Editing Macfarlane Burnet (section)

===Immunology===
[[File:Clonal selection.svg|right|thumb|'''Clonal selection''' (1) A [[Pluripotential hemopoietic stem cell|hematopoietic stem cell]] undergoes differentiation and genetic rearrangement to produce (2) immature lymphocytes with many different antigen receptors. Those that bind to (3) antigens from the body's own tissues are destroyed, while the rest mature into (4) inactive lymphocytes. Most of these will never encounter a matching (5) foreign antigen, but those that do are activated and produce (6) many clones of themselves.]]

In 1957, Burnet decided that research at the Institute should focus on immunology.<ref name=b107>''Biographical Memoirs'', p. 107.</ref> Burnet reached the decision unilaterally, leaving many of the research staff disillusioned and feeling the action was arrogant; for Burnet's part he was comfortable with the decision as he thought it to be effective.{{sfnp|Sexton|1999|p=134}} Many virologists left the Institute and settled the [[Australian National University]]'s [[John Curtin School of Medical Research]].<ref name ="Doherty">{{cite journal |doi=10.1046/j.1440-1711.1999.00812.x |author=Doherty, P. C. |year= 1999 |title= Burnet Oration: Living in the Burnet lineage |journal=Immunology and Cell Biology |volume=77 |issue=2 |pages=167–176 |pmid=10234553|s2cid=24300492 |doi-access=free }}</ref> After 1957 all new staff and students at the Institute worked on immunological problems;<ref name=b107/> Burnet was involved in work relating to [[Autoimmunity|autoimmune diseases]] and the [[Graft-versus-host disease|graft-versus-host]] reaction, and increasingly in theoretical studies of immunology, immunological surveillance and cancer.<ref name = "Fenner"/><ref name=b108>''Biographical Memoirs'', p. 108.</ref>

At the time, immunology was becoming more sophisticated, with the increasing role of [[molecular biology]] and [[biochemistry]]. Burnet was suspicious of the direction in which immunology was headed, and the increasing emphasis on technology and more intricate experiments, and colleagues felt that Burnet's conservative attitude was a factor in his decision to turn the Institute's focus to immunology.{{sfnp|Sexton|1999|p=132}}

Burnet began to switch his focus to immunology in the 1940s.<ref>''Biographical Memoirs'', pp. 105–106.</ref> In 1941 he wrote a [[monograph]] called "The Production of Antibodies",<ref name=b117>''Biographical Memoirs'', p. 117.</ref> which was revised and reissued in 1949 with Frank Fenner as a co-author.<ref name=b155>''Biographical Memoirs'', p. 155.</ref> This book is seen as a key publication in immunology—it marks the move from the study of immunology as a chemical endeavour to a biological one. Importantly in this work, he introduced the concept of "self" and "non-self" to immunology. The distinction between self and non-self was an integral part of Burnet's biological outlook, of his interest in the living organism in its totality, its activities, and interactions.<ref name = "Christ">{{cite journal| doi=10.1023/A:1006657124783|author1=Christ, E. |author2=Tauber, A. I. |year=1999 |title= Selfhood, Immunity, and the Biological Imagination: The Thought of Frank Macfarlane Burnet |journal=Biology and Philosophy |volume=15| issue=4 |pages=509–533|s2cid=170258791 }}</ref> Burnet regarded the "self" of the host body as being actively defined during its embryogenesis through complex interactions between immune cells and all the other cells and molecules within an embryo.<ref>{{cite journal|doi=10.1093/jhmas/jrl002|author=Park, Hyung Wook |title=Germs, hosts, and the origin of Frank Macfarlane Burnet's concept of 'self' and 'tolerance', 1936–1949 |journal=Journal of the History of Medicine and Allied Sciences |volume=61 |issue=4 |year=2006 |pages= 492–534|pmid=16769800|s2cid=30800083 |hdl=10356/96965 |hdl-access=free }}</ref>

