Evolution, evolved

The scientist likes to tell stories, and boy, does he have a doozy. The tale is made richer by the almost-religious glow it is bathed in—an odd touch for a story about how he, a Darwinian molecular biologist, came up with a new idea about evolution. There's the "epiphany" he had three years ago in Westminster Abbey, the gothic structure in London that contains the graves of Charles Darwin and Isaac Newton, as well as a plaque memorializing physicist Paul Dirac, one of the fathers of quantum mechanics. As the narrator breathlessly sets the scene—with him at the center, standing on Darwin's modest, unadorned grave while admiring Newton's elaborate tomb next to it—a listener can almost envision a noir British fog lifting away from the spires of the shadowy abbey as our scientist divines inspiration from each of their stories.

There's the presence (intellectually, at least) of Darwin, the nonpareil observer who turned science on its ear by publishing astonishing theories on evolution and natural selection. There's Newton, whose rococo resting place brings to our scientist's mind the calculus he created, a lively jumble of mathematics that explained the motions of the heavens and mechanical workings here on Earth. And nearby, the remembrance of Dirac signifies the random, indeterminate nature of the universe, and how science is most useful when it factors in the element of chance.

Suddenly, a Big Idea shocks our scientist's brain circuitry. He strides off, lighter than air, past the Tower of London to a pub called The Hung Drawn and Quartered. As he settles in, preparing to enjoy a pint of Guinness stout and a meat pie, he asks the bartender, "Can I have a napkin to write on? I just had this exciting idea about evolution!"

What the Big Thinker in question, Andrew Feinberg, a professor of molecular biology, biostatistics, genetics, and oncology at the School of Medicine, wrote down went something like this: Suppose that not all of the principles of natural selection come from the behavior of our DNA, as most geneticists have thought. What if there was another mechanism above and beyond our genes that adds a layer of random variability (Dirac) to how we develop—a mechanism that, while based in the genes, offers a range of possibilities beyond what genes alone can achieve? And what if that wider range makes species more fit for survival as they adapt to changing environments? If such a process exists, and could be proved in part by creating new mathematical methods (Newton), wouldn't such a phenomenon complement long-held ideas on evolution (Darwin)?

Though Feinberg's story, one that emanates from an effusive, relentlessly curious personality, sounds fantastical, the mechanism is real. Researchers who study the chemistry surrounding how genes are activated, shut down, or otherwise tweaked—a field called epigenetics—have known for decades that the DNA base pairs that geneticists have traditionally studied aren't the only things that make us unique. There's more to the nature-vs.-nurture debate. Microscopic bits of various proteins, acting on both genetic and environmental cues, skew gene expression in one direction or another, turning different genetic switches on or off, or bathing regions of the genome in chemicals at certain crucial times. This affects much of what we become—how the neurons in our brains develop, for example. The proteins that drive epigenetic interactions increase the range of what organisms can become, adding an element of the random to the hardwiring of genes. If our genes are our biological road map, then epigenetics is the series of detours, redirections, and new developments that shapes our journey.

The randomness makes the road map even larger, and capable of rewriting parts of itself. Feinberg, A&S '73, Med '76, SPH '81, says this idea guided him: "I thought maybe this randomness, this regulated variance, might be more than just some kind of noise or clutter, but something necessary to developing a multicelled organism. If that variance is necessary in development, and is present in many common diseases, there's a possibility it's a deeper part of what we and other species are."

Interactions involving epigenetics differ from one individual organism to the next, even in those with the same genes, such as identical twins or inbred mice. Identical twins will develop different brains and fingerprints, for example. If one twin receives medicine while ill as a youngster, that can change the trajectory of his genes. If those changes in gene expression can be maintained in cells as they replicate, they could make species more adaptable over unimaginably long stretches of time. That is the hypothesis that Feinberg, the experimentalist, is now putting to the test.

Epigenetics (literally: "above the genome") was largely unknown as a field 30 years ago, when Feinberg, now 59 and the director of the Johns Hopkins Center for Epigenetics in the Institute for Basic Biomedical Sciences, started to investigate its connections to illnesses. "We didn't even call it epigenetics back then," he says. He and Bert Vogelstein, a professor of oncology and pathology at Johns Hopkins, discovered that certain levels of methylation, a ubiquitous chemical change in DNA molecules that regulates a gene's expression, played a role in the emergence and growth of cancerous tumors.

