The article discusses the evolutionary origins of the immune system. It describes how scientists now believe the immune system first evolved basic defensive mechanisms in single-celled organisms, like toxic peptides to fight microbes. When multicellular organisms evolved, specialized immune cells also arose. The adaptive immune system, featuring antibodies and specialized immune cells, emerged suddenly around 450 million years ago in jawed vertebrates due to the insertion of genes that enabled new DNA recombination abilities. This event is now believed to have been caused by the insertion of transposable genes from viruses or other sources, allowing vertebrates to generate vast antibody diversity and immune memory.

1. NEWSFOCUS
a specific pathogen are rallied and then main-
On the Origin of tained in the body as an immune memory.
This “adaptive” arm seemed to have appeared
The Immune System 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.
however, he simply insisted that this was still It may seem ironic that an infectious agent
not sufficient evidence of evolution,” the judge endowed vertebrates with the keys to a new
wrote in his decision. Jones concluded that ID microbial defense, but it illustrates that
proponents set “a scientifically unreasonable microbes have shaped the evolution of ani-
burden of proof for the theory of evolution.” mals for millennia. Indeed, a few researchers
Score one for evolution, which is now taught now suggest that immune systems evolved as
without competition from ID in Dover schools. much to manage and exploit benef icial
It is fitting that studies of the origins microbes as to fend off nasty ones. “It’s a par-
of immunity provided a strong defense for adigm shift in immunology,” says Thomas
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the ideas first set forth by Charles Darwin Bosch of Christian Albrechts University Kiel
150 years ago. Darwin’s elaboration of diver- in Germany. Finding proof for such a radical
sification and natural selection as organizing change in thinking will be challenging, but
principles of life inspired early immunolo- scientists should soon have a more detailed
gists, helping them see that humans and view of immune evolution as they decipher
pathogens are locked in their own survival- the genomes of more invertebrates and verte-
of-the-fittest battle. His theory also helped brates and tally up the defensive weapons
researchers realize that some of our immune shared by the various branches of life.
defenses depend on a system of diversity cou-
pled with selection among proteins. Darwinian immunology
As this newfound evolutionary mindset It was only shortly after On the Origin of
IT WAS A DRAMATIC MOMENT IN THE MOST shaped immunological thinking near the turn Species was published in 1859 that infectious
dramatic confrontation so far between science of the 19th century, researchers also began to diseases were discovered and became a com-
CREDITS (TOP TO BOTTOM): KATHARINE SUTLIFF/SCIENCE; WIKIPEDIA/GEORGE RICHMOD, FROM ORIGINS, RICHARD LEAKEY AND ROBERT LEWIN
educators and scientists determined to keep speculate about how our complex system of pelling example of a Darwinian struggle—
evolution in the classroom and advocates of defenses arose. After decades of research, humans pitted against pathogens—notes
the quasi-religious theory known as intelli- modern immunologists now think that single- science historian Alfred Tauber of Boston
gent design (ID). In 2005, Lehigh University celled organisms must have started by harness- University. To understand that contest,
biochemist Michael Behe sat on a witness ing toxic peptides and gene-disabling mole- immunology emerged in the late 19th century
stand in Dover, Pennsylvania, as lawyer Eric cules to thwart invading microbes—these as the science of host defense. Soon, scien-
Rothschild quizzed him about the claim in weapons are still found in the simplest eukary- tists were fighting over the importance of
Behe’s pro-ID book, Darwin’s Black Box, that otes and more complex animals. And then two competing defense mechanisms: the
“We can look high or we can look low in when multicellular creatures evolved, they humoral system of antibodies in the blood
books or in journals, but the result is the same. were able to devote specialized cells to tasks versus mobile amoebalike cells known as
The scientific literature has no answers to the such as engulfing bacteria and viruses. phagocytes. German biologist Paul Ehrlich
question of the origin of the immune system.” Today, an ancient set of defensive mecha- and others championed the former; Russian
When Behe reiterated that belief, Roth- nisms based upon protein recep- Elie Metchnikoff, an embryolo-
schild was ready. He began piling in front of tors that recognize common fea- THE YEAR OF gist, lobbied for the latter.
