JUMP INTO THE GENE POOL - Survival of the Sickest: A Medical Maverick Discovers Why We Need Disease - Sharon Moalem

Survival of the Sickest: A Medical Maverick Discovers Why We Need Disease - Sharon Moalem (2007)


Edward Jenner was just a country doctor in Gloucestershire, England, at the end of the eighteenth century when he noticed a surprising pattern. Milkmaids who caught cowpox (that’s what happens when you used to spend a lot of time with cows), a very mild infection in humans, seemed to be resistant to smallpox, a very deadly infection in humans. So Jenner wondered whether he could duplicate the effect intentionally. He scraped a cowpox sore on an infected milkmaid and purposefully infected several teenage boys. Sure enough, his hunch was correct. The cowpox infection resulted in protection from smallpox, and Edward Jenner—not just a simple country doctor after all—had the first vaccine on his hands. The word vaccine actually comes from the Latin word for cow, vacca, and the Latin name for cowpox, vaccinia.

Today, we know a lot more about how vaccination works. It begins with a relatively harmless version of the virus we want to vaccinate against (harmless because it’s weakened or killed and broken up into pieces or, like cowpox, a relative close enough to the harmful virus that our bodies will recognize it, but distant enough that it does not cause serious disease). By introducing the harmless virus to our bodies, we stimulate our immune systems to produce antibodies specifically tailored to defend against that virus. Then, if we are exposed to the harmful version, our bodies are prepared to defend themselves immediately. Cowpox, for example, causes only a very mild infection in people, but its structure is so close to that of smallpox that the antibodies our immune systems produce to fight cowpox will also work against smallpox. Without having the right-fitting, preformed antibodies, viral attackers can make us sick before our immune system has time to generate the antibodies we need to fight back.

Now, here’s where it really gets interesting. There’s a massive number of potential microbial attackers out there, and our bodies produce a specific antibody to fight back against each and every one. For a long time, scientists couldn’t understand how that worked—there just didn’t seem to be enough active genes in humans to direct the production of all these antibodies.

Of course, they didn’t know that genes could change.

EVERY HUMAN BEING starts off with exactly the same number of cells as the simplest form of bacteria—one. That single cell, or zygote, is the product of the union of two other cells—a sperm cell supplied by the father and an egg cell supplied by the mother—that combine to produce a human in progress. Millions of years of evolutionary pressure, response, adaptation, and selection come together in that first cell—it contains every single genetic instruction to manufacture the proteins used to build a human being. All of those instructions are carried in about 3 billion pairs of nucleotides; those pairs of nucleotides are called DNA base pairs, of which there are assumed to be less than 30,000 genes. The genes themselves are organized among twenty-three pairs of chromosomes, for a total of forty-six.

One set of twenty-three chromosomes comes from the mother and one comes from the father. Every pair except for the twenty-third—the sex chromosomes—is a matched pair. In other words, each chromosome carries the same type of instructions, although they will vary greatly in how they instruct your body to carry out those instructions. For example, let’s just say that specific chromosomes contain instructions for whether or not you’ll have hair on your fingers; the instructions may code for hairy fingers in the chromosomes that come from your father, while coding for hairless fingers in the chromosomes that come from your mother. In that case, you will have hair on your fingers—the trait for hairy fingers is dominant, while the trait for hairless fingers is recessive. That means one copy of the fictious gene for hairy fingers is enough to ensure that you exhibit that trait. You need two copies of the gene for hairless fingers—one from your mother and one from your father—in order to have hairless fingers yourself.

Usually, with one very important exception, every cell in your body contains the same DNA—two complete sets of chromosomes with all the genes containing all the instructions you need to build every type of protein and every type of cell. The exception is germ cells, the cells that combine to produce off spring. Sperm and eggs each contain only one set of twenty-three chromosomes; when they unite to form a zygote, the resulting cell has a full complement of forty-six chromosomes, two sets of twenty-three each. But from the moment you’re a sparkle in daddy’s eye and a single-celled zygote on the way to implanting in mommy’s uterus, every other cell includes your complete blueprint. Your toenails have the code to build brain cells—and your brain cells have the code for toenails. And fingernails. And blood cells. And just about everything else in your body.

But what’s even more interesting is that less than 3 percent of your DNA contains instructions for building cells. The vast majority of your DNA—97 percent of it—isn’t active in building anything. Think about that. If you took the DNA from any cell in your body and laid it end to end, it would reach the top of Shaquille O’Neal’s head—but the DNA that actively codes for building your body wouldn’t even reach his ankle.

Scientists initially called all this additional genetic material “junk DNA.” They originally assumed that if it didn’t code for cellular production, it was essentially parasitic—more or less lounging in the gene pool for millions of years without making any contribution to its upkeep. In other words, they thought this DNA did nothing for us at all; they imagined it was just hitching a ride through life, not hurting us, not helping us, just helping itself.