Back then, scientists didn't yet understand just how environmental toxins, such as asbestos and heavy metals, and unhealthful habits, such as overeating and smoking, create the epigenetic conditions that underlie many cancer cases. But, "we were beginning to see that genes might account for only about half of the cases of common disease," Feinberg says. Epigenetics, many now think, just might account for the difference.

An emerging body of evidence shows that epigenetic interactions with the environment can have a carryover effect from one generation to the next, and perhaps beyond. Separate groups of women in China and the Netherlands who suffered from famine in the 1940s had children with much higher rates of schizophrenia than normal. A recent study in Sweden found that grandparents who grew up during periods of abundant food have had grandchildren who are much more likely to suffer from diabetes and die early. And evidence is mounting that children of men who became fathers in their later years are more likely to suffer from autism.

But the notion that random epigenetic variance might lend a species an advantage over time, as it makes adaptations to the environment it lives in, is far more controversial. Darwin himself wrote in The Origin of Species that natural selection, as he understood it, was likely not the only driver of evolution. Some evolutionary biologists and geneticists have forwarded the idea that some degree of random "bet hedging" is hidden somewhere within evolution. Still, most of them aren't convinced that epigenetics plays the role Feinberg has cast for it.

"The topic is perennial and there is definitely something to it," says Daniel C. Dennett, a professor of philosophy at Tufts University and an expert and oft-published author on evolution. But can such changes be seen in successive offspring throughout the ages? "Epigenetic effects are real and can last for more than a generation or two, but so far as I know, they can't ramify indefinitely," Dennett says. Such "ramification" is the smoking gun that Feinberg is looking for—the proof that epigenetic changes can be passed down over long stretches, affecting how species evolve over millennia.

Feinberg's tireless "what if?" tendency toward speculation, and then experimentation, is a strength for a scientist charged with building a world-class epigenetics lab out of nothing—as he has done, his colleagues say. But it might also lead him toward brashness. "Andy is an extremely creative thinker," says David Valle, director of the Institute of Genetic Medicine at Johns Hopkins and a professor of molecular biology and genetics. Valle was instrumental in recruiting Feinberg back to Johns Hopkins from the University of Michigan in 1994. "But not all of the ideas creative thinkers come up with are right."

When Valle's thoughts are relayed to him, Feinberg tilts his head back and laughs loudly, as he often does, and says, "I agree! Please don't confuse my enthusiasm with certainty." There is, he admits, a ton of work to be done before he can believe his epiphany was real.

A teenage math geek who once, while working years later as a physician at an East Baltimore clinic, applied at the same time to be an astronaut and a master's degree candidate at the Bloomberg School of Public Health, Feinberg seems beyond intimidation. Given the task at hand, this is a very good thing. Epigenetics, as a new and tortuous field, is exceedingly difficult to wrap one's head around.

Unlike the human genome, of which we have only one (which was mapped out and explained nearly a decade ago), there are hundreds of "epigenomes"— specific sets of genes that are affected by both their DNA sequence and the chemicals that express them—sprawling throughout the body. We're only starting to understand them. Each type of tissue cell and each of its developmental stages has its own epigenome, though Feinberg says he and others are starting to find more and more points of commonality between them. Nonetheless, cataloging, collating, and correlating all of the chemical and protein interactions is a logistical nightmare.

The huge potential payoff to doing all that work drives him, Feinberg says—including seeing where his natural selection hypothesis leads him. But there are other reasons to put in all that work. Unlike the genome, epigenomes are changeable, theoretically. Target a gene or a group of them, then alter how it is expressed, and you may cure something. This malleability could help scientists find new drugs to treat diseases, such as cancer and diabetes, that have an epigenetic dimension to them. (Scientists are still investigating possible epigenetic links to Alzheimer's disease and psychiatric disorders, among other maladies.)

Epigenetics presents disease researchers with a new realm and new hope. But it's a big, largely unexplored tableau, and not an easy one to deal with. "It's crazy-hard to design experiments in epigenetics," Feinberg says, noting the incredible mass of data required to find valuable insights.