the witness a large stack of recent journal arti-
cles, books, and book chapters, all relating
tures of dangerous pathogens has
become hard-wired into the
DARWIN Darwin’s ideas permeated
Metchnikoff’s formulation, says
research on the evolutionary origins of immu- genome of every animal. (Plants Tauber. The Russian maintained
nity, and asking Behe several times what he have their own, parallel system.) that phagocytes evolved first as
thought about the various publications. The Considered the f irst line of nutritive cells—eating and deliv-
biochemist admitted that he hadn’t read much defense in animals, this “innate” ering food to cells in animals
of the material, but he wouldn’t budge from immunity involves cells and mol- without a gut—and were eventu-
his position. ecules that rush to the site of an ally enlisted to eat deleterious
“So these are not good enough?” Roth- infection. Comparative studies of bacteria as well. In 1882, he
schild asked at one point. earthworms, sea squirts, sponges, This essay is the fifth observed that phagocytes within a
“They’re wonderful articles. … They sim- and more suggest that this inflam- in a monthly series. starfish enveloped and digested
For more on evolutionary
ply just don’t address the question that I matory response dates back to the topics online, see the foreign bodies, including bacteria.
pose,” Behe responded. origin of multicellularity. Origins blog at As the field of immunology
The judge, John E. Jones, found Behe’s In what has been called the blogs.sciencemag.org/
origins. For more on
matured, it embraced both
responses revealing. Behe “was presented with “big bang of immunology,” most the immune system, Metchnikoff and the humoralists,
58 peer-reviewed publications, nine books, vertebrates later evolved a second listen to a podcast by as researchers realized that the
author John Travis at
and several immunology textbook chapters form of immunity, in which white www.sciencemag.org/ phagocytes complemented the
about the evolution of the immune system; blood cells exquisitely targeted to multimedia/podcast. defense offered by blood factors.
580 1 MAY 2009 VOL 324 SCIENCE www.sciencemag.org
Published by AAAS

2. ORIGINS
In 1908, the embryologist even shared a this phenomenon, which became known as Whitehead Institute for Biomedical Research
Nobel Prize with Ehrlich. the generation of diversity, or GOD, problem. in Cambridge had identified two genes essen-
CREDITS (TOP TO BOTTOM): E. METCHNIKOFF/IMMUNITÄT BEI INFEKTIONSKRANKHEITEN (VERLAG VON GUSTAV FISCHER, JENA, 1902)/S. H. E. KAUFMAN, MAX PLANCK INSTITUTE FOR INFECTION BIOLOGY, BERLIN; V. BRINKMANN, PLOS PATHOGENS, 1(3), NOVEMBER 2005
A half-century later, another major intel- In the late 1970s, in work that would earn tial to VDJ recombination, RAG1 and RAG2
lectual advance within immunology bore the him a Nobel Prize, Susumu Tonegawa of the (for recombination-activating genes). Sharks
fingerprints of Darwin. Darwin’s theory of Massachusetts Institute of Technology in and all the other jawed vertebrates with adap-
evolution held that a large amount of variation Cambridge demonstrated that B cells can tive immunity have these genes, but all the
exists among individuals in a species and that produce such a vast array of antibodies evidence at the time indicated that hagfish,
species can adapt to new circumstances thanks to a complicated process called VDJ lampreys, and invertebrates didn’t. So, where
because evolution weeds out the less fit, favor- recombination. A maturing B cell starts with did RAG1 and RAG2 come from?
ing variants that improve reproduction and sur- dozens to hundreds of three classes of gene Several clues, including that the two genes
vival. Immunologist Frank Macfarlane Burnet segments—the V’s, D’s, and J’s—and as it are located immediately next to each other,
drew heavily on this concept in developing develops, the cell excises all but one of each prompted Schatz and his colleagues to wonder
his theory about how the body forms its anti- class. The surviving V, D, and J then get whether the pair had once been part of a DNA
bodies, the pathogen-binding molecules recombination system in fungi or viruses that
secreted by lymphocytes called B got incorporated into vertebrates. As immu-
cells, according to science historian nologists teased out what the proteins
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Arthur Silverstein of Johns Hop- encoded by the two did, they real-
kins University School of Medi- ized the molecules are the scissors
cine in Baltimore, Maryland. and knitting needles that cut out
While other immunologists all but one V D, and J and stitch
,
focused on how antibodies might those remaining three gene seg-
evolve to better target a pathogen, ments together.