A series of new research is beginning to demonstrate that the previous assumption that so-called junk DNA is junk—was bunk. It turns out that the massive volume of genetic information in this portion of our genome may play a critical role in evolution. As its importance has been reevaluated, the respect it gets from the scientific community has begun to change; the standard term for this genetic material has even been upgraded—from junk DNA to noncoding DNA, which means it isn’t directly responsible for making proteins.

Perhaps the biggest surprise is where much of this noncoding DNA comes from. You know that idea of a blissful future when bacteria, viruses, and humans live together in happy, healthy coexistence? What if I told you it’s already sort of happening?

Almost every human cell contains microscopic workhorses called mitochondria that function as dedicated power plants, producing the energy to run cells. Most scientists now believe that mitochondria were once independent, parasitic bacteria that evolved a mutually beneficial relationship with some of our premammal evolutionary predecessors. Not only do these likely former bacteria live in almost all your cells, they even have their own inheritable DNA, called mitochondrial DNA, or mtDNA.

Former bacteria aren’t the only microbes we’ve married. Researchers now believe that as much as a third of your DNA is from viruses. In other words, our evolution hasn’t only been shaped by adaptation to viruses and bacteria—it’s probably been shaped by integration of viruses and bacteria.

UNTIL RECENTLY, THE scientific community all but universally agreed that genetic changes were the product of accidental mutations, caused by errors that were only random and always rare. Here’s how those mutations happen. When cells are produced, DNA is copied from the “parent” cell to the “daughter” cell. This process usually produces accurate copies, but errors in the production of the long string of information that composes DNA do occur. In order to protect an organism against these errors, the transcription process is complemented by a proofreading system. Those proofreaders are so good that if we cloned them for publishers, they’d put copy editors out of business. Their error rate is phenomenally low—just one out-of-place nucleotide in every billion copies. When an error does get through, that new combination of DNA sequences, however slight, is a mutation.

Mutations also occur when organisms are exposed to radiation or powerful chemicals (like those found in cigarette smoke and other carcinogens). When that happens, it can also rearrange DNA. Before genetic engineering enabled us to modify food on a molecular level, plant breeders who wanted to create more efficient crops (hardier or more fruit-bearing, for example) would irradiate seeds by blasting them with a ray gun that could have come straight out of Star Trek, and then hope for the best. Most of the time, seeds couldn’t even sprout after being irradiated, but every once in a while this heavy-handed genetic manipulation produced a beneficial trait.

Even the sun can cause mutation—not just by frying your skin and causing skin cancer, but on a global scale. Every eleven years, sunspot activity peaks and increased solar radiation explodes from the sun. Much of that energy is deflected by the earth’s gigantic magnetic field, but some of it can “leak” through and play havoc.

In March 1989, a peak in sunspot activity led to a huge power surge that left more than 6 million people without power in parts of the northeastern United States and Canada. The sun spewed out so much energy that satellites were knocked out of orbit, garage doors began to open and close in California, and millions of people were treated to a version of the northern lights in places as far south as Cuba.

That may not be all the havoc these sunspot peaks cause. There’s a curious correlation between these sunspot peaks and flu epidemics. In the twentieth century, six of the nine sunspot peaks occurred in tandem with massive flu outbreaks. In fact, the worst outbreaks of the century, killing millions in 1918 and 1919, followed a sunspot peak in 1917. This might just be coincidence, of course.

Or it might not. Outbreaks and pandemics are thought to be caused by antigenic drift, when a mutation occurs in the DNA of a virus, or antigenic shift, when a virus acquires new genes from a related strain. When the antigenic drift or shift in a virus is significant enough, our bodies don’t recognize it and have no antibodies to fight it—and that spells trouble. It’s like a criminal on the run taking on a whole new identity so his pursuers can’t recognize him. What causes antigenic drift? Mutations, which can be caused by radiation. Which is what the sun spews forth in significantly greater than normal amounts every eleven years.

The potential for evolution begins when a mutation occurs during the reproductive process of a given organism. In most cases, that mutation will have a harmful effect or no effect at all. Rarely, a random mutation will confer an advantage on its carrier, giving it a better chance to survive, thrive, and reproduce. In those cases, natural selection comes into play, the mutation spreads throughout the population through successive generations, and you have evolution. Adaptations that confer truly significant benefit to a species will eventually spread across an entire species, as when a strain of the flu virus acquires the new characteristic to go pandemic. But organisms, so the collective wisdom went, only happen upon helpful mutations by chance. (Remember, of course, that one species’ advantage may be another species’ disadvantage—an adaptation that allows a bacterium that harms humans to resist antibiotics is an advantage for the bacteria; for us, not so much.)

According to this way of thinking, the genome of every creature, great and small, lacks any ability to react intentionally on a genetic level to environmental changes that threaten its ability to survive and reproduce. It has to depend on luck to find a helpful mutation, or so the thinking goes. When the common strep infection evolves a trait that gives it antibiotic resistance, it’s all luck. When humans evolved to cope with the rapid onset of the Younger Dryas, it was all luck. To be clear, scientists thought natural selection was influenced by the environment—but mutation never was. Mutation was an accident; natural selection occurred when the accident was helpful.