Using the concept of self, Burnet introduced a hypothesis about the situation where the body failed to make antibodies to its own components ([[autoimmunity]]) and by extension the idea of [[immune tolerance]]. He proposed that
<blockquote>if in embryonic life expendable cells from a genetically distinct race are implanted and established, no antibody response should develop against the foreign cell antigen when the animal takes on independent existence.<ref>{{Cite book |author1=Burnet, F. M. |author2=Fenner, F. |year=1949 |title=The Production of Antibodies |edition=2nd |publisher=Macmillan}}</ref></blockquote>
Burnet was, however, unable to prove this experimentally.<ref>{{cite journal |doi=10.1038/icb.1950.29 |author1=Burnet, F. M. |author2=Stone, J. D. |author3=Edney, M. |year= 1950 |title=The failure of antibody production in the chick embryo |journal=Australian Journal of Experimental Biology and Medical Science |volume=28 |issue=3 |pages=291–297 |pmid=14772171}}</ref> [[Peter Medawar]], [[Rupert E. Billingham]] and [[Leslie Brent]] did find support for Burnet's hypothesis in 1953 when they showed that [[splenocyte]]s could be engrafted by intravenous infusion into mice in utero or just after birth and that when these mice matured, they could accept skin and other tissues from the donor but not from any other mouse strain.<ref>{{cite journal|doi=10.1038/172603a0|author1=Billingham, R. E. |author2=Brent, L. |author3=Medawar, P. B. |year= 1953 |title='Actively Acquired Tolerance' of Foreign Cells |journal=Nature |volume=172|issue=10 |pages=603–606 |pmid=13099277|bibcode = 1953Natur.172..603B |s2cid=4176204 }}</ref> Burnet and Medawar were co-recipients of the 1960 Nobel Prize in Physiology or Medicine for this work, as it provided the experimental basis for inducing immune tolerance,<ref name=b134>''Biographical Memoirs'', p. 134.</ref> thereby allowing the transplantation of solid organs. Burnet and Medawar were able to coordinate their work effectively despite their rather different personalities and physical separation; Burnet was taciturn whereas Medawar was a young and urbane Englishman, but they greatly respected one another.{{sfnp|Sexton|1999|p=137}}

However, later studies showed that cells or tissues transplanted before the immune system development of the recipient, such as in embryonic recipients, could be treated as foreign and trigger rejection,<ref>{{cite journal|author=McCullagh, P. |title=Inability of fetal skin to induce allograft tolerance in fetal lambs |journal=Immunology |volume=67|issue=4 |pages=489–495 |year=1989|pmid=2670751|pmc=1385319}}</ref><ref>{{Cite journal |author1=Le Douarin, N. M. |author2=Corbel, C. |author3=Martin, C. |author4=Coltey, M. |author5=Salaun, J. |title=Induction of tolerance by embryonic thymic epithelial grafts in birds and mammals |journal=Cold Spring Harb Symp Quant Biol |volume=54 |pages=777–787 |year=1989 |pmid=2534843 |doi=10.1101/sqb.1989.054.01.091}}</ref> countering Burnet's explanation for self tolerance. In contrast to the Burnet hypothesis of a special tolerance-inducing period defined by the age of the animal, [[Joshua Lederberg]] proposed in 1959,<ref>{{cite journal |author=Lederberg, J. |title=Genes and antibodies |journal=Science |year=1959 |volume=129 |issue=3364 |pages=1649–1653 |pmid=13668512 | doi=10.1126/science.129.3364.1649 |bibcode = 1959Sci...129.1649L |s2cid=7518224 }}</ref> that it is the age of the lymphocyte that defines whether an antigen that is encountered will induce tolerance, with immature lymphocytes being tolerance-sensitive. Lederberg's concept is now known as central tolerance, and is widely accepted. It may also explain the success of some transplants given early in life and the failure to induce tolerance in other studies. Burnet noted that his contributions to immune tolerance were strictly theoretical:
<blockquote>My part in the discovery of acquired immunological tolerance was a very minor one—it was the formulation of an hypothesis that called for experiment.<ref>{{cite web |author=Burnet, Frank Macfarlane |date=12 November 1960 |url=http://nobelprize.org/nobel_prizes/medicine/laureates/1960/burnet-lecture.pdf |title=Immunological Recognition of Self: Nobel Lecture |access-date=30 September 2010 |publisher=Nobel Foundation |archive-url=https://web.archive.org/web/20101215042633/http://nobelprize.org/nobel_prizes/medicine/laureates/1960/burnet-lecture.pdf |archive-date=15 December 2010 |url-status=dead |df=dmy-all }}</ref></blockquote>