undergoing their own kind of In 1995, Craig Thompson, then
natural selection, Burnet pro- at the University of Chicago in Illi-
posed that the lymphocyte was nois, formally proposed that the
the key evolutionary player being DNA now encoding RAG1 and
selected within the body. Those RAG2 was once a mobile genetic
white blood cells making antibod- element called a transposon.
ies that react to the body’s own tis- Transposons can cut themselves
sues would be deleted, whereas out of one DNA sequence and
one whose antibodies recognized stick themselves back in another,
a pathogen would survive and so immunologists could envision
indeed be stimulated to expand those skills being co-opted to
greatly in number. recombine V, D, and J gene
“It is a Darwinian theory,” segments. In this “transposon
notes Tauber. “You have enor- hypothesis,” Thompson suggested
mous variation and then selec- that at some point after jawed and
tion.” This process, what Burnet jawless vertebrates split into two
called clonal selection, lets the branches, about 450 million years
body tailor its response to a par- ago, a transposon invaded the for-
ticular pathogen. Moreover, some mer lineage, perhaps brought in
of the selected lymphocytes stick by a virus that infected a germ
around, providing a “memory” cell. Boom—the enzymes that
that helps the immune system would ultimately provide adaptive
thwart the same invader even Hungry cells. Elie Metchnikoff drew cells immunity, by creating diverse
consuming bacteria (top), and electron
faster if it comes again. antibodies and T cell receptors,
microscopes today provide a more modern
view of such phagocytosis (bottom).
were now in place and could
Understanding the big bang mutate into that new role.
Clonal selection theory didn’t Many research teams began
answer all the mysteries about antibody for- stitched together into a DNA sequence that trying to verify the transposon hypothesis. In
mation. Although Burnet’s idea assumed a encodes an antibody unique to each mature 1998, for example, Schatz’s team and one led
large variation in preexisting antibodies, B cell. (The other key player in the adaptive by Martin Gellert of the National Institute of
immunologists in the 1960s and ’70s realized system, the T cell, also bypasses the one Diabetes and Digestive and Kidney Diseases
that animals could generate distinct antibod- gene–one protein hurdle and similarly in Bethesda, Maryland, independently showed
ies to almost any protein or other molecular recombines gene segments to create distinct that the enzymes encoded by RAG1 and RAG2
feature of a microbe. In fact, the vertebrate cell-surface receptors for pathogens.) could, in addition to cutting out DNA
immune system could raise antibodies spe- The elucidation of VDJ recombination sequences, actually insert one stretch of DNA
cif ic even to humanmade molecules not gradually exposed immunology’s big bang, into another. In a commentary in Nature,
found in nature. Given the prevailing dogma recalls David Schatz of the Yale School of immunologist Ronald Plasterk of the Nether-
that behind every protein there was a specific Medicine. By 1990, he and other colleagues lands Cancer Institute in Amsterdam
gene, immunologists were at a loss to explain then working in David Baltimore’s lab at the expressed the awe of many at this solid evi-
www.sciencemag.org SCIENCE VOL 324 1 MAY 2009 581
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3. ORIGINS
dence of the transposon hypothesis. “We may effective as the adaptive arm. After all, about sensors. And plant disease-resistance proteins
owe our existence to one transposition event 90% of animal species have no adaptive that recognize bacteria, viruses, and fungi
that occurred 450 million years ago,” he wrote. immunity, yet they thrive, with many living include portions that structurally resemble
At the Dover trial, much of the research for decades, in a world of microbes. TLRs, hinting that ancestors of these micro-
literature piled in front of Behe detailed the At the heart of this protection are proteins, bial sensors were on patrol long before plants
increasing evidence for this transposon called Toll-like receptors (TLRs), on cells of and animals diverged.
hypothesis. Although those papers satisfied the innate immune system. Over the past As additional genomes reveal their secrets,
the judge and show why the hypothesis is decade, it has become clear that TLRs are the evolutionary biologists should ultimately sort
widely accepted, a major surprise since the long-sought cell-surface receptors that recog- out which creatures have which immune mol-
Dover verdict suggests that this ecules. Making sense of that data
transposon invasion took place “Whatever the actual evolutionary may demand conceptual break-
even earlier. throughs in understanding the pur-
In 2006, a team led by Jonathan pathway that led to the very complex pose of our immune defenses.
