopted and which is briefly
outlined in another chapter.

At Washington I caught up with Dr Meyer again and found
myself in a whirl of laboratory visits, lectures and dinners. As
K.F.’s protegé I seemed to have the entrée everywhere. I talked
about typhus with Plotz, about plans for the use of penicillin
with Keefer, and learnt many things which are now completely
forgotten. Before and after Harvard I travelled extensively,
including Ann Arbor, Grand Rapids, New Haven, Cleveland, St
Louis, Toronto and Fort Bragg, and when I got back to the
West Coast, Los Angeles, Bakersfield and San Francisco. It was

War-time Visit to America 177

enough to see a wide cross-section of academic life and to absorb
something of the general American pattern of life.

Experience as Dunham lecturer of the Harvard Medical
School was different from anything that had ever come my way. I
was most fortunate that the Faculty had deputed Jolin Enders to
look after me. This was the beginning of a friendship that has
been strengthened on each of our visits to America. In January
1944, Enders was working with mumps virus, coaxing it to grow
in tissue culture. It was the opening phase of the process which
led steadily to his success in working out technical methods for
growing the virus of polio in tissue cultures of monkey cells. For
this, Enders, Robbins and Weller shared a Nobel Prize in 1954
and by the use of Enders’ techniques the Salk and Sabin vaccines
were developed. The polio vaccines turned out to be quite fan-
tastically successful and for the last six years polio has virtually
disappeared from the developed countries of the earth. The
major credit for this goes to John Enders.

When I arrived in Harvard, Enders handed me a paper, still
in my scrapbook, with three columns for morning, afternoon and
evening engagements for each day of the twelve I was spending
in Boston. There was only one of the thirty-six spaces unfilled:
the Faculty certainly kept me occupied and I appreciated every
hour. It was the first time that I had ever had an opportunity to
meet on friendly terms with men whom I knew to be great by
any standard. At the traditional dinner for the Dunham lecturer,
most of the medical faculty were present. On looking over the
list twenty-three years later, one recognizes many of the greatest
names in American medicine, Aycock, Albright, Aub, Burwell,
Castle, Minot, Means, General Russell, E. B. Wilson, Dubos,
Enders, Miieller, Wolbach and Wislocki. The following week I
was entertained at the Fellows’ Club, which I was told had been
founded twenty years previously but already had traditions
which anywhere else would have taken three hundred years to
acquire. I sat next the president, Whitehead, whom I revered as
the greatest living philosopher but heard very little from during
the course of the meal. On the other side was a young entomolo-
gist immensely interested in and articulate about the problems of
insect flight. Twenty years later I found Carol Williams, now
head of the Biology School at Harvard, talking just as enthusias-
tically about ‘juvenile hormone’ and the other hormones which
play such an extensive part in the development of insects.
78 Changing Patterns

Characteristically he had just made one of those ‘silly’ discoveries
which, when they occur, fill everyone with delight. In one phase
of his work on insect development it was convenient to use old
newspaper for some apparently trivial purpose. Eventually it
emerged that the newspaper was doing something really impor-
tant. If The New York Times was replaced by the London Times
the experiments failed to work! It seems hardly worth telling
what difference in the manufacture of the paper was really
responsible.

In Melbourne I had been completely away from the hospital
wards for twenty years but in Boston I found I was expected to
have retained clinical interests, One morning, J. H. Means took
me around the Massachusetts General Hospital and under the
‘Ether dome’, beneath which Morton had for the first time given
ether as an anaesthetic for a surgical operation just on one hun-
dred years previously, he bade me discourse to the students on a
patient with pneumonia. By gently switching the topic to influenza,
I got by.

Dr Wesselhoeft likewise took me around the Haynes Memorial
Hospital for infectious disease and there I was able to raise
enthusiastic interest in one of Australia’s greatest medical
achievements. Two years previously, Norman Gregg of Sydney
had discovered that German measles during pregnancy of the
mother could result in congenital cataract and blindness in the
child, He published the finding in the relative obscurity of an
Australian ophthalmological journal and no one in America had
heard of it. Wesselhoeft was greatly impressed, wrote an editorial
about the condition for the New England Journal of Medicine,
and Gregg’s discovery had at last come into the full stream of
contemporary medicine.

