Cellular Immunology and the Selection Theories

It was not, however, the argument from the central dogma that turned immunologists away from the template theory. In spite of the growth of molecular biology in the postwar period, it was the complex phenomena of immune cells and immunized ani­mals that provided the impetus for building the new theory.

During the 1940s, a number of pieces of evidence accumulated that were to throw doubt on the tem­plate theory. One was the phenomenon of tolerance: Ray Owen in California had found that cattle twins that shared intrauterine circulation before birth each contained some of the other’s blood cells and made no antibody to them as adults. In 1949 Bumet of the Walter and Eliza Hall Institute in Melbourne, Australia, together with Frank Fenner of the Austra­lian National University, suggested that an animal body had some mechanism for distinguishing “self” from “not-self.” Antigens that were present before birth were accepted as “self,” and an animal made no antibody to them (Burnet and Fenner 1949). Burnet’s experiment failed, but a similar one that produced a tolerance to foreign skin grafts succeeded at the hands of a British group led by Peter Medawar. Dur­ing the war, Medawar had served in a London hospi­tal, treating the wounded and burned of the London blitz. He had tried to use grafts of donor skin in the same way he had used donor blood, which was then saving so many lives. But donor skin did not “take.” It was Medawar’s idea that graft rejection was an immunogenetic phenomenon, as it was Burnet’s idea that self-tolerance was established in fetal life. In 1960 Bumet and Medawar shared a Nobel Prize.

From the early 1950s, attention focused on toler­ance. Burnet, speaking at a conference at the Royal Society of London in 1956, saw the interest in this “vital” phenomenon as one of the ways in which immunology was becoming more and more biologi­cally oriented (Burnet 1957).

Among the most important alternatives was the natural selection theory of the Danish immunologist Niels Kaj Jeme, which appeared in 1955. It was a theory that would have appealed to Paul Ehrlich: It proposed that “natural” antibodies were continu­ously being formed, before any antigen was pre­sented. A given antigen would select its match from among this population of miscellaneous antibodies and would form an antigen-antibody complex. The complex would then be taken up by a phagocyte, which would trigger further production of the same antibody specificity (Jeme 1955). The theory fitted Burnet’s concept of self-tolerance: There should be no antiself antibodies. Ehrlich had called this the horror autotoxicus.

Both Talmage and Bumet offered improvements on Jerne’s idea. Talnaage suggested that attention should focus on antibody-producing cells rather than on serum antibody: Certain cells might be selected for multiplication when their produce reacted with the antigen. Talmage’s suggestion, however, was overshadowed by that of Burnet, which was similar in many ways but much more fully worked out. Bumet called his version the clonal selection theory, and it was this version that eventually obtained general acceptance.

Bumet was bom and educated in Australia, where he took his medical degree in 1922. His postgraduate tour, however, took him to London’s Lister Institute, where he worked on bacteriophage viruses and their serological classification. After getting his doctor­ate, Bumetjoined the National Institute for Medical Research. Here he learned the practical techniques of limit dilution and cloning used to grow a virus in pure culture.

Burnet was always careful to give Jerne full credit as the “onlie begetter” of the selection theory (Burnet 1967). But he did not like the idea that phagocytosing an antigen-antibody complex caused a cell to pro­duce antibody. He suggested instead that the natural antibody was not free in the serum but attached to the cell surface as a receptor, rather as Ehrlich had sup­posed 50 years before. Antigen then selected the cell that carried a suitable antibody, and that was the stimulus for the cell to start proliferating. Somatic cells do not mate; apart from mutations, their prog­eny are identical, a clone of genetically identical cells, all producing identical antibodies. Burnet sug­gested that each cell probably produced only one or two antibodies, because that gave a reasonable num­ber of cell types to deal with the number of different possible antigens (Burnet and Fenner 1962).

This theory explained two biological phenomena of immunity that had not gone well with the tem­plate theory. It explained tolerance of self as the absence of “forbidden clones” of cells that would have made antiself antibody. And it matched the kinetics of antibody production: the delay following inoculation of the antigen while the first few genera­tions of cells were produced and then the exponen­tial rise in titer as the doubling numbers of each new generation came into being. It explained why a sec­ond exposure to antigen had a more immediate and more marked effect: A substantial number of cells of the right clones already existed, ready to begin their proliferation.

Burnet did not waste much time on the central dogma, but it supported his position, and as a biolo­gist, he very soon accepted it as a matter of course. It had become a kind of Lamarckian heresy, he said, to believe that the environment could produce herita­ble changes in protein structure (Burnet and Fenner 1962).

The clonal selection theory appeared in 1957. Al­most at once, evidence strongly supporting the theory was produced by Gustav Nossal and Joshua Lederberg. Using the most direct means of testing clonal selection, they isolated single lymphocytes from rabbits immunized with two antigens and found that each cell produced only one specificity of antibody. It was technically a difficult feat and not easy to reproduce (Nossal and Lederberg 1959).

Although Bumet himself had not insisted on the capacity of each cell to make only one antibody, it seems to have been this finding that provided the strongest support for his theory. One cell, one anti­body: By 1967 Jeme could call that slogan “Burnet’s dogma in its uncompromising form” (Jerne 1967), thus giving it equal status with Crick’s “central dogma,” mentioned earlier. At the Cold Spring Har­bor Symposium that year, it began to seem as if the clonal selection theory had been accepted by the leaders in the field. In the 10 years since it had been proposed, a plethora of experiments on lymphocytes had demonstrated that antigen turned a small subpopulation on to clonal expansion and that anti­gen was not present in all the antibody-producing cells. As Buraet had said, the way the theory was stated made it easy to think of ways to test it.