The problem with this theory is that it takes the evolution out of evolution. After all, what would be a more helpful mutation than one that allowed the genome to react to environmental changes and pass on helpful adaptations to successive generations? Surely, evolution would favor a mutation that helped an organism to discover adaptations that would help it survive. Saying otherwise is like saying that the only part of life not subject to evolutionary pressure is evolution itself.

The only-random-changes theory looks even weaker in light of recent work to map the human genome. Geneticists originally believed that every single gene had a single purpose—a gene for eye color, a gene for a widow’s peak, a gene for attached earlobes. When genes went wrong, you ended up with a gene for cystic fibrosis, a gene for hemochromatosis, a gene for favism. That theory suggested the existence of more than 100,000 genes. But today, because of all the work that’s gone into genome mapping, the total number of genes is thought to be about 25,000.

Suddenly, it’s clear that genes don’t have discrete jobs at all—there wouldn’t be nearly enough genes to produce all the proteins necessary for human life if each gene only had one job. Instead, single genes have the capacity to produce many, many different proteins through a complex process of copying, cutting, and combining instructions. In fact, like a casino dealer who never stops, genes can shuffle and reshuffle endlessly to produce a huge array of proteins. There’s one gene in a type of fruit fly that can produce almost 40,000 different proteins!

All this shuffling isn’t restricted to single genes, either—the genetic dealer can borrow cards from other decks, combining parts of one gene with another. On a genomic level, that’s where most of the complexity lies—and it’s where the genetic work of making us human really happens. We may have the same genes as many other organisms, but it’s what we do with them that counts. Of course, the idea that our genome can change has suddenly blurred the lines of what precisely a gene actually is. Yet, from an efficiency perspective, it makes a lot of sense for genes to be resourceful and to maximally utilize existing genetic parts. It’s similar to the Japanese managerial system Kaizen, made famous in the 1980s. According to Kaizen, many working decisions are made on the factory floor and then communicated up to management—it’s much more efficient to make a minor modification to an assembly line than to redesign the whole line.

On top of that, there are all kinds of redundancies built into the system. Scientists discovered this when they isolated specific genes related to specific functions in some organisms and removed those genes. They were shocked when these “knockout” (KO) experiments often did nothing at all; removing the gene in question simply had no effect. Other genes essentially stepped up and filled in for their KOed colleague.

Instead of imagining genes as a set of discrete instructions, scientists have begun to conceive of them as an intricate network of information, with an overall regulatory structure that can react to change. Like a foreman at a construction site who directs a particularly fast welder to pick up the slack when his buddy doesn’t show up for work, the genome system can react to a knocked-out gene and get a body built just the same. Except the foreman isn’t only a particular gene giving orders; rather, the whole system is interconnected and automatically covers for its parts.

You can see how these discoveries make it even harder to imagine how evolution relied only on random little changes in the code of individual genes to find the myriad adaptations that have allowed every living thing on earth to survive. If removing whole genes often has no effect on a creature, how could such minor changes be the only chance for the evolution of a new species, or even the successful adaptation of an existing one?

They probably can’t.

JEAN-BAPTISTE LAMARCK WAS a French thinker and student of nature who popularized some of the current thinking about evolution and heredity in 1809 with the publication of his book Zoological Philosophy. In popular accounts of the history of evolutionary theory, Lamarck is built up into a somewhat foolish scientist who advances a series of wrongheaded theories about evolution and eventually “loses” an intellectual war with Charles Darwin.

According to the popular story, Lamarck was the chief proponent of a theory of inherited acquired traits. The essence of that theory is the idea that traits acquired by a parent during his or her lifetime could then be passed on to his or her off spring. It’s suggested, for example, that Lamarck believed that giraffes’ long necks were the result of each generation’s straining its neck ever farther to reach leaves on higher branches. Or that a blacksmith’s son would be born with stronger arms because his father developed those muscles hammering against his anvil. According to the myth about Lamarck, Darwin came along and proved Lamarck all wrong, debunking the notion that traits acquired in the lifetime of a parent could be passed to its off spring.

In fact, very little of this story is true. The truth is Lamarck was more of a philosopher than a scientist. And his book was more of a layman’s description of current evolutionary thinking designed for a general audience than a treatise of scientific analysis. Lamarck did promote the concept of “inherited acquired traits,” but he also promoted the concept of evolution—and he didn’t come up with either one, nor did he pretend to. At the time, the notion of inherited acquired characteristics was widely held, including by Darwin. Darwin even praised Lamarck in Origin of the Species for helping to popularize the idea of evolution.