Burnet was interested in how the body produces antibodies in response to antigens. The dominant idea in the literature through the 1940s was that the antigen acted as a template for antibody production, which was known as the "instructive" hypothesis.<ref>{{Cite journal |author=Pauling, L. |year=1940 |title=A theory of the structure and process of formation of antibodies |journal=Journal of the American Chemical Society |volume=62 |issue=10 |pages=2643–2657 |doi=10.1021/ja01867a018|bibcode=1940JAChS..62.2643P }}</ref> Burnet was not satisfied with this explanation, and in the second edition of "The Production of Antibodies", he and Fenner advanced an indirect template theory which proposed that each antigen could influence the genome, thus effecting the production of antibodies.<ref>{{cite book |author=Silverstein, A. M. |year=1989 |title=A History of Immunology |publisher=Academic Press Inc. |isbn=978-0-12-643770-6}}</ref> In 1956 he became interested in [[Niels Kaj Jerne]]'s natural selection hypothesis,<ref>''Biographical Memoirs'', pp. 134–135.</ref> which described a mechanism for immune response based on an earlier theory of Nobel-winning immunologist [[Paul Ehrlich]]. Jerne proposed that the antigen bound to an antibody by chance and, that upon binding, more antibodies to that antigen would be produced. Burnet developed a model which he named [[clonal selection]] that expanded on and improved Jerne's hypothesis.<ref>{{cite journal |author=Burnet, F. M. |year=1957 |title=A modification of Jerne's theory of antibody production using the concept of clonal selection |journal=Australian Journal Science |volume=20 |issue=2 |pages=67–69 }} Reprinted in {{cite journal|pmid=816431 |doi=10.3322/canjclin.26.2.119 | volume=26 |issue=2 | title=A modification of Jerne's theory of antibody production using the concept of clonal selection |year=1976 |author=Burnet FM |journal=CA Cancer J Clin |pages=119–21|s2cid=40609269 |doi-access=free }}</ref> Burnet proposed that each [[lymphocyte]] bears on its surface specific immunoglobulins reflecting the specificity of the antibody that will later be synthesised once the cell is activated by an antigen. The antigen serves as a selective stimulus, causing preferential proliferation and differentiation of
the clones that have receptors for that antigen.<ref name = "Nossal Nature">{{cite journal |author=Nossal, G. J. V. |year=1985 |title=Sir Frank Macfarlane Burnet (1899–1985) |journal=Nature |volume=317 |issue=6033 |page=108 |pmid=3897872| doi=10.1038/317108b0 |bibcode = 1985Natur.317..108N |s2cid=4234456 |doi-access=free }}</ref>

In 1958 [[Gustav Nossal]] and Lederberg showed that one [[B cell]] always produces only one antibody, which was the first evidence for clonal selection theory.<ref>{{cite journal |doi=10.1038/1811419a0 |author1=Nossal, G. J. V. |author2=Lederberg, J. |year=1958 |title=Antibody production by single cells |journal=Nature |volume=181 |issue=4620 |pages=1419–1420 |pmid=13552693|pmc=2082245 |bibcode = 1958Natur.181.1419N }}</ref> Burnet wrote further about the theory in his 1959 book ''The Clonal Selection Theory of Acquired Immunity''. His theory predicted almost all of the key features of the immune system as we understand it today, including autoimmune disease, immune tolerance and [[somatic hypermutation]] as a mechanism in antibody production.<ref>{{cite book |author=Nossal, G. J. V. |year=1995 |chapter=One Cell – One Antibody |title=Immunology: The making of a modern science |url=https://archive.org/details/immunologymaking00rbga |url-access=limited |editor1=Gallagher, R. B. |editor2=Gilder, J. |editor3=Nossal, G. J. V. |editor4=Salvatore, G. |publisher=Academic Press |pages=[https://archive.org/details/immunologymaking00rbga/page/n47 39]–47}}</ref> The clonal selection theory became one of the central concepts of immunology, and Burnet regarded his contributions to the theoretical understanding of the immune system as his greatest contribution to science,<ref name=b135/> writing that he and Jerne should have received the Nobel for this work.{{sfnp|Sexton|1999|pp=139–140}} Jerne was recognised for his contributions to the conceptualisation of the immune system when he was a co-recipient of the Nobel Prize in 1984.

