Discover Magazine - DNA is not Destiny

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http://discovermagazine.com/2006/nov/cover11.22.2006DNA Is Not DestinyThe new science of epigenetics rewrites the rules of disease,heredity, and identity.by Ethan WattersBack in 2000, Randy Jirtle, a professor of radiation oncology at DukeUniversity, and his postdoctoral student Waterland designed agroundbreaking genetic experiment that was simplicity itself. Theystarted with pairs of fat yellow mice known to scientists as agoutimice, so called because they carry a particular gene—the agoutigene—that in addition to making the rodents ravenous and yellowrenders them prone to cancer and diabetes. Jirtle and Waterland setabout to see if they

could change the unfortunate genetic legacy ofthese little creatures.Typically, when agouti mice breed, most of the offspring are identicalto the parents: just as yellow, fat as pincushions, and susceptible tolife-shortening disease. The parent mice in Jirtle and Waterland'sexperiment, however, produced a majority of offspring that lookedaltogether different. These young mice were slender and mousy brown.Moreover, they did not display their parents' susceptibility to cancerand diabetes and lived to a spry old age. The effects of the agoutigene had been virtually erased.Remarkably, the researchers effected this transformation withoutaltering a single letter of the mouse's DNA. Their approach insteadwas radically straightforward—they changed the moms' diet. Startingjust before conception, Jirtle and Waterland fed a test group ofmother mice a diet rich in methyl donors, small chemical

clusters thatcan attach to a gene and turn it off. These molecules are common inthe environment and are found in many foods, including onions, garlic,beets, and in the food supplements often given to pregnant women.After being consumed by the mothers, the methyl donors worked theirway into the developing embryos' chromosomes and onto the criticalagouti gene. The mothers passed along the agouti gene to theirchildren intact, but thanks to their methyl-rich pregnancy diet, theyhad added to the gene a chemical switch that dimmed the gene'sdeleterious effects.With no more than a change in diet, laboratory agouti mice (left) wereprompted to give birth to young (right) that differed markedly inappearance and disease susceptibility."It was a little eerie and a little scary to see how something assubtle as a nutritional change in the pregnant mother rat could havesuch a dramatic impact on the

gene expression of the baby," Jirtlesays. "The results showed how important epigenetic changes could be."Our DNA—specifically the 25,000 genes identified by the Human GenomeProject—is now widely regarded as the instruction book for the humanbody. But genes themselves need instructions for what to do, and whereand when to do it. A human liver cell contains the same DNA as a braincell, yet somehow it knows to code only those proteins needed for thefunctioning of the liver. Those instructions are found not in theletters of the DNA itself but on it, in an array of chemical markersand switches, known collectively as the epigenome, that lie along thelength of the double helix. These epigenetic switches and markers inturn help switch on or off the expression of particular genes. Thinkof the epigenome as a complex software code, capable of inducing theDNA hardware to manufacture an impressive variety

of proteins, celltypes, and individuals.In recent years, epigenetics researchers have made great strides inunderstanding the many molecular sequences and patterns that determinewhich genes can be turned on and off. Their work has made itincreasingly clear that for all the popular attention devoted togenome-sequencing projects, the epigenome is just as critical as DNAto the healthy development of organisms, humans included. Jirtle andWaterland's experiment was a benchmark demonstration that theepigenome is sensitive to cues from the environment. More and more,researchers are finding that an extra bit of a vitamin, a briefexposure to a toxin, even an added dose of mothering can tweak theepigenome—and thereby alter the software of our genes—in ways thataffect an individual's body and brain for life.The even greater surprise is the recent discovery that epigeneticsignals from the

environment can be passed on from one generation tothe next, sometimes for several generations, without changing a singlegene sequence. It's well established, of course, that environmentaleffects like radiation, which alter the genetic sequences in a sexcell's DNA, can leave a mark on subsequent generations. Likewise, it'sknown that the environment in a mother's womb can alter thedevelopment of a fetus. What's eye-opening is a growing body ofevidence suggesting that the epigenetic changes wrought by one's diet,behavior, or surroundings can work their way into the germ line andecho far into the future. Put simply, and as bizarre as it may sound,what you eat or smoke today could affect the health and behavior ofyour great-grandchildren.All of these discoveries are shaking the modern biological and socialcertainties about genetics and identity. We commonly accept the notionthat through our DNA we