One other clinical experience in Boston was even more unex-
pected. It happened on my very first night in the Harvard Club
on Commonwealth Avenue and here I quote from one of those
diary letters:

‘I was sound asleep when the telephone rang. I got up and
heard in a semi-comatose state, a request that I would see a
young fellow in No. 47 who appeared to be seriously ill. It
took me some time to determine: (a) who was speaking;
(b) whether he had meant to ring me; (c) whether he
knew I was an Australian and not an American; (d) whether

War-time Visit to America 79

there wasn’t any other doctor (a properly qualified
American doctor) in the house; and finally, whether he
thought my prospective patient really needed to see anyone.
The answers were that it was the senior Club attendant, a
venerable and intelligent personality; that the patient was a
scion of one of the best Boston families (his grandfather had
been Ambassador to England); that the only other doctors in
the place were elderly and hated to be disturbed and that
the boy was probably only nervous and homesick but said he
felt very ill and wanted to see a doctor.

‘So I agreed to go down with the steward and found a
neurotic youngster of eighteen or so with a normal pulse,
temperature and facial colour—and a mild tummy upset. So
I reassured him, gave him one of my sample sedative tablets
and went back wishing that I had the nerve to charge him
$10 for a night call. The steward told me he was all right
in the morning.’

The Dunham lectures seemed to be successful. I had an interest-
ing story to tell of virus diseases looked at from an ecological
angle. It was a topical subject and drew a large audience. 1 find
that I must have paid special attention to the size of the audience
because after the third lecture I wrote that all seats had been
occupied in each (about 300) and that there were about 50, 70
and 100 standing at the periphery in consecutive lectures. Someone
congratulated me on being the first Dunham lecturer for some
years whose third lecture was as well attended as his first.

Most of my discussions in America were on matters fairly
directly related to the war. At Fort Bragg the Army had a first-
rate group working on respiratory diseases with influenza the
central but not exclusive interest. There, as at several other
centres, I demonstrated how a chick embryo could be inoculated
into the amniotic cavity, the only situation in which influenza
virus straight from the human patient would grow. Others were
interested in that plague of military camps, CSM (cerebrospinal
meningitis) , and large-scale successful tests were under way to
use chemopreventive measures against it. In camps at risk, every-
one had a sulphadiazine tablet night and morning for ten days
in the hope, usually fulfilled, of getting rid of all carriers. At
Ann Arbor I was told how the search for the perfect antimalarial
drug was proceeding—chloroquine emerged as the best of the
80 Changing Patterns

thousands tested and it was felt to be unfortunate that it had
been synthesized by the Germans before 1939. At Yale and Wash-
ington, scrub typhus was the major interest. We had worked
with it in Melbourne and we had sent the first culture from the
New Guinea area to Washington a few months before. Within
another year chloramphenicol would be available to deal with
scrub typhus, but many servicemen had died by then and the
death of Dora Lush from a laboratory infection in our own Insti-
tute eight or nine months previously was very much in my mind.

The Allied attack on Italy was in progress at the time and
already I was hearing about the success of DDT in handling the
explosive typhus situation in Naples. It was a story of exactly the
type that Meyer relished and it lost nothing in the telling. The
significance of DDT for the control of malaria was also being
whispered about. K.F. told me the story of the set of ponds
chosen for controlled tests on mosquito larvae. The experimental
ponds were rapidly freed but then the larvae vanished also from
the control (untreated) ponds. The solution? DDT was so power-
ful that when ducks moved from one of the experimental ponds
to the untreated ones they carried enough DDT on their plumage
to produce a larvicidal concentration in the water!

I shall always regard the war and the immediate post-war
period as the time when the full possibilities of control of infec-
tious disease were realized or could be clearly envisaged. But a
new epoch of biological science was also opening and I saw
something of its beginnings on that American visit.

On a number of occasions, I have spent longer or shorter times
during the summer months at Cold Spring Harbor but I first saw
it on New Year’s Eve 1943. It was a lovely winter morning when
I arrived, the inlet icebound but cracking with the tides, and
there were dozens of seagulls lining the cracks or peppered over
the ice. Bare woods, brown fields, nice houses and country lanes
made me feel that it would be pleasanter to take a long winter
walk than to talk about genes and viruses. In fact, I had an
unforgettable time with Demerec and his staff. My most vivid
recollection is of seeing for the first time how Drosophila was
handled by geneticists. I had read much of fruit-fly genetics but
had never seen the insect itself. So I was introduced to them
living in quarter-pint cream bottles with a nutrient mixture of
corn meal, molasses and yeast at the bottom— insignificant little
flies but at that time the most highly pedigreed animals in the

War-time Visit to America 81

world. Demerec was at that time a Drosophila geneticist. A few
years later he moved into bacterial genetics. Signs of the move
were only just appearing, perhaps I helped it on. After lunch in
the Director’s house I gave an informal talk on mutation in
influenza virus—the O to D phase change—adopting a genetic
approach. I noted at the time that geneticists were just becoming
interested in bacteria and bacteriophages. I was assured that the
concepts I was developing about influenza virus variation and
selection were sound and I came away with the distinct impres-
sion that my geneticist audience was delighted to find a micro-
biologist with a real interest in their science! What a change took
place in the next dozen years: by then, most geneticists were
bacterial geneticists!