Unfortunately for him, poor Jean-Baptiste became the victim of a schoolbook version of the theory he didn’t develop. Somewhere along the line a science writer (whose name is lost to history) acquired the notion that Lamarck was responsible for the idea of inherited acquired traits, and generations of successive science writers have inherited that idea and passed it on. In other words, somebody blamed the theory on Lamarck, and lots of other people have repeated it, right up to today. Textbooks still tell of silly-sounding Lamarckian researchers attempting to prove their theories by cutting off the tails of generation after generation of mice, waiting in vain for a generation to be born without tails.

Here’s the funny thing—the theory of inherited acquired traits that’s responsible for Lamarck’s general disregard? It isn’t exactly right, but it may not be exactly wrong.

LET’S LEAVE THE story of the fellow guilty of nothing more than repeating the widely accepted theories of his time and turn to a woman who offered theories widely dismissed in hers. Barbara McClintock was the Emily Dickinson of genetics—a brilliant, influential, revolutionary thinker who was ignored by her peers for most of her life. She received her Ph.D. in 1927, when she was twenty-five years old. For the next fifty years, she pursued her singular ideas with little need for—and little receipt of—recognition or encouragement.

Most of her research focused on the genetics of corn—its DNA, its mutation, and its evolution. As I’ve said, just about every geneticist in the twentieth century believed that genetic mutations were random, rare, and relatively small. But in the 1950s, McClintock produced evidence that in certain circumstances, parts of the genome actively triggered much larger changes. This wasn’t evidence of minor mutations in which a slight change in one gene on one chromosome slipped through the proofreading system; this was evidence of seismic changes on the genetic scale. Especially when the plants were stressed, McClintock discovered whole sequences of DNA moving from one place to another, even inserting themselves into active genes. When these genes cut and pasted themselves from one place in the corn’s DNA to another, they actually affected nearby genes—by changing the sequence of DNA, they sometimes turned genes on and sometimes turned them off. What’s more, McClintock found that these wandering genes weren’t behaving completely randomly—there was a method to their meandering. First of all, they relocated to certain parts of the genome more often than to other parts. Second, these active mutations appeared to be triggered by outside influences, by changes in the environment that threatened the survival of the corn, like extreme heat or drought. In short, the corn plant seemed to be engaged in some sort of intentional mutation—neither random, nor rare.

Today, the genetic nomads McClintock discovered are called “jumping genes,” and they have reshaped our understanding of mutation and evolution. But widespread acceptance of her thinking was a long time coming. When she first presented her ideas in 1951 at the famed Cold Spring Harbor Laboratory on Long Island, where she worked, she might as well have been jumping up and down for all the respect she received. Instead of being toasted, she was greeted with that tired brew of skepticism and scorn that all too often welcomes fresh thinking of any kind.

Over the next thirty years, as molecular biology and genetics evolved themselves, others slowly began to appreciate McClintock’s work. Jumping genes were found in other genomes, beyond corn. Our understanding of mutation began to shift.

In 1983, at the age of eighty-one, Barbara McClintock received a Nobel Prize. With characteristic focus, she continued to look past current thinking and, in her acceptance speech, imagined a future when

attention undoubtedly will be centered on the genome, with greater appreciation of its significance as a highly sensitive organ of the cell that monitors genomic activities and corrects common errors, senses unusual and unexpected events, and responds to them, often by restructuring the genome.

McClintock’s discovery of the “jumping gene” opened the door to the possibility of much more robust mutations than the random and rare that theory allowed. This, in turn, suggested that evolution itself could be faster and more sudden than ever before imagined. Instead of a minor spelling error in one word in one verse of the DNA songbook, whole melody lines could insert themselves all over the genome. Like a good hip-hop artist, the genome has the ability to “sample” itself, creating different, but similar, riff s. And a sturdy, networked genome—the emerging notion of a genome that could cope with problems like an active gene’s being knocked out—could often survive, and sometimes benefit, from such improvisation.

Scientists are still only beginning to understand how jumping genes—or transposons, as they’re known—actually work. Sometimes they copy and paste—copying themselves and then inserting the new material elsewhere in the genome while remaining in their original location. Other times they cut and paste—removing themselves from their starting place and inserting themselves somewhere else. Sometimes the new genetic element stays in place, and sometimes it’s removed by the proofreading system or suppressed by other methods.

This much is clear—sometimes, these transposable genetic elements remain in an active gene once they’ve inserted themselves, and they make a difference. A recent study demonstrated just how much difference a jumping gene can make under the right conditions. A jumping gene in one line of fruit flies turned the line into semi-superhero fruit flies (researchers aptly named the fly “Methuselah”), with the ability to resist starvation and withstand high temperature, as well as a life expectancy that was 35 percent longer than usual.

The key question for scientists to unravel now is why these transposons get the urge to jump. McClintock believed that the jumps are a genomic response to internal or environmental stress that cells can’t handle under their existing setup. Essentially, a challenge to survival triggers the organism to throw the mutation dice, hoping it will land on a change that will help. That’s what she thought was going on with the corn plants she was studying—too much heat or too little water triggered the corn to gamble its survival on finding a mutation that could help it survive. When that happens, the proofreading mechanism is suppressed and mutations are allowed to blossom. Then natural selection kicks in to select the adaptive mutations over the maladaptive mutations in future generations and presto, evolution!