"There's a lot more thinking that's required, and a lot more collaboration. Tying all this to evolution? That's even harder than what I just said." Indeed, proving that random epigenetic variations (stochasticity is the term of art) occur over long stretches of time is mind-blowingly difficult. Samples of chemicals or tissue from people dead for thousands of years aren't available, for one thing. Developing a calculus for computing how an epigenome or two may have changed in a species over time is seemingly next to impossible.

Terabytes of data need to be gathered and crunched. Computer models need to be schemed out. Factor in the chemical interactions surrounding diseases and environmental exposures—subjects of much current study—that involve this or that epigenome, and the level of input becomes exponential. Because each person has a different makeup, and there are so many different epigenomes and chemicals in the body, the variations involved are almost literally endless—about 2 to the 20 millionth power, in fact. (And that only covers one species.) Boiling down the characteristics of an epigenome involves an approach to math that is still being discovered, though Feinberg and Rafael Irizarry, a professor of biostatistics at the Bloomberg School, among others around the world, have begun to tease it all out.

Yet, Feinberg remains unbowed. His polymath's all-consuming gaze falls on such challenges, he says, and is perhaps genetically programmed. Feinberg's father, David, a science teacher who also enforced wage laws for the federal government, once had completed more than 300 college credits at Temple University, but had received no degree (something he later remedied). As he grew up in Harrisburg, Pennsylvania, young Andy also benefited from a heightened environment for learning and became an addict of it. When he turned 15, he gave talks to the American Association for the Advancement of Science. He edited his high school newspaper and bucked the prevailing political zeitgeist of the region that spawned Newt Gingrich by co-founding the Teenage Democrats of Dauphin County, working precincts and speaking up in debates.

Feinberg still loves being smart and expansive— for being able to figure out how things work and for being able to joyously tell anyone else about it. "He's interested in everything," says his wife, Isabelle Horon, director of vital statistics for the Maryland Department of Health and Mental Hygiene. She ticks off the couple's three adopted children, live theater, playing piano, scuba diving, singing bass in Yale University's men's chorus, and traveling as his passions. "He always wants to talk. Sometimes, you just have to shut him out," she says. But he is persistent: "When he finishes the New York Times crossword puzzle, he'll show it to me. I'll have to admire it and say, 'You're a smart boy.'"

His associates say that Feinberg retains a boyish energy and encyclopedic vigor. "Every day there's some new kind of excitement, some level of discovery in the lab," says Sean Taverna, an assistant professor of pharmacology and molecular sciences at the School of Medicine and a colleague of Feinberg's. "You can basically talk to the guy about anything, even nonscience subjects, and get this incredible depth of breadth and information. That, and he enjoys really bad puns and jokes. He's got a geeky sense of humor."

By the time he turned 19, when he came to Johns Hopkins to study medicine, Feinberg had already attended Yale, studied computers at Cornell, and worked for IBM in Paris, spending a summer living a couple of blocks from the Arc de Triomphe. (Historical structures tend to pop up whenever he relates his personal history.) After graduating, he interned at the University of Pennsylvania, with thoughts of becoming a neurologist or a psychiatrist, but found the practice of each to be unsatisfying.

Feinberg ended up at the University of California, San Diego, as a postdoc, where he was given the choice of what he calls the "crackpot science" of zapping leeches to see if it would make them swim, or working with slime mold. He opted for slime. His job was to investigate how slime mold developed in certain environments. "It was the first place I got the idea that cells might have some idea of what they're going to become, outside of what's supplied by their genome. I didn't label it 'epigenetics' then, but that's what it was," Feinberg recalls. Such "molecular memory" would become key in his research into cancer and evolution, and the relationship between them.

As exciting as working with slime mold was, Feinberg had little idea of what medical specialty he would pursue. In a quandary, he moved back East and signed on to work at a free medical clinic several blocks from Johns Hopkins Hospital. A year later, Johns Hopkins University would pay him to study biostatistics and epidemiology at the Bloomberg School. Even though those studies would prove useful later, Feinberg itched to get back into the lab.