Rast of the University of Toronto in Many immunologists accustomed
Canada and Sebastian Fugmann of vertebrate adaptive [immune] system, to studying people, mammals, or
the National Institute on Aging in other vertebrates assume that the
Bethesda, Maryland, analyzed the it was surely a gradual progression
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adaptive immune system emerged
genome of the purple sea urchin because it allowed these more com-
and found genes that closely resem- that co-opted many preexisting plex animals to deal with more
ble RAG1 and RAG2, the first time immune mechanisms.” complex microbial threats. And
they’ve been uncovered in inverte- Thompson, now scientific director
brates. Their existence in the urchin —Jonathan Rast, at the Abramson Family Cancer
suggests that the transposon with University of Toronto Research Institute in Philadelphia,
these enzymes invaded animals far Pennsylvania, thinks the key advan-
earlier than had been thought but was lost in nize common microbial features such as bac- tage is that the adaptive response conserves
most lineages except for jawed vertebrates, terial wall components or the distinctive DNA scarce resources by quickly fine-tuning the
which adapted them to perform VDJ recombi- sequences of a virus. This role could date back otherwise all-out assault mounted by the
nation. That’s an easier version of the story for to the earliest multicellular organisms, as innate immune system. “Specificity gives you
some immunologists to swallow, as it allows humans and some of the most evolutionarily the advantage of being able to use the least
more time for mutations to deactivate the primitive animals share TLRs and the mole- amount of an immune system,” he says.
jumping ability of a transposon and convert its cules involved in the TLR signaling cascade. Still, some invertebrate biologists aren’t
DNA to a new job. “There was never a big The sea urchin genome revealed more than convinced that their colleagues have nailed
bang of immunology,” suggests Bosch. 200 TLR genes, for example, and in 2006, a down the selective advantage of the adaptive
Thompson and others aren’t so ready to group headed by Werner E. G. Müller of the immune system. “It’s very hard to say what is
defuse the explosive hypothesis, however. University of Mainz in Germany reported that the benefit,” says Bosch. He predicts one
The RAG1-RAG2 transposon may sponges also encode these microbial important line of future inquiry in the evolu-
have entered sea urchins and verte- tionary study of immunology will be how
brates independently, they stress. The immune systems have helped organisms
role of RAG1 and RAG2 in sea urchins adapt to their specific environments or
remains unknown, and Rast agrees that ecological niches.
the timing of the transposon invasion Bosch also cites the growing realiza-
responsible for adaptive immunity tion that animals harbor within their bodies a
won’t be nailed down until more inverte- world of microbes that are crucial to devel-
brate genomes are deciphered over the opment, nutrition, and more; by some esti-
next few years. “The basic idea of an immune mates, humans are 90% bacterial cells.
‘big bang’ in the vertebrates has led to a vari- Immunologists, says Bosch, need to shift
CREDIT: NICK MATZKE/NATIONAL CENTER FOR SCIENCE EDUCATION
ety of oversimplifications and conceptual their thinking “from bacteria make you sick
problems,” says Rast. “Whatever the actual to bacteria make you healthy.” Such a shift
evolutionary pathway that led to the very may ultimately force a reconsideration of the
complex vertebrate adaptive system, it was roots of the immune system. Did the innate
surely a gradual progression that co-opted and adaptive arms truly evolve to keep out
many preexisting immune mechanisms.” harmful organisms? Or instead, are one or
both more like bouncers at a nightclub,
First line of defense honed for the more subtle task of allowing
Researchers have also made progress under- the right microbes in and kicking the less
standing the origins of innate immunity, desirable ones out? If another evolution-
encouraged by the recent appreciation that versus-ID trial ever takes place, biologists
these defenses can be as sophisticated and addressing this provocative question will
no doubt have added to the impressive
Exhibit A. This stack of evolutionary immune stack of literature on how our immune
research literature was used in the Dover trial. system arose. –JOHN TRAVIS
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