McClintock not only observed that jumping genes were jumpiest during times of stress, she also noted that they tended to jump to certain genes more than others. She believed this was intentional—if the jumps were random, they would land with similar frequency across the genome. Instead, she believed the genome directed its jumpers toward those places in the genome where mutations were most likely to have a beneficial effect. In other words, the dice were loaded for the corn’s benefit—even if just a little bit.

The extent to which these jumping genes have fascinated scientists is evident in the names they have been given: gypsy, mtanga (Swahili for wanderer), Castaway, Evelknievel, and mariner. Those aren’t genes from any particular species and we’re still learning about their various functions, but when most genes are given sexy names like ApoE4, it’s clear that many scientists are fans of these genes, and entranced by what they can teach us. There’s even one called “Jordan” named by Washington University researchers after Michael Jordan’s amazing leaping ability.

Today, scientists continue to follow McClintock’s lead away from the notion that the genome is a rigid set of plans and that mutation—and thus, evolution—is only triggered by rare and random errors. As Dr. Gregory Dimijian of the University of Texas writes:

The genome has long been thought of as an archival blueprint of life, a relatively permanent record. Mobile genetic elements [such as McClintock’s jumping genes] are replacing that view with one of an ephemeral environment, undergoing continuous remodeling.

In other words, the genome likes to move the furniture around.

A SERIES OF studies in the 1980s and 1990s provided additional insight into the genome’s ability to gamble on mutation. The first was documented in an incendiary 1987 report by Harvard researcher John Cairns in the journal Naturethat used language harkening back to the theory of inherited acquired traits—the theory wrongly assigned to Lamarck. Cairns conducted studies with Eschericia coli, a bacteria known to its friends and human hosts as E. coli. (And despite the fearful reputation it has earned because bad strains sometimes turn up in the wrong place killing people, E. coli does far more good than harm—it’s one of the essential bacteria toiling away in your digestive system right now that we discussed earlier.)

E. coli is a digestive workhorse in humans and can come in many different “flavors” or variants, one of which can’t naturally digest lactose, a sugar derived from milk. Nothing is a bigger threat—or evolutionary pressure—to bacteria than starvation. So Cairns deprived milk-shunning E. coli of any food except lactose. Much more rapidly than chance should have allowed, bacteria developed mutations that allowed them to lose their lactose intolerance. Just as McClintock maintained about her corn plants, Cairns also reported that bacteria appeared to target specific areas of their genome—areas where mutations were most likely to be advantageous. Cairns concluded that the bacteria were “choosing” which mutations to go after and then passing on their acquired ability to digest lactose to successive generations of bacteria. In a statement that amounted to evolutionary heresy, he wrote that E. coli“can choose which mutation they should produce” and may “have a mechanism for the inheritance of acquired characteristics.” He straight-out raised the possibility of inherited acquired traits; he basically used those words. It was like shouting, “Go Sox” at Yankee Stadium during the ninth inning of the seventh game of the playoff s—with Boston leading by a run.

Since then, researchers have plunged into their petri dishes in attempts to prove, disprove, or just explain Cairns’s work. A year after Cairns’s report came out, Barry Hall, a scientist at the University of Rochester, suggested that the bacteria’s ability to happen upon a lactose-processing adaptation rapidly was caused by a massive increase in the mutation rate. Hall called this “hypermutation”—sort of like mutation on steroids—and, according to him, it helped the bacteria to produce the mutations they needed to survive about 100 million times faster than the mutations otherwise would have been produced.

In 1997, other studies added credibility to the hypermutation theory. A significant increase in mutation rates was noticed when E. coli were starved of their normal diet but surrounded by lactose. These studies reported an uptick in mutation across the bacterial genome—many different mutations, not just the targeted mutations designed to overcome lactose intolerance that Cairns observed. But even though these researchers reported a greater range of mutation than Cairns documented, the overall increase in mutation also suggests that the genome has the ability to order mutations on demand when the regular genetic programming just isn’t good enough. And French researchers led by Ivan Matic, of the Institut National de la Santé et de la Recherche Médicale, studied hundreds of bacteria from all over the world and found that they also went into hyperdrive, mutationally speaking, when put under stress. Although the evidence is mounting, the case of hypermutation is definitely still pending.

CRAZY CORN, Agene named after an NBA basketball player, and lactose-intolerant bacteria are all well and good—but you’re probably wondering what all this has to do with us. Before we dive into the human gene pool, let’s review a few rules, starting with a generally accepted genetic principle called the Weismann barrier. August Weismann was a nineteenth-century biologist who developed the germ plasma theory, which divides the body’s cells into two groups, germ cells and somatic cells. Germ cells are cells that contain information that is passed on to your children. Eggs and sperm are the ultimate germ cells. Every other cell in your body is a somatic cell—red blood cells, white blood cells, skin cells, hair cells are all somatic cells.

