In February, science lost one of its giants, Joshua Lederberg, at age 82. Lederberg was the father of microbial genetics, earning a Nobel Prize for his discovery of bacterial conjugation, or “sex in bacteria.” One consequence of his genius was the development of many vital methods, still in daily use, to transfer genetic material in bacteria.
He was a genuine freelancer of science, applying great talent not only to the science of genetics but also to microbiology, computers, planetary exploration, evolution and immunology. In each case, he was a master of experimental incisiveness and clear exposition.
In the immunology sphere, Lederberg’s paper “Genes and Antibodies,” which appeared in the June 19, 1959, issue of Science, a year before his Nobel lecture, is my favorite and a must for all students of immunology. It tackled the major issue of the time: How does the immune system manage to produce antibodies that can respond to a near-infinite array of foreign substances, known as antigens?
Every other cellular system in the body is programmed to recognize a limited number of cues, such as growth factors, hormones, neurotransmitters, charged ions and vitamins. But immune cells need to produce antibodies, proteins of the globulin class, which are specific for hundreds of challenges such as infections, cancers and allergens.
Furthermore, within each type of challenge there are many different proteins and other chemicals that serve as antigens. The scope and diversity of immune recognition is enormous.
Not only that, scientists at the time knew that the immune system remembers its first exposure to an antigen and makes antibody globulins more vigorously during the second encounter. At the same time, immune cells must remain silent or tolerant to hundreds of harmless materials, particularly the proteins of our own bodies. How does the immune system manage such feats and respond specifically to such a diverse array of antigens?
Lederberg considered two theories: the older instructional model in which antigens “convey the instructions for the specificity of the globulin synthesized under its governance,” and the newer election models in which antigens “select cell lines or clones that arise by mutation.”
Lederberg’s mentor in immunology was Sir Macfarlane Burnet, who likewise had great wisdom in both microbiology and immunology. Burnet led the way with the idea, as Lederberg phrased it, that “the information required to synthesize a given antibody is already inherent in the organism before the antigenic stimulation is received.”
With his typical remarkable clarity, Lederberg made nine propositions “to formulate an elective theory on the basis of genetic doctrines developed in studies of microbial populations.”
A pivotal proposition, number five, was that each immune cell, as it begins to mature, spontaneously produces small amounts of a specific antibody dictated by its own genotype. Each developing antibody-producing cell becomes genetically distinct. Lederberg proposed that, in order to do this, each cell modifies or hypermutates a patch of DNA encoding a unique sequence of amino acids to specifically recognize antigenss.
Antigens would then enter the body, select the rare cell that was making small amounts of the appropriate antibody, and greatly stimulate further synthesis of antibodies and expansion of specific antibodyproducing cells. The response would be specific, and with a large number of cells, would respond more vigorously the second time around.
Fundamental to Lederberg’s proposal for selective theories of immunity was an experiment he did with Gustav Nossal at the Walter and Eliza Hall Institute (headed by Burnet) in Melbourne, Australia. Lederberg and Nossal figured out a way to examine individual antibodyproducing cells in animals that had been exposed to two different infections. They found that each cell would recognize only one of the two microbes. In other words, each cell made only a single specific type of antibody.
Lederberg wrote that “each element of the theory just presented has some precedent in biological fact, but this is testimony of plausibility, not reality.” Nevertheless, over the ensuing three decades, every one of his nine propositions was shown to be accurate.
The world mourns the loss of one of its most incisive scientific thinkers, writers and experimentalists. In immunology, as in many other disciplines, we celebrate the contributions of Joshua Lederberg.