One night in 1980, as he was in the middle of completing his master's, he saw a flier for a talk by Donald Coffey, a longtime Johns Hopkins research luminary and still a professor of oncology and urology. Coffey was lecturing about cancer cells' ability to change from one cell type into another. Feinberg again wondered whether cells carry some kind of molecular memory of what and where they had been before, and whether some aspect of that was inheritable. Didn't Coffey's point jibe with what he had learned about slime molds? Feinberg sought out Coffey after the lecture, and the old hand pointed him in the direction of a young cancer researcher, Bert Vogelstein.

"He was extremely smart and creative—and a little off-the-wall," remembers Vogelstein, who hired Feinberg to serve as a postdoc in his cancer lab for two years. "I thought that was a terrific quality for a scientist who wants to do new things." Feinberg would go on to perform his groundbreaking DNA-methylation research at the Vogelstein lab. "Going to Bert's lab was like dying and going to heaven for me," Feinberg says. He had found his calling. And he ran with it. "He was always interested in gene expression and cancer genetics, in melding the two fields," Vogelstein adds. "He saw that possibility before everyone else."

Feinberg eventually left Johns Hopkins, where he had been named an assistant professor of oncology, for a joint appointment with the University of Michigan and the Howard Hughes Medical Institute. Feinberg thought he'd conduct research on the intersection between genes and epigenetics. But after getting settled in 1986, he wondered if he had made a mistake. A strong bias against the study of epigenetics—one he still sees, particularly among some geneticists—announced itself there.

"My employer essentially told me that I'd be fired for doing the work I was hired to do," he says. "Most people didn't think epigenetics made any kind of sense, except perhaps for cancer research. Psychiatric disease or endocrine diseases—people thought, how could those have anything to do with epigenetics?" Never mind the prospect that the field might offer clues to evolution.

Despite the threats to his career and livelihood, Feinberg did what he usually does: He pressed on, continuing his lab work there for eight years, even though there was no scientific groundswell for what he produced. The lack of interest and money devoted to epigenetics study during the 1980s and 1990s meant something else, too: Folks like Feinberg were rare, often-endangered birds. A close friend in London who studied epigenetics— and who now does so successfully at a new institute—was fired from a prominent college because no one understood the importance of the research he was doing. Feinberg and his colleagues lived on the ledge.

"I've never felt like a pioneer because it didn't seem like anyone was foolish enough to get in the wagon with me," he says.

As he leads a visitor through the still-like-new halls of the Center for Epigenetics, Feinberg can't resist explaining what the sequencing machines and other high-tech doodads that line the walls do, even though the guest is nearly without a clue. Some machines gather the raw mathematical data on epigenetic interactions—how the information in our genes is altered or forwarded—from bits of blood and tissue, potentially opening the doors to a continent's worth of new discoveries. They are the wagon wheels of the medical pioneer.

Feinberg returned to Johns Hopkins, triumphantly enough, in 1994 as a full professor—just in time to watch the research world begin to change its mind about epigenetics. These days, 40 Johns Hopkins scientists work at the center and 25 others are affiliated with it. They examine the effects epigenetics may have on everything from autism to depression to diabetes. The growth of the center, which opened in 2004, coincides roughly with a new federal commitment toward finding new remedies for disease. The National Institutes of Health launched the Roadmap Epigenomics Program four years ago, bankrolling it with $190 million.

Last year, the NIH gave the Center for Epigenetics $10 million and earmarked $2.5 million for Feinberg. He'll use the money to think more about the intersection between epigenetic variability, disease, and natural selection, and to continue to engage collaborators who will help him develop new models and technologies that can unravel epigenomes.

Their doggedness has them, along with other scientists, poised to reap a deep understanding of how cancer, cell development, and the environment shape who we are. "There's a shift happening from hypothesis-driven science to discoverydriven science," says Rafael Irizarry. "Those who invent the technology are now the first to make discoveries. It's like Leeuwenhoek. When he made the first microscope, he found a lot of things, such as single-celled organisms and sperm, that had never been observed before. That's kind of where we are now."