The Weismann barrier stands between germ cells and somatic cells: the theory maintains that information in somatic cells is never passed on to germ cells. So a mutation that occurs on the somatic side of the barrier, say, in a red blood cell can’t move over to the germ side and, thus, will never be passed on to your children. That doesn’t mean a mutation in the germ line can’t affect somatic cells in your off spring. Remember that all of the instructions to build and maintain your body originated in the germ line of your parents. So a mutation in your germ line that changes the instructions for hair color would affect the hair color of your children.

The Weismann barrier is an important organizing principle in genetic research, but some research suggests that it isn’t as impenetrable as we once thought. Some retroviruses or viruses, which we’ll discuss in more detail shortly, may be able to penetrate the Weismann barrier and carry DNA from somatic cells to germ cells. If so, that would theoretically open the door to the idea that acquired adaptations could be passed on to future generations.

Which would mean that Lamarck—discredited for spreading one of many ideas that wasn’t his own—got a really raw deal.

FROM AN EVOLUTIONARY perspective, we’re mostly familiar with germ line mutations—mutations that result in a different gene in egg or sperm that produces a new trait in the off spring. And as you know, when new traits increase the off spring’s ability to survive or reproduce, it’s more likely to spread throughout the population as the first generation of off spring with the new trait passes it on to the next. When a new trait inhibits survival or reproduction, it will ultimately disappear, as those who carry it are less likely ultimately to survive. But mutations occur outside the germ line all the time. Cancer, of course, is one of the most common—and one of the most frightening—examples. At its most basic, cancer is uncontrolled cell growth caused by a mutation in the gene that is supposed to control the growth of the cancerous cells. Some cancers are at least partially hereditary—mutations in the BRCA1 or BRCA2genes significantly increase the risk of breast cancer, for example, and those mutations can be passed from one generation to another. Other cancers can be caused by mutations that are caused by external triggers—like smoking or exposure to radiation.

It’s true that most mutations—especially somatic mutations, like the mutations in lung cells that can be caused by smoking—don’t work out so well. That makes sense. Biological organisms, especially humans, are pretty complicated. But mutation, by definition, isn’t necessarily bad; it’s just different. And that, it turns out, may be the key to how jumping genes help humans in two very important ways.

Jumping genes are very active in the early stages of brain development, inserting genetic material all over the developing brain, almost helter-skelter, as a normal part of brain development. Every time one of those jumpers inserts or changes genetic material in brain cells, it’s technically a mutation. And all of that genetic jumping around may have a very important purpose—it may help to create the variety and individuality that make every brain unique. This developmental frenzy of genetic copy and paste only happens in the brain, because that’s where we benefit from individuality. But as the lead author of the study that discovered this phenomenon, Professor Fred Gage said, “You wouldn’t want that added element of individuality in your heart.”

The neural network in your brain isn’t the only complex system that welcomes diversity—your immune system does too. In fact, your immune system employs what has got to be the most diverse workforce in history; we wouldn’t have survived long as a species without it. In order to fight the huge array of potential microbial invaders that threaten us, the human immune system employs more than a million different antibodies—specialized proteins that target specific invaders. The mechanism through which we produce all those different proteins isn’t completely understood, especially because we don’t have nearly enough genes to explain it (remember, there are only about 25,000 active, coding genes, and we’re talking about the possibility of more than a million different antibodies). But new research led by scientists from Johns Hopkins has linked the immune system’s antibody production mechanism to the behavior of jumping genes.

B-cells are the basic building blocks for antibodies. When we need to produce a specific antibody, B-cells seek out the instructions for that antibody in their DNA, although the individual lines of instruction are usually mixed in with instructions for other antibodies. They snip away the lines of instruction for other antibodies and sew the rest back together, essentially rewriting their own genetic code and producing a specialized product in the process. This is called V(D)J recombination, named after the regions where the genes that are used in this seek-snip-and-sew trick are found.

This process sounds similar to the cut-and-paste mechanism employed by some jumping genes, but there is one key difference—instead of a neat connection, V(D)J recombination leaves a little loop when it reconnects the remaining strands. Scientists had never seen this loop effect in jumping genes, until the Johns Hopkins team found it in the common fly where a jumping gene called Hermes behaves just like V(D)J. Nancy Craig, one of the scientists behind the study, said:

Hermes behaves more like the process used by the immune system to recognize a million different proteins…than any previously studied jumping gene. It provides the first real evidence that the genetic processes behind…[antibody] diversity might have evolved from the activity of a jumping gene, likely a close relative of Hermes.