are destined to have particular body shapes,personalities, and diseases. Some scholars even contend that thegenetic code predetermines intelligence and is the root cause of manysocial ills, including poverty, crime, and violence. "Gene as fate"has become conventional wisdom. Through the study of epigenetics, thatnotion at last may be proved outdated. Suddenly, for better or worse,we appear to have a measure of control over our genetic legacy."Epigenetics is proving we have some responsibility for the integrityof our genome," Jirtle says. "Before, genes predetermined outcomes.Now everything we do—everything we eat or smoke—can affect our geneexpression and that of future generations. Epigenetics introduces theconcept of free will into our idea of genetics."Scientists are still coming to understand the many ways thatepigenetic changes unfold at the biochemical level. One form ofepigenetic

change physically blocks access to the genes by alteringwhat is called the histone code. The DNA in every cell is tightlywound around proteins known as histones and must be unwound to betranscribed. Alterations to this packaging cause certain genes to bemore or less available to the cell's chemical machinery and sodetermine whether those genes are expressed or silenced. A second,well-understood form of epigenetic signaling, called DNA methylation,involves the addition of a methyl group—a carbon atom plus threehydrogen atoms—to particular bases in the DNA sequence. Thisinterferes with the chemical signals that would put the gene intoaction and thus effectively silences the gene.Until recently, the pattern of an individual's epigenome was thoughtto be firmly established during early fetal development. Although thatis still seen as a critical period, scientists have lately discoveredthat the

epigenome can change in response to the environmentthroughout an individual's lifetime."People used to think that once your epigenetic code was laid down inearly development, that was it for life," says Moshe Szyf, apharmacologist with a bustling lab at McGill University in Montreal."But life is changing all the time, and the epigenetic code thatcontrols your DNA is turning out to be the mechanism through which wechange along with it. Epigenetics tells us that little things in lifecan have an effect of great magnitude."Szyf has been a pioneer in linking epigenetic changes to thedevelopment of diseases. He long ago championed the idea thatepigenetic patterns can shift through life and that those changes areimportant in the establishment and spread of cancer. For 15 years,however, he had little luck convincing his colleagues. One of hispapers was dismissed by a reviewer as a "misguided

attempt atscientific humor." On another occasion, a prominent scientist took himaside and told him bluntly, "Let me be clear: Cancer is genetic inorigin, not epigenetic."Despite such opposition, Szyf and other researchers have persevered.Through numerous studies, Szyf has found that common signalingpathways known to lead to cancerous tumors also activate theDNA-methylation machinery; knocking out one of the enzymes in thatpathway prevents the tumors from developing. When genes that typicallyact to suppress tumors are methylated, the tumors metastasize.Likewise, when genes that typically promote tumor growth aredemethylated—that is, the dimmer switches that are normally presentare removed—those genes kick into action and cause tumors to grow.advertisement | article continues belowClick here!Szyf is now far from alone in the field. Other researchers haveidentified dozens of genes,

all related to the growth and spread ofcancer, that become over- or undermethylated when the disease getsunder way. The bacteria Helicobacter, believed to be a cause ofstomach cancer, has been shown to trigger potentially cancer-inducingepigenetic changes in gut cells. Abnormal methylation patterns havebeen found in many cancers of the colon, stomach, cervix, prostate,thyroid, and breast.Szyf views the link between epigenetics and cancer with a hopeful eye.Unlike genetic mutations, epigenetic changes are potentiallyreversible. A mutated gene is unlikely to mutate back to normal; theonly recourse is to kill or cut out all the cells carrying thedefective code. But a gene with a defective methylation pattern mightvery well be encouraged to reestablish a healthy pattern and continueto function. Already one epigenetic drug, 5-azacytidine, has beenapproved by the Food and Drug Administration for use

