On the Origin of The Immune System

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Science  01 May 2009:
Vol. 324, Issue 5927, pp. 580-582
DOI: 10.1126/science.324_580

Did the immune system evolve to keep out harmful organisms, or is it like a bouncer at a nightclub, trained to allow the right microbes in and kick the less desirable ones out? In the fifth essay in Science's series in honor of the Year of Darwin, John Travis explores the evolution of the immune system.


It was a dramatic moment in the most dramatic confrontation so far between science educators and scientists determined to keep evolution in the classroom and advocates of the quasi-religious theory known as intelligent design (ID). In 2005, Lehigh University biochemist Michael Behe sat on a witness stand in Dover, Pennsylvania, as lawyer Eric Rothschild quizzed him about the claim in Behe's pro-ID book, Darwin's Black Box, that “We can look high or we can look low in books or in journals, but the result is the same. The scientific literature has no answers to the question of the origin of the immune system.”

When Behe reiterated that belief, Rothschild was ready. He began piling in front of the witness a large stack of recent journal articles, books, and book chapters, all relating research on the evolutionary origins of immunity, and asking Behe several times what he thought about the various publications. The biochemist admitted that he hadn't read much of the material, but he wouldn't budge from his position.

“So these are not good enough?” Rothschild asked at one point.

“They're wonderful articles. … They simply just don't address the question that I pose,” Behe responded.

The judge, John E. Jones, found Behe's responses revealing. Behe “was presented with 58 peer-reviewed publications, nine books, and several immunology textbook chapters about the evolution of the immune system; however, he simply insisted that this was still not sufficient evidence of evolution,” the judge wrote in his decision. Jones concluded that ID proponents set “a scientifically unreasonable burden of proof for the theory of evolution.” Score one for evolution, which is now taught without competition from ID in Dover schools.

It is fitting that studies of the origins of immunity provided a strong defense for the ideas first set forth by Charles Darwin 150 years ago. Darwin's elaboration of diversification and natural selection as organizing principles of life inspired early immunologists, helping them see that humans and pathogens are locked in their own survival-of-the-fittest battle. His theory also helped researchers realize that some of our immune defenses depend on a system of diversity coupled with selection among proteins.

As this newfound evolutionary mindset shaped immunological thinking near the turn of the 19th century, researchers also began to speculate about how our complex system of defenses arose. After decades of research, modern immunologists now think that single-celled organisms must have started by harnessing toxic peptides and gene-disabling molecules to thwart invading microbes—these weapons are still found in the simplest eukaryotes and more complex animals. And then when multicellular creatures evolved, they were able to devote specialized cells to tasks such as engulfing bacteria and viruses.

Online Extras

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This essay is the fifth in a monthly series. For more on evolutionary topics online, see Science's Origins blog. For more on the immune system, listen to a podcast by author John Travis [MP3]. And visit our Darwin page to catch up on previous months' Origins essays and the rest of our Year of Darwin coverage.

[Image credit: Wikipedia/George Richmod, From Origins, Richard Leakey and Robert Lewin]

Today, an ancient set of defensive mechanisms based upon protein receptors that recognize common features of dangerous pathogens has become hard-wired into the genome of every animal. (Plants have their own, parallel system.) Considered the first line of defense in animals, this “innate” immunity involves cells and molecules that rush to the site of an infection. Comparative studies of earthworms, sea squirts, sponges, and more suggest that this inflammatory response dates back to the origin of multicellularity.

In what has been called the “big bang of immunology,” most vertebrates later evolved a second form of immunity, in which white blood cells exquisitely targeted to a specific pathogen are rallied and then maintained in the body as an immune memory. This “adaptive” arm seemed to have appeared out of nowhere some 450 million years ago and may be the serendipitous outcome of invading DNA introduced by a virus or microbe infecting a fishlike creature.

It may seem ironic that an infectious agent endowed vertebrates with the keys to a new microbial defense, but it illustrates that microbes have shaped the evolution of animals for millennia. Indeed, a few researchers now suggest that immune systems evolved as much to manage and exploit beneficial microbes as to fend off nasty ones. “It's a paradigm shift in immunology,” says Thomas Bosch of Christian Albrechts University Kiel in Germany. Finding proof for such a radical change in thinking will be challenging, but scientists should soon have a more detailed view of immune evolution as they decipher the genomes of more invertebrates and vertebrates and tally up the defensive weapons shared by the various branches of life.

Darwinian immunology

It was only shortly after On the Origin of Species was published in 1859 that infectious diseases were discovered and became a compelling example of a Darwinian struggle—humans pitted against pathogens—notes science historian Alfred Tauber of Boston University. To understand that contest, immunology emerged in the late 19th century as the science of host defense. Soon, scientists were fighting over the importance of two competing defense mechanisms: the humoral system of antibodies in the blood versus mobile amoebalike cells known as phagocytes. German biologist Paul Ehrlich and others championed the former; Russian Elie Metchnikoff, an embryologist, lobbied for the latter.