There is some contention over Burnet's publication of his version of the theory in the ''Australian Journal of Science'' in 1957. Some commentators argue he published in an Australian journal to fast-track his hypothesis and obtain priority for his theory over ideas that were published later that year in a paper written by [[David Talmage]], which Burnet had read prior to its publication.<ref name = "Fenner"/><ref>{{cite journal |doi=10.1146/annurev.me.08.020157.001323 |pmid=13425332 |author=Talmage, D. W. |year=1957 |title=Allergy and immunology |journal=Annual Review of Medicine |volume=8 |issue=1 |pages=239–256}}</ref><ref>{{cite journal |author=Forsdyke, D. R. |year=1995 |url=http://post.queensu.ca/~forsdyke/theorimm0.htm#Introduction |title=The Origins of the Clonal Selection Theory of Immunity |journal=FASEB J. |volume=9 |issue=2 |pages=164–166 |pmid=7781918 |access-date=30 September 2010 |doi=10.1096/fasebj.9.2.7781918 |doi-access=free |s2cid=38467403 |archive-date=30 July 2012 |archive-url=https://web.archive.org/web/20120730120916/http://post.queensu.ca/~forsdyke/theorimm0.htm#Introduction |url-status=live |url-access=subscription }}</ref> In his paper Burnet cited Talmage's review,<ref name=b135>''Biographical Memoirs'', p. 135.</ref> and in a later interview, Talmage said he believed that Burnet "truthfully had developed the idea before he received my paper".<ref>{{cite journal |author1=Cruse, J. M. |author2=Lewis, R. E. |year= 1994 |title=David W. Talmage and the advent of the cell selection theory of antibody synthesis |journal=Journal of Immunology |volume=153 |issue=3 |pages=919–924 |doi=10.4049/jimmunol.153.3.919 |pmid=8027564|s2cid=32756505 |doi-access=free }}</ref> The theory is now sometimes known as Burnet's clonal selection theory,{{sfnp|Sexton|1999|pp=137–139}} which overlooks the contributions of Ehrlich, Jerne, Talmage, and the contributions of Lederberg, who conceptualised the genetics of clonal selection.{{sfnp|Sexton|1999|pp=134–141}}

Burnet's work on graft-versus-host was in collaboration with Lone Simonsen between 1960 and 1962. Simonsen had shown in 1957 that when a chick embryo was inoculated intravenously with adult-fowl blood, a graft-versus-host reaction occurred; this was known as the Simonsen phenomenon.<ref name=b136>''Biographical Memoirs'', p. 136.</ref> Their work in this system would later help to explain [[passenger leukocyte]]s in transplantation.<ref name=b136/> The last project he worked on at the Institute was a study with assistant Margaret Holmes of autoimmune disease in the New Zealand black mouse model; this mouse has a high incidence of spontaneous autoimmune [[hemolytic anemia]].<ref name=b137>''Biographical Memoirs'', p. 137.</ref> They looked at the inheritance of autoimmune disease, and their use of immunosuppressive drug [[cyclophosphamide]] to treat the disease influenced the use of immunosuppressive drugs in human autoimmune disease.<ref>{{cite journal |author1=Russell, P. J. |author2=Hicks, J. D. |author3=Burnet, F. M. |year=1966 |title=Cyclophosphamide treatment of kidney disease in (NZB x NZW) F1 mice |journal=Lancet |volume=1 |issue=7450 |pages=1279–1284 |pmid=4160875 |doi=10.1016/s0140-6736(66)91198-6}}</ref>

[[File:Frank Macfarlane Burnet 1960.jpg|thumb|left|upright|Frank Macfarlane Burnet in Stockholm in 1960]]
In 1960, Burnet scaled back his laboratory work, taking one day off per week to concentrate on writing.{{sfnp|Sexton|1999|p=154}} In 1963, ''Autoimmune Diseases: Pathogenesis, Chemistry and Therapy'', which he authored with [[Ian Reay Mackay|Ian Mackay]], was published.{{sfnp|Sexton|1999|p=155}} He also oversaw an expansion of the Hall Institute and secured funding from the [[Nuffield Foundation]] and the state government to build two further floors in the building and take over some of the space taken up by the pathology department at the Royal Melbourne Hospital.{{sfnp|Sexton|1999|p=154}} Despite this, Burnet believed that a world class research body needed to be small enough that one person could effectively run it, and maintained tight control over its activities throughout his leadership. He determined the policies himself, and personally selected all of the research staff and students, relying on a small staff to enforce his plans.<ref>''Biographical Memoirs'', pp. 110–111.</ref>

He continued to be active in the laboratory until his retirement in 1965, although his experimental time began to decrease as the operations became increasingly focused on immunology; Burnet's work in this area had been mostly theoretical.{{sfnp|Sexton|1999|p=155}} Gustav Nossal became the next director of the Walter and Eliza Hall Institute.<ref name=b108/> Under Burnet's leadership the Institute had become "probably the world's best known research centre devoted to the study of immunology."<ref>{{cite journal |doi=10.1086/418433 |author=Marchalonis, J. J. |year=1994 |title=Burnet and Nossal: the impact on immunology of the Walter and Eliza Hall Institute |journal=The Quarterly Review of Biology |volume=69 |issue=1 |pages=53–67 |pmid=8208917|s2cid=20830422 }}</ref> However, with the increasing sophistication in medical science and its reliance on more complicated technology, Burnet's lone-wolf approach became less compatible with the research environment, which required more collaboration. In his final years at the helm, Burnet allowed more technical modernisation during the transition period to Nossal's leadership.{{sfnp|Sexton|1999|pp=132–133}}