againstmyelodysplastic syndrome, also known as preleukemia or smolderingleukemia. At least eight other epigenetic drugs are currently indifferent stages of development or human trials.To the surprise of scientists, many environmentally induced changesturn out to be heritable. When exposed to predators, Daphnia waterfleas grow defensive spines (right). The effect can last for severalgenerations.Methylation patterns also hold promise as diagnostic tools,potentially yielding critical information about the odds that a cancerwill respond to treatment. A Berlin-based company called Epigenomics,in partnership with Roche Pharmaceuticals, expects to bring anepigenetic screening test for colon cancer to market by 2008. They areworking on similar diagnostic tools for breast cancer and prostatecancer. Szyf has cofounded a company, MethylGene, that so far hasdeveloped two epigenetic cancer drugs

with promising results in humantrials. Others have published data on animal subjects suggesting anepigenetic component to inflammatory diseases like rheumatoidarthritis, neurodegenerative diseases, and diabetes.Other researchers are focusing on how people might maintain theintegrity of their epigenomes through diet. Baylor College of Medicineobstetrician and geneticist Ignatia Van den Veyver suggests that oncewe understand the connection between our epigenome and diseases likecancer, lifelong "methylation diets" may be the trick to stayinghealthy. Such diets, she says, could be tailored to an individual'sgenetic makeup, as well as to their exposure to toxins orcancer-causing agents.In 2003 biologist Ming Zhu Fang and her colleagues at RutgersUniversity published a paper in the journal Cancer Research on theepigenetic effects of green tea. In animal studies, green teaprevented the growth

of cancers in several organs. Fang found thatepigallocatechin-3-gallate (EGCG), the major polyphenol from greentea, can prevent deleterious methylation dimmer switches from landingon (and shutting down) certain cancer-fighting genes. The researchersdescribed the study as the first to demonstrate that a consumerproduct can inhibit DNA methylation. Fang and her colleagues havesince gone on to show that genistein and other compounds in soy showsimilar epigenetic effects.Meanwhile, epigenetic researchers around the globe are rallying behindthe idea of a human epigenome project, which would aim to map ourentire epigenome. The Human Genome Project, which sequenced the 3billion pairs of nucleotide bases in human DNA, was a piece of cake incomparison: Epigenetic markers and patterns are different in everytissue type in the human body and also change over time. "Theepigenome project is much more

difficult than the Human GenomeProject," Jirtle says. "A single individual doesn't have one epigenomebut a multitude of them."Research centers in Japan, Europe, and the United States have allbegun individual pilot studies to assess the difficulty of such aproject. The early signs are encouraging. In June, the European HumanEpigenome Project released its data on epigenetic patterns of threehuman chromosomes. A recent flurry of conferences have forwarded theidea of creating an international epigenome project that couldcentralize the data, set goals for different groups, and standardizethe technology for decoding epigenetic patterns.Until recently, the idea that your environment might change yourheredity without changing a gene sequence was scientific heresy.Everyday influences—the weights Dad lifts to make himselfmuscle-bound, the diet regimen Mom follows to lose pounds—don'tproduce

stronger or slimmer progeny, because those changes don'taffect the germ cells involved in making children. Even after theprinciples of epigenetics came to light, it was believed thatmethylation marks and other epigenetic changes to a parent's DNA werelost during the process of cell division that generates eggs and spermand that only the gene sequence remained. In effect, it was thought,germ cells wiped the slate clean for the next generation.That turns out not to be the case. In 1999 biologist Emma Whitelaw,now at the Queensland Institute of Medical Research in Australia,demonstrated that epigenetic marks could be passed from one generationof mammals to the next. (The phenomenon had already been demonstratedin plants and yeast.) Like Jirtle and Waterland in 2003, Whitelawfocused on the agouti gene in mice, but the implications of herexperiment span the animal kingdoms."It changes the way we