Darwin's ideas permeated Metchnikoff's formulation, says Tauber. The Russian maintained that phagocytes evolved first as nutritive cells—eating and delivering food to cells in animals without a gut—and were eventually enlisted to eat deleterious bacteria as well. In 1882, he observed that phagocytes within a starfish enveloped and digested foreign bodies, including bacteria.

As the field of immunology matured, it embraced both Metchnikoff and the humoralists, as researchers realized that the phagocytes complemented the defense offered by blood factors. In 1908, the embryologist even shared a Nobel Prize with Ehrlich.

A half-century later, another major intellectual advance within immunology bore the fingerprints of Darwin. Darwin's theory of evolution held that a large amount of variation exists among individuals in a species and that species can adapt to new circumstances because evolution weeds out the less fit, favoring variants that improve reproduction and survival. Immunologist Frank Macfarlane Burnet drew heavily on this concept in developing his theory about how the body forms its antibodies, the pathogen-binding molecules secreted by lymphocytes called B cells, according to science historian Arthur Silverstein of Johns Hopkins University School of Medicine in Baltimore, Maryland.

While other immunologists focused on how antibodies might evolve to better target a pathogen, undergoing their own kind of natural selection, Burnet proposed that the lymphocyte was the key evolutionary player being selected within the body. Those white blood cells making antibodies that react to the body's own tissues would be deleted, whereas one whose antibodies recognized a pathogen would survive and indeed be stimulated to expand greatly in number.

“It is a Darwinian theory,” notes Tauber. “You have enormous variation and then selection.” This process, what Burnet called clonal selection, lets the body tailor its response to a particular pathogen. Moreover, some of the selected lymphocytes stick around, providing a “memory” that helps the immune system thwart the same invader even faster if it comes again.

Understanding the big bang

Clonal selection theory didn't answer all the mysteries about antibody formation. Although Burnet's idea assumed a large variation in preexisting antibodies, immunologists in the 1960s and '70s realized that animals could generate distinct antibodies to almost any protein or other molecular feature of a microbe. In fact, the vertebrate immune system could raise antibodies specific even to humanmade molecules not found in nature. Given the prevailing dogma that behind every protein there was a specific gene, immunologists were at a loss to explain this phenomenon, which became known as the generation of diversity, or GOD, problem.

In the late 1970s, in work that would earn him a Nobel Prize, Susumu Tonegawa of the Massachusetts Institute of Technology in Cambridge demonstrated that B cells can produce such a vast array of antibodies thanks to a complicated process called VDJ recombination. A maturing B cell starts with dozens to hundreds of three classes of gene segments—the V's, D's, and J's—and as it develops, the cell excises all but one of each class. The surviving V, D, and J then get stitched together into a DNA sequence that encodes an antibody unique to each mature B cell. (The other key player in the adaptive system, the T cell, also bypasses the one gene–one protein hurdle and similarly recombines gene segments to create distinct cell-surface receptors for pathogens.)

Hungry cells.

Elie Metchnikoff drew cells consuming bacteria (top), and electron microscopes today provide a more modern view of such phagocytosis (bottom).


The elucidation of VDJ recombination gradually exposed immunology's big bang, recalls David Schatz of the Yale School of Medicine. By 1990, he and other colleagues then working in David Baltimore's lab at the Whitehead Institute for Biomedical Research in Cambridge had identified two genes essential to VDJ recombination, RAG1 and RAG2 (for recombination-activating genes). Sharks and all the other jawed vertebrates with adaptive immunity have these genes, but all the evidence at the time indicated that hagfish, lampreys, and invertebrates didn't. So, where did RAG1 and RAG2 come from?

Several clues, including that the two genes are located immediately next to each other, prompted Schatz and his colleagues to wonder whether the pair had once been part of a DNA recombination system in fungi or viruses that got incorporated into vertebrates. As immunologists teased out what the proteins encoded by the two did, they realized the molecules are the scissors and knitting needles that cut out all but one V, D, and J and stitch those remaining three gene segments together.

In 1995, Craig Thompson, then at the University of Chicago in Illinois, formally proposed that the DNA now encoding RAG1 and RAG2 was once a mobile genetic element called a transposon. Transposons can cut themselves out of one DNA sequence and stick themselves back in another, so immunologists could envision those skills being co-opted to recombine V, D, and J gene segments. In this “transposon hypothesis,” Thompson suggested that at some point after jawed and jawless vertebrates split into two branches, about 450 million years ago, a transposon invaded the former lineage, perhaps brought in by a virus that infected a germ cell. Boom—the enzymes that would ultimately provide adaptive immunity, by creating diverse antibodies and T cell receptors, were now in place and could mutate into that new role.