At the Rockefeller Institute I called on O. T. Avery who, in
the words of a letter of mine to Linda: ‘has just made an
extremely exciting discovery which, put rather crudely, is nothing
less than the isolation of a pure gene in the form of desoxyri-
bonucleic acid.’ I think that must be almost the last time I ever
wrote DNA in full. Nothing since has diminished the significance
or importance of Avery's work. Neither he nor I knew it at the
time but in retrospect the discovery that DNA could transfer
genetic information from one pneumococcus to another almost
spelt the end of one field of scholarly investigation, medical bac-
teriology, and heralded the opening of the field of molecular
biology which has dominated scholarly thought in biology ever
since. Avery was an oldish man then, beginning to live a little in
the past, and happy to relate to interested visitors how his work
with the pneumococcus had reached this climax. He told the
story well and with pride. I feel that Avery’s work was so impor-
tant a link between the old and the new that I should attempt to
describe it.

We have almost forgotten that pneumonia was once the ‘cap-
tain of the men of death’ but for the period between the two
wars the study of pneumonia and the other pneumococcal infec-
tions was the most active and successful area of bacteriological
research. The Rockefeller Institute was the world centre for that
research and over the whole period Avery was its guiding
spirit though he had many brilliant collaborators, Dubos and
Heidelberger among them.

The key finding was that the pneumococci could be divided
into ‘types’ in the sense that if a man or an animal became
82 Changing Patterns

immune to Type I, he was not thereby immune to Types II, HI
and so on. Then, around 1920-23, these type differences were
found to depend on the fact that the pneumococcus is sur-
rounded by a gummy material, chemically a carbohydrate very
like certain vegetable gums, which is vitally important for the
disease-producing capacity of the pneumococci, and whose
detailed composition varies according to type. This gum was
called specific soluble substance SSS, that responsible for Type I
was SSS I, for Type III, SSS II and so on. A pneumococcus could
live without its SSS but without it, all its pathogenicity was gone.
Its appearance in culture also differed from the intact form, so
bacteriologists spoke of them as ‘rough’ or R forms, in contrast
to the S or ‘smooth’ pathogenic varieties. Perhaps the most
important point of all to grasp was that when a smooth Type I
mutated to a form incapable of producing SSS I, it became a
rough pneumococcus which was exactly equivalent to a rough
form derived from Type III or any other smooth type. The
capacity of the microbe to produce SSS was something that could
be pictured as resulting from the addition of a specific piece of
genetic mechanism to the mechanism common to all pneumo-
cocci. Avery showed that this was not only a useful mode of
thought but a physical reality.

The first sign-post on the road was due to an Englishman,
Griffiths, in 1928. He was testing whether harmless R pneumo-
cocci had any power to immunize mice. For some experiments he
injected living R pneumococci whose ancestors had been Type
II, along with killed pneumococci of Type III. The mice died
but it was Type III pneumococci that were responsible for the
death. There was no technical mistake, something from the dead
Type III pneumococci had made the living R pneumococci pro-
duce, not their lost ancestral SSS II, but the alien SSS III. In
1932, the approach to the problem was considerably simplified. It
was found that a soluble extract of Type III could be made to
change any R pneumococcus to a virulent Type III and that this
could be done in a test-tube. The problem for Avery and his
team was now to find what was the substance in the extract
which induced the change. On first thought, one might imagine
a simple transfer of the SSS itself but that is immediately ruled
out by the fact that the changed organisms can multiply indefi-
nitely and in the process produce unlimited supplies of the new
SSS. That was the crux of the matter, what was transferred was

War-time Visit to America 83

in a real sense information native to Type III which could be
transferred as a soluble chemical to any type of R mutant and
give it a new inheritance capacity to produce SSS III. By pains-
taking experiments the active material was isolated. It was DNA.
All the control experiments to test the possibility of any mistake
came up with the same answer. It was an answer that some
biochemists were beginning to expect—the time was propitious
for the announcement that genetic information is carried in the
chemical structure of DNA, That statement remains today as the
cornerstone of molecular biology.

