In a world awash in viruses, bacteria, and parasites, the immune systems in humans and other animals are models of efficiency, quickly mounting customized responses to invading pathogens.
How our bodies protect us from the legions of agents that cause infectious disease was once a confounding puzzle, as no one knew how the immune system tailored its response to counter each and any of the wide range of pathogens. But in a pioneering study published in 1976, HHMI investigator Susumu Tonegawa, then at the Basel Institute for Immunology in Switzerland, showed how genes are rearranged in cells to create an almost infinite variety of antibodies, the proteins that help our bodies recognize and neutralize the agents of disease. For his accomplishments, Tonegawa, who is now at the Massachusetts Institute of Technology, was the sole winner of the 1987 Nobel Prize in Physiology or Medicine.
Before Tonegawa's landmark experiments, scientists knew the human immune system was capable of making the vast array of antibodies it uses to ward off disease. A key player in the front line of defense is a specialized immune cell known as a B lymphocyte, a white blood cell produced in bone marrow that produces antibody proteins. The antibodies are specialized to confront distinct pathogens. For every invading pathogen, there is an antibody that specifically seeks out the foreign molecule, sticks to it, and signals other cells of the immune system to destroy it.
But the genetic processes that permitted the manufacture of so many different kinds of antibody proteins — perhaps hundreds of millions — were a mystery. Some scientists even argued that people came equipped at birth with genes to make the full range of antibodies, even though at the time scientists believed there were no more than 100,000 genes within the entire human genome.
To unravel the mystery, Tonegawa looked at the genes in immune cells from embryonic and adult mice. He noted that antibody genes in the DNA of embryonic cells were at some distance from one another on the genome. In cells representing B lymphocytes of adult mice, the genes were closer together, demonstrating that they had been rearranged.
That finding showed that genes could be redistributed in the genome in the life of an individual animal. With each of the trillions of B lymphocytes shuffling its genes into a unique pattern, the immune system could produce the astonishing diversity of antibodies it needs to ward off disease. What's more, the discovery challenged the idea that the genes we are born with are fixed. Tonegawa likened the process to the manufacture of cars: the same parts, assembled in different configurations, can be used to produce different models to meet the diverse demands and preferences of customers. In the case of antibodies, genes can be assembled along the genome in different ways to initiate the production of antibodies customized to fight a particular pathogen.
Knowing how the immune system is governed at the genetic level has aided our understanding of improving immune-based therapies and gives insight into the many diseases that arise when the immune system goes awry. Autoimmune diseases, such as multiple sclerosis, type 1 diabetes mellitus, and rheumatoid arthritis, are a result of the immune system mounting an attack on the body itself. Having access to the genetic plans that direct our immune response may help us confront those conditions.
Dr. Tonegawa retired from HHMI in 2009.
Photo: Matthew Septimus