Many research teams began trying to verify the transposon hypothesis. In 1998, for example, Schatz's team and one led by Martin Gellert of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, independently showed that the enzymes encoded by RAG1 and RAG2 could, in addition to cutting out DNA sequences, actually insert one stretch of DNA into another. In a commentary in Nature, immunologist Ronald Plasterk of the Netherlands Cancer Institute in Amsterdam expressed the awe of many at this solid evidence of the transposon hypothesis. “We may owe our existence to one transposition event that occurred 450 million years ago,” he wrote.

At the Dover trial, much of the research literature piled in front of Behe detailed the increasing evidence for this transposon hypothesis. Although those papers satisfied the judge and show why the hypothesis is widely accepted, a major surprise since the Dover verdict suggests that this transposon invasion took place even earlier.

In 2006, a team led by Jonathan Rast of the University of Toronto in Canada and Sebastian Fugmann of the National Institute on Aging in Bethesda, Maryland, analyzed the genome of the purple sea urchin and found genes that closely resemble RAG1 and RAG2, the first time they've been uncovered in invertebrates. Their existence in the urchin suggests that the transposon with these enzymes invaded animals far earlier than had been thought but was lost in most lineages except for jawed vertebrates, which adapted them to perform VDJ recombination. That's an easier version of the story for some immunologists to swallow, as it allows more time for mutations to deactivate the jumping ability of a transposon and convert its DNA to a new job. “There was never a big bang of immunology,” suggests Bosch.

Thompson and others aren't so ready to defuse the explosive hypothesis, however. The RAG1-RAG2 transposon may have entered sea urchins and vertebrates independently, they stress. The role of RAG1 and RAG2 in sea urchins remains unknown, and Rast agrees that the timing of the transposon invasion responsible for adaptive immunity won't be nailed down until more invertebrate genomes are deciphered over the next few years. “The basic idea of an immune ‘big bang’ in the vertebrates has led to a variety of oversimplifications and conceptual problems,” says Rast. “Whatever the actual evolutionary pathway that led to the very complex vertebrate adaptive system, it was surely a gradual progression that co-opted many preexisting immune mechanisms.”

First line of defense

Researchers have also made progress understanding the origins of innate immunity, encouraged by the recent appreciation that these defenses can be as sophisticated and effective as the adaptive arm. After all, about 90% of animal species have no adaptive immunity, yet they thrive, with many living for decades, in a world of microbes.

At the heart of this protection are proteins, called Toll-like receptors (TLRs), on cells of the innate immune system. Over the past decade, it has become clear that TLRs are the long-sought cell-surface receptors that recognize common microbial features such as bacterial wall components or the distinctive DNA sequences of a virus. This role could date back to the earliest multicellular organisms, as humans and some of the most evolutionarily primitive animals share TLRs and the molecules involved in the TLR signaling cascade.

The sea urchin genome revealed more than 200 TLR genes, for example, and in 2006, a group headed by Werner E. G. Müller of the University of Mainz in Germany reported that sponges also encode these microbial sensors. And plant disease-resistance proteins that recognize bacteria, viruses, and fungi include portions that structurally resemble TLRs, hinting that ancestors of these microbial sensors were on patrol long before plants and animals diverged.

Exhibit A.

This stack of evolutionary immune research literature was used in the Dover trial.


As additional genomes reveal their secrets, evolutionary biologists should ultimately sort out which creatures have which immune molecules. Making sense of that data may demand conceptual breakthroughs in understanding the purpose of our immune defenses. Many immunologists accustomed to studying people, mammals, or other vertebrates assume that the adaptive immune system emerged because it allowed these more complex animals to deal with more complex microbial threats. And Thompson, now scientific director at the Abramson Family Cancer Research Institute in Philadelphia, Pennsylvania, thinks the key advantage is that the adaptive response conserves scarce resources by quickly fine-tuning the otherwise all-out assault mounted by the innate immune system. “Specificity gives you the advantage of being able to use the least amount of an immune system,” he says.

Still, some invertebrate biologists aren't convinced that their colleagues have nailed down the selective advantage of the adaptive immune system. “It's very hard to say what is the benefit,” says Bosch. He predicts one important line of future inquiry in the evolutionary study of immunology will be how immune systems have helped organisms adapt to their specific environments or ecological niches.

Bosch also cites the growing realization that animals harbor within their bodies a world of microbes that are crucial to development, nutrition, and more; by some estimates, humans are 90% bacterial cells. Immunologists, says Bosch, need to shift their thinking “from bacteria make you sick to bacteria make you healthy.” Such a shift may ultimately force a reconsideration of the roots of the immune system. Did the innate and adaptive arms truly evolve to keep out harmful organisms? Or instead, are one or both more like bouncers at a nightclub, honed for the more subtle task of allowing the right microbes in and kicking the less desirable ones out? If another evolutionversus-ID trial ever takes place, biologists addressing this provocative question will no doubt have added to the impressive stack of literature on how our immune system arose.


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