The Accidental Immune System

Immunologists have wrestled with the origin of GOD for several decades. This spiritual-sounding acronym stands for “generation of diversity” and emerged in the jargon of scientists after their realization in the 1970s that the human immune system manufactures tens of millions of distinct antibodies. These elaborate, Y-shaped molecules latch onto and help destroy infectious microorganisms. Since the human genome seems to contain fewer than 100,000 genes, the remarkable variety of antibodies initially baffled researchers. How could so few genes produce so many antibodies? In 1976, scientists proved that this remarkable antibody diversity stems in large part from the ability of antibody-producing immune cells, called B cells, to shuffle pieces of their genes. By fusing various combinations of gene segments, a maturing B cell generates unique DNA sequences encoding parts of the antibody’s binding region. Although they don’t make antibodies, other immune cells use this same shuffling mechanism to create on their surfaces similar microbe-binding proteins called T cell receptors. Curiously, while animals ranging from sharks to people use this so-called combinatorial strategy, more primitive organisms such as starfish, lampreys, and horseshoe crabs lack it. As a result, they don’t make typical antibodies or T cell receptors. “The combinatorial immune system is found in all jawed vertebrates but, to the best of anybody’s knowledge, nowhere else,” says John J. Marchalonis of the University of Arizona in Tucson. Marchalonis and his colleagues have taken to calling the emergence of this system the “big bang” of immunology, especially since scientists estimate it appeared within a span of just 20 million years, a blink of the eye in evolution’s time frame. When scientists first grasped the explosive nature of this evolutionary event, they were at a loss to explain how it could occur. “We didn’t have a mechanism,” says Marchalonis. In recent years, researchers have crafted a surprising explanation for this immunological advance. Hundreds of millions of years ago, in a creature perhaps resembling today’s sharks, a piece of DNA apparently jumped from its chromosomal home, a movement known as transposition. Carrying the blueprint for an enzyme that cuts and pastes DNA, it just happened to insert itself within a gene, perhaps one already being used by the immune system. Over time, this fragment endowed descendants of that ancient creature with the DNA-shuffling ability needed to create vast arrays of antibodies and T cell receptors. “One might argue that such complex organisms as mammals (and other vertebrates) can only exist thanks to an immune defence system whose repertoire matches that of invading viruses and microorganisms. . . . If that is true, we may owe our existence to one transposition event that occurred 450 million years ago,” immunologist Ronald Plasterk of the Netherlands Cancer Institute in Amsterdam says in the Aug. 20 NATURE. Even more startling, scientists suspect that this fortuitous piece of mobile DNA originally came from a bacterium, virus, or some other infectious microorganism. In other words, the November 7, 1998 Vol. 154 No. 19 p. 302 BROWSE BY YEAR BROWSE 1998 ISSUES TABLE OF CONTENTS 1998