Key in their search for evolutionary clues is cancer. Theoretically, stochasticity works not only to make a species more fit, but, by increasing the range of how genes can be expressed, it ups the susceptibility to disease. Although observing this naturally is an experimental nightmare, Feinberg and Irizarry have put together models that, they say, demonstrate how inheritable genetic variations, expressed via epigenetics, underlie common diseases. Such theories build on Darwin's thoughts on natural selection and do not contradict them, unlike earlier theories that argued in favor of a more immediate environmental effect on genes and their expression. "What we're learning is that the cell differentiation model has a very stochastic dimension, in addition to a [genetically] deterministic one," says Irizarry. "The casino might be guaranteed to win money, but every single game that is played is random. That really changes how we look at things."

Feinberg and Irizarry perform research on actual biological material as well. Using human tissue samples, the duo compares epigenetic "marks" around a normal cell and a cancer cell. The idea is to see if methylation levels or other epigenetic processes are different between the two. Recent research conducted by Feinberg and Irizarry on five of the most common forms of cancer found that the disease, long thought to be as many as 200 distinct illnesses, might only be one. "This may be an overly strong statement," Feinberg says, "but the certain common factors of all cancers—the way they invade cells and metastasize, their ability to evade therapies—seem to be related to this high, almost evolutionary variability that allows them to undergo selection very quickly under different conditions. The mechanisms look very similar in the types of cancer we looked at. That's epigenetic and it's related to this increased variance in gene expression."

Feinberg-led studies have also uncovered that the epigenetic system in someone with cancer loses its ability to regulate levels of methylation, which is altered throughout a large swath of the genome. Fluctuating levels signal that the nucleus of cells has become unstable and perhaps more prone to reprogramming, possibly enabling cancer to grow and spread. Such information could lead to new drug treatments designed to bring the epigenetic levels and signals into some kind of equilibrium.

Various teams led by Feinberg have also looked into how epigenetics plays out in rodents, finding that there are hundreds of sites in the body and brain where methylation levels differ between genetically identical mice—another indication of the presence of random variations. Now, Feinberg is taking a whack at insects, asking what kinds of epigenetic changes cause genetically similar honeybees to convert from bees that forage to ones that stay in the hive and raise larvae. Feinberg and a collaborator trick the foragers into turning back into nurses, and then measure the epigenetic factors that caused the change to occur.

"So far, it's been great for seeing the connection between development and epigenetic marks," he says. "We still need to know more. Can we identify DNA sequences that can control the variability of cells? Or is something else going on?" Again, observations made at the beehive could prove vital to devising new treatments, he says. "Instead of trying to guess about cancer, about how it's going to spawn and become very flexible in the face of the drug interventions of today, maybe we can treat the stochasticity itself, by targeting the pathway that controls the variance."

But what about that bolt of inspiration at Westminster Abbey? The layered story of Feinberg's epiphany, the genesis of his idea, hasn't done much to persuade science to believe in it—nor should it. Although measured versions of his story have appeared in journal articles, a more florid account was published in New Scientist, an international magazine based in England, two years ago, eliciting some eye-rolling among researchers, including some at Johns Hopkins. None of it rankles Feinberg. "I'm nothing special, OK? People should give me a hard time when they think I deserve it," he says with a chuckle.

Others say that Feinberg's line of inquiry is far from out of line. Epigenetics will yield some fascinating information, though no one knows exactly where it will come from. "At this point, I liken epigenetics to the study of genes before DNA was discovered [in 1953]," says Allan Spradling, the award-winning director of the Carnegie Institution for Science, a private research group that has a campus on the edge of Johns Hopkins' Homewood campus. (He is also an adjunct professor of molecular biology and genetics at the School of Medicine.) "We know it is important and Andy has done a great job of getting research going at Hopkins. What Andy is offering up is plausible and intriguing. But there are so many ways that that can work, that no one has been able to come up with answers about the role of epigenetics in evolution."

Regardless of whether his evolutionary claim proves true or not, Feinberg sees a bright future for his field. He is hopeful that, within 20 years, epigenetics will answer major questions about how we can reverse the process of aging. Scientists may also be able to manipulate cell differentiation, which would transform the practice of regenerative medicine and organ transplants. And researchers who study learning and memory will be much closer to maximizing a patient's brain function or curing psychiatric disease.

Predictably, though, he isn't putting all his eggs into one specialty. Science will continue to learn more about evolution from a variety of viewpoints— as will he. "Epigenetics and genetics are equally important," he says. "It's the combination that matters. And the points where they come together are likely where we'll find answers."