think about information transfer acrossgenerations," Whitelaw says. "The mind-set at the moment is that theinformation we inherit from our parents is in the form of DNA. Ourexperiment demonstrates that it's more than just DNA you inherit. In asense that's obvious, because what we inherit from our parents arechromosomes, and chromosomes are only 50 percent DNA. The other 50percent is made up of protein molecules, and these proteins carry theepigenetic marks and information." Meaney, a biologist at McGill University and a frequentcollaborator with Szyf, has pursued an equally provocative notion:that some epigenetic changes can be induced after birth, through amother's physical behavior toward her newborn. For years, Meaneysought to explain some curious results he had observed involving thenurturing behavior of rats. Working with graduate student Ian Weaver,Meaney compared two types

of mother rats: those that patiently lickedtheir offspring after birth and those that neglected their newborns.The licked newborns grew up to be relatively brave and calm (forrats). The neglected newborns grew into the sort of rodents thatnervously skitter into the darkest corner when placed in a newenvironment.Traditionally, researchers might have offered an explanation on oneside or the other of the nature-versus-nurture divide. Either thenewborns inherited a genetic propensity to be skittish or brave(nature), or they were learning the behavior from their mothers(nurture). Meaney and Weaver's results didn't fall neatly into eithercamp. After analyzing the brain tissue of both licked and nonlickedrats, the researchers found distinct differences in the DNAmethylation patterns in the hippocampus cells of each group.Remarkably, the mother's licking activity had the effect of removingdimmer

switches on a gene that shapes stress receptors in the pup'sgrowing brain. The well-licked rats had better-developed hippocampiand released less of the stress hormone cortisol, making them calmerwhen startled. In contrast, the neglected pups released much morecortisol, had less-developed hippocampi, and reacted nervously whenstartled or in new surroundings. Through a simple maternal behavior,these mother rats were literally shaping the brains of their offspring.How exactly does the mother's behavior cause the epigenetic change inher pup? Licking and grooming release serotonin in the pup's brain,which activates serotonin receptors in the hippocampus. Thesereceptors send proteins called transcription factors to turn on thegene that inhibits stress responses. Meaney, Weaver, and Szyf thinkthat the transcription factors, which normally regulate genes inpassing, also carry methylation machinery that can

alter geneexpression permanently. In two subsequent studies, Meaney and hiscolleagues were even able to reverse the epigenetic signals byinjecting the drug trichostatin A into the brains of adult rats. Ineffect, they were able to simulate the effect of good (and bad)parenting with a pharmaceutical intervention. Trichostatin,interestingly, is chemically similar to the drug valproate, which isused clinically in people as a mood stabilizer.advertisement | article continues belowClick here!Meaney says the link between nurturing and brain development is morethan just a curious cause and effect. He suggests that makingpostnatal changes to an offspring's epigenome offers an adaptiveadvantage. Through such tweaking, mother rats have a last chance tomold their progeny to suit the environment they were born into. "Theseexperiments emphasize the importance of context on the development ofa

creature," Meaney says. "They challenge the overriding theories ofboth biology and psychology. Rudimentary adaptive responses are notinnate or passively emerging from the genome but are molded by theenvironment."The hippocampus in a sheep's brain. Meany's research showed that, inrats, hippocampus size is influenced by maternal nurturing behaviorsuch as licking after birth. Well-licked rats had more developedhippocampi and produced less of the stress hormone corstisol.(Courtesy of the University of Pennsylvania School of Veterinary Medicine)Meaney now aims to see whether similar epigenetic changes occur whenhuman mothers caress and hold their infants. He notes that the geneticsequence silenced by attentive mother rats has a close parallel in thehuman genome, so he expects to find a similar epigenetic influence."It's just not going to make any sense if we don't find this in humansas well. The