Fourteen years later I had dinner in Nashville with Avery's
younger brother, Dr Roy Avery, to whom his medals and other
memorabilia had been left on his death in 1955. Looking at
those medals and thinking of that morning in December 1943, I
knew that I could no more forget Avery as a person, than the
world can ever forget his work as a scientist.

Across the continent at Cal. Tech. (California Institute of
Technology) I called on Beadle and Tatum, again at an almost
climacteric moment in the development of the new approach to
biology. Their work on the genetics of the bread-mould Neuro-
spora had virtually brought them to the famous generalization:
‘One gene, one enzyme,’ which in slightly more sophisticated
form is still the basis of biochemical genetics. The first ‘bio-
synthetic processes’ were being worked out and the enormous
convenience of micro-organisms for combined genetic and bio-
chemical studies was just being realized. I realized even then how
important their work was and I have never forgotten how at that
time most of it was being done on makeshift benches in a
corridor, It is of the nature of things scientific that really great
discoveries are always made with inadequate facilities and
amateurish techniques.

The change to molecular biology was on the way but it was
relatively insignificant. The war was the important thing and
microbiology was predominantly geared to war activities. The
last interlude I want to speak of, on the way from Los Angeles
back to San Francisco, again had to do with the Armed Services.
It was at Bakersfield where Hammon, an epidemiologist from
Meyer's Institute, picked me up and took me out to an Air Force
establishment on the desert. There, C. E. Smith was handling a
research programme on a queer disease, coccidioidomycosis or
86 Changing Patterns

laboratory work are as much needed in war as the applica-
tion of current knowledge’ and their ‘readiness to make large
scale human experiments’ whenever this seemed to be needed.
From an Australian angle I had to recognize the ‘gravitational
process by which large centres grow at the expense of smaller
ones’ and the role of Australia and other outlying countries as
‘nurseries from which men of ability could be sent to the major
centres to assist there in the effective advance of knowledge’.
Having said that, I spent the rest of the lecture giving reasons
why we should and could resist what in those days was not yet
called the brain drain.

Today much of what I said sounds platitudinous. I am not
now so sure as I was that teaching is only effective if it is done by
persons actually engaged in research. I would still agree with
what I said about the virtues of bringing medical students and
young graduates into clinical research as ‘normal controls’, and
about the function of research in a rather limited sense as a
channel by which advances from elsewhere are incorporated into
hospital practice.

I was still starry-eyed about my Harvard experience and spoke
of the reason for Harvard's greatness. ‘Subject always to the criti-
cism that I found what I was looking for, I felt certain that the
reason was the whole-hearted recognition that medicine today
can advance only as a science advances, that the men who teach
it must be trained in the methods of scientific investigation and
that the senior teachers must have the time and opportunity to
keep alight the enthusiasm for research that gained them their
present status.’

For Melbourne I wanted something as like Harvard Medical
School as circumstances would allow. ‘Each of the general teach-
ing hospitals, the Women’s Hospital and the Children’s Hospital
should have one or more clinical units headed by a full-time pro-
fessor responsible both for the organization of teaching and for
the conduct of clinical and associated research in his depart-
ment.’ If this came about it might become appropriate for the
Walter and Eliza Hall Institute to work wholly at the funda-
mental level perhaps with a special relationship to the National
Health and Medical Research Council. The Institute in fact
moved in this direction while I was its head but the special
relationship has only now been achieved by my successor. My next
suggestion was based on the importance of paediatric research,

War-time Visit to America 87

‘An institute of child health associated with the Children’s Hospi-
tal and perhaps under the direction of the professor of paediatrics
might well be an early post-war objective.’ In due course it came
and prospered. I finished by asking how we were to retain first-
class men against the gravitational pull to the larger centres over-
seas. “The only solution is to provide opportunities in Australia
where such men can find full scope for their abilities, where they
can feel they are doing work whose value is recognized by the
community and where successful work is rewarded by prestige
and reasonable financial security.’ This was said honestly and in
1944 it was the right and timely thing to say. ‘To some extent it
will always be true, provided only that the proportion of men in
research does not deplete the limited pool of men of first-rate
quality needed for more urgent services to the community, and
that the research they are engaged in is such that can be recog-
nized by the community generally as of value and worthy of
reward,