Once your body develops antibodies against a specific invader, you always have those antibodies—which often give you a leg up if that invader tries again. Sometimes, that even makes you immune to future infections, like most people are after having had measles. But while the mutations that happen in our B-cells are ours to keep, we can’t pass them on to our children—they’re on the somatic side of the Weismann barrier. Babies are born with a very small number of antibodies, and their immune systems have to start in overdrive. That’s one of the many reasons breast-feeding is good for babies—breast milk contains some of the mother’s antibodies, which act as a temporary passive vaccination against infections until the baby’s immune system is up and running. We’re only just beginning to understand the role that transposable elements—jumping genes—play in life and evolution. They clearly play a much bigger role than we’ve understood to date. Fully one-quarter of active—coding—human genes show evidence that they’ve incorporated DNA from jumping genes.

Jef Boeke, a professor of molecular biology and genetics at the Johns Hopkins School of Medicine, suggests that jumping genes

have been remodeling host genomes more than previously realized…. These changes were probably frequently disastrous, but occasionally they might have benignly increased genetic variation or even improved survivability or adaptability. Such remodeling probably happened thousands of times during human evolution.

We now know that there have been periods of such massive environmental shift it’s hard to imagine random, incremental changes providing enough adaptation to let us survive. Prominent evolutionary thinkers Stephen J. Gould and Nils Eldredge advanced the theory of punctuated equilibrium—the notion that evolution was characterized by a state of general equilibrium punctuated by periods of significant change that were brought about by large environmental shifts. Is it possible that jumping genes helped species adapt their way through those evolutionary exclamation points? You bet.

Jumping genes are beginning to look like Mother Nature’s version of on-the-fly genetic engineering. The more we understand how they work, the more they may reveal about how our immune systems protect us against disease and how our very genetic structure responds to environmental stress. This could open up whole new avenues to immunize people against disease, restore compromised immune systems, and even reverse dangerous mutations on a genetic level.

REMEMBER ALL THAT “junk DNA”? That’s the stuff that we now call noncoding DNA because it doesn’t contain the genetic code to build any cells directly. If you’re wondering why we would give millions of strands of DNA a piggyback through evolution, you’re not alone. That’s why scientists called it junk in the first place. But scientists have now begun to decipher the mystery of those noncoding genes. And it was jumping genes that first provided a key.

Once the scientific community recognized that jumping genes were real—and important—researchers started to look for them in genomes of all kinds, including humans. Their first surprise was that a large portion of our noncoding DNA is made up of jumping genes—as much as half of it. But the bigger surprise was this—those jumping genes look an awful lot like a very special type of virus. You heard that right—a huge percentage of human DNA is related to viruses.

You may think about viruses every day—at least about how to avoid them, whether it’s the computer or the biological variety—but it’s probably been a while since you read about one in a biology book, so here’s a quick refresher. A virus is a snippet of genetic instructions that cannot reproduce on its own. Viruses can only reproduce by infecting a host and then hijacking the host’s own cellular machinery. They may replicate themselves thousands of times inside a cell before eventually bursting its walls and moving into new cells. Most scientists don’t consider viruses to be “alive,” because they can’t reproduce or metabolize on their own.

Retroviruses are a very special subset of viruses. In order to understand what makes them so important, it helps to understand how genetic information is used to build cells and, ultimately, organisms. Generally speaking, body building follows this pathway—DNA to RNA to protein. Think of DNA as a library of master blueprints for a whole town and all the different cells in your body as different kinds of buildings—schools, municipal buildings, houses, apartment buildings. When an organism needs to build a particular building, it uses a helper enzyme called RNA polymerase to copy the plans for that building onto strands of messenger RNA, or mRNA. The mRNA takes those instructions to the building site and directs construction of whatever building—or protein—is called for.

For a long time, scientists thought genetic information flowed in only that one direction, DNA to RNA to protein. The discovery of retroviruses—like HIV—proved that wrong. Retroviruses are made of RNA. Using an enzyme called reverse transcriptase, they transcribe themselves from RNA into DNA—they actually reverse the information flow. It’s sort of like the messenger rewriting the master blueprint instead of copying and carrying the plans. The implications of this are huge; retroviruses can literally change your DNA. The discovery of RNA that could backslide into DNA led to the development of the novel drugs that are the current mainstay in the “cocktail” therapy used to treat HIV infection. Like a wheel block used by truckers to park their loads, some of these drugs stop the reverse transcriptase enzyme in its tracks: that leaves HIV stuck within the nuclear truck stop, trying to hitch a ride on DNA but unable to climb on board.

Now imagine what happens when a retrovirus or virus writes itself into the DNA of cells in the germ line of an organism. That organism’s off spring is born with the virus permanently encoded in its DNA. (By the way, scientists don’t think that HIV breaks through the Weismann barrier and inserts itself into the DNA of eggs or sperm. Instead, they believe infected mothers pass HIV to their babies during birth when there’s a significant opportunity for the mother’s blood to mingle with the infant’s.)

