Chapter I
Cowpox
Smallpox killed perhaps a third of those it infected, and scarred or blinded many survivors. People had long known that survivors never caught it again, and in Asia and Africa healthy people were deliberately infected with material from mild cases, a risky practice called variolation. In 1796 Edward Jenner, a country doctor in Gloucestershire, tested a local belief that milkmaids who caught cowpox were protected. He inoculated a boy, James Phipps, with cowpox, then with smallpox, and the boy stayed well. Vaccination, from vacca, the Latin for cow, spread across the world within a few years. Benjamin Jesty, a farmer, had done the same for his family twenty years earlier without publishing it.
A century later microbiology supplied the reason. Louis Pasteur found he could weaken bacteria and viruses in the laboratory and use them as vaccines against chicken cholera, anthrax and, in 1885, rabies.
Chapter II
Cells or Chemicals?
What does the protecting? In 1882 Élie Metchnikoff, working in Messina, pushed rose thorns into transparent starfish larvae and watched wandering cells swarm around them the next morning. He proposed that such phagocytes, eating cells, are the body's defence. In 1890 Emil von Behring and Kitasato Shibasaburō in Berlin found that serum from immunised animals neutralises toxins, and Paul Ehrlich developed a chemical theory of antibodies. The cellular and chemical schools feuded for decades. Both were right: the innate system of phagocytes and the adaptive system of antibodies work together.
Chapter III
Selection Inside the Body
A deeper puzzle remained. The body can make antibodies against almost any molecule, including synthetic chemicals that never existed in nature. How could it know their shapes in advance? In 1957 Frank Macfarlane Burnet, developing an idea of Niels Jerne, proposed that it does not need to. Each lymphocyte carries receptors of one random shape. An invader binds the few that happen to fit, and those multiply into a clone. Immunity is natural selection among the body's own cells.
That required enormous diversity, which the genome seemed too small to encode. In 1976 Susumu Tonegawa showed how it is done: each developing B cell cuts and splices its antibody genes from a library of segments. The previous year Georges Köhler and César Milstein had found how to make unlimited amounts of a single antibody, which transformed research, diagnosis and medicine.
Chapter IV
A Closer Look: Billions of Antibodies From a Few Hundred Genes
An antibody is built from two chains, a heavy chain and a light chain, and the part that grips the target is assembled from gene segments chosen at random in each B cell. In humans, roughly:
| Chain | Segments to choose from | Combinations |
|---|---|---|
| Heavy | about 40 V × 23 D × 6 J | |
| Light (kappa) | about 40 V × 5 J | |
| Light (lambda) | about 30 V × 4 J |
So there are about heavy-chain combinations and light-chain combinations. Any heavy chain can pair with any light chain, giving
different antibodies from about 150 gene segments. That is still not enough. The joins between segments are made imprecisely, with letters added or removed at random, which multiplies the diversity by a factor of thousands or more. Estimates of the total potential repertoire run to more than , a hundred billion, far more than the roughly twenty thousand genes in the whole genome.
When a B cell is selected by an invader, a second process adds more. The cell deliberately mutates its antibody genes at a high rate while dividing, and the daughters whose antibodies bind best are selected again. The fit improves over weeks, which is why a second vaccine dose or a booster often gives stronger protection than the first. Clonal selection is Darwinian evolution, running in days inside a lymph node.
Chapter V
Vaccines, Cancer and the Unsolved
Smallpox was declared eradicated in 1980 after a global vaccination campaign. In 2020 mRNA vaccines, made possible by the work of Katalin Karikó and Drew Weissman, were designed within days of the COVID-19 virus's genetic sequence being released. Immunology now also treats cancer, by releasing the brakes that tumours put on immune cells. But some pathogens still defeat it. HIV mutates too fast and hides too well, and forty years of effort have produced no reliable vaccine.