story is going to be more complex than with the ratsbecause we'll have to take into account more social influences, butI'm convinced we're going to find a connection."In an early study, which provided circumstantial evidence, Meaneyexamined magnetic resonance imaging brain scans of adults who beganlife as low-birth-weight babies. Those adults who reported in aquestionnaire that they had a poor relationship with their mother werefound to have hippocampi that were significantly smaller than average.Those adults who reported having had a close relationship with theirmother, however, showed perfectly normal size hippocampi. Meaneyacknowledges the unreliability of subjects reporting on their ownparental relationships; nonetheless, he strongly suspects that thequality of parenting was responsible for the different shapes of thebrains of these two groups.In an effort to solidify the connection, he

and other researchers havelaunched an ambitious five-year multimillion-dollar study to examinethe effects of early nurturing on hundreds of human babies. As a testgroup, he's using severely depressed mothers who often have difficultybonding and caring for their newborns and, as a result, tend to caresstheir babies less than mothers who don't experience depression oranxiety. The question is whether the babies of depressed mothers showthe distinct brain shapes and patterns indicative of epigeneticdifferences.The science of epigenetics opens a window onto the inner workings ofmany human diseases. It also raises some provocative new questions.Even as we consider manipulating the human epigenome to benefit ourhealth, some researchers are concerned that we may already be alteringour epigenomes unintentionally, and perhaps not for the better. Jirtlenotes that the prenatal vitamins that physicians commonly encouragepregnant women to take to reduce the incidence of birth defects intheir infants include some of the same chemicals that Jirtle fed tohis agouti mice. In effect, Jirtle wonders whether his mouseexperiment is being carried out wholesale on American women."On top of the prenatal vitamins, every bit of grain product that weeat in the country is now fortified with folic acid," Jirtle notes,and folic acid is a known methyl donor. "In addition, some women takemultivitamins that also have these compounds. They're getting a triplehit."While the prenatal supplements have an undisputed

positive effect,Jirtle says, no one knows where else in the fetal genome thosegene-silencing methyl donors might be landing. A methyl tag that has apositive effect on one gene might have a deleterious effect if ithappens to fall somewhere else. "It's the American way to think, 'If alittle is good, a lot is great.' But that is not necessarily the casehere. You might be overmethylating certain genes, which couldpotentially cause other things like autism and other negative outcomes."Szyf shares the concern. "Fueling the methylation machinery throughdietary supplements is a dangerous experiment, because there is likelyto be a plethora of effects throughout a lifetime." In the future, hebelieves, epidemiologists will have their hands full looking forpossible epigenetic consequences of these

public-health choices. "Didthis change in diet increase cancer risk? Did it increase depression?Did it increase schizophrenia? Did it increase dementia orAlzheimer's? We don't know yet. And it will take some time to sort itout."The implications of the epigenetic revolution are even more profoundin light of recent evidence that epigenetic changes made in the parentgeneration can turn up not just one but several generations down theline, long after the original trigger for change has been removed. In2004 Skinner, a geneticist at Washington State University,accidentally discovered an epigenetic effect in rats that lasts atleast four generations. Skinner was studying how a commonly usedagricultural fungicide, when introduced to pregnant mother rats,affected the development of the testes of fetal rats. He was notsurprised to discover that male rats exposed to high doses of

thechemical while in utero had lower sperm counts later in life. Thesurprise came when he tested the male rats in subsequentgenerations—the grandsons of the exposed mothers. Although thepesticide had not changed one letter of their DNA, thesesecond-generation offspring also had low sperm counts. The same wastrue of the next generation (the great-grandsons) and the next.Such results hint at a seemingly anti-Darwinian aspect of heredity.Through epigenetic alterations, our genomes retain something like amemory of the environmental signals received during the lifetimes ofour parents, grandparents, great-grandparents, and perhaps even moredistant ancestors. So far, the definitive studies have involved onlyrodents. But researchers are turning up evidence suggesting thatepigenetic inheritance may be at work in humans as well.In November 2005, Marcus Pembrey, a clinical geneticist at