Usually, of course, as with all mutations, when an organism’s off spring is born with DNA that has been changed by a retrovirus in one of its parents’ germ cells, that change is probably harmful, so it doesn’t last. But if the virus doesn’t hurt—or even helps—the off spring’s chance to survive and reproduce, that virus may end up a permanent part of the gene pool. If genetic code that originally came from a virus is part of an organism’s gene pool, it’s pretty hard to say where one ends and the other begins—virus and organism have become one and the same. Today, we know that at least 8 percent of the human genome is composed of retroviruses and related elements that have found a permanent place in our DNA—they’re called HERVs, or human endogenous retroviruses. Scientists are only beginning to uncover the role HERVs play in human health, but they’ve already found interesting connections. One study showed that a particular HERV may play an important role in the construction of a healthy placenta; another documented links between HERVs and the skin disorder psoriasis.

And those frisky jumping genes? They may very well be descended from viruses, too. There are two basic types of jumping genes—the first type are called DNA transposons and they jump through a cut-and-paste process; the second type, retrotranspo-sons, are copy-and-paste jumpers. It turns out that copy-and-paste jumping genes—retro transposons—look an awful lot like retroviruses. That makes sense, because the mechanism those copy-and-paste genes use to insert themselves in other genes is very similar to the mechanism retroviruses use. First, a retrotransposon copies itself onto RNA like any normal gene. Then, when the RNA reaches the place in the genome the jumper wants to land in, the retrotransposon uses reverse transcriptase to paste itself into the DNA, reversing the normal information flow just like a retrovirus does.

Does that mean retro jumping genes are descended from retroviruses?

NOBODY BELIEVES IN the power of viral marketing like Luis Villarreal does. At least, nobody believes there’s anything on earth that’s better than a virus at spreading its message, getting into everything, and generally outlasting the competition. Villarreal is the director of the Center for Virus Research at the University of California at Irvine, and he’s followed the implications of viral impact on human evolution to the limit.

Villarreal gives Salvador Luria, a Nobel Prize-winning microbiologist whose work stretched from the 1940s to the 1980s, credit for the first suggestion that viruses have helped to spark human evolution from the inside, not just the outside. In 1959, Luria wrote that the movement of viruses into genomes had the potential to create “the successful genetic patterns that underlie all living cells.”

Villarreal speculated that this idea didn’t catch on very quickly because people react with a kind of visceral disgust to the suggestion that we’ve been shaped by parasites:

There’s a very strong cultural, negative response to the concept of a parasite of any kind. The irony is that…this is such a crucial creative force…. If you want to evolve, you have to be open to being parasitized.

In his book Viruses and the Evolution of Life, published in 2005, Villarreal argues it’s high time to take a fresh look at viruses. Villarreal distinguishes familiar, deadly parasites like HIV and smallpox from those he calls “persisting viruses.” Persisting viruses are the viruses that have migrated into our genome over millions of years and may have become our partners in evolution.

It seems clear what the viruses get out of a permanent home in our genomic mother ship—a free ride through life. But what do we get out of it? Well, viruses are master mutators—they are vast storehouses of genetic possibility and they can deliver that possibility incredibly fast, mutating as much as a million times faster than we do. To drive home the sheer volume of genetic potential in the viral world, Villarreal often asks people to try to imagine all of the viruses in the world’s oceans—all 100,000,000,000,000,000, 000,000,000,000,000 of them (that’s 100 nonillion for those of you who are counting). These little containers of genetic code are microscopic, but if you laid them end to end they would be 10 million light-years long. By tomorrow, most of them will have spawned a new generation—and that’s what they’ve been doing for several billion years. Villarreal calls viruses “the ultimate genetic creators, inventing new genes in large numbers, some of which find their way into host lineages following stable viral colonization.”

Here’s how that works for us. Persisting viruses in our genome have as much at stake in our survival and reproduction as we do—since they’re part of our DNA, they’ve got an evolutionary interest in our success. Over the last few millions of years, perhaps we’ve given them the ride of their life and, in return, they’ve given us the chance to borrow some code from their huge genetic library. With all that mutating power, they are bound to happen on useful genes far faster than we could without their help. Essentially, this partnership with viruses may have helped us evolve into complex organisms much faster than we would have on our own.

The study of jumping genes has produced evidence that bolsters Villarreal’s theory. As we’ve discussed, jumping genes are probably descended from viruses. As it turns out, the more complex an organism is, the more jumping genes it has. Humans and our African primate relatives even share a particular genetic trait that makes it easier for our genomes to do business in the viral marketplace. Our genomes have been modified by one particular retrovirus in a way that makes it easier for us to be infected by other retroviruses. According to Villarreal, this capacity of African primates to support the persistent infection of other viruses may have put our evolution on “fast forward” by allowing more rapid mutation through exposure to other retroviruses. It’s possible that this capacity helped spur our evolution into humans.

Which means that all that “junk DNA” may have possibly provided the code for our evolution up and away from our furry cousins. Which means that viruses may have infected us with that code. Which means—

Infectious design, anybody?