theInstitute of Child Health in London, attended a conference at DukeUniversity to present intriguing data drawn from two centuries ofrecords on crop yields and food prices in an isolated town in northernSweden. Pembrey and Swedish researcher Lars Olov Bygren noted thatfluctuations in the towns' food supply may have health effectsspanning at least two generations. Grandfathers who lived theirpreteen years during times of plenty were more likely to havegrandsons with diabetes—an ailment that doubled the grandsons' risk ofearly death. Equally notable was that the effects were sex specific. Agrandfather's access to a plentiful food supply affected the mortalityrates of his grandsons only, not those of his granddaughters, and apaternal grandmother's experience of feast affected the mortalityrates of her granddaughters, not her grandsons.This led Pembrey to suspect that genes on the

sex-specific X and Ychromosomes were being affected by epigenetic signals. Furtheranalysis supported his hunch and offered insight into the signalingprocess. It turned out that timing—the ages at which grandmothers andgrandfathers experienced a food surplus—was critical to theintergenerational impact. The granddaughters most affected were thosewhose grandmothers experienced times of plenty while in utero or asinfants, precisely the time when the grandmothers' eggs were forming.The grandsons most affected were those whose grandfathers experiencedplenitude during the so-called slow growth period, just beforeadolescence, which is a key stage for the development of sperm.The studies by Pembrey and other epigenetics researchers suggest thatour diet, behavior, and environmental surroundings today could have afar greater impact than imagined on the health of our distantdescendants. "Our study has

shown a new area of research that couldpotentially make a major contribution to public health and have a bigimpact on the way we view our responsibilities toward futuregenerations," Pembrey says.The logic applies backward as well as forward: Some of the diseasepatterns prevalent today may have deep epigenetic roots. Pembrey andseveral other researchers, for instance, have wondered whether thecurrent epidemic of obesity, commonly blamed on the excesses of thecurrent generation, may partially reflect lifestyles adopted by ourforebears two or more generations back. Meaney, who studies the impact of nurturing, likewise wonderswhat the implications of epigenetics are for social policy. He notesthat early child-parent bonding is made more difficult by the effectsof poverty, dislocation, and social strife. Those factors cancertainly affect the cognitive development of the children

directlyinvolved. Might they also affect the development of future generationsthrough epigenetic signaling?"These ideas are likely to have profound consequences when you startto talk about how the structure of society influences cognitivedevelopment," Meaney says. "We're beginning to draw cause-and-effectarrows between social and economic macrovariables down to the level ofthe child's brain. That connection is potentially quite powerful."Lawrence Harper, a psychologist at the University of California at, suggests that a wide array of personality traits, includingtemperament and intelligence, may be affected by epigeneticinheritance. "If you have a generation of poor people who suffer frombad nutrition, it may take two or three generations for thatpopulation to recover from that hardship and reach its fullpotential," Harper says. "Because of epigenetic inheritance, it maytake

several generations to turn around the impact of poverty or waror dislocation on a population."Historically, genetics has not meshed well with discussions of socialpolicy; it's all too easy to view disadvantaged groups—criminals, thepoor, the ethnically marginalized—as somehow fated by DNA to theircondition. The advent of epigenetics offers a new twist and perhaps anopportunity to understand with more nuance how nature and nurturecombine to shape the society we live in today and hope to live intomorrow."Epigenetics will have a dramatic impact on how we understand history,sociology, and political science," says Szyf. "If environment has arole to play in changing your genome, then we've bridged the gapbetween social processes and biological processes. That will changethe way we look at everything."Read more on Randy Jirtle's experiments on mice fed methyl-rich dietsand about his

investigation of the gene that codes for stupidty.Patterns of gene expression are controlled by multiple variables,including gender, micro RNA, even microgravity!Learn about green tea EGCG's cancer-fighting power.

[Guest guest]

Wow, this is so interesting.

Thanks, Rogene, for sharing this.

Bindi

[Guest guest]

You're welcome Bindi,This article gives me hope that we'll have a "Magic Eraser" to undo the damage the environment is doing to all of us one day.I'm afraid thousands more will suffer before it becomes reality though!Hugs,Rogene Re:Discover Magazine - DNA is not Destiny

Wow, this is so interesting.

Thanks, Rogene, for